Establishment of VIA Internal Data Acceptance (VIA-IDA) protocol
- To optimize and establish the Viral Inhibition Assay as a key functional assay for both the VISTA T-Cell Immunogen design project and as the primary immunogenicity assay for the GREAT HIV-1 clinical trial.
- To develop and characterize the antigen specific viral inhibition assay so that CD8 cells specific for single antigens may be assessed for their ability to mediate killing of HIV infected CD4 cells.
- The volume of work required will necessitate multiple sites to be operational for assessing samples. Establishment of the VIA-IDA platform will enable data from multiple centers and multiple operators to be reported as equivalent.
- The viral inhibition assay (VIA) is a qualitative functional assay for evaluating a CD8 T-cell mediated inhibition of HIV-1 replication (Naarding et al. 2014) and forms a key gatekeeper assay for evaluating potential anti-HIV activity for both research and clinical trial activities.
- The projected activities for VIA include screening of Protocol C samples for T-cell Immunogen design within VISTA; evaluation of Superinfection cohort and Elite controller cohort samples, and evaluation of HIV-1 vaccine candidates in clinical trials sponsored by IAVI, EAVI and EHVA Horizon 2020 consortiums and for he EDCTP GREAT project.
- Projected throughputs for these programs could well exceed evaluation of >300 samples per year, which would be a significant increase in samples from what has historically been assessed. To enable this expansion of VIA activity requires significant expansion of BSL3 capacity. To facilitate expansion of VIA capacity, staff at KEMRI-WT (Kilifi, Kenya) and UVRI-MRC (Entebbe, Uganda) have been trained in the VIA and three operators at UVRI-MRC have successfully performed the assay independently at their own site.
- In lieu of a formal transfer of a validated assay to multiple sites, to enable data acceptance, an internal data acceptance project utilizing an in-plate assay control system will be implemented. This system will involve running a defined PBMC sample selected from a specific Protocol volunteer against specific viruses, with individual site data acceptance ranges confirmed for each site (these would be derived through performing analysis at each site for the same samples and viruses on multiple occasions, ideally by at least two operators). These controls would then be run on each assay occasion at each facility and providing data meets historical standard, the assay results would be accepted. Inter-operator comparisons across three operators is currently on-going.
The LucR.IMC’s utilized within this project will consist of the four CHAVI derived samples (listed in Resources section). The rationale for selecting these samples are that they can be produced in significant quantities, avoiding repeated lot to lot qualifications and are readily available.
Defining which bnAb specificities neutralise locally circulating HIV strains to inform which epitopes to target for vaccine design.
- To assess the neutralization profiles in the study cohort
- To describe the development of breadth among the elite neutralizers
- To describe specificities of broad neutralization
- Discovery of broadly neutralizing antibodies (bnAbs) that target multiple strains has given new hope to the use of antibodies as vaccine and therapeutic candidates.
- In natural infection, broadly neutralizing antibodies develop in about 10% of the population, after several years of infection. Challenges to their development include diversity of the HIV-1 envelope, evolving HIV envelope glycans, and conformational masking of neutralizing determining epitope. Detailed analyses of sera from broadly neutralising individuals provided insights in their antibody properties and the sites of HIV envelope vulnerability that they target. These were found to include the CD4 binding site (CD4bs), the V3 high mannose patch, the V2 apex, the gp41 MPER and the gp120/gp41 interface. This information has been leveraged to develop bnAbs into promising therapeutic and vaccine candidates.
- Passive infusions of CD4bs 3BNC1117 and 10-1074 monoclonal antibodies after ART discontinuation in chronically infected patients resulted in delayed viral rebound, with antibody combinations yielding better results [5, 6]. Preliminary analysis in on-going Antibody Mediated Prevention AMP) trial of the VRC01 antibody revealed that it is safe for human application, and is able to delay viral rebound. Potent bi-specific antibodies like 10E8-iMAb, with predicted 95-97% relative protection across subtypes are being rolled out. Such trials underscore the importance of broadly neutralizing antibodies in prevention of HIV-1 infection 
- Sub-Saharan countries like Uganda relying heavily on ART treatment to control the HIV epidemic. Challenges like drugs stock outs, ART resistance mutations, poor adherence to ART regiments, social demographic factors like poverty and lack of access to health facilities that limit ART access, and highlight the need to find more reliable alternative solutions to improve adherence.
- This study aims to understand which bnAb specificities dominate the local epidemic predominated by clades A, D and A/D recombinants, in order to inform what epitopes to target for vaccine design. This study will inform bnAb based therapeutics and vaccines relevant to our epidemic.
- A pilot study was first completed to evaluate if HIV neutralising antibodies can prevent superinfection in our population.
