Progress in developing an HIV vaccine has been hindered by the complexity of targeting neutralizing antibodies to specific sites on the varied strains of HIV. Neutralizing antibodies are immune system proteins that attach to and inhibit viruses, bacteria, or other pathogens.
The majority of current strategies focus on soluble protein-based HIV-1 envelope glycoprotein (Env) trimers, which are structures found on the surface of the virus essential for attachment to and penetration of host cells. These efforts aim to create stable, native-like Env trimers that closely resemble the functional spike of the virus, serving as a training target for neutralizing antibodies against conserved regions present in a wide array of HIV variants.
A number of complex molecular challenges have prevented these vaccines from achieving their intended results, as while native-like trimers can stimulate the production of antibodies, they are generally nonneutralizing and tend to target parts of the Env trimer that do not inhibit viral attachment or entry functions.
Two recent studies published in Science Translational Medicine have presented test outcomes from mRNA-based HIV vaccines.
Science Translational MedicineA research team at the Scripps Research Institute developed an mRNA-encoded HIV vaccine designed to guide immune responses away from nonneutralizing targets toward the critical attachment and entry sites.
Their study, "Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models," involved engineering and comparing mRNA-delivered forms of a stabilized HIV Env trimer (BG505 MD39.3) in both soluble and membrane-bound states to evaluate their ability to direct immune responses toward desired targets.
In the soluble form, cells produce HIV Env trimers that are secreted into extracellular space post-translation and float freely without being anchored to a cell membrane.
With the membrane-bound version, instructions encoded in mRNA result in membrane-anchored HIV Env trimers, which remain fixed on the surface of cells via a transmembrane domain.
The results showed that the membrane-bound HIV envelope trimer induced neutralizing antibody responses both in rabbits and primates (rhesus macaques), with greater effect than the soluble version of the same antigen.
T cell assays revealed strong CD4+ T cell responses across both mRNA groups, with CD8+ T cell responses detected mostly in subjects receiving membrane-bound mRNA immunizations and few to none in those who received the soluble vaccine. Persistence of Env-specific plasma cells was observed in bone marrow samples taken nearly a year after immunization.
A trial led by researchers at Fred Hutchinson Cancer Center demonstrated, for the first time in humans, that mRNA-based HIV vaccines can generate neutralizing antibodies. Results indicated that mRNA-encoded, membrane-anchored HIV envelope trimers triggered neutralizing antibody responses in most recipients.
The human trial, "Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial," involved the design of three vaccine constructs encoding stabilized HIV Env trimers either in soluble or membrane-bound formats. A third version included a CD4-binding knockout mutation to limit unwanted trimer conformational shifts.
In this study, 108 HIV-negative adults between ages 18 and 55 at 10 U.S. sites received three doses of one of six immunization regimens. Three immunizations with membrane-anchored trimers induced neutralizing antibodies in 80% of recipients, with responses appearing after the second dose and intensifying following the third.
Antibody titers remained detectable six months post-vaccination. Binding antibody responses to non-base epitopes were higher within this group, coupled with a greater frequency of memory B cells binding to neutralizing parts of Env responsible for attachment and entry functions.
A safety concern was identified when 6.5% of participants developed mild-to-moderate chronic urticaria, related to all versions of the vaccine tested. Symptoms generally resolved or improved with oral antihistamines; however, two participants experienced continuing symptoms beyond 32 months. One serious adverse event involving urticaria required short-term hospitalization.
The authors summarize that mRNA vaccines encoding membrane-anchored HIV trimers effectively induced autologous tier 2 neutralizing antibodies, durable memory B cell responses, and CD4+ T cell activity.
While the elicited antibodies currently remain largely strain-specific, findings from these studies represent substantial advancements in developing an HIV vaccine using mRNA technology. Achieving a broadly effective HIV vaccine will require additional research aimed at enhancing neutralization potency across broader HIV strains.