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A recent commentary advocates for the inclusion of rabies vaccine in EPI,1 referring to lack of timely available post-exposure prophylaxis (PEP) in most low-income settings. Priming with pre-exposure profylaxis (PreP) in the form of rabies vaccine extends the response window and might even provide protection without subsequent PEP.
The authors are commended for shedding light on a neglected tropical disease, and we sympathize with the notion that universal health policy should implicate equal access to vaccines, and not be restricted to wealthy travelers in rabies endemic zones.
However, the benefit of implementing routine rabies vaccinations is not self-evident. A plethora of epidemiological and clinical studies find that some vaccines have non-specific effects (NSE), i.e. modifying resistance to diseases unrelated to the target pathogen. The live BCG and measles vaccine (MV) have been shown to reduce mortality to non-tuberculosis and non-measles infections, respectively. In contrast, the non-live vaccine DTP has been associated with deleterious NSE, increasing overall mortality in girls.2
The rabies vaccine, currently a non-live vaccine, has also received attention for its putative NSE. A malaria vaccine trial using rabies vaccine as control in one study arm found that girls receiving the malaria vaccine had a 2-times higher overall mortality than controls, indicating a detrimental effect of the malaria vaccine,3 or a beneficial NSE of the rabies (...
The rabies vaccine, currently a non-live vaccine, has also received attention for its putative NSE. A malaria vaccine trial using rabies vaccine as control in one study arm found that girls receiving the malaria vaccine had a 2-times higher overall mortality than controls, indicating a detrimental effect of the malaria vaccine,3 or a beneficial NSE of the rabies (control) vaccine.4
In contrast, a randomized trial in puppies found that rabies vaccination at 6 weeks was associated with three-fold higher mortality risk at 13 weeks in females born to rabies vaccinated dogs (hazard ratio: 3.09 (95%CI: 1.24-7.69)),5 the HR in females being 2.69 (1.27–5.69) at 20 weeks after the receipt of rabies vaccine at 13 weeks in both groups.6 Recently, we conducted an RCT in which rabies vaccine was associated with increased risk of mortality and antibiotic treatment in male piglets (proportion ratio: 1.56 (1.13-2.15)), but not in female piglets born to rabies-naïve sows, with an opposite effect in piglets of rabies-vaccinated sows.7
The specific protective effects of rabies prophylaxis notwithstanding, the lack of unambiguous data refuting a negative impact on rabies-unrelated health calls for a controlled real-world safety RCT, recording also rabies-unrelated health, including effects on all-cause morbidity and mortality.
The analyses should be stratified by sex as NSE may be sex-differential and preferably by maternal immunity status as maternal immunity may modify the NSE. Furthermore, the potential interaction with other vaccines should be investigated.2 Soentjes et al. suggest 3 rabies vaccinations at 9–12 months, 6 and 12 years.1 The first dose would then often coincide with routine measles vaccine in the EPI schedule. Whereas several studies have documented beneficial NSE of MV,2 our research have highlighted that the timing of vaccines may have significant implications for the NSE. In brief, the last vaccine determines the direction of the NSE.2 Rabies vaccine given after MV may reduce the beneficial NSE of MV.
In conclusion, the overall health benefits of routine rabies vaccine should be investigated and weighed against the potential costs. Hard evidence must determine the net ratio of these weights and guide to an optimal vaccine schedule.
1 Soentjens P, Berens-Riha N, Van Herrewege Y, Van Damme P, Bottieau E, Ravinetto R. Vaccinating children in high-endemic rabies regions: what are we waiting for? BMJ Glob Health 2021; 6: e004074.
2 Benn CS, Fisker AB, Rieckmann A, Sørup S, Aaby P. Vaccinology: time to change the paradigm? Lancet InfectDis 2020; 20: e274–83.
3 Klein SL, Shann F, Moss WJ, Benn CS, Aaby P. RTS,S Malaria Vaccine and Increased Mortality in Girls. MBio 2016; 7: e00514–6.
4 Gessner BD, Knobel DL, Conan A, Finn A. Could the RTS,S/AS01 meningitis safety signal really be a protective effect of rabies vaccine? Vaccine 2017; 35: 716–21.
5 Arega S, Conan A, Sabeta CT, et al. Rabies Vaccination of 6-Week-Old Puppies Born to Immunized Mothers: A Randomized Controlled Trial in a High-Mortality Population of Owned, Free-Roaming Dogs. TropMedInfectDis 2020; 5.
6 Knobel DL, Arega SM, Conan A. Sex-differential non-specific effects of rabies vaccine in dogs: An extended analysis of a randomized controlled trial in a high-mortality population. Vaccine 2021; : S0264410X21000451.
7 Jensen KJ, Tolstrup LK, Knobel DL, et al. Non-specific effects of maternal and offspring rabies vaccination on mortality and antibiotic use in a Danish pig herd: a randomized trial. [In revision].