Reemergence of a Big Brown Bat Lyssavirus rabies Variant in Striped Skunks in Flagstaff, Arizona, USA, 2021-2023.

Background: Throughout the Americas, Lyssavirus rabies (RV) perpetuates as multiple variants among bat and mesocarnivore species. Interspecific RV spillover occurs on occasion, but clusters and viral host shifts are rare. The spillover and host shift of a big brown bat (Eptesicus fuscus) RV variant Ef-W1 into mesocarnivores was reported previously on several occasions during 2001-2009 in Flagstaff, Arizona, USA, and controlled through rabies vaccination of target wildlife. During autumn 2021, a new cluster of Ef-W1 RV cases infecting striped skunks (Mephitis mephitis) was detected from United States Department of Agriculture enhanced rabies surveillance in Flagstaff. The number of Ef-W1 RV spillover cases within a short timeframe suggested the potential for transmission between skunks and an emerging host shift. Materials and Methods: Whole and partial RV genomic sequencing was performed to evaluate the phylogenetic relationships of the 2021-2023 Ef-W1 cases infecting striped skunks with earlier outbreaks. Additionally, real-time reverse-transcriptase PCR (rtRT-PCR) was used to opportunistically compare viral RNA loads in brain and salivary gland tissues of naturally infected skunks. Results: Genomic RV sequencing revealed that the origin of the 2021-2023 epizootic of Ef-W1 RV was distinct from the multiple outbreaks detected from 2001-2009. Naturally infected skunks with the Ef-W1 RV showed greater viral RNA loads in the brain, but equivalent viral RNA loads in the mandibular salivary glands, compared to an opportunistic sample of skunks naturally infected with a South-Central skunk RV from northern Colorado, USA. Conclusion: Considering a high risk for onward transmission and spread of the Ef-W1 RV in Flagstaff, public outreach, enhanced rabies surveillance, and control efforts, focused on education, sample characterization, and vaccination, have been ongoing since 2021 to mitigate and prevent the spread and establishment of Ef-W1 RV in mesocarnivores.

A Global Perspective on Oral Vaccination of Wildlife against Rabies.

The long-term mitigation of human-domestic animal-wildlife conflicts is complex and difficult. Over the last 50 yr, the primary biomedical concepts and actualized collaborative global field applications of oral rabies vaccination to wildlife serve as one dramatic example that revolutionized the field of infectious disease management of free-ranging animals. Oral vaccination of wildlife occurred in diverse locales within Africa, Eurasia, the Middle East, and North America. Although rabies is not a candidate for eradication, over a billion doses of vaccine-laden baits distributed strategically by hand, at baiting stations, or via aircraft, resulted in widespread disease prevention, control, or local disease elimination among mesocarnivores. Pure, potent, safe, and efficacious vaccines consisted of either modified-live, highly attenuated, or recombinant viruses contained within attractive, edible baits. Since the late 1970s, major free-ranging target species have included coyotes (Canis latrans), foxes (Urocyon cinereoargenteus; Vulpes vulpes), jackals (Canis aureus; Lupulella mesomelas), raccoons (Procyon lotor), raccoon dogs (Nyctereutes procyonoides), and skunks (Mephitis mephitis). Operational progress has occurred in all but the latter species. Programmatic evaluations of oral rabies vaccination success have included: demonstration of biomarkers incorporated within vaccine-laden baits in target species as representative of bait contact; serological measurement of the induction of specific rabies virus neutralizing antibodies, indicative of an immune response to vaccine; and most importantly, the decreasing detection of rabies virus antigens in the brains of collected animals via enhanced laboratory-based surveillance, as evidence of management impact. Although often conceived mistakenly as a panacea, such cost-effective technology applied to free-ranging wildlife represents a real-world, One Health application benefiting agriculture, conservation biology, and public health. Based upon lessons learned with oral rabies vaccination of mesocarnivores, opportunities for future extension to other taxa and additional diseases will have far-reaching, transdisciplinary benefits.

RABIES IN RODENTS AND LAGOMORPHS IN THE USA, 2011-20.

