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Oral rabies vaccination (ORV) can increase rabies vaccination coverage among dogs that are inaccessible to parenteral vaccination (i.e., inaccessible dogs). Because bait uptake can differ according to the bait attractant used and dog characteristics, we evaluated proportion of bait uptake and time to bait uptake using three bait formulations. We looked for associations between bait uptake and dog characteristics (temperament, age, and body condition) and assessed the efficiency of using these bait formulations, as measured by number of dogs vaccinated per hour. A total of 356 baits were offered to free roaming dogs in urban and peri-urban districts of Bangladesh. Fish baits were ignored by 86% (n = 122; 95% CI: 79–91%) of dogs, whereas 60% (n = 45; 95% CI: 49–70%) consumed egg baits and 89% (n = 124; 95% CI: 83–93%) consumed intestine baits. Among the consumed baits, dogs fully consumed 56% (n = 10; 95% CI: 34–75%) of fish baits, 84% (n = 38; 95% CI: 71–92%) of egg baits, and 98% (n = 122; 95% CI: 94–100%) of intestine baits. Among inaccessible dogs, no associations were found between bait uptake and dog characteristics in either bivariate or multivariate analyses. Bait consumption averaged 2 dogs per hour for fish baits, 10 dogs per hour for egg baits, and 18 dogs per hour for intestine baits. The absence of association between bait type preference and individual dog characteristics simplifies the process of choosing attractants for oral rabies vaccines. While intestine attractants achieved highest uptake, egg baits may prove a suitable compromise when considering biological and operational constraints. The efficiency of ORV was demonstrated when compared to parenteral vaccination of free-roaming dogs previously described.

Background There are approximately 35,000 human deaths from rabies in Asia annually. Rabies can be prevented through timely post-exposure prophylaxis (PEP) consisting of wound washing, rabies vaccine, and in some cases, rabies immunoglobulin (RIG). However, access to rabies PEP often remains limited to urban areas and is cost-prohibitive. There is little information on procurement, distribution, monitoring, and reporting of rabies PEP. Methods We interviewed key informants in the public sector from various levels in Bangladesh, Bhutan, Cambodia, and Sri Lanka between March 2017 and May 2018 using a descriptive assessment tool to obtain information on procurement, distribution, monitoring, and reporting of rabies PEP. These four countries in Asia were chosen to showcase a range of rabies PEP systems. National rabies focal points were interviewed in each country and focal points helped identify additional key informants at lower levels. Results A total of 22 key informants were interviewed at various levels (central level to health facility level) including national rabies focal points in each country. Each country has a unique system for managing rabies PEP procurement, distribution, monitoring, and reporting. There are varying levels of PEP access for those with potential rabies exposures. Rabies PEP is available in select health facilities throughout the country in Bangladesh, Bhutan, and Sri Lanka. In Cambodia, rabies PEP is limited to two urban centers. The availability of RIG in all four countries is limited. In these four countries, most aspects of the rabies PEP distribution system operate independently of systems for other vaccines. However, in Bhutan, rabies PEP and Expanded Programme on Immunization (EPI) vaccines share cold chain space in some locations at the lowest level. All countries have a monitoring system in place, but there is limited reporting of data, particularly to the central level. Conclusion Systems to procure, deliver, monitor, and report on rabies PEP are variable across countries. Sharing information on practices more widely among countries can help programs to increase access to this life-saving treatment.

During the 20(th) century parenteral vaccination of dogs at central-point locations was the foundation of successful canine rabies elimination programs in numerous countries. However, countries that remain enzootic for canine rabies have lower infrastructural development compared to countries that have achieved elimination, which may make traditional vaccination methods less successful. Alternative vaccination methods for dogs must be considered, such as oral rabies vaccine (ORV). In 2016, a traditional mass dog vaccination campaign in Haiti was supplemented with ORV to improve vaccination coverage and to evaluate the use of ORV in dogs. Blisters containing live-attenuated, vaccine strain SPBNGAS-GAS were placed in intestine bait and distributed to dogs by hand. Serum was collected from 107 dogs, aged 3 – 12 months with no reported prior rabies vaccination, pre-vaccination and from 78/107 dogs (72.9%) 17 days post-vaccination. The rapid florescent focus inhibition test (RFFIT) was used to detect neutralizing antibodies and an ELISA to detect rabies binding antibodies. Post-vaccination, 38/41 (92.7%) dogs that received parenteral vaccine had detectable antibody (RFFIT >0.05 IU/mL), compared to 16/27 (59.3%, p < 0.01) dogs that received ORV or 21/27 (77.8%) as measured by ELISA (>40% blocking, p < 0.05). The fate of 291 oral vaccines was recorded; 283 dogs (97.2%) consumed the bait; 272 dogs (93.4%) were observed to puncture the blister, and only 14 blisters (4.8%) could not be retrieved by vaccinators and were potentially left in the environment. Pre-vaccination antibodies (RFFIT >0.05 IU/mL) were detected in 10/107 reportedly vaccine-naïve dogs (9.3%). Parenteral vaccination remains the most reliable method for ensuring adequate immune response in dogs, however ORV represents a viable strategy to supplement existing parental vaccination campaigns in hard-to-reach dog populations. The hand-out model reduces the risk of unintended contact with ORV through minimizing vaccine blisters left in the community.

