Among wildlife, nonhuman primates (NHPs) are known to harbor a large diversity of zoonotic pathogens and are among the primary mammals targeted for zoonotic disease surveillance [1]. They are the principal host and sometimes an important intermediate host of many zoonotic RNA viruses. Among these viruses, rabies virus, the agent of a lethal encephalitis, is responsible for around 55,000 human deaths every year [2]. Human rabies is a fatal disease once clinical signs develop. Rabies postexposure prophylaxis (PEP) consists of thorough wound care, in combination with rabies vaccine and administration of rabies immunoglobulin (RIG) if necessary. Despite evidence of rabies virus spillover in NHPs and of transmission of rabies from NHPs to humans, neither the World Health Organization (WHO) nor the United States Centers for Disease Control and Prevention (CDC) provide specific guidelines regarding rabies PEP following NHP-related injuries. Guidance emphasizes the role of most frequent reservoirs and vectors. The recommendation of WHO is to provide vaccine and RIG in severe, type III injuries (transdermal bites or scratches, lick on broken skin or mucous membrane, and contacts with bats) and vaccine only in minor, type II injuries (minor scratches or abrasions without bleeding) following exposure from any wild mammal (including implicitly NHPs) in a previously unvaccinated person [2]). At the international level, PEP recommendations after exposure to various animals may differ across a variety of organizations. This is also the case for recommendations following exposure to NHPs. The human animal interactions are too complicated to list every scenario or most species, given the diversity of mammalian species. Hence, the US CDC recommends that vaccine and RIG be provided, regardless of the type of injury, following exposure from any wild mammal (including implicitly NHPs) for a previously unvaccinated person exposed to rabies, as evaluated based on risk assessment [3]. The US Advisory Committee on Immunization Practices and the National Association of State Public Health Veterinarians deal with risk assessments and particular taxa, on a case-by-case basis. Quebec Province (Canada) guidelines recommend the use of vaccine and RIG following NHP-related injuries [4]. French guidelines recommend following the WHO guidelines [5]. Currently, neither the British nor Scottish guidelines recommend the use of RIG for PEP following NHP-related injuries. The British guidelines state that “rabies-infected primates have been sporadically described in countries where rabies is endemic. Although the risk of transmission of rabies from a primate bite is extremely low, these bites occurring in low- or high-risk countries should receive PEP with vaccine only for a previously unvaccinated subject” [6]. The Scottish guidance document, published in 2010, states that all bites, licks and scratches from NHPs are considered low risk and therefore “5 active vaccinations plus no RIG” is the suggested PEP response for a previously unvaccinated person [7].

Therefore, no international consensus has been reached, even among national recommendations about rabies PEP following a NHP-related injury. Furthermore, none of the guidelines that we reviewed are based on published data about rabies in NHPs and subsequent transmission to humans. To enhance the specificity and scientific basis of future recommendations and guidelines, we gathered information on rabies in NHPs and human rabies cases and exposures following NHP-related injuries. The aims of this work are to 1) collect and analyze data concerning rabies transmission from NHPs to humans, 2) collate medical practices regarding rabies PEP in different countries, and 3) provide an evidence base to support the decision to apply rabies PEP in this context.

We searched for all accessible publications and reports containing relevant information on rabies in NHPs and human rabies and rabies exposure and PEP following NHP-related injuries. We also analyzed selected data concerning NHPs submitted for rabies diagnosis in France and rabies PEP following NHP-related injuries sustained by French international travelers.

We retrieved a total of 134 confirmed cases of rabies in NHPs which have been reported from various sources in South America, Africa, and Asia, including 13 cases in animals imported to Europe and the US. We retrieved 25 cases of rabies transmission to humans following NHP-related injuries, 20 of which occurred in Brazil. Rabies cases in NHP from Brazil were confirmed by genetic analysis [9]. Additionally 4 capuchin monkeys were found with positive serology in southeastern Brazil [10]. By contrast, 21 NHPs from other regions in Latin America were reported rabid by the PAHO with no information about the methods used for the assessment of rabies. It is therefore possible that these so-called “cases” were actually healthy animals with a positive-serology. Such so-called “cases” reported in Peru, finally turned out not to be rabies [11]. We cannot exclude that rabies cases reported in NHPs from São Paulo and Mato Grosso in Brazil and from other countries in South America by the PAHO could be actually healthy animals with positive serology. There are issues with the PAHO data that may contain inaccuracies and should not be considered the gold standard. Imported cases from Peru and Colombia, however were confirmed by fluorescent rabies antibody examination of brain tissue, demonstration of negri bodies on microscopic examination or rabies induced in mice inoculated with brain tissue [12], [13]. Cases reported in wild NHPs in various countries in Africa by the SEARG (Appendix S1) and other authors [14]–[18], in India [20] and Jordan [26], as well as in the imported cases from Sierra Leone [19] India [21] and the Philippines [12] were all confirmed by brain tissue histology, fluorescent antibody testing of brain tissue and mouse inoculation.

