Comparative immunogenicity of an mRNA/LNP and a DNA vaccine targeting HIV gag conserved elements in macaques

Abstract

Immunogenicity of HIV-1 mRNA vaccine regimens was analyzed in a non-human primate animal model. Rhesus macaques immunized with mRNA in lipid nanoparticle (mRNA/LNP) formulation expressing HIV-1 Gag and Gag conserved regions (CE) as immunogens developed robust, durable antibody responses but low adaptive T-cell responses. Augmentation of the dose resulted in modest increases in vaccine-induced cellular immunity, with no difference in humoral responses. The gag mRNA/lipid nanoparticle (LNP) vaccine provided suboptimal priming of T cell responses for a heterologous DNA booster vaccination regimen. In contrast, a single immunization with gag mRNA/LNP efficiently boosted both humoral and cellular responses in macaques previously primed by a gag DNA-based vaccine. These anamnestic cellular responses were mediated by activated CD8+ T cells with a phenotype of differentiated T-bet+ cytotoxic memory T lymphocytes. The heterologous prime/boost regimens combining DNA and mRNA/LNP vaccine modalities maximized vaccine-induced cellular and humoral immune responses. Analysis of cytokine responses revealed a transient systemic signature characterized by the release of type I interferon, IL-15 and IFN-related chemokines. The pro-inflammatory status induced by the mRNA/LNP vaccine was also characterized by IL-23 and IL-6, concomitant with the release of IL-17 family of cytokines. Overall, the strong boost of cellular and humoral immunity induced by the mRNA/LNP vaccine suggests that it could be useful as a prophylactic vaccine in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases.

DLin-MC3-Containing mRNA Lipid Nanoparticles Induce an Antibody Th2-Biased Immune Response Polarization in a Delivery Route-Dependent Manner in Mice

“…Interestingly, Valentin et al reported a strong antibody but not cellular immune response on immunized nonhuman primates when a specific ionizable lipid (property of Acuitas Therapeutics) was used to formulate p55Gag mRNA into LNPs before injection via the IM route. They observed that this Th2-biased polarization was promoted only at low dose of administrated mRNA [ 54 ]. These data suggest that the ionizable lipid-containing LNPs might have an intrinsic adjuvant effect with some evidence of a dose–response relationship.…”

HIV T-cell immunogen design and delivery

“…The surprising results of investigations into RNA immunogenicity for T cells speaks to the great importance of such vector choice for modulating both, the intensity and character of the response. Despite the power of RNA vaccines for inducing antibody responses, both a recent publication [22] and our unpublished work in nonhuman primates show that RNA priming can in many circumstances elicit comparatively poor T-cell responses. It is commonly observed that among groups of animals receiving serial mRNA vaccination, whether expressing intracellular or secreted antigens, impressive antibody responses testify to robust gene expression from the vaccine—while T-cell responses among PBMC remain anemic (<0.1%) or, in some animals, absent.…”

“…Further analysis in groups of HIV controllers and noncontrollers showed that several of these elements were indeed frequently targeted by HIV controllers, raising the possibility that CE vaccines could elicit similar responses across a wide range of HLA class I diversity [21]. Indeed, very recent data show the induction of strong responses in Non-Human Primates upon a DNA/RNA prime regimen, with the induction of both, CD4 and cytotoxic memory CD8 T cells [22,23]. A clinical trial testing this immunogen design in combination with a TLR9 agonist and bnAb treatments is ongoing.…”

mRNA vaccines: A novel weapon to control infectious diseases

“… Gómez et al (2021) used modified 1-methyl-3′-pseudouridylyl vectors that included a T-cell multiepitope construct encoding HIV-1 Gag, Pol, and Nef proteins conserved epitopes for protection against HIV-1 infection. Valentin et al (2022) found that LNP/mRNA vaccines expressing the HIV-1 Gag and Gag conserved region, when combined with Gag DNA vaccines, elicited strong humoral and cellular immune responses.…”