Lindsey R. Baden, MD; Etienne Karita, MD; Gaudensia Mutua, MBChB; Linda-Gail Bekker, MD; Glenda Gray, MBBCh; Liesl Page-Shipp, MD; Stephen R. Walsh, MD; Julien Nyombayire, MD; Omu Anzala, MBChB, PhD; Surita Roux, MD; Fatima Laher, MBBCh; Craig Innes, MD; Michael S. Seaman, PhD; Yehuda Z. Cohen, MD; Lauren Peter; Nicole Frahm, PhD; M. Juliana McElrath, MD, PhD; Peter Hayes, PhD; Edith Swann, PhD; Nicole Grunenberg, MD; Maria Grazia-Pau, MSc; Mo Weijtens, PhD; Jerry Sadoff, MD; Len Dally, MSc; Angela Lombardo, PhD; Jill Gilmour, PhD; Josephine Cox, PhD; Raphael Dolin, MD; Patricia Fast, MD, PhD; Dan H. Barouch, MD, PhD; Dagna S. Laufer, MD; for the B003-IPCAVD004-HVTN091 Study Group *
Disclaimer: The contents are the responsibility of the authors and do not necessarily reflect the views of the U.S. Agency for International Development or the U.S. government.
Acknowledgment: The authors thank all of the participants across the trial sites and the staff at the clinical research centers and immunology support laboratories. They also thank the EMMES Corporation and Statistical Center for HIV/AIDS Research & Prevention for data analysis and clinical trial database support. In addition, the authors thank the U.S. Agency for International Development; National Institutes of Health; and Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University for their support. They also thank Nicholas Mangeya and Llewellyn Fleurs from the Desmond Tutu HIV Centre Institute of Infectious Disease and Molecular Medicine Faculty of Health Sciences for clinical support, as well as Michele Fong-Lim and Donna Cordasco from the International AIDS Vaccine Initiative for quality assurance support and Claudia Schmidt and Kristen Syvertsen for clinical trial support. The authors also thank Lorna Clark, Laura Sharpe, and technical staff at the International AIDS Vaccine Initiative Human Immunology Laboratory; Michael Pensiero, PhD, from the National Institute of Allergy and Infectious Diseases, National Institutes of Health; and Kaitlin Smith, Chelsea Reinhold, Anna McNally, Ann Cheung, and Mark Justin Iampietro from the BIDMC laboratory.
Grant Support: By the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; National Institutes of Health (grants AI066305 [D.H.B.], UM1AI068618, UMAI068635, and UMAI068614); and International AIDS Vaccine Initiative. The International AIDS Vaccine Initiative's work is made possible by many donors, including the Bill & Melinda Gates Foundation, Ministry of Foreign Affairs of Denmark, Irish Aid, Ministry of Finance of Japan in partnership with the World Bank, Ministry of Foreign Affairs of The Netherlands, Norwegian Agency for Development Cooperation, U.K. Department for International Development, and U.S. Agency for International Development. The full list of International AIDS Vaccine Initiative donors is available at www.iavi.org. This study was made possible by the U.S. Agency for International Development.
