Pathogen Genomics Phenotype and Immunity / Research aimed at designing an effective HIV vaccine

Lead Research Organisation: MRC/UVRI Uganda Research Unit on AIDS

Abstract

One of the challenges of developing an HIV vaccine is the poor understanding of the protective immune responses that could be used to design a vaccine. We use data and blood specimens from different cohorts of the MRC/UVRI Uganda Unit to look for possible protective immune responses, for example by trying to understand why some individuals who are exposed to the virus remain uninfected or why some individuals who are infected progress to AIDS faster than others. We have also initiated studies aimed at identifying the best vectors to use in HIV vaccine design especially after one HIV vaccine trial found that use of so-called Ad5 vectors might be risky. (A vaccine vector is another virus that is in itself harmless and can be used to introduce the specific HIV vaccine antigen into the human body in order to trigger an immune response). Finally we participate in HIV vaccine trials performing safety and immunogenicity assays. The laboratory assays used include elispot assays, flowcytometry and neutralization assays among others.

Technical Summary

Overall aim: To contribute to better understanding of HIV protective immunity and vaccine design. Specific objectives are a) to study immunological correlates of protection in exposed sero negative individuals (ESN), ii) to characterize immune responses among individuals with different viral set points in early/acute HIV infection, iii) to investigate correlates of protection from HIV disease progression, iv) to study the correlation between HIV diversity and cross clade immune responses in individuals with chronic HIV infection, v) to investigate whether being treated at primary HIV infection (PHI) for a limited duration may delay damage to the immune system and prolong time to initiation of long-term anti-HIV therapy, vi) to study immune responses to vaccine candidates, vii) to study the prevalence of pre-existing adeno virus-specific T cells and their effect on Chimp Ad vector induced immune responses. One of the major challenges of developing an HIV vaccine is the poor understanding of protective immune responses. This broad research programme contributes to solving this problem. We are using different cohorts, especially serodiscordant couples, where in the ESN we follow HIV negative individuals at regular intervals while providing HIV prevention counselling. Immune responses to HIV are investigated in both ESN and in newly infected individuals. For the adeno virus project we identified individuals in Entebbe who have been screened for pre-existing Ad-specific T cells and humoral responses. We are defining the phenotype, function and potential cross-reactivity of T cell responses generated against adenovirus serotypes AdHu5, AdC6, and AdC7 in the Ugandan population. Another study, conducted in our Rural Clinical Cohort, looks at broadly neutralizing antibodies and their association with disease progression. To look at the potential protective effects of early short-term treatment of new HIV infection with anti-retroviral drugs, we contribute to the international SPARTAC trial. Furthermore, we participate in studies to evaluate immune responses to HIV vaccines, including a phase I study to evaluate the safety and immunogenicity of ALVAC-HIV vCP 1521 in infants born to HIV-1 infected women, in whom we investigate neutralizing and binding antibodies Immunological methods used include ELISpot and flowcytometery. We have introduced the cultured IFN-gamma ELISPOT assay in which PBMC are stimulated with HIV peptides in the presence of anti-apoptotic factor (IL-7) and T cell growth factor IL-2. After 10-11 days the cells are rested for 29-34 hours in the absence of peptide stimuli or cytokines and then tested for secretion of IFN-g upon re-exposure to HIV peptides as in the ex-vivo assay. For flowcytometry, the Unit has acquired an LSR II with 4 lasers which can measure up to 18 fluorescence parameters. For the neutralizing antibodies, we use the pseudovirion neutralization assay. This programme of work is funded from different complementary sources including the MRC/UVRI Uganda Unit core budget, EDCTP, the Wellcome Trust and others.

Publications

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Fast PE (2010) HIV vaccines: current status worldwide and in Africa. in AIDS (London, England)

 
Description EDCTP
Amount € 3,000,000 (EUR)
Organisation European Union 
Sector Public
Country European Union (EU)
Start 04/2017 
End 03/2020
 
Description EDCTP
Amount € 15,000,000 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 04/2018 
End 05/2023
 
Description EDCTP
Amount € 10,000,000 (EUR)
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country European Union (EU)
Start 08/2016 
 
Description IAVI funded through USAID
Amount $100,000,000 (USD)
Organisation International AIDS Vaccine Initiative (IAVI) 
Sector Charity/Non Profit
Country Global
Start 07/2016 
End 06/2021
 
Title Virus molecular clones 
Description These are virus molecular clones that have been prepared from individuals who have recently seroconveted in order to further characterize transmitted viruses 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2010 
Provided To Others? Yes  
Impact This material will lead to understanding transmitted viruses and in the development of an HIV vaccine 
 
