Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans
A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM; heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development; and elicited antibodies exhibited precise bnAb structural mimicry. The results establish clinical proof of concept that heterologous boosting can advance bnAb precursor maturation and demonstrate bnAb priming in Africa, where the HIV burden is highest.
Authors
- Adrian B. McDermott (ORCID: https://orcid.org/0000-0003-0616-9117)
- Troy Sincomb (ORCID: https://orcid.org/0000-0003-4556-649X)
- Kellie J. MacPhee (ORCID: https://orcid.org/0009-0008-0993-4009)
- David C. Montefiori (ORCID: https://orcid.org/0000-0003-0856-6319)
- Walter L. Straus (ORCID: https://orcid.org/0000-0003-1745-3797)
- Mabela Matsoso
- Yiakon Sein (ORCID: https://orcid.org/0000-0002-6448-672X)
- David Joseph Diemert (ORCID: https://orcid.org/0000-0002-2789-0512)
- Alison Benner
- Kelli Greene (ORCID: https://orcid.org/0009-0008-6919-9288)
- Weiwei Wu (ORCID: https://orcid.org/0009-0008-6015-9167)
- Swastik Phulera (ORCID: https://orcid.org/0000-0002-1272-7712)
- Caleb K. Kibet (ORCID: https://orcid.org/0000-0002-0312-4282)
- Srilatha Edupuganti (ORCID: https://orcid.org/0000-0001-6566-9969)
- Zahra Rikhtegaran Tehrani (ORCID: https://orcid.org/0000-0002-1127-1290)
- Barbara Sieck Taylor (ORCID: https://orcid.org/0000-0003-2471-9629)
- Jordan R. Willis (ORCID: https://orcid.org/0000-0002-0135-5263)
- Ju Yeong Kim
- Danny Lu (ORCID: https://orcid.org/0000-0002-2340-3377)
- Richard A. Koup (ORCID: https://orcid.org/0000-0002-3090-7282)
- Pholo Maenetje (ORCID: https://orcid.org/0000-0001-6063-4353)
- Jeong Hyun Lee (ORCID: https://orcid.org/0000-0001-7371-845X)
- Isabel Regadas
- Ryan Tingle (ORCID: https://orcid.org/0000-0003-2874-7010)
- Martin Corcoran (ORCID: https://orcid.org/0000-0002-2774-0936)
- Etienne Karita (ORCID: https://orcid.org/0000-0001-9475-5436)
- Michael Kubitz (ORCID: https://orcid.org/0000-0002-3917-453X)
- Suprabhath Gajjala (ORCID: https://orcid.org/0000-0002-3828-1958)
- John R. Yates (ORCID: https://orcid.org/0000-0001-5267-1672)
- Daniel Muema (ORCID: https://orcid.org/0000-0001-7995-1682)
- Mukundhan Ramaswami (ORCID: https://orcid.org/0000-0002-4804-5676)
- Jolene K. Diedrich (ORCID: https://orcid.org/0000-0001-6489-4558)
- Allan C. deCamp (ORCID: https://orcid.org/0000-0003-1404-4322)
- Linda Murungi
- A. Naidoo
- Sunny Himansu (ORCID: https://orcid.org/0000-0002-7954-9674)
- Janine Maenza (ORCID: https://orcid.org/0000-0002-3992-4193)
- Georgia D. Tomaras (ORCID: https://orcid.org/0000-0001-8076-1931)
- Vinodh Edward (ORCID: https://orcid.org/0000-0003-3952-4760)
- Diana Nyabundi
- James C. Paulson (ORCID: https://orcid.org/0000-0003-4589-5322)
- Devin J Hunt (ORCID: https://orcid.org/0000-0002-2248-9180)
- Nahid Keshavarzi (ORCID: https://orcid.org/0000-0003-4817-4053)
- Sarah F. Andrews (ORCID: https://orcid.org/0000-0002-2583-1949)
- Claudia Flynn
- Gabriel Ozorowski (ORCID: https://orcid.org/0000-0002-9695-8138)
- Gabrielle Lemire (ORCID: https://orcid.org/0000-0002-2834-6973)
- Alexander K. Tsai (ORCID: https://orcid.org/0000-0002-4014-1946)
- Devin Sok (ORCID: https://orcid.org/0000-0002-9354-1740)
- Torben Schiffner (ORCID: https://orcid.org/0000-0001-6772-8870)
- Christopher A. Cottrell (ORCID: https://orcid.org/0000-0002-3364-3083)
- Yumiko Adachi (ORCID: https://orcid.org/0000-0002-0795-9375)
