Periodic Reporting for period 3 - EHVA (European HIV Vaccine Alliance (EHVA): a EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates)
Reporting period: 2018-07-01 to 2019-12-31
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); the specific Objectives of the Discovery Platform to achieve this goal are: 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; the ranking will be performed through the use of a large set of validated, qualified and standardized immunological assays and the access to the most advanced technologies in the profiling of the immune responses.
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, i.e. pre-clinical and clinical, of vaccine development.
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.
1) The main effort is focused on the down-selection and development of novel vaccine candidates.
a. Novel Env protein based vaccine candidates: EHVA has successfully down-selected two lead candidates ConCv5-GTv1 (germline targeting) and ConCv5-KIKO for clinical development, allowing EHVA to evaluate in a prime boost regimen the following hypothesis: a) Guiding principle: guide development of CD4BS-specific BCRs towards neutralization breadth mediated by CD4BS specific Abs; b) Immune focusing: to promote maturation of B-cells through immunization with different maturation stage of Env proteins and to focus antibody responses to vulnerable neutralization sites.
In addition to these lead candidates, 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:At the time of this report, GMP manufacturing of the DREP vaccine is well advanced and the final release is target for Q2 2020. GLP toxicity study in rabbits is also ready to start at the beginning of 2020.
c.VSV vector: The VSV-GP vector developed within EHVA has several unique features compared to wildtype VSV vector: a) non-neurotoxic; b) can boost immune responses against foreign antigen; c) induces reduced vector neutralizing antibody responses; d) can incorporate HIV Env into membrane. An NHP study is ongoing under EHVA, which will provide key immunological data for the future development of this vector platform.
d.DC Targeting: This platform is driven by the VRI-Inserm. GMP clinical lots of the selected vaccine have been released in April 2019. The toxicology study showed the good safety profile of the vaccine. A phase I study in healthy volunteers is in preparation.
2) Immune Profiling Platform. As reported previously, EHVA immunology core has successfully completed the development and validation of a number of key immunological assays. In this reporting period, significant effort has been made on the development and validation on the binding and functional antibody assays, such as: 1) Binding Antibody Multiplex Assay (BAMA); 2) Antibody Dependent Cellular Cytotoxicity (ADCC); 3) Fc/FcR binding and Fc receptor polymorphism; and 4) linear peptide array assays.
3) Data Management/Integration/Down-Selection Platform. Main effort within this reporting period is focused on: 1) Further development of the Data Analytical Platform based on SHINY framework; 2) New algorithm for the automatic gating of cells using flow cytometry data; 3) New pipeline FAUST, for large scale CyTOF data analysis
4)Clinical Trials Platform. EHVA clinical trial platform composes of therapeutic and prophylactic trials.
a.For the therapeutic trial, EHVA-T01 was terminated due to the bankruptcy of FIT Biotech Oy, the company that was to provide one the vaccine components to be evaluated under EHVA-T01. EHVA was able to quickly redesign the trial to EHVA-T02 to evaluate vedolizumab with or without therapeutic HIV MVA vaccine in individuals who started antiretrovirals during primary or chronic infection. Approvals have already been obtained in UK and Switzerland for EHVA-T02 protocol v2.0 and the target start date of the trial is Q1 2020.
b.For the prophylactic trial, EHVA clinical team has started protocol development for the first-in-human clinical trial of the novel DREP vaccine and is geared to launch the trial before the end of 2020
• 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. Innovation management combined with the robust screening platform (see below) will at the same time ensure early termination of less promising candidates and prioritizing to move the most promising candidate forward.
• 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 research in 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.