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European HIV Vaccine Alliance (EHVA): a EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates

Periodic Reporting for period 4 - EHVA (European HIV Vaccine Alliance (EHVA): a EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates)

Reporting period: 2020-01-01 to 2021-06-30

EHVA program has as major goal to develop a Multidisciplinary Vaccine Platform (MVP) in the fields of prophylactic and therapeutic HIV vaccines.
1) Discovery Platform. The overarching Goal is the generation of novel vaccine candidates in the field of prophylactic and therapeutic vaccines inducing potent neutralizing and non-neutralizing antibody responses and T-cell responses (for therapeutic vaccines) through: a) improvement of Env protein-based vaccine immunogenicity, b) improvement of vaccine regimens, i.e. prime/boost combinations, and c) transient break of immunological tolerance.
2) Immune Profiling Platform. The primary Goal is to rank novel and existing (benchmark) vaccine candidates in pre-clinical and human clinical trials through the use of a large set of validated, qualified and standardized immunological assays and the access to the most advanced technologies in immune profiling.
3) Data Management/Integration/Down-Selection Platform. The primary Goal is to provide powerful statistical tools for the analysis and interpretation of complex data and algorithms for the efficient selection of vaccine candidates at the different stages
4) Clinical Trials Platform. The primary Goal is the acceleration of clinical development of novel vaccine candidates and the early prediction of failure of vaccine candidates. This will be achieved through innovative design in clinical trials such as Experimental Medicine Trials and Adaptive Design and allow identification of improved vaccine regimens in the prophylactic setting and of immune correlates of protection in the therapeutic setting.
In this RP, significant progress has been made towards EHVA’s 4 objectives:
1)The main effort is focused on the down-selection of novel Env protein based, RNA-based and VSV vector based vaccine candidates.
a.Novel Env protein based vaccine candidates: ConCv5-KIKO and ConCv5-GTv1 developed by P8 have been down selected for clinical development. GMP manufacturing is well advanced, final release expected in Q1 2022. In parallel an immunogenicity study in non-human primates (NHP) was initiated in Nov 2020 and preliminary immunogenicity data will be available in Q1 2022, which will provide the supportive data for the clinical trials. In addition, EHVA partners have also developed a large panel of 2nd generation novel Env protein immunogens paired with novel delivery methods and/or adjuvants.
b.RNA-based vaccine candidate: DREP is the candidate down-selected for clinical development. The GMP lot of DREP was released in April 2020. GLP toxicity study in rabbits was successfully completed . Preparation of the First-in-Human (FIH) trial is ongoing.
c.VSV vector:the VSV-GP vector developed by P18 has shown promising properties as a novel viral vector platform. During this RP, EHVA successfully completed an NHP study, combining VSV with the new trimers developed by P8, comparing IM delivery vs SC administration with an osmotic pump. VSV primed Env specific B and T cell responses, boosted by 1-2 logs following administration of Env trimers or VSV+Env trimers, with no significant differences observed. However, the study has shown that compared to the conventional IM delivery, slow delivery by osmotic pump: 1) improves HIV-specific T cell responses; 2) increases the neutralizing activity against the autologous virus.
d.DC Targeting: This platform is driven by the VRI-Inserm. Anti-CD40 mAb fused to HIV Env ZM96 has been selected and cGMP-manufactured. The phase I study in healthy volunteers evaluating the safety of a dose escalating administration of anti-CD40 Env gp140 alone or in combination with a DNA has started in May 2021, with 12 participants enrolled at the time of this report.
2) Immune Profiling Platform. EHVA immunology core has successfully completed the development and validation of a number of key immunological assays: 1) validation of multiparameter flow cytometry, multiplex technology and CyTOF for innate and adaptive immunity; 2) validation of the neutralizing antibody assay; 3) standardization of CD8 T cell virus inhibition assay; 4) Binding Antibody Multiplex Assay (BAMA); 5) Antibody Dependent Cellular Cytotoxicity (ADCC); and 6) linear peptide array assays.
3)Data Management/Integration/Down-Selection Platform. With the data starting to be integrated on our LabKey server, the work on the development of integrative statistical analyses using appropriate methods for multi-table high-dimensional data sets has been on going this period. For integrative statistical analyses, we plan to use random forest regression, as a non-parametric predictive method.
4)Clinical Trials Platform. EHVA clinical trial platform composes of therapeutic and prophylactic trials.
a.For the therapeutic trial, the start of the EHVA-T02 was paused due to the outbreak of the COVID-19 pandemic. In consultation with international experts working in the HIV therapeutic vaccine trials with analytic treatment interruption, and working closely with EATG, we have further amended the protocol taking into consideration of plans and safety measures for implementing EHVA T02 in the pandemic era. The amendment will be submitted in Sep 2021 and we aim to start the trial in Nov 2021.
b.For the prophylactic trial, the start of the EHVA-P01, the first-in-human clinical trial of the novel DREP vaccine, is delayed due to the COVID-19 pandemic. However, protocol development has been completed within this reporting period and submission has been made in UK and Switzerland. We aim to start the screening in Oct 2021.
EHVA program will lead to a number of innovation potentials:
• Large portfolio of vaccine candidates: EHVA aims to develop multiple vaccine approaches, including novel Env protein, RNA, replication competent vector, novel delivery system and adjuvants. Combination of these strategies increases the chance of a successful novel candidates.
• Robust screening platform for early selection of vaccine candidates/regimens: Efficient screening and early selection of the most promising candidate/regimen has been a challenge for the HIV vaccine field. The robust immunological and data integration platform of EHVA represents a strong tool to address this challenge not just for the HIV field but can be applied to other fields as well.
• Innovative clinical platform for the evaluation of vaccine candidates: EHVA promotes the Experimental Medicine and Adaptive Trial concept in the design of its trials. Combined with the comprehensive immunological profiling algorithm performed by centralized core labs with high dimensional data integration, these innovative designs will allow rapid evaluation and selection of the best-in-class vaccine candidates.
In summary, the powerful and highly innovative immunological, clinical and data integration platforms developed under EHVA will contribute to expediting the selection and development of promising HIV and non-HIV vaccine candidates. The success of EHVA will contribute to reducing the cost of R&D programs, giving a higher visibility and credibility of the European researchin the HIV vaccine field and be very adaptive to the evolution of the techniques and sciences. This will provide a basis for international standards that could be broader than HIV vaccines.
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