Revised recommendations for rabies pre-exposure prophylaxis in travellers: avoid bumpy roads, select the highway!

Recently the World Health Organization (WHO) published a position paper on rabies vaccines ( https://www.who.int/immunization/policy/position_papers/rabies/en/) and the comprehensive WHO expert consultation on rabies ( https://www.who.int/rabies/resources/who_trs_1012/en/). The WHO and the global rabies expert community had pushed for changes of previous recommendations in view of new data supporting more adequate use of vaccine and rabies immune globulin (RIG). Not only there are almost continuous shortages in RIG and rabies vaccine, but increasingly it had also been recognized that basing on outdated concepts there was unnecessary overuse of vaccine mainly in high-income countries. Focussing on travellers, it is common knowledge that 0.4% experience a potential rabies exposure with need of post-exposure prophylaxis (PEP).1 While tourists and those visiting friends and relatives had the highest risk also business travellers were exposed.1,2 Depending on the survey, only 4–20% of patients with indication for RIG received RIG in the country of exposure.1 Since ‘there are less than three deaths per year in travellers’,2,3 this problem is neglected in travel health. Risk awareness among travellers is rather low, and only a minority of travel clinics recommend rabies pre-exposure prophylaxis (PrEP) to exposed travellers.4 Particularly in countries where the vaccine is very expensive only few obtain PrEP even when considerable risk—e.g. in low-budget backpackers—or cumulative exposure in the future years should be anticipated. In April 2017 global rabies experts invited by WHO to meet in Bangkok highlighted that there were various fundamental misconceptions among users of rabies vaccine. No longer is it necessary to reach a measurable titre of antibodies or at least 0.5 IU/ml after PrEP to guarantee 100% success by PEP if exposed (Module 17: Rabies vaccines, Chapter 3.3 https://www.who.int/immunization/documents/policies/WHO_IVB_ISBN9789241513371/en/). For years it has been known that the effectiveness of PEP does not exclusively depend on a threshold titre and that rabies vaccines `establish immunological memory that presumably persists for the life of the individual even after titres of neutralizing antibodies decline’ (https://www.who.int/rabies/resources/who_trs_982/en/). The route of vaccine administration—intradermal (ID) or intramuscular (IM)—involves slightly different immunological pathways, and not only the antibody titres but also various cytokines, not routinely measurable, seem to play a prominent role in establishing long term immunological memory and assuring its rapid, efficient recall (Module 17: Rabies vaccines, Chapter 2.3: https://www.who.int/immunization/documents/policies/WHO_IVB_ISBN9789241513371/en/). Therefore, evaluation of alternative PrEP regimens no longer focuses on antibody levels and their persistence as a response after the primary course, but rather on titres triggered through the immune response to PEP boosters (particularly Khawplod 2012 in Kessel et al.5). That means that boostability by PEP is guaranteed in anyone who previously received rabies vaccine anytime, who sero-converted to some extent—irrelevant whether above 0.5 IU/ml or not. Already in 2007 WHO explicitly stated that `periodic PrEP booster injections are therefore not recommended for general travellers’,5 implicating that routine booster doses promoted until 2002 are unnecessary. Rabies PrEP recommendations for travellers in select countries aChecked 2–3 December 2018. bNo immune deficiency. cBangladesh, Bhutan, Cambodia, Cameroon§, Côte d‘Ivoire, Egypt§, India§, Indonesia§, Kenya, Madagascar, Mozambique§, Nepal, Pakistan, the Philippines, South Africa, Sri Lanka, Tanzania§, Thailand§, Vietnam§ (§Formal approval pending). Rabies PrEP recommendations for travellers in select countries aChecked 2–3 December 2018. bNo immune deficiency. cBangladesh, Bhutan, Cambodia, Cameroon§, Côte d‘Ivoire, Egypt§, India§, Indonesia§, Kenya, Madagascar, Mozambique§, Nepal, Pakistan, the Philippines, South Africa, Sri Lanka, Tanzania§, Thailand§, Vietnam§ (§Formal approval pending). The main recent change in PrEP relevant to travellers is that three vaccination sessions are no longer recommended, but just two at Days 0 and 7. Thus many leaving at short notice can complete PrEP pre-departure and the costs are reduced by 30%. How good is the evidence that PrEP with two doses and without any booster is safe? Over more than a decade there have been many PrEP non-completers who received PEP following an exposure. Some were travellers, most were residents in low-income settings. Despite such incomplete PrEP, standard PEP following rabies virus exposure was 100% effective. Besides the case described below, there has been neither a publication documenting the contrary nor any expert at the two WHO fora discussing rabies vaccination remember such a failure. The only case report of a possible PrEP failure after a dog bite despite subsequent PEP double dose application was in a child with severe immune deficiency due to HIV infection.6 The authors could not determine whether the child died at home from rabies or succumbed to HIV/AIDS; the latter may well have been the case since the dog survived at least 12 days. An additional argument against routine boosters is the fact that following PrEP there are no significant differences with respect to the speed of onset of an adequate immune response to PEP boosters one or many years later.5 Recently several authors collated and analysed available evidence on different PrEP schedules,5,7–8 but lately additional studies on expedited PrEP schedules were published and more clinical trials are underway. All available, including then yet unpublished evidence, were taken into consideration by experts to unanimously conclude on a two-visit PrEP schedule. As specified in the latest review,7 there is a persisting challenge: (i) To compare different study protocols and depending on inclusion or exclusion of certain studies: in the most recent studies the moment to evaluate the response was Day 7 instead of Day 14 after the booster dose, since that is crucial in view of the minimal incubation time of rabies of 7 days (https://www.who.int/rabies/resources/who_trs_1012/en/). (ii) To interpret the continued inconsistency of serology results for different administration routes or dose-response relationship: sample sizes of such studies are