Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18 years or older: A randomized, double-blind, placebo-controlled, phase 1/2 trial

Abstract

Background We aimed to assess the safety and immunogenicity of an inactivated vaccine against COVID-19 in Chinese adults aged ≥18 years. Methods This is an ongoing randomized, double-blind, placebo-controlled, phase 1/2 clinical trial among healthy adults aged ≥18 years in Henan Province, China. Participants ( n = 336 in 18–59 age group and n = 336 in ≥60 age group) were enrolled between April 12 and May 17 2020, and were equally randomized to receive vaccine or placebo (aluminum hydroxide adjuvant) in a three-dose schedule of 2·5, 5, or 10 µg on days 0, 28, and 56. Another 448 adults aged 18–59 years were equally allocated to four groups (a one-dose schedule of 10 µg, and two-dose schedules of 5 µg on days 0 and 14/21/28) and received vaccine or placebo (ratio 3:1 within each group). The primary outcomes were 7-day post-injection adverse reactions and neutralizing antibody titres on days 28 and 90 after the whole-course vaccination. Trial registration: www.chictr.org.cn #ChiCTR2000031809. Findings The 7-day adverse reactions occurred in 4·8% to 32·1% of the participants in various groups, and most adverse reactions were mild, transient, and self-limiting. Twenty participants reported 68 serious adverse events which were judged to be unrelated to the vaccine. The 90-day post-injection geometric mean titres of neutralizing antibody ranged between 87 (95% CI: 61–125) and 129 (99–169) for three-dose schedule among younger and older adults; 20 (14–27), 53 (38–75), and 44 (32–61) in 5 µg days 0 and 14/21/28 groups, respectively, and 7 (6–9) in one-dose 10 µg group. There were no detectable antibody responses in all placebo groups. Interpretation The inactivated vaccine against COVID-19 was well tolerated and immunogenic in both younger and older adults. The two-dose schedule of 5 µg on days 0 and 21/28 and three-dose schedules on days 0, 28, and 56 could be further evaluated for long-term safety and efficacy in the phase 3 trials.

Recombinant protein subunit vaccine booster following two-dose inactivated vaccines dramatically enhanced anti-RBD responses and neutralizing titers against SARS-CoV-2 and Variants of Concern

“…Recent studies reported that a third homologous dose showed a satisfying safety profile and higher immune response, including BNT162b2 mRNA vaccine, CoronaVac inactivated vaccine and BBIBP-CorV vaccine. 1 – 3 Additionally, heterologous prime-boost vaccination of ChAdOx1 nCoV-19 followed by BNT162b2 induced a higher neutralizing activity compared to two homologous doses of ChAdOx1 nCoV-19. 4 Until now, the effect of heterologous vaccination of recombinant protein subunit vaccine primed with two doses of inactivated vaccines has not been evaluated, and data along this line could provide further evidence in establishing future global boosting strategies.…”

“… 1 Homologous BBIBP booster study showed 1- to 3-fold increase after the third dose (day 56) compared to the GMT level of around 80 after the second dose (day 28). 3 Homologous CoronaVac booster study uncovered an ~3-fold increase of GMT level from the second dose to the third dose. 2 After 14 days of homologous ChAdOx1 nCoV-19 boost, the GMT levels increased to 3.69 times as high as the levels at baseline.…”

A Perspective on the Roles of Adjuvants in Developing Highly Potent COVID-19 Vaccines

“…Another double-blind, placebo-controlled phase 1/2 clinical trial was conducted to evaluate the safety and immunogenicity of an inactivated SARS-CoV-2 vaccine formulated with or without alum adjuvant in Chinese adults aged ≥18 years. The results suggested that the inactivated vaccine was well tolerated and immunogenic in both younger and older adults with no detectable antibody responses in all placebo groups [22]. The vaccine adjuvanted with alum alone was compared with the yeast-expressed trimeric form of the RBD protein adjuvanted with a TLR7/8 agonist and alum formulation, termed as alum-3M-052.…”

Adverse Events Reporting Quality of Randomized Controlled Trials of COVID-19 Vaccine Using the CONSORT Criteria for Reporting Harms: A Systematic Review

“…The most common type of vaccine in these studies was viral vector, with the viral vectors used were adenovirus in 11 studies [17,22,23,26,29,33,34,36,39,40,54] and baculovirus in 2 studies [35,48]. Eighteen studies using vaccines with adjuvants: AlOH3/Algel-IMDG in 21 studies [18][19][20][27][28][29][30][31]35,45,48,51,52,[55][56][57]59,64,66,68,70], Matrix-M1 in three studies [21,63,74], AS03/CpG + Alum in one study [25], Af03/AS03 in one study [36], and MF59 in one study [42].…”

“…The second most significant domain that induced the 'some concern' was bias caused by deviations from the intended intervention (domain 2), in which 27 trials also appeared to have a probability of risk [24,33,37,44,[46][47][48]51,[53][54][55][58][59][60]62,64,[66][67][68][69][70][73][74][75][76][77]. Almost all of the bias on domain 2 is because of disclosure of the intervention, whether to patients and or the carer of the patients.…”