Abstract
Development of a vaccine against HIV remains a major target goal in the field. The recent success of mRNA vaccines against the coronavirus SARS-CoV-2 is pointing out a new era of vaccine designs against pathogens. Here, we have generated two types of mRNA vaccine candidates against HIV-1; one based on unmodified vectors and the other on 1-methyl-3′-pseudouridylyl modified vectors expressing a T cell multiepitopic construct including protective conserved epitopes from HIV-1 Gag, Pol and Nef proteins (referred to as RNA-TMEP and RNA-TMEPmod, respectively) and defined their biological and immunological properties in cultured cells and in mice. In cultured cells, both mRNA vectors expressed the corresponding protein, with higher levels observed in the unmodified mRNA, leading to activated macrophages with differential induction of innate immune molecules. In mice, intranodal administration of the mRNAs induced the activation of specific T cell (CD4 and CD8) responses, and the levels were markedly enhanced after a booster immunization with the poxvirus vector MVA-TMEP expressing the same antigen. This immune activation was maintained even three months later. These findings revealed a potent combined immunization regimen able to enhance the HIV-1-specific immune responses induced by an mRNA vaccine that might be applicable to human vaccination programs with mRNA and MVA vectors.
Highlights
The human immunodeficiency virus (HIV), identified almost 40 years ago as the causative agent of acquired immunodeficiency syndrome (AIDS), continues to be lethal to humanity, accumulating more than 32 million deaths worldwide
These results indicate an efficient expression of TMEP protein from cells transfected with DNA or mRNA vectors
One of the HIV-1 mRNA vectors was modified by the incorporation of 1-methyl-3 -pseudouridylyl in RNA-TMEP and the other was unmodified
Summary
The human immunodeficiency virus (HIV), identified almost 40 years ago as the causative agent of acquired immunodeficiency syndrome (AIDS), continues to be lethal to humanity, accumulating more than 32 million deaths worldwide. The phase III study, named HVTN 702, that used the same RV144 vaccine regimen adapted to the HIV-1 subtype clade C, which is the most common in Southern Africa, was ineffective in preventing HIV-1 infection and discontinued in early February 2020 (www.niaid.nih.gov, accessed on 1 August 2021). It is unclear whether this failure is related to the ethnic groups or to other factors. It is imperative to identify new target antigens and immunization strategies that are able to confer protection against infection to ensure “next-generation” vaccines
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