Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam

Abstract

Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state. Vaccine production and clinical development was initiated in Vietnam, Thailand, and Brazil. Here the interim results from the first stage of the randomized, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial conducted at the Hanoi Medical University (Vietnam) are presented. Healthy adults aged 18-59 years, non-pregnant, and with self-reported negative history for SARS-CoV-2 infection were eligible. Participants were randomized to receive one of five treatments by intramuscular injection twice, 28 days apart: 1 μg +/- CpG1018 (a toll-like receptor 9 agonist), 3 μg alone, 10 μg alone, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited adverse events (AEs) during 7 days and subject-reported AEs during 28 days after each vaccination. Investigators further reviewed subject-reported AEs. Secondary outcomes were immunogenicity measures (anti-spike immunoglobulin G [IgG] and pseudotyped virus neutralization). This interim analysis assessed safety 56 days after first vaccination (day 57) in treatment-exposed individuals and immunogenicity through 14 days after second vaccination (day 43) per protocol. Between March 15 and April 23, 2021, 224 individuals were screened and 120 were enrolled (25 per group for active vaccination and 20 for placebo). All subjects received two doses. The most common solicited AEs among those receiving active vaccine or placebo were all predominantly mild and included injection site pain or tenderness (<58%), fatigue or malaise (<22%), headache (<21%), and myalgia (<14%). No higher proportion of the solicited AEs were observed for any group of active vaccine. The proportion reporting vaccine-related AEs during the 28 days after either vaccination ranged from 4% to 8% among vaccine groups and was 5% in controls. No vaccine-related serious adverse event occurred. The immune response in the 10 μg formulation group was highest, followed by 1 μg + CpG1018, 3 μg, and 1 μg formulations. Fourteen days after the second vaccination, the geometric mean concentrations (GMC) of 50% neutralizing antibody against the homologous Wuhan-Hu-1 pseudovirus ranged from 56.07 IU/mL (1 μg, 95% CI 37.01, 84.94) to 246.19 IU/mL (10 μg, 95% CI 151.97, 398.82), with 84% to 96% of vaccine groups attaining a ≥ 4-fold increase over baseline. This was compared to a panel of human convalescent sera (N = 29, 72.93 95% CI 33.00-161.14). Live virus neutralization to the B.1.617.2 (Delta) variant of concern was reduced but in line with observations for vaccines currently in use. Since the adjuvant has shown modest benefit, GMC ratio of 2.56 (95% CI, 1.4-4.6) for 1 μg +/- CpG1018, a decision was made not to continue studying it with this vaccine. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 μg dose was advanced to phase 2 along with a 6 μg dose. The 10 μg dose was not selected for evaluation in phase 2 due to potential impact on manufacturing capacity. ClinicalTrials.gov NCT04830800.

Keywords: COVID-19; Egg-based vaccine; Newcastle disease virus; SARS-CoV-2.

Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1

Randomization and dose escalation schedule of the phase 1 stage of the phase 1/2 randomized, placebo-controlled, observer-blind trial to assess the safety and immunogenicity of COVIVAC vaccine produced by IVAC in adults aged 18–75 years in Vietnam. Subjects were randomized to one of five groups and were enrolled in five cohorts. Each cohort included active and placebo groups. Next cohort vaccination proceeded after a protocol safety review team PSRT safety review.

Fig. 2

Profile of the phase 1 stage of the phase 1/2 randomized, placebo-controlled, observer-blind trial to assess the safety and immunogenicity of COVIVAC vaccine produced by IVAC in adults aged 18–75 years in Vietnam.

Fig. 3

Distribution and geometric mean concentration (GMC) of anti-S IgG (BAU/mL) in placebo, vaccine groups and human convalescent sera (HCS) controls (A), distribution and GMC of NT50 by pseudoneutralization assay (PNA) (IU/mL) in placebo, vaccine groups, and HCS controls (B), percentage of subjects with ≥ 4–10-fold increase in anti-S IgG at day 43 (C), and percentage of subjects with ≥ 4–10-fold increase in NT50 by PNA at day 43 (D). Numbers above columns denote number of per-protocol subjects contributing data.

Fig. 4

Distribution and geometric mean fold rise (GMFR) in anti-S IgG from baseline (A), distribution and GMFR of fold rise in NT50 by pseudoneutralization assay (PNA) from baseline (B). Numbers above data denote number of per-protocol subjects contributing data.

Fig. 5

Scatterplot of anti-S IgG (BAU/ml) and NT50 (IU/ml) by pseudoneutralization assay (PNA) (Wuhan-Hu-1 spike) among all COVIVAC recipients on day 43 (14-days post second dose) of phase 1 clinical trial. The blue line provides a fitted linear line on the log scale and the Pearson correlation coefficient estimate is provided. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 6

Neutralization of wild type SARS-CoV-2 and B.1.617.2 by vaccinees’ sera. Distribution of serum inhibitory dilution 50% (ID50) of sera from placebo, vaccine groups and human convalescent sera (HCS) controls against wild type SARS-CoV-2 USA-WA1/2020 isolate (A) and B.1.617.2 variant (B). Geometric mean titers (GMT) with 95% confidence interval (CI) is shown.