case study for rabies

• Case report
• Open access
• Published: 01 December 2021

Rabies is still a fatal but neglected disease: a case report

• Y. A. Amoako   ORCID: orcid.org/0000-0002-4642-789X 1 , 2 ,
• P. El-Duah 1 , 3 ,
• A. A. Sylverken 1 , 4 ,
• M. Owusu 1 , 5 ,
• R. Yeboah 1 ,
• R. Gorman 1 ,
• T. Adade 1 ,
• J. Bonney 1 ,
• W. Tasiame 1 , 3 ,
• K. Nyarko-Jectey 6 ,
• T. Binger 1 ,
• V. M. Corman 3 ,
• C. Drosten 3 &
• R. O. Phillips 1 , 2  

Journal of Medical Case Reports volume  15 , Article number:  575 ( 2021 ) Cite this article

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Rabies, caused by a lyssavirus, is a viral zoonosis that affects people in many parts of the world, especially those in low income countries. Contact with domestic animals, especially dogs, is the main source of human infections. Humans may present with the disease only after a long period of exposure. Nearly half of rabies cases occur in children <15 years old. We report on a fatal case of rabies in a Ghanaian school child 5 years after the exposure incident, and the vital role of molecular tools in the confirmation of the diagnosis.

Case presentation

The patient, an 11-year-old junior high school Ghanaian student from the Obuasi Municipality in Ghana, presented with aggressive behavior, which rapidly progressed to confusion and loss of consciousness within a day of onset. Her parents reported that the patient had experienced a bite from a stray dog on her right leg 5 years prior to presentation, for which no antirabies prophylaxis was given. The patient died within minutes of arrival in hospital (within 24 hours of symptom onset). Real-time polymerase chain reaction testing of cerebrospinal fluid obtained after her death confirmed the diagnosis of rabies. Subsequent phylogenetic analysis showed the virus to belong to the Africa 2 lineage of rabies viruses, which is one of the predominant circulating lineages in Ghana.

The incubation period of rabies is highly variable so patients may only present with symptoms long after the exposure incident. Appropriate molecular testing tools, when available as part of rabies control programmes, are vital in confirming cases of rabies.

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Rabies, a viral zoonosis caused by a lyssavirus, is a vaccine-preventable, neglected tropical disease (NTD) that occurs in more than 150 countries and territories [ 1 ]. In the USA, the majority of rabies cases reported to the Centers for Disease Control and Prevention (CDC) each year occur in wild animals such as bats, raccoons, skunks, and foxes [ 2 ]. However, rabies can affect any mammal, including humans. Dogs are the main source of human rabies deaths, contributing up to 99% of all rabies transmissions to humans. The rabies virus infects the central nervous system of mammals, ultimately causing disease in the brain and death. Infection causes tens of thousands of deaths every year, mainly in Asia and Africa. Approximately 40% of people bitten by suspect rabid animals are children under 15 years of age. Rabies elimination is feasible through vaccination of dogs and prevention of dog bites [ 1 ]. In Ghana, rabies remains an important public health threat, with case fatality rate of 100% [ 3 , 4 , 5 , 6 ].

We report on a case of rabies in an 11-year-old Ghanaian student and discuss the essential role of accurate diagnosis in rabies control.

The patient was an 11-year-old junior high school Ghanaian student from the Obuasi Municipality in Ghana, with no known previous illnesses. She was the third child from a family of five children. She presented with a day’s history of aggressive behavior, which rapidly progressed to confusion and loss of consciousness. Her parents reported that the patient had experienced a bite from a stray dog on her right leg 5 years prior to presentation. Additionally, her parents described episodes of hydrophobia within the preceding year; however, they did not make much of it as they considered it to be mild and due to the ‘playful nature of children’. Other prodromal symptoms such as fever, general malaise, sore throat, anorexia, and muscle weakness were absent. There was no history of dysphagia. The patient was brought to the hospital within a day of onset of her symptoms and died from cardiorespiratory failure within minutes of arrival in hospital (within 24 hours of symptom onset). Initial assessment revealed an ill-looking, unconscious patient, who was afebrile with a respiratory rate of 14 cycles per minute. The neck was supple and Kernig’s sign was negative. The pupils were dilated and sluggishly reactive to light. Real-time polymerase chain reaction (RT-PCR) testing of cerebrospinal fluid obtained after her death confirmed the diagnosis of rabies. The corpse was handled and buried/disposed in accordance with standard local protocols in Ghana [ 7 ]. The contacts of the patient were subsequently counseled and offered rabies vaccination. All the contacts of the patient were free of rabies symptoms after 12 months of follow-up.

Virus characteristics

Given the reported long incubation period of the case, sequencing and phylogenetic analysis of the detected virus was performed to assess the possibility of another origin of the virus other than the reported dog bite, such as from bats, which may not have been recognized. Viral Ribonucleic acid (RNA) was extracted from the patient’s cerebrospinal fluid (CSF) using the Qiagen Viral RNA mini spin kit (Qiagen, Hilden, Germany), according to the manufacturer’s instructions. Presence of rabies RNA was confirmed by RT-PCR testing using a Lyssa-Virus RT-PCR kit (Tib Molbiol, Berlin, Germany) and a LightCycler Multiplex RNA Virus Master (Roche, Penzberg, Germany). We applied a high-throughput sequencing (HTS) approach for whole genome sequencing using the KAPA RNA Hyper Prep Kit (Roche Molecular Diagnostics, Basel, Switzerland) for library preparation and the 150-cycle NextSeq reagent v3 cartridge (Illumina, San Diego, California, US), according to manufacturer’s instructions.

Bidirectional reads from the HTS run were assembled against a reference rabies sequence from GenBank and annotated using Geneious prime 2019 ( https://www.geneious.com ). Phylogenetic analysis was done by maximum likelihood reconstruction using the PHYML [ 8 ] plugin in Geneious prime with 500 bootstrap replicates.

The sequence obtained was found to be most closely related to a Rabies virus (Accession number: NC_001542), sharing an 85.4% pairwise sequence identity and forming a monophyletic pairing with this virus when compared with other reference Lyssaviruses from GenBank (Fig. 1 ). Comparison of the full nucleoprotein coding region to those of a representative subset of African rabies viruses of various lineages [ 9 ] showed the virus to belong to the Africa 2 lineage of rabies viruses, which is one of the predominant circulating lineages in Ghana [ 10 ] (Fig. 2 ). The full genome obtained in this study was submitted to GenBank and assigned accession number MT107888.

Phylogenetic tree comparing Lyssavirus genotypes. Tree was generated using maximum likelihood reconstruction by the general time reversible model with a gamma distribution and proportion of invariable sites (GTR+I+G). The tree is based on whole genome sequences and was rooted with a Mokola virus (Genotype 3). Tips were labeled with accession numbers and virus names in brackets. The sequence obtained in this study is shown by bold type font

Phylogenetic tree comparing rabies viruses from Africa. Tree was generated using maximum likelihood reconstruction by a transition model with a gamma distribution and proportion of invariable sites (TIM1+G+I). The tree is based on complete nucleoprotein sequences and rooted with the Africa 4 lineage branch. Tips are labeled with accession numbers and country of origin in brackets. The sequence obtained in this study is shown by a bold type font

Ethical considerations

Ethical approval for this study was obtained from the Scientific and Ethical review Committee of the School of Medical Sciences, Kwame Nkrumah University of Science and Technology (KNUST) (CHPRE/AP/462/19). Written informed consent was also obtained from parent of the patient for publication of this case report.

Rabies is a neglected tropical disease of poor and vulnerable populations, with deaths due to rabies often not reported. Rabies is nearly always fatal once symptoms appear. Although 100% preventable, over 59,000 people, mostly in under-served areas, in over 150 countries, die of rabies every year as human vaccines and immunoglobulin are not readily available or accessible [ 1 , 5 ]. Operationally in Ghana [ 7 , 11 ], all cases of dog bites are considered suspected cases of rabies, and a confirmed case is defined as a suspected case with clinical and or laboratory confirmation. The clinical confirmation of rabies is based on a history of dog bite that is followed by classical symptoms such as anxiety, agitation, paralysis, excessive salivation, and hydrophobia. The patient presented in this report met the case definition and tested positive by PCR and subsequent phylogenetic analysis as described.

The incubation period for rabies is typically 2–3 months but may vary from 1 week to 1 year. This period may vary based on the location of the exposure site (how far away it is from the brain), the type of rabies virus, viral load, and any existing immunity [ 1 ]. Rabies causes an acute progressive viral encephalomyelitis. The first symptoms of rabies may be very similar to those of flu including general weakness or discomfort, fever, or headache. The disease may present as furious or paralytic rabies. Furious rabies presents with signs of hyperactivity, excitable behavior, hydrophobia, and sometimes aerophobia. Death occurs after a few days due to cardio-respiratory arrest. Paralytic rabies accounts for about 20% of the total number of human cases and runs a less dramatic and usually longer course than the furious form. Muscles gradually become paralyzed, starting at the site of the bite or scratch. A coma slowly develops, and eventually death occurs. The paralytic form of rabies is often misdiagnosed, contributing to the under-reporting of the disease.

In a previous study from Ghana [ 3 ], the time between exposure and the onset of symptoms ranged between 3 weeks and 4 months, with 52.4% of cases reporting the onset of symptoms approximately 2 months after exposure. There was a history of a dog bite about 5 years prior to the onset of symptom in the patient presented in this report; this represents a rather long incubation period and was possibly influenced by recall bias from the parents who gave the clinical history. A more reasonable scenario will be that the patient had some further exposure to the rabies virus. The lineage of the detected virus implicates a common circulating rabies virus, most likely from dogs, and suggests she could have been innocuously exposed to the saliva or been scratched by an infected stray dog in the immediate period preceding her demise; but we have no way of confirming this. This assessment is in line with that of another study in Bangladesh that also found three patients with reported incubation period in excess of 1000 days, which was attributed to recall bias and likely recurrent exposures following the first bite incident [ 12 ]. A further possibility is that the virus was replicating slowly with the establishment of a latent infection following the initial exposure 5 years earlier, with subsequent reactivation of the neurotropic virus infection in later years. Although rare, long incubation period for rabies have been reported. Shankar and colleagues [ 13 ] reported a case of rabies encephalitis with a possible 25 year incubation period and suggested that reactivation of a latent infection may have played a role in the pathogenesis of the disease. In that study, the diagnosis of rabies was established by histopathology. An incubation period longer than > 6.5 years was reported in a 10-year-old girl of Vietnamese origin in whom rabies developed after she had lived continuously in Australia for almost 5 years [ 14 ]. Viral molecular epidemiological tools as used in our study provide insight into the migratory pattern of the virus-carrying animal and human vectors, but not the mechanism of viral latency [ 14 , 15 ].

In Ghana, rabies is endemic and cases of human rabies are under reported, as in other developing countries [ 1 , 6 ]. Twenty-one cases of rabies were seen at a tertiary facility in Ghana over a 25 month period, with more than half of cases aged >18 years [ 3 ]. Among that population, hydrophobia and agitation were the most common symptoms, and the case fatality rate was 100% with about 60% of cases dying within 24 hours of admission. The longest duration of stay recorded in that study was 5 days. Our patient had similar symptoms and died within 24 hours of hospitalization, in keeping with the aggressive course of the illness.

The veterinary services in Ghana are often limited in the diagnosis of rabies, as Sellers’ stain and fluorescent antibody test, commonly used techniques in diagnosing rabies, are mostly unavailable. The clinical diagnosis of human rabies is partly based on a positive rabies test result of the offending animal from the veterinary services. Preventive and control measures in Ghana to reduce the incidence of human rabies have been targeted at improving the vaccination of dogs against rabies, stray dog removal, and providing pre-/ post-exposure vaccinations of humans; however, these measures have been irregular and not sustained [ 6 , 16 ].

The differential diagnosis for this case includes other etiologies of central nervous infections (such as bacterial, fungal, and other viruses and abscess) and intracranial tumors. Although these other etiologies were not sought for, the classic clinical presentation, together with the PCR and phylogenetic characterization of the rabies virus in the patient’s CSF make these other differential etiologies less likely.

Laboratory diagnosis of rabies infection in humans is difficult after exposure to the virus before the onset of clinical symptoms. Clinical diagnosis of rabies is often made when rabies-specific signs, such as hydrophobia or aerophobia, are present. Human rabies can be confirmed during clinical disease stage and postmortem by detecting viral antigens, whole virus, or nucleic acids in infected tissues (brain, skin, urine, or saliva) using various diagnostic techniques[ 1 ]. Accurate diagnosis of rabies in exposed persons will enable the institution of appropriate care. In the incident case, rabies confirmation by PCR testing of cerebrospinal fluid only occurred after death of the patient. In under-served populations where the threat of rabies is highest, diagnostic facilities are largely absent, thus hampering early and accurate diagnosis. Indeed, in most cases, the diagnosis is only presumptively made on clinical grounds [ 3 , 17 ]. Over the past several years, the Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR) has provided support services in the area of rabies diagnosis to the Ashanti Regional Directorate of Health Services (RDHS) in Ghana. The KCCR performs PCR testing on samples received from the RDHS. Such collaborations are essential in facilitating diagnosis and guiding treatment decisions and rabies control efforts within the country.

The rabies strain reported in this case is presumably from a domestic animal (dog) contact. This is in keeping with previous accounts from Ghana [ 3 , 6 , 16 ] and globally [ 1 ] that implicate domestic dogs as being responsible for most rabies virus transmission to humans. A recent study in the Ashanti region of Ghana showed a high dog to household ratio, and that 80.3% of the dogs were not restricted and 49.9% were allowed to enter neighbors' households [ 18 ]. In that same study, dog rabies vaccination coverage was low, ranging from 28.1% to 64.9%. This calls for improved efforts to target the vaccination of all dogs in Ghana to prevent spread from stray animals.

While the knowledge of rabies transmission is high in Ghana, about 65% of people studied in a peri-urban setting believed in traditional ways of treatment such as concoctions, herbs, and consumption of the offending dogs’ organs [ 18 ]. This practice has the tendency to delay access to care for people exposed to rabies and contribute to rabies mortality within the Ghanaian population. Even after exposure, the tragic loss of lives from rabies is preventable, since effective post-exposure prophylaxis (PEP) is available in the form of wound care, rabies immunoglobulin, and rabies vaccine. Rabies immunoglobulin in addition to rabies vaccine is indicated for category III exposures, which include bites or scratches that penetrate the skin (as occurred in this case), licking of mucous membranes or broken skin, and direct contact with bats. Laryea and colleagues [ 3 ] reported that most patients do not seek care after exposure to rabies. Even for the third of people who seek care post exposure, they do not get access to the recommended PEP. In an Ethiopian study, 77% of suspected rabid dog bite victims visited a health center, and 57% received sufficient doses of PEP. The likelihood of seeking medical services following rabies exposure was higher for high-income earners, people bitten by dogs of unknown ownership, where the bite was severe especially on the leg, and where the victim lived close to the nearest health center [ 19 ]. Increasing access to health facilities delivering post-exposure services can lead to improved health-seeking behavior in patients following rabies exposure and reduce the mortality associated with rabies.

Rabies control efforts requires concerted collaboration between agencies in multiple sectors. In Ghana, a parallel and uncoordinated system of rabies surveillance is maintained by the health and veterinary services, with gross disparities in the number of reported events and an overall impression of under-reporting [ 11 ]. Tackling the scourge of a zoonosis such as rabies using the ‘One Health Approach’ requires a collaborative and multi-disciplinary effort that cuts across the boundaries of animal, human, and environmental health to undertake risk assessments, and to develop plans for response and control [ 20 , 21 ]. The WHO, the World Organisation for Animal Health (OIE), the Food and Agriculture Organization of the United Nations (FAO), and the Global Alliance for Rabies Control (GARC) have established a global multi-sectoral “United Against Rabies” collaboration to provide a common strategy to achieve "Zero human rabies deaths by 2030" [ 22 ]. In Ghana, such multi-sectoral collaboration will involve the Ministry of Health and public health authorities, veterinary services, Ministry of Local Government and Rural Development, and Municipal and district assemblies among others, as important stakeholders.

The median age of rabies victims in a previous study [ 11 ] from Ghana was 9 years (range 3–72 years) and the patient presented in this report was aged 11 years. Since the at-risk population includes a large proportion of children of school going age, an important control measure might be increasing awareness of rabies in this age group. In a Malawian study, knowledge of rabies and how to be safe around dogs was greater among school children who had received a school lesson on rabies compared with those who had not received the lesson, but had been exposed to a rabies vaccination campaign in their community (both p < 0.001), indicating that the lesson itself was critical in improving knowledge [ 23 ]. The primary school education curriculum should include basic content to educate young children on the dangers of an animal bite and encourage them to seek help. Education in rural and urban communities targeting community leaders, chiefs, farmers, pet owners, and schools on rabies prevention will create awareness among the public and aid rabies control efforts.

