Population differences in vaccine response (POPVAC)-2: the impact of environmental exposures and selected interventions on waning of vaccine-induced immune responses
Lead Research Organisation:
London School of Hygiene & Tropical Medicine
Department Name: UNLISTED
Abstract
"Vaccines are a key weapon against infectious diseases which continue to have major detrimental impacts on health and development in in low-income countries (LICs). However, the effectiveness of some vaccines is reduced in tropical LICs and in rural vs urban settings. For example, the TB vaccine, BCG, provides 80% protection in some temperate countries, but 0% in some tropical settings.
A potential explanation for this phenomena includes exposure to parasites so to further understanding we will compare the vaccine responses for Ugandan adolescents among three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort who have low parasite exposure; (2) island communities where over 80% have schistosomiasis (a parasitic worm infection); (3) rural communities with high malaria exposure, where over 50% of school-children unknowingly have malaria. We will also look at how parasitic infections interact with other viral or bacterial infections (“transkingdom” effects) and how these indirect effects impact the immune system.
Finally, we will use statistical approaches to explore how the urban-rural environment, parasites, ""transkingdom"" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in tropical LIC settings and inform public health policy to improve effectiveness of vaccine programmes."
A potential explanation for this phenomena includes exposure to parasites so to further understanding we will compare the vaccine responses for Ugandan adolescents among three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort who have low parasite exposure; (2) island communities where over 80% have schistosomiasis (a parasitic worm infection); (3) rural communities with high malaria exposure, where over 50% of school-children unknowingly have malaria. We will also look at how parasitic infections interact with other viral or bacterial infections (“transkingdom” effects) and how these indirect effects impact the immune system.
Finally, we will use statistical approaches to explore how the urban-rural environment, parasites, ""transkingdom"" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in tropical LIC settings and inform public health policy to improve effectiveness of vaccine programmes."
Technical Summary
We propose that parasite infections contribute substantially to population differences in vaccine response; and that their effects are mediate We will test this hypothesis through four linked objectives among Ugandan adolescents. An immunisation programme comprising relevant live and inert vaccines will be given over one school year, with primary endpoints one month postimmunisation. A secondary endpoint at one year will assess response waning. 1. We will compare vaccine response profiles in urban adolescents (low parasite burden) with two rural cohorts, chosen for high schistosomiasis and high malaria prevalence. 2. We will establish whether current parasite infections have causal effects using individually-randomised, placebocontrolled interventions targeting the dominant infection in each rural cohort. Sample sizes will be robust, powered to detect vaccine response differences of 0.14log10 between study arms (modest effects compared to preliminary data). 3. We will assess herpesvirus-specific antibodies (Luminex), viral loads (droplet digital PCR) and cellular responses (ELISpot); and microbial translocation (MT; PCR for bacterial 16s ribosomal DNA, ELISA for lipopolysaccharide and other biomarkers). Markers of viral activation and MT will be related to parasite exposures and vaccine outcomes. 4. We will investigate pre-immunisation immunological characteristics using simple biomarkers and cell phenotyping, and with in-depth studies (including by mass cytometry) in smaller, representative groups; and link findings to both parasite exposures and vaccine outcomes. Our data will be integrated using causal mediation analyses to determine how urban-rural environment, parasites, "transkingdom" effects and immune responses relate to determine vaccine responses partly by "transkingdom" pathways (activation of herpesviruses; intestinal translocation of microbial products), and ultimately by pre-immunisation immune characteristics of the host.
Organisations
- London School of Hygiene & Tropical Medicine (Lead Research Organisation)
- Uganda National Expanded Programme on Immunisation (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- Leiden University Medical Center (Collaboration)
- Wellcome Trust (Collaboration)
- Uganda Christian University (Collaboration)
- MRC/UVRI Uganda Research Unit on AIDS (Collaboration)
- Uganda Virus Research Institute (Collaboration)
- Ministry of Health, Uganda (Collaboration)
Publications
Description | NIHR Global Health Groupon on vaccines for vulnerable people in Africa (VAnguard) |
Amount | £2,984,447 (GBP) |
Funding ID | NIHR134531 |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 09/2022 |
End | 02/2026 |
Description | Arbovirology, UVRI |
Organisation | Uganda Virus Research Institute |
Department | Department of Arbovirology, Emerging and Re-emerging Infections |
Country | Uganda |
Sector | Public |
PI Contribution | We are conducting the POPVAC research programme, samples from which will be processed by the department of arbovirology at UVRI |
Collaborator Contribution | They will undertake yellow fever plaque reduction neutralisation tests. |
Impact | Not yet |
Start Year | 2020 |
Description | Edridah Tukahebwa, Narcis Kabatereine |
Organisation | Ministry of Health, Uganda |
Department | Vector Control Division |
Country | Uganda |
Sector | Public |
PI Contribution | These collaborators have expertise in the epidemiology, diagnosis and control of helminth infections. They also understand policy implications and applications. We have worked with them on implementation of all our helminth related work in Uganda. |