usually small, which results in low study power and there is high heterogeneity between study settings (demography study population, health status, trial conditions, etc). (iii) PEP or other booster schedules used: the difference ranges from a single PrEP routine booster to a five-dose PEP schedule as a booster. (iv) Serological tests performed: recommended tests all have their little shortcomings (Module 17: Rabies vaccines, Chapter 4 https://www.who.int/immunization/documents/policies/WHO_IVB_ISBN9789241513371/en/) and variability in routine of laboratory personnel within and across sites is known to affect serological results. The recent studies by authors from Belgium and the Netherlands involve more than 900 subjects and add solid evidence for shorter PrEP schedules not yet considered in the above reviews.8–11 In summary, adequate boostability upon a mimicked PEP could be established for the two-visit PrEP for people aged 5–65 years. From previous studies we learned also that there is no gender bias and that modern rabies vaccines can be safely administered to children as young as a few months, even if co-administered with other vaccines.5 There is no rationale to assume this would change with the PrEP schedule. The differences between ID and IM application of vaccine is not discussed in this perspective, since for travel health physicians in most-high income countries, ID injections would be off-label use. Actually, from an increasing number of studies there is even ample evidence that a single PrEP visit would be sufficient to guarantee successful PEP after a potential exposure9,10 but at least for the time being both, the 2017 WHO rabies expert consultation and the Strategic Advisory Group of Experts (SAGE) concluded on insufficient evidence, and thus this currently is not recommended. Despite the fact that the leading global experts on rabies and SAGE had thoroughly analysed published and at the time unpublished data whether a two-visit PrEP would be sufficient, the new recommendations have found an ambivalent reception. So far, only travel health experts in Denmark, Belgium and the Netherlands—the latter two countries conducted research on PrEP schedules—and authorities in lower income countries rapidly endorsed the expedited PrEP schedule (Table 1). Several national expert groups claim there is a lack of data on the very young and old age groups, on females and on travellers with comorbidities and continue to recommend three doses for PrEP in travellers (Table 1). Others prefer to give the second dose later than on Day 7, preferable on Day 28. In several countries a third and possibly fourth dose as booster are recommended between 4 months and 1 year later or prior to next trip(s). A few colleagues still consider it a prudent approach after primary vaccination to test and administer a routine PrEP booster if the antibody titre falls below 0.5 IU/ml. These differing recommendations add unnecessary complexity for the travel health practitioner and result in hesitation to adequately advise customers who should typically receive PrEP. Lack of consensus among travel medicine experts also leads to loss of credibility in the risk-exposed population. Clinics at tourist destinations taking care of travellers seeking medical care after a rabies exposure lack standard orders of procedure with increasing heterogeneity of schedules documented in the vaccination certificates. For which travellers are the former recommendations still valid? Paucity of data persists on clinically immunocompromised individuals where a three-visit PrEP schedule ismaintained ( https://www.who.int/immunization/policy/position_papers/rabies/en/). To a lesser extent absence of published data pertains also for the age group >65 years, which is generally underrepresented in most studies on PrEP and PEP schedules and long-term boostablility following a less than three-visit PrEP. Other groups include professionals at higher risk of rabies virus infection in whom exposure may go unnoticed (e.g. rabies laboratory technicians, bat handlers and dog vaccinators). Systematically collected observational data from travel medicine practitioners (and occupational medicine) on long-term boostability and standardized data on exposure risk profiles of travellers or at risk individuals would help to refine WHO recommendations on the need and frequency of serological monitoring and routine PrEP boosters. In conclusion, the primary preventive measure remains to increase awareness in travellers about the danger of rabies.4 Second the customers need to understand how to prevent rabies exposures by e.g. clever behaviour of avoiding contacts with dogs, cats, monkeys and bats. Third, if a suspected rabies exposure occurs to sensitize travellers about the paramount importance of immediate, thorough wound washing, vaccine administration and wound infiltration with RIG, if applicable. Fourth, PEP is needed as soon as possible, regardless of whether the patient received PrEP or not, to win the race against the virus. Even in recently boostered exposed travellers it would be inappropriate to claim that PEP can be delayed until they return home. As repeatedly shown neither the number of previous PrEP doses nor the mode of application significantly influences the speed of an adequate immune response.5 Fifth, in view of many questions it is necessary to reiterate that if any vaccine dose was delayed, the vaccination schedule should be resumed and not restarted from the beginning. Lastly rabies PrEP should obtain the priority it deserves in travel health advice and be recommended far more often—hopefully at reasonable cost. Taking into account the high incidence of animal bites, the stress associated with costly PEP anywhere, the close to 100% fatal nature of rabies, PrEP against rabies deserves to be granted a higher priority than hepatitis A, for destinations except South Asia, certainly a far higher one than typhoid immunization.12 It is not up to the individual travel medicine practitioners to decide which recommendations to follow; their off-label position is not comfortable if they go against both package labelling and national guidelines.3 As Shlim3 correctly pointed out, in the past the number of rabies vaccine doses has been reduced several times—and never ever did that result in higher rates of failures. Hopefully more national public health bodies will have confidence in the international rabies experts and SAGE consensus and adopt the new recommendations. Conflict of interest: None declared.