The incubation period of rabies is highly variable, so patients may only present with symptoms long after the incident exposure. Rabies should be considered in the differential diagnosis of patients who present with encephalopathy. Appropriate molecular testing tools are vital in confirming and documenting cases of rabies in people who meet the case definition. There is a need to increase knowledge and awareness of rabies and provide appropriate post-exposure prophylaxis to reduce the incidence of human rabies and the associated fatalities.

Availability of data and materials

The datasets obtained and analysed during the current study are available from the corresponding author on reasonable request. The full genome obtained in this study was submitted to GenBank and assigned accession number MT107888.

Abbreviations

Neglected tropical disease

Centers for Disease Control

Polymerase chain reaction

Real-time polymerase chain reaction

Ribonucleic acid

High-throughput sequencing

Cerebrospinal fluid

Post-exposure prophylaxis

World Organisation for Animal Health

Food and Agriculture Organization

Global Alliance for Rabies Control

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Acknowledgements

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This publication is part of the PANDORA-ID-NET (EDCTP Reg/Grant RIA2016E-1609), funded by the European and Developing Countries Clinical Trials Partnership (EDCTP2) programme, which is supported under Horizon 2020, the European Union’s Framework Programme for Research and Innovation. The views and opinions of authors expressed herein do not necessarily state or reflect those of EDCTP. The EDCTP had no role in the design of the study and collection, analysis, and interpretation of data, and in writing the manuscript.

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Kumasi Centre for Collaborative Research, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Y. A. Amoako, P. El-Duah, A. A. Sylverken, M. Owusu, R. Yeboah, R. Gorman, T. Adade, J. Bonney, W. Tasiame, T. Binger & R. O. Phillips

Department of Medicine, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Y. A. Amoako & R. O. Phillips

Institute of Virology, Charite Universitatsmedizin Berlin, Berlin, Germany

P. El-Duah, W. Tasiame, V. M. Corman & C. Drosten

Department of Theoretical and Applied Biology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

A. A. Sylverken

Department of Medical Laboratory Technology, College of Health Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

Obuasi Municipal Health Directorate, Obuasi, Ghana

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Contributions

YAA, PED, CD, and ROP conceived the case report and its design. AAS, MO, RY, RG, TA, JB, WT, KNJ, TB, and VMC participated in data collection and analysis. YAA and PED wrote the manuscript and reviewed it for important intellectual content. All authors reviewed and approved the final version of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Y. A. Amoako .

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Amoako, Y.A., El-Duah, P., Sylverken, A.A. et al. Rabies is still a fatal but neglected disease: a case report. J Med Case Reports 15 , 575 (2021). https://doi.org/10.1186/s13256-021-03164-y

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October 8, 2008

Medical Mystery: Only One Person Has Survived Rabies without Vaccine--But How?

ScientificAmerican.com talks with the first known survivor of rabies four years later

By Jordan Lite

Four years after she nearly died from rabies, Jeanna Giese is being heralded as the first person known to have survived the virus without receiving a preventative vaccine. But Giese (pronounced Gee-See) says she would gladly share that honor with others if only doctors could show that the treatment used to save her could spare other victims as well. "They shouldn't stop 'till it's perfected," said Giese, now 19, during a recent interview about physicians' quest to refine the technique that may have kept her alive. Giese's wish may come true. Another young girl infected with rabies is still alive more than a month after doctors induced a coma to put her symptoms on hold, just as they did with Giese. Yolanda Caicedo, an infectious disease specialist at Hospital Universitario del Valle in Cali, Colombia, who is treating the latest survivor, confirmed reports in the Colombian newspaper El País that the victim is an eight-year-old girl who came down with symptoms in August, about a month after she was bitten by an apparently rabid cat. Caicedo said that the family had sought treatment for the bite in Bolivar, at a hospital about three hours by foot from their rural home, but that the child, Nelsy Gomez, did not receive the series of vaccines that can prevent the virus from turning into full-blown rabies. The five shots contain minute amounts of the dead rabies virus and are designed to nudge the body into developing antibodies to fight it. Patients are also given a shot of immunoglobulin (in this case a synthesized rabies antibody) to protect them while their immune systems produce antibodies to the vaccine virus. But the combination is only effective within six days of infection, before symptoms show up; when Gomez developed signs of the disease, it was too late for the shots. With no other options available, doctors induced a coma. Caicedo is hopeful, but indicated that Gomez will face a long, slow recovery. She would not say how long Gomez was comatose but told ScientificAmerican.com that she had been awake for "a few days" and is stable. The child can move her fingers but cannot walk or eat on her own, and her eyes are open but she cannot speak yet and physicians are not sure if she can see, Caicedo says. Giese, informed of the case, says that she "hopes and prays" that Gomez will survive. Giese was the keynote speaker at a conference last week in Atlanta, where scientists gathered to discuss the latest research being conducted on ways to battle the deadly disease. During her talk, she urged physicians to continue efforts to pin down treatments that work. Giese was 15 when she was infected after being bitten by a rabid bat she had picked up outside her church in her hometown of Fond du Lac, Wisc.

Her parents cleaned the superficial wound and she says they did not believe it was necessary to seek further medical treatment. "We never thought of rabies," she says. By the time Giese began displaying signs of rabies three weeks later—fatigue, double vision, vomiting and tingling in her left arm—it was too late for the antirabies vaccine cocktail. Instead of giving her up for dead, the doctors decided to "shut the brain down and wait for the cavalry to come" by inducing a coma to give her own immune system time to build up antibodies against the virus, says Rodney Willoughby , an infectious disease specialist who treated Giese at the Children's Hospital of Wisconsin in Milwaukee. Willoughby devised the treatment credited with saving Giese there, which has since become known as the Milwaukee protocol. Rabies kills by compromising the brain's ability to regulate breathing, salivation and heartbeat; ultimately, victims drown in their own spit or blood, or cannot breathe because of muscle spasms in their diaphragms. One fifth die from fatal heart arrhythmia. Doctors believed that Giese might survive if they suppressed her brain function by sedating her while her immune system attacked the rabies virus. This was the first time the therapy was attempted, and doctors had no clue if it would work or, if it did, whether it would leave her brain damaged. But Willoughby says it was the only chance doctors had of saving her. When she arrived at the hospital, Giese couldn't talk, sit or stand and fell in and out of consciousness—she also needed to be intubated to help her breathe. "She was critically ill," Willoughby recalls, "and looked as if she might die within the day." In addition to inducing the coma, doctors also gave her the antivirals ribavarin and amantadine. They tapered off the anesthetics after about a week, when tests showed that Giese's immune system was battling the virus. For about six months after awakening from the coma, physicians also gave her a compound called tetrahydrobiopterin that is chemically similar to the B-complex vitamin folic acid, which may have improved her speech and ability to eat, Willoughby says. He notes that physicians gave her the supplement after tests showed that she had a deficiency of the compound, which is known to boost production of serotonin and dopamine neurotransmitters needed to perform motor, speech and other routine bodily functions.

Remarkably, Giese survived. She recovered most of her cognitive functions within a few months, and other skills within a year, Willoughby says. She got her driver's license and is now a sophomore at Marian University in Fond du Lac, where she is majoring in biology. There are lingering signs of her illness: Giese, once an avid athlete, says she now lists to one side when she runs and walks and no longer plays volleyball, basketball and softball as she once did. She also speaks more slowly and sometimes not as clearly as before her illness, but Willoughby says these effects may fade over time. Giese is " pretty much normal ," says Willoughby, an associate professor of pediatrics at the Medical College of Wisconsin in Milwaukee. "She continues to get better, counter to conventional medical thinking." Rabies has an incubation period of two weeks to three months and kills within a week of the symptoms showing up. The vaccine series and other immune therapies are useless at this point and may even speed up and increase the severity of the symptoms. Usually, patients are made as comfortable as possible in the hospital or, in countries without sophisticated health care, sent home to die an agonizing death. Antiviral drugs and immune therapies including steroids, disease-fighting interferon-alpha and poly IC (which stimulates the body's own production of interferon-alpha) have been tried, but none have been shown to be lifesaving on their own, Willoughby says. Over the past four years, the Milwaukee protocol to differing degrees has been used a dozen times, but until now Giese was the sole survivor. Exactly why she lived—and the others died—is still a mystery. In a 2005 report on her case in The New England Journal of Medicine , Willoughby speculated that she may have been infected with a rare, weakened version of the virus. Today, he chalks Giese's survival up to aggressive intensive care, the decision to sedate her "and 10 percent sheer luck." Which element of that combination made the difference, and whether the antivirals she was given helped save her is unknown. "In all honesty, we were probably just pretty lucky," he says. Only another survivor, and then animal and clinical trials, will show if the therapy works, and why, he says. The U.S. Centers for Disease Control and Prevention (CDC) plans to test the protocol on rabies-infected ferrets; Thai and Canadian doctors, who unsuccessfully treated a 33-year-old man with rabies with the Milwaukee protocol, recommended in the Journal of NeuroVirology two years ago that physicians exercise "caution" in using the treatment, because it is too expensive and lacks " a clear scientific rationale." Willoughby says it cost about $800,000 to treat Giese.

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Rabies is 100 percent preventable with vaccinations if patients receive them before the onset of symptoms, including hallucinations, delirium, muscle spasms, paralysis and hydrophobia. Yet an estimated 55,000  people, mostly in Asia and Africa, die from it annually because of misdiagnosis or because the illness is not recognized until it has taken hold, according to the journal Neurologic Clinics . Often, patients dismiss the potential seriousness of bites, cannot afford follow-up medical treatment or, in some situations, are unaware they've been bitten, as was the case of a 13-year-old Connecticut girl who died of rabies in 1995 . Vaccine shortages as one manufacturer, Bridgewater, N.J.–based sanofi–aventis, upgrades its factory to meet U.S. Food and Drug Administration requirements , and chronic shortfalls of immunoglobulin also play a role in the fatalities. The vaccine-immunoglobulin regimen costs $1,200 to $2,000 in industrialized nations and $100 to $300 in developing countries—an out-of-reach sum for many people, Willoughby says. Though it's promising that Gomez is still alive, "The hope that the outcome will necessarily be the same as with Jeanna, particularly in a developing country, is expecting a bit much," laments Charles Rupprecht, chief of the CDC's Rabies Program Willoughby acknowledges that even if Giese's success is reproducible—and the Milwaukee protocol perfected—it likely will only be available for use in 10 percent of cases, because of limited medical facilities in developing countries. "Re-creating that in a place stricken with poverty, you get into ethical issues of whether we should do this when we should be about prevention; and does that society have the ability to rehabilitate a patient who may survive but with severe [side effects]?" Rupprecht says. "Jeanna created several ethical issues for all of us to deal with this bug." Giese says that the fourth-year anniversary of her illness has brought up some bitter memories that she'll probably never shake, but she's glad to be alive—and doing as well as she is. "It takes some getting used to, but I've kind of come to terms with the fact that I'm the only…[survivor]," she says. "At 15, I never would have thought that anything like this would ever happen, and that I lived is just amazing." An animal lover who owns a dog, two rabbits and six birds, she hopes to one day open a sanctuary in Fond du Lac for endangered animals, including "big predators like lions and tigers and wolves," and maybe even bats , too. "I'm not scared of them at all," Giese says of bats. "I'm more passionate about animals than I was before. Animals are my happiness and reason for living." Additional reporting by Barbara Juncosa

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A Man Died From Rabies In Illinois. Here's Why That's So Unusual In The U.S.

Deepa Shivaram

Rabies is a preventable viral disease. Human fatalities are rare and typically occur in people who don't get treatment quickly. Here, a vial and box of rabies vaccine. Adriana Adie/NurPhoto via Getty Images hide caption

Rabies is a preventable viral disease. Human fatalities are rare and typically occur in people who don't get treatment quickly. Here, a vial and box of rabies vaccine.

Be aware if you've got bats in your home. That's the message from the Illinois Department of Health as it announced that an 80-year-old man died of rabies after waking up to find a bat on his neck. It is the first human case of rabies in the state since 1954.

The man refused rabies treatment at the time of the incident in mid-August, health officials said in a press release . A month later, he started experiencing rabies symptoms such as neck pain, headache, difficulty controlling his arms, finger numbness and difficulty speaking.

Shots - Health News

Bats in the bedroom can spread rabies without an obvious bite.

Rabies infections in humans are extremely rare in the United States, since the disease is preventable and treatable. Typically one to three cases are reported each year, and there were no cases reported in 2019 , according to the most recent data available from the CDC.

But rabies exposure is far more common; 60,000 Americans receive the post-exposure treatment every year. Without prompt treatment, though, the virus infects the nervous system and is typically fatal.

The U.S. Bans Importing Dogs From 113 Countries After Rise In False Rabies Records

Lake County Health Department Executive Director Mark Pfister said the case of the man who died this week emphasizes the need for more public health awareness of the risks of rabies.

"Rabies infections in people are rare in the United States; however, once symptoms begin, rabies is almost always fatal, making it vital that an exposed person receive appropriate treatment to prevent the onset of rabies as soon as possible," Pfister said.

Illinois health officials say bats are the most common animal found with rabies in the state. The man who died had a colony of bats living in his home.

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Open Access

Peer-reviewed

Research Article

Clinical, epidemiological, and spatial features of human rabies cases in Metro Manila, the Philippines from 2006 to 2015

Contributed equally to this work with: Ferdinand D. Guzman, Yuta Iwamoto

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing – original draft, Writing – review & editing

Affiliation San Lazaro Hospital, Manila, Philippines

Affiliation School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliations School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan, Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan, Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan

Roles Conceptualization, Data curation, Investigation, Methodology, Writing – review & editing

Roles Investigation, Methodology, Writing – review & editing

Roles Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing

Affiliation Department of Microbiology, Faculty of Medicine, Oita University, Yufu, Japan

Roles Conceptualization, Data curation, Writing – original draft, Writing – review & editing

Affiliations School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan, Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan

Roles Conceptualization, Formal analysis, Writing – original draft, Writing – review & editing

Affiliation Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

Roles Conceptualization, Writing – original draft, Writing – review & editing

Affiliations School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan, Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

Roles Formal analysis, Supervision, Writing – original draft, Writing – review & editing

Affiliations School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan, Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan, Department of Clinical Research, London School of Hygiene and Tropical Medicine, London, United Kingdom

Roles Data curation, Formal analysis, Supervision, Writing – original draft, Writing – review & editing

Affiliations School of Tropical Medicine and Global Health, Nagasaki University, Nagasaki, Japan, Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, United Kingdom

Roles Conceptualization, Data curation, Formal analysis, Project administration, Writing – original draft, Writing – review & editing

• Ferdinand D. Guzman, 
• Yuta Iwamoto, 
• Nobuo Saito, 
• Eumelia P. Salva, 
• Efren M. Dimaano, 
• Akira Nishizono, 
• Motoi Suzuki, 
• Oladeji Oloko, 
• Koya Ariyoshi, 

• Published: July 19, 2022
• https://doi.org/10.1371/journal.pntd.0010595
• Reader Comments

Rabies remains a public health problem in the Philippines despite the widespread provision of rabies vaccines and rabies immunoglobulin (RIG) as post-exposure prophylaxis (PEP). Detailed descriptions of recent human rabies cases in the Philippines are scarce. This study aimed to describe the clinical, epidemiological, and spatial features of human rabies cases between January 1, 2006, and December 31, 2015. We conducted a retrospective hospital-based case record review of all patients admitted to one referral hospital in Manila who received a clinical diagnosis of rabies. During the 10-year study period there were 575 patients (average 57.5 cases per year, range 57 to 119) with a final diagnosis of rabies. Most patients were male (n = 404, 70.3%) and aged ≥ 20 years (n = 433, 75.3%). Patients mostly came from the National Capital Region (n = 160, 28.0%) and the adjacent Regions III (n = 197, 34.4%) and IV-A (n = 168, 29.4%). Case mapping and heatmaps showed that human rabies cases were continuously observed in similar areas throughout the study period. Most patients had hydrophobia (n = 444, 95.5%) and/or aerophobia (n = 432, 93.3%). The leading causative animals were dogs (n = 421, 96.3%) and cats (n = 16, 3.7%). Among 437 patients with animal exposure history, only 42 (9.6%) had been administered at least one rabies vaccine. Two patients (0.5%), young children bitten on their face, had received and a full course of rabies vaccine. Human rabies patients were continuously admitted to the hospital, with no notable decline over the study period. The geographical area in which human rabies cases commonly occurred also did not change. Few patients received PEP and there were two suspected cases of PEP failure. The retrospective design of this study was a limitation; thus, prospective studies are required.

