Publication:
Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19)

Issued Date

2018-07-21

Resource Type

Article

ISSN

1474547X
01406736

DOI

10.1016/S0140-6736(18)31364-3

Other identifier(s)

2-s2.0-85053156358

Rights

Mahidol University

Rights Holder(s)

SCOPUS

Bibliographic Citation

The Lancet. Vol.392, No.10143 (2018), 232-243

Suggested Citation

Dan H. Barouch, Frank L. Tomaka, Frank Wegmann, Daniel J. Stieh, Galit Alter, Merlin L. Robb, Nelson L. Michael, Lauren Peter, Joseph P. Nkolola, Erica N. Borducchi, Abishek Chandrashekar, David Jetton, Kathryn E. Stephenson, Wenjun Li, Bette Korber, Georgia D. Tomaras, David C. Montefiori, Glenda Gray, Nicole Frahm, M. Juliana McElrath, Lindsey Baden, Jennifer Johnson, Julia Hutter, Edith Swann, Etienne Karita, Hannah Kibuuka, Juliet Mpendo, Nigel Garrett, Kathy Mngadi, Kundai Chinyenze, Frances Priddy, Erica Lazarus, Fatima Laher, Sorachai Nitayapan, Punnee Pitisuttithum, Stephan Bart, Thomas Campbell, Robert Feldman, Gregg Lucksinger, Caroline Borremans, Katleen Callewaert, Raphaele Roten, Jerald Sadoff, Lorenz Scheppler, Mo Weijtens, Karin Feddes-de Boer, Daniëlle van Manen, Jessica Vreugdenhil, Roland Zahn, Ludo Lavreys, Steven Nijs, Jeroen Tolboom, Jenny Hendriks, Zelda Euler, Maria G. Pau, Hanneke Schuitemaker Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19). The Lancet. Vol.392, No.10143 (2018), 232-243. doi:10.1016/S0140-6736(18)31364-3 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/46498

Research Projects

Organizational Units

Authors

Journal Issue

Thesis

Title

Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised, double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and in rhesus monkeys (NHP 13-19)

Author(s)

Dan H. Barouch
 Frank L. Tomaka
 Frank Wegmann
 Daniel J. Stieh
 Galit Alter
 Merlin L. Robb
 Nelson L. Michael
 Lauren Peter
 Joseph P. Nkolola
 Erica N. Borducchi
 Abishek Chandrashekar
 David Jetton
 Kathryn E. Stephenson
 Wenjun Li
 Bette Korber
 Georgia D. Tomaras
 David C. Montefiori
 Glenda Gray
 Nicole Frahm
 M. Juliana McElrath
 Lindsey Baden
 Jennifer Johnson
 Julia Hutter
 Edith Swann
 Etienne Karita
 Hannah Kibuuka
 Juliet Mpendo
 Nigel Garrett
 Kathy Mngadi
 Kundai Chinyenze
 Frances Priddy
 Erica Lazarus
 Fatima Laher
 Sorachai Nitayapan
 Punnee Pitisuttithum
 Stephan Bart
 Thomas Campbell
 Robert Feldman
 Gregg Lucksinger
 Caroline Borremans
 Katleen Callewaert
 Raphaele Roten
 Jerald Sadoff
 Lorenz Scheppler
 Mo Weijtens
 Karin Feddes-de Boer
 Daniëlle van Manen
 Jessica Vreugdenhil
 Roland Zahn
 Ludo Lavreys
 Steven Nijs
 Jeroen Tolboom
 Jenny Hendriks
 Zelda Euler
 Maria G. Pau
 Hanneke Schuitemaker

Other Contributor(s)

Janssen Vaccines & Prevention B.V.
 Centre for the AIDS Programme of Research in South Africa
 International AIDS Vaccine Initiative
 Makerere University
 Janssen
 Massachusetts Institute of Technology
 Miami Research Associates
 National Institute of Allergy and Infectious Diseases
 Brigham and Women's Hospital
 University of Witwatersrand
 HJF
 Walter Reed Army Institute of Research
 Mahidol University
 University of Colorado at Denver
 Duke University
 Los Alamos National Laboratory
 Royal Thai Army
 Fred Hutchinson Cancer Research Center
 Harvard Medical School
 University of Massachusetts Medical School
 Optimal Research LLC
 Tekton Research
 Janssen Infectious Diseases
 Rwanda Zambia HIV Research Group

