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The 40-year quest for an HIV vaccine enters a new phase

The 40-year quest for an HIV vaccine enters a new phase

New Capabilities
By Newzino Staff |

A Novel Germline-Targeting Strategy Shows Promise Where Every Previous Approach Has Failed

January 6th, 2026: IAVI Announces G004 Trial Initiation

Overview

In 1984, the U.S. Health Secretary predicted an HIV vaccine within two years. Four decades and dozens of failed trials later, IAVI has begun dosing participants in South Africa with a vaccine built on an entirely different principle—one that attempts to train the immune system from the ground up rather than simply presenting it with viral proteins. The IAVI G004 trial, which began vaccinations in December 2025, represents the fourth step in a sequential vaccination strategy that has already demonstrated proof-of-concept in humans.

The approach matters because HIV mutates faster than any other virus, making traditional vaccine strategies inadequate. Previous trials achieved at best 31% efficacy (the 2009 Thai trial), and every large-scale efficacy trial since then has failed. This new germline-targeting strategy, developed by Scripps Research and IAVI, attempts to activate the rare B cells—perhaps one in 300,000—capable of eventually producing broadly neutralizing antibodies. Early trials have shown 94-97% of recipients develop the targeted immune response. But this scientific momentum collides with a funding crisis: NIH has announced it will end support for its major HIV vaccine consortia in 2026.

Key Indicators

40+
Years Since First Trial
First HIV vaccine trial began in 1987; no effective vaccine has been approved
97%
Immune Response Rate
Percentage of G001 trial participants who developed targeted B cell responses
1.3M
Annual New Infections
New HIV infections globally in 2024, down 40% from 2010 but still far from elimination
$67M
Annual Funding at Risk
NIH funding for CHAVD consortia ending in 2026, representing ~10% of global HIV vaccine research funding

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People Involved

Mark Feinberg
Mark Feinberg
President and CEO, IAVI (Leading organization through G004 trial and funding uncertainty)
William Schief
William Schief
Professor, Scripps Research; Executive Director, IAVI Neutralizing Antibody Center (Lead designer of germline-targeting immunogens being tested in G004)
Linda-Gail Bekker
Linda-Gail Bekker
CEO, Desmond Tutu Health Foundation; Principal Investigator, IAVI G004 (Leading G004 trial implementation in South Africa)
Dennis Burton
Dennis Burton
Professor and Chair, Department of Immunology and Microbiology, Scripps Research (Facing end of NIH CHAVD funding in 2026)

Organizations Involved

IAVI (International AIDS Vaccine Initiative)
IAVI (International AIDS Vaccine Initiative)
Nonprofit Research Organization
Status: Leading G004 trial; primary driver of germline-targeting vaccine development

IAVI is a nonprofit scientific research organization focused on developing vaccines for HIV, tuberculosis, and emerging infectious diseases.

Scripps Research
Scripps Research
Nonprofit Research Institute
Status: Core scientific partner on immunogen design; CHAVD funding ending 2026

Scripps Research is a nonprofit biomedical research institute headquartered in La Jolla, California.

Moderna
Moderna
Biotechnology Company
Status: Providing mRNA platform and manufacturing for G004 trial

Moderna is a biotechnology company that pioneered mRNA vaccines, including one of the first authorized COVID-19 vaccines.

NIAID (National Institute of Allergy and Infectious Diseases)
NIAID (National Institute of Allergy and Infectious Diseases)
Federal Research Agency
Status: Ending CHAVD funding; shifting focus to existing HIV treatment approaches

NIAID is the NIH institute responsible for infectious disease research, including HIV/AIDS.

Timeline

  1. IAVI Announces G004 Trial Initiation

    Announcement

    IAVI publicly announced the Phase 1 trial testing three immunogens in 96 participants across six South African sites.

  2. First G004 Vaccinations in South Africa

    Clinical Trial

    IAVI administered first doses of three-immunogen mRNA vaccine at Perinatal HIV Research Unit in Soweto.

  3. NIH Ends CHAVD Funding

    Policy

    NIAID announced it will not renew $67 million annual funding for HIV vaccine consortia at Scripps and Duke after June 2026.

  4. G002/G003 Results Published in Science

    Research

    Two trials showed 94% of recipients developed bnAb precursors, and boosting advanced immune response toward mature antibodies.

  5. Imbokodo and Mosaico Trials Fail

    Clinical Trial

    Johnson & Johnson's mosaic vaccine trials were halted after showing no efficacy, leaving no other HIV vaccine efficacy trials running.

  6. IAVI-Moderna Partnership Announced

    Partnership

    IAVI and Moderna launched trials using mRNA technology to deliver germline-targeting immunogens.

  7. G001 Results: 97% Response Rate

    Clinical Trial

    IAVI and Scripps announced that 35 of 36 vaccine recipients developed the targeted B cell response, validating germline-targeting in humans.

  8. HVTN 702 Stopped for Futility

    Clinical Trial

    A modified version of the RV144 regimen tested in South Africa showed no efficacy and was halted.

  9. Germline-Targeting Strategy Published

    Research

    Scripps researchers published proof-of-principle that engineered immunogens could activate the rare B cells needed for broadly neutralizing antibodies.

  10. RV144 Shows 31% Efficacy

    Clinical Trial

    The Thai trial became the first to show any protective effect—31.2% reduction in infections—but efficacy was too low for regulatory approval.

  11. STEP Trial Halted

    Clinical Trial

    Merck's Ad5-vectored vaccine trial was stopped after interim analysis showed no protection and possible increased risk of infection.

