Correction: Briggs, D.J.; Moore, S.M. The Route of Administration of Rabies Vaccines: Comparing the Data. Viruses 2021, 13, 1252.

The authors wish to make the following corrections to this paper [...].

The Route of Administration of Rabies Vaccines: Comparing the Data.

Cell culture rabies vaccines were initially licensed in the 1980s and are essential in the prevention of human rabies. The first post-exposure prophylaxis (PEP) vaccination regimen recommended by the World Health Organization (WHO) was administered intramuscularly over a lengthy three-month period. In efforts to reduce the cost of PEP without impinging on safety, additional research on two strategies was encouraged by the WHO including the development of less expensive production methods for CCVs and the administration of reduced volumes of CCVs via the intradermal (ID) route. Numerous clinical trials have provided sufficient data to support a reduction in the number of doses, a shorter timeline required for PEP, and the approval of the intradermal route of administration for PEP and pre-exposure prophylaxis (PreP). However, the plethora of data that have been published since the development of CCVs can be overwhelming for public health officials wishing to review and make a decision as to the most appropriate PEP and PreP regimen for their region. In this review, we examine three critical benchmarks that can serve as guidance for health officials when reviewing data to implement new PEP and PreP regimens for their region including: evidence of immunogenicity after vaccination; proof of efficacy against development of disease; and confirmation that the regimen being considered elicits a rapid anamnestic response after booster vaccination.

Evaluating new rabies post-exposure prophylaxis (PEP) regimens or vaccines.

The development of human rabies vaccines has evolved dramatically from the first crude nerve tissue vaccine produced then administered in the presence of Louis Pasteur in 1885. New cell culture technology has enabled highly potent and well-tolerated rabies vaccines to be produced that have reduced the volume and number of doses required to save human lives after exposure. However, these highly potent vaccines are still unaffordable to many patients living at risk of exposure on a daily basis. The cost of post-exposure prophylaxis (PEP) is not only related to the direct cost of rabies biologicals and equipment but is also associated with indirect costs that patients incur as a result of travel, loss of work time (income loss), and accommodation over the period of time that a PEP regimen requires to be completed. This paper summarizes the particular criteria that the SAGE Working Group and WHO personnel reviewed as part of the evaluation process for recommending the new one-week intradermal vaccination regimen (2-2-2-0-0) for rabies post-exposure prophylaxis. These criteria included: Cost-effectiveness; evaluation of number of doses; seroconversion after vaccination; efficacy; safety; and patient follow-up.

Estimating the global burden of endemic canine rabies.

BACKGROUND: Rabies is a notoriously underreported and neglected disease of low-income countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries. METHODOLOGY/PRINCIPAL FINDINGS: We established relationships between rabies mortality and rabies prevention and control measures, which we incorporated into a model framework. We used data derived from extensive literature searches and questionnaires on disease incidence, control interventions and preventative measures within this framework to estimate the disease burden. The burden of rabies impacts on public health sector budgets, local communities and livestock economies, with the highest risk of rabies in the poorest regions of the world. This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths, over 3.7 million (95% CIs: 1.6-10.4 million) disability-adjusted life years (DALYs) and 8.6 billion USD (95% CIs: 2.9-21.5 billion) economic losses annually. The largest component of the economic burden is due to premature death (55%), followed by direct costs of post-exposure prophylaxis (PEP, 20%) and lost income whilst seeking PEP (15.5%), with only limited costs to the veterinary sector due to dog vaccination (1.5%), and additional costs to communities from livestock losses (6%). CONCLUSIONS/SIGNIFICANCE: This study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts.

Implementation of an intersectoral program to eliminate human and canine rabies: the Bohol Rabies Prevention and Elimination Project.