Abstract

© 2018 Elsevier Ltd Background: More than 1·8 million new cases of HIV-1 infection were diagnosed worldwide in 2016. No licensed prophylactic HIV-1 vaccine exists. A major limitation to date has been the lack of direct comparability between clinical trials and preclinical studies. We aimed to evaluate mosaic adenovirus serotype 26 (Ad26)-based HIV-1 vaccine candidates in parallel studies in humans and rhesus monkeys to define the optimal vaccine regimen to advance into clinical efficacy trials. Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled phase 1/2a trial (APPROACH). Participants were recruited from 12 clinics in east Africa, South Africa, Thailand, and the USA. We included healthy, HIV-1-uninfected participants (aged 18–50 years) who were considered at low risk for HIV-1 infection. We randomly assigned participants to one of eight study groups, stratified by region. Participants and investigators were blinded to the treatment allocation throughout the study. We primed participants at weeks 0 and 12 with Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) expressing mosaic HIV-1 envelope (Env)/Gag/Pol antigens and gave boosters at weeks 24 and 48 with Ad26.Mos.HIV or modified vaccinia Ankara (MVA; 108 plaque-forming units per 0·5 mL) vectors with or without high-dose (250 μg) or low-dose (50 μg) aluminium adjuvanted clade C Env gp140 protein. Those in the control group received 0·9% saline. All study interventions were administered intramuscularly. Primary endpoints were safety and tolerability of the vaccine regimens and Env-specific binding antibody responses at week 28. Safety and immunogenicity were also assessed at week 52. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. We also did a parallel study in rhesus monkeys (NHP 13-19) to assess the immunogenicity and protective efficacy of these vaccine regimens against a series of six repetitive, heterologous, intrarectal challenges with a rhesus peripheral blood mononuclear cell-derived challenge stock of simian-human immunodeficiency virus (SHIV-SF162P3). The APPROACH trial is registered with ClinicalTrials.gov, number NCT02315703. Findings: Between Feb 24, 2015, and Oct 16, 2015, we randomly assigned 393 participants to receive at least one dose of study vaccine or placebo in the APPROACH trial. All vaccine regimens demonstrated favourable safety and tolerability. The most commonly reported solicited local adverse event was mild-to-moderate pain at the injection site (varying from 69% to 88% between the different active groups vs 49% in the placebo group). Five (1%) of 393 participants reported at least one grade 3 adverse event considered related to the vaccines: abdominal pain and diarrhoea (in the same participant), increased aspartate aminotransferase, postural dizziness, back pain, and malaise. The mosaic Ad26/Ad26 plus high-dose gp140 boost vaccine was the most immunogenic in humans; it elicited Env-specific binding antibody responses (100%) and antibody-dependent cellular phagocytosis responses (80%) at week 52, and T-cell responses at week 50 (83%). We also randomly assigned 72 rhesus monkeys to receive one of five different vaccine regimens or placebo in the NHP 13-19 study. Ad26/Ad26 plus gp140 boost induced similar magnitude, durability, and phenotype of immune responses in rhesus monkeys as compared with humans and afforded 67% protection against acquisition of SHIV-SF162P3 infection (two-sided Fisher's exact test p=0·007). Env-specific ELISA and enzyme-linked immunospot assay responses were the principal immune correlates of protection against SHIV challenge in monkeys. Interpretation: The mosaic Ad26/Ad26 plus gp140 HIV-1 vaccine induced comparable and robust immune responses in humans and rhesus monkeys, and it provided significant protection against repetitive heterologous SHIV challenges in rhesus monkeys. This vaccine concept is currently being evaluated in a phase 2b clinical efficacy study in sub-Saharan Africa (NCT03060629). Funding: Janssen Vaccines & Prevention BV, National Institutes of Health, Ragon Institute of MGH, MIT and Harvard, Henry M Jackson Foundation for the Advancement of Military Medicine, US Department of Defense, and International AIDS Vaccine Initiative.

Keyword(s)

Medicine

Availability

URI

https://repository.li.mahidol.ac.th/handle/20.500.14594/46498

Collections

Scopus 2018