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

TY - JOUR

T1 - Efficient Induction of T Cells against Conserved HIV-1 Regions by Mosaic Vaccines Delivered as Self-Amplifying mRNA

AU - Moyo, Nathifa

AU - Vogel, Annette B.

AU - Buus, Søren

AU - Erbar, Stephanie

AU - Wee, Edmund G.

AU - Sahin, Ugur

AU - Hanke, Tomáš

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - conserved regions

KW - heterologous prime-boost

KW - HIV vaccine

KW - in vivo killing

KW - MVA

KW - RNA vaccine

KW - simian adenovirus

KW - T cell vaccine

KW - T cells

KW - tHIVconsvX

U2 - 10.1016/j.omtm.2018.10.010

DO - 10.1016/j.omtm.2018.10.010

M3 - Journal article

C2 - 30547051

AN - SCOPUS:85057212271

SN - 2329-0501

VL - 12

SP - 32

EP - 46

JO - Molecular Therapy - Methods & Clinical Development

JF - Molecular Therapy - Methods & Clinical Development

ER -