Author summary

Rabies remains a public health problem in the Philippines despite improvements in the availability of rabies vaccines and rabies immunoglobulin (RIG) as post-exposure prophylaxis (PEP). The incidence of rabies is highest in Metro Manila and surrounding areas. We reviewed the records of all human rabies patients admitted to the national infectious disease hospital in Manila between 2006 and 2015. This hospital treats most cases in this area. During the 10-year study period, human rabies cases were continuously admitted to the hospital, with no notable decline in numbers by year. Most patients were adult men bitten by domestic dogs. The geographical areas in which cases commonly occurred during the 10-year period also did not change over time. Only 9.6% of patients had received at least one dose of a rabies vaccine as PEP. Although the risk of PEP failure is reported to be almost zero, we identified two suspected cases of PEP failure. The retrospective design of this study was a limitation, and the exact details of PEP were not reliably available. As human rabies death is a significant public health concern, the circumstances of each case should be prospectively investigated. Further research is required to understand how to reduce the number of rabies cases.

Citation: Guzman FD, Iwamoto Y, Saito N, Salva EP, Dimaano EM, Nishizono A, et al. (2022) Clinical, epidemiological, and spatial features of human rabies cases in Metro Manila, the Philippines from 2006 to 2015. PLoS Negl Trop Dis 16(7): e0010595. https://doi.org/10.1371/journal.pntd.0010595

Editor: Simon Rayner, Universitetet i Oslo, NORWAY

Received: September 5, 2021; Accepted: June 18, 2022; Published: July 19, 2022

Copyright: © 2022 Guzman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The work was mainly supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Government of Japan to CMP. This work was also partially supported by a JICA/AMED SATREPS (Science and Technology Research Partnership for Sustainable Development)( https://www.jst.go.jp/global/english/ index.html) for “The establishment of the one health prevention and treatment network model for the elimination of rabies in the Philippines” (No.17823721) to AN. The funders had no role in the study design, data collection and analysis, decision to publish or reparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Rabies is a zoonotic viral infection of the central nervous system caused by members of the Lyssavirus genus, principally rabies virus, which results in fatal encephalomyelitis [ 1 , 2 ]. Rabies imposes a significant public health burden worldwide, particularly in developing countries where domestic dogs are the main reservoir for disease transmission to humans [ 3 ]. Over 55,000 rabies deaths are estimated per year, with 95% seen in Asia and Africa [ 4 ].

Following bite exposure from a rabid animal, human rabies is almost entirely preventable through the administration of proper post-exposure prophylaxis (PEP). PEP regimens are selected according to the World Health Organization (WHO) category of bite exposure [ 5 ]. The PEP required for Category III exposure includes wound care, a series of rabies vaccines and direct wound infiltration with rabies immunoglobulin (RIG) [ 5 , 6 ]. Since the introduction of a cost-effective multi-site intradermal (ID) vaccination, this regimen has been widely adopted in many low-to middle-income countries [ 7 ]. The Philippines was one of the earliest countries to introduce the ID regimen in 1997 [ 8 , 9 ]. The Department of Health in the Philippines initiated and expanded a decentralized network of animal bite treatment centers (ABTC) where patients can receive PEP, and the number of ABTC and patients receiving PEP has increased since 2005 [ 9 – 11 ]. The annual number of people receiving PEP and registered in the national system increased sharply from 176,501 in 2007 to 328,733 in 2011 and 783,663 in 2015 ( S1 Fig ) [ 10 , 11 ]. Despite intensive efforts to treat animal bite victims in the Philippines, 200–300 rabies deaths have been reported each year since 2007 [ 10 , 12 ]. Achieving the goal of the global strategic plan, namely “Zero by 30”, requires strengthening the control program based on scientific analysis [ 13 ].

San Lazaro Hospital (SLH), based in Manila, is a 500-bed hospital that serves as the national referral center in the Philippines for infectious diseases and tropical medicine. The hospital admits approximately 60–80 human rabies cases each year and is one of the main hospitals providing PEP in Manila [ 14 ]. According to 2018 national data, SLH treated 62% (n = 64) of human rabies patients in the National Capital Region (NCR), Region III, and Region IV-A [ 9 – 11 ]. In a previous study conducted at the SLH between January 1987 and June 2006, 1,839 patients with human rabies were admitted [ 14 ]. The study showed that only 31 (1.7%) patients received at least one rabies vaccine as PEP and none of the rabies patients had received a full PEP course [ 14 ]. While the availability of rabies vaccines and RIG has gradually increased since 2006, no study has described the impact of improvements in rabies care and PEP treatments on human cases. The main objective of this study was to describe the clinical and epidemiological features of patients with human rabies admitted to SLH since the study by Dimaano et al [ 14 ] and to compare the characteristics of patients with rabies between 2006 and 2015 to those admitted between 1987 and 2006. The second objective was to analyze the changing distribution of human rabies cases over the 10-year study period. We hypothesized that high incidence areas might change due to the increasing provision of PEP. We conducted a retrospective chart review of all patients admitted and clinically diagnosed with rabies at SLH between 2006 and 2015.

Ethics statement

Ethical approval was obtained from the Research and Ethical Review Board of San Lazaro Hospital, the Philippines (SLH-RERU-29022016), and the Institutional Review Board of the Institute of Tropical Medicine, Nagasaki University, Japan (No. 160303152). Both review boards approved that consent was not necessary for this retrospective study. All patient identifiers were removed from the electronic database.

Study design and site

This study was a retrospective hospital-based case record review of all patients admitted to SLH with a clinical diagnosis of rabies between January 1, 2006, and December 31, 2015.

Data collection

At SLH, physicians diagnose human rabies clinically based on a history of animal bite or non-bite exposure with hydrophobia and/or aerophobia, or other sudden onset of neurological symptoms. When a clear clinical diagnosis of rabies is made, no further serological, virology, or other laboratory tests are performed for laboratory confirmation. A final diagnosis of rabies is made if the patient dies within several days of admission. Other diagnoses are made if the patient survives, such as acute central nervous system infection, psychiatric disease, Guillain-Barré syndrome, or hysteria (called rabies hysteria). From the hospital electronic database we obtained the list of all patients with a final diagnosis of rabies at SLH during the study period. The data included date of discharge, age, sex, and residential location. The flow of the analysis is shown in Fig 1 . First, we analyzed the yearly admissions, and distributions, and distribution of age, sex, and residence. Next, we retrieved case medical charts from the hospital record departments and conducted chart reviews to record the medical history, information about PEP, symptoms, physical findings, vital signs on admission, reason for diagnosis, treatment, outcome, and duration of the clinical course. Finally, we obtained information on the causal animal, the bite incident, and the incubation period, excluding cases in which the animal bite incident was unknown or the biting animal survived during admission. We additionally identified rabies cases in which rabies vaccines were administered one or more times after the bite incident and noted the vaccine types and regimens. As the precise date of symptom onset is rarely available in the medical charts, we used the date of admission and date or month of exposure to calculate the incubation period. Normally, patients are admitted to this hospital 2−4 days after symptom onset if rabies is suspected [ 14 ]. As it was difficult to determine the precise incubation period, we divided the reported incubation period into periods of < 30 days, 30–90 days, 91–365 days, and >365 days.

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https://doi.org/10.1371/journal.pntd.0010595.g001

Statistical analysis

Data were managed using Microsoft Access (Microsoft, Redmond, WA, USA), and statistical analyses were performed using Stata software version 17.0 (StataCorp, College Station, TX, USA). We calculated the incidence rates within the NCR, Region III, and Region IV-A in 2007, 2010, and 2015, from which most rabies cases are expected to be transferred to SLH. We obtained population census data and basic maps from the Philippines Statistics Authority, United Nations Office for the Coordination of Human Affairs (OCHA) and the United States Geological Survey (USGS). We converted the home locations of patients with rabies to Global Positioning System (GPS) locations. We used Geographic Information System (GIS) software (ArcGIS version 10.5; ESRI, CA, USA) for the case mapping. Case maps were created using the residential location data. To generate heatmaps showing the density of human rabies cases during 2006–2015, we used the planar kernel density analysis tool in ArcGIS. We used the default settings of the tool and did not specify the population field or search radius. We created and overlaid two heatmaps for the periods 2006–2010 and 2011–2015 to compare the case densities between the two observation periods.

During the 10-year study period, 575 patients had a recorded diagnosis of rabies. Among them, 112 (19.5%) patients were excluded from further analysis owing to missing or lost medical charts ( Fig 1 and S1 Table ). An additional 26 (4.5%) patients were excluded because the animal bite incidents were unknown or were not considered the casual incidents ( Fig 1 ).

Between 2006 and 2015, the average number of yearly admissions for human rabies were lower (57.5 cases/year, range 35−72) than those reported between 1987 and 2006 (92 cases/year, range 57−119) ( Fig 2A ) [ 14 ]. We also observed no notable reduction in case numbers between 2006 and 2015 ( Fig 2A ). Most patients were male (n = 171, 70.3%), similar to previous reports ( Fig 2B ). The median age was 39 years (range 2−87) with 22 (3.8%) patients <5 years, 120 (20.9%) aged 5−19 years, and 433 (75.3%) aged ≥ 20 years ( Fig 2C ). The proportion of patients aged < 20 years was lower than that previously reported (33.3%) ( Fig 2C ).

(A) Annual numbers of admissions. (B) Annual numbers of patients according to sex. (C) Annual numbers of patients per age group of.

https://doi.org/10.1371/journal.pntd.0010595.g002

Most patients lived in the NCR (n = 160, 28.0%) and the adjacent Regions III (n = 197, 34.4%) and IV-A (n = 168; 29.4%) ( Fig 3 ). The incidence rates of human rabies per 100,000 population in 2007, 2010, and 2015 were 0.1305, 0.1356, and 0.1708 in the NCR; 0.2890, 0.2965, and 0.1961 in Region III; and 0.1449, 0.1272, and 0.1041 in Region IV-A, respectively. During the study period, the city or municipality with the highest number of cases was Quezon City (43, 8.2%), followed by San Jose Delmonte City (16, 3.0%), Antipolo City (15, 2.8%), and Manila City (14, 2.7%) ( Fig 3 ). Case mapping showed that although many cases were observed near the hospital, the cases were still widely distributed ( Fig 4A–4C ). Many cases were found in areas with high population density and urbanization ( S2 Fig ). We observed a mixture of old (green and yellow) and recent (red) cases in the high case density area identified by heatmaps (Figs 4A–4C and S2 ). Similar case densities were observed between 2006–2010 and 2011–2015 ( Fig 4D ).

Locations of San Lazaro Hospital, National Capital Region (gray), Manila City (black), Quezon City (dark gray), Region III (Shaded area), San Jose Delmonte City (light gray), Region IV-A (grid), and Antipolo City (light gray). Regional, provincial, city, and municipal boundary data and base maps were obtained from the United Nations Office for the Coordination of Human Affairs (OCHA). ( https://data.humdata.org/dataset/philippines-administrative-levels-0-to-3 ).

https://doi.org/10.1371/journal.pntd.0010595.g003

(A) Numbers of rabies cases in municipalities or cities. (B) Case mapping and heatmaps of rabies cases in Metro Manila, Region III, and Region IV-A. (C) Enlarged scale map focusing on cases and the heatmap in Metro Manila. (D) Heatmaps showing the case densities of human rabies cases during two observational periods (2006–2010 [transparent blue] and 2011–2015 [red]); each dot represents the residential address of a rabies case, with different colors representing the year of admission. Regional, provincial, city, and municipal boundary data and base maps were obtained from the United Nations Office for the Coordination of Human Affairs (OCHA). ( https://data.humdata.org/dataset/philippines-administrative-levels-0-to-3 ).

https://doi.org/10.1371/journal.pntd.0010595.g004

Of the 463 rabies cases with available medical charts, all were diagnosed with furious rabies without laboratory confirmation. Prodromal symptoms including pain, itching, or numbness at the bite site (n = 82, 17.7%), fever ≥37.0°C (n = 224, 48.4%), and nausea/vomiting (n = 103, 22.3%) were reported more commonly compared to patients in the previous report ( Table 1 ). The acute neurological symptoms included restlessness (n = 306, 66.1%), behavioral changes (n = 106, 22.9%), and confusion or agitation (n = 176, 38.0%). Most patients in our study showed typical symptoms of human rabies, including hydrophobia (n = 444, 95.5%) and aerophobia (n = 432, 93.3%). Other clinical symptoms included difficulty breathing (n = 190, 41.0%), hypersalivation (n = 116, 25.1%), and photophobia (n = 44, 9.5%). The patients were treated with diphenhydramine (n = 397, 85.8%), haloperidol (n = 370, 79.9%), and diazepam (n = 193, 41.7%). Several patients received intravenous fluids (n = 36, 7.8%). Only one patient (0.2%) was managed with mechanical ventilation. All patients died, most within 48 h of admission (n = 428, 92.5%). Only 2.4% (n = 11) of patients were admitted for >72 h (maximum 163 h).

https://doi.org/10.1371/journal.pntd.0010595.t001

Analysis of the medical charts of the 437 patients with an animal exposure history showed that most possible causal animals were dogs (n = 421, 96.3%) and cats (n = 16, 3.7%), similar to a previous report ( Table 2 ). Of the 437 animals, 113 (25.9%) and 78 (17.9%) were pets and stray animals, respectively, which were lower than those reported previously [ 14 ]. The exposure type was mostly animal bite (n = 415, 95.0%). In most cases, a single bite rather than multiple bites was documented (n = 310, 74.7% vs. n = 13, 3.1%, respectively). The most common bite locations were the lower extremities (34.6%), followed by the upper extremities (26.3%); fingers (10.1%); and face, head, or neck (4.8%). The incubation period was ≤30 days in 99 (22.7%) patients and 30–90 days in 184 (42.1%) patients. Approximately 10% of the patients (41 cases) had an incubation period of >1 year (maximum 10 years).

https://doi.org/10.1371/journal.pntd.0010595.t002

Among 437 patients with animal exposure history, 395 (90.4%) did not receive a rabies vaccine or RIG, while 42 (9.6%) received one or more rabies vaccines as PEP. Ten patients (2.3%) received >3 doses of a rabies vaccine, as recommended by the WHO, but only two patients (0.5%) received RIG ( Table 3 ). One was a 5-year-old boy who was bitten on his face by a dog. He was administered a purified chick embryo cell vaccine (PCECV) on days 0, 3, and 7, and RIG on day 0, starting on the same day as the animal bite, although the vaccination dose was not recorded. Despite receiving PEP, the patient died 21 days after the dog bite. The second patient was a 2-year-old girl with multiple bites on her face, neck, and upper extremities. She was administered 0.1 mL intradermal PCECV as PEP on days 0, 2, 7, and 21, and RIG on day 0, starting the day after the dog bite. She died 30 days after exposure to the animal. None of the 437 patients received PEP before exposure.

https://doi.org/10.1371/journal.pntd.0010595.t003

During the 10-year study period, human rabies cases were continuously admitted to the referral center in Metro Manila and virus transmission from infected animal bites persisted in the surrounding regions. Case maps and heatmaps demonstrated that rabies occurred continuously in similar areas during the 10-year study period. Most admitted rabies patients were adult men who did not seek PEP. The characteristics of human patients with rabies were similar to those described in this hospital between 1987 and 2006. We identified two cases of possible PEP failure.

Our results reflect the status of rabies cases around the NCR in the Philippines. Most human rabies cases in the NCR, Region III, and Region IV-A were referred to our hospital. An average of 57.5 cases annually were documented in this study, 23.1% of the yearly average of 248.7 cases in the Philippines [ 11 ]. The incidence rate per 100,000 population varied between 0.1041 and 0.2965 in these regions and was similar to that reported in China between 1996 and 2007 [ 15 ]. The characteristics of the patients with rabies reported previously in this hospital between 1978 and 2006 were broadly similar to those of the current study; however, the average number of cases each year (92 cases) was higher than that in our study (57.5 cases) [ 14 ]. The case maps and heatmaps showed that human rabies occurred continuously in similar areas during the 10-year study period. Studies in China and Brazil have shown decreasing trends and changing distributions of human rabies cases owing to successful rabies control programs [ 16 – 18 ]. Our findings are contrary to these findings, likely because the control programs, particularly mass animal vaccination, have been limited to certain areas of the Philippines. The National Program reported vaccine coverage rates in the NCR, Region III, and Region IV-A of 32.3%, 49.9%, and 38.9%, respectively, in 2015 [ 10 ]. Several recent community studies have shown that the dog population is much higher than the figures calculated by the recommendation of the rabies control program based on a 1:10 dog-human ratio [ 19 , 20 ]. Therefore, the dog vaccination coverage in many regions may be overestimated and far below the target of 70%. A careful analysis of rabies vaccine coverage in domestic dogs and strengthening of control programs is needed in areas where human rabies cases continue to be reported. A careful analysis of rabies vaccine coverage in domestic dogs and a strengthening of control programs is needed in areas where human rabies cases continue to be reported. The elimination of rabies in dogs through mass vaccination is cost-effective and has been successfully achieved in many areas [ 21 – 23 ].

