New vaccines successfully boost frontline immune cells against HIV

T-cells are the immune system's frontline defenders with a crucial role in controlling HIV. In a milestone clinical trial published in the Journal of Clinical Investigation, researchers with the UNC Institute for Global Health and Infectious Diseases (IGHID) at the UNC School of Medicine have demonstrated that new vaccines can significantly boost T cells targeting the most vulnerable, conserved regions of HIV-areas considered key to effective immune control. This pivotal finding not only advances our understanding of HIV immunology but also offers hope that these vaccines could contribute to novel, curative approaches against HIV.

Led by principal investigator Nilu Goonetilleke, PhD, and a team of IGHID researchers in collaboration with the University of Oxford, University of Pittsburgh, Accelovir Diagnostics and the National Institutes of Health, the study is the first to test HIV vaccines developed at the University of Oxford in people living with HIV who are receiving antiretroviral therapy (ART).

Nilu Goonetilleke, PhD, associate professor of infectious diseasesOur findings highlight the critical importance of considering age when developing and deploying HIV immunotherapies."

Dr. Goonetilleke's lab focuses on two types of T cells–CD4 T cells which HIV infects, and CD8 T cells which act as the immune system's professional killers. She says aging naturally diminishes the immune response to vaccines, a phenomenon observed regardless of HIV status.

"As people age, their bodies produce fewer and less diverse T cells, making it harder to mount broad immune responses. HIV infection further complicates this by causing immune dysregulation, which can persist even after years of effective antiretroviral therapy (ART)."

The vaccine, designed by colleagues at Los Alamos National Laboratory and the University of Oxford, target conserved regions of HIV-those less prone to mutation-making it effective across diverse populations and viral strains of HIV.

Study design

The team designed the study to determine the effectiveness of the vaccine to boost CD8 T cells, to help the body destroy HIV-infected cells.

The Institute's Clinical Trials Unit led the M&M Study, a double-blind, randomized, placebo-controlled Phase I clinical trial. Twenty-four adults living with HIV-1, (aged 21 to 60 years and durably suppressed on ART), were randomly assigned to one of four groups to receive one of two MVA vaccines or to receive them in combination: MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), M3M4 (combination), or placebo. Each participant received a single intramuscular dose and was closely monitored through follow-up visits at Days 7, 14, 28, 56, and 70, with additional telephone check-ins at Days 84 and 168. The study collected comprehensive clinical, immunological, and virological data, including ex vivo IFN-γ ELISpot assays to measure HIVconsvX-specific T-cell responses, plasma HIV-1 RNA quantification, and integrated proviral DNA assays in CD4+ T cells.

Results

The trial demonstrated that vaccination with MVA-vectored HIVconsvX vaccines were safe and well tolerated, with most adverse events being mild or moderate, and resolving quickly. Immunologically, the vaccines significantly increased both the frequency and breadth of HIVconsvX-specific T-cell responses, redirecting T cells to target the most conserved and vulnerable regions of HIV-1. Nearly 85% of participants showed robust T cell responses, and these responses were maintained for up to 10 weeks post-vaccination. Notably, the ability of the vaccines to boost T cell immunity declined with increased age-a critical finding as more than half of people living with HIV in the US and globally are now over 50 years old.

The findings suggest that both age and the degree of immune restoration after HIV infection play roles in how well vaccines work, and that extended ART may help overcome some of the immune challenges. Researchers are exploring strategies to further improve vaccine efficacy in older adults, such as booster doses or alternative vaccine formulations.

Cindy L. Gay, MD, MPH, served as clinical principal investigator. Other UNC study investigators include: Yinyan Xu; Ann Marie K Weideman, PhD, MS; Fiona R Shaw, JoAnn D Kuruc, Shayla Z Conrad, Sofia A Mariano, Shahryar Samir, Sallay Kallon, Alexis T Sponaugle, Joanna A Warren, Genevieve T Clutton, Maria Abad-Fernandez, Carolina Kapper, Alex B Bradley, Caroline E Baker, Susan M Pedersen, RN, Matthew Moeser, Lauren Burke, Shuntai Zhou, Joe J. Eron, MD, David M. Margolis, PhD, and Michael G. Hudgens, PhD.

Source:

UNC Institute for Global Health and Infectious Diseases

Journal reference:

Gay, C. L., et al . (2026). MVA.HIVconsvX vaccination–evoked T cell expansion inversely associates with age in people with HIV-1 on antiretroviral therapy. Journal of Clinical Investigation. DOI: 10.1172/jci193547. https://www.jci.org/articles/view/193547