  12. VaxGen Trials Fail

    Clinical Trial

    VAX004 and VAX003 trials of AIDSVAX showed no reduction in HIV infection, the first large-scale efficacy failures.

  13. First HIV Vaccine Trial Opens

    Clinical Trial

    NIH began testing a gp160 subunit vaccine in 138 healthy volunteers—the first of many candidates that would fail to show efficacy.

  14. HHS Secretary Predicts Vaccine Within Two Years

    Statement

    After confirming HIV causes AIDS, Margaret Heckler declared a vaccine would be available within two years.

Scenarios

1

G004 Succeeds, Multi-Immunogen Vaccine Advances to Efficacy Trial

Discussed by: IAVI leadership and Science coverage of May 2025 results

If G004 demonstrates that the three-immunogen sequence safely produces broadly neutralizing antibodies at protective levels, IAVI would advance to larger trials testing whether the vaccine actually prevents HIV infection. This would require securing alternative funding sources as NIH CHAVD support ends. The Gates Foundation and Netherlands government are already funding G004, suggesting private and international sources could fill the gap.

2

Funding Collapse Stalls Research Despite Promising Science

Discussed by: Science, AVAC, and researchers Dennis Burton and Barton Haynes

NIH's decision to end CHAVD funding removes approximately 10% of global HIV vaccine research funding. Combined with PEPFAR cuts and broader NIH budget reductions, this could scatter research teams and delay trials for years. Researchers have called the timing "devastating" given the promising G002/G003 results. Even if the science works, insufficient funding could prevent the multi-decade development timeline from reaching completion.

3

Immune Response Proves Insufficient for Protection

Discussed by: Historical vaccine trial analyses and NIAID research assessments

Previous trials generated immune responses that did not translate to protection. The RV144 trial showed antibody responses but only 31% efficacy that waned within a year. Even if G004 produces broadly neutralizing antibodies, they may not persist at levels sufficient to prevent infection upon real-world HIV exposure. The multi-immunogen strategy remains untested for actual efficacy.

4

mRNA Platform Accelerates Path to Efficacy Trial by 2030

Discussed by: IAVI-Moderna partnership announcements, Gavi vaccine experts

Moderna's mRNA platform reduced COVID-19 vaccine development from the typical decade-plus timeline to under a year. If the platform provides similar acceleration for HIV—enabling rapid iteration of immunogen designs and faster manufacturing—IAVI could complete the sequential immunization development and begin efficacy testing within five years. This would represent the fastest HIV vaccine development in the field's history.

Historical Context

RV144 Thai Trial (2003-2009)

October 2003 – September 2009

What Happened

A Thai government trial tested a prime-boost combination of two vaccines that had each failed individually. Among 16,402 volunteers, the vaccine reduced HIV infection by 31.2%—the first evidence that any vaccine could provide protection. But efficacy appeared to peak at 60% in the first year and declined rapidly.

Outcome

Short Term

Thailand declined to approve the vaccine because 31% efficacy fell below the 50% threshold for licensing. The result was celebrated as proof-of-concept but not as a usable product.

Long Term

Attempts to replicate and improve upon RV144 in South Africa (HVTN 702) failed entirely, showing 0% efficacy. This forced researchers to fundamentally rethink vaccine strategies rather than iterating on the Thai approach.

Why It's Relevant Today

The germline-targeting strategy being tested in G004 emerged specifically because traditional approaches like RV144 could not generate the broadly neutralizing antibodies scientists believe are necessary for durable protection.

COVID-19 mRNA Vaccine Development (2020)

January – December 2020

What Happened

Moderna designed an mRNA vaccine within 48 hours of receiving the SARS-CoV-2 genetic sequence in January 2020. The first human doses were administered in March. By December, the FDA granted emergency authorization after trials showed 94% efficacy. The entire process—from sequence to authorization—took 11 months.

Outcome

Short Term

mRNA vaccines became the dominant COVID-19 prevention tool in wealthy countries, with billions of doses administered globally.

Long Term

The 2023 Nobel Prize in Physiology or Medicine recognized the mRNA vaccine developers. The platform's success prompted application to other diseases, including HIV, where Moderna now partners with IAVI.

Why It's Relevant Today

The same mRNA platform that enabled rapid COVID-19 vaccine development now delivers the HIV immunogens in G004. If the platform provides similar acceleration, it could compress what has been a 40-year development effort.

Smallpox Eradication (1796-1980)

1796 – 1980

What Happened

Edward Jenner demonstrated in 1796 that cowpox inoculation protected against smallpox. Nearly two centuries later, the WHO launched an intensified eradication campaign in 1967. Through mass vaccination and surveillance-containment, the disease was eliminated worldwide. The last natural case occurred in Somalia in 1977.

Outcome

Short Term

WHO declared smallpox eradicated in 1980—the first and still only human disease eliminated through vaccination.

Long Term

Smallpox eradication proved that a coordinated global vaccination campaign could eliminate a disease entirely, establishing the template for subsequent efforts against polio and other vaccine-preventable diseases.

Why It's Relevant Today

HIV's extreme mutation rate and ability to establish lifelong latent infections make eradication far more difficult than smallpox. But smallpox demonstrates that vaccines can end pandemics—the question for HIV is whether scientists can design one that works against a vastly more challenging pathogen.

12 Sources:
+6
IAVI Science UNAIDS NIAID Scripps Research Wikipedia Vaccines (MDPI) Fred Hutchinson Cancer Center AVAC Science IAVI IAVI