SummaryBackgroundProduction of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and lower-middle-income countries is needed. NDV-HXP-S is an inactivated egg-based recombinant Newcastle disease virus vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A public sector manufacturer in Vietnam assessed the immunogenicity of NDV-HXP-S (COVIVAC) relative to an authorized vaccine.MethodsThis phase 2 stage of a randomised, observer-blind, controlled, phase 1/2 trial was conducted at three community health centers in Thai Binh Province, Vietnam. Healthy males and non-pregnant females, 18 years of age and older, were eligible. Participants were randomised by age (18-59, ≥60 years) to receive one of three treatments by intramuscular injection twice, 28 days apart: COVIVAC at 3 µg or 6 µg, or AstraZeneca COVID-19 vaccine VAXZEVRIA. Participants and personnel assessing outcomes were masked to treatment. The main outcome was the induction of 50% neutralising antibody titers against vaccine-homologous pseudotyped virus 14 days (day 43) and 6 months (day 197) after the second vaccination by age group. The primary immunogenicity and safety analyses included all participants who received one dose of the vaccine.ClinicalTrials.govNCT05940194.FindingsDuring August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all received dose one, and three missed dose two. On day 43, the geometric mean fold rise of 50% neutralising antibody titers for subjects age 18-59 years was 31·20 (COVIVAC 3 μg N=82, 95% CI 25·14-38·74), 35·80 (COVIVAC 6 μg; N=83, 95% CI 29·03-44·15), 18·85 (VAXZEVRIA; N=82, 95% CI 15·10-23·54), and for subjects age ≥60 years was 37·27 (COVIVAC 3 μg; N=42, 95% CI 27·43-50·63), 50·10 (COVIVAC 6 μg; N=40, 95% CI 35·46-70·76), 16·11 (VAXZEVRIA; N=40, 95% CI 11·73-22·13). Among subjects seronegative for anti-S IgG at baseline, the day 43 geometric mean titer ratio of neutralising antibody (COVIVC 6 μg/VAXZEVRIA) was 1·77 (95% CI 1·30-2·40) for subjects age 18-59 years and 3·24 (95% CI 1·98-5·32) for subjects age ≥60 years. On day 197, the age-specific ratios were 1·11 (95% CI 0·51-2·43) and 2·32 (0·69-7·85). Vaccines were well tolerated; reactogenicity was predominantly mild and transient. The percentage of subjects with unsolicited adverse events (AEs) during 28 days after vaccinations was similar among treatments (COVIVAC 3 μg 29·0%, COVIVAC 6 μg 23·2%, VAXZEVRIA 31·2%); no vaccine-related AE was reported.InterpretationConsidering that induction of neutralising antibodies against SARS-CoV-2 has been correlated with the efficacy of COVID-19 vaccines, including VAXZEVRIA, our results suggest that vaccination with COVIVAC may afford clinical benefit matching or exceeding that of the VAXZEVRIA vaccine.FundingVietnam’s Institute of Vaccines and Medical Biologicals (including support from Vietnam’s national COVID-19 vaccine fund and a charitable contribution from the Thien Tam fund of Vin group), Coalition for Epidemic Preparedness Innovations, a charitable contribution from Bayer AG, US National Institutes of Health.