Phase II randomized non-inferiority trial comparing the humoral immunogenicity of NDV-HXP-S and BNT162b2 vaccines in Brazil

Background Coronavirus disease 2019 (COVID-19) prompted an unprecedented global vaccine development response and accelerated regulatory pathways for clinical vaccine development. Despite the end of the public health emergency, sustained preparedness, including scalable and affordable vaccine platforms remains essential. Methods This is a non-inferiority, multicenter, randomized, double-blind and active-controlled Phase II clinical trial, to evaluate the immunogenicity and safety of a fifth- dose booster of NDV-HXP-S 10 µg, an egg-derived, inactivated COVID-19 vectored-vaccine virus using the Newcastle disease virus (NDV) expressing stabilized pre-fusion S protein from Wuhan-hu-1 strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), versus BNT162b2 30 µg. Healthy participants aged 18–59 years (n = 200) or ≥ 60 years (n = 200) were randomized at a 1:1 ratio to receive a single intramuscular dose on Day 1. Primary immunogenicity endpoints (per-protocol) were the Day 29 geometric mean titer (GMT) ratio of the 50% neutralizing titer (NDV-HXP-S/BNT162b2) against SARS-CoV-2 Wuhan-hu-1 and the difference in seroconversion proportions (≥ 4-fold rise if seropositive at baseline, or NT 50 ≥40 IU/mL if seronegative). Non-inferiority margins were a point estimate ≥ 0.80 with a 95% confidence interval (CI) lower bound > 0.67 for GMT ratio, and a 95% CI lower bound > − 10% for seroconversion. Primary safety endpoints were solicited vaccine-related adverse events (AEs) through Day 7 and unsolicited and serious vaccine-related AEs through Day 28. Follow-up occurred for 12 and 6 months for safety and immunogenicity evaluation, respectively. Results Between January 27th and August 30th 2023, 389 eligible subjects were included in the safety population. Of 389 participants, 263 (67.6%) were female, median age of 60.1 years (IQR, 40.8–65.4) and the majority of them were white, 218 (56.0%). Among the 311 (77.8%), the GMT ratio (NDV-HXP-S/BNT162b2) of neutralizing antibodies against SARS-CoV-2 (Wuhan) was 0.50 (95% CI: 0.40‒0.60), measured on Day 29. Meanwhile difference in seroconversion was − 36.7% (-45.3% to -28.0%). Vaccine-related solicited adverse events were 131 (67.2%) in NDV-HXP-S and 148 (77.1%) in BNT162b2 (P = 0.032) within 7 days post-vaccination, while vaccine-related unsolicited adverse events were 46 (23.5%) in NDV-HXP-S vs . 51 (26.4%) in BNT162b2 (P = 0.558) within 28 days. There were no vaccine-related serious adverse events (SAEs) () within 28 days post-vaccination. Conclusion Inactivated NDV-HXP-S at 10 µg did not meet the criteria for non-inferiority in comparison to BNT162b2 at 30 µg in SARS-CoV-2 Wuhan-hu-1 seroconversion and neutralization as a booster dose. Both vaccines had a favorable safety profile.