All cases in this study were the furious rabies type and no patients were diagnosed with paralytic rabies. Paralytic rabies has rarely been reported in the Philippines [ 14 ]. This contrasts with reports from other countries, where up to one-third of human rabies cases can be paralytic rabies [ 24 , 25 ]. A study in Indonesia showed that 22% of human rabies cases were paralytic rabies [ 26 ], whereas reports from China and the Democratic Republic of Congo showed similar findings to our study [ 27 , 28 ]. Paralytic rabies may be misdiagnosed in the Philippines, or circulating strains in the Philippines may differ and cause fewer paralytic cases [ 29 , 30 ]. Further investigations are needed to understand the importance of paralytic rabies virus in this area. In the present study, the diagnosis of rabies was based on the clinical history, symptoms, and signs. The presence of hydrophobia and/or aerophobia is a key component when patients with suspected rabies are referred to this hospital.

The incubation periods observed in this study were comparable to those reported previously at this hospital [ 14 , 17 , 28 , 31 ]. Long incubation periods have been reported in some reports [ 14 , 31 , 32 ]. Incubation periods of >1 year were observed in 41 cases, with the longest incubation period of 10 years in our study. The accuracy of these data was limited due to the retrospective nature of the analysis, and we were not able to perform further detailed investigations on these cases. In this study, most of the patients died within 20–30 hours from the time of admission and may have presented to the hospital relatively late in the progression of symptoms.

Most rabies patients in this study were adult men, similar to a previous study conducted in this hospital [ 14 ]. A study analyzing the characteristics of individuals attending animal bite treatment centers in the Philippines reported more children or young adults seeking PEP compared to middle-aged adults [ 11 ]. Although animal bite exposures among adults might be lower than those of children, these findings indicated that middle-aged men may be less likely to seek medical care after an animal bite compared to younger age groups [ 11 , 33 , 34 ]. Strengthening education campaigns targeting older men should be considered to increase their likelihood of seeking medical treatment.

Most rabies patients did not receive a rabies vaccine or RIG, although more patients (n = 42; 9.6%) received at least one vaccine compared to the previous study in this hospital (n = 31; 1.7%) [ 14 ]. Among the 42 cases administered the vaccine, 20 (47.6%) were administered one dose, possibly because of a lack of time or financial considerations, as reported elsewhere [ 34 ]. Only 10 patients (2.3%) received ≥3 doses of rabies vaccines, in accordance with the WHO recommended regimen. We were unable to determine the routes of vaccine administration and manufacture. ID regimes were adopted by the national guideline in 1997 [ 8 , 9 ]. SLH started the ID regime in 1996; thus, it is likely that most health centers started it around the same year. Therefore, the patients in our study who received a rabies vaccine as PEP were likely to receive the vaccine via the ID route. It remains common to consult a traditional healer after an animal bite in the Philippines [ 34 ]. We were unable to determine the proportion of patients with rabies attending traditional healers or the common reasons for not receiving PEP. Further investigation is needed to clarify the health-seeking behavior of patients with rabies.

We identified two patients who died of rabies despite receiving complete PEP ( Table 3 ). Both patients were young, (5 and 2 years of age, respectively), experienced short incubation periods (20–28 days), and were bitten on the face. The method of RIG administration and manufacture of the vaccine were not identified in these cases. Treatment failure mostly occurs due to inappropriate wound washing, delayed treatment, or non-completion of PEP. PEP failure in patients with full course is rare. Guo et al reported 31 patients who had completed PEP but died of rabies among 10,971 human rabies cases in China [ 28 ]. Another study from China reported 19 cases of PEP failure among 711 human rabies cases [ 35 ]. Ren et al observed one case of PEP failure among 201 human rabies cases: a 5-year-old boy who was seriously bitten on his face/head by a stray dog [ 36 ]. A study in Cambodia reviewed 1,739 bite victims bitten by rabid dogs and reported three cases of possible PEP failure (0.17%; 95% CI: 0.03–0.50) [ 37 ]. Wilde et al described eight rabies cases with PEP failure [ 38 ]. Several case reports have also described single or multiple cases of PEP failure [ 39 – 41 ]. Many of these PEP failures occurred in young children and individuals with head/face bites. The virus incubation period following such injuries is often short (≤30 days). RIG infiltration is often difficult in small children with head/face injuries, which can lead to insufficient treatment. Direct inoculation of the virus into peripheral nerves might also cause PEP failure. Because rabies is almost universally fatal, more treatment options are needed for high-risk bite victims, such as individuals with face or head bite injuries, small children, or individuals bitten by laboratory-confirmed rabid animals. RIG shortages often occur in endemic areas because of the increasing demands due to animal bites. During such shortages, RIG prioritization is necessary. To identify high-risk bite victims, a higher WHO exposure category (Cat IV) should be considered. This category might be useful when RIG supply is limited and prioritization is necessary. Furthermore, add-on or alternative treatments for RIG should be assessed in this group. These high-risk bite victims should be carefully observed, and longer follow-up is necessary after PEP. A recent study demonstrated that favipiravir (T-705) is active against rabies virus in mice and may be a potential alternative or add-on treatment to RIG [ 42 , 43 ].

Our study had some limitations. This report is from a single health center study and did not cover all human rabies cases in the Philippines. Although our study might fail to determine the true incidence rate and some hot spots, this hospital does treat most human rabies cases in the NCR, Regions III and IV, and the referral system of human rabies cases did not change during the study period. Our analysis clarified the changing patterns and distribution of human rabies cases during the study period. A further limitation was that our case mapping showed the living places (home addresses) of the patient but not the locations where the rabid animals were encountered. None of the cases in our study were laboratory-confirmed because of a lack of diagnostic capacity for SLH. The retrospective design of the study meant that the data relied on the medical charts written by the attending physicians and questions from the physicians to patients or relatives. Our data on animal exposure and PEP treatments may be affected by recall bias, and we were unable to describe the WHO exposure categories, administration method of RIG, reasons for not seeking PEP, and details about the casual animals. Although one community survey in the Philippines revealed common reasons for not accessing medical treatment among individuals bitten by animals [ 11 , 34 ], the reasons among human rabies patients have not been studied. Prospective studies with laboratory confirmation are needed to clarify these issues, including the factors associated with not receiving PEP and the possible cases of PEP failure.

The results of our study showed that human rabies patients were continuously admitted to the hospital between 2006 and 2015, with no notable decline over the study period. The clinical characteristics were largely similar to those of the patients admitted to this hospital between 1987 and 2006. The geographical areas in which human rabies cases commonly occurred also did not change. Few patients received PEP and there were two suspected cases of PEP failure. The retrospective design of this study was a limitation; thus, prospective studies are required.

Supporting information

S1 table. characteristics of human patients with rabies who were excluded from further analysis due to missing or lost medical charts (n = 112)..

https://doi.org/10.1371/journal.pntd.0010595.s001

S1 Fig. The numbers of human rabies cases and animal bite victims attending animal bite treatment centers in the Philippines between 2007 and 2015.

These data were obtained from the National Rabies Prevention and Control Program in the Philippines. Manual of Procedures (2019). https://doh.gov.ph/sites/default/files/publications/Rabies%20Manual_MOP_2019%20nov28.pdf

https://doi.org/10.1371/journal.pntd.0010595.s002

S2 Fig. Geographical distributions of the residential addresses of patients admitted to San Lazaro Hospital with a final diagnosis of rabies between 2006 and 2015 on geological, population, and population density base maps.

(A) Case and geological maps. The base maps were obtained from the U.S. Geological Survey (USGS) and are in the public domain. https://earthexplorer.usgs.gov/scene/metadata/full/5e83d0b656b77cf3/LC81160502016044LGN01/ (B) Case and population maps per city/municipality in Metro Manila and Regions III and IV-A. (C) Case mapping and population maps per city/municipality in Metro Manila (enlarged map in B). (D) Case and population density maps per city/municipality per square kilometer in Metro Manila and Regions III and IV-A. (E) Case mapping and population density maps per city/municipality per square kilometer in Metro Manila (enlarged map of D). Each dot represents the residential address of rabies cases, with different colors representing the years of admission between 2006 and 2015. Regional, provincial, city, and municipal boundary data and base maps were obtained from the United Nations Office for the Coordination of Human Affairs (OCHA). ( https://data.humdata.org/dataset/philippines-administrative-levels-0-to-3 ).

https://doi.org/10.1371/journal.pntd.0010595.s003

S1 Dataset. Study data.

https://doi.org/10.1371/journal.pntd.0010595.s004

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• Published: 19 May 2022

Elimination of human rabies in Goa, India through an integrated One Health approach

• A. D. Gibson   ORCID: orcid.org/0000-0002-4641-2583 1 , 2   na1 ,
• G. Yale 3   na1 ,
• J. Corfmat 3   na1 ,
• M. Appupillai 3   na1 ,
• C. M. Gigante 4 ,
• M. Lopes 5 ,
• U. Betodkar 6 ,
• N. C. Costa 5 ,
• K. A. Fernandes 7 ,
• P. Mathapati 3 ,
• P. M. Suryawanshi 6 ,
• N. Otter 3 , 7 ,
• G. Thomas 1 ,
• P. Ohal 3 ,
• I. Airikkala-Otter 7 ,
• F. Lohr   ORCID: orcid.org/0000-0002-7158-3122 1 ,
• C. E. Rupprecht 8 ,
• A. King 9 ,
• D. Sutton 10 ,
• I. Deuzeman 9 ,
• Y. Li   ORCID: orcid.org/0000-0001-8815-6816 4 ,
• R. M. Wallace 4 ,
• R. S. Mani 11 ,
• G. Gongal 12 ,
• I. G. Handel 2 ,
• M. Bronsvoort   ORCID: orcid.org/0000-0002-3271-8485 2 ,
• V. Naik 5   na2 ,
• S. Desai 5   na2 ,
• S. Mazeri 1 , 2   na2 ,
• L. Gamble 1   na2 &
• R. J. Mellanby 2   na2  

Nature Communications volume  13 , Article number:  2788 ( 2022 ) Cite this article

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• Developing world
• Epidemiology
• Viral epidemiology
• Viral genetics

Dog-mediated rabies kills tens of thousands of people each year in India, representing one third of the estimated global rabies burden. Whilst the World Health Organization (WHO), World Organization for Animal Health (OIE) and the Food and Agriculture Organization of the United Nations (FAO) have set a target for global dog-mediated human rabies elimination by 2030, examples of large-scale dog vaccination programs demonstrating elimination remain limited in Africa and Asia. We describe the development of a data-driven rabies elimination program from 2013 to 2019 in Goa State, India, culminating in human rabies elimination and a 92% reduction in monthly canine rabies cases. Smartphone technology enabled systematic spatial direction of remote teams to vaccinate over 95,000 dogs at 70% vaccination coverage, and rabies education teams to reach 150,000 children annually. An estimated 2249 disability-adjusted life years (DALYs) were averted over the program period at 526 USD per DALY, making the intervention ‘very cost-effective’ by WHO definitions. This One Health program demonstrates that human rabies elimination is achievable at the state level in India.

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Introduction.

Rabies is a devastating and societally important zoonotic disease, which is transmitted principally to humans through the bite of infected dogs. This acute, progressive viral encephalitis has the highest case fatality of any infectious disease and kills tens of thousands of people annually, with children and impoverished communities being affected disproportionately 1 , 2 .

India is estimated to suffer the greatest rabies burden of any country, both in terms of annual human deaths and disability-adjusted life years (DALYs) 1 . Although the timely delivery of human post-exposure prophylaxis (PEP) prevents death from rabies, focusing on the post-bite treatment of people (a dead-end host) has no impact on the incidence of rabies in the canine reservoir population, leaving other members of the community vulnerable to acquiring the disease 3 . The effectiveness of mass dog vaccination in eliminating rabies from the reservoir animal population, and thereby preventing viral transmission to humans, has been known for over a century 4 , enabling dog-mediated rabies to be eliminated in numerous countries 5 , 6 , 7 . Modern rabies management highlights the importance of achieving zoonotic disease prevention and control through consideration of human, animal, and environmental components in a One Health approach 8 .

In most endemic settings without vaccination, the reproductive number of rabies in dogs is below two under natural conditions, falling below one where over 40% of the dog population is vaccinated 9 . To account for population turnover, annual vaccination of over 70% of dogs has been shown to successfully eliminate viral perpetuation, making canine rabies an ideal candidate for worldwide elimination 9 , 10 . Due to the particular ecology of dogs in India, where millions of dogs are free-roaming and hard-to-reach 11 , rabies is considered very challenging to eliminate, as is reflected in the complete paucity of examples of rabies elimination in any Indian state 12 . The reasons for this failure are invariably multifactorial, but achieving a step-change in the political prioritization of rabies control and surmounting the logistical challenges in reaching vaccination coverages sufficient to control the disease is critical to the quest for canine rabies elimination at the state level 11 , 12 , 13 .

Here, we report how these challenges were overcome in Goa, India through a collaboration between local government, non-governmental organizations, and academic partners, culminating in the elimination of human rabies, for the first time, at the state level in India. The One Health program consisted of three core areas of activity: dog vaccination; rabies education; and intensified human and animal rabies surveillance.

Dog vaccination

The central goal of this One Health program was to eliminate human rabies deaths by reducing rabies incidence in the canine reservoir through mass dog vaccination. This was achieved with mobile dog vaccination teams aiming for high coverage in both the free-roaming and owned confined dog populations throughout the state. Remote vaccination teams were spatially directed through assigned polygons displayed on a smartphone app, enabling managers to deliver vaccination resources to a specific geographic area at the sub-village scale 14 , 15 . The GPS and details of each dog vaccination were recorded offline in the app and subsequently shared with project managers through an administrator website. Vaccination teams rotated through the administrative regions of Goa (talukas) (Fig.  1 ), re-starting the state campaign cycle on an approximately annual basis (Supplementary Figs.  2 – 4 ). A combination of door-to-door (DD) and capture-vaccinate-release (CVR) methods were used to access dogs for parenteral vaccination. DD vaccination involved teams walking house-to-house offering owners an opportunity to have their dog vaccinated, whilst CVR consisted of teams using nets to catch and vaccinate dogs that could not be restrained manually.

Choropleth map of Goa state showing taluka boundaries and colored by the estimated dog population. Dog population estimates were calculated from mean vaccination coverage and mean number of dogs vaccinated per taluka during vaccination cycles in which comprehensive post-vaccination surveys took place (Supplementary Methods, Supplementary Fig.  7 ). Inset map shows the state borders of India (white lines) and the location of Goa state (red). India state and Goa taluka boundaries were sourced from https://gadm.org .

The annual vaccination output increased, both in terms of geographic extent and a total number of dog vaccinations, through program refinement from 2013 to 2017 (Fig.  2 ). Intensive state-wide vaccination was achieved for the first time in 2017, vaccinating 97,277 dogs in an estimated total population of 137,353 dogs. This output was sustained through 2018 and 2019 (Fig.  2 ). A total of 426,119 rabies vaccine doses were administered to dogs between 2013 and 2019 (Fig.  2 , Supplementary Fig.  3 , Supplementary Table  1 ).

Maps of Goa state (gray shading) showing the villages/municipalities in which vaccination took place each year (blue shading) and positive canine rabies cases by village (black circles). A small-scale pilot dog vaccination campaign was conducted in 2013 (Supplementary Fig.  3 ), however, no location-specific canine rabies surveillance data were available at this time.

Vaccination methods were evaluated using post-vaccination dog-sight surveys to estimate coverage. A total of 3188 post-vaccination surveys were conducted during the period of study, recording 280,859 dog sightings. Final vaccination coverage was estimated from the last survey of each area, resulting in the omission of 793 surveys from the final analysis. The mean vaccination coverage in the 2016 campaign was 71.8% in all sighted dogs and 60.1% in roaming dogs, however, some areas of the state were not vaccinated. In 2017 intensive methods were applied state-wide achieving an estimated coverage of 71.7% in all dogs sighted and 53.1% in the roaming population (Supplementary Fig.  5 ).

