Mass vaccination of dogs, control of canine populations and post‐exposure vaccination – necessary but not sufficient for achieving childhood rabies elimination

Rabies is an unmitigated tragedy, particularly affecting children in some of the world's poorest tropical nations. The vast majority of the estimated 61 000 deaths caused by rabies each year occur in rural areas of Africa and Asia, with children younger than 15 years significantly overrepresented 1. Between 40% and 50% of rabies deaths occur in children younger than 15 years 2. Surveillance limitations and prevailing cultural beliefs may contribute to underreporting, particularly in children, so the burden is likely to be considerably greater 3. The rabies virus belongs to the genus Lyssavirus in the family Rhabdoviridae. Transmission to humans usually occurs following a transdermal bite or scratch by an infected animal, predominantly dogs in Africa and Asia, although all mammal species are susceptible to infection. Bat species not only play an important role in transmitting other lyssaviruses globally, but also transmit rabies virus in the rural Amazon area of South America. Infection less commonly occurs when saliva from an infected mammal comes into direct contact with a person's mucosa or with open skin wounds. Currently, there is a three-pronged approach to preventing rabies deaths in humans. Firstly, if dog rabies could be totally prevented, there would be almost no human cases. Thus, there has been a significant global drive to control canine rabies through dog vaccination and control of stray animals. Where this One Health strategy is fully implemented, particularly in industrialised countries with effective public health systems including a sophisticated veterinary health infrastructure, it can be extraordinarily effective 4. However, in many environments, particularly in poorer rabies-endemic countries, it is confounded by weak and inadequately funded veterinary public health programmes and occasionally by wild animal species serving as reservoirs, for example vampire bats in South America. Secondly, safe rabies prevention strategies exist that effectively protect people who have been exposed to bites, scratches or saliva in open wounds from an infectious animal, if they are applied without delay. These include vigorous washing of the wound, post-exposure vaccination with cell-culture vaccines and administration of equine or human rabies immunoglobulin. This important strategy is hampered by the tentative availability of vaccine and particularly rabies immunoglobulin in health services serving endemic areas and lack of awareness amongst some affected communities of the need to seek care immediately 5. The third effective measure is vaccinating people who are likely to be exposed to rabid animals prior to their exposure. This method has particularly been embraced by travellers from developed countries visiting canine rabies-endemic areas, or by individuals, including veterinarians, wildlife professionals and laboratory staff, whose employment places them at risk of exposure. Both the traditional intramuscular administration of vaccine and the less expensive intradermal route, requiring much lower quantities of vaccine, are highly effective in preventing rabies 6. Although booster doses of post-exposure vaccine are still required following a high-risk exposure, the number of doses is reduced and no rabies immunoglobulin is necessary. This is particularly attractive in endemic areas where the availability of rabies immunoglobulin is often severely limited 7. However, these three strategies have not prevented the ongoing estimated 61,000 deaths due to rabies each year 8. In India, the country with the highest number of deaths from rabies, only one in six patients receives appropriate post-exposure prophylaxis 1. In Africa, very few dog vaccination programmes have proven successful, achieving adequate and sustained coverage. A variety of obstacles have been identified: cost, nomadic communities, weak surveillance, stray animals and exclusion of puppies during vaccination campaigns 9. WHO 10 recommends that ‘pre-exposure prophylaxis is recommended for anyone who will be at continual, frequent or increased risk of exposure to the rabies virus’, while noting that ‘children living in or visiting rabies-affected areas are at particular risk’. WHO has further encouraged ‘the implementation of carefully designed studies on the feasibility, cost-effectiveness and long-term impact of incorporating pre-exposure rabies vaccination into the immunisation programmes of infants and children’. A number of important studies have been conducted that provide insights into these critical factors. A study in Vietnamese infants demonstrated excellent immunogenicity and long-term antirabies antibody persistence provided by a reduced-dose paediatric pre-exposure regimen administered concurrently with diphtheria, tetanus, pertussis and oral polio vaccines 11. It was immaterial whether the vaccine was administered intradermally or intramuscularly as both routes achieved 100% seroprotection and the immune response following a booster at 5 years of age confirmed that all children successfully primed by either route would require only two vaccinations and no rabies immunoglobulin for post-exposure prophylaxis 11. Not only has vaccine administered at the usual 6-, 10- and 14-week period proven both safe and effective in generating seroprotection, but also there has been no evidence of any interference between rabies vaccine and co-administered infant vaccines 12. The cost of introduction in the routine immunisation programme has unfortunately only been formally investigated in Thailand to date. It was found that the cost of pre-exposure and post-exposure vaccination in children became equal when the annual dog bite incidence was between 2% and 30%, depending on which post-exposure treatment regimen was used, intramuscular or intradermal 13. It would be worthwhile repeating this study in other settings to confirm the critical cost-effectiveness thresholds for different epidemiological situations. The Philippines is currently the only country that has introduced wide-scale pre-exposure vaccination of children in highly endemic areas. The Anti-Rabies Act legislates provision of free routine pre-exposure prophylaxis for all schoolchildren aged 5–14 years in areas where baseline rabies incidence exceeds 2.5 cases per million population. The Philippines 2020 rabies elimination initiative synthesises childhood immunisation with rabies control in the dog population, administration of quality post-exposure prophylaxis when required, population education and increased rabies surveillance 14. Although focusing on dog population control and vaccination is a necessary element in achieving global rabies elimination in human population, it is not sufficient. The reality in poorer developing countries is that access to veterinary services for dog control and rabies vaccination is often limited, as are public health services to deliver timely post-exposure vaccination and rabies immunoglobulin. While dog control and vaccination are inadequately implemented in many countries, there is absolutely no doubt that pre-exposure childhood immunisation in highly rabies-endemic regions should be carefully considered as a strategy to eliminate the ongoing tragedy of preventable rabies deaths in children. The implementation of pre-exposure rabies vaccination must be balanced against the cost-benefits of other effective interventions in any particular setting, and the relative risk of other vaccine preventable diseases, with available resources committed transparently to achieve the greatest return on reducing the childhood health burden. One Health teams in individual countries should be encouraged to carefully consider the epidemiology of human rabies in their populations and complement efforts at rabies vaccination and control in dogs with other appropriate strategies, and most particularly, pre-exposure vaccination of children where the veterinary programme does not or cannot achieve the elimination aim and accessibility to rabies vaccine and/or immunoglobulin continues to result in the unnecessary loss of children's lives to rabies.