Rabies is an acute progressive encephalitis caused by infection with rabies viruses, with reservoirs among bats and mesocarnivores, but all mammals are susceptible. Despite its distribution and abundance, cases of rabies are much less common in rodents and lagomorphs. Familiarity with current rabies prevalence data is important for informed decisions on human postexposure prophylaxis after rodent and lagomorph bites. This study is an update of rabies cases reported in rodents and lagomorphs in the US from 2011 to 2020. Rabies reports were collected passively from laboratory testing agencies in the US and Puerto Rico from 2011 to 2020. Descriptive analysis was conducted to determine the percent positivity of rabies cases by species. A total of 401 cases of rabies in rodents and lagomorphs were reported from 2011 to 2020. Most reported cases were in groundhogs (Marmota monax), representing >90% of cases, and the trend closely aligned with rabies in raccoons (Procyon lotor). In any given year, the percent positivity of rabies in rodents and lagomorphs was <2.5%, and the trend of percent positivity from 2011 to 2020 was stable. Groundhog and North American beaver (Castor canadensis) percent positivity was significantly higher than the rest of the rodents and lagomorphs. Most rabies cases occurred during the months of May-September. Documented cases of rabies in rodents and lagomorphs are generally rare, but with variation between species. Groundhogs and North American beavers had rabies percent positivity similar to high-risk species, such as bats and raccoons, and constituted 97% of all rodent and lagomorph positive cases. Since 1993, the trend in rabies cases in groundhogs has significantly declined. These results can be used to help inform public health officials on rodent and lagomorph prevention and control efforts, as well as rabies postexposure prophylaxis.

Rabies in a postpandemic world: resilient reservoirs, redoubtable riposte, recurrent roadblocks, and resolute recidivism.

Rabies is an ancient disease. Two centuries since Pasteur, fundamental progress occurred in virology, vaccinology, and diagnostics-and an understanding of pathobiology and epizootiology of rabies in testament to One Health-before common terminological coinage. Prevention, control, selective elimination, and even the unthinkable-occasional treatment-of this zoonosis dawned by the twenty-first century. However, in contrast to smallpox and rinderpest, eradication is a wishful misnomer applied to rabies, particularly post-COVID-19 pandemic. Reasons are minion. Polyhostality encompasses bats and mesocarnivores, but other mammals represent a diverse spectrum of potential hosts. While rabies virus is the classical member of the genus, other species of lyssaviruses also cause the disease. Some reservoirs remain cryptic. Although global, this viral encephalitis is untreatable and often ignored. As with other neglected diseases, laboratory-based surveillance falls short of the notifiable ideal, especially in lower- and middle-income countries. Calculation of actual burden defaults to a flux within broad health economic models. Competing priorities, lack of defined, long-term international donors, and shrinking local champions challenge human prophylaxis and mass dog vaccination toward targets of 2030 for even canine rabies impacts. For prevention, all licensed vaccines are delivered to the individual, whether parenteral or oral-essentially 'one and done'. Exploiting mammalian social behaviors, future 'spreadable vaccines' might increase the proportion of immunized hosts per unit effort. However, the release of replication-competent, genetically modified organisms selectively engineered to spread intentionally throughout a population raises significant biological, ethical, and regulatory issues in need of broader, transdisciplinary discourse. How this rather curious idea will evolve toward actual unconventional prevention, control, or elimination in the near term remains debatable. In the interim, more precise terminology and realistic expectations serve as the norm for diverse, collective constituents to maintain progress in the field.

Modelling modifiable factors associated with the probability of human rabies deaths among self-reported victims of dog bites in Abuja, Nigeria.

