CONGRESS 2023 - Targeting HIV where it hurts - progress on vaccines
Effective vaccine must deal with extreme HIV-1 variability and do so without guidance from natural immunity. For HIV-1, vaccines may need to induce both bNAbs and protective CD8+ killer T cells, the latter of which clearly impose a selective pressure on the virus and their protective potential should be harnessed by vaccines. However, not all antibodies and CD8+ T cells are protective; they must target vulnerable parts on HIV-1 proteins. The central paradigm of the HIVconsvX T-cell vaccine strategy is focusing T cells on the functionally conserved regions of the HIV-1 Gag and Pol proteins, which are very similar among global isolates and harbour fewer escape mutations. At the epitope level, the remaining variability within the conserved regions is addressed computationally by using a bi-valent mosaic. Results of the first trials testing the HIVconsvX vaccine candidates confirmed that conserved sub-dominant and, therefore, underused T-cell epitopes taken out of the context of the whole virus or full-length viral proteins can induce robust and broad T-cell responses when delivered by an effective heterologous regimen such as ChAdOx1-MVA. Progress towards an effective HIV-1 vaccine has been slow and riddled with many setbacks. However, systematic iterative development of vaccine components for both neutralizing antibodies and effective T cells informed by human data is beginning to pay off by bringing the first encouragements endorsing the field’s overall direction of travel.
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Effective vaccines must deal with extreme HIV-1 variability and do so without guidance from natural immunity. For HIV-1, vaccines may need to induce both bNAbs and protective CD8+ killer T cells, the latter of which clearly impose a selective pressure on the virus and their protective potential should be harnessed by vaccines. However, not all antibodies and CD8+ T cells are protective; they must target vulnerable parts on HIV-1 proteins.
The devil about the recently failed vaccine trials is, of course, in the vaccines themselves [which many reports fail to describe in sufficient detail]. In brief, we, as a field, can do better than Uhambo and Mosaico for induction of bNAbs through using stabilized Env trimers and not gp120 and gp140, respectively. For induction of protective CD8+ T cells, we use heterologous prime-boost regimens and target conserved (shared and harder to escape) sub-protein regions. Mosaic design is just the cherry on the top of the cake best dealing with residual variability of conserved regions, but not addressing variability across the entire proteome.
mRNA is not a universal solution; it still matters which immunogens mRNA delivers, these immunogens have to deal with HIV-1 variability and as a modality, mRNA may need at least initially heterologous boost for induction of protective CD8+ T cell responses.