用mRNA编码的纳米颗粒进行疫苗接种可推动人类体内HIV广谱中和抗体前体的早期成熟。

Vaccination with mRNA-encoded nanoparticles drives early maturation of HIV bnAb precursors in humans.

作者信息

Willis Jordan R, Prabhakaran Madhu, Muthui Michelle, Naidoo Ansuya, Sincomb Troy, Wu Weiwei, Cottrell Christopher A, Landais Elise, deCamp Allan C, Keshavarzi Nahid R, Kalyuzhniy Oleksandr, Lee Jeong Hyun, Murungi Linda M, Ogonda Wilfrida A, Yates Nicole L, Corcoran Martin M, Phulera Swastik, Musando Joel, Tsai Amanda, Lemire Gabrielle, Sein Yiakon, Muteti Michael, Alamuri Praveen, Bohl Jennifer A, Holman Drienna, Himansu Sunny, Leav Brett, Reuter Caroline, Lin Li-An, Ding Baoyu, He Chunla, Straus Walter L, MacPhee Kellie J, Regadas Isabel, Nyabundi Diana V, Chirchir Ruth, Anzala Aggrey, Kimotho John N, Kibet Caleb, Greene Kelli, Gao Hongmei, Beatman Erica, Benson Kiara, Laddy Dominick, Brown David M, Bronson Rhianna, Baptiste Jalen, Gajjala Suprabhath, Rikhtegaran-Tehrani Zahra, Benner Alison, Ramaswami Mukundhan, Lu Danny, Alavi Nushin, Amirzehni Sonya, Kubitz Michael, Tingle Ryan, Georgeson Erik, Phelps Nicole, Adachi Yumiko, Liguori Alessia, Flynn Claudia, McKenney Katherine, Zhou Xiaoya, Owuor D Collins, Owuor Sharon, Kim Soo-Young, Duff Michael, Kim Ju Yeong, Gibson Grace, Baboo Sabyasachi, Diedrich Jolene, Schiffner Torben, Shields Marisa, Matsoso Mabela, Santos Jennifer, Syvertsen Kristen, Kennedy Allison, Schroeter Melissa, Vekemans Johan, Yates John, Paulson James C, Hyrien Ollivier, McDermott Adrian B, Maenetje Pholo, Nyombayire Julien, Karita Etienne, Ingabire Rosine, Edward Vinodh, Muturi-Kioi Vincent, Maenza Janine, Shapiro Adrienne E, McElrath M Juliana, Edupuganti Srilatha, Taylor Barbara S, Diemert David, Ozorowski Gabriel, Koup Richard A, Montefiori David, Ward Andrew B, Hedestam Gunilla Karlsson, Tomaras Georgia, Hunt Devin J, Muema Daniel, Sok Devin, Laufer Dagna S, Andrews Sarah F, Nduati Eunice W, Schief William R

机构信息

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA.

IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA, USA.

出版信息

Science. 2025 May 15:eadr8382. doi: 10.1126/science.adr8382.

DOI:10.1126/science.adr8382

PMID:40373112

Abstract

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, 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 18% of IAVI-G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM, and heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development. 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.

摘要

一种领先的HIV疫苗策略需要一种启动免疫原诱导广泛中和抗体（bnAb）前体，随后进行一系列异源加强免疫以引发体细胞超突变（SHM）并产生bnAb。在美国进行的IAVI-G002以及在卢旺达和南非进行的IAVI-G003这两项随机、开放标签的1期人体临床试验中，我们评估了mRNA编码的纳米颗粒作为启动免疫原（两项试验）和首次加强免疫原（IAVI-G002）的安全性和免疫原性。这些疫苗总体上是安全的且耐受性良好，不过IAVI-G002的参与者中有18%出现了皮肤反应。启动免疫以相当高的频率诱导了bnAb前体和SHM，而异源加强免疫引发了更高的SHM、亲和力以及针对bnAb产生的中和活性。这些结果确立了异源加强免疫可促进bnAb前体成熟的临床概念验证，并在HIV负担最重的非洲证明了bnAb启动免疫的可行性。