Canine-mediated rabies kills tens of thousands of people annually in lesser-developed communities of Asia, Africa, and the Americas, primarily through bites from infected dogs. Multiple rabies outbreaks have been associated with human deaths in Nigeria. However, the lack of quality data on human rabies hinders advocacy and resource allocation for effective prevention and control. We obtained 20 years of dog bite surveillance data across 19 major hospitals in Abuja, incorporating modifiable and environmental covariates. To overcome the challenge of missing information, we used a Bayesian approach with expert-solicited prior information to jointly model missing covariate data and the additive effects of the covariates on the predicted probability of human death after rabies virus exposure. Only 1155 cases of dog bites were recorded throughout the study period, out of which 4.2% (N = 49) died of rabies. The odds for risk of human death were predicted to decrease among individuals who were bitten by owned dogs compared to those bitten by free-roaming dogs. Similarly, there was a predicted decrease in the probability of human death among victims bitten by vaccinated dogs compared to those bitten by unvaccinated dogs. The odds for the risk of human death after bitten individuals received rabies prophylaxis were predicted to decrease compared to no prophylaxis. We demonstrate the practical application of a regularised Bayesian approach to model sparse dog bite surveillance data to uncover risk factors for human rabies, with broader applications in other endemic rabies settings with similar profiles. The low reporting observed in this study underscores the need for community engagement and investment in surveillance to increase data availability. Better data on bite cases will help to estimate the burden of rabies in Nigeria and would be important to plan effective prevention and control of this disease.

Special Issue "Innovative Techniques and Approaches in the Control and Prevention of Rabies Virus".

Rabies is an ancient lethal scourge that has plagued humankind for centuries [...].

Time to Revise the WHO Categories for Severe Rabies Virus Exposures-Category IV?

Rabies is a devastating disease and affects millions of people globally, yet it is preventable with appropriate and timely postexposure prophylaxis (PEP). The current WHO exposure categories (Categories I, II, and III) need revision, with a special Category IV for severe exposures. Rare cases of PEP failure have occurred in severe bites to the head and neck. Multiple factors, including route, wound severity, depth, contamination, viral dose, proximity to highly innervated areas and the CNS, and the number of lesions, remain unconsidered. Injuries in areas of high neural density are the most significant considering lyssavirus pathophysiology. Current recommendations do not account for these factors. A Category IV designation would acknowledge the severity and the increased risk of progression. Subsequently, patient management would be optimized with wound care and the appropriate administration of rabies-immune globulin/monoclonal antibodies (RIG/MAbs). All Category IV exposures would be infiltrated with the full dose of intact RIG (i.e., human RIG or MAbs) if the patient was previously unvaccinated. More concentrated RIG/MAb formulations would be preferred. As a world rabies community, we cannot tolerate PEP failures. A fourth WHO categorization will improve the care of these high-risk patients and highlight the global health urgency of this neglected disease.

COVID-19 Vaccine Hesitancy and Determinants of Acceptance among Healthcare Workers, Academics and Tertiary Students in Nigeria.

The COVID-19 pandemic has resulted in millions of human deaths, prompting the rapid development and regulatory approval of several vaccines. Although Nigeria implemented a COVID-19 vaccination program on 15 March 2021, low vaccine acceptance remains a major challenge. To provide insight on factors associated with COVID-19 vaccine hesitancy (VH), we conducted a national survey among healthcare workers, academics, and tertiary students, between 1 September 2021 and 31 December 2021. We fitted a logistic regression model to the data and examined factors associated with VH to support targeted health awareness campaigns to address public concerns and improve vaccination rates on par with global efforts. A total of 1525 respondents took part in the survey, composed of healthcare-workers (24.5%, 373/1525), academics (26.9%, 410/1525), and students (48.7%, 742/1525). Only 29% (446/1525) of the respondents were vaccinated at the time of this study. Of the 446 vaccinated respondents, 35.7% (159/446), 61.4% (274/446) and 2.9% (13/446) had one, two and three or more doses, respectively. Reasons for VH included: difficulty in the vaccination request/registration protocols (21.3%, 633/1079); bad feelings towards the vaccines due to negative social media reports/rumours (21.3%, 633/1079); personal ideology/religious beliefs against vaccination (16.7%, 495/1079); and poor confidence that preventive measures were enough to protect against COVID-19 (11%, 323/1079). Some health concerns that deterred unvaccinated respondents were: innate immunity issues (27.7%, 345/1079); allergic reaction concerns (24.6%, 307/1079); and blood clot problems in women (21.4%, 266/1079). In the multivariable model, location of respondents/geopolitical zones, level of education, testing for COVID-19, occupation/job description and religion were significantly associated with VH. Findings from this study underscore the need for targeted awareness creation to increase COVID-19 vaccination coverage in Nigeria and elsewhere. Besides professionals, similar studies are recommended in the general population to develop appropriate public health interventions to improve COVID-19 vaccine uptake.

