Population differences in vaccine responses (POPVAC): scientific rationale and cross-cutting analyses for three linked, randomised controlled trials assessing the role, reversibility and mediators of immunomodulation by chronic infections in the tropics

Abstract

Introduction: Vaccine-specific immune responses vary between populations and are often impaired in low income, rural settings. Drivers of these differences are not fully elucidated, hampering identification of strategies for optimising vaccine effectiveness. We hypothesise that urban-rural (and regional and international) differences in vaccine responses are mediated to an important extent by differential exposure to chronic infections, particularly parasitic infections.

Methods and analysis: Three related trials sharing core elements of study design and procedures (allowing comparison of outcomes across the trials) will test the effects of (1) individually randomised intervention against schistosomiasis (trial A) and malaria (trial B), and (2) Bacillus Calmette-Guérin (BCG) revaccination (trial C), on a common set of vaccine responses. We will enrol adolescents from Ugandan schools in rural high-schistosomiasis (trial A) and rural high-malaria (trial B) settings and from an established urban birth cohort (trial C). All participants will receive BCG on day '0'; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. Primary outcomes are BCG-specific IFN-γ responses (8 weeks after BCG) and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine effects of interventions on correlates of protective immunity, vaccine response waning, priming versus boosting immunisations, and parasite infection status and intensity. Overarching analyses will compare outcomes between the three trial settings. Sample archives will offer opportunities for exploratory evaluation of the role of immunological and 'trans-kingdom' mediators in parasite modulation of vaccine-specific responses.

Ethics and dissemination: Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders and study participants. Further dissemination will be done through conference proceedings and publications.

Trial registration numbers: ISRCTN60517191, ISRCTN62041885, ISRCTN10482904.

Keywords: epidemiology; immunology; infection control; paediatric infectious disease & immunisation; parasitology; public health.

Figure 1

Hypothesised pathways to population differences in vaccine responses.

Figure 2

Study sites.

Figure 3

Overall programme design and sample sizes. BCG, bacillus calmette-guérin; DP, dihydroartemisinin.

Figure 4

Outline of immunisations and interventions.¹Primary endpoints will be at 8 weeks post-BCG and 4 weeks postyellow fever (YF-17D), oral typhoid (Ty21a), human papilloma virus and tetanus/diptheria vaccination.²Primary endpoint for responses to td given at 28 weeks. BCG, Bacillus Calmette-Guérin.

Figure 5

Synthesised analysis of study objectives. Red arrows represent our principal hypotheses. Arrows A–C are considered in objectives I and iv; Arrows D–F in objective v; Arrows G–J, in objective vi; as well as the fully synthesised analysis.