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Safety and Immunogenicity of Aerosolised Ad5-nCoV or Intramuscular Ad5-nCoV or Inactivated COVID-19 Vaccine Coronavac Given as the Second Booster Following Three Doses of CoronaVac: A Multicentre, Open-Label, Phase 4, Randomized Trial
24 Pages Posted: 30 Dec 2022More...
Background: This study aimed to evaluate the safety and immunogenicity of aerosolised Ad5-nCoV or intramuscular Ad5-nCoV or inactivated COVID-19 vaccine CoronaVac given as the second booster.
Methods: This is an ongoing, randomized, open-label, parallel-controlled phase 4 trial involving healthy participants who have completed the two-dose primary immunisation and a booster immunisation with inactivated COVID-19 vaccines for at least 6 months. We recruited eligible participants from previous trials (NCT04892459, NCT04952727, and NCT05043259) as cohort 1 (with the serum before and after the first booster dose available), and eligible volunteers as cohort 2 in Lianshui and Donghai counties, Jiangsu Province. Participants were randomised at a ratio of 1:1:1 and allocated to receive the fourth dose (second booster) of aerosolised Ad5-nCoV (0.1 mL of 1.0 × 1011 viral particles per mL) or intramuscular Ad5-nCoV (0.5 mL of 1.0 × 1011 viral particles per mL) or inactivated COVID-19 vaccine CoronaVac (0.5 mL), respectively. The coprimary outcomes were safety and immunogenicity of geometric mean titres (GMTs) of serum neutralising antibodies against prototype live SARS-CoV-2 virus 28 days after the vaccination. This study was registered with ClinicalTrials.gov, NCT05303584.
Findings: Between April 23 and May 23, 2022, 356 participants met eligibility criteria, and received either a dose of aerosolised Ad5-nCoV (n=117), or intramuscular Ad5-nCoV (n=120) or CoronaVac (n=119). Within 28 days of booster vaccination, participants in the intramuscular Ad5-nCoV group reported a significantly higher frequency of adverse reactions than those in the aerosolised Ad5-nCoV and intramuscular CoronaVac groups (30.0% vs. 9.4% and 14.3%, p values<0.0001, respectively). No serious adverse events related to the vaccination were reported. The heterologous boosting with aerosolised Ad5-nCoV triggered a GMT of 672.4 (539.7-837.7) and intramuscular Ad5-nCoV triggered a serum neutralizing antibody GMT of 582.6 (505.0-672.2) 28 days after booster dose, significantly higher than the GMT in the CoronaVac group (58.5 [48.0-71.4]; p<0.0001). While, the serum pseudovirus neutralizing antibody GMTs against the Omicron variant BA 4/5 in participants receiving aerosolised Ad5-nCoV, intramuscular Ad5-nCoV, and CoronaVac group were 108.2 (84.3-138.9), 79.9 (65.4-97.6), and 18.7 (17.1-20.5), at day 28 after booster dose.
Interpretation: The heterologous fourth dose (second booster) with either the aerosolised Ad5-nCoV or intramuscular Ad5-nCoV was safe and highly immunogenic, with robust humoral and cellular immune responses in healthy adults who have been immunized with three doses of CoronaVac.
Trial Registration Details: This study was registered with ClinicalTrials.gov, NCT05303584.
Funding Information: National Natural Science Foundation of China (number 82173584 and 82222062), Jiangsu Provincial Science Fund for Distinguished Young Scholars (number BK20220064), and Jiangsu Provincial Key Project of Science and Technology Plan (number BE2021738).
Declaration of Interests: Jin-Bo Gou, Haitao Huang, Xiaolong Li, Xue Wang, Peng Wan and Tao Zhu are employees of CanSino Biologics. Tao Zhu owns stock in CanSino Biologics. All other authors declare no competing interests.
Ethics Approval Statement: The trial protocol was reviewed and approved by the Research Ethics Committee of the Jiangsu Provincial Center of Disease Control and Prevention, and no changes to the protocol were made after the initiation of the study. The protocol is provided in appendix 2 (pp 22-27), with a full list of inclusion and exclusion criteria are reported (pp 28-29). Written informed consent was obtained from each participant before screening. This trial was conducted following the principles of the Declaration of Helsinki, Clinical Practice guidelines, and local guidelines.
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