Effect of intensive treatment for schistosomiasis on immune responses to vaccines among rural Ugandan island adolescents: randomised controlled trial protocol A for the ‘POPulation differences in VACcine responses’ (POPVAC) programme

Abstract

IntroductionSeveral licensed and investigational vaccines have lower efficacy, and induce impaired immune responses, in low-income versus high-income countries and in rural, versus urban, settings. Understanding these population differences is essential to optimising vaccine effectiveness in the tropics. We suggest that repeated exposure to and immunomodulation by chronic helminth infections partly explains population differences in vaccine response.Methods and analysisWe have designed an individually randomised, parallel group trial of intensive versus standard praziquantel (PZQ) intervention against schistosomiasis, to determine effects on vaccine response outcomes among school-going adolescents (9–17 years) from rural Schistosoma mansoni-endemic Ugandan islands. Vaccines to be studied comprise BCG on day ‘zero’; yellow fever, oral typhoid and human papilloma virus (HPV) vaccines at week 4; and HPV and tetanus/diphtheria booster vaccine at week 28. The intensive arm will receive PZQ doses three times, each 2 weeks apart, before BCG immunisation, followed by a dose at week 8 and quarterly thereafter. The standard arm will receive PZQ at week 8 and 52. We expect to enrol 480 participants, with 80% infected with S. mansoni at the outset.Primary outcomes are BCG-specific interferon-γ ELISpot responses 8 weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4 weeks after immunisation. Secondary analyses will determine the effects of intensive anthelminthic treatment on correlates of protective immunity, on waning of vaccine response, on priming versus boosting immunisations and on S. mansoni infection status and intensity. Exploratory immunology assays using archived samples will enable assessment of mechanistic links between helminths and vaccine responses.Ethics and disseminationEthics approval has been obtained from relevant ethics committes of Uganda and UK. 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 numberISRCTN60517191.

Schistosoma mansoniinfection alters the host pre-vaccination environment resulting in blunted Hepatitis B vaccination immune responses

“…Furthermore, a high CCL17 and low CXCL10-inclusive cytokine/chemokine signature pre-vaccination in instances of high worm burden, is also identified. The results from our study could be applied to instruct ongoing and future projects to benefit vaccination programs in Schistosoma - and other helminth-endemic communities, particularly in the design of studies that address specific hypotheses such as recently published study protocols from Nkurunungi and colleagues which describe the effect of a more intensive intervention with anti-helminth treatment on vaccine responses in adolescents in Uganda (78, 79).…”

Intestinal helminth infection impairs oral and parenteral vaccine efficacy

“…The recombinant attenuated oral Salmonella vaccine (RASV) system has also been used as an experimental vaccine platform to develop oral vaccine candidates for protection against food borne parasites (56, 57), human papilloma virus (58), streptococcal pneumonia (55), and shigellosis (59), among many other pathogens. Yet, disparities in the immunogenicity of oral Salmonella vaccines (60, 61) and other oral and parenteral vaccines in low- and middle-income countries compared to high-income countries have been repeatedly described (62–65).…”

“…Thus, the potential need to eliminate these parasites prior to vaccination should be considered when targeting populations with endemic helminth infection. In fact, large-scale clinical trials in a helminthic-endemic area (Uganda) have recently been proposed to investigate whether anti-helminthic therapies will enhance antibody and T-effector cytokine responses to both injectable and oral vaccines in school age children (61).…”

NIHR Global Health Research Group on Vaccines for vulnerable people in Africa (VAnguard): Concept and Launch event report

“…Data and samples from ongoing and completed trials will be used to explore mechanisms and identify biomarkers of adverse biological status with respect to vaccine responses. In Uganda, three POPVAC trials are investigating the effects of rural versus urban location, and Schistosoma mansoni and malaria exposure and treatment, on responses to live parenteral (BCG, Yellow Fever), live oral (Typhoid [Ty21a]), Human Papilloma Virus (HPV) and toxoid (tetanus/diphtheria) vaccines; and the effect of BCG revaccination on response to other vaccines [27][28][29][30] . Results are expected in 2023, and samples will be available for investigation.…”