Safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised Ad5-nCoV after two-dose priming with an inactivated SARS-CoV-2 vaccine in Chinese adults: a randomised, open-label, single-centre trial

Abstract

Background: Due to waning immunity and protection against infection with SARS-CoV-2, a third dose of a homologous or heterologous COVID-19 vaccine has been proposed by health agencies for individuals who were previously primed with two doses of an inactivated COVID-19 vaccine.

Methods: We did a randomised, open-label, controlled trial to evaluate the safety and immunogenicity of heterologous boost immunisation with an orally administered aerosolised adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in Chinese adults (≥18 years old) who had previously received two doses of an inactivated SARS-CoV-2 vaccine-Sinovac CoronaVac. Eligible participants were randomly assigned (1:1:1) to receive a heterologous booster vaccination with a low dose (1·0 × 10¹¹ viral particles per mL; 0·1 mL; low dose group), or a high dose (1·0 × 10¹¹ viral particles per mL; 0·2 mL; high dose group) aerosolised Ad5-nCoV, or a homologous intramuscular vaccination with CoronaVac (0·5 mL). Only laboratory staff were masked to group assignment. The primary endpoint for safety was the incidence of adverse reactions within 14 days after the booster dose. The primary endpoint for immunogenicity was the geometric mean titres (GMTs) of serum neutralising antibodies (NAbs) against live SARS-CoV-2 virus 14 days after the booster dose. This study was registered with ClinicalTrials.gov, NCT05043259.

Findings: Between Sept 14 and 16, 2021, 420 participants were enrolled: 140 (33%) participants per group. Adverse reactions were reported by 26 (19%) participants in the low dose group and 33 (24%) in the high dose group within 14 days after the booster vaccination, significantly less than the 54 (39%) participants in the CoronaVac group (p<0·0001). The low dose group had a serum NAb GMT of 744·4 (95% CI 520·1-1065·6) and the high dose group had a GMT of 714·1 (479·4-1063·7) 14 days after booster dose, significantly higher than the GMT in the CoronaVac group (78·5 [60·5-101·7]; p<0·0001).

Interpretation: We found that a heterologous booster vaccine with an orally administered aerosolised Ad5-nCoV is safe and highly immunogenic in adults who have previously received two doses of CoronaVac as the primary series vaccination.

Funding: National Natural Science Foundation of China and Jiangsu Provincial Key Research and Development Program.

Figure 1

Trial profile *One participant was randomly assigned to receive a booster vaccine with high-dose aerosolised Ad5-nCoV vaccine but was wrongly administrated with a third dose of the CoronaVac. This participant was involved in the intention-to-treat analysis and safety analysis in the originally assigned group.

Figure 2

Solicited and unsolicited adverse reactions that occurred within 14 days after booster vaccination The analysis was based on the safety cohort, which included all randomly assigned participants who received the booster vaccination and had at least one evaluation datapoint available. CV=CoronaVac group. HD=high dose group. LD=low dose group.

Figure 3

Neutralising antibodies against wild-type SARS-CoV-2 before and after a booster vaccination Error bars are 95% CIs. The p values are the results of comparison between the three treatment groups. The WHO reference serum 1000 IU/mL equivalent to live viral neutralising antibody titre of 1:320 against the wild-type SARS-CoV-2. GMTS=geometric mean titre in serum. GMFI=geometric mean fold increase. NAb=neutralising antibody.

Figure 4

SARS-CoV-2 spike-specific cytokine T cells responses before and after receiving a boost vaccination Cytokine T cells were background corrected for unstimulated cells and values lower than 0 were considered negative. Th1:Th2 ratio was calculated by the sum of IFN-γ plus IL-2 cytokine concentrations divided by the sum of IL-13 cytokine concentrations. Error bars are median (IQR). Samples of PBMCs were collected from the first 40 participants in the three treatment groups and included in the analysis. The discrepancies between the numbers of data points presented in the figures and the numbers of participants in the groups are due to the overlapping of the dots. PBMCs=peripheral blood mononuclear cells. TH=T helper cell.