Both ownership and confinement data were available for over 90% of dog vaccination records ( n  = 384,149), of which 52% ( n  = 199,887) were owned dogs and 48% ( n  = 184,262) were unowned dogs. Unowned dogs were inherently always roaming, while owned dogs were either always roaming ( n  = 35,823, 17.9%), allowed to roam for some of the time ( n  = 100,618, 50.3%) or always confined (never roaming) ( n  = 63,446, 31.7%). Consequently, most dogs vaccinated (83.5%) were among the roaming dog population for some or all of the time (Supplementary Fig.  4 ). The proportion of dogs vaccinated that were owned differed significantly between urban and rural settings. Of 213,467 dogs vaccinated in urban areas, 45.1% (CI: 44.9–45.4) were recorded as owned, as compared to 60.6% (CI: 60.4– 60.9) of 170,682 dogs vaccinated in rural settings (test of equal proportions p  < 0.001).

Operational efficiency was improved through iterative refinement of vaccination methods. The initial approach, focusing on net-catching of unowned dogs in 2013, was adjusted to include the vaccination of owned dogs from October 2015. Smaller two-person DD vaccination teams were introduced in 2018 to more efficiently vaccinate dogs that could be restrained by hand, which was the case for 64.2% of all dogs vaccinated (restraint data available from 2018). Nevertheless, specialist equipment was still needed to access a considerable proportion of dogs, with 16.3% of owned dogs and 56.5% of unowned dogs being restrained by a net. The mean number of active vaccination teams per day increased from 2.5 (95% CI: 2.4–2.7) CVR teams in 2016 to a total of 7.7 (CI 7.4–8.0) (4.4 CVR teams and 3.3 DD teams) in 2019. Dog vaccination program-specific costs were available for 2018 and 2019, producing a mean cost per dog vaccinated of 3.45 USD (Supplementary Table  5 ).

Rabies education

The second pillar of the program was an education initiative whose primary focus was on teaching school children about rabies, how to avoid dog bites and what to do if bitten. The program also emphasized the importance and social value of ensuring as many dogs as possible were vaccinated against rabies each year. In total, school-based rabies education classes were delivered to 694,271 school children and 31,251 teachers between 2014 and 2019 (Supplementary Table  1 ). The scale of the school education program increased from 2014, plateauing from 2017 onwards with the delivery of educational lessons to ~170,000 children per year across 1400 schools in Goa. Activities to distribute rabies educational messages throughout communities intensified with a similar timeframe which resulted in the delivery of rabies lessons to 155,079 people through community groups, local authorities, and public events (Supplementary Table  1 ).

Dog rabies surveillance

The third pillar of the program was rabies surveillance within the dog population. Enhanced canine rabies surveillance was driven by improving the reporting of suspected rabid dogs from across public and private sectors. This was centrally managed through a widely publicized Rabies Hotline phone service launched in 2014.

Details of phone calls to the Rabies Hotline were available from October 2017, totaling 7372 and increasing from an average of 50.2 calls per week in 2018 (95% CI: 42.9–57.5) to 78.9 calls per week in 2019 (CI: 69.9–87.9) (Supplementary Fig.  8 , Supplementary Table  2 ). Mapping the origin of calls showed widespread engagement with the Rabies Hotline throughout the state (Supplementary Fig.  9 ). The most common reasons for contacting the Rabies Hotline were requests for vaccination of dogs (44.3%), reporting sick or injured dogs (without typical signs of rabies) (32.4%), and dog nuisance (6.7%). Despite increasing total calls, the rate of calls reporting suspect rabid animals reduced from a mean of 6.7 per month in 2017 to 4.8 in 2018 and 4.5 in 2019 (Supplementary Fig.  8 ).

Reports of suspect rabid animals initiated a veterinary field investigation to examine the animal and interview people involved or exposed. Systems for the management and testing of suspect rabid animals were established in 2014. Samples were initially shipped to the WHO reference laboratory for rabies in Bangalore (NIMHANS) for direct fluorescent antibody (DFA) test diagnosis. A rapid lateral flow assay (LFA) was used as a field-side tool in screening cases 16 , however, LFA results did not inform human PEP decisions. In 2016, the capacity to perform the DFA was established at the Goa Disease Investigation Unit (Department of Animal Husbandry & Veterinary Services) laboratory to provide routine timely rabies diagnosis ( Supplementary Methods ).

Seventy-three canine rabies cases were confirmed in the first 6 months of surveillance in 2014, with the highest monthly report of the study period occurring in July 2014 at 20 cases (Supplementary Fig.  10 ). The mean state-wide occurrence of canine rabies cases decreased from 10.6 cases per month in 2014 to 0.8 in 2019, a decrease of 92% (Supplementary Fig.  10 , Supplementary Table  2 ). The regional distribution of cases also changed significantly across the study period. No canine rabies cases were detected in 11 of Goa’s 12 taluka regions for over a year, from November 2018 until December 2019 (Figs.  2 , 3 , Supplementary Fig.  11 ). The continued occurrence of cases in the later stages of the program was confined to the northern region of Goa, bordering unvaccinated dog populations in the neighboring state (Figs.  2 , 3 ).

Asterisk denotes talukas that immediately border areas of high dog density in other states in which rabies remains endemic. Month-wise estimated vaccination coverage was calculated from the number of vaccinations delivered by campaign cycle and total estimated dog population by region, with a month-wise estimate of population turnover.

Analysis of the distribution of confirmed canine rabies cases by taluka over time revealed that cases were not homogeneously distributed. Cases predominated in areas of high dog density with a multivariable mixed-effects logistic regression model estimating that the odds of a taluka having at least one confirmed rabies case in a month increased as the taluka’s free-roaming dog population density increased (Fig.  4 , Supplementary Table  6 ). The model also showed that the odds of at least one rabies case occurring decreased as rolling mean 12-month vaccination coverage increased. Two talukas, Pernem and Canacona, neighboring unvaccinated dog populations at the north and south borders of the state did not follow this pattern as canine rabies cases continued to occur in the face of sustained high vaccination coverage (Fig.  3 ).

Multivariable mixed-effects logistic regression model predicting a taluka having at least one confirmed dog rabies case in a particular month ( n  = 624). Figure shows the Odds Ratio (points) and 95% confidence intervals (horizontal lines). Asterisks indicate a p value < 0.05. The model shows that the odds of a taluka having at least one positive dog rabies case in a particular month increased as roaming dog population density increased. Similarly, as the rolling mean 12-month vaccination coverage increased, the odds of a positive rabies case were reduced. The odds of identifying at least one rabies case during the monsoon season (the reference season in the model) were lower, especially compared to the winter season, which had significantly higher odds. The AUC was calculated as 0.73, indicating that the model was very good at predicting the outcome.

Rabies virus sequencing was conducted to explore the molecular epidemiology of canine rabies in Goa 17 . Ninety-seven glycoprotein and 80 nucleoprotein gene sequences were generated from samples randomly selected from a bank of rabid dog brain samples spanning 2016 to 2018 (Supplementary Data  2 ). The sequences formed three major groups based on phylogenetic analysis, average nucleotide identity, and haploid network analysis of the glycoprotein gene: seventy sequences fell into Group 1; sixteen into Group 2; and eight into Group 3 (Fig.  5 , Supplementary Fig.  15 – 17 ). The high degree of sequence conservation within these groups indicated that they represented co-circulating lineages predominating in discrete geographic regions of Goa state: Group 1 in North Goa; Group 2 in South Goa; and Group 3 in the north border region, with the exception of Goa_A_04-03-2018 (Fig.  5 ). One sequence, from a rabid dog brought from Karnataka to Goa post-mortem (Goa_A_10-03-2017), was identified as a recently imported case into the region from north India, displaying <97% identity to all other samples (Supplementary Table  7 , Supplementary Fig.  16 ).

Phylogenetic analysis of 97 rabies virus glycoprotein gene sequences from Goa, India 2016–2018. The phylogenetic tree was calculated by maximum likelihood (GTR + G + I). Numbers on branch points represent bootstrap support based on 1000 replicates. The colors on the tree correspond to colored points on the Goa map. Sequences in Goa1a are collapsed for viewing convenience; a list of samples in each group is in Supplementary Data  2 . Positions on the map are approximate. Some points deviate slightly from their true location to allow for visualization of multiple samples from the same location. The location of sample Goa A 04-03-2018 (Karnataka) is highlighted by a line. The scale bar indicates the number of changes per site.

Time-scaled phylogenetic analysis of the glycoprotein gene estimated that Group 1 originated in 2009 (95% CI: 2006.6–2011.7), Group 2 in 2012 (95% CI: 2010.2–2014.6), and Group 3 in 2009 (95% CI: 2005.5–2013.3), with the most recent common ancestor between the groups estimated to be in 2003 (1999.4–2007.3) (Figs.  5 , 6 ). A sub-group of Group 3, excluding sample GOA_A_04-03-18 from Karnataka, was estimated to arise around 2014. Similar estimates (within 2.5 years) were obtained using the complete nucleoprotein gene (Supplemental Fig.  19 ).

Time-scaled phylogeny of partial glycoprotein gene sequences (1317 nt) of Goa samples, Karnataka samples, and Maharashtra samples generated in this study with representative reference sequences from India belonging to the Arctic-like 1a rabies virus lineage. Representative samples from the Arctic-like 1b lineages were included as an outgroup. Scale at the bottom indicates year. Sample IDs are colored based on the state of sample collection, according to the coloration on the map. Bars to the right indicate members of Goa1, Goa2, and Goa3 groups. Numbers at the branches indicate posterior support values. AL1b: Arctic-like 1b.

All Goa sequences generated in this study clustered within the Arctic-like 1a rabies virus variant lineage and were most similar to sequences from the neighboring states of Karnataka, Maharashtra, and Andhra Pradesh (Fig.  6 ). Samples in Groups 1 and 2 clustered separately from sequences generated in other studies. However, Group 3 samples clustered with a rabies virus reference sequence from a human case in Andhra Pradesh, India in 2011 (Fig.  6 ).

Additional statistical cluster analysis of the spatio-temporal distribution of rabies cases identified one statistically significant cluster centered in North Goa from 2016 to 2017 (Supplementary Figs.  20 and 21 ). This statistically significant rise in canine rabies, above what would be expected if cases were distributed equally according to the population at risk, occurred where the Group 1 and Group 3 rabies virus lineages coincided. This region was close to the northern border where the Goan dog population interacts with unvaccinated dogs in neighboring districts of Maharashtra (Supplementary Fig.  21 ).

Public health impact

To assess the human impact of the One Health program, information on dog bites and human rabies deaths was acquired from the Directorate of Health, Government of Goa. Human rabies deaths reduced from 17 in 2014 to zero in 2018 and 2019 (Fig.  7 , Supplementary Table  2 ). This decline in human deaths occurred during a period of increased human rabies surveillance resulting from numerous rabies-focused activities engaging the human medical profession in Goa ( Supplementary Methods ). The number of reported dog bites increased from 785 per 100,000 people in 2012 to 1430 per 100,000 people in 2019 (Supplementary Fig.  22 , Supplementary Table  2 ).

Graphs show intervention outputs (dark background) of annual total dog vaccinations and children taught about rabies and indicators of rabies control (light background) of annual human rabies deaths and confirmed canine rabies cases. The dotted line in canine cases indicates a period prior to the enhancement of animal rabies surveillance activities. The decrease in canine rabies cases in 2015 is due to the cessation of canine rabies surveillance activities between October 2014 and September 2015.

A previously published model (RabiesEcon 18 , 19 ) was used to estimate the cost-effectiveness of the intervention. Goa-specific programmatic data were used to populate the model, including human and dog population data; annual dog vaccination coverage; program costs; PEP costs; and estimated rates of access to PEP (Supplementary Data  3 , Supplementary Table  5 ). The estimated mean cost per death averted and cost per DALY averted from 2013 to 2019 were 14,866 USD and 526 USD respectively. During this period the program was estimated to result in a total of 2,249 DALYS averted, and 80 deaths averted as compared to no intervention. Over a 10-year projection (2013–2023), the intervention was estimated to prevent 121 human rabies deaths and 3427 DALYS at a mean cost of 567 USD per DALY averted. The model predictions of human rabies deaths, human rabies exposures, and total estimated intervention cost were concordant with empirical values from the program area.

This collaborative One Health program demonstrates the feasibility and cost-effectiveness of human rabies elimination at the state level in India, offering a tangible example of success in the quest to eliminate canine-mediated human rabies deaths by 2030. Despite the terrible toll rabies exerts in India, the inaccessible nature of the huge free-roaming dog population resulted in the modern discourse that, while local elimination of rabies within restricted communities is feasible, extending these approaches to a state-level still presents a near-insurmountable practical and logistical challenge 8 , 11 , 20 , 21 . Such failings resulted in calls to the scientific community to refocus rabies research towards programs that advanced the field implementation and evaluation of rabies elimination strategies 22 , 23 . The current initiative integrating mass dog vaccination, education, and rabies surveillance, underpinned by innovations in mHealth remote team direction, data capture, and real-time analysis, specifically addressed this challenge and has shown robustly that freedom from dog-mediated human rabies deaths is feasible and within reach.

Dog accessibility is a major barrier to the efficient application of high-coverage state-wide dog vaccination campaigns in India. Whilst central point dog vaccination approaches have achieved high-number, high-coverage outputs in some African settings 10 , 24 , the high proportion of stray dogs in India limits the likely success of such methods in achieving herd immunity against rabies 11 . Similarly, DD campaigns centered on catching dogs by hand had limited success 25 . The majority of dogs vaccinated in the Goa program were caught by hand, however, achieving adequate vaccination coverage was not possible without specialist equipment and expertise through net-catching. Advanced vaccination techniques are therefore necessary to interrupt rabies virus transmission in such settings. Regular assessment of post-vaccination coverage during the early stages of program development proved to be critical in identifying where the vaccination approach was successful and where improvement was needed 26 . The mean cost of 3.45 USD per dog vaccinated was higher than reported global averages (2.18 USD), but within the range reported by other mass dog vaccination interventions (1.13–15.62 USD) 27 , 28 . This appears reasonable given the large free-roaming dog population in Goa and reliance on net capture to reach adequate vaccination coverages. The use of oral rabies vaccination (ORV) of dogs in combination with parenteral methods offers the potential to further optimize the current approach to intensively vaccinate otherwise inaccessible dog populations across large states in a short period of time 20 , 29 , 30 . An economic study of ORV in dogs found that communities similar to Goa could likely implement this approach at a similar cost per dog vaccinated 31 .

According to the WHO criteria of cost-effectiveness 32 , the intervention can be considered “very cost-effective”. The cost of each year of healthy life (i.e., DALY averted) of 526 USD was a quarter of the gross domestic product per capita for India (2100 USD) 33 , and 13 times lower than that of Goa state (7029 USD) 34 in 2019. The estimated cost per DALY averted from the Goa program was lower than statistical estimations of rabies interventional cost-effectiveness in India and Sri Lanka at 1064 USD and 1401 USD per DALYs respectively 35 , 36 , but higher than a recent report in Rajasthan at 40 USD per DALY averted 37 . This variability is likely a reflection of the non-standardization of economic modeling methodologies. However, unlike many assessments based on estimated values, state-wide implementation of the current program through a single government collaborator enabled comprehensive inputs to be based on programmatic operational and surveillance data. In the current analysis, we assumed that rates of PEP administration would not change until policies were updated to reflect the reduced risk and limited need for PEP. Assuming these changes are made in the lifetime of this program, the interventions would be even more cost-effective. The collaborative structure of the Goa program drove rapid innovation and expansion of activities, leveraging external funding to support the refinement of methodology and development of tools to increase efficiency, whilst the local government retained control and leadership of the intervention. Similar collaborative approaches were central to the global effort to eradicate polio 38 and have been beneficial in rabies control initiatives elsewhere 39 , 40 . Proposed innovative funding structures, such as development impact bonds, may offer novel investment sources to stimulate the expansion of rabies control activities 41 .

The use of smartphone technology revolutionized the systematic, spatial management of the vaccination workforce in Goa 15 . A study in Haiti found that the same smartphone application used to spatially direct vaccination teams at the sub-village level, significantly increased vaccination coverage compared with non-technology-aided methods 14 . Such technology-aided vaccination strategies have the potential to minimize unvaccinated pockets in the population and therefore hasten viral elimination 42 . Similar strategies to spatially dissect national public health programs for delivery at the community level, described as “microplans”, have been reported as significant to the successful delivery of polio and other disease control interventions 43 , 44 , 45 . The availability of GPS location and dog-specific data for every animal vaccinated provided unprecedented transparency in reporting to government stakeholders in addition to a wellspring of insights into dog population ecology from which to optimize vaccination strategy.

