A Review of the Effects of Ipsilateral or Contralateral Vaccine Boosting on the Adaptive Immune Response

Vaccines have been pivotal in reducing the incidence and severity of infectious diseases, improving population health, and lowering mortality rates globally. While substantial progress has been made in optimizing vaccine formulations, adjuvants, and schedules, comparatively less attention has been given to how the site of vaccination may influence immunologic outcomes. This review examines the impact of the administration of prime and booster vaccine doses in the same (ipsilateral) versus the opposite arms (contralateral) on vaccine immunogenicity. We review animal model and human studies evaluating the impact of ipsilateral versus contralateral COVID-19 and non-COVID-19 vaccine boosting on immunologic outcomes with a focus on the germinal center response, antibody production, and T cell activation. While some studies suggest that ipsilateral administration may enhance the quality of germinal center B cell responses and antibody magnitude, data across different studies have been inconsistent. Relatively few studies have compared ipsilateral versus contralateral boosting, and differences in study design and outcomes have limited the ability to draw conclusions as to whether one is superior to the other. This review highlights a noteworthy and underexplored area in vaccinology and the need for future research to clarify whether ipsilateral/contralateral boosting strategies matter. To answer this question, high-quality, randomized controlled trials evaluating different types of vaccines that consider immunologic mechanisms, capture key time points and appropriate specimens, and evaluate early and long-term immunogenicity endpoints are required.