Periodic Reporting for period 5 - EHVA (European HIV Vaccine Alliance (EHVA): a EU platform for the discovery and evaluation of novel prophylactic and therapeutic vaccine candidates)
Periodo di rendicontazione: 2021-07-01 al 2022-06-30
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.
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 preclinical studies on the novel Env protein based vaccine candidates.
a.Novel Env protein based vaccine candidates: As reported in the previous report, ConCv5-KIKO and ConCv5-GTv1 developed by P8 UREG have been down selected for clinical development. GMP manufacturing of the two trimers have been successfully completed and the lots were released in April 2022. Immunogenicity studies in non-human primates (NHP) and in Rabbits have shown interesting results. A third immunogenicity study in human immune system (HIS) mice to evaluate the B-cell guiding principle towards neutralization breadth is being planned.
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. Immunogenicity studies in small animals (mice and rabbits) are ongoing. 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.
b.DC Targeting: This platform is driven by the VRI-Inserm. Anti-CD40 mAb fused to HIV Env ZM96 has been selected and cGMP-manufactured. At the time of this report, the phase I First-in-Human trial is ongoing. 60 volunteers have been enrolled. No clinical safety concerns were noted. Immunological evaluation is ongoing.
• 2) Immune Profiling Platform. EHVA immunology core has successfully completed the development and validation of a number of key immunological assays, including 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.
• 3)Data Management/Integration/Down-Selection Platform. A new version of the EHVA data management/warehouse system is under implementation, including some new tools (ETL, connection to R-Server). 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.
• 4)Clinical Trials Platform. EHVA clinical trial platform composes of therapeutic and prophylactic trials.
a.For the therapeutic trial, EHVA-T02 is a Phase II randomised, placebo-controlled trial of vedolizumab with or without therapeutic HIV MVA vaccine in individuals who started antiretrovirals during primary or chronic infection. In the last reporting period, the protocol was amended taking into consideration plans and safety measures for implementing EHVA-T02 trial in the COVID-19 pandemic era. The final ethics and regulatory approvals of the amendment have been obtained at all centers participating in the trial in France, UK, Switzerland and Germany. The trial was opened in May 2022 with the first participant enrolled in June.
b.For the prophylactic trial, EHVA-P-01 is a first-in-human clinical trial of the novel DREP vaccine in healthy volunteers. We have obtained full ethics and regulatory approval in UK and Switzerland, and Part I of the trial that will evaluate the safety of DREP alone was opened in August 2022 in UK.
• 1)The main effort is focused on preclinical studies on the novel Env protein based vaccine candidates.
a.Novel Env protein based vaccine candidates: As reported in the previous report, ConCv5-KIKO and ConCv5-GTv1 developed by P8 UREG have been down selected for clinical development. GMP manufacturing of the two trimers have been successfully completed and the lots were released in April 2022. Immunogenicity studies in non-human primates (NHP) and in Rabbits have shown interesting results. A third immunogenicity study in human immune system (HIS) mice to evaluate the B-cell guiding principle towards neutralization breadth is being planned.
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. Immunogenicity studies in small animals (mice and rabbits) are ongoing. 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.
b.DC Targeting: This platform is driven by the VRI-Inserm. Anti-CD40 mAb fused to HIV Env ZM96 has been selected and cGMP-manufactured. At the time of this report, the phase I First-in-Human trial is ongoing. 60 volunteers have been enrolled. No clinical safety concerns were noted. Immunological evaluation is ongoing.
• 2) Immune Profiling Platform. EHVA immunology core has successfully completed the development and validation of a number of key immunological assays, including 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.
• 3)Data Management/Integration/Down-Selection Platform. A new version of the EHVA data management/warehouse system is under implementation, including some new tools (ETL, connection to R-Server). 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.
• 4)Clinical Trials Platform. EHVA clinical trial platform composes of therapeutic and prophylactic trials.
a.For the therapeutic trial, EHVA-T02 is a Phase II randomised, placebo-controlled trial of vedolizumab with or without therapeutic HIV MVA vaccine in individuals who started antiretrovirals during primary or chronic infection. In the last reporting period, the protocol was amended taking into consideration plans and safety measures for implementing EHVA-T02 trial in the COVID-19 pandemic era. The final ethics and regulatory approvals of the amendment have been obtained at all centers participating in the trial in France, UK, Switzerland and Germany. The trial was opened in May 2022 with the first participant enrolled in June.
b.For the prophylactic trial, EHVA-P-01 is a first-in-human clinical trial of the novel DREP vaccine in healthy volunteers. We have obtained full ethics and regulatory approval in UK and Switzerland, and Part I of the trial that will evaluate the safety of DREP alone was opened in August 2022 in UK.
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.
• 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.