Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial

Abstract

Importance: Although effective vaccines against COVID-19 have been developed, additional vaccines are still needed.

Objective: To evaluate the efficacy and adverse events of 2 inactivated COVID-19 vaccines.

Design, setting, and participants: Prespecified interim analysis of an ongoing randomized, double-blind, phase 3 trial in the United Arab Emirates and Bahrain among adults 18 years and older without known history of COVID-19. Study enrollment began on July 16, 2020. Data sets used for the interim analysis of efficacy and adverse events were locked on December 20, 2020, and December 31, 2020, respectively.

Interventions: Participants were randomized to receive 1 of 2 inactivated vaccines developed from SARS-CoV-2 WIV04 (5 µg/dose; n = 13 459) and HB02 (4 µg/dose; n = 13 465) strains or an aluminum hydroxide (alum)-only control (n = 13 458); they received 2 intramuscular injections 21 days apart.

Main outcomes and measures: The primary outcome was efficacy against laboratory-confirmed symptomatic COVID-19 14 days following a second vaccine dose among participants who had no virologic evidence of SARS-CoV-2 infection at randomization. The secondary outcome was efficacy against severe COVID-19. Incidence of adverse events and reactions was collected among participants who received at least 1 dose.

Results: Among 40 382 participants randomized to receive at least 1 dose of the 2 vaccines or alum-only control (mean age, 36.1 years; 32 261 [84.4%] men), 38 206 (94.6%) who received 2 doses, contributed at least 1 follow-up measure after day 14 following the second dose, and had negative reverse transcriptase-polymerase chain reaction test results at enrollment were included in the primary efficacy analysis. During a median (range) follow-up duration of 77 (1-121) days, symptomatic COVID-19 was identified in 26 participants in the WIV04 group (12.1 [95% CI, 8.3-17.8] per 1000 person-years), 21 in the HB02 group (9.8 [95% CI, 6.4-15.0] per 1000 person-years), and 95 in the alum-only group (44.7 [95% CI, 36.6-54.6] per 1000 person-years), resulting in a vaccine efficacy, compared with alum-only, of 72.8% (95% CI, 58.1%-82.4%) for WIV04 and 78.1% (95% CI, 64.8%-86.3%) for HB02 (P < .001 for both). Two severe cases of COVID-19 occurred in the alum-only group and none occurred in the vaccine groups. Adverse reactions 7 days after each injection occurred in 41.7% to 46.5% of participants in the 3 groups; serious adverse events were rare and similar in the 3 groups (WIV04: 64 [0.5%]; HB02: 59 [0.4%]; alum-only: 78 [0.6%]).

Conclusions and relevance: In this prespecified interim analysis of a randomized clinical trial, treatment of adults with either of 2 inactivated SARS-CoV-2 vaccines significantly reduced the risk of symptomatic COVID-19, and serious adverse events were rare. Data collection for final analysis is pending.

Trial registration: ClinicalTrials.gov Identifier: NCT04510207; Chinese Clinical Trial Registry: ChiCTR2000034780.

Figure 1.. Flow of Participants in a Study of the Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults

See eTable 1 in Supplement 2 for definitions of each analysis population. Among those receiving aluminum hydroxide (alum) for the first dose, 5 participants received WIV04 (n = 2) and HB02 (n = 3) vaccines for the second dose and were not included in the safety analysis population of the alum-only group (13 458 – 5 = 13 453), but were included in the WIV04 and HB02 groups, respectively. Three participants who received WIV04 for the first dose and HB02 for the second dose and 3 participants who received HB02 for the first dose and WIV04 for the second dose were included in both groups (WIV04: 13 459 + 2 + 3 = 13 464; HB02: 13 465 + 3 + 3 = 13 471). To measure neutralization antibody levels, the first 900 participants from each study site were selected. There were 9 participants in the WIV04 group, 7 in the HB02 group, and 8 in alum-only group who had adverse events or serious adverse events (SAEs) after the first dose and did not receive the second dose, and only 1 SAE in the HB02 group was deemed to be vaccine-related. See eTables 7 and 8 in Supplement 3 for a list of serious adverse events.

Figure 2.. Efficacy of 2 Inactivated Vaccines Against Symptomatic COVID-19

A, Cumulative event rates of confirmed symptomatic COVID-19 cases 14 days following a second vaccine dose among participants who received 2 doses, contributed at least 1 efficacy follow-up visit, and had negative polymerase chain reaction test results at enrollment (modified full analysis population-1). Median (interquartile range) observation times for all groups was 77 (47-78) days. B, Cumulative event rates of confirmed symptomatic COVID-19 cases after the first dose among participants who received at least 1 dose, contributed at least 1 efficacy follow-up visit, and had negative polymerase chain reaction test results at enrollment (full analysis population-1). Median (interquartile range) observation times for all the groups were 112 (82-113) days. Alum indicates aluminum hydroxide.

Figure 3.. Common Adverse Reactions and Grades Within 7 Days After 2 Doses in the Safety Analysis Set

The safety analysis population included all participants who received at least 1 dose. Only adverse reactions that occurred in at least 2% of participants are included; see eTable 5 in Supplement 2 for details of all adverse reactions (including common and less common adverse reactions). Participants with more than 1 adverse reaction in a specific reaction category were only counted once; for example, if they had the same symptom (eg, injection-site pain) after each dose or if they had more than 1 symptom in the reaction class (total, systemic, and local), they were only counted once in that adverse reaction class. Participants with both lower- and higher-grade adverse events were counted once in the higher-grade total adverse events. Grading scales for systemic and local adverse events are detailed in the protocol in Supplement 1. Alum indicates aluminum hydroxide.