Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials

Abstract

Importance: A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed.

Objective: To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China.

Interventions: In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 μg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 μg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]).

Design, setting, and participants: Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020.

Main outcomes and measures: The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Results: Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups.

Conclusions and relevance: In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials.

Trial registration: Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.

Figure 1.. Screening, Randomization, and Inclusion in Safety and Immunogenicity Analyses of Inactivated Vaccine for SARS-CoV-2

^aLaboratory tests included routine blood tests, liver enzymes, total bilirubin, creatinine, urea nitrogen, urine protein, urine sugar, and urinary occult blood. Details of the list and definition of abnormal values are provided in the protocol in Supplement 1. ^bThe comorbidities in the exclusion criteria included cardiovascular disease, cancer, respiratory disease, autoimmune disease, tuberculosis, severe liver disease, congenital malformation, mental illness, nervous system diseases, uncontrolled hypertension and diabetes, severe malnutrition, fever within 14 days, and other diseases that could affect participation and compliance in the trial as judged by the investigators. ^cThe low, medium, and high doses represent 2.5, 5, and 10 μg/dose, respectively.

Figure 2.. Antibody Responses at Different Time Points in the Phase 1 Trial

The dots represent individual participant values. Boxplots show the 25th, 50th (median), and 75th percentiles. Whiskers extend to the upper and lower adjacent values, the farthest values within 1.5 × the interquartile range beyond the 25th and 75th percentiles. The numbers below the boxes indicate the number of participants at the lowest measurable value. Alum indicates aluminum hydroxide; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.. Antibody Responses 14 Days After the Second Dose in the Phase 2 Trial

Prevaccination is not shown; there were 14 participants in both aluminum hydroxide (alum)–only groups and 42 in both of the medium-dose vaccine groups. No measurable antibody responses could be detected at baseline, and thus, the baseline values were all imputed by the lower limit of detection of the assays, which was 5 for the neutralizing antibody measurement and 10 for the specific IgG-binding antibody measurement. The dots represent individual participant values. Boxplots show the 25th, 50th (median), and 75th percentiles. Whiskers extend to the upper and lower adjacent values, the farthest values within 1.5 × the interquartile range beyond the 25th and 75th percentiles. The numbers below the boxes indicate the number of participants at the lowest measurable value. Only half of the participants in the phase 2 trial were scheduled for the hormoral immunogenicity measurement at day 14 after the second injection. SARS-CoV-2 indicates severe acute respiratory syndrome coronavirus 2.