As noted previously, human rabies is preventable by controlling rabies in both wildlife and domestic animal populations and by carrying out PEP. Typically, pre-exposure vaccination is reserved for people at risk for infection, including individuals working in rabies diagnostic or research laboratories, veterinarians, animal handlers (including bat handlers), and animal rehabilitators and wildlife officers. Since children under the age of 15 years are disproportionately affected by RV infections, the WHO recommends that children in rabies-endemic areas also receive pre-exposure vaccinations [15
WHO-recommended PEP for areas of the world that can afford this treatment consists of adequate wound cleaning and a complex immunotherapy strategy consisting of a single passive immunization dose of rabies immune globulin (RIG) and five active immunizations with an inactivated RV-based vaccine () [102
]. Several developments in the use of inactivated RV-based vaccines have increased their utility or hold the potential for improvements. The Advisory Committee on Immunization Practices (ACIP) provisionally approved a recommendation to reduce the number of inactivated RV-based vaccine doses from five to four during human rabies PEP treatment in the USA for previously unvaccinated individuals [16
]. Individuals with underlying immunosuppression should still receive five full doses of inactivated vaccine. The US CDC supports this decision and formal publication of the recommendations is available [16
]. Current WHO recommendations remain unchanged [103
]. One advantage of the modified immunization protocol is the reduction in the amount of vaccine used and the number of visits to a medical facility required to complete the vaccination schedule, thereby increasing compliance. Although this change in the vaccination regimen will reduce the cost of PEP, a regimen based on four vaccine doses plus RIG remains complex and costly, and the impact of this modification on the global effectiveness of human rabies vaccination and prevention is unknown.
WHO-recommended rabies virus vaccine regimens
Years of research aimed at developing vaccination strategies that use less inactivated vaccine to decrease the cost of rabies PEP in developing countries have produced viable vaccination alternatives. As a result, the WHO now recommends two vaccine schedules based on an intramuscular route and two regimens based on an intradermal route (). The intradermal route is used in tropical countries in an effort to reduce rabies vaccination costs [15
]. Recently, the WHO modified the two-site intradermal regimen by deleting the requirement for a vaccine dose on day 90 and doubling a dose on day 28 [104
]. This effectively reduces the number of visits to a healthcare facility from five to four visits. In a further development for the use of intradermal regimens, Warrell et al.
recently reported on an effective four-site intradermal regimen that requires only three visits to a healthcare clinic and uses only half the amount of vaccine [20
]. The four-site intradermal regimen has not yet been incorporated into WHO recommendations [103
]; however, this regimen will help to increase compliance and reduce the cost of human rabies prevention worldwide. Despite the progress in developing alternative immunization schedules, they remain complex, require expensive RIG, multiple visits to medical facilities and skilled practitioners capable of administering the vaccine intradermally. These obstacles contribute to decreasing the widespread use and thus reducing the effectiveness of these vaccination regimens.
A recent study by Strady et al.
showed that three inoculations of currently used inactivated RV-based vaccine in a pre-exposure setting was needed reduce the percentage of poor responders (<0.5 IU/ml) to just 3% [21
], indicating that a reduction in the number of inoculations of inactivated vaccines is not a viable alternative. Furthermore, vaccines comprised of inactivated viral particles are generally poor immunogens since they lack the capacity to elicit potent inflammatory responses required for effective CD4+
T-cell help. In addition, inactivated RV vaccines generate a Th2-biased antibody response characterized by IgG1 antibodies in mice [22
], rather than the more potent antiviral IgG2a antibodies (). Further modifications to the formulation would be needed to increase the utility of current inactivated RV-based vaccines for humans. The use of adjuvants can improve antigen delivery or augment vaccine-induced immunity in the context of various vaccines now being tested in human clinical trials [23
]. For human rabies vaccines, development of effective adjuvants is still lacking. Only a few recent studies describing preclinical data using CpG oligodeoxynucleotides (ODNs) [24
] or poly(lactide-co-glycolide) microspheres [26
] as adjuvants have suggested that the efficacy of inactivated RV-based vaccines can be improved through the use of proper adjuvants. The reason for the lack of interest in testing novel adjuvants in inactivated RV-based vaccines for humans is unclear, but may relate to safety concerns (or the perception that these formulations are unsafe), lack of appropriate animal models that adequately predict the effects of adjuvants in humans [23
], the cost of developing and producing new adjuvant vaccines, or the unsuccessful development of alternative technologies that show more promise than adjuvanted, inactivated RV-based vaccines for humans. Regardless, the safety of newer adjuvant formulations is improving and our understanding of the immune parameters affected by adjuvants is increasing. It is likely that as alternative adjuvants are developed and tested in the context of vaccines for other infectious agents, they can be developed for use with inactivated RV-based vaccines.
Immunity by current and potentially future rabies virus vaccines
The absence of necessary improvements to inactivated RV-based vaccines (or lack of attention to the development of alternative vaccine designs) now or in the future makes implementation of effective rabies prevention programs that rely solely on PEP increasingly difficult for human rabies prevention in rabies-endemic countries. This is especially true for the children in rabies-endemic areas in the absence of animal rabies control and pre-exposure prophylaxis. Pre-exposure vaccination requires three inoculations of inactivated vaccine and the WHO recommends children in areas where rabies is endemic to receive pre-exposure immunizations [15
]. Nonetheless, the cost of childhood immunizations against RV is likely to be prohibitive in all but a very few dog-enzootic countries where PEP is already available. To address this concern, several studies characterized the safety, immunogenicity and/or cost–effectiveness of pre-exposure vaccination in children using inactivated RV-based vaccines [19
]. When the incidence of dog bites is between 2 and 30%, a cost comparison between rabies pre- and post-exposure vaccine regimens in Thai children is estimated to be the same [27
]. It is generally agreed that the most effective means of preventing human rabies is to eliminate rabies in dogs [15
]. Until such efforts are successful, however, protecting children through pre-exposure vaccination in areas of the world most affected by rabies needs to be considered.