BACKGROUND: The province of Bohol, located in the Visayas islands region in the Philippines has a human population of 1.13 million and was the 4th highest region for human rabies deaths in the country, averaging 10 per year, prior to the initiation of the Bohol Rabies Prevention and Elimination Project (BRPEP). AIMS: The BRPEP was initiated in 2007 with the goal of building a sustainable program that would prevent human rabies by eliminating rabies at its source, in dogs, by 2010. This goal was in line with the Philippine National Rabies Program whose objective is to eliminate rabies by 2020. METHODS: The intersectoral BRPEP was launched in 2007 and integrated the expertise and resources from the sectors of agriculture, public health and safety, education, environment, legal affairs, interior and local government. The program included: increasing local community involvement; implementing dog population control; conducting mass dog vaccination; improving dog bite management; instituting veterinary quarantine; and improving diagnostic capability, surveillance and monitoring. Funding was secured from the national government, provincial, municipal and village units, dog owners, NGOs, the regional office of the WHO, the UBS Optimus Foundation, and the Global Alliance for Rabies Control. The BRPEP was managed by the Bohol Rabies Prevention and Eradication Council (BRPEC) under the jurisdiction of the Governor of Bohol. Parallel organizations were created at the municipal level and village level. Community volunteers facilitated the institution of the program. Dog population surveys were conducted to plan for sufficient resources to vaccinate the required 70% of the dogs living in the province. Two island-wide mass vaccination campaigns were conducted followed by "catch up" vaccination campaigns. Registration of dogs was implemented including a small fee that was rolled back into the program to maintain sustainability. Children were educated by introducing rabies prevention modules into all elementary schools in Bohol. Existing public health legislation at the national, provincial, and municipal level strengthened the enforcement of activities. A Knowledge, Attitude and Practices (KAP) survey was conducted in 2009 to evaluate the educational knowledge of the population. Increased surveillance was instituted to ensure that dogs traveling into and out of the province were vaccinated against rabies. Human and animal cases of rabies were reported to provincial and national authorities. KEY RESULTS: Within the first 18 months of the BRPEP, human rabies deaths had decreased annually from 0.77 to 0.37 to zero per 100,000 population from 2007-2009. Between October 2008 and November 2010 no human and animal cases were detected. Increased surveillance on the island detected one suspected human rabies case in November 2010 and one confirmed case of canine rabies in April 2011. Two mass vaccination campaigns conducted in 2007 and 2008 successfully registered and vaccinated 44% and 70% of the dogs on the island. The additional surveillance activities enabled a mobilization of mop up vaccination activities in the region where the human and canine case was located. Due to the increased effective and continuous surveillance activities, rabies was stopped before it could spread to other areas on the island. The program costs totaled USD 450,000. Registration fees collected to maintain the program amounted to USD 105,740 and were re-allocated back into the community to sustain the program.

The role of vaccination in rabies prevention.

Rabies vaccines have evolved from the first crude nerve tissue vaccines developed by Louis Pasteur and his colleagues in 1885. Currently, safe and efficacious rabies vaccines for humans and animals are produced in several cell culture systems with 10 vaccine regimens recommended by WHO and/or ACIP for pre-exposure and post-exposure prophylaxis in humans. Rabies vaccines are a critical component in the strategy to reduce the dog rabies, the cause of 98% of all global human rabies deaths. However, eliminating rabies in the reservoir animal species is not possible without an intersectoral approach including collaboration between animal and human health experts. There is an urgent need to establish national risk assessment systems in regions where surveillance is limited to non-existent.

Renewed global partnerships and redesigned roadmaps for rabies prevention and control.

Canine rabies, responsible for most human rabies deaths, is a serious global public health concern. This zoonosis is entirely preventable, but by focusing solely upon rabies prevention in humans, this "incurable wound" persists at high costs. Although preventing human deaths through canine rabies elimination is feasible, dog rabies control is often neglected, because dogs are not considered typical economic commodities by the animal health sector. Here, we demonstrate that the responsibility of managing rabies falls upon multiple sectors, that a truly integrated approach is the key to rabies elimination, and that considerable progress has been made to this effect. Achievements include the construction of global rabies networks and organizational partnerships; development of road maps, operational toolkits, and a blueprint for rabies prevention and control; and opportunities for scaling up and replication of successful programs. Progress must continue towards overcoming the remaining challenges preventing the ultimate goal of rabies elimination.