Disclosures: Dr. Baden reports grants from the Ragon Institute and National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study; grants from the Ragon Institute, NIH/NIAID, and Bill & Melinda Gates Foundation outside the submitted work; and involvement in HIV vaccine clinical trials conducted in collaboration with the NIH, the HIV Vaccine Trials Network, the International AIDS Vaccine Initiative, Crucell Holland/Janssen Pharmaceuticals, the Military HIV Research Program, the Bill & Melinda Gates Foundation, and the Ragon Institute. Dr. Walsh reports grants from the NIH/NIAID during the conduct of the study and grants from Crucell Holland/Janssen Pharmaceuticals outside the submitted work. Dr. Laher reports grants from the International AIDS Vaccine Initiative; NIH/NIAID; and the Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University in collaboration with Crucell Holland/Janssen Pharmaceuticals during the conduct of the study. Dr. Frahm reports grants from the NIH/NIAID during the conduct of the study. Dr. Grunenberg reports grants and nonfinancial support from the NIH/NIAID, Division of AIDS, during the conduct of the study and nonfinancial support from Sanofi Pasteur, Novartis Vaccines and Diagnostics, GeoVax, and GlaxoSmithKline outside the submitted work. Ms. Grazia-Pau reports grants from the NIH during the conduct of the study and personal fees and other from Crucell Holland/Janssen Pharmaceuticals outside the submitted work, as well as a pending patent. Dr. Weijtens reports grants from the NIH/NIAID during the conduct of the study and personal fees and other from Janssen outside the submitted work. Dr. Sadoff reports other from Crucell Holland/Janssen Pharmaceuticals during the conduct of the study. Dr. Dolin reports grants from the Ragon Institute and NIAID during the conduct of the study and grants from the Bill & Melinda Gates Foundation and Janssen Pharmaceuticals outside the submitted work. Dr. Fast reports that the International AIDS Vaccine Initiative owns the rights for the use of Ad35 for the prevention of HIV infection. Dr. Barouch reports grants from the NIH and Ragon Institute during the conduct of the study and grants from the NIH, the Bill & Melinda Gates Foundation, the U.S. Department of Defense/Henry M. Jackson Foundation for the Advancement of Military Medicine, the Ragon Institute, Crucell Holland, Pfizer, and amfAR outside the submitted work, as well as a patent vaccine vector and antigen patents licensed to Crucell Holland. Authors not named here have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0880.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Reproducible Research Statement:Study protocol: See the Protocol section of the Supplement. Statistical code and data set: Available from Dr. Baden (e-mail, lbaden@partners.org), Dr. Laufer (e-mail, dlaufer@iavi.org), or Mr. Dally (e-mail, ldally@emmes.com) for those who meet criteria for access to the data.
Requests for Single Reprints: Lindsey R. Baden, MD, Division of Infectious Diseases, Brigham and Women's Hospital, PBB-A4, 15 Francis Street, Boston, MA 02115; e-mail, lbaden@partners.org.
Current Author Addresses: Drs. Baden and Walsh: Division of Infectious Diseases, Brigham and Women's Hospital, PBB-A4, 15 Francis Street, Boston, MA 02115.
Drs. Karita and Nyombayire: Projet San Francisco, KK19Av 57, PO Box 780, Kigali, Rwanda.
Drs. Mutua and Anzala: Kenya AIDS Vaccine Initiative–Institute of Clinical Research, University of Nairobi, PO Box 19676-00202 KNH Nairobi, Kenya.
Drs. Bekker and Roux: Desmond Tutu HIV Centre, PO Box 13801, Mowbray 7705 Cape Town, South Africa.
Drs. Gray and Laher: Perinatal HIV Research Unit, Old Porch Road, Moreleta Park, Soweto, South Africa.
Drs. Page-Shipp and Innes: Aurum Institute for Health Research, 2nd Floor, Room 201 Jade Square, Cnr. Oliver Tambo & Margaretha Prinsloo Street, Klerksdorp, South Africa.
Drs. Seaman, Dolin, and Barouch and Ms. Peter: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
Dr. Cohen: The Rockefeller University, 1230 York Avenue, Box 95, New York, NY 10065.
Drs. Frahm, McElrath, and Grunenberg: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, PO Box 19024, Seattle, WA 98109.
Drs. Hayes and Gilmour: International AIDS Vaccine Initiative Human Immunology Laboratory, 2nd Floor, Lift Bank D, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom.
Dr. Swann: National Institute of Allergy and Infectious Diseases, 5601 Fishers Lane, Room 9C46, Bethesda, MD 20852.
