Experimental medicine study with stabilised native-like HIV-1 Env immunogens drives long-term antibody responses, but lacks neutralising breadth
File(s)
Published version
Author(s)
Shattock, Robin
Type
Journal Article
Abstract
Background
We report findings from an experimental medicine study of rationally designed prefusion
stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global
circulating strains, delivered by sequential intramuscular injection.
Methods
Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a
different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO,
either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic
Env immunogens (Mos3·1 and Mos3·2). All immunogens were co-formulated with liposomal
Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post
final Mosaic booster injection. Participants gave written informed consent to join the study.
The study is registered on ClinicalTrials.gov ID NCT03816137.
Findings
Fifty-one participants (men n=23 and women n=28) aged 18-55 were enrolled. The
seroconversion rate against Env was 100% with all participants having measurable anti-Env
IgG antibodies after their second injection and throughout the study. Neutralisation was
detected against the ConM pseudovirus in sera of those who had received both ConM and
ConS immunogens. However, this activity was limited in breadth and was neither boosted nor
broadened in those receiving the Mos3·1 and Mos3·2 immunogens. Neutralising antibody
function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.
Interpretation
Rationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in
a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody
titres of significant breadth, but they represent potentially valuable polishing immunogens after
germline-targeting.
3
Funding
European Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant
number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation
(INV-002916).
We report findings from an experimental medicine study of rationally designed prefusion
stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global
circulating strains, delivered by sequential intramuscular injection.
Methods
Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a
different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO,
either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic
Env immunogens (Mos3·1 and Mos3·2). All immunogens were co-formulated with liposomal
Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post
final Mosaic booster injection. Participants gave written informed consent to join the study.
The study is registered on ClinicalTrials.gov ID NCT03816137.
Findings
Fifty-one participants (men n=23 and women n=28) aged 18-55 were enrolled. The
seroconversion rate against Env was 100% with all participants having measurable anti-Env
IgG antibodies after their second injection and throughout the study. Neutralisation was
detected against the ConM pseudovirus in sera of those who had received both ConM and
ConS immunogens. However, this activity was limited in breadth and was neither boosted nor
broadened in those receiving the Mos3·1 and Mos3·2 immunogens. Neutralising antibody
function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.
Interpretation
Rationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in
a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody
titres of significant breadth, but they represent potentially valuable polishing immunogens after
germline-targeting.
3
Funding
European Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant
number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation
(INV-002916).
Date Issued
2025-02
Date Acceptance
2024-12-19
Citation
EBioMedicine, 2025, 112
ISSN
2352-3964
Publisher
Elsevier
Journal / Book Title
EBioMedicine
Volume
112
Copyright Statement
© 2024 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
creativecommons.org/licenses/by-nc-nd/4.0/).
Identifier
https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(24)00580-2/fulltext
Publication Status
Published
Article Number
105544
Date Publish Online
2025-01-02