The reports collated in this study support the view that confirmed rabies cases in NHPs are rarely reported compared with human rabies cases. In light of numerous biological reports establishing the susceptibility of NHPs to rabies, we might have expected the number of NHPs with rabies to have been greater than observed. Several explanations for this finding are possible.

First, with the possible exception of the cluster of marmosets in Ceará State, Brazil (9), NHPs are not known to be a reservoir for maintaining a rabies virus variant in the wild. Second, given that dogs are a domesticated species, sharing a closer bond and degree of interaction with humans than do NHPs, the difference in the contact rates with dogs may account, in part, for the difference in reported rates of rabies between humans and NHPs. However, NHPs are frequently kept as pets and can be close to humans in some regions. Finally, underreporting of rabies in NHPs is likely to be significant. The passive nature of rabies surveillance likely accounts for underreporting of rabid NHPs. Rules pertaining to the submission of animal specimens for rabies diagnosis and reporting to national authorities are sometimes weak and may only cover the few species considered to be economically important or those most important in terms of public health. Last, rabies cases in NHPs are not notifiable in many countries and as such are not recorded in official statistics.

Underreporting of rabies in NHPs is a major impediment to understanding the epidemiology of this disease and may hinder the development of control strategies. We show that a review of published reports can be an important way to overcome the problem of underreporting and can contribute to the advancement of the understanding of the importance of rabies in NHPs as a potential hazard to humans. Moreover, valuable information exists in internal reports, which is not easily available since it is not indexed in MEDLINE and SCOPUS databases.

More complete and precise information pertaining to rabies in NHPs is needed. This information could be obtained through field surveys. We believe a greater effort should be directed toward coordinating and frequently reviewing the need for rabies PEP after exposure to animal species such as NHPs that are not primary reservoirs of rabies. Information obtained in this way should be regularly collected, updated, and made available to the medical community. To this end, efforts towards greater openness and accessibility of information regarding the incidence of rabies in NHPs and its geographic distribution would provide a much-needed basis for improving and sustaining the public health debate around the risk evaluation of rabies after human exposure to these species.

To address the possibility of reintroduction of rabies through NHPs, countries that are designated as rabies-free should strongly consider permitting their entry only under license. Live animal importations to such countries would benefit from quarantine guideline under conditions approved by governmental veterinary services.

We show that, although rarely reported, documented cases of rabies infections in NHPs and subsequent transmission to humans do occur. Little is currently known about the pathobiology of rabies virus shedding in primates. The occurrence of documented transmission of rabies from NHPs to human suggests that rabies PEP is indicated in patients injured by NHPs in rabies-enzootic countries. We were unable to find any report suggesting failure or death in previously unvaccinated persons who received vaccine without RIG after exposure to NHP, however, rabies status of NHP was not documented in these reports. From a clinical perspective, distinct recommendations are found depending on national guidelines. United Kingdom guideline state that the risk of rabies following NHP-related injury is extremely low and that rabies PEP with vaccine only should be applied in previously unvaccinated people [6], [7]. A contrario, WHO, the US CDC, Canadian and French guideline state that the catastrophic nature of the disease with a nearly 100% mortality rate is what will drive treatment, not the low probability of the disease and that rabies vaccine and RIG should be applied in previously unvaccinated people [2]–[5]. As long as wild life studies addressing the role NHPs play in the disease transmission to humans are not available from various area where human exposure occur and as recommended by WHO, we consider that a precautionary principle should be applied and that RIG should be administered, as with any other animal exposures, despite the large number of doses that would be necessary, even in the setting of a RIG shortage.

Based on our review of published reports, a large number of international travelers sustain NHP-related injuries during their trips. Information about the risks posed by exposure to NHPs in enzootic countries, especially in India and Southeast Asia, should be disseminated to the traveling public to help minimize these injuries and the subsequent need for rabies PEP. Travelers should be encouraged to seek a pretravel medical consultation from their health-care provider 4–6 weeks before travel to discuss if rabies pre-exposure vaccination may be recommended in situations where travel activities may involve a higher potential for contact with animals such as NHPs. Travelers should also be encouraged to seek immediate medical care if injured by an NHP species.