Rabies in the Tropics.

Purpose of Review: Rabies is an ancient yet still neglected tropical disease (NTD). This review focuses upon highlights of recent research and peer-reviewed communications on the underestimated tropical burden of disease and its management due to the complicated dynamics of virulent viral species, diverse mammalian reservoirs, and tens of millions of exposed humans and animals - and how laboratory-based surveillance at each level informs upon pathogen spread and risks of transmission, for targeted prevention and control. Recent Findings: While both human and rabies animal cases in enzootic areas over the past 5 years were reported to PAHO/WHO and OIE by member countries, still there is a huge gap between these "official" data and the need for enhanced surveillance efforts to meet global program goals. Summary: A review of the complex aspects of rabies perpetuation in human, domestic animal, and wildlife communities, coupled with a high fatality rate despite the existence of efficacious biologics (but no therapeutics), warrants the need for a One Health approach toward detection via improved laboratory-based surveillance, with focal management at the viral source. More effective methods to prevent the spread of rabies from enzootic to free zones are needed.

A One Medicine Mission for an Effective Rabies Therapy.

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome. Systematic clinical research into combination therapies is further hampered by sporadic occurrence of cases. In this Perspective, we examine the case for a One Medicine approach to accelerate development of an effective therapy for rabies through the veterinary care and investigational treatment of naturally infected dogs in appropriate circumstances. We review the pathogenesis of rabies virus in humans and dogs, including recent advances in our understanding of the molecular basis for the severe neurological dysfunction. We propose that four categories of disease process need to be managed in patients: viral propagation, neuronal degeneration, inflammation and systemic compromise. Compassionate critical care and investigational treatment of naturally infected dogs receiving supportive therapy that mimics the human clinical scenario could increase opportunities to study combination therapies that address these processes, and to identify biomarkers for prognosis and therapeutic response. We discuss the safety and ethics of this approach, and introduce the Canine Rabies Treatment Initiative, a non-profit organization with the mission to apply a One Medicine approach to the investigation of diagnostic, prognostic, and therapeutic options for rabies in naturally infected dogs, to accelerate transformation of rabies into a treatable disease for all patients.

Spatiotemporal heterogeneity and determinants of canine rabies evidence at Local Government Area Level in Nigeria: Implications for rabies prevention and control.

Canine rabies poses a significant risk to humans and animals in Nigeria. However, the lack of reliable tools to evaluate the performance of existing canine rabies control programs to inform public health policy decisions poses a severe obstacle. We obtained canine rabies surveillance data from the National Veterinary Research Institute (NVRI) and supplemented these data with rabies diagnoses reported in the published studies from Nigeria. To uncover contextual factors (i.e., environmental and sociodemographic) associated with canine rabies evidence at the Local Government Area (LGA) level, we classified LGAs in Nigeria into four categories based on evidence availability (i.e., LGAs with NVRI data or published studies, both, or no evidence). We described the geographical and temporal variation in coverage. We fitted a multinomial regression model to examine the association between LGA level canine rabies evidence and potential sociodemographic and ecological determinants of canine rabies evidence. The effective annual testing during the 19 years was less than one dog/100,000 Nigerian resident-year. Our results showed that 58% of Nigerian LGAs (450/774) had not been targeted by the existing national rabies surveillance or studies on rabies, including ten states capitals with high human populations. While 16% (122/774) of Nigerian LGAs concentrated in Taraba, Adamawa, and Abia had canine rabies evidence from published studies, none of these LGAs was represented in the NVRI rabies surveillance data. We also observed an increasing trend in rabies evidence over time towards the eastern part of Nigeria. Our multinomial regression model indicated that education level, poverty, population density, land use and temperature were significantly associated with canine rabies evidence at the LGA level. This study underscores the value of combining canine rabies evidence from different sources to better understand the current disease situation for targeted intervention.

