Speaker: Wilton Bryan Williams

The application of messenger Ribonucleic acid (mRNA) technology, akin to that used in Coronavirus Disease 2019 (COVID-19) vaccines, was being investigated for the development of Human Immunodeficiency Virus (HIV)-1 vaccines aimed at generating highly effective antibodies. These antibodies were designed to prevent the infection of target cells in HIV-1 seronegative individuals and to eradicate reservoirs of the virus in people living with HIV. Research is focused on creating broadly neutralizing antibodies (bNAbs) capable of recognizing vulnerable sites on the envelope surface protein of various HIV-1 strains circulating globally. mRNA vaccines work by introducing an mRNA sequence encoding an immunogen into host cells. Once delivered, the mRNA is translated into protein, stimulating the host's immune system to produce specific B and T cell responses. Recent advancements in technology and improved delivery systems have positioned mRNA-based vaccines as a promising platform for antigen delivery, offering potential benefits for both preventative and therapeutic HIV-1 interventions. 

The history of mRNA vaccines, notably their role in combating infectious diseases like the Zika virus outbreak 2013 and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic in 2020, has garnered significant attention. In the realm of preventive HIV-1 vaccines, the focus is on developing bNAbs that target the envelope surface protein to prevent infection by multiple circulating HIV-1 strains. The strategy involves priming immunogens to activate precursor B cells that can evolve into bNAbs. This process includes clonally expanding B cells within the bNAb lineage and selecting B cell receptors with the highest affinity for binding the HIV-1 envelope. The HIV-1 envelope trimer, consisting of three glycoprotein (gp)-120 surface molecules, is the primary target for these bNAbs. The HIV Vaccine Trials Network (HVTN) 133 clinical trial, a human HIV-1 vaccine study, successfully generated bNAbs targeting the membrane-proximal external region (MPER) in gp41, demonstrating the potential of this approach in developing effective HIV-1 vaccines. 

The visualization illustrates a bNAb targeting the MPER of HIV-1 binding to lipids within the viral membrane, highlighting its role in blocking the viral entry process. During viral entry, gp120 was displaced, exposing the MPER epitope on gp41. This exposure enhances the likelihood of MPER bNAb binding to its target, effectively inhibiting the gp41-mediated fusion process. By binding to the viral membrane's lipids, the MPER bNAb disrupts the fusion mechanism, thus preventing the infection of target cells. 

The HVTN 133 trial successfully generated polyclonal HIV-1 heterologous neutralizing antibodies targeting the gp41 MPER in human subjects. Munir Alam and Barton Haynes at Duke University developed the gp41 MPER peptide liposome immunogen used in the study. The trial led to the induction of the MPER bNAb lineage known as DH1317. The DH1317 bNAbs exhibit robust lipid binding and can neutralize up to 15% of global HIV-1 strains, with particular efficacy against clade B strains, neutralizing up to 35% of these variants. Notably, the DH1317 bNAb binds to the MPER within the trimeric structure on the virion's surface, indicating that these bNAbs can recognize MPER both during viral entry and in its native trimeric context on the virion. The study underscored the potential for vaccine-induced polyclonal HIV-1 heterologous neutralizing antibodies targeting the gp41 MPER, highlighting a promising approach for HIV-1 vaccine development. 

Researchers at Duke University are advancing novel approaches to prime and enhance MPER bNAb B cell lineages, building on findings from the HVTN 133 trial. These approaches involve the mRNA delivery of immunogens designed to target proximal MPER bNAb epitopes. The initial priming consists of using MPER peptide liposomes, followed by mRNA-mediated delivery of MPER peptides and, eventually, the envelope trimer that expresses the MPER peptide. These strategies are currently undergoing evaluation in preclinical animal models, including non-human primates. 

A recent study has explored the application of mRNA-lipid nanoparticles (mRNA-LNP) for delivering HIV-1 envelope immunogens in various trimer configurations, including cellular gp160, soluble trimers, and multimeric nanoparticles. Two recent studies have shown that mRNA prime-boost vaccine regimens effectively expanded V3-glycan bNAb precursor B cells in mice engineered to express germline B cell receptors (BCRs) specific to V3 glycan bNAbs. It was investigated that an mRNA-LNP encoding a multimeric nanoparticle envelope immunogen, while Barton Haynes and Kevin Saunders from the Duke Collaboration for HIV Vaccine Discovery (CHAVD) program are evaluating several mRNA-LNP HIV-1 vaccines in human subjects. In the HVTN 307 study, the nanoparticle protein prime was assessed by an mRNA boost expressing the sub-envelope trimer and envelope strains used in the nanoparticle prime. The mRNA boost was linked to the induction of V3-glycan bNAb precursors in preclinical animal models. Meanwhile, the HVTN 312 study examined a prime-boost regimen featuring heterogeneous envelopes associated with CD4 binding site neutralizing antibodies, utilizing mRNA to express these trimers' cell surface gp160 form. These clinical trials are ongoing. 

The Duke Center for Innovative HIV/Acquire Immunodeficiency Syndrome (AIDS) Vaccine and Cure Research (CIAVCR) was advancing the development of therapeutic HIV-1 vaccines for individuals living with HIV. Under the leadership of Guido Ferrari and Wilton Bryan, the program is focused on devising a vaccine strategy that leverages innovative mRNA constructed for the delivery of immunogens, aiming to induce protective immune responses in non-human primate models. The study agenda encompasses two primary objectives: first, the development of a preventive HIV-1 vaccine designed to elicit robust B and T cell responses, targeted primarily at HIV-1 seronegative individuals; second, the formulation of a therapeutic vaccine strategy that integrates the preventive vaccine with immunotherapy approaches to address and eradicate latent HIV-1 reservoirs, making it more applicable for HIV-positive individuals. 

Various initiatives are underway to develop effective mRNA-based HIV-1 vaccines, including those targeting bNAbs against different envelope regions. These efforts build upon the findings of the HVTN 133 trial, which successfully elicited heterologous HIV-1 neutralizing antibodies. Establishing Good Manufacturing Practice (GMP)-grade mRNA manufacturing facilities, including a dedicated facility at Duke University, is expected to expedite the development of mRNA HIV-1 vaccines. The mRNA LNP platform, which has demonstrated success with COVID-19 mRNA vaccines, presents a promising approach for HIV-1 vaccine development. Current mRNA LNP HIV-1 vaccines are being tested in preclinical animal models and human trials. Future studies will focus on new designs and dosing regimens to address and minimize potential allergic reactions. 

The 25th International AIDS conference (AIDS 2024). 22nd-26th July, Munich, Germany