Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomised, placebo-controlled, phase 1 trial

Abstract

Background: 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 recombinant Newcastle disease virus vaccine expressing the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It's being developed by public sector manufacturers in Thailand, Vietnam, and Brazil; herein are initial results from Thailand.

Methods: This phase 1 stage of a randomised, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial was conducted at the Vaccine Trial Centre, Mahidol University (Bangkok). Healthy males and non-pregnant females, aged 18-59 years and negative for SARS-CoV-2 antibodies, were eligible. Participants were randomised to receive one of six treatments by intramuscular injection twice, 28 days apart: 1 µg, 1 µg+CpG1018 (a toll-like receptor 9 agonist), 3 µg, 3 µg+CpG1018, 10 µg, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited and spontaneously reported adverse events (AEs) during 7 and 28 days after each vaccination, respectively. Secondary outcomes were immunogenicity measures (anti-S IgG and pseudotyped virus neutralisation). An interim analysis assessed safety at day 57 in treatment-exposed individuals and immunogenicity through day 43 per protocol. ClinicalTrials.gov (NCT04764422).

Findings: Between March 20 and April 23, 2021, 377 individuals were screened and 210 were enroled (35 per group); all received dose one; five missed dose two. The most common solicited AEs among vaccinees, all predominantly mild, were injection site pain (<63%), fatigue (<35%), headache (<32%), and myalgia (<32%). The proportion reporting a vaccine-related AE ranged from 5·7% to 17·1% among vaccine groups and was 2·9% in controls; there was no vaccine-related serious adverse event. The 10 µg formulation's immunogenicity ranked best, followed by 3 µg+CpG1018, 3 µg, 1 µg+CpG1018, and 1 µg formulations. On day 43, the geometric mean concentrations of 50% neutralising antibody ranged from 122·23 international units per mL (IU/mL; 1 µg, 95% confidence interval (CI) 86·40-172·91) to 474·35 IU/mL (10 µg, 95% CI 320·90-701·19), with 93·9% to 100% of vaccine groups attaining a ≥ 4-fold increase over baseline.

Interpretation: NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 µg and 3 µg+CpG1018 formulations advanced to phase 2.

Funding: National Vaccine Institute (Thailand), National Research Council (Thailand), Bill & Melinda Gates Foundation, National Institutes of Health (USA).

Conflict of interest statement

PN, SSur, SPra, SPuk, RK, RSin, NS, SThe, TV, KP, and PW are salaried employees of the Government Pharmaceutical Organization (Thailand). RH is a paid consultant to PATH. WS reports royalty payments from Avimex. AGS reports financial support from the U.S. NIAID (Centers of Excellence for Influenza Research and Response 75N93021C00014, Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051). The AGS laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, and Merck. AGS has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Curelab Oncology, Curelab Veterinary, and Pfizer; he also has received royalties (Merck, Astrazeneca, BI Vetmedica, Avimex, Regeneron), payment for lectures (Seqirus, Pharmamar), and participates in scientific advisory boards for New York State on Covid-19 vaccines, Accurius, Vaxalto, and Pfizer PP reports financial support from the U.S. NIAID (Centers of Excellence for Influenza Research and Response 75N93021C00014, P01 AI097092–07, R01 AI145870–03, Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051), payments involving cash and/or stock from Avimex, Vaxalto, and Accurius, royalty payments from Astrazeneca, BI Vetmedica, and Avimex; he also reports participation on the following advisory boards: New York State advisory board on Covid-19 vaccines, Accurius, and Vaxalto. PP also reports philanthropic grants or contracts through Mount Sinai. FK reports financial support from the U.S. NIAID (Collaborative Influenza Vaccine Innovation Centers contract 75N93019C00051, centre of Excellence for Influenza Research and Surveillance contract HHSN272201400008C), the JPB Foundation and the Open Philanthropy Project (research grant 2020–215,611, 5384), Pfizer, and the U.S. NCI ( contract 75N91019D00024, task order 75N91020F00003); he also has received royalties (Avimex), consulting fees (Pfizer, Seqirus, Third Rock Ventures, and Avimex), and payment for academic lectures during the past two years. NB reports participation as an AACR board member and support from SITC for travel and meeting attendance. CLH and JSM report financial support from the Bill & Melinda Gates Foundation and the U.S. NIH. The vaccine administered in this study was developed by faculty members at the Icahn School of Medicine at Mount Sinai including WS, PP, AGS, and FK. Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and the NDV-based SARS-CoV-2 vaccine; the institution and its faculty inventors could benefit financially. JSM and CLH are inventors on a patent application concerning the Hexapro stabilized SARS-CoV-2 spike protein that was filed by the University of Texas at Austin and has been licensed to multiple entities; the university and its faculty inventors could benefit financially. All other authors have nothing to declare.

© 2022 The Author(s).

Figures

Figure 1

Trial profile.

Figure 2

Humoral immune responses to five NDV-HXP-S vaccine formulations in vaccinated subjects and placebo controls measured at baseline (day 1), post dose 1 (day 29) and post dose 2 (day 43), contrasted to a reference panel of human convalescent sera (HCS). (A) Distribution and GMC of anti-S IgG by ELISA (BAU/mL) and (B) percentage of subjects with ≥ 4-fold and ≥ 10-fold increase; (C) distribution and GMC of NT50 by pseudotyped virus neutralization assay (IU/mL) and (D) percentage of subjects with ≥ 4-fold and ≥ 10-fold increase. Numbers above data denote number of per-protocol subjects contributing data; the central horizonal bar denotes the geometric mean, while error bars denote the 95% CI of the mean (A, C) or of the percentage (B, D).

Figure 3

Distribution of neutralizing antibody responses (NT50) against vaccine homologous pseudotyped virus (Wuhan-Hu-1) and pseudotyped variants of concern B.1.351 and P.1 measured post-dose 2 (day 43), comparing five NDV-HXP-S vaccine formulations in placebo controls and vaccinated subjects, Numbers above data denote the number of per-protocol subjects contributing data; geometric mean and 95%CI are shown by horizontal bars.

Figure 4

Induction of cell-mediated immunity by two NDV-HXP-S formulations versus placebo control, expressed as IFN-γ/IL-5 ratios determined by ELISpot 2-colour assay of PBMCs collected at baseline (day 1) and 14 days post-dose 2 (day 43). PBMCs were stimulated with peptides spanning the full-length S protein, in two separate but concurrent assays labelled Vial 1 and Vial 2. Numbers above data denote number of per-protocol subjects contributing data; horizontal bars denote the geometric mean ratio with 95% CI.