Abstract
Background: A safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings. Methods: We did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233. Findings: We enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies. Interpretation: The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults. Funding: Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases.
| Original language | English |
|---|---|
| Pages (from-to) | 563-571 |
| Number of pages | 9 |
| Journal | The Lancet |
| Volume | 391 |
| Issue number | 10120 |
| DOIs | |
| State | Published - Feb 10 2018 |
Bibliographical note
Publisher Copyright:© 2018 Elsevier Ltd
Funding
Acknowledgments This work was supported by a cooperative agreement (W81XWH-07-2-0067) between the Henry M Jackson Foundation for the Advancement of Military Medicine, and the US Department of Army. The work was also funded by the US Defense Health Agency (0130602D16). This study was supported by National Institute of Allergy and Infectious Diseases ([NIAID] preclinical services vaccine testing contracts HHSN272201200003I/HHSN27200007 and HHSN27200020) and the Vaccine Treatment Evaluation Unit at Saint Louis University (contract HHSN2722013000021I), which are parts of the National Institutes of Health. Material for this Article was reviewed by the Walter Reed Army Institute of Research (WRAIR). The opinions or assertions contained herein are the private views of the authors, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The Investigational New Drug Application for Saint Louis University and WRAIR, is held by the Division of Microbiology and Infectious Diseases, NIAID, and that for Beth Israel Deaconess Medical Center (BIDMC) is held by KES. Work at BIDMC was done with support from the US Department of Defense, Henry M Jackson Foundation, and Harvard Catalyst, Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health-care centres. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health-care centres or the National Institutes of Health. We thank the members of the Division of Medical Microbiology and Infectious Diseases, NIAID, especially Robert Johnson, Kay Tomashek, and Cathy Cai, and Cristina Cassetti, who provided input on study design, monitoring, analysis, and interpretation. We also thank the staff at the WRAIR Pilot Bioproduction Facility, who were instrumental in the manufacture of the Zika vaccine candidate and the microneutralisation testing, particularly Kareem Kabra, Nubia Botero, Guisele Ballarini, Yadav Bedh, Amy Dean, Russ Olson, and Sandy Gibson. The following members of the BIDMC research team made notable contributions to the study design and implementation: Diane Ananos, Bethany Zettler, Caitlin Guiney, David Jetton, Abishek Chandrashekar, and Kittipos Visitsunthorn. We thank Mark Feinberg, Devika Zachariah, Harriet Park, and Jim Ackland of the International AIDS Vaccine Initiative for providing regulatory support for the BIDMC study. Finally, we thank Casey Storme for technical and administrative support and Karen Peterson for her helpful review and comments during the writing of this Article. DHB has received grants from Novavax and personal fees from IGM Biosciences. All other authors declare no competing interests.
| Funders | Funder number |
|---|---|
| Investigational New Drug Application for Saint Louis University | |
| US Defense Health Agency | |
| US Department of Army | |
| Vaccine Treatment Evaluation Unit | |
| National Institutes of Health (NIH) | |
| U.S. Department of Defense | |
| National Institute of Allergy and Infectious Diseases | HHSN272201200003I/HHSN27200007, HHSN27200020 |
| National Institute of Allergy and Infectious Diseases | |
| National Center for Research Resources | |
| U.S. Department of Veterans Affairs | I01BX003714 |
| U.S. Department of Veterans Affairs | |
| Henry M. Jackson Foundation | |
| National Center for Advancing Translational Sciences (NCATS) | UL1 TR001102 |
| National Center for Advancing Translational Sciences (NCATS) | |
| Harvard University | |
| Harvard Catalyst | |
| Defense Health Agency | 0130602D16 |
| Defense Health Agency | |
| Walter Reed Army Institute of Research | |
| Saint Louis University | HHSN2722013000021I |
| Saint Louis University | |
| Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases |
ASJC Scopus subject areas
- General Medicine
