A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques

Abstract

The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4 + T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian-human immunodeficiency virus (SHIV AD8). Thus, the multiclade env-gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine. Nature MediciNedegrees of protection in non-human primate models [31][32][33][34][35] . Some approaches have used messenger RNA (mRNA) as a vector, resulting in the induction of polyfunctional antibody responses comparable to those induced by protein immunization, as well as efficient T cell responses [36][37][38] . Altogether, the evidence so far accumulated suggests that no individual factor will determine the ultimate success of a bNAb-inducing HIV-1 vaccine, which probably requires a combination of efficient precursor B cell priming, optimization of Env design and presentation, and sustained heterologous Env boosting. ResultsDesign of an env-gag VLP mRNA vaccine platform. Critical advancements in mRNA technology over the past two decades 39,40 have enabled the development of mRNA-based vaccine platforms, which have recently shown remarkable effectiveness against ). Taking advantage of the versatility of mRNA as an expression system, we designed a novel vaccine platform by combining a series of features that we postulated to be critical for the elicitation of protective antibody responses. These include, first, the use of mRNA as a vehicle in order to instruct host cells to endogenously express membrane-bound viral glycoproteins and decorate them with native N-linked glycosylation; second, the use of full-length or minimally truncated HIV-1 Envs that do not expose distractive immunodominant epitopes, unlike truncated soluble trimers; third, co-expression of Env with Gag in order to promote the in vivo production of virus-like particles (VLPs), which closely mimic native viral particles produced by HIV-1 infection; fourth, initial priming with an Env capable of engaging germline bNAb precursors; and last, intensive heterologous boosting with tier-2 Envs from different clades in order to selectively expan...

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“…Several studies published recently explored the use of mRNAs for HIV-1 vaccines in various forms, such as self-amplifying mRNA ( Aldon et al., 2021 ; Melo et al., 2019 ) or mRNA-encoded virus-like particles ( Zhang et al., 2021 ). These studies highlighted the versatility of mRNA vaccine platform for HIV-1 vaccine development and stressed the need for careful studies to compare and evaluate different mRNA technologies.…”

The Potential of Nanomedicine to Unlock the Limitless Applications of mRNA

“…In recent years, several studies have tried to deliver mRNA-vaccine encoding for HIV proteins; however, their success has not been as expected [127,129,145]. Nevertheless, a recently published study has shown broad neutralization and reduction in the risk of infection in rhesus macaques upon the administration of mRNA encoding for both HIV-1 envelope protein and simian immunodeficiency virus Gag proteins, which would be responsible for forming virus-like particles (VLP) [146]. A different approach based on targeting hepatocytes, which will be further discussed for immuno-oncology applications in Section 3.2.2, has achieved good results.…”

Microneedle-Based Vaccine Delivery: Review of an Emerging Technology

“…Currently, there are no approved HIV vaccines, highlighting the potential of utilizing MN technology in creating a vaccine that elicits a suitable immune response to confer protection against the virus. Despite the lack of vaccines, testing of mRNA-based HIV vaccine on animals has demonstrated promising results ( 94 ).…”