After more than four decades of work, there is still no approved HIV vaccine. Recent large trials that tried to protect people with vector and protein vaccines did not prevent infection. These results pushed the field to change course toward “precision” vaccine design that aims to teach the immune system, step by step, how to make the rare antibodies that can block many forms of HIV.
The new path focuses on broadly neutralizing antibodies, or bnAbs. These are special antibodies that can hit parts of the virus that change very little. The main idea is germline targeting, which means the first vaccine dose “primes” the tiny number of naïve B cells that can grow into bnAb-making cells. Later doses then “shepherd” these cells so they mature in the right direction. Early phase human studies in 2025 reported that this stepwise plan can start and then move these bnAb-precursor responses forward, including in African volunteers, which is essential for a global vaccine. These studies also used mRNA to deliver the vaccine proteins, a platform that allows fast design changes.
Another helpful design tweak is to present the HIV envelope protein in a way that keeps the immune system focused on the right target. An early clinical trial found that teaching cells to make membrane-anchored forms of the envelope protein led most participants to produce neutralizing antibodies against that target. This is still far from a full bnAb response, but it is a clear sign the immune system can be guided.
Detail from recent work: one group showed in animals that a very small first shot followed by a larger shot a week later can trigger much stronger antibody and T-cell responses than one shot, while staying practical for real-world use.
Multiple platforms are advancing in parallel. Protein nanoparticles with a saponin based adjuvant are in early trials that test prime and boost schedules chosen to favor B cell maturation. Researchers are also testing a cytomegalovirus vector to drive strong and long-lasting T-cell responses, which may work hand in hand with B-cell-focused designs. Together, these approaches aim to produce both the right antibodies and the cellular support that a durable vaccine will need.
What this means now: the field has realistic proof of concept in people for starting the right bnAb pathways and nudging them forward. What is still missing is evidence that any of these regimens protect people from getting HIV. The next steps are larger and longer studies that combine multiple carefully chosen primes and boosts, possibly over many months, and then measure real-world protection. In parallel, HIV prevention keeps improving outside vaccines, for example with twice-yearly injections that prevent infection, but a safe and effective vaccine would remain a major public health goal because it could reduce new infections at scale and without ongoing treatment.
Science Translational Medicine – Vaccination with mRNA-encoded membrane-anchored HIV envelope trimers – 2025
Early human trial shows that mRNA vaccines coding for membrane-anchored envelope trimers can trigger neutralizing antibodies more often than soluble versions, supporting design choices that focus immune responses on useful targets.
Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans – 2025
Phase 1 trials in North America and Africa demonstrate priming of bnAb-precursor B cells in humans and show that a different booster can push these cells further, offering clinical proof of concept for stepwise germline-targeting strategies.
Nature News – mRNA vaccines for HIV trigger strong immune response in people – 2025
News report on the early mRNA HIV trials explains why membrane-anchored designs outperformed unbound forms and places the results in the larger vaccine effort.
IAVI press release – Two HIV vaccine trials show proof of concept for pathway to broadly neutralizing antibodies – 2025
Consolidates data from two phase 1 studies using germline targeting, including in African participants, and highlights the role of mRNA platforms and heterologous boosting.
MIT News – A two-dose schedule could make HIV vaccines more effective – 2024
Plain-language overview of the two-dose priming concept and why it may be more practical than multi-dose escalating schedules while keeping strong immune responses.
Janssen press release – Mosaico phase 3 HIV vaccine clinical trial discontinued – 2023
The Data and Safety Monitoring Board found no protection in the phase 3 Mosaico trial, marking the end of this mosaic vector program in prevention.
0 Comments