The state-wide education initiative in schools directed rabies awareness towards children, the demographic at disproportionate risk of death from rabies 46 . Similar class structures, combining presentation, theater, and question-answer methods have been demonstrated to be effective in other settings 47 . Rabies educational content was integrated into the Government of Goa school science curriculum for children aged 11–12 years in 2020, helping to ensure sustained awareness of the disease whilst regional control efforts grow. The increase in dog-bite presentations at bite clinics during the project period may reflect the widespread community awareness of rabies brought about by the community education program and counters the traditional view that bite cases fall following rabies control 48 . Concurrent development of integrated bite case management (IBCM) systems to reduce unnecessary PEP in people bitten by healthy dogs would maintain cost-effective use of PEP in the face of this increase 49 , 50 .

Enhancing state capacity for the detection and diagnosis of rabies in dogs was critical to gaining insight into the scale of the problem; monitoring the impact of dog vaccination activities; and providing incentives for continued support from all stakeholders. In addition to these benefits, the removal of rabid dogs may also have hastened elimination by preventing ongoing rabies virus transmission 51 , 52 . Canine rabies surveillance focused on three main areas of enhancement: reporting, detection, and diagnosis. The Rabies Hotline proved to be highly effective in soliciting reports of suspect rabies cases from the public, police, animal welfare, human health, and veterinary sectors. Full-time Rabies Surveillance Officers capable of deploying to anywhere in the state at short notice ensured the timely veterinary investigation and testing of suspect rabid animals.

Prior to the local availability of OIE-approved rabies diagnostic tests, the use of rapid diagnostic tests motivated veterinarians to retrieve samples from suspect rabid animals under difficult field conditions 16 and demonstrated the urgent need for in-state laboratory rabies diagnostic capabilities. Reports of poor quality control and low sensitivity of these tests, meant that negative results could not be considered valid and guidelines for their use should be a point of consideration in the development of national programs 53 . The establishment of DFA testing capacity in the government veterinary laboratory in 2016 was essential for robust state-level rabies surveillance and to ultimately demonstrate canine rabies freedom as recognized by OIE.

The use of portable MinION technology in Goa state revealed the potential for sequencing at regional veterinary laboratories to enhance state-level control strategies through a greater understanding of rabies virus transmission dynamics 17 , 54 . Time-scaled phylogenetic analysis of Goa sequences revealed a recent common ancestor around 2003–2005, with subsequent diversification into the three lineages, identified in this study as Goa1, Goa2, and Goa3. Further diversification of the Goa3 samples from the northern Goa border region around 2014, coincided with an increase in reported rabies cases in the area between 2014 and 2018. This finding supported the conclusion of the spatio-temporal cluster analysis indicating a potential site of the continued reintroduction of canine rabies. Expansion of dog vaccination beyond Goa’s borders is underway to reduce the risk of direct rabies virus reintroduction through dog movement at the border. The identification of a rabid dog importation into the greater region from northern India highlighted the risk of inter-state spread of rabies virus via human-mediated transport of dogs. National and regional rabies control will invariably require widespread coordination of vaccination efforts as was found to be critical to the success of programs in Europe and Latin America 55 , 56 . The continued monitoring of rabies virus sequences in Goa will provide a detailed picture of rabies virus transmission to further optimize control strategies on a larger scale.

The predominance of canine rabies in regions of high human and dog population density in Goa addressed the question of where efforts should be prioritized during the early phases of mass dog vaccination scale-up, when resources may be insufficient to vaccinate an entire state or district. The findings of the current study support an approach to accelerate the development of dog vaccination campaigns in Indian metropolis settings and the subsequent propagation of efforts into peri-urban and rural settings. This strategy was effective in regional rabies elimination efforts in Latin America, where nascent dog vaccination programs focused on large urban centers. These activities enabled the development of expertize, capacity, and political momentum to progress towards widespread initiatives ultimately resulting in the inter-state success of a magnitude needing to be replicated in India 20 , 56 . However, it is important to note that whilst urban centers may present the largest canine rabies burden, dog populations in peri-urban and rural regions can sustain rabies virus transmission 57 and the limited access to PEP in rural communities often results in a disproportionate human rabies burden in this areas 3 . Further research is required to explore opportunities to spatially prioritize dog vaccination for maximum cost-efficacy of elimination programs.

National implementation of effective canine rabies control in India would represent the greatest achievement by a single country in the endeavor to eliminate dog-mediated human rabies by 2030. Clearly, this would require enormous mobilization of resources and sustained political commitment. Although the outputs of the current study would need to be amplified several hundred times over to be replicated at the national scale, it showcases the feasibility, cost-effectiveness, and considerable public health impacts of One Health interventions for rabies control at the state level in India. Enduring political support, modern technologies in program management, and intersectoral, transdisciplinary collaboration was pivotal to the success of this multi-year effort and provide a clear rationale for other states to follow. The growth trajectory of the Goa rabies control program aligned with that outlined previously by Wallace et al. 58 , with phases of preparation, scale-up, and sustained vaccination, resulting in rapid impacts on human and canine rabies incidence within three years of scale-up. Whilst dog accessibility presents a major challenge to achieving herd immunity in a predominantly unowned dog population, this study demonstrates that effective mass dog vaccination campaigns are feasible in India and can achieve canine rabies virus elimination across large geographic areas. In 2021, Goa became the first Indian state to be declared a Rabies Controlled Area 59 under the Prevention and Control of Infectious and Contagious Diseases in Animals Act, 2009, ensuring legislation to maintain rabies control activities and setting a precedent for other states. The methods and technology developed through the current study can be leveraged to support the planning of national rabies control efforts in South Asia and accelerate similar examples of success in driving towards the 2030 goal of global dog-mediated human rabies elimination.

The period of study was from 10/09/2013 to 31/12/2019, which coincides with the launch of the first pilot dog vaccination and education initiative and the end of the fifth year of large-scale vaccination activities. The Government of Goa Department for Animal Husbandry oversaw the project protocols and methods for mass dog vaccination and animal rabies surveillance, with input from the Goa Veterinary Association to adhere to all relevant ethical regulations. A veterinary ethical review was provided by the University of Edinburgh Veterinary Ethical Review Committee.

Goa covers an area of 3700 square kilometers and has an estimated human population of 1.5 million, with 62% of people residing in areas defined as “urban” 60 . The state is bordered to the west by the Arabian Sea and to the east by the Western Ghats mountain range (Fig.  1 ). Tourism is a major industry. Goa is one of India’s more developed states, as measured by the United Nation’s human development index (HDI), with an HDI of 0.76 in 2017 as compared to India's national HDI of 0.64 61 , 62 . The state is divided administratively into two Districts, North Goa and South Goa, which are further divided into a total of 12 talukas. These talukas are made up of local administrative units of village panchayats (villages) and municipalities (towns and cities), of which there are a total of 420 in Goa.

The non-governmental organization Mission Rabies ( www.missionrabies.com ) began investigation of mass dog vaccination methods in September 2013 with a two-week pilot vaccination campaign, followed by a dog vaccination and sterilization campaign in densely populated regions from March to September 2014. In September 2015, the Government of Goa established a formal collaboration through a Memorandum of Understanding with Mission Rabies to support the implementation of a state-wide dog vaccination initiative, rabies surveillance, and education program. The aim was to systematically vaccinate at least 70% of the dog population on an annual basis using a combination of DD and CVR methods (Supplementary Fig.  1 ) 2 , 9 . Vaccinations were provided free of charge and each dog was administered with a 1 ml dose of rabies vaccine (Nobivac® Rabies–MSD Animal Health) either subcutaneously or intramuscularly, depending on animal position and restraint method. Each dog was marked with non-toxic paint on the top of the head, lasting for several days to enable identification of vaccination status on post-vaccination surveys. Consent was obtained from an owner prior to vaccination of dogs that were identifiably owned.

Vaccination team direction and program monitoring were performed using the WVS App, a purpose-built mHealth technology described previously 15 , 26 . The information recorded offline for each dog at the time of vaccination included: vaccination team ID; time; date; GPS; sex; age; ownership; neuter status; confinement; and health status. A web-based interface enabled project managers to review daily the geographic extent of vaccination work and to spatially direct vaccination and survey teams to sub-village ‘Working Zones’ according to vaccination output 26 .

Between 2013 and 2017 dog vaccination was conducted entirely by CVR teams typically consisting of seven or more people traveling by truck: one vaccinator, one assistant, one driver, and four dog catchers using nets. Dogs that could be held by hand, either by an owner or the team, were manually restrained for vaccination. Dogs that could not be manually restrained were caught using nets (Supplementary Fig.  1 ). Two-person DD vaccination teams, consisting of a vaccinator and assistant traveling by scooter were introduced in 2018 to improve operational efficiency. DD teams vaccinated in Working Zones first, targeting dogs that could be restrained by hand and therefore did not require a large team of net-catchers. CVR teams subsequently followed in these regions to catch and vaccinate difficult to handle dogs that had not been vaccinated by DD teams, as indicated by the absence of a vaccination paint mark.

Post-vaccination dog-sight survey methods have been described previously and enabled immediate re-deployment of vaccination teams to Working Zones with low vaccination coverage 26 . In 2013 and 2014 only free-roaming dogs sighted were recorded, however, from 2015, dogs confined to private property at the time of sighting were also recorded. These surveys were performed following the completion of dog vaccination in each Working Zone to evaluate vaccination methodologies until 2017. In 2018 and 2019, post-vaccination surveys were used to spot-check coverage, and whilst vaccination teams were re-deployed to boost areas of low coverage, repeat surveys were not conducted as had been done in previous years. Therefore, surveys from 2018 and 2019 were not included in the analysis of vaccination coverage assessment.

Alongside the state-wide systematic mass dog vaccination program, Mission Rabies implemented a concurrent education initiative focused on the delivery of structured lessons to children in schools and educational sessions to community groups. Typically, the education program was implemented through three rabies education officers who moved systematically across the state ahead of the vaccination schedule, delivering rabies lessons in schools and sessions to the community ( Supplementary Materials ) 15 . Rabies lessons were 15–30 minutes in duration, were adjusted to the age group, and fell under the following headings: Rabies is serious; Stopping dog bites; Rabies first aid; and Rabies is preventable 47 . In the later stages of the project, events to train schoolteachers in rabies lesson delivery were also conducted.

Rabies surveillance

A central public rabies reporting and response service was established in March 2014, prior to which there was no structured process for the reporting of suspect rabid animals. A Rabies Hotline phone number was widely publicized to the public, government, and private sectors for the reporting of suspect rabid animals 24 hours a day, 7 days a week ( Supplementary Methods , Supplementary Figure  1 ). Notification of a suspect rabies case to the Rabies Hotline triggered an immediate field investigation to examine the animal, and if necessary, submit samples for testing at the Goa Disease Investigation Unit ( Supplementary Methods ). The Rabies Hotline and rabies response activities were not active from October 2014 to September 2015. Canine rabies surveillance intensity increased in April 2018 through the incorporation of IBCM methods described elsewhere 50 . Suspected human rabies cases were managed and diagnosed at the Goa Medical College, with numerous events and initiatives taking place during the study period to raise awareness of the importance of human rabies surveillance in the medical profession ( Supplementary Methods ). PEP was available free of charge to those presenting for treatment of dog bites at government medical facilities throughout the state.

Data analysis

Data for dog vaccinations, educational events, post-vaccination dog surveys, notifications of suspect animal rabies cases and suspect animal rabies case investigations were exported from the WVS App database in CSV format. Analysis was performed using R version 3.6.2. Manual reports and field records were used to verify App data. Post-vaccination surveys and dog vaccination data were used to calculate mean dog vaccination coverage and month-wise vaccination coverage by taluka ( Supplementary Methods ).

Logistic regression model

A mixed-effects multivariable logistic regression model was used to identify factors associated with a taluka having at least one confirmed dog rabies case each month (Supplementary Software  1 ). The number of confirmed dog rabies cases for each taluka each month was used to create the binary outcome variable in the model. If a taluka had at least one case in a given month it was considered positive, and if no cases were recorded that month the taluka was considered negative. Explanatory variables investigated included free-roaming dog population, free-roaming dog population density, estimated monthly vaccination coverage, estimated 12-month rolling mean coverage, season, and whether the taluka borders unvaccinated dog regions (Supplementary Data  1 ). The seasonal timeframes used have been described previously 63 . The data were randomly split into a training and testing dataset using a 70:30 ratio using R package caret 64 . Univariable analysis was used and any variable with a p value of <0.15 was considered for the final model. To investigate whether numerical variables had a linear relationship with the log-odds of the outcome, these were split into quartiles and univariable models were visualized to assess the relationship. Manual forward variable selection was conducted and the final model was chosen based on the lowest Akaike information criterion (AIC). The final model was validated, testing its ability to predict the outcome in the test dataset by estimating the area under the curve using R package ROCR 65 .

Phylogenetic analysis

Rabies viral sequencing of glycoprotein and nucleoprotein genes was performed on an archive of positive canine rabies brain samples spanning 2016 to 2018 using a MinION sequencer (Oxford Nanopore Technologies) at the Goa Disease Investigation Unit ( Supplementary Methods ). Phylogenetic analysis was performed to evaluate the similarity between samples and to compare them with historic references 17 ( Supplementary Methods ).

Time-scaled phylogenies were generated from complete nucleoprotein and partial glycoprotein gene (1317 nt) data using BEAST v1.10.4 and GTR + G + I substitution model with two partitions (1 + 2 and 3) and an uncorrelated relaxed lognormal molecular clock. Years of sample collection were used as tip dates, with an uncertainty of 1. The mean of the clock rate prior was set to 10 -4 (normal distribution, SD = 1). Both analyses lacked calibration data points and estimated most recent common ancestor ages should be considered relative and are highly influenced by the samples included, which was biased toward recent samples due to improved access to sequencing. Maximum clade credibility trees were generated using TreeAnnotator and visualized in FigTree v1.4.4. Map of India was generated from shapefile data at GADM.org using raster, ggspatial, and ggplot2 packages in RStudio (R v4.0.2). Figures were finished in InkScape. Reference sequences included in the time-scaled phylogenetic analyses were chosen based on sequence length (full-length nucleoprotein gene and at least 1317 nt of glycoprotein gene), isolation in India or neighboring countries, inclusion in Arctic-like 1a lineage, year of isolation available, and sequence quality. Sequences published by Deventhiran et al. (2018) 66 were not included in these analyses as several sequencing errors were observed and phylogenetic clustering of nucleoprotein and glycoprotein gene sequences from that study was inconsistent. Arctic rabies virus variant sequences KX148105 and JQ148105 , Arctic-like 3 sequence KX148228 , and Arctic-like 1b sequences KX148225 , KX148226 , HE802676 , KX148227 , KF150745 , KF150744 , and MK760761 were used as outgroups 67 .

Spatio-temporal cluster analysis

A space-time scan statistic was used to detect statistically significant spatio-temporal clusters of canine rabies using a discrete Poisson retrospective space-time probability model 68 as used in a number of other studies of rabies distribution 69 , 70 (Supplementary Software  2 ). For the purposes of this analysis, the village was considered the study unit, and canine rabies cases recorded each month were aggregated at the centroid of each village for use in the model. The human population of each village was used as a proxy for the population at risk. Cluster analyses were performed using SaTScan™ v9.6 software 71 through R package rsatscan 72 . Satscan uses Monte Carlo hypothesis testing to obtain the p values. For this analysis, we used 9999 Monte Carlo replications, and a cluster was considered statistically significant if the p value was <0.05. The maximum size for the mobile window of the scan was set as 20% of the population at risk with a circular shape.

Cost per dog vaccinated

In-country annual program expenditures were used alongside annual dog vaccination output to estimate the cost per dog vaccinated. This expenditure was determined from account records reporting on Goa expenditure on all sources of income, including government and charitable grants, and the estimated value of donated vaccine (Supplementary Tables  3 – 5 ). A breakdown of dog vaccination program expenditures, within total program expenditures, was only available for 2018 and 2019 (Supplementary Table  5 ).

