Environmental drivers of low vaccine responsiveness in a lab-to-wild rodent model

Vaccination is the most effective way to prevent infectious diseases and safeguard public health. Yet, most new vaccines fail in late clinical trials, and even estab-lished ones often underperform in populations apart from those in which they were initially tested. This can lead to reduced vaccine responsiveness, breakthrough infections, and prevent or delay herd immunity. While the causes of vaccine hypore-sponsiveness remain difficult to identify, quantify, and therefore address, numerous reports indicate a predominant role of environmental factors. This has notably been demonstrated by a reduction in the immunogenicity and efficacy of various vaccines when transitioning from urban to rural human populations. Here, we tested whether and, if so, how the environment can cause vaccine hyporesponsive-ness. We hypothesised that if the leading causes of vaccine hyporesponsiveness were environmental, then the reduced efficacy would be exacerbated when indi-viduals are under nutritional stress; specifically predicting that high quality diet supplementation would increase vaccine responsiveness. Finally, we predicted that parasitic helminth infection, which are more common in rural populations, would degrade vaccine responsiveness, e.g. due to their ability to suppress host immunity, and that anthelmintic treatment could rescue vaccine responsiveness in infected individuals. To test these hypotheses, we coupled lab and field experiments with structural causal modelling, and measured antibody responses of paired conspecific cohorts of laboratory-reared and wild wood mice ( Apodemus sylvaticus ) to a single or two doses of diphtheria toxoid vaccine formulated with alum; with and without diet supplementation. We found that vaccine-specific IgG1 antibodies were ∼47% lower in the wild wood mice compared to the laboratory reared population. We also demonstrate that, across both habitats (wild and lab), substantial variation in vaccine responsiveness was caused by diet. However, contrary to our predictions, this high quality dietary supplementation resulted in lower vaccine responsiveness. Further, once the effects of habitat, diet, and sex were adjusted for, increasing hel-minth infection burdens negatively affected vaccine-specific antibody production. Using counterfactual modelling, we show that targeting anthelmintic treatment at heavily infected individuals would have improved their vaccine responsiveness by 2 to 4-fold. Our results indicate that the wild environment and access to a high-quality diet play a dramatic role in shaping the immune system’s response to immunisation. Further, we show that laboratory settings, even when using a genetic diverse, non-traditional model, may systematically overestimate vaccine performance by failing to capture natural environmental variability. Our study provides a robust, causally explicit modelling approach to disentangle and quantify the complex factors that drive vaccine responsiveness in focal populations. This framework offers a path-way for predicting vaccine performance across diverse populations and identifying targeted interventions to enhance immunisation outcomes in real-world settings.