Abstract
To stop the HIV-1 pandemic, vaccines must induce responses capable of controlling vast HIV-1 variants circulating in the population as well as those evolved in each individual following transmission. Numerous strategies have been proposed, of which the most promising include focusing responses on the vulnerable sites of HIV-1 displaying the least entropy among global isolates and using algorithms that maximize vaccine match to circulating HIV-1 variants by vaccine cocktails of optimized complementing sequences. In this study, we investigated CD8 T cell responses induced by a bi-valent mosaic of highly conserved HIVconsvX regions delivered by a combination of simian adenovirus ChAdOx1 and poxvirus MVA. We compared partially and fully mono- and bi-valent prime-boost regimens and their ability to elicit T cells recognizing natural epitope variants using an interferon-γ enzyme-linked immunospot (ELISPOT) assay. We used 11 well-defined CD8 T cell epitopes in two mouse haplotypes and, for each epitope, assessed recognition of the two vaccine forms together with the other most frequent epitope variants in the HIV-1 database. We conclude that for the magnitude and depth of epitope recognition, CD8 T cell responses benefitted in most comparisons from the combined bi-valent mosaic and envisage the main advantage of the bi-valent vaccine during its deployment to diverse populations.
Highlights
HIV-1 has a remarkable capacity to adapt to and escape immune responses
Vaccine immunogens HIVconsv1&3&5 and HIVconsv2&4&6/62 were derived from mosaic 1 and mosaic 2, respectively, and the six regions were arranged into six unique orders to minimize induction of T cell responses to unnatural epitopes spanning junctions of adjacent regions that might have been inadvertently generated (Figure 1B)
The seven epitopes with the strongest response were narrowed to the optimal length, and their recognition by CD8 T cells was verified using intracellular cytokine staining (ICS) (Table 1)
Summary
Acute infection generates virus variants in numbers more than sufficient to break through the sieve of naturally mounted antibody and T cell responses, leading almost invariably to AIDS when left untreated.[1,2,3,4,5] Vaccines are the best solution to HIV-1 control, but to prevent new infections as well as maintain antiretroviral treatment-free virological remission in people living with HIV-1, vaccines must control all of the fittest HIV-1 variants Viral proteins encompass both functionally/structurally conserved and less constrained variable regions. If this vaccine strategy proves effective, the vaccine’s cross-clade reach offers a global deployment
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