Novel Conserved-region T-cell Mosaic Vaccine With High Global HIV-1 Coverage Is Recognized by Protective Responses in Untreated Infection

Abstract

An effective human immunodeficiency virus type 1 (HIV-1) vaccine is the best solution for halting the acquired immune deficiency syndrome epidemic. Here, we describe the design and preclinical immunogenicity of T-cell vaccine expressing novel immunogens tHIVconsvX, vectored by DNA, simian (chimpanzee) adenovirus, and poxvirus modified vaccinia virus Ankara (MVA), a combination highly immunogenic in humans. The tHIVconsvX immunogens combine the three leading strategies for elicitation of effective CD8(+) T cells: use of regions of HIV-1 proteins functionally conserved across all M group viruses (to make HIV-1 escape costly on viral fitness), inclusion of bivalent complementary mosaic immunogens (to maximize global epitope matching and breadth of responses, and block common escape paths), and inclusion of epitopes known to be associated with low viral load in infected untreated people (to induce field-proven protective responses). tHIVconsvX was highly immunogenic in two strains of mice. Furthermore, the magnitude and breadth of CD8(+) T-cell responses to tHIVconsvX-derived peptides in treatment-naive HIV-1(+) patients significantly correlated with high CD4(+) T-cell count and low viral load. Overall, the tHIVconsvX design, combining the mosaic and conserved-region approaches, provides an indisputably better coverage of global HIV-1 variants than previous T-cell vaccines. These immunogens delivered in a highly immunogenic framework of adenovirus prime and MVA boost are ready for clinical development.

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…A third area of interest for HIV‐1 T‐cell vaccine design is the idea of focusing responses on epitopes that are presumed to be beneficial because they are either highly conserved,49, 50, 51, 52 require compensatory mutations to escape,53 or are associated with better viral control in natural infections 54. While particular epitopes can be identified that are good candidates for such design strategies, vaccines based on the delivery of concatenated epitopes have not been immunogenic in humans 55, 56.…”

“…In contrast, immunogens that link larger conserved protein regions, which provide at least some natural context for processing within the larger peptide, have elicited strong CTL responses in preclinical studies50 and in a human Phase I trial 57. This inspired a second‐generation conserved‐region approach using the Mosaic tool suite,58 first to define the most conserved regions in the HIV‐1 proteome, and then, to design complementary paired Mosaic vaccines that span the conserved regions with vaccine antigens that provide optimal epitope coverage 51, 52. Because even the most conserved regions of HIV‐1 vary at the epitope level, polyvalent Mosaic approaches are useful to optimize variant coverage 34.…”

“…Because even the most conserved regions of HIV‐1 vary at the epitope level, polyvalent Mosaic approaches are useful to optimize variant coverage 34. In a recent mosaic vaccine described by Ondondo et al 51,. included regions were restricted not only by being the most conserved regions, but were further limited to include only regions that spanned epitopes that were deemed protective, in that responses to these epitopes were associated with low viral loads in natural infections 54.…”

“…Novel safe ways to modulate immune tolerance and enable vaccine induction of polyreactive and autoreactive antibodies are also being explored 87. For cytotoxic T lymphocyte (CTL) focused vaccines, new delivery approaches are being used,33, 88 and preclinical testing of conserved region polyvalent mosaics vaccines is underway 51. A desirable long‐term goal may be to merge parallel B‐cell and T‐cell focused vaccine strategies into an immunological “one‐two punch”.…”

Towards the knowledge-based design of universal influenza epitope ensemble vaccines

“…Such an approach draws strong support from both theoretical studies (Schubert et al , 2013) and from a wealth of recent experimentally verified vaccines developed with concordant goals, including inter alia filoviruses (Fenimore et al , 2012), HIV (Ondondo et al , 2016), Dengue virus (Nascimento et al , 2013), Survivin (Hoffmann et al , 2015) and Metapneumovirus (Li et al , 2015). …”