Renewed Public Health Threat from Emerging Lyssaviruses.

Pathogen discovery contributes to our knowledge of bat-borne viruses and is linked to the heightened interest globally in bats as recognised reservoirs of zoonotic agents. The transmission of lyssaviruses from bats-to-humans, domestic animals, or other wildlife species is uncommon, but interest in these pathogens remains due to their ability to cause an acute, progressive, invariably fatal encephalitis in humans. Consequently, the detection and characterisation of bat lyssaviruses continues to expand our knowledge of their phylogroup definition, viral diversity, host species association, geographical distribution, evolution, mechanisms for perpetuation, and the potential routes of transmission. Although the opportunity for lyssavirus cross-species transmission seems rare, adaptation in a new host and the possibility of onward transmission to humans requires continued investigation. Considering the limited efficacy of available rabies biologicals it is important to further our understanding of protective immunity to minimize the threat from these pathogens to public health. Hence, in addition to increased surveillance, the development of a niche pan-lyssavirus vaccine or therapeutic biologics for post-exposure prophylaxis for use against genetically divergent lyssaviruses should be an international priority as these emerging lyssaviruses remain a concern for global public health.

A broad-spectrum and highly potent human monoclonal antibody cocktail for rabies prophylaxis.

Post-exposure prophylaxis (PEP) is highly effective in preventing disease progression of rabies when used in timely and appropriate manner. The key treatment for PEP is infiltration of rabies immune globulin (RIG) into lesion site after bite exposure, besides wound care and vaccination. Unfortunately, however, RIG is expensive and its supply is limited. Currently, several anti-rabies virus monoclonal antibody (mAb) products are under development as alternatives to RIG, and two recently received regulatory approval in India. In this study, fully human mAbs that recognize different rabies virus glycoprotein conformational antigenic site (II and III) were created from peripheral blood mononuclear cells of heathy vaccinated subjects. These mAbs neutralized a diverse range of lyssavirus types. As at least two anti-rabies virus mAbs are recommended for use in human PEP to ensure broad coverage against diverse lyssaviruses and to minimize possible escape variants, two most potent mAbs, NP-19-9 and 11B6, were selected to be used as cocktail treatment. These two mAbs were broadly reactive to different types of lyssaviruses isolates, and were shown to have no interference with each other. These results suggest that NP-19-9 and 11B6 are potent candidates to be used for PEP, suggesting further studies involving clinical studies in human.

Rabies epidemiology, prevention and control in Nigeria: Scoping progress towards elimination.

BACKGROUND: Human rabies remains a significant public health problem in Africa with outbreaks reported in most countries. In Nigeria-the most populous country in Africa-rabies causes a significant public health burden partly due to perennial obstacles to implementing a national prevention and control program. METHODS: We conducted a scoping review using standard Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify and select published articles from Nigeria during 1978-2020 reporting on rabies virus infections (human, canine, livestock, and wildlife), canine bites, knowledge, attitudes and practices (KAP) surveys on rabies and canine ecology studies. We extracted information on study location, year and additional details of each study such as rabies prevalence, general characteristics of offending dogs, dog vaccination status and health-seeking behaviours. FINDINGS: Between 1978 and 2020, 90 published articles met our inclusion criteria. The prevalence of rabies virus antigen detection varied between 3% and 28%, with more studies in the north. Most bites were unprovoked from dog bite studies (36.4%-97%), by dogs with low vaccination rates (12-38%). A more significant proportion of biting dogs were owned (31-90%). Laboratory confirmation for biting was available for only a small proportion of studies (6%; n = 2/32). Of the dogs surveyed during ecology studies, indigenous dogs accounted for the majority (62-98%), used mostly for security purposes (52-98%), with the vaccination rate between 15% and 38% in most states. Studies conducted in areas distant from rabies diagnostic facilities accounted for more human rabies cases and fewer dog rabies cases. CONCLUSION: Significant improvements are necessary to achieve the elimination of human rabies mediated via dogs by 2030.