Results of vaccination of Asian elephants (Elephas maximus) with monovalent inactivated rabies vaccine.

OBJECTIVE: To evaluate the humoral immune response of Asian elephants to a primary IM vaccination with either 1 or 2 doses of a commercially available inactivated rabies virus vaccine and evaluate the anamnestic response to a 1-dose booster vaccination. ANIMALS: 16 captive Asian elephants. PROCEDURES: Elephants with no known prior rabies vaccinations were assigned into 2 treatment groups of 8 elephants; 1 group received 1 dose of vaccine, and the other group received 2 doses of vaccine 9 days apart. All elephants received one or two 4-mL IM injections of a monovalent inactivated rabies virus vaccine. Blood was collected prior to vaccination (day 0) and on days 9, 35, 112, and 344. All elephants received 1 booster dose of vaccine on day 344, and a final blood sample was taken 40 days later (day 384). Serum was tested for rabies virus-neutralizing antibodies by use of the rapid fluorescent focus inhibition test. RESULTS: All elephants were seronegative prior to vaccination. There were significant differences in the rabies geometric mean titers between the 2 elephant groups at days 35, 112, and 202. Both groups had a strong anamnestic response 40 days after the booster given at day 344. CONCLUSIONS AND CLINICAL RELEVANCE: Results confirmed the ability of Asian elephants to develop a humoral immune response after vaccination with a commercially available monovalent inactivated rabies virus vaccine and the feasibility of instituting a rabies virus vaccination program for elephants that are in frequent contact with humans. A 2-dose series of rabies virus vaccine should provide an adequate antibody response in elephants, and annual boosters should maintain the antibody response in this species.

Detection of cellular immunity to rabies antigens in human vaccinees.

A nonradioactive multi-parameter flow cytometry assay was developed to identify antigen-specific lymphocytes in human subjects previously vaccinated against rabies virus and was subsequently compared to the standard tritiated thymidine method. A cell tracking dye, carboxyfluorescein succinimidyl ester, was used in combination with surface label for CD4 and CD8 cells in order to determine the response of lymphocytes to killed rabies virus in an antigen recall assay. The rabies virus-specific lymphocyte response was compared to the humoral immune response in each of ten vaccinated and five non-vaccinated subjects. Lymphocyte responses to rabies virus were observed in all ten vaccinated subjects; some noted as early as 3 days after stimulation while others were not until 7 days after stimulation. There was good agreement between the proliferation index of the CFSE assay and the simulation index of the [3H]thymidine assay (kappa statistic=0.73). An inverse relationship was detected between the level of rabies virus neutralizing antibody (RVNA) and the lymphocyte response to inactivated rabies virus in the vaccinated subjects. The association between cytokines production and level of humoral and cellular response was investigated in four representative subjects. Two vaccinated subjects with high proliferation indices and low RVNA titers produced Th1 type cytokines to rabies virus stimulation, whereas two vaccinated individuals with low proliferation indices and high RVNA titers responses did not produce these cytokines.

The influence of homologous vs. heterologous challenge virus strains on the serological test results of rabies virus neutralizing assays.

The effect that the relatedness of the viral seed strain used to produce rabies vaccines has to the strain of challenge virus used to measure rabies virus neutralizing antibodies after vaccination was evaluated. Serum samples from 173 subjects vaccinated with either purified Vero cell rabies vaccine (PVRV), produced from the Pittman Moore (PM) seed strain of rabies virus, or purified chick embryo cell rabies vaccine (PCECV), produced from the Flury low egg passage (Flury-LEP) seed strain of rabies virus, were tested in parallel assays by RFFIT using a homologous and a heterologous testing system. In the homologous system, CVS-11 was used as the challenge virus in the assay to evaluate the humoral immune response in subjects vaccinated with PVRV and Flury-LEP was used for subjects vaccinated with PCECV. In the heterologous system, CVS-11 was used as the challenge virus in the assay to evaluate subjects vaccinated with PCECV and Flury-LEP was used for subjects vaccinated with PVRV. Although the difference in G protein homology between the CVS-11 and Flury-LEP rabies virus strains has been reported to be only 5.8%, the use of a homologous testing system resulted in approximately 30% higher titers for nearly two-thirds of the samples from both vaccine groups compared to a heterologous testing system. The evaluation of equivalence of the immune response after vaccination with the two different vaccines was dependent upon the type of testing system, homologous or heterologous, used to evaluate the level of rabies virus neutralizing antibodies. Equivalence between the vaccines was achieved when a homologous testing system was used but not when a heterologous testing system was used. The results of this study indicate that the strain of virus used in the biological assays to measure the level of rabies virus neutralizing antibodies after vaccination could profoundly influence the evaluation of rabies vaccines.

