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Background: A vaccine will likely be one of the key tools for ending the HIV-1/AIDS epidemic by preventing HIV-1 spread within unin-fected populations and achieving a cure for people living with HIV-1. The currently prevailing view of the vaccine field is to introduce protective antibodies, nevertheless, an effective vaccine may need to harness protective T cells. We postulated that focusing a T-cell response on the most vulnerable regions of the HIV-1 proteome while maximizing a perfect match between the vaccine and circulating viruses will control HIV-1 replication. Here, we exploit the mRNA lipid nanoparticle (LNP) platform by designing tetravalent immunogens to assess induction of T-cell responses in a pre-clinical model. Methods: Two Gag and four Pol protein regions of the HIV-1 proteome were selected for their high conservation among the HIV-1 Group M isolates and inclusion of beneficial regions. These were computed into two complementing mosaics, which together achieved over 80% match of potential 9-mer T-cell epitopes over most of the six HIVconsvX regions. Here, using a novel epigraph algorithm, two versions of the same six regions were sequentially designed to cover additional common variants of potential 9-mer epitopes and make further improvements over the previous vaccine in matching the global HIV-1 isolates. These two mosaics and 2 epigraphs were converted into mRNA and the fully synthetic tetravalent mRNAs, collectively called HIVconsvM, were encapsulated into LNPs. Results: In a mouse model, intramuscular injection of the LNP-encapsulated mRNA induced high frequencies of T cells, which recognized seven out of seven examined H-[2.sup.d] class I-restricted epitopes in most animals. This combination of mRNA and tetravalent immunogens induced potent, broad and polyfunctional T-cell responses. There was an overall trend of a direct correlation between the magnitude of vaccine responses and valency of the vaccine cocktail both for individual epitopes and the overall 'global' response. Conclusions: Our data show a great potency of this vaccine platform for induction of T-cell responses and support evaluation of the HIV-consvM mRNA LNPs in humans, the species in which HIV-1 evolved and for which further vaccine optimizations and response analyses will be the most relevant., OA12.03 N.A. Moyo (1); E. Wee (1); B. Korber (2); K. Bahl (3); S. Falcone (3); S. Himansu (3); A.L. Wong (4); A.K. Dey (4); M. Feinberg (4) and T. [...]