- Jennifer A. Bohl (ORCID: https://orcid.org/0000-0001-6057-1858)
- Johan Vekemans (ORCID: https://orcid.org/0000-0002-3325-9073)
- Dagna Laufer
- S Kim (ORCID: https://orcid.org/0000-0003-3541-4206)
- Alessia Liguori (ORCID: https://orcid.org/0000-0002-8606-574X)
- Rosine Ingabire
- Grace Gibson (ORCID: https://orcid.org/0009-0002-8312-2953)
- Michael Duff
- Drienna Holman
- Nicole Phelps (ORCID: https://orcid.org/0000-0001-9613-3921)
- Allison Kennedy (ORCID: https://orcid.org/0000-0002-0247-0626)
- Nushin Alavi (ORCID: https://orcid.org/0000-0003-3848-6280)
- Nicole L. Yates
- Hongmei Gao (ORCID: https://orcid.org/0000-0002-2468-8589)
- Brett Leav (ORCID: https://orcid.org/0000-0003-0907-0817)
- David M. Brown (ORCID: https://orcid.org/0000-0003-4463-8316)
- Oleksandr Kalyuzhniy (ORCID: https://orcid.org/0000-0002-5273-1951)
- Michelle K. Muthui (ORCID: https://orcid.org/0000-0003-0770-4468)
- Caroline Reuter
- Praveen Alamuri
- William R. Schief (ORCID: https://orcid.org/0000-0002-1120-0150)
- Katherine McKenney (ORCID: https://orcid.org/0000-0002-7321-0530)
- Andrew B. Ward (ORCID: https://orcid.org/0000-0001-7153-3769)
- John Kimotho (ORCID: https://orcid.org/0000-0002-4843-9958)
- Eunice Wambui Nduati (ORCID: https://orcid.org/0000-0001-7578-3095)
- Dominick J. Laddy
- Erica L. Beatman
- Jairo Ivo dos Santos
- Erik Georgeson (ORCID: https://orcid.org/0000-0001-5137-4625)
- Vincent Muturi‐Kioi (ORCID: https://orcid.org/0000-0003-1620-3999)
- Marisa Shields
- Rhianna Bronson (ORCID: https://orcid.org/0009-0009-5513-3250)
- Elise Landais (ORCID: https://orcid.org/0000-0002-8183-5565)
- Adrienne E. Shapiro (ORCID: https://orcid.org/0000-0002-3106-1258)
- Sabyasachi Baboo (ORCID: https://orcid.org/0000-0002-4547-5160)
- Gunilla B. Karlsson Hedestam (ORCID: https://orcid.org/0000-0001-7255-9047)
- M. Juliana McElrath (ORCID: https://orcid.org/0000-0003-2276-7117)
- Kristen Syvertsen
- Madhu Prabhakaran (ORCID: https://orcid.org/0000-0002-1981-9054)
- Ollivier Hyrien (ORCID: https://orcid.org/0000-0003-1909-2542)
- Ruth Chirchir
- Sharon Owuor
- Chunla He
- Li‐An Lin (ORCID: https://orcid.org/0000-0003-2731-1346)
- Xiaoya Zhou
- D. Collins Owuor (ORCID: https://orcid.org/0000-0002-6181-5313)
- K Benson
- Aggrey Anzala
- Julien Nyombayire
- Michael Muteti
- B. Ding
- Sonya Amirzehni
- Wilfrida A Ogonda
- Joel Musando
- Jalen Baptiste
- Melissa Schroeter
Institutions
- Scripps Research Institute (US)
- University of Nairobi (KE)
- National Institutes of Health (US)
- International AIDS Vaccine Initiative (US)
- Emory University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Duke University (US)
- George Washington University (US)
- Vanderbilt University (US)
- University of Washington (US)
- Foundation for the National Institutes of Health (US)
- Karolinska Institutet (SE)
- Kenya Medical Research Institute (KE)
- Fred Hutch Cancer Center (US)
- Center for Human Genetics (US)
- Moderna Therapeutics (United States) (US)
- Kenya AIDS Vaccine Initiative (KE)
- Aurum Institute (ZA)
- Institute of Clinical Research (US)
- Duke Medical Center (US)
- National Institute of Allergy and Infectious Diseases (US)
- Rwanda Biomedical Center (RW)
- Swift Engineering (United States) (US)
- University of KwaZulu-Natal (ZA)
Publication Details
- Journal
- Science
- Published
- 2025-05-15
- DOI
- https://doi.org/10.1126/science.adr8382
- Citations
- 35
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 36.27