Differences in vaccine responses across populations present a key challenge in global health, affecting the development of effective vaccines and their equitable impact. Responses have often been seen to be poorer in low-income countries, especially rural settings. The Population Differences in Vaccine response (POPVAC) clinical trials, a series of landmark studies recently published in The Lancet Global Health, investigated these differences with the aim of contributing to better understanding of this phenomenon. Funded by the UKRI/Medical Research Council,these trials ran from 2018 to 2022 and focused on how environmental factors and chronic infections shape immune responses among adolescent schoolchildren in Uganda.

Urban–Rural differences in vaccine responses in Uganda
The first major finding was that responses to several vaccines differed markedly between urban and rural settings within Uganda.  POPVAC Trial A was conducted in the Koome Islands of Mukono District, a region heavily impacted by schistosomiasis. POPVAC Trial B was conducted in rural Jinja district where malaria is highly endemic, and POPVAC C was conducted in urban Entebbe Municipality.  However, no causal link was established between schistosome or malaria exposure and the variations in vaccine response, suggesting that other factors play a significant role in these differences.

Vaccine response in Schistosomiasis-endemic regions
POPVAC Trial A examined whether treating schistosomiasis with praziquantel could improve immune response to vaccines. Findings showed that praziquantel treatment improved the BCG vaccine response, although the effects on other vaccines were less pronounced. These insights suggest that it would be worth investigating whether sustained control of helminth infections could help to enhance vaccine efficacy.

Malaria’s influence on vaccine responses
POPVAC Trial B tested whether intermittent preventive treatment (IPT) for malaria using dihydroartemisinin–piperaquine could enhance immune responses to vaccines. IPT is an effective way to prevent malaria in high-risk groups. Although IPT successfully reduced malaria prevalence, it did not significantly improve vaccine responses. One possible explanation is that effects of malaria on a person’s immune system may be long-lasting, pointing toward a need for further research on the cumulative effects of long-term malaria control on vaccine efficacy. As well, other exposures found in rural malaria-endemic settings may also impact vaccine-induced immune responses.

BCG revaccination in urban environments
POPVAC Trial C, conducted in Entebbe, assessed the impact of BCG revaccination on immune responses to unrelated vaccines among urban adolescents, hoping that it might lead to improved responses. However, the study found that BCG revaccination did not boost immune responses to other vaccines.

"Together the studies highlight the complex factors at play in low-income settings and the importance of tailoringvaccine strategies to specific environmental contexts.” says Professor Alison Elliott, POPVAC Principal Investigator

Building on POPVAC 
The findings from the POPVAC trials have sparked a series of new studies aimed at deepening our understanding of vaccine responses in various health and environmental contexts. Each of these follow-on studies continues to explore how complex biological and social factors impact immunization outcomes, advancing efforts to develop tailored vaccine approaches that can more effectively serve diverse communities.

In particular, the NIHR Global Health Research on Vaccines for Vulnerable People in Africa (VAnguard study) – which gave follow-on support to POPVAC – addresses both biological and social factors that impact vaccine efficacy inAfrican communities. With a focus on strengthening vaccine impact across diverse populations, VAnguard aims to deliver comprehensive, actionable strategies that empower local communities, advance public health and support equitable vaccine outcomes.

These studies continue to address unique challenges in vaccine research and enhance its capacity to boost public health for vulnerable populations in Africa and globally.