Abstract:
BACKGROUND : It has been proposed that childhood vaccines in high-mortality populations may have substantial
impacts on mortality rates that are not explained by the prevention of targeted diseases, nor conversely by typical
expected adverse reactions to the vaccines, and that these non-specific effects (NSEs) are generally more pronounced
in females. The existence of these effects, and any implications for the development of vaccines and the design of
vaccination programs to enhance safety, remain controversial. One area of controversy is the reported association of
non-live vaccines with increased female mortality. In a previous randomized controlled trial (RCT), we observed that
non-live alum-adjuvanted animal rabies vaccine (ARV) was associated with increased female but not male mortality
in young, free-roaming dogs. Conversely, non-live non-adjuvanted human rabies vaccine (NRV) has been associated
with beneficial non-specific effects in children. Alum adjuvant has been shown to suppress Th1 responses to
pathogens, leading us to hypothesize that alum-adjuvanted rabies vaccine in young dogs has a detrimental effect on
female survival by modulating the immune response to infectious and/or parasitic diseases. In this paper, we present
the protocol of a 3-arm RCT comparing the effect of alum-adjuvanted rabies vaccine, non-adjuvanted rabies vaccine
and placebo on all-cause mortality in an owned, free-roaming dog population, with causal mediation analysis of the
RCT and a nested case–control study to test this hypothesis.
METHODS : Randomised controlled trial with a nested case–control study.
DISCUSSION : We expect that, among the placebo group, males will have higher mortality caused by higher pathogen
loads and more severe disease, as determined by haematological parameters and inflammatory biomarkers. Among
females, we expect that there will be no difference in mortality between the NRV and placebo groups, but that the ARV group will have higher mortality, again mediated by higher pathogen loads and more severe disease. We anticipate
that these changes are preceded by shifts in key serum cytokine concentrations towards an anti-inflammatory
immune response in females. If confirmed, these results will provide a rational basis for mitigation of detrimental NSEs
of non-live vaccines in high-mortality populations.