Background: While oral vaccines aid immunization of hard to reach animal populations, the use of live-attenuated viruses in many oral vaccines, including first generation oral rabies vaccines, pose risks of reversion to virulence or residual pathogenicity. While a detailed human risk assessment is crucial prior to field distribution of live-attenuated vaccines, there is currently no standardized approach. Methods: We mapped exposure pathways by which distribution of oral vaccines targeting wildlife or free-roaming dogs may result in mucosal, transdermal, or severe inoculation into people. We applied a continuous-time Markov chain to estimate the number of severe adverse events. We tested the model using three scenarios of oral rabies vaccination (ORV) campaigns: 1) first generation ORV (SAD-B19) in foxes, 2) SAD-B19 in dogs, and 3) third generation ORV (SPBN GASGAS) in dogs. Findings: A low risk of 0·18 (95% CI: 0·08, 0·36) vaccine-associated human deaths per 10 million baits was simulated for campaigns where SAD-B19 was distributed to foxes. However, consistent with international concern, our model predicts that SAD-B19 distributed to dogs could result in 3·35 (95% CI: 2·83, 3·98) vaccine-associated human deaths per 10 million baits. The model simulated no deaths for SPBN GASGAS. Human deaths during dog campaigns was particularly sensitive to dog bite rate, and human deaths during wildlife campaigns was particularly sensitive to animal uptake rate and human contact rate with unconsumed baits. Interpretation: This model highlights the safety of newer live-attenuated rabies vaccines and serves as a platform for standardized approaches to inform risk assessments. Funding Statement: Time for this study was funded through a co-agreement between the Pubic Health Institute and the Centers for Disease Prevention and Control. The funding source had no role in the study design, analysis, preparation of the manuscript, or decision to publish the manuscript. Declaration of Interests: AV is a full time employee of a pharmaceutical company, IDT Biologika GmbH, which manufactures oral rabies vaccine baits. TM from the FriedrichLoeffler-Institute received funding from IDT Biologika GmbH in the frame of a research cooperation for research into mechanisms of oral rabies vaccination and resulting immunity

Two major techniques are currently used to estimate rabies virus antibody values: neutralization assays, such as the rapid fluorescent focus inhibition test (RFFIT), and enzyme-linked immunosorbent assays (ELISAs). The RFFIT is considered the gold standard assay and has been used to assess the titer of rabies virus neutralizing antibodies for more than three decades. In the late 1970s, ELISA began to be used to estimate the level of rabies virus antibody and has recently been used by some laboratories as an alternate screening test for animal sera. Although the ELISA appears simpler, safer and more efficient, the assay is less sensitive in detecting low values of rabies virus neutralizing antibodies than neutralization tests. This study was designed to evaluate a new ELISA-based method for detecting rabies virus binding antibody. This new technique uses electro-chemi-luminescence labels and carbon electrode plates to detect binding events. In this comparative study, the RFFIT and the new ELISA-based technique were used to evaluate the level of rabies virus antibodies in human and animal serum samples. By using a conservative approximation of 0.15 IU/ml as a cutoff point, the new ELISA-based technique demonstrated a sensitivity of 100% and a specificity of 95% for human samples and for experimental animal samples. The sensitivity and specificity for field animal samples was 96% and 95%, respectively. The preliminary results from this study appear promising and demonstrate a higher sensitivity than traditional ELISA methods.

Background The United States of America (USA) does not have a national reporting system for rabies post-exposure prophylaxis (PEP). We describe the epidemiology of PEP in the USA so recommendations can be made during a PEP shortage. Methods A two-part questionnaire designed to evaluate PEP distribution practices and estimate PEP use was administered to state health department representatives. Results Seventy-five percent of participants responded that no public health guidance was needed to make a recommendation for PEP. The annual national average PEP use is 23,415 courses of PEP (range: 10,645–35,845). Conclusion PEP is loosely monitored and a precise estimate of PEP use is unknown. Improved national surveillance for PEP is needed.