A Randomized, Observer-blind, Placebo-controlled, Phase 2 Study to Evaluate the Safety, Tolerability and Immunogenicity of Three Prime-boost Regimens of the Vaccines for Ebola Ad26.ZEBOV and MVA-BN-Filo in Healthy Adults, Including Elderly Subjects, HIV-infected Subjects, and Healthy Children in Three Age Strata in Africa
- The primary objective is to assess safety and tolerability of different vaccination schedules of Ad26.ZEBOV and MVA-BN-Filo administered intramuscularly (IM) as heterologous prime-boost regimens on Days 1 and 29, Days 1 and 57, or Days 1 and 85, in healthy adults, including elderly subjects, and on Days 1 and 29 and Days 1 and 57 in human immunodeficiency virus (HIV)-infected subjects and healthy children in 3 age strata.
- The secondary objective is to assess humoral (virus neutralization) and cellular (ELISpot and ICS) immune responses to the EBOV GP of different vaccination schedules of Ad26.ZEBOV and MVA-BN-Filo administered IM as heterologous prime-boost regimens on Days 1 and 29, Days 1 and 57, or Days 1 and 85, in healthy adults, including elderly subjects, and on Days 1 and 29 and Days 1 and 57 in HIV-infected subjects and healthy children in 3 age strata.
- The exploratory objectives are i) to further assess humoral and cellular immune responses to different EBOV GPs and the adenovirus and MVA backbone of the various vaccination schedules tested; and ii) o explore humoral and cellular immune responses to the SUDV GP, MARV GP and TAFV NP, if assays are available.
- This is a Phase 2 Study where Adenovirus serotype 26 (Ad26) vector expressing the glycoprotein (GP) of Ebola virus (EBOV) Mayinga variant (Ad26.ZEBOV); and the Modified Vaccinia Ankara (MVA) - Bavarian Nordic (BN) vector expressing the GPs of EBOV Sudan virus (SUDV) and Marburg virus (MARV) and the nucleoprotein (NP) of Tai Forest virus (TAFV) (MVA-BN-Filo) will be evaluated as a heterologous prime-boost regimen, in which one study vaccine is used to prime a filovirus-specific immune response and the other study vaccine is used to boost the immune response 28, 56 or 84 days later. The EBOV GP that recently circulated in West Africa has 97% homology to the EBOV GPs used in this vaccine regimen.
- The study population consists of 170 subjects comprising 4 cohorts to be enrolled sequentially as follows:
- Cohort 1: (50 healthy adults and 30 elderly subjects (aged 18 years up to 70 years inclusive). In Cohort 1, subjects will be enrolled in parallel and randomized in a 1:1:1 ratio to Groups 1, 2 and 3 at baseline until a target of 132 subjects have been included in Group 3.
- Cohort 2a (20 HIV-infected subjects (aged 18 to 50 years inclusive)
- Cohort 2b: (30 healthy adolescents aged 12 to 17 years inclusive,
- Cohort 3: (20 healthy children aged 6 to 11 years inclusive).
- Cohort 4: (20 healthy young children aged 1 to 5 years inclusive)
- In Cohorts 2a, 2b, 3 and 4, subjects will be enrolled in parallel and randomized in a 1:1 ratio to Groups 1 and 2 at baseline.
- The study comprises a screening phase of up to 8 weeks (starting from the moment the subject signs the informed consent form [ICF] and/or assent), a vaccination phase in which subjects are vaccinated at baseline (Day 1) followed by a boost vaccination on Day 29, 57 or 85, and a post-boost follow-up until the 42-day post-boost visit (Day 71, 99 or 127). After unblinding of a cohort (ie, when the last subject in that cohort completed the 42-day post-boost visit or discontinued earlier), the subjects who received placebo are contacted by the site to communicate that they have completed the study and no further follow-up is required. Subjects who received active vaccine enroll into a long-term follow-up phase, with visits on Days 180 and 365 post-prime vaccination to assess long-term safety and immunogenicity.
- Medical Research Council, UK
- National Institute of Health (NIH)
- IAVI ADVANCE VISTA programme
- Government of Uganda, Ministry of Finance
- Janssen Pharmaceuticals (Pty) Ltd
- HIV-1 superinfection can occur in the presence of broadly neutralizing antibodies. Serwanga J, Ssemwanga D, Muganga M, Nakiboneka R, Nakubulwa S, Kiwuwa-Muyingo S, Morris L, Redd AD, Quinn TC, Kaleebu P; HIV Superinfection Study Group.Vaccine. 2018 Jan 25;36(4):578-586. doi: 10.1016, PMID:29274699
- Others are still ongoing