Safety, tolerability, and immunogenicity of two Zika virus DNA vaccine candidates in healthy adults: randomised, open-label, phase 1 clinical trials

Abstract

Background: The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed two new DNA vaccines expressing premembrane and envelope Zika virus structural proteins.

Methods: We did two phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in three centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18-35 years in VRC19 and 18-50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov, numbers NCT02840487 and NCT02996461.

Findings: VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and two in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site was the most frequent local symptoms (37 [46%] of 80 participants in VRC 319 and 36 [80%] of 45 in VRC 320) and malaise and headache were the most frequent systemic symptoms (22 [27%] and 18 [22%], respectively, in VRC 319 and 17 [38%] and 15 [33%], respectively, in VRC 320). For VRC5283, 14 of 14 (100%) participants who received split-dose vaccinations by needle-free injection had detectable positive antibody responses, and the geometric mean titre of 304 was the highest across all groups in both trials.

Interpretation: VRC5283 was well tolerated and has advanced to phase 2 efficacy testing.

Funding: Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

Figure 1

Trial profiles VRC5288=VRC5288 plasmid backbone with Zika virus and Japanese encephalitis chimeric envelope protein E. VRC5283=VRC5283 plasmid backbone with wild-type Zika virus envelope protein E. *A participant withdrew after one dose of vaccine due to time commitments, precluding further trial participation, but was included in the safety analyses.

Figure 2

Neutralising activity 4 weeks after last vaccination, measured by reporter virus particle assay In the VRC 319 study, samples were collected in week 12 for groups 1 and 3, week 16 for group 2, and week 24 for group 4. In the VRC 320 study, all samples were collected at week 12. Data are geometric mean titres and SDs derived from two to four independent assays per sample. The dotted line represents the limit of detection of the assay (dilution 1:30). Negative samples were reported as half the limit of detection (dilution 1:15). EC₅₀=dilution of sera required to neutralise half of infection events. N/S=needle and syringe.

Figure 3

Neutralising activity 4 weeks after each vaccination, measured by reporter virus particle assay Each line represents the EC₅₀ of an individual participant over time. Arrows indicate the timings of vaccinations. Values shown are means of two to four independent assays per sample. The dotted line represents the limit of detection of the assay (dilution 1:30). Negative samples were reported as half the limit of detection (dilution 1:15). EC₅₀=dilution of sera required to neutralise half of infection events. N/S=needle and syringe.

Figure 4

Immunogenicity at baseline and 4 weeks after last vaccination, measured by intracellular cytokine staining showing T-cell responses (A) VRC 319 study. (B) VRC 320 study. Data are group arithmetic mean proportions and SDs of total T cells producing interleukin 2, interferon γ, tumour necrosis factor α, or a combination of these cytokines, against pooled envelope protein E, small envelope protein M, and peptide pr. N/S=needle and syringe.