Despite progress in vaccine development in the past century the mechanisms behind immune responses elicited by rabies biologics or via natural infection remain largely unknown. In this study, we compared protection elicited by standard, early, or delayed prophylaxis with a reduced number of vaccine doses using inactivated and live-attenuated vaccines. Two-month-old Syrian hamsters, 4-week-old ICR mice or adult rhesus macaques were inoculated with canine rabies virus variants. Thereafter, prophylaxis was initiated 6 h, 1, 2, 3, 4, 5, 6 or 7 days post-exposure (p.e.). One or several doses of inactivated (HDCV), or reverse genetically attenuated (live), or gamma-irradiated (inactivated)-ERAG333 vaccines were administered intramuscularly. The dynamics of virus spread were measured over time in the rodent models. Rabies virus reached the spinal cord at day 4 and brain at day 6 p.e. All hamsters succumbed in groups in which live ERAG333 was delayed until days 5 and 6 p.e. However, 78%, 44%, 56% and 22% of hamsters survived when one dose of live ERAG333 was administered 6 h, 1, 2, 3, and 4 days p.e., respectively. Similarly, 67% survived when inactivated ERAG333 was administered at 24 h p.e. All hamsters succumbed when standard prophylaxis (the Essen regimen) was delayed until days 3–6, but 67% and 33% of hamsters survived when PEP began 1 or 2 days p.e., respectively. Macaques were protected by one dose of attenuated ERAG333 at 24 h p.e. The highly attenuated (live) and inactivated ERAG333 vaccines elicited potent protective immune responses, even when prophylaxis initiation was delayed. When 2–5 doses of commercial vaccine and HRIG were administered according to the Essen scheme, 89–100% of the animals survived. Reduced vaccine schedules provided efficacious intervention, regardless of the total number of vaccine doses administered.

Oral vaccination is an important tool currently in use to control the spread of rabies in wildlife populations in various programs around the world. Oral rabies vaccination (ORV) of raccoons represents the largest targeted program to control wildlife rabies in the United States. Currently, the vaccinia-rabies glycoprotein recombinant virus vaccine (V-RG) is the only licensed oral rabies vaccine in the US. In the current study, captive raccoons were used to evaluate two previously described constructs of a rabies virus vaccine developed by reverse genetics (SPBNGAS and SPBNGAS-GAS) for immunogenicity and efficacy compared to the V-RG vaccine. Four of five control animals succumbed to rabies virus after severe challenge, while three of five animals vaccinated orally with SPBNGAS succumbed. No mortality was observed for animals administered SPBNGAS-GAS or the V-RG vaccine. The results of this preliminary study suggest that SPBNGAS-GAS provides comparable efficacy to V-RG. Additional studies will be needed to determine the duration of immunity and optimal dosage of SPBNGAS-GAS and to examine its efficacy in other reservoir species.

Rabies is a zoonosis that results in millions of human exposures worldwide each year. Human monoclonal antibodies (HuMAbs) that neutralize rabies virus may represent one viable strategy for post-exposure prophylaxis in humans, and have many advantages over current human or equine rabies immune globulin. Transgenic mice carrying human immunoglobulin genes were used to isolate human monoclonal antibodies that neutralized rabies virus. Several HuMAbs were identified that neutralized rabies virus variants from a broad panel of isolates of public health significance. HuMAb 17C7 was the most promising antibody identified because it neutralized all rabies virus isolates tested. HuMAb 17C7 recognizes a conformational epitope on the rabies virus glycoprotein which includes antigenic site III. HuMAb 17C7 protected hamsters from a lethal dose of rabies virus in a well-established in vivo model of post-exposure prophylaxis.

New causative agents of rabies continue to emerge as shown by the recent description of four novel lyssaviruses from bats in Eurasia, Aravan (ARAV), Khujand (KHUV), Irkut (IRKV), and West Caucasian bat virus (WCBV). The effect of rabies vaccination prior to exposure to these new lyssaviruses was investigated in two animal models (i.e., Syrian hamsters and ferrets). The hamsters were vaccinated intramuscularly with a commercial human or veterinary vaccine or with an experimental vaccinia-rabies glycoprotein recombinant vaccine. At 5 weeks after vaccination, animals were challenged with ARAV, KHUV, IRKV, or WCBV, or with a traditional rabies virus of dog/coyote origin. Previously vaccinated and rabies-naive ferrets were also challenged with the four new isolates. In addition, the combined effect of rabies immunoglobulin and vaccine after exposure to the four isolates was investigated in hamsters using commercially available human products or an experimental monoclonal antibody. Results showed reduced protection with pre-exposure vaccination and with conventional rabies post-exposure prophylaxis against all four new bat viruses. In general, protection was inversely related to the genetic distance between the new isolates and traditional rabies viruses. For example, the WCBV is the most divergent of these lyssaviruses, and neither pre-exposure vaccination nor conventional post-exposure prophylaxis provided significant protection. The potential impact of these new lyssaviruses on human and domestic animal health and the impact on the putative bat reservoir populations will require further field and laboratory investigation.