Collaborator Contribution | These collaborators have expertise in the epidemiology, diagnosis and control of helminth infections. They also understand policy implications and applications. |
Impact | Numerous papers and presentations Stakeholders' meetings Grants |
Description | Helen McShane, Adrian Hill, Alex Mentzer |
Organisation | University of Oxford |
Department | Jenner Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Collaboration on (1) genetic studies on the response to infant vaccines (on-going) (2) a trial investigating the impact of schistosomiasis on the response to candidate TB vaccine MVA85A (completed) (3) a trial of ChAdOx1 85A and MVA85A as a new regimen for boosting TB immunity in adolescents. We are conducting the trial in Uganda (about to start) |
Collaborator Contribution | For (1) the partners provide expertise in genetics For (2) and (3) the partners are providing the vaccine, as well as contributing expertise in TB vaccine trials |
Impact | Publications and conference presentations DPhil for Alex Mentzer (completed) Contributions to PhDs for Swaib Lule (completed), Anne Wajja (on-going) and Beatrice Nassanga (about to commence) |
Start Year | 2017 |
Description | MRC/UVRI Uganda Unit - London School of Hygiene & Tropical Medicine |
Organisation | MRC/UVRI Uganda Research Unit on AIDS |
Country | Uganda |
Sector | Public |
PI Contribution | I and my research team are based at the MRC/UVRI Unit. I lead a research programme there. In 2018 the Unit became a part of the London School of Hygiene and Tropical Medicine so this ceased to be a collaboration in the earlier sense of the word. |
Collaborator Contribution | The MRC/UVRI Unit hosts the research, providing facilities, administration and research support |
Impact | This collaboration has resulted in more than 80 research publications, several research grants, two Wellcome Trust funded and one EDCTP funded research capacity building grants, much training at undergraduate, Masters, PhD and post-doctoral level. |
Description | Maria Yazdanbakhsh; Meta Roestenberg |
Organisation | Leiden University Medical Center |
Country | Netherlands |
Sector | Academic/University |
PI Contribution | We are undertaking collaborations with LUMC department of parasitology on immuno-epidemiological effects of helminths, and on schistosomiasis vaccine development including controlled human infection models for schistosomiasis (CHI-S) In 2019 we developed a proposal for establishing the CHI-S in Uganda which the Wellcome Trust panel supported for funding. We are awaiting the award letter. |
Collaborator Contribution | The partners provide technical expertise, particularly in parasite immunology and |
Impact | PhD: co-supervision to completion of two fellows, Gyaviira Nkurunungi and Moses Egesa (both completed successfully in 2019). Publications and conference presentations. New grants for preparatory work on Sm-CHI |
Start Year | 2011 |
Description | MoH UNEPI programme |
Organisation | Uganda National Expanded Programme on Immunisation |
Country | Uganda |
Sector | Public |
PI Contribution | We are running the POPVAC trials which will provide EPI with information on the effects of parasitic infections on the response to widely used vaccines. |
Collaborator Contribution | The EPI programme is providing HPV vaccine for individuals in the POPVAC trials. As well, they are supporting us with training and advice. |
Impact | None as yet |
Start Year | 2018 |
Description | NIHR Global Health Group, VAnguard |
Organisation | Uganda Christian University |
Country | Uganda |
Sector | Academic/University |
PI Contribution | This is a new Global Health Group which I lead together with Professor Pontiano Kaleebu, taking forward our work on optimising vaccine benefits for vulnerable populations in Africa. |
Collaborator Contribution | Partners are leading various work packages |
Impact | No outputs yet. |
Start Year | 2022 |
Description | NIHR Global Health Group, VAnguard |
Organisation | Uganda Virus Research Institute |
Country | Uganda |
Sector | Public |
PI Contribution | This is a new Global Health Group which I lead together with Professor Pontiano Kaleebu, taking forward our work on optimising vaccine benefits for vulnerable populations in Africa. |
Collaborator Contribution | Partners are leading various work packages |
Impact | No outputs yet. |
Start Year | 2022 |
Description | NIHR Global Health Group, VAnguard |
Organisation | University of Oxford |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a new Global Health Group which I lead together with Professor Pontiano Kaleebu, taking forward our work on optimising vaccine benefits for vulnerable populations in Africa. |
Collaborator Contribution | Partners are leading various work packages |
Impact | No outputs yet. |
Start Year | 2022 |
Description | NIHR Global Health Group, VAnguard |
Organisation | Wellcome Trust |
Department | KEMRI-Wellcome Trust Research Programme |
Country | Kenya |
Sector | Academic/University |
PI Contribution | This is a new Global Health Group which I lead together with Professor Pontiano Kaleebu, taking forward our work on optimising vaccine benefits for vulnerable populations in Africa. |
Collaborator Contribution | Partners are leading various work packages |
Impact | No outputs yet. |
Start Year | 2022 |
Title | TB042 tuberculosis vaccine trial |
Description | Tuberculosis candidate vaccine regimen ChAdOx1 85A/MVA85A was compared to BCG for boosting TB-specific responses in Ugandan adolescents |
Type | Therapeutic Intervention - Vaccines |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2022 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Evidence in support of further development of tuberculosis vaccines of this type. |
Description | VAnguard Global Health Group Launch event |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | An event engaging collaborators, community members and other stakeholders to initiate and plan for the NIHR Global Health Group, VAnguard |
Year(s) Of Engagement Activity | 2022 |