Cost-effectiveness model

The RabiesEcon model, developed by the US Centers for Disease Control and Prevention, was used to estimate the impact and cost-effectiveness of the intervention (Supplementary Data  3 ) 18 , 19 , 73 . Goa values were inputted into the RabiesEcon version used by Kunkel et al. 18 to assess the additional costs and benefits of the Goa rabies control program as compared to no intervention. Input values from Goa, including human and dog population data, cost of dog vaccination and PEP, annual dog vaccination output, and estimated rates of access to PEP during and after the program (Supplementary Data  3 ). Predicted outcomes such as estimated human exposures and human rabies deaths were cross-checked with real-world data. The RabiesEcon model was published by Kunkel et al. (2021) was modified to account for costs associated with PEP administration resulting from exposures to animals that were unavailable for diagnostic testing. This adjustment was made by including a feature to allow the user to estimate the reduction in PEP after the implementation of the rabies control program. The equation in the tab “Data”, row 27 was modified to reflect the larger of either the pre-program costs multiplied by the user-defined PEP reduction rate or the number of true rabies virus exposures estimated by the model. As part of the data inputs to the model, it was assumed that there was no reduction in PEP administration during or after the intervention. All annual costs were discounted at 3%. The costs associated with surgical sterilization of dogs by non-governmental organizations were not considered in the model.

Reporting summary

Further information on research design is available in the  Nature Research Reporting Summary linked to this article.

Data availability

Data supporting the findings of this work are available within the paper and its Supplementary Information files. All sequences generated as part of this study are deposited in GenBank (accession codes: MW054945 – MW055041 ).  Source data are provided in this paper.

Code availability

The R code used in the logistical regression and spatio-temporal analysis is included in the  Supplementary Files .

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Acknowledgements

The Goa rabies control program was funded by the Government of Goa and Dogs Trust Worldwide. MSD Animal Health donated all Nobivac® Rabies vaccines used in the program. Rotary International (Rotary Clubs of Gainesville USA, Mapusa, Panjim, Riveira, Miramar, Panjim Midtown, Gainesville Sunrise, and Downtown Gainesville) donated vehicles used in dog vaccination and post-vaccination surveys. The World Health Organization contributed to Lateral Flow Assays (Bionote). B.M.d.B. was supported by Biotechnology and Biological Sciences Research Council through the Institute Strategic Program funding (BB/ J004235/1 and BB/P013740/1). Phylogenetic analysis was funded in part by the Office of Advanced Molecular Detection and Global Health Security (United States Centers for Disease Control and Prevention). C.M.G. was supported in part by an appointment to the Research Participation Program at CDC, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and CDC. We thank all the staff of Mission Rabies and Worldwide Veterinary Service, volunteers, local government veterinarians, and NGOs who have supported and contributed to the success of the campaign. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the United States government or the Centers for Disease Control and Prevention. Use of trade names, product names, or commercial sources is for identification only and does not imply endorsement by the United States government.

Author information

These authors contributed equally: A. D. Gibson, G. Yale, J. Corfmat, M. Appupillai

These authors jointly supervised this work: V. Naik, S. Desai, S. Mazeri, L. Gamble, R. J Mellanby.

Authors and Affiliations

Mission Rabies, Cranborne, Dorset, United Kingdom

A. D. Gibson, G. Thomas, F. Lohr, S. Mazeri & L. Gamble

The Roslin Institute and The Royal (Dick) School of Veterinary Studies, The University of Edinburgh, Easter Bush Veterinary Centre, Roslin, Midlothian, United Kingdom

A. D. Gibson, I. G. Handel, M. Bronsvoort, S. Mazeri & R. J. Mellanby

Mission Rabies, Tonca, Panjim, Goa, India

G. Yale, J. Corfmat, M. Appupillai, P. Mathapati, N. Otter & P. Ohal

Poxvirus and Rabies Branch, Centers for Disease Control and Prevention, Atlanta, GA, USA

C. M. Gigante, Y. Li & R. M. Wallace

Department of Animal Husbandry & Veterinary Services, Government of Goa, Panaji, India

M. Lopes, N. C. Costa, V. Naik & S. Desai

Directorate of Health Services, Government of Goa, Panaji, India

U. Betodkar & P. M. Suryawanshi

Worldwide Veterinary Service India, Ooty, Tamil Nadu, India

K. A. Fernandes, N. Otter & I. Airikkala-Otter

LYSSA LLC, Atlanta, Georgia, United States

C. E. Rupprecht

Merck Animal Health, Madison, NJ, USA

A. King & I. Deuzeman

MSD Animal Health, Walton Manor, Walton, Milton Keynes, MK7 7AJ, United Kingdom

Department of Neurovirology, WHO Collaborating Centre for Reference and Research in Rabies, National Institute of Mental Health and Neurosciences, Bengaluru, India

WHO Regional Office for South East Asia, New Delhi, India

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Contributions

A.D.G., S.M., L.G., and R.J.M. conceived the study. A.D.G., G.Y., J.C., M.A., and S.M. were responsible for data curation. L.G. led the acquisition of funds for the project, with M.A. responsible for the acquisition of in-country funding. J.C. oversaw management of the rabies mass dog vaccination program, supervised by A.D.G., V.N., and SD. G.Y. oversaw the management of rabies surveillance activities, supervised by A.D.G., V.N., and S.D. M.A. oversaw management of the rabies education program, supervised by GT, V.N., and S.D. A.D.G., G.Y., N.C., P.M., and R.S.M. contributed to rabies diagnostic work. A.D.G., G.Y., J.C., M.A., S.D., U.B., N.C., V.N., K.A.F., M.L., P.M., N.O., G.T., P.O., I.A.O., F.L., and L.G. contributed to program implementation, data collection, and project administration and reporting. U.B. and P.S. were responsible for the collation and reporting of human medical data. A.D.G. performed the formal analysis with supervision from S.M., I.G.H., B.M.B., and R.J.M. S.M. performed the statistical modeling, supervised by I.G.H. and B.M.B. C.G. and G.Y. performed the laboratory sequencing of rabies viruses and CG performed the phylogenetic analysis of molecular genetic data, supervised by Y.L. A.D.G. and R.M.W. performed the cost-effectiveness analysis. A.D.G., G.Y., J.C., M.A., S.D., U.B., C.G., V.N., K.A.F., M.L., P.S., F.L., C.E.R., A.K., D.S., I.D., Y.L., R.M.W., R.S.M., G.G., I.G.H., B.M.B., S.M., L.G., and R.J.M. provided a substantial intellectual contribution. S.D., U.B., V.N., M.L., P.S., N.O., G.T., I.A.O., F.L., C.E.R., A.K., D.S., I.D., and G.G. provided administrative, technical, or supervisory support. A.D.G., CG, S.M., and R.J.M. wrote the original manuscript. G.Y., J.C., M.A., S.D., U.B., C.G., N.C., V.N., K.A.F., M.L., P.S., G.T., F.L., C.E.R., A.K., D.S., I.D., Y.L., R.M.W., R.S.M., G.G., I.G.H., M.D.C., and L.G. contributed to review and editing of the manuscript.

Corresponding author

Correspondence to A. D. Gibson .

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Competing interests.

D.S., A.K., and I.D. are employees of MSD Animal Health/Merck Animal Health. Other authors declare no competing interests.

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Gibson, A.D., Yale, G., Corfmat, J. et al. Elimination of human rabies in Goa, India through an integrated One Health approach. Nat Commun 13 , 2788 (2022). https://doi.org/10.1038/s41467-022-30371-y

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DOI : https://doi.org/10.1038/s41467-022-30371-y

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Rabies patient becomes first fatal case in US after post-exposure treatment, report says

• Published Apr 4, 2023

Related paper in Clinical Infectious Diseases

A Minnesota man is the first reported fatality  due to rabies  in the United States despite receiving appropriate post-exposure prophylaxis, according to a recent article published in Clinical Infectious Diseases.

He was an 84-year-old man who died in 2021 about six months after waking up in the morning while a rabid bat was biting his right hand.

“This report summarizes the first reported  infection of rabies virus  in a person who received timely and appropriate treatment to prevent rabies infection following exposure since the development of modern rabies vaccines,” lead author Stacy Holzbauer told Fox News Digital.

She is a Centers for Disease Control and Prevention (CDC) epidemiology field officer with the Minnesota Department of Health and a deputy state veterinarian  in St. Paul, Minnesota.

“This is the first reported case of failure of appropriate rabies prophylaxis therapy since the onset of such therapy,” added Dr. Aaron Glatt, chief of infectious diseases at Mount Sinai South Nassau Hospital on  Long Island, New York .

“This unfortunate individual had an unrecognized immune deficiency that probably contributed to the failure.”

Symptomatic rabies is almost 100% fatal

Although rabies is almost uniformly fatal once symptoms develop, people can prevent the disease by vaccinating  their pets , staying away from wildlife and getting medical care after potential exposures before developing symptoms, according to the CDC.

The condition is caused by the  rabies virus , known as RABV, that spreads to people and pets through saliva, usually after a bite or scratch by a rabid animal.

However, it can also spread by direct contact with the eyes, mouth or open wounds,  according to the World Health Organization (WHO). 

Rabies in found in mostly bats, raccoons, skunks and foxes in the United States, but worldwide, the most common animal to carry rabies are dogs, per the CDC.

Most deaths globally are due to dog bites, with 95% occurring in Asia and Africa, per the WHO. 

Prevent rabies with post-exposure prophylaxis 

“Rabies post-exposure prophylaxis (PEP) is highly effective at preventing disease if administered before symptom onset,” the authors said.

Post-exposure prophylaxis is a treatment that consists of a series of vaccinations and human rabies immunoglobulin injections, Holzbauer told Fox News Digital.

After someone is bitten or scratched by a rabid animal, the United States Advisory Committee on Immunization Practices recommends cleaning the wound immediately.

After cleaning the wound, human rabies immunoglobulin (HRIG), or rabies antibodies, should be administered within the wound and also around it.

The patient should also receive a series of rabies  vaccines on specific days  within a two-week period, assuming the person is previously not vaccinated against rabies. 

HRIG is given so that the body has immediate antibodies to fight rabies until the immune system develops antibodies of its own, according to the CDC.

Approximately 60,000 people receive PEP annually in the U.S., compared to 29 million people globally, per the report. During 2000–2021, an average of 2.5 persons died from rabies every year in the U.S., but none received prophylaxis to prevent rabies before developing symptoms. 

Bat bit the man’s hand

An 84-year-old man with  coronary heart disease , controlled type 2 diabetes, hypertension, hyperlipidemia, chronic kidney disease and an enlarged prostate woke up on July 27, 2020, while a bat was biting his right hand. 

He didn’t see any bite marks but washed his hands with soap and water after the bite.

“The patient was bitten by a bat that he then captured,” Holzbauer said.

“The bat tested positive for rabies and the patient immediately sought and was administered appropriate care, which included rabies post-exposure prophylaxis.”After several same-day emergency room visits for progressive symptoms, he was hospitalized approximately a week after first developing symptoms when he complained of worsening facial pain and difficulty swallowing.  

On workup, a lumbar puncture revealed concern for  viral encephalitis , or inflammation in the brain due to a virus, but he subsequently died 15 days after developing symptoms of rabies. 

The team also found he had an undiagnosed immune deficiency called monoclonal gammopathy of undetermined significance, otherwise known as MGUS. The CDC confirmed he met laboratory criteria for rabies, including rabies virus in his saliva and anti-rabies antibodies in his spinal fluid — and  the genetic sequences  of the rabies virus from both the patient and the bat that bit him were identical.

Neutralizing antibodies fight rabies

The team looked for “neutralizing antibodies” but could not detect any either in his central nervous system or bloodstream – despite receiving vaccine prophylaxis against rabies.

A person vaccinated against rabies generally develops an adequate immune response when neutralizing antibodies can be detected in their bloodstream to fight the virus, per the report. The authors concluded that the patient had a fatal outcome because his immune system could not mount a protective antibody response after receiving vaccine prophylaxis to prevent rabies – presumably because of undiagnosed MGUS that suppressed his immune system. “Patients who fit this concern might benefit from additional [antibody] testing after completion of the prophylactic therapy to help assess the effectiveness of the therapy,” Glatt told Fox News Digital. “Investigations into the rabies biologics that were administered (human rabies immunoglobulin and rabies vaccines) found no manufacturing or potency concerns,” Holzbauer added in an email. 

Limitations of the case

Both the patient’s wife and two health care professionals, who broke infection control protocol while caring for the patient, were vaccinated against rabies. 

The authors note the report is limited because they did not measure blood titers from people who received rabies vaccines from all the implicated lots.

The lot numbers are indicated on the vials of the vaccine. 

They also could not determine how long the patient had MGUS.

“While tragic, this death represents an extremely rare event and does not challenge the high efficacy or safety profile of rabies post-exposure prophylaxis,” Holzbauer said.

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A case report on indirect transmission of human rabies

At present, virus infection is still a common threat to public health in developing countries (Liu et al., 2013 ; Mao et al., 2013 ; Zhang and Wang, 2014 ). Human rabies remains a matter of great global concern with a case-fatality of almost 100% (Willoughby et al., 2005 ; Takayama, 2008 ). The rabies virus belongs to the neurotropic type of virus of the Lyssavirus genus, and the disease presents as a deteriorating encephalomyelitis and is endemic throughout much of the world, particularly in Africa and Asia (Fooks et al., 2014 ). Previous data have shown that, globally, approximately 59 000 human deaths are caused by rabies per year (Hampson et al., 2011 ). Fortunately, human rabies can be treated through the timely administration of post-exposure prophylaxis (PEP). These days immunization using the rabies vaccine has become standard practice for individuals who have suffered bites or scratches from an animal, or who have been exposed to the body fluids of an infected animal (Willoughby et al., 2005 ; Johnson et al., 2014 ). However, we have recently encountered a case of human rabies which arose through a rare transmission method, and we believe that lessons can and should be learnt from this incident.

On June 22, 2014, a middle-aged male worker suffered a laceration to his right thumb from a cutter knife. The wound was 1.5 cm in length, and was accompanied by minimal bleeding. Once cleaned, disinfected, and sutured, the wound was dressed with gauze. As part of the treatment the patient received an administration of tetanus antitoxin. On July 6, the sutures were removed, and it was observed that the wound was healing well and subsequently redressed with gauze. On July 7, a relative of the man was bitten on the right calf by a stray dog at a highway service station. When he assisted his relative, the man’s gauze was contaminated with the relative’s blood. The gauze was immediately discarded, but he did not seek further medical attention or receive a rabies vaccination. On Sept. 1, he began to experience nighttime agitation and sleep disturbance. On Sept. 9, he suffered from right upper extremity parasthesia in the form of crawling and stinging sensations. On Sept. 10, he experienced more severe symptoms including photophobia, hydrophobia, anemophobia, pharyngeal muscle spasms, excessive sweating, salivation, chest tightness, irritability, and delirium. He was transferred to our hospital and rabies was suspected based on clinical presentation. The patient was isolated in a quiet single room and advised to avoid light and stimulation; sedation was also provided. Saliva samples of the patient were collected and tested by the State Key Lab of Diagnosis and Treatment of Infectious Diseases (Hangzhou, China), and a nested reverse transcription-polymerase chain reaction (RT-PCR) confirmed the presence of rabies virus RNA (Fig. ​ (Fig.1). 1 ). The reverse transcription-polymerase chain reaction (RT-PCR) kit for the detection of rabies virus RNA was purchased from TaKaRa Biotechnology Co., Ltd. (Dalian, China). The patient markedly deteriorated after admission, and experienced lapses in consciousness and convulsions. At 1:00 p.m. on Sept. 11, he suffered cardiac and respiratory arrest, and then died after attempts at resuscitation proved unsuccessful. In contrast, the relative who was bitten by the rabid dog received timely inoculation with the rabies vaccine and suffered no complications.

Agarose gel electrophoresis of nested RT-PCR identifying the RNA of rabies virus at the target fragment of 255 bp

M: DL2000 marker; 1–5: saliva samples

At present, most developed countries have effectively eliminated rabies from their domestic dog populations (Coleman et al., 2004 ). However, as a developing country, human rabies remains a significant health risk in some areas in China. The poorest countries or regions are most vulnerable to the threat of a rabies epidemic, as the administration of domestic dog vaccinations is not widespread or consistent (Hampson et al., 2015 ).

Generally speaking, human rabies has unique clinical manifestations that are easily distinguished from other conditions, and death is usually inevitable following clinical onset. Information about whether or not the deceased patient had a prior history of animal bites or exposure to animal body fluids is usually pivotal in directing the diagnosis away from rabies. However, the aforementioned case was unusual because of the method of virus transmission, namely that it is possible that the rabies virus was indirectly transmitted from one person to another through the exposure of damaged skin to saliva-contaminated blood from an individual bitten by a rabid dog.

Thus, a key lesson which the current case reveals is that in instances where broken skin or mucous membranes have been exposed to saliva-contaminated blood of an individual who has been bitten by an animal, he/she should receive timely wound management and immediate administration of rabies vaccine and/or human rabies immunoglobulin.