Description European HIV Vaccine Alliance (EHVA) an EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates 
Organisation National Institute of Health and Medical Research (INSERM)
Department DR2 INSERM
Country France 
Sector Public 
PI Contribution We are providing the link with EDCTP and clinical trial sites where new products will be tested
Collaborator Contribution We provide the clinical sites and clinical trial expertise
Impact We have worked together to apply for funding to EDCTP. We also use the funds to attend important meetings
Start Year 2015
 
Description Globally Relevant AIDS Vaccine Europe-Africa Trials Partnership (GREAT) 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution We provide epidemiological, clinical and laboratory expertise
Collaborator Contribution They provide funding, capacity building and networking with other vaccine research and development partners. They also provide the vaccines to test
Impact Protocol development
Start Year 2016
 
Description HIV Vaccine research collaboration 
Organisation International AIDS Vaccine Initiative (IAVI)
Department Department of Medical Affairs
Country United States 
Sector Charity/Non Profit 
PI Contribution Generation of ideas, supervision, training, leading a trial
Collaborator Contribution Training, financial, GCLP, further collaborations
Impact Increased capacity in vaccine research and trials, Publications, funding, training and networking
Start Year 2006
 
Description IAVI Clinical Trial and Laboratory Program for 2016-2017 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution We provide cohorts, epidemiological, clinical and laboratory expertise to this partnership
Collaborator Contribution They provide funds, capacity building and networking with other vaccine Research and Development partners
Impact Publications, training and laboratory infrastructure
Start Year 2017
 
Description Superinfection studies 
Organisation Johns Hopkins University
Department School of Medicine Johns Hopkins
Country United States 
Sector Academic/University 
PI Contribution Provision of samples Clinical and epidemiological data
Collaborator Contribution Training in neutralization and screening for neutralization
Impact Training of staff and generation of results
Start Year 2012
 
Description Superinfection studies 
Organisation National Institute of Virology Johannesburg
Country South Africa 
Sector Academic/University 
PI Contribution Provision of samples Clinical and epidemiological data
Collaborator Contribution Training in neutralization and screening for neutralization
Impact Training of staff and generation of results
Start Year 2012
 
Description Vaccine research in Africa 
Organisation Eurovacc Foundation
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution Generation of ideas, protocol development, conduct of experiments and training
Collaborator Contribution Training, collaborations and networking, reagentsTraining, funding, reagents, equipmentsTraining, funding, reagents, equipments
Impact Publications, training, equipments, further collaborations
Start Year 2006
 
Description Vaccine research in Africa 
Organisation International AIDS Vaccine Initiative (IAVI)
Country Global 
Sector Charity/Non Profit 
PI Contribution Generation of ideas, protocol development, conduct of experiments and training
Collaborator Contribution Training, collaborations and networking, reagentsTraining, funding, reagents, equipmentsTraining, funding, reagents, equipments
Impact Publications, training, equipments, further collaborations
Start Year 2006
 
Description Vaccine research in Africa 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution Generation of ideas, protocol development, conduct of experiments and training
Collaborator Contribution Training, collaborations and networking, reagentsTraining, funding, reagents, equipmentsTraining, funding, reagents, equipments
Impact Publications, training, equipments, further collaborations
Start Year 2006
 
Description Vaccine research in Africa 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Generation of ideas, protocol development, conduct of experiments and training
Collaborator Contribution Training, collaborations and networking, reagentsTraining, funding, reagents, equipmentsTraining, funding, reagents, equipments
Impact Publications, training, equipments, further collaborations
Start Year 2006
 
Description Vaccine research in Africa 
Organisation World Health Organization (WHO)
Department Vaccine unit
Country Switzerland 
Sector Charity/Non Profit 
PI Contribution Generation of ideas, protocol development, conduct of experiments and training
Collaborator Contribution Training, collaborations and networking, reagentsTraining, funding, reagents, equipmentsTraining, funding, reagents, equipments
Impact Publications, training, equipments, further collaborations
Start Year 2006
 
Description Conference presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact This was an international conference attended by many international delegates

Questions from audience
Year(s) Of Engagement Activity 2013
 
Description Vaccine trial results 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Primary Audience Health professionals
Results and Impact Health professionsm policy makers and media have all attended presentations of our work and trial results

Scientists, policy makers and media have visited our laboratories. Government has also promised financial support to vaccine research
Year(s) Of Engagement Activity 2008,2009,2010