EHVA’s effort has been focused on the four scientific pillars of the MVP. Specifically:
1) Discovery Platform. The main objectives are to generate novel HIV vaccine candidates, and down select the best-in-class to clinical evaluation. To this end, EHVA has generated a large panel of Env protein based and vector-based vaccines. From these, the following have been down-selected as lead candidate: a) Anti-CD40 DC-targeting vaccine; b) DNA-launched RNA replicon vaccine (DREP); c) SOSIP trimer vaccines 4) VSV vaccine.
The DC targeting vaccine is driven by the Vaccine Research Institute (VRI)-Inserm. The vaccine targets viral antigen to dendritic cells to enhance antigen presentation and activation of antigen-specific cellular and humoral immune responses. The phase I trial has been successfully completed.
The DREP vaccine was down selected through a series of preclinical studies comparing the DREP vs the self replicating RREP and the mRNA vaccine based on immunogenicity and manufacturability. GMP manufacturing has been successfully completed and the vaccine is now in clinical trial.
With regard to the two SOSIP trimers, the down-selection of the two matched trimers (germline targeting and a more matured trimer) allows EHVA to evaluate in a prime boost regimen the hypothesis of the guiding principle towards B-cell maturation and the immune focusing to further enhance antibody responses. These vaccines have been GMP manufactured and are planned to clinical evaluation in the coming years.
The VSV vaccine utilized the unique VSV-GP vector which is non-neurotoxic. Data from non-human primates’ study which evaluated VSV prime followed by protein vaccine boost delivered by osmotic pump induces potent Env specific B and T-cell responses as well as broad neutralization activities. Though the candidate is only under preclinical evaluation due to resource limitation, the data clearly supports further development of VSV-GP based vaccine as a promising candidate.
2) Clinical Trials. The objectives are to accelerate the clinical development of novel vaccine candidates through innovative trial design and identify improved vaccine regimens in the prophylactic setting and immune correlates of protection in the therapeutic setting.
To this end, we have completed the first-in-human prophylactic trial with the DC-targeting vaccine, which have shown that anti-CD40 DC targeting vaccine induces early, potent and durable anti-Env & anti-V1/V2 IgG and IgG3 responses and polyfunctional CD4 T-cell responses. The trial is subsequently amended by including a late boost ongoing at the time of the report.
The 2nd trial EHVA has undertaken in healthy volunteers is with the DREP vaccine. The trial is fully enrolled and the follow-up is ongoing. Preliminary immunogenicity data is expected by Q3/Q4 2024.
With regard to the therapeutic trials, though we were not able to complete the planned trial, due to the interruption caused by the COVID-19 pandemic and the complexity to conduct trials with the analytic treatment interruption, we have demonstrated the feasibility to build up a large therapeutic clinical trial network across Europe, and the critical importance to work closely with community representatives such as European AIDS Treatment Group (EATG).
3) Immune Profiling. EHVA has successfully completed the development and validation of a number of key immunological assays and have played a critical role in the down-selection of vaccine candidates. These assays include but not limited to: 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.
4) Data Management/Integration/Down-Selection Platform. The development of integrative statistical analyses using appropriate methods for multi-table high-dimensional data sets and the pipelines for the analysis using R Software and statistical modelling methods to relate and down-select predictive biomarkers are well advanced, with methods for RNAseq, single cell and CyTOF analysis validated and published.
Much effort have been made on dissemination and communication activities within EHVA consortium, not just for the visibility of EHVA research, but also for HIV research in Europe at large. The target audience includes scientific communities, policy makers/funders, civil society, advocacy groups and wider public. Project data was disseminated through consortium members participating in over 25 conferences, workshops, and events and 71 scientific publications. Furthermore, we have developed 10 newsletters distributed to all members of the EHVA consortium and shared on the EHVA X account.