Ms. Grazia-Pau and Drs. Weijtens Sadoff: Janssen Infectious Diseases and Vaccines (formerly Crucell Holland BV), Crucell N.V., PO Box 2048, 2301 CA, Leiden, the Netherlands.
Mr. Dally: The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850.
Drs. Lombardo, Cox, Fast and Laufer: International AIDS Vaccine Initiative, 125 Broad Street, 9th Floor, New York, 10004.
Author Contributions: Conception and design: L.R. Baden, S.R. Walsh, O. Anzala, P. Hayes, E. Swann, M. Grazia-Pau, J. Sadoff, A. Lombardo, J. Gilmour, R. Dolin, P. Fast, D.H. Barouch, D.S. Laufer.
Analysis and interpretation of the data: L.R. Baden, E. Karita, G. Gray, S.R. Walsh, Y.Z. Cohen, N. Frahm, P. Hayes, N. Grunenberg, M. Grazia-Pau, J. Sadoff, L. Dally, A. Lombardo, J. Gilmour, J. Cox, R. Dolin, P. Fast, D.H. Barouch, D.S. Laufer.
Drafting of the article: L.R. Baden, E. Karita, L.G. Bekker, G. Gray, S.R. Walsh, J. Nyombayire, O. Anzala, N. Frahm, P. Hayes, N. Grunenberg, J. Sadoff, L. Dally, A. Lombardo, J. Cox, R. Dolin, P. Fast, D.S. Laufer.
Critical revision of the article for important intellectual content: L.R. Baden, G. Gray, S.R. Walsh, F. Laher, C. Innes, P. Hayes, M. Grazia-Pau, M. Weijtens, J. Sadoff, J. Gilmour, J. Cox, R. Dolin, P. Fast, D.H. Barouch, D.S. Laufer.
Final approval of the article: L.R. Baden, E. Karita, G. Mutua, L.G. Bekker, G. Gray, L. Page-Shipp, S.R. Walsh, J. Nyombayire, O. Anzala, S. Roux, F. Laher, C. Innes, M.S. Seaman, Y.Z. Cohen, L. Peter, N. Frahm, M.J. McElrath, P. Hayes, E. Swann, N. Grunenberg, M. Grazia-Pau, M. Weijtens, J. Sadoff, L. Dally, A. Lombardo, J. Gilmour, J. Cox, R. Dolin, P. Fast, D.H. Barouch, D.S. Laufer.
Provision of study materials or patients: L.R. Baden, E. Karita, G. Mutua, G. Gray, L. Page-Shipp, S.R. Walsh, F. Laher, C. Innes, M.J. McElrath, N. Grunenberg, M. Grazia-Pau, M. Weijtens, D.H. Barouch.
Statistical expertise: L. Dally.
Obtaining of funding: L.R. Baden, M.J. McElrath, M. Weijtens, J. Gilmour, R. Dolin, D.H. Barouch.
Administrative, technical, or logistic support: L.R. Baden, G. Mutua, M.S. Seaman, N. Frahm, P. Hayes, N. Grunenberg, R. Dolin, D.H. Barouch.
Collection and assembly of data: L.R. Baden, E. Karita, G. Mutua, L.G. Bekker, G. Gray, L. Page-Shipp, S.R. Walsh, J. Nyombayire, O. Anzala, S. Roux, F. Laher, Y.Z. Cohen, L. Peter, N. Frahm, P. Hayes, J. Gilmour, J. Cox, R. Dolin, D.H. Barouch.
A prophylactic HIV-1 vaccine is a global health priority.
To assess a novel vaccine platform as a prophylactic HIV-1 regimen.
Randomized, double-blind, placebo-controlled trial. Both participants and study personnel were blinded to treatment allocation. (ClinicalTrials.gov: NCT01215149)
United States, East Africa, and South Africa.
Healthy adults without HIV infection.