Compliance with ethics guidelines: Jian-yong ZHU, Jian PAN, and Yuan-qiang LU declare that they have no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study.

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The 2024 Ker Memorial Prize in Infectious Diseases has been jointly awarded to Dr Andy Gibson (Royal (Dick) School of Veterinary Studies) and Dr Guy Oldrieve (School of Biological Sciences).

The Ker Memorial Prize is award each year for the best PhD thesis submitted at the University of Edinburgh in memory of two eminent Edinburgh physicians, Dr Claude and Frank Ker.

Ker family support for infectious disease research in Edinburgh

As always the nominees for the Ker Memorial Prize were outstanding.  On this occasion the judges felt that although of very different types, the quality of research carried out by the both Andy and Guy, merited the co-award of this year's prize.

In addition, the judges awarded a Commendation of Merit to Ruby White, from Amy Buck's  lab (School of Biological Sciences), for her work on Modulation of host intestinal epithelium by gastrointestinal nematode secreted extracellular vesicles.

As part of their prize both Guy and Andy will present their work at the Edinburgh Infectious Diseases annual symposium on Wednesday 19 June 2024.

13th Edinburgh Infectious Diseases Annual Symposium

About the prize winners

Dr andy gibson:  development and evaluation of methods to controlrabies in goa state, india.

Supervisors:  Richard Mellanby, Stella Mazeri, Ian Handel, Mark Bronsvoort; Royal (Dick) School of Veterinary Studies

About the work:  Rabies is unique in the world of infectious diseases for the degree of suffering it inflicts, both to the individuals infected and their families who bear witness to inevitable death once signs appear.

In his thesis, Andy used data-driven approaches to support the development of effective methods for rabies control in Goa State, India over a ten-year period through a collaboration between the Government of Goa and WVS. Andy led the creation of a mobile phone app which enabled project managers to coordinate the movement of vaccination teams and efficiently gather operational data about dogs vaccinated, children educated, and suspect rabid dogs investigated. His analysis of these data informed the iterative refinement of dog vaccination methods which resulted in the elimination of rabies across most regions by 2019. Goa was India’s first state to pass legislation to become a ‘Rabies Controlled Area’ in 2021.

Cost-effectiveness analysis supported the widespread adoption of this One Health approach, however operational constraints to scaling the vaccination method drove the exploration of novel approaches involving oral rabies vaccines (ORVs). His analysis of two pilot studies identified the potential for ORVs to advance rabies control at a national scale.

About Andy: Andy now leads the research and technology strategy at Worldwide Veterinary Service (WVS), a UK-based international veterinary charity working to drive change in animal welfare and One Health.

He graduated in veterinary medicine from the Royal Veterinary College (RVC) in London. After a time working in clinical practice Andy completed the RVC Small Animal Internship before volunteering on the 2013 launch of the Mission Rabies project in India. He went on to work in Goa and other project sites, supporting the development of dog rabies surveillance and vaccination methods and became the project lead for developing a smartphone app to monitor and direct field activities.

Andy began his part-time PhD at the University of Edinburgh in 2016 alongside his role at WVS, focusing on understanding the methods of rabies control in Goa, India, where he was deeply involved in project management and strategy.

Dr Guy Oldrieve:  Developmental incompetence in selected and naturally occurring Trypanosoma isolates

Ker memorial lecture.

We are also delighted that Dr Iruka Okeke from the Univeristy of Ibadan, Nigeria will present the Ker Memorial Lecture at this year's Edinburgh Infectious Diseases symposium.

Dr Okeke will talk about Insights from the genomes of enteric bacteria isolated in Nigeria .

About Iruka

Related links

Mission Rabies

Royal (Dick) School of Veterinary Studies

Matthews Lab

School of Biological Sciences

MINI REVIEW article

This article is part of the research topic.

Improving Services for Neglected Tropical Diseases: Ending the Years of Neglect

Consequences of geographical accessibility to post-exposure treatment for rabies and snakebite in Africa: a mini review Provisionally Accepted

• 1 University of Geneva, Switzerland

The final, formatted version of the article will be published soon.

Rabies and snakebite envenoming are two zoonotic neglected tropical diseases (NTDs) transmitted to humans by animal bites, causing each year around 179,000 deaths and are most prevalent in Asia and Africa. Improving geographical accessibility to treatment is crucial in reducing the time from bite to treatment. This mini review aims to identify and synthesize recent studies on the consequences of distance and travel time on the victims of these diseases in African countries, in order to discuss potential joint approaches for health system strengthening targeting both diseases. A literature review was conducted separately for each disease using Pubmed, Google Scholar, and snowball searching. Eligible studies, published between 2017 and 2022, had to discuss any aspect linked to geographical accessibility to treatments for either disease in Africa.Twenty-two articles (8 on snakebite and 14 on rabies) were eligible for data extraction. No study targeted both diseases. Identified consequences of low accessibility to treatment were classified into 6 categories: 1) Delay to treatment; 2) Outcome; 3) Financial impacts; 4) Underreporting; 5) Compliance to treatment, and 6) Visits to traditional healers.Geographical access to treatment significantly influences the burden of rabies and snakebite in Africa. In line with WHO's call for integrating approaches among NTDs, there are opportunities to model disease hotspots, assess population coverage, and optimize geographic access to care for both diseases, possibly jointly. This could enhance the management of these NTDs and contribute to achieving the global snakebite and rabies roadmaps by 2030.

Keywords: Rabies, Snakebite, Neglected Tropical Desease, Africa, accessibility

Received: 08 Oct 2023; Accepted: 15 May 2024.

Copyright: © 2024 Faust and Ray. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Nicolas Ray, University of Geneva, Geneva, 1211, Geneva, Switzerland

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Bat captured in Benton County house tests positive for rabies. 1st in WA this year

A bat captured in a Prosser home this week tested positive for rabies, according to the Benton Franklin Health District.

The district is providing guidance to the person who reported the bat on protective measures they should take.

Due to medical privacy concerns, the health district did not say whether anyone in the house may have come in contact with the bat before it was captured and sent for testing to the Washington state Public Health Laboratories.

The rabies virus has a high death rate in people, according to the Centers for Disease Control and Prevention.

But those who have been bitten or scratched by a potentially rabid bat may receive preventive treatment before symptoms appear, according to the CDC. That may include human rabies immune globulin and a series of rabies vaccinations .

In Washington state, bats are the only known carriers of the rabies virus, although infected bats can transmit the virus to other mammals.

The rabid bat in Prosser is the only positive case in Washington state so far this year, but eight bats tested positive for rabies in 2022.

Healthy bats do not attack people, but they will bite if touched, according to the health district.

Any bat found outdoors under unusual circumstances — such as acting sick, staying on the ground or during the day — should be left alone, it said. Pets and children should be kept away.

Usually the bat will leave after nightfall.

If a bat is found indoors, officials need to determine if it could have exposed people to rabies.

The last time a rabid bat was found in Benton County before this week was in 2018.

However, a dead bat found in Walla Walla County in 2023 tested positive for rabies. And in 2013 an 11-month-old girl was treated to prevent rabies after being bitten twice by a rabid bat on her grandparents’ Pasco deck.

How to prevent rabies

“Bats are good for our environment and should not be killed unnecessarily,” said JoDee Peyton, the health district supervisor for land, use, waste and water.

The health district recommends treating bats with respect, caution and distance and offers these tips:

▪ Vaccinate pets.

▪ Do not touch or handle wild animals, especially bats.

▪ Leave bats alone, even the dead ones. Have your children tell an adult if they find a bat at home, school or with a pet.

▪ Keep bats out of your living space by bat-proofing your house. Learn how at bit.ly/WAKeepBatsOut .

▪ Contact the health district at 509-460-4205 if there is a bat indoors or if you have direct contact with a bat so your risk of possible exposure to rabies can be assessed.

▪ If an animal bite or other possible rabies exposure occurs, wash the wound with soap and water, seek medical care and call the health district.

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• Scientific Biographies

Louis Pasteur

During the mid- to late 19th century, Pasteur demonstrated that microorganisms cause disease and discovered how to make vaccines from weakened, or attenuated, microbes. He developed the earliest vaccines against fowl cholera, anthrax, and rabies.

Louis Pasteur (1822–1895) is revered by his successors in the life sciences as well as by the general public. In fact, his name provided the basis for a household word— pasteurized .

His research, which showed that microorganisms cause both fermentation and disease, supported the germ theory of disease at a time when its validity was still being questioned. In his ongoing quest for disease treatments he created the first vaccines for fowl cholera; anthrax, a major livestock disease that in recent times has been used against humans in germ warfare; and the dreaded rabies.

Early Life and Education

Pasteur was born in Dole, France, the middle child of five in a family that had for generations been leather tanners. Young Pasteur’s gifts seemed to be more artistic than academic until near the end of his years in secondary school. Spurred by his mentors’ encouragement, he undertook rigorous studies to compensate for his academic shortcomings in order to prepare for the École Normale Supérieure, the famous teachers’ college in Paris. He earned his master’s degree there in 1845 and his doctorate in 1847.

Study of Optical Activity

While waiting for an appropriate appointment, Pasteur continued to work as a laboratory assistant at the École Normale. There he made further progress on the research he had begun for his doctoral dissertation—investigating the ability of certain crystals or solutions to rotate plane-polarized light clockwise or counterclockwise, that is, to exhibit “optical activity.” He was able to show that in many cases this activity related to the shape of the crystals of a compound.

He also reasoned that there was some special internal arrangement to the molecules of such a compound that twisted the light—an “asymmetric” arrangement. This hypothesis holds an important place in the early history of structural chemistry—the field of chemistry that studies the three-dimensional characteristics of molecules.

Fermentation and Pasteurization

Pasteur secured his academic credentials with scientific papers on this and related research and was then appointed in 1848 to the faculty of sciences in Strasbourg and in 1854 to the faculty in Lille. There he launched his studies on fermentation. Pasteur sided with the minority view among his contemporaries that each type of fermentation is carried out by a living microorganism.

At the time the majority believed that fermentation was spontaneously generated by a series of chemical reactions in which enzymes—themselves not yet securely identified with life—played a critical role.

In 1857 Pasteur returned to the École Normale as director of scientific studies. In the modest laboratory that he was permitted to establish there, he continued his study of fermentation and fought long, hard battles against the theory of spontaneous generation. Figuring prominently in early rounds of these debates were various applications of his pasteurization process, which he originally invented and patented (in 1865) to fight the “diseases” of wine.

He realized that these were caused by unwanted microorganisms that could be destroyed by heating wine to a temperature between 60° and 100°C. The process was later extended to all sorts of other spoilable substances, such as milk.

Germ Theory

At the same time Pasteur began his fermentation studies, he adopted a related view on the cause of diseases. He and a minority of other scientists believed that diseases arose from the activities of microorganisms—germ theory. Opponents believed that diseases, particularly major killer diseases, arose in the first instance from a weakness or imbalance in the internal state and quality of the afflicted individual.

In an early foray into the causes of particular diseases, in the 1860s, Pasteur was able to determine the cause of the devastating blight that had befallen the silkworms that were the basis for France’s then-important silk industry. Surprisingly, he found that the guilty parties were two microorganisms rather than one.

A New Laboratory

Pasteur did not, however, fully engage in studies of disease until the late 1870s, after several cataclysmic changes had rocked his life and that of the French nation. In 1868, in the middle of his silkworm studies, he suffered a stroke that partially paralyzed his left side. Soon thereafter, in 1870, France suffered a humiliating defeat at the hands of the Prussians, and Emperor Louis-Napoléon was overthrown. Nevertheless, Pasteur successfully concluded with the new government negotiations he had begun with the emperor.

The government agreed to build a new laboratory for him, to relieve him of administrative and teaching duties, and to grant him a pension and a special recompense in order to free his energies for studies of diseases.

Attenuating Microbes for Vaccines: Fowl Cholera and Anthrax

In his research campaign against disease Pasteur first worked on expanding what was known about anthrax, but his attention was quickly drawn to fowl cholera. This investigation led to his discovery of how to make vaccines by attenuating, or weakening, the microbe involved. Pasteur usually “refreshed” the laboratory cultures he was studying—in this case, fowl cholera—every few days; that is, he returned them to virulence by reintroducing them into laboratory chickens with the resulting onslaught of disease and the birds’ death.

Months into the experiments, Pasteur let cultures of fowl cholera stand idle while he went on vacation. When he returned and the same procedure was attempted, the chickens did not become diseased as before. Pasteur could easily have deduced that the culture was dead and could not be revived, but instead he was inspired to inoculate the experimental chickens with a virulent culture. Amazingly, the chickens survived and did not become diseased; they were protected by a microbe attenuated over time.

Realizing he had discovered a technique that could be extended to other diseases, Pasteur returned to his study of anthrax. Pasteur produced vaccines from weakened anthrax bacilli that could indeed protect sheep and other animals. In public demonstrations at Pouilly-le-Fort before crowds of observers, twenty-four sheep, one goat, and six cows were subjected to a two-part course of inoculations with the new vaccine, on May 5, 1881, and again on May 17. Meanwhile a control group of twenty-four sheep, one goat, and four cows remained unvaccinated.

On May 31 all the animals were inoculated with virulent anthrax bacilli, and two days later, on June 2, the crowd reassembled. Pasteur and his collaborators arrived to great applause. The effects of the vaccine were undeniable: the vaccinated animals were all alive. Of the control animals all the sheep were dead except three wobbly individuals who died by the end of the day, and the four unprotected cows were swollen and feverish. The single goat had expired too.

Rabies and the Beginnings of the Institut Pasteur

Pasteur then wanted to move into the more difficult area of human disease, in which ethical concerns weighed more heavily. He looked for a disease that afflicts both animals and humans so that most of his experiments could be done on animals, although here too he had strong reservations. Rabies, the disease he chose, had long terrified the populace, even though it was in fact quite rare in humans. Up to the time of Pasteur’s vaccine, a common treatment for a bite by a rabid animal had been cauterization with a red-hot iron in hopes of destroying the unknown cause of the disease, which almost always developed anyway after a typically long incubation period.

Rabies presented new obstacles to the development of a successful vaccine, primarily because the microorganism causing the disease could not be specifically identified; nor could it be cultured in vitro (in the laboratory and not in an animal). As with other infectious diseases, rabies could be injected into other species and attenuated. Attenuation of rabies was first achieved in monkeys and later in rabbits.

Meeting with success in protecting dogs, even those already bitten by a rabid animal, on July 6, 1885, Pasteur agreed with some reluctance to treat his first human patient, Joseph Meister, a nine-year-old who was otherwise doomed to a near-certain death. Success in this case and thousands of others convinced a grateful public throughout the world to make contributions to the Institut Pasteur.

Historian Bert Hansen discusses his book,  Picturing Medical Progress from Pasteur to Polio.

It was officially opened in 1888 and continues as one of the premier institutions of biomedical research in the world. Its tradition of discovering and producing vaccines is carried on today by the pharmaceutical company Sanofi Pasteur.

A Great Experimenter and Innovative Theorist

Pasteur’s career shows him to have been a great experimenter, far less concerned with the theory of disease and immune response than with dealing directly with diseases by creating new vaccines. Still it is possible to discern his notions on the more abstract topics. Early on he linked the immune response to the biological, especially nutritional, requirements of the microorganisms involved; that is, the microbe or the attenuated microbe in the vaccine depleted its food source during its first invasion, making the next onslaught difficult for the microbe.

Later he speculated that microbes could produce chemical substances toxic to themselves that circulated throughout the body, thus pointing to the use of toxins and antitoxins in vaccines. He lent support to another view by welcoming to the Institut Pasteur Élie Metchnikoff and his theory that “phagocytes” in the blood—white corpuscles—clear the body of foreign matter and are the prime agents of immunity.

Featured image: Portrait of Louis Pasteur , photograph of Louis Pasteur taken in 1886, reproduced in the 1911 biography   The Life of Louis Pasteur . Science History Institute

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Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.

Volume 30, Number 6—June 2024

Estimates of sars-cov-2 hospitalization and fatality rates in the prevaccination period, united states.

Main Article

Case-fatality rates by age group and sex of patients with SARS-CoV-2 infections, United States, 2020*

*Data from 22 jurisdictions that met the study inclusion criteria, CDC line level surveillance dataset, accessed March 17, 2021, based on responses to the CDC 2019 Novel Coronavirus Case Report Form during May 1–December 1, 2020. Reports in which no response was provided about death were excluded from the rate calculation. †Missing indicates that the field was left blank.

1 These authors contributed equally to this article.

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