Efficacy and Safety of a Booster Vaccination with Two Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: Results of a Double-Blind, Randomized, Placebo-Controlled, Phase 3 Trial in Abu Dhabi

Abstract

Importance: The protective efficacy of COVID-19 vaccinations has declined over time such that booster doses are required.

Objective: To evaluate the efficacy and adverse events of booster doses of two inactivated COVID-19 vaccines.

Design: This is a double-blind, randomized, placebo-controlled phase 3 trial aiming to evaluate the protective efficacy, safety, and immunogenicity of inactivated SARS-CoV-2 vaccine (Vero cells) after inoculation with booster doses of inactivated COVID-19 vaccine.

Setting: Healthy volunteers were recruited in an earlier phase 3 trial of two doses of inactivated vaccine. The participants in Abu Dhabi maintained the blind state of the trial and received a booster dose of vaccine or placebo at least six months after the primary immunization.

Participants: Adults aged 18 and older with no history of SARS-CoV, SARS-CoV-2, or Middle East respiratory syndrome infection (via onsite inquiry) were screened for eligibility.

Interventions: A total of 9370 volunteers were screened and randomly allocated, of which 61 voluntarily withdrew from the screening stage without booster inoculation; 9309 received the booster vaccination, with 3083 in the WIV04 group, 3150 in the HB02 group, and 3076 in the alum-only group. Further, 5μg and 4μg of inactivated SARS-CoV-2 virion was adsorbed into aluminum hydroxide in a 0.5 mL aqueous suspension for WIV04 and HB02 vaccines.

Main outcomes and measures: The primary efficacy outcome was the prevention of PCR-confirmed symptomatic COVID-19 from 14 days after the booster vaccine in the per-protocol population. A safety analysis was performed in the intention-to-treat population.

Results: Symptomatic COVID-19 was identified in 36 participants in the WIV04 group (9.9 [95% CI, 7.2-13.8] per 1000 person-years), 28 in the HB02 group (7.6 [95% CI, 5.2-11.0] per 1000 person-years), and 193 in the alum-only group (55.2 [95% CI, 47.9-63.5] per 1000 person-years), resulting in a vaccine efficacy of 82.0% (95% CI, 74.2-87.8%) for WIV04 and 86.3% (95% CI, 79.6-91.1%) for HB02. One severe case of COVID-19 occurred in the alum-only group, and none occurred in the vaccine groups. Adverse reactions within seven days after vaccination occurred in 29.4% to 34.3% of participants in the three groups. Serious adverse events were rare and not related to vaccines (WIV04: 17 [0.5%]; HB02: 11 [0.4%]; alum only: 40 [1.3%]).

Conclusions and relevance: This study evaluated the safety of the booster dose, which was well tolerated by participants. Booster doses given over six months after the completion of primary immunization can help to provide more-effective protection against COVID-19 in healthy people 18 years of age or older. At the same time, the anti-SARS-CoV-2 antibodies produced by the two groups of experimental vaccines exhibited extensive cross-neutralization against representative SARS-CoV-2 variants.

Trial registration: This study is registered on ClinicalTrials.gov (NCT04510207).

Keywords: COVID-19; SARS-CoV-2; booster dose; inactivated vaccines; phase 3 trial.

Figure 1

Flow of Participants. See eMethod in Supplement for definitions of each analysis population.

Figure 2

Efficacy of 2 Inactivated Vaccines Against Symptomatic COVID-19. Cumulative event rates of confirmed symptomatic COVID-19 cases 14 days following a booster dose among participants who contributed at least 1 efficacy follow-up visit, and had negative polymerase chain reaction test results at enrollment (modified full analysis set).

Figure 3

Neutralizing Antibodies to Live SARS-CoV-2 Before and After Booster Dose. Seroconversion was defined as postinjection titer of at least 16 if the baseline titer was below 4 or at least a 4-fold increase in postinjection titer from baseline if the baseline titer was at least 4. The 95% CIs were calculated using the Clopper-Pearson method. **** p < 0.0001.