Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: A randomised, comparator-controlled, phase 2 trial.

Production 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. This 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 vaccine dose was selected based on Phase 1 results. A 6 μg dose was chosen to explore the immunogenicity gain over the 3-μg dose. The study's aim is to evaluate the safety and immunogenicity of COVIVAC at two dose levels compared to VAXZEVRIA, the most commonly used COVID-19 vaccine in Vietnam. 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. During August 10-23, 2021, 737 individuals were screened, and 374 were randomised (124-125 per group); all subjects received vaccine dose one and all but three received doses two four weeks later. Subjects 18-59 years of age achieved the following geometric mean titers of PNA 14 days after vaccine dose two: 153⋅28 (95 % CI 124·2-189⋅15) for COVIVAC 3 μg, 176⋅2 (95 % CI 141⋅45-220.27) for COVIVAC 6 μg, and 99⋅92(95 % CI 80.80-123⋅56) for VAXZEVRIA. Subjects ≥60 years of age also achieved potent geometric mean titers of PNA at the same timepoint: 183⋅57 (95 % CI 133.4-252⋅61) for COVIVAC 3 μg, 257⋅87 (95 % CI 181⋅6-367⋅18) for COVIVAC 6 μg, and 79⋅49(95 % CI 55⋅68-113⋅4) for VAXZEVRIA. 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. Considering 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. ClinicalTrials.govNCT05940194.