2 HIV-1 vaccines (adenovirus serotype 26 with an HIV-1 envelope A insert [Ad26.EnvA] and adenovirus serotype 35 with an HIV-1 envelope A insert [Ad35.Env], both administered at a dose of 5 × 1010 viral particles) in homologous and heterologous combinations.
Safety and immunogenicity and the effect of baseline vector immunity.
217 participants received at least 1 vaccination, and 210 (>96%) completed follow-up. No vaccine-associated serious adverse events occurred. All regimens were generally well-tolerated. All regimens elicited humoral and cellular immune responses in nearly all participants. Preexisting Ad26- or Ad35-neutralizing antibody titers had no effect on vaccine safety and little effect on immunogenicity. In both homologous and heterologous regimens, the second vaccination significantly increased EnvA antibody titers (approximately 20-fold from the median enzyme-linked immunosorbent assay titers of 30–300 to 3000). The heterologous regimen of Ad26–Ad35 elicited significantly higher EnvA antibody titers than Ad35–Ad26. T-cell responses were modest and lower in East Africa than in South Africa and the United States.
Because the 2 envelope inserts were not identical, the boosting responses were complex to interpret. Durability of the immune responses elicited beyond 1 year is unknown.
Both vaccines elicited significant immune responses in all populations. Baseline vector immunity did not significantly affect responses. Second vaccinations in all regimens significantly boosted EnvA antibody titers, although vaccine order in the heterologous regimen had a modest effect on the immune response.
International AIDS Vaccine Initiative, National Institutes of Health, Ragon Institute, Crucell Holland.
Although new antiviral regimens have reduced mortality due to HIV infection, an effective prophylactic vaccine is needed to control this global pandemic.
Two candidate HIV-1 vaccines in different combinations were tested in a multicountry, randomized, controlled trial in East Africa, South Africa, and the United States.
The vaccines elicited both humoral and cellular immune responses in all populations and regardless of baseline vector immunity. Second administrations of vaccines boosted immune response, no vaccine-related serious adverse events occurred, and responses across countries varied.
Table. Study Schema
Maximum local reactions.
Data from all first vaccinations were pooled on the basis of the vaccine received and then respective homologous and heterologous regimens were examined. The y-axis represents the percentage of participants having reactogenicity events and the x-axis the study groups. Reactions are shown through day 7 after each vaccination by study group for all sites combined and by region. Participants self-assessed reactogenicity with a memory aid on day 0 (evening of vaccine/placebo administration) and daily through day 7. Safety data for placebos by study group for all sites combined and by region are shown in the far right column of each quadrant. The maximum severity assessment grade is shown. The severity grade of the reactogenicity events is indicated by colors (yellow indicates mild, orange indicates moderate, and red indicates severe). Ad26 = adenovirus serotype 26; Ad35 = adenovirus serotype 35.
Maximum systemic reactions.
Distribution of ELISA titers 4 wk after each vaccination per regimen.
Second vaccinations were at month 6 in groups A and B and at month 3 otherwise. Boxes represent the 1st and 3rd quartiles (interquartile range). Red lines indicate the median titer. Whiskers extend to the 5th and 95th percentiles. White and orange boxes represent negative and positive baseline Ad26 NAb (top) and Ad35 NAb (bottom) titer values, respectively. The dashed lines indicate the assay threshold for positivity. On the x-axis, B represents baseline, 1 represents 4 wk after the first vaccination, and 2 represents 4 wk after the second vaccination. Ad26 = adenovirus serotype 26; Ad35 = adenovirus serotype 35; ELISA = enzyme-linked immunosorbent assay.
Distribution of ELISA titers 4 wk after the second vaccination at month 3 in heterologous administration groups.
