The prevention and management of rabies

Should dog rabies vaccinations and their failures be considered in the decision of rabies post-exposure prophylaxis in humans?

Florence Ribadeau Dumas1 MD, Nadia Haddad3 DVM Professor, Philippe Gautret3,4 MD PHD

1 Paris Dauphine University, PSL Research University, Paris, France
2 ENVA – ANSES – INRA – UMR BIPAR, Ecole Nationale Vétérinaire d’Alfort, Maisons Alfort, France
3 Assistance Publique Hôpitaux de Marseille, Marseille, France
4 Aix Marseille University, Marseille, France

To the Editor,

Crowcroft and Thampi’s review about prevention and management of rabies [1], reports that according to 2013 WHO recommendations, risk assessment for rabies post-exposure prophylaxis should be guided by many factors including notably, the vaccination status of the biting animal. Compared to previous WHO recommendations [2] stating that, in most situations in developing countries, the vaccination status of the animal involved should not be considered to determine whether to give or withhold rabies post-exposure prophylaxis (PEP), the 2013 WHO recommendation [3] provides a slight change which may have, in our opinion, important consequences.

Every year, worldwide, 15 million people receive a post-bite vaccination, and 55 000 are dying from rabies, in most of the cases after a dog bite in Asia or Africa without PEP [2]. According to the second WHO expert consultation on rabies in 2013 [3], PEP must be initiated immediately and “completed if the suspect animal is not available for testing or observation, but may be discontinued if the animal is proved by appropriate laboratory examination to be free of rabies. When the domestic dog, cat or ferret at the origin of human exposure is healthy, properly vaccinated (at least two documented vaccinations with a potent vaccine) and easily accessible for observation for 10 days, proper wound management should be ensured and human booster vaccination can be deferred, especially if the patient had received pre-exposure prophylaxis or previous PEP in the past 3 months”.

However, cases of rabies vaccination failure leading to clinical rabies have been reported in both developing [4] and developed countries [5–7], in dogs that have received one [6] or more [5,6] rabies vaccine injections including up-to-date vaccinations. Studies have confirmed the risk of animal vaccination failure (including both clinical failure with animal rabies cases and serological failure with rabies neutralizing antibodies that do not reach the 0.5 IU/ml recommended efficacy threshold). According to different epidemiological studies performed in the US between 1971 and 2001, 4 to 10% of rabid dogs had a history of vaccination [6]. In clinical animal studies, the proportion of vaccinated dogs with rabies neutralizing antibodies <0.5 IU/mL was 14.3-54.5% [7] 4-6 months after primary rabies vaccination.

As many risk factors are associated with vaccination failure, the probability to miss one of them when evaluating bitten patients should be considered. Among the factors affecting the probability of vaccination failure, the following reported factors can be mentioned:

- risk factors linked to dogs: age <6 month or >5 years [8], larger breeds [8], immunodeficiency or health status reported to alter the immune response [7,9] such as malnutrition, acute and chronic infection, cancer or pregnancy.

-risk factors linked with vaccine potency: vaccine brand and type [8,10], vaccine batch, vaccine storage [4] and country of delivery [7]. In some developing countries, vaccines are more likely to have been counterfeit, to have reached their expiration date or to have been stored in inappropriate conditions (compromised cold chain or stored out of direct light). In addition, in those countries, it is more likely that vaccines with low or null potency are commercialized on legal or illegal market [4]. These shortcomings, which are unacceptable for both animal and human rabies vaccines are probably more prevalent in animal vaccines than in human vaccines for which controls and pharmacovigilance are supposed to be stricter.

-factors linked with vaccine administration: number of vaccine doses administered since the primary vaccination [9,10], period of time since the last vaccination [8–10], administration route, respect of manufacturer’s recommendations regarding the route and frequency of injections, administration out of the supervision of a competent and authorized vet, fake vaccine certificates or misuse of the passport of a vaccinated dog for an unvaccinated dog (in developing countries but also in developed countries as recently reported between enzootic Eastern and Western European countries) [7].

Large scale dog vaccination can lead to canine rabies elimination in a country, especially when it is associated to appropriate complementary measures (animal identification, controlled circulation of domestic carnivores, stray dogs population control, removing of uncontrolled food sources) [3]. As rabies attack rates are drastically reduced when dogs are vaccinated, dog vaccination also has a protective effect towards owners and their relatives. However, the protection conferred by dog vaccination is not of sufficient certainty to allow in human PEP postponement in medium and high risk settings [9]. Except very specific and rare situations, delayed initiation of PEP increase PEP failures. Postponing PEP in low rabies risk settings when a biting dog is healthy, under observation and did not travel abroad, is acceptable [3] because the risk that it is contagious for rabies is extremely low. Doing this in a medium or high rabies endemic country could place patients at grave risk, whether the dog is vaccinated or not.

[1] Crowcroft NS, Thampi N. The prevention and management of rabies. BMJ 2015;350:g7827.
[2] World Health Organization. WHO Expert Consultation on Rabies. First report. World Health Organ Tech Rep Ser 2005;931:1–88.
[3] WHO expert consultation on rabies. Second report. WHO; 2013.
[4] Arya SC. Therapeutic failures with rabies vaccine and rabies immunoglobulin. Clin Infect Dis 1999;29:1605.
[5] David D, Bellaiche M, Yakobson BA. Rabies in two vaccinated dogs in Israel. Vet Rec 2010;167:907–8.
[6] Murray KO, Holmes KC, Hanlon CA. Rabies in vaccinated dogs and cats in the United States, 1997-2001. J Am Vet Med Assoc 2009;235:691–5.
[7] Klevar S, Høgåsen HR, Davidson RK, Hamnes IS, Treiberg Berndtsson L, Lund A. Cross-border transport of rescue dogs may spread rabies in Europe. Vet Rec 2015;176:672.
[8] Lorna J Kennedy ML. Factors influencing the antibody response of dogs vaccinated against rabies. Vaccine 2008;25:8500–7.
[9] Sage G, Khawplod P, Wilde H, Lobaugh C, Hemachudha T, Tepsumethanon W, et al. Immune response to rabies vaccine in Alaskan dogs: failure to achieve a consistently protective antibody response. Trans R Soc Trop Med Hyg 1993;87:593–5.
[10] F Cliquet YV. Neutralising antibody titration in 25,000 sera of dogs and cats vaccinated against rabies in France, in the framework of the new regulations that offer an alternative to quarantine. Rev Sci Tech Int Off Epizoot 2004;22:857–66.

Crowcroft and Thampy stress the importance of pre and post exposure vaccination to rabies, as it is a disease with a 100% mortality rate(1) Referring to Post exposure prophylaxis the authors are of the opinion that prophylaxis can be discontinued if the animal (dog or cat) remains well at the end of a 10 day observation period.(1) Is it wise to discontinue prophylaxis before completing the full course, as we are unsure about the concept of dogs(2) and cats in a “healthy carrier state”?

1 Natasha S Crowcroft, Nisha Thampi. The prevention and management of rabies. BMJ 2015;350:g7827. Doi:10.1136/bmj.g7827.
2 P.P. Mshelbwala, A.B.Oqunkoya, B.V. Maikai. Detection of Rabies Antigen in the Saliva and Brain of Apparently Healthy Dogs Slaughtered for Human Consumption and Its Public Health Implication in Abia State, Nigeria. ISRN Veterinary Science 2013; 2013:468043.Published online Dec12,2013. Doi :10.1155/2013/468043.