Background A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. Methods This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0•5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1•50 mg CpG-1018 and 0•75 mg alum) or placebo (0•9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). Findings 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44•4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67•2% (95•72% CI 54•3-76•8), 83•7% (97•86% CI 55•9-95•4) against moderateto-severe COVID-19, and 100% (97•86% CI 25•3-100•0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78•7% (95% CI 57•3-90•4) for delta, 91•8% (44•9-99•8) for gamma, and 58•6% (13•3-81•5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35•7% [287 of 803] vs 10•3% [81 of 786]) and second (26•9% [189 of 702] vs 7•4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. Interpretation Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. Funding Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.

Background We compared homologous and heterologous boosting in adults primed with whole-virus inactivated COVID-19 vaccine, CoronaVac, with recombinant protein vaccine, SCB-2019, to overcome waning vaccine-derived immunogenicity and “vaccine evasion” by SARS-CoV-2 variants. Methods We randomized adults (18–72 years) in the Philippines previously immunized with two or three CoronaVac doses to receive homologous or heterologous full or half doses of SCB-2019 boosters. We assessed non-inferiority/superiority of neutralizing antibody (NAb) responses against prototype SARS-CoV-2 after 15 days and NAb against a panel of SARS-CoV-2 Delta and Omicron variants in subsets (30‒50 per arm). Participants recorded solicited, unsolicited and serious adverse events. Results In 2-dose CoronaVac-primed adults prototype NAb geometric mean titers (GMT) were 203 IU/mL (95% CI: 182–227) and 939 IU/mL (841–1049) after CoronaVac and SCB-2019 boosters; the GMT ratio (4.63 [3.95–5.41]) met pre-defined non-inferiority and post hoc superiority criteria. In 3-dose CoronaVac-immunized adults NAb GMTs against prototype were 279 IU/mL (240–325), 1044 IU/mL (898–1213), and 668 IU/mL (520–829) after CoronaVac, full and half dose SCB-2019 boosters, respectively. NAb GMT ratios against Delta and Omicron variants comparing full or half SCB-2019 doses with CoronaVac were all greater than 2. Reactogenicity consisted mainly of mild-moderate injection site pain, and mild-moderate headache and fatigue, evenly balanced between groups. No vaccine-related serious adverse events were reported. Conclusion Boosting CoronaVac-immunized adults with full or half doses of SCB-2019 was well tolerated with superior immunogenicity than homologous boosting, particularly against newly emerged variants, supporting use of SCB-2019 for booster vaccination.

Background An exploratory household transmission study was nested in SPECTRA, the phase 2/3 efficacy study of the adjuvanted recombinant protein-based COVID-19 vaccine SCB-2019. We compared occurrence of confirmed COVID-19 infections between households and household contacts of infected SPECTRA placebo or SCB-2019 recipients. Methods SPECTRA participants at eight study sites in the Philippines who developed rRT-PCR-confirmed COVID-19 were contacted by a study team blinded to assignment of index cases to vaccine or placebo groups to enroll in this household transmission study. Enrolled households and household contacts were monitored for three weeks using rRT-PCR and anti-SARS-CoV-2 N-antigen IgG/IgM testing to detect new COVID-19 infections. Results 154 eligible COVID-19 index cases (51 vaccinees, 103 placebo) were included. The secondary attack rate per household for symptomatic COVID-19 infection was 0.76% (90% CI: 0.15–3.90) if the index case was a SCB-2019 vaccinee compared with 5.88% (90% CI: 3.20–10.8) for placebo index cases, a relative risk reduction (RRR) of 79% (90% CI: -28–97). The RRR of symptomatic COVID-19 per household member was similar: 84% (90% CI: 28–97). Impact on attack rates in household members if index cases were symptomatic (n = 130; RRR = 80%; 90% CI: 7–96) or asymptomatic (n = 24; RRR = 100%; 90% CI: -76–100) was measurable but the low numbers undermine the clinical significance. Conclusions In this prospective household contact study vaccination with SCB-2019 reduced SARS-CoV-2 transmission compared with placebo in households and in household members independently of whether index cases were symptomatic or not.

Background: The global COVID-19 pandemic has peaked but some countries such as China are reporting serious infectious outbreaks due to SARS-CoV-2 variants. Waning vaccine-derived immunogenicity and mutations in variants allowing vaccine evasion require new booster immunization approaches. We compared homologous and heterologous boosting in adults previously fully primed with a whole-virus inactivated COVID-19 vaccine. Methods: At multiple sites in the Philippines we enrolled 430 adults (18-72 years) immunized with two doses of CoronaVac at least 3 months previously and randomly assigned them to receive homologous (CoronaVac, n = 216) or heterologous (recombinant protein vaccine, SCB-2019, n = 214) booster doses. Non-inferiority/superiority of the neutralizing antibody (NAb) response 15 days after boosting was measured by microneutralization against prototype SARS-CoV-2, and Delta and Omicron variants in subsets (50 per arm). Participants recorded solicited local and systemic adverse events for 7 days, unsolicited AEs until Day 29, and serious adverse events until Day 60. Results: NAb geometric mean titers (GMT) against prototype on Day 15 were 744 (95% CI: 669-828) and 164 (143-189) in heterologous and homologous groups, respectively, with a heterologous/homologous GMT ratio of 4.63 (3.95-5.41), meeting both pre-defined non-inferiority and superiority criteria. Similarly, geometric mean-fold rises for NAb against Delta and Omicron BA.1, BA.2, BA.4 and BA.5 variants were superior after heterologous SCB-2019 (range 3.01-4.66) than homologous CoronaVac (range 0.85-1.6) in an exploratory analysis. Reactogenicity and safety measures were evenly balanced between groups; the most frequent local reaction was mild or moderate injection site pain; mild or moderate headache and fatigue were the most frequent systemic adverse events. No vaccine-related serious adverse events were reported. Conclusion: Heterologous boosting of CoronaVac-immunized adults with SCB-2019 was well tolerated with superior immunogenicity than homologous boosting, particularly for newly emerged variants, supporting use of SCB-2019 for booster vaccination.