Dual studies reveal early successes for mRNA HIV vaccine strategies

HIV vaccine efforts have been slowed by the difficulty of getting neutralizing antibodies to target the correct locations of the diverse variants of HIV. Neutralizing antibodies are proteins produced by the immune system that bind to and block the activity of viruses, bacteria, or other pathogens.

Most current approaches rely on soluble protein-based HIV-1 envelope glycoprotein (Env) trimers, structures found on the viral surface that are essential for attaching to and entering host cells. These efforts have focused on creating stable, native-like Env trimers that closely mimic the virus’s functional spike, functioning as a training target for neutralizing antibodies which would then potentially be able to target conserved regions shared across a broad range of HIV variants.

A number of molecularly tricky obstacles have prevented these vaccines from working as desired. While native-like trimers do elicit antibodies, they are nonneutralizing, tending to target parts of the Env trimer base that do not halt the attach and enter functions.

Two new studies have been published in Science Translational Medicine, with testing results from mRNA-based HIV vaccines.

A team led by scientists at the Scripps Research Institute designed an mRNA-encoded HIV vaccine that steers immune responses away from the nonneutralizing targets and toward the attach and enter sites.

In the study, “Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models,” researchers engineered and compared mRNA-delivered versions of a stabilized HIV Env trimer (BG505 MD39.3) in both soluble and membrane-bound forms to assess their capacity to guide immune responses toward the desired sites.

In the soluble version, cells are instructed to produce HIV Env trimers that are secreted by the cell into the extracellular space after translation. These proteins are not anchored to the cell membrane and float freely.

Cell instructions for the membrane-bound version produce membrane-anchored HIV Env trimers where the trimer proteins remain fixed to the surface of the cells via a transmembrane domain.

Results of the membrane-bound HIV envelope trimer elicited neutralizing antibody responses in both rabbits and primates (rhesus macaques), outperforming the soluble version of the same antigen.

T cell assays revealed robust CD4⁺ T cell responses across both mRNA groups. CD8⁺ T cell responses were detected in the majority of animals receiving membrane-bound mRNA immunizations with few to none in the soluble version, and off-target memory B cell bindings were less frequent. Bone marrow samples taken nearly a year after immunization showed persistent Env-specific plasma cells.

A Fred Hutchinson Cancer Center-led trial provides the first-in-human evidence that mRNA-based HIV vaccines can elicit neutralizing antibodies. Results showed that mRNA-encoded, membrane-anchored, HIV envelope trimers triggered neutralizing antibody responses in most recipients.

In the human trial, “Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial,” researchers designed three vaccine constructs encoding stabilized HIV Env trimers in either soluble or membrane-bound forms. A third version included a CD4-binding knockout mutation to reduce unwanted trimer conformational changes.

Here, 108 HIV-negative adults aged 18 to 55 years at 10 U.S. sites received three doses of one of six regimens. Three immunizations with membrane-anchored trimers elicited neutralizing antibodies in 80% of recipients. Neutralizing responses appeared after the second dose and increased in magnitude following the third.

Serum antibody titers remained detectable six months after the final vaccination. Binding antibody responses to nonbase epitopes were higher in this group, with a greater frequency of memory B cells binding to neutralizing parts of the Env trimer responsible for the attach and enter functions.

A safety signal was flagged, as 6.5% of participants developed mild-to-moderate chronic urticaria. All versions of the vaccine were implicated. Most symptoms resolved or improved with oral antihistamines, although two participants had ongoing symptoms beyond 32 months. One serious adverse event related to urticaria required short-term hospitalization.

The authors conclude that mRNA vaccines encoding membrane-anchored HIV trimers effectively induced autologous tier 2 (a resistant form of HIV) neutralizing antibodies, durable memory B cell responses, and CD4⁺ T cell activity.

While the antibodies elicited so far remain largely strain-specific, findings from the dual publications represent major iterative steps forward in HIV vaccine development using mRNA technology. Achieving the true breadth of HIV coverage will require additional research towards a more broadly neutralizing potency.

By Justin Jackson

More information: Parham Ramezani-Rad et al, Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adw0721
K. Rachael Parks et al, Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers elicited tier 2 neutralizing antibodies in a phase 1 clinical trial, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.ady6831