Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA

Abstract

Focusing T cell responses on the most vulnerable parts of HIV-1, the functionally conserved regions of HIV-1 proteins, is likely a key prerequisite for vaccine success. For a T cell vaccine to efficiently control HIV-1 replication, the vaccine-elicited individual CD8+ T cells and as a population have to display a number of critical traits. If any one of these traits is suboptimal, the vaccine is likely to fail. Fine-tuning of individual protective characteristics of T cells will require iterative stepwise improvements in clinical trials. Although the second-generation tHIVconsvX immunogens direct CD8+ T cells to predominantly protective and conserved epitopes, in the present work, we have used formulated self-amplifying mRNA (saRNA) to deliver tHIVconsvX to the immune system. We demonstrated in BALB/c and outbred mice that regimens employing saRNA vaccines induced broadly specific, plurifunctional CD8+ and CD4+ T cells, which displayed structured memory subpopulations and were maintained at relatively high frequencies over at least 22 weeks post-administration. This is one of the first thorough analyses of mRNA vaccine-elicited T cell responses. The combination of tHIVconsvX immunogens and the highly versatile and easily manufacturable saRNA platform may provide a long-awaited opportunity to define and optimize induction of truly protective CD8+ T cell parameters in human volunteers.

Strategies for inducing effective neutralizing antibody responses against HIV-1

“…The ability of these non-viral based molecules to replicate intracellularly allows for the sustained expression of high amounts of protein antigen. For instance, saRNA immunogens have been recently used to elicit long-lived T-cell responses using HIV-1 mosaic vaccines [248].…”

Innovations in HIV-1 Vaccine Design

“…122 One research team used a self-amplifying mRNA vector to deliver a mosaic of 6 highly conserved regions of HIV-1 gag and pol in a mouse model. 123 The results suggested that this method could induce potent and durable CD4 + and CD8 + T-cell responses in those mice who had been primed with the self-amplifying mRNA vector and boosted with a viral vector (modified vaccinia virus Ankara). 123 At this time, Phase I clinical trials are ongoing to assess mRNA vaccines against various infections, including Zika virus and cytomegalovirus, but mRNA-based human vaccine trials have not yet started for HIV-1.…”

A new generation of vaccines based on alphavirus self-amplifying RNA

“…Other groups have shown that naked saRNA can induce immune responses in mice against human pathogens like rabies virus [ 9 ], influenza virus [ 10 •• ] or human immunodeficiency virus (HIV) [ 11 , 12 ]. In particular, Moyo et al cloned highly conserved regions of HIV-1 gag and pol proteins into a SFV vector to generate mosaic saRNA vaccines, which were administered IM, generating specific T cell responses [ 12 ]. Interestingly, these responses had different time-courses compared to virus-based immunization, mediating a gradual induction of T cells during five weeks, with sustained persistence.…”

“…It was suggested that this delay in the immune response could be due to a lack of immunogens in the first stage of treatment, until saRNA could be translated. Despite these encouraging results, several groups have shown that the potency of naked saRNA vaccines can be greatly improved by electroporation [ 13 ], or by complexing them with lipid or polymer formulations [ 10 •• , 12 ], as it will be discussed ( Table 1 and Figure 2 ).…”

“…RNA/PEI IM HA Mouse Protection from influenza virus challeng e [ 10 •• ] SFV HIV mosaic ag. Plurifunctional CD4+ and CD8+ T cells [ 12 ] ta-SFV Nak. RNA ID HA Protection from influenza virus challenge [ 41 •• ] VEEV EP & LNP Luc Expression: EP, days 3−10; LNP, peak 24h [ 16 ] EP Pig High expression for 12 days [ 17 • ] Mouse Optimal expression in tail base versus flank [ 19 • ] EP+RNase inh.…”