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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

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. After four decades and dozens of failed trials, IAVI is dosing participants in South Africa with a vaccine that trains the immune system from the ground up rather than simply presenting viral proteins.

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 trial since then has failed. This new germline-targeting strategy, developed by Scripps Research and IAVI, attempts to activate rare B cells (perhaps one in 300,000) capable of producing broadly neutralizing antibodies.

The IAVI G004 trial began in December 2025 as the fourth step in a sequential vaccination strategy that has already shown proof-of-concept in humans. Early trials show 94-97% of recipients develop the targeted immune response. Yet this progress faces a funding crisis: NIH announced it will end support for its major HIV vaccine consortia in 2026.

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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
Leading organization through G004 trial and funding uncertainty
 William Schief
William Schief
Lead designer of germline-targeting immunogens being tested in G004
 Linda-Gail Bekker
Linda-Gail Bekker
Leading G004 trial implementation in South Africa
 Dennis Burton
Dennis Burton
Facing end of NIH CHAVD funding in 2026

Organizations Involved

IAVI (International AIDS Vaccine Initiative)
IAVI (International AIDS Vaccine Initiative)
Nonprofit Research Organization
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
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
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 institute
Ending CHAVD funding; shifting focus to existing HIV treatment approaches

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

Timeline

April 1984 January 2026

14 events Latest: January 6th, 2026 · 5 months ago Showing 8 of 14
Tap a bar to jump to that date

  1. IAVI Announces G004 Trial Initiation

    Latest 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.

Historical Context

3 moments from history that rhyme with this story — and how they unfolded.

October 2003 – September 2009

RV144 Thai Trial (2003-2009)

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.

Then

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.

Now

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 this matters now

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.

January – December 2020

COVID-19 mRNA Vaccine Development (2020)

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.

Then

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

Now

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 this matters now

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.

1796 – 1980

Smallpox Eradication (1796-1980)

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.

Then

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

Now

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 this matters now

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.

Sources

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