First-in-Human Trial of a Germline-Targeting HIV Env Trimer Vaccine

The pursuit of an HIV vaccine has long been one of medicine’s greatest scientific challenges. Despite powerful antiretrovirals and advances in prevention, the goal of priming the immune system to generate broadly neutralizing antibodies (bnAbs) remains elusive.

But a new study, published in Science in 2025, offers a confident step forward with a first-in-human trial of a germline-targeting (GT) HIV envelope trimer vaccine that succeeded in expanding rare precursor B cells essential for bnAb development.

For some background on the study, the IAVI C101 trial (NCT04224701) was a phase 1, randomized, double-blind, placebo-controlled study. A total of healthy, HIV-negative adults received either a low dose (30 μg) or high dose (300 μg) of the engineered GT1.1 gp140 trimer vaccine with AS01B adjuvant, administered at weeks 0, 8, and 24. Participants were randomized in a 5:1 ratio vaccine-to-placebo.

The primary goal was safety, tolerability, and immunogenicity, especially the recruitment and expansion of VRC01-class precursor B cells that target the conserved CD4 binding site on HIV’s envelope protein.

Results

Based on the findings, the vaccine was well tolerated, with no vaccine-related serious adverse events or immune-mediated conditions. This safety profile provides reassurance for continuing development.

But the real excitement lies in the immunologic outcomes.

Over 75 percent of IGHV1–2 memory B cells in both low- and high-dose groups carried the short five–amino acid CDRL3 motif typical of VRC01-class bnAbs. Within the CD4bs-specific memory B cell pool, VRC01-class cells ranged from 4–74 percent, with median frequencies of 17 percent in low-dose and 33 percent in high-dose recipients.

These B cells showed hallmark bnAb-like mutations and gene usage patterns. Notably, more than 85 percent employed immunoglobulin light chain genes previously associated with VRC01-class bnAbs.

The frequency of VRC01-class memory B cells reached 1 in 2,500 of all IgG memory B cells in the high-dose group—a striking expansion given that no such cells were detectable before vaccination. Frequency was significantly higher in the high-dose group compared to low-dose, which suggests a dose-dependent effect.

Statistical testing confirmed significant increases in antigen-specific B cells in the vaccine groups compared to placebo.

Evidence of Affinity Maturation

Somatic hypermutation, a critical step in bnAb evolution, was robust. By week 26, VRC01-class B cells displayed median mutation levels of 4.9 percent, which is significantly higher than other epitope-specific cells (p < 0.01). In some individuals, mutations exceeded 10 percent.

Structural Insights

Cryo-electron microscopy revealed that monoclonal antibodies (mAbs) derived from vaccinated participants structurally resembled true VRC01-class bnAbs. These mAbs demonstrated the ability to accommodate glycan barriers, including the notoriously difficult N276 glycan, through mechanisms such as CDRL1 deletions or flexibility.

Functional Activity

Although neutralization is not the primary endpoint of a priming vaccine, a subset of elicited antibodies could neutralize heterologous pseudoviruses lacking N276 or homologous BG505 pseudoviruses.

Approximately one-third of antibodies at week 26 bound fully glycosylated Env trimers with nanomolar affinity, suggesting meaningful advancement along the bnAb maturation pathway.

Beyond the VRC01-Class

While designed to target VRC01-class precursors, GT1.1 also induced responses to the trimer apex and fusion peptide. However, non-neutralizing responses to artificial epitopes, such as the trimer base, were also observed, underscoring future design refinements.

Implications and Next Steps

This trial represents the first successful demonstration in humans that a germline-targeting Env trimer can reliably prime VRC01-class bnAb precursors. High-dose recipients were encouraged to enroll in follow-up trials testing sequential booster vaccines with BG505 SOSIP. That outcome may help clarify whether theoretical models of bnAb development can translate into practical immunization protocols.

Reference:

Caniels TG, Prabhakaran M, Ozorowski G, et al. Precise targeting of HIV broadly neutralizing antibody precursors in humans. Science. 2025;389(6759):eadv5572. doi:10.1126/science.adv5572