Vaccination of Egyptian fruit bats (Rousettus aegyptiacus) with monovalent inactivated rabies vaccine.

Twenty-six captive, adult Egyptian fruit bats (Rousettus aegyptiacus) were tested for the presence of rabies virus neutralizing antibodies (RVNA) using a rapid fluorescent focus inhibition test before and after vaccination. The bats were randomly assigned into three treatment groups: group A (n = 10) bats each received one 0.1-ml dose of monovalent inactivated rabies vaccine, group B (n = 10) bats each received two 0.1-ml doses of vaccine given 30 days apart, and group C (n = 6) bats remained unvaccinated. Plasma was collected from all bats before vaccination and on days 14, 30, 60, and 360. All bats were seronegative before vaccination, and all unvaccinated animals remained negative throughout the study. Rabies virus neutralization titers remained above 0.5 IU/ml from day 30 through day 360 for both vaccinated groups. Group B had significantly higher titers on day 60. This study demonstrated a measurable humoral immune response after vaccination with an inactivated rabies vaccine, with two doses producing a higher level of RVNA. This study confirms the feasibility of a rabies vaccination program for Egyptian fruit bats.

Rabies update for travel medicine advisors.

Rabies is a neglected disease in many developing countries. It is preventable, and the tools to prevent it are known. There is urgent need for more funding, for study of innovative dog population-control measures, and for sustainable canine immunization. Safe and effective tissue-culture rabies vaccines and human and equine rabies immunoglobulins (HRIG and ERIG) are not readily available in many regions where rabies is endemic. This and the continuing presence and spread of rabies have increased the risk for travelers, who cannot rely on being able to receive optimal postexposure treatment in many parts of the world. Alternatives to HRIG or ERIG are not available. Travelers who leave the safe environments of tourist hotels and buses in regions of Asia, Russia, Africa, and Latin America where canine rabies is endemic may be at risk of life-threatening exposure to rabies.

Induction of protective immunity by topic application of a recombinant adenovirus expressing rabies virus glycoprotein.

The objective of this study was to determine if a replication defective recombinant adenovirus expressing rabies virus glycoprotein (Adrab.gp) given through a non-invasive vaccination route (by topical application) onto the skin (NIVS) could elicit an immune response and/or protection against rabies. Groups of mice were immunized by NIVS with various doses of Adrab.gp. For comparison, groups of mice were immunized intramuscularly, subcutaneously, or intradermally with Adrab.gp. Mice received two booster immunizations at 1 and 2 months after the first immunization. Virus neutralizing antibody (VNA) titers were measured at day 21 after the first and second immunizations and at day 14 after the third immunization. Fifty percent of the mice immunized by NIVS with 2 x 10(7) and 2 x 10(8)pfu Adrab.gp vaccine developed VNA, whereas none of the control mice or the mice immunized by NIVS with the lowest dose (2 x 10(6)pfu) of Adrab.gp virus developed VNA. However, this low dose induced high titers of VNA in mice immunized by parenteral routes. Two weeks after the last immunization, all the mice were challenged with a lethal dose of rabies virus. More than 70% of the animals immunized by NIVS with > or = 2 x 10(7)pfu Adrab.gp virus survived the challenge, whereas all the mice in the negative control group and the group immunized by NIVS with the lowest dose of Adrab.gp succumbed to rabies. Taken together, the results suggest that NIVS with Adrab.gp can induce VNA production and protection against lethal challenge with rabies virus in mice.