Safety and immunogenicity of an HIV-1 prefusion-stabilized envelope trimer (Trimer 4571) vaccine in healthy adults: A first-in-human open-label, randomized, dose-escalation, phase 1 clinical trial.
BG505 DS-SOSIP.664
HIV-1
NIH
Phase 1 clinical trial
Trimer 4571
Vaccine
Journal
EClinicalMedicine
ISSN: 2589-5370
Titre abrégé: EClinicalMedicine
Pays: England
ID NLM: 101733727
Informations de publication
Date de publication:
Jun 2022
Jun 2022
Historique:
received:
28
03
2022
revised:
10
05
2022
accepted:
11
05
2022
entrez:
5
7
2022
pubmed:
6
7
2022
medline:
6
7
2022
Statut:
epublish
Résumé
Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults. We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130. Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups. Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1. Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Sections du résumé
Background
UNASSIGNED
Advances in therapeutic drugs have increased life-expectancies for HIV-infected individuals, but the need for an effective vaccine remains. We assessed safety and immunogenicity of HIV-1 vaccine, Trimer 4571 (BG505 DS-SOSIP.664) adjuvanted with aluminum hydroxide (alum), in HIV-negative adults.
Methods
UNASSIGNED
We conducted a phase I, randomized, open-label, dose-escalation trial at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Eligible participants were HIV-negative, healthy adults between 18-50 years. Participants were randomized 1:1 to receive Trimer 4571 adjuvanted with 500 mcg alum by either the subcutaneous (SC) or intramuscular (IM) route at weeks 0, 8, and 20 in escalating doses of 100 mcg or 500 mcg. The primary objectives were to evaluate the safety and tolerability of Trimer 4571 with a secondary objective of evaluating vaccine-induced antibody responses. The primary and safety endpoints were evaluated in all participants who received at least one dose of Trimer 4571. Trial results were summarized using descriptive statistics. This trial is registered at ClinicalTrials.gov, NCT03783130.
Findings
UNASSIGNED
Between March 7 and September 11, 2019, 16 HIV-negative participants were enrolled, including six (38%) males and ten (62%) females. All participants received three doses of Trimer 4571. Solicited reactogenicity was mild to moderate in severity, with one isolated instance of severe injection site redness (6%) following a third 500 mcg SC administration. The most commonly reported solicited symptoms included mild injection site tenderness in 14 (88%) and mild myalgia in six (38%) participants. The most frequent unsolicited adverse event attributed to vaccination was mild injection site pruritus in six (38%) participants. Vaccine-induced seropositivity occurred in seven (44%) participants and resolved in all but one (6%). No serious adverse events occurred. Trimer 4571-specific binding antibodies were detected in all groups two weeks after regimen completion, primarily focused on the glycan-free trimer base. Neutralizing antibody activity was limited to the 500 mcg dose groups.
Interpretation
UNASSIGNED
Trimer 4571 was safe, well tolerated, and immunogenic in this first-in-human trial. While this phase 1 trial is limited in size, our results inform and support further evaluation of prefusion-stabilized HIV-1 envelope trimers as a component of vaccine design strategies to generate broadly neutralizing antibodies against HIV-1.
Funding
UNASSIGNED
Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
Identifiants
pubmed: 35783486
doi: 10.1016/j.eclinm.2022.101477
pii: S2589-5370(22)00207-3
pmc: PMC9249552
doi:
Banques de données
ClinicalTrials.gov
['NCT03783130']
Types de publication
Journal Article
Langues
eng
Pagination
101477Informations de copyright
© 2022 The Authors.
Déclaration de conflit d'intérêts
CC, HG, JRM, and PDK are listed on patent applications involving Trimer 4571. All other authors declare no competing interests.
Références
Cell Rep. 2020 Aug 4;32(5):107981
pubmed: 32755575
N Engl J Med. 2020 Nov 12;383(20):1920-1931
pubmed: 32663912
J Virol. 2020 Jun 16;94(13):
pubmed: 32295908
Vaccine. 2021 Jun 8;39(25):3379-3387
pubmed: 34020817
Cold Spring Harb Perspect Med. 2012 Jan;2(1):a007039
pubmed: 22315717
Sci Rep. 2020 Feb 20;10(1):3032
pubmed: 32080235
PLoS Pathog. 2013 Sep;9(9):e1003618
pubmed: 24068931
Cell Rep. 2018 Aug 21;24(8):1958-1966.e5
pubmed: 30134158
Semin Immunol. 2020 Aug;50:101428
pubmed: 33246736
N Engl J Med. 2020 Jul 2;383(1):1-4
pubmed: 32609976
Cell Rep. 2021 Apr 6;35(1):108937
pubmed: 33826898
Nature. 2014 Oct 23;514(7523):455-61
pubmed: 25296255
J Am Soc Mass Spectrom. 2019 Sep;30(9):1663-1678
pubmed: 31111416
J Virol. 2000 Jan;74(2):627-43
pubmed: 10623724
Ann Intern Med. 1996 Aug 15;125(4):270-9
pubmed: 8678389
J Exp Med. 2005 May 2;201(9):1407-19
pubmed: 15867093
Science. 2016 May 13;352(6287):828-33
pubmed: 27174988
N Engl J Med. 2009 Dec 3;361(23):2209-20
pubmed: 19843557
J Infect Dis. 2005 Mar 1;191(5):654-65
pubmed: 15688278
Nat Struct Mol Biol. 2015 Jul;22(7):522-31
pubmed: 26098315
Science. 2019 Aug 2;365(6452):505-509
pubmed: 31371616
J Infect Dis. 2005 Mar 1;191(5):666-77
pubmed: 15688279
JAMA. 2010 Jul 21;304(3):275-83
pubmed: 20639561
J Virol. 2005 Jul;79(14):8828-34
pubmed: 15994776
Nat Commun. 2015 Feb 05;6:6144
pubmed: 25652336
Immunity. 2018 May 15;48(5):855-871
pubmed: 29768174
J Virol. 2017 Apr 28;91(10):
pubmed: 28275193
J Infect Dis. 2006 Dec 15;194(12):1661-71
pubmed: 17109337
Vaccine. 2002 May 31;20 Suppl 3:S18-23
pubmed: 12184360
J Infect Dis. 2010 Aug 15;202(4):595-605
pubmed: 20608874
Science. 2014 Nov 7;346(6210):759-63
pubmed: 25298114
Cell Rep. 2017 Apr 25;19(4):719-732
pubmed: 28445724
Nat Med. 2018 Jun;24(6):857-867
pubmed: 29867235
Cell Rep. 2020 Mar 17;30(11):3755-3765.e7
pubmed: 32187547