Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials

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.

Figure 1. CONSORT Flow Diagram

The three study sites (WRAIR, SLU, BIDMC) enrolled concurrently and performed the studies independently. One participant at SLU was enrolled in error but was not randomized to receive vaccination. Sixty-seven participants received two injections. Three participants were either lost to follow up or did not complete the day 57 visit.

Figure 2. Frequency of Solicited Adverse Events

All adverse events were assessed for relatedness to the vaccine. All solicited events are reported. Adverse events were graded for severity on the basis of the National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases Adult Toxicity Table (www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf).

Figure 2. Frequency of Solicited Adverse Events

All adverse events were assessed for relatedness to the vaccine. All solicited events are reported. Adverse events were graded for severity on the basis of the National Institute of Allergy and Infectious Diseases Division of Microbiology and Infectious Diseases Adult Toxicity Table (www.niaid.nih.gov/sites/default/files/dmidadulttox.pdf).

Figure 3. Zika Virus Neutralizing Antibody Responses

Geometric mean neutralizing antibody titers at days 1, 15, 29, 43, 57 are shown by randomization (vaccine vs. placebo) and site. Error bars are 95% confidence intervals. Data points and error bars slightly offset from the study visit day on the x-axis for visual clarity.

Figure 4. Zika Virus Protection in Mice by Passive Human Antibody Transfer

A. Viral loads (log RNA copies/ml) in naïve mice (N=20) and mice following transfer of purified IgG (N=5/group) from a naïve individual (sham), placebo recipients (placebo) and following challenge with 10 PFU ZIKV. B. Viral loads (log RNA copies/ml) in mice following transfer of purified IgG (N=5/group) from BIDMC ZPIV vaccine recipients that were challenged with 10 PFU ZIKV. C. Correlation of protective efficacy with MN50 titer post-antibody transfer and pre-virus challenge. Each dot represents one BIDMC participant.