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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 3 - EAVI2020 (European AIDS Vaccine Initiative 2020)

Teaser

Summary

The European AIDS Vaccine Initiative 2020 (EAVI2020) aims to accelerate the identification and development of an effective HIV vaccine that may have utility both to prevent infection and contribute to the establishment of long term remission in those infected with the virus. It is widely acknowledged that a protective vaccine would be the most effective means to reduce HIV-1 spread and ultimately eliminate the pandemic, while a therapeutic vaccine may help mitigate the clinical course of disease and lead to strategies of viral eradication. EAVI2020 is providing a platform for the discovery and selection of several new, diverse and novel preventive and/or therapeutic vaccine candidates for HIV/AIDS.

Work performed

The work of EAVI2020 is targeted across 8 interlinked objectives. The first is to design a minimum of 8 new envelope based vaccine candidates to move forward for manufacture and clinical testing. We have developed two novel vaccine candidates based on a consensus sequences of all circulating strains of HIV: ConM and ConS. These have been designed and optimised at the molecular level and have been selected based on a battery of tests. We have developed an additional process to provide further stabilisation of the proteins by chemical cross-linkage. This has generated four products manufactured to GMP that will undergo clinical testing in the coming year. Additional work has been performed to select a second generation of vaccine candidates. Three candidates (mosaics), generated by computer modelling, cover the diversity of global HIV strains. These are under assessment in animal models and are advancing through our manufacturing pipeline. A third wave of candidates have been selected from envelope sequences of HIV infected individuals that naturally make protective (neutralising) antibodies early infection (acute neutralisers).
In parallel, we have also been pursuing candidate vaccines that evoke specific white blood cells (T cells) able to kill cells infected with HIV. This work has focused on two main T cell vaccine candidates: the conserved beneficial sequences (HTI vaccine); and the conserved mosaic sequences (tHIVconsvX vaccine). These have been inserted into a range of vaccine platforms (DNA, RNA, MVA, ChAd & BCG) and are being assessed in comparative preclinical models.
The main third objective has been the production and formulation of vaccine components (adjuvants, vectors, proteins) to be advanced for human clinical trials. To meet these objectives our first vaccine candidates, ConM and ConS designs, have progressed to full GMP manufacture, and have completed manufacture of our selected MLPA-liposomal adjuvant. In addition, we have manufacture 2 MVA constructs expressing tHIVconsvX and HTI immunogens. ChAd products are in an advanced stage of manufacture. These will be assessed for safety and immunogenicity in the coming year.
A fourth objective has been the development of Advanced Animal Models to define predictive correlates of protection. We have tested a range of vaccines and adjuvants in animal models with promising results. Particular highlights have been the generation of a pipeline of novel B and T cell immunogens and their incorporation into a wide range of vaccine delivery technologies: adjuvanted recombinant proteins, nucleic acid vectors (DNA RNA), viral (MVA, ChAd, IDLV) and bacterial (BCG) vectors that are under evaluation in preclinical models and progressing towards early clinical testing. This has aided selection for manufacture.
A fifth objective is to assess a range of novel immunogens in human clinical trials to determine safety of the approach and the ability to induce protective immune responses. Work has been initiated to develop trial designs and ensure the development of an appropriate regulatory pathway to progress immunogens towards clinical study. This first clinical trial is anticipated to commence early in 2019.
A sixth objective has been development of advanced immunological analysis to facilitate prioritisation of HIV-1 vaccines. Progress has been driven by our algorithm for vaccine prioritisation using core and specialised technology. A major objective of work in year 3 has been the characterisation of ConM and ConS envelope immunogens, mosaic envelope immunogens selected for the second clinical wave and envelope sequences selected from acute neutralisers selected for the third clinical wave. On-going work is optimising advanced antibody functional assays for use in human and animal models, this has generated a wide range of novel reagents to facilitate immunological analysis.
The seventh objective is to develop new molecular tools to study the evolution of antibody sequences and ge

Final results

The work of EAVI2020 has already moved the field beyond the state of the art with respect to the molecular design of stabilised native-like viral envelope glycoproteins. Our approach can now be applied to most envelope sequences. The development of a novel manufacturing process for chemical stabilisation of the proteins provides an additional advance â€“ this process can be applied to multiple vaccines not just HIV. The innovations achieved in process manufacture places Europe in a highly competitive position. The development of B cell mosaic immunogens as stabilised recombinant proteins also represents a world-first. The identification of potential HIV envelope sequences from HIV infected individuals that naturally make protective (neutralising) antibodies early infection is highly novel and the IgDiscover platform is a key new tool for international scientists to better interpret the evolution of antibody responses in animal models. The development and refinement of the Viral Inhibition Assay is allowing scientists for the first time to determine the functional activity of vaccine induced T cells to kill cells infected with HIV. In year 3 of the project a number of publications have been generated (9). In summary, the work of the EAVI2020 project is on track to increase the number of candidate vaccines which can be tested in human clinical trials.