The 2 left boxes show RW020 ELISA titers (RW020 Env is homologous to the Ad26.EnvA insert), and the 2 right boxes show UG37 ELISA titers (UG37 Env is 81.2% homologous to the Ad35.Env insert). Boxes represent the 1st and 3rd quartiles (interquartile range). Red lines indicate the median titer. Whiskers extend to the 5th and 95th percentiles. The P values are for the comparison of the distribution of titers between the Ad26–Ad35 and Ad35–Ad26 sequences. Ad26 = adenovirus serotype 26; Ad35 = adenovirus serotype 35; ELISA = enzyme-linked immunosorbent assay.
Distribution of interferon-γ ELISpot responses 2 and 4 wk after second vaccination: Ad26.EnvA.
The x-axis shows the study group (treatment), percentage of participants, and frequency of positive responses. Samples at weeks 2 and 4 were analyzed at the Human Immunology Laboratory and the Beth Israel Deaconess Medical Center, respectively. Second vaccinations were at month 6 in groups A and B and at month 3 otherwise. All responses were background-subtracted. Mean responses <1 were set to 1. Boxes show median and interquartile range. Whiskers extend to the 5th and 95th percentiles. Black and red dots represent negative and positive responses, respectively. The dashed line indicates the minimal threshold for positivity for each assay (43 SFU/106 PBMC). Ad26 = adenovirus serotype 26; Ad35 = adenovirus serotype 35; ELISA = enzyme-linked immunosorbent assay; ELISpot = Enzyme-Linked ImmunoSpot; Env = envelope; EnvA = envelope clade A; PBMC = peripheral blood mononuclear cell; SFU = spot forming unit.
Distribution of interferon-γ ELISpot responses 2 and 4 wk after second vaccination: Ad35.Env P1 (top) and Ad35.Env P2 (bottom).
The x-axis shows the study group (treatment), percentage of participants, and frequency of positive responses. Samples at weeks 2 and 4 were analyzed at the Human Immunology Laboratory and the Beth Israel Deaconess Medical Center, respectively. Second vaccinations were at month 6 in groups A and B and at month 3 otherwise. All responses were background-subtracted. Mean responses <1 were set to 1. Boxes show median and interquartile range. Whiskers extend to the 5th and 95th percentiles. Black and red dots represent negative and positive responses, respectively. The dashed lines indicate the minimal threshold for positivity for each assay (38 SFU/106PBMC). Ad26 = adenovirus serotype 26; Ad35 = adenovirus serotype 35; ELISA = enzyme-linked immunosorbent assay; ELISpot = Enzyme-Linked ImmunoSpot; Env = envelope; PBMC = peripheral blood mononuclear cell; SFU = spot forming unit.
Ad26 and Ad35 neutralizing titers.
Individual Ad26 and Ad35 NAb responses from participants at baseline and 4 wk after the first and second vaccination are shown. Second vaccinations were at month 6 in groups A and B and at month 3 otherwise. White and orange boxes represent negative and positive baseline Ad26 (top) and Ad35 (bottom) neutralizing antibodies, respectively. Boxes represent the median, interquartile range, and 5th and 95th percentiles of the titer distribution. The dashed lines indicate the assay threshold for positivity. On the x-axis, B represents baseline, 1 represents 4 wk after the first vaccination, and 2 represents 4 wk after the second vaccination. Placebo responses represent the proportion of participants with a positive titer at any time. Ad26 = adenovirus serotype 26; Ad35 = adenovirus serotype 35; NAb = neutralizing antibody.
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Baden LR, Karita E, Mutua G, et al, for the B003-IPCAVD004-HVTN091 Study Group. Assessment of the Safety and Immunogenicity of 2 Novel Vaccine Platforms for HIV-1 Prevention: A Randomized Trial. Ann Intern Med. 2016;164:313–322. [Epub ahead of print 2 February 2016]. doi: https://doi.org/10.7326/M15-0880
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© 2019
Published: Ann Intern Med. 2016;164(5):313-322.
DOI: 10.7326/M15-0880
Published at www.annals.org on 2 February 2016
HIV, Infectious Disease, Prevention/Screening, Vaccines/Immunization.
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