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| Title | Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models. |
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| Journal, issue, pages | Sci Transl Med, Vol. 17, Issue 809, Page eadw0721, Year 2025 |
| Publish date | Jul 30, 2025 |
 Authors | Parham Ramezani-Rad / Christopher A Cottrell / Ester Marina-Zárate / Alessia Liguori / Elise Landais / Jonathan L Torres / Amber Myers / Jeong Hyun Lee / Sabyasachi Baboo / Claudia Flynn / Katherine McKenney / Eugenia Salcedo / Xiaoya Zhou / Oleksandr Kalyuzhniy / Erik Georgeson / Nicole Phelps / Danny Lu / Saman Eskandarzadeh / Sergey Menis / Michael Kubitz / Bettina Groschel / Nushin Alavi / Abigail M Jackson / Wen-Hsin Lee / Andy S Tran / Elana Ben-Akiva / Katarzyna Kaczmarek Michaels / Jolene K Diedrich / Chiamaka A Enemuo / Vanessa Lewis / Arpan Pradhan / Sudhir Pai Kasturi / Torben Schiffner / Jon M Steichen / Diane G Carnathan / Sunny Himansu / John R Yates / James C Paulson / Gabriel Ozorowski / Darrell J Irvine / Guido Silvestri / Devin Sok / Andrew B Ward / Shane Crotty / William R Schief /  |
| PubMed Abstract | A protective vaccine against human immunodeficiency virus (HIV) will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope ...A protective vaccine against human immunodeficiency virus (HIV) will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope glycoprotein (Env) trimer. Nearly all vaccine strategies to induce bnAbs require the use of complex immunization regimens involving a series of different immunogens, most of which are Env trimers. Producing protein-based clinical material to evaluate such relatively complex regimens in humans presents major challenges in cost and time. Furthermore, immunization with HIV trimers as soluble proteins induces strong nonneutralizing responses to the trimer base, which is normally occluded on the virion. These base responses could potentially detract from the elicitation of nAbs and the eventual induction of bnAbs. mRNA vaccine platforms offer potential advantages over protein delivery for HIV vaccine development, including increased production speed, reduced cost, and the ability to deliver membrane-bound trimers that might facilitate improved immuno-focusing to nonbase epitopes. We report the design of mRNA-delivered soluble and membrane-bound forms of a stabilized native-like Env trimer (BG505 MD39.3); initial immunogenicity evaluation in rabbits that triggered clinical evaluation; and more comprehensive evaluation of B cell, T cell, and antibody responses in nonhuman primates. mRNA-encoded membrane-bound Env immunization elicited reduced off-target base-directed Env responses and stronger nAb responses compared with mRNA-encoded soluble Env. Overall, mRNA delivery of membrane-bound Env appears promising for enhancing B cell responses to subdominant epitopes and facilitating rapid translation to clinical testing, which should assist HIV vaccine development. |
 External links | Sci Transl Med / PubMed:40737430 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 25.0 Å |
| Structure data |  EMDB-70838: Rabbit 37496 base and V1/V3 epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70839: Rabbit 37496 base and gp41-GH epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70840: Rabbit 37496 base and gp120-GH epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70846: Rabbit 37496 base and C3V5 epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70847: Rabbit 37450 base, gp41-FP and gp120int epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70848: Rabbit 37442 base and gp120int epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70852: NHP RJh18 base epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70855: NHP RUv18 base epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70858: NHP RUv18 V1/V3 epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP  EMDB-70860: NHP REy18 base and V1/V3 epitope polyclonal Fabs in complex with BG505 MD39.3 SOSIP |
| Source |
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Human immunodeficiency virus 1
Oryctolagus cuniculus (rabbit)
Macaca mulatta (Rhesus monkey)