Do we still need an HIV vaccine now that we have a twice-a-year prevention shot?

After decades of research, there is still no cure for the disease HIV causes–AIDS. Each year, HIV infects more than one million people worldwide, and a vaccine remains stubbornly out of reach. Hope, however, is not lost. A new injectable drug, lenacapavir, offers long-lasting protection from HIV — eliminating the need for daily pills — with just two shots a year.

The story of lenacapavir began in the lab of Dr. Wilson Sundquist at the University of Utah. Sundquist’s research focused on the HIV capsid protein, which encapsulates the virus’s genetic material. In 1996, his team mapped the capsid’s architecture, and in 2003, they showed that even small disruptions to the capsid prevent HIV from replicating. This discovery opened the door to target the capsid — previously thought to be “undruggable” because of its stability compared with the viral enzymes. Building on these findings, the team at Gilead Sciences screened thousands of molecules and eventually identified a highly effective capsid inhibitor: lenacapavir.

In 2021, clinical trials PURPOSE 1 and PURPOSE 2 began to test lenacapavir for HIV prevention. PURPOSE 1 focused on women and adolescent girls in sub-Saharan Africa and Uganda, showing that twice-yearly injections provided 100% protection against infection. PURPOSE 2 expanded the study to include a diverse population, including gender-diverse participants and found that lenacapavir reduced HIV infection by 96%.

These impressive results raise a key question: if we already have such a powerful drug, do we still need an HIV vaccine? According to an article published in the New England Journal of Medicine, the answer is yes. Dr. James Kublin, Executive Director of the HIV Vaccine Trials Network at Fred Hutch, and his collaborators argue that lenacapavir alone cannot end the epidemic.

“HIV-prevention strategies that rely exclusively on lenacapavir would have several limitations. We therefore believe that the development of an HIV vaccine is still an essential component of the global, multipronged strategy needed to end the HIV epidemic,” the Kublin team explained.

Lenacapavir’s protection is limited to six months, requiring participants to stay engaged with healthcare. If they stop, they lose protection. Vaccines, in contrast, can provide long-lasting immunity and are typically offered to entire populations, not just high-risk groups. Population-specific interventions like pre-exposure prophylaxis(PrEP) can miss people who later become infected, particularly marginalized individuals who face stigma or bias in accessing healthcare. Access and infrastructure also shape prevention outcomes. Administering twice-yearly injections requires trained healthcare providers, proper equipment, and consistent follow-up — resources that may be limited in low- and middle-income countries. Vaccines, on the other hand, can leverage existing immunization systems already in place worldwide. Additionally, as a drug, lenacapavir may be affected by drug interactions or the emergence of resistance. Cost is another barrier: while the cost of lenacapavir is not yet known, other long-acting injectable HIV prevention drugs are often unavailable or prohibitively expensive in many regions.

For these reasons, Kublin and his team advocate a complementary approach: using both lenacapavir and a future HIV vaccine. Combining the two strategies would expand coverage, prevent more infections, and provide multiple layers of protection, offering the best chance to finally curb the global HIV epidemic.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. James Kublin contributed to this research.

Jatt LP, Mgodi NM, Buchbinder SP, Gray GE, Kublin JG. An HIV Vaccine in the Era of Twice-Yearly Lenacapavir for PrEP - Essential or Irrelevant? N Engl J Med. 2025.