Antibody Persistence and Safety through 6 Months after Heterologous Orally Aerosolised Ad5-nCoV in individuals primed with two-dose CoronaVac previously (preprint)

Background: Heterologous orally administered adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in individuals who were primed with two-dose CoronaVac (an inactivated SARS-CoV-2 vaccine, by Sinovac) previously, has been reported to be safe and highly immunogenic within 28 days post-boosting. However, antibody persistence and safety up to 6 months of this regimen are not been reported yet. Methods: This is a randomized, open label, single-center trial on safety and immunogenicity of heterologous boost immunization with an orally administered aerosolised Ad5-nCoV vs. homologous boost immunization with CoronaVac after two-dose priming with CoronaVac in Chinese adults aged 18 years and older (NCT05043259). We followed the participants in this trial, including 140 in the low-dose aerosolised Ad5-nCoV group, 139 in the high-dose aerosolised Ad5-nCoV group, and 140 in the CoronaVac group for 6 months. Neutralising antibodies (NAbs) against live wild-type SARS-CoV-2 virus and omicron variant, and receptor-binding domain (RBD)-specific IgG antibodies were detected in serum samples collected at 28 days, 3 months, and 6 months after the booster dose. Serious adverse events (SAEs) were documented till month 6. Results: The low-dose and high-dose heterologous boost immunisation groups had NAb GMTs against live wild-type SARS-CoV-2 of 1937.3 [95% CI 1466.9, 2558.4] and 1350.8 [95% CI 952.6, 1915.3], which were 26.4 folds and 18.4 folds higher than that the CoronaVac group did (73.5 [95%CI 52.3, 103.3]) at 28 days. The low-dose and high-dose heterologous boost immunisation groups had NAb GMTs against live wild-type SARS-CoV-2 of 530.1 (95% CI 412.5, 681.1) and 457.6 (95%CI 349.4, 599.2), which were 26.0 folds and 22.4 folds higher than that the CoronaVac group did (20.4 [95%CI 14.3, 29.1]) at 3 months, respectively. At 6 months, the low-dose and high-dose heterologous booster groups had NAb GMTs against live wild-type SARS-CoV-2 of 312.9 (95%CI 237.7, 411.8) and 251.1 (95%CI 178.2, 354.0), which were 30.1 folds and 24.1 folds higher than the CoronaVac group did (10.4 [95%CI 7.8, 14.0]), respectively. Additionally, the low-dose and high-dose heterologous booster groups had NAb GMTs against live omicron variant of 52.0 (95%CI 37.2, 72.6) and 23.1 (95%CI 15.7, 33.9) at 28 days, 27.9 (95% CI 18.8, 41.3) and 23.3 (95%CI 16.2, 33.3) at 3 months, 16.0 (95%CI 10.9, 23.5) and 12.0 (95%CI 8.5, 16.8) at 6 months, respectively. However, nearly all participants had no detectable NAbs for omicron variant in the CoronaVac group at either 28 days, 3 months, or 6 months. No vaccine-related SAEs were observed. Conclusions: These data suggested that heterologous aerosolised Ad5-nCoV following two-dose CoronaVac priming was safe and persistently more immunogenic than three-dose CoronaVac, although immune responses waned over time.

Safety and immunogenicity of heterologous boost immunization with an adenovirus type-5-vectored and protein-subunit-based COVID-19 vaccine (Convidecia/ZF2001): a randomized, observer-blinded, placebo-controlled trial (preprint)

Background Heterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored COVID-19 vaccine (Convidecia) and a protein-subunit-based COVID-19 vaccine (ZF2001). Methods and Findings We did a randomized, observer-blinded, placebo-controlled trial in healthy adults previously received one dose of Convidecia. Participants were randomly assigned (2:1) to receive either ZF2001 (vaccine group) or a trivalent inactivated influenza vaccine (TIV) (placebo group) at either 28-day or 56-day intervals. For both regimens, all participants received the 2nd injection with ZF2001 at 4 months after a dose of ZF2001 or TIV, with three-dose schedules of Convidecia/Convidecia/ZF2001 at day 0, day 28 and month 5 (referred to as CV/ZF/ZF (D0-D28-M5)) and CV/ZF/ZF (D0-D56-M6), and two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6). The primary outcome was the geometric mean titer (GMT) of the neutralizing antibodies against live SARS-CoV-2 virus 14 days after each boost vaccination. The safety outcome was 7-day reactogenicity, measured as solicited local or systemic adverse reactions after each vaccination. Between April 7, 2021, and May 6, 2021, 120 participants were enrolled, among whom 60 were randomly assigned to receive ZF2001 (n=40) or TIV (n=20) at a 28-day interval, and 60 were randomly assigned to receive ZF2001 (n=40) or TIV (n=20) at a 56-day interval. 113 (94.2%) participants received the 2nd injection with ZF2001 4 months after a dose of ZF2001 or TIV. A total of 26 participants (21.7%) reported solicited adverse events within 7 days post boost vaccinations, and all the reported adverse reactions were mild . Among participants receiving ZF001 as second dose, the GMTs of neutralizing antibodies increased to 58.4 IU/ml (42.8-79.8) in 0-28 regimen, and to 80.8 IU/ml (53.1-122.9) in 0-56 regimen at 14 days post first boost dose. The GMTs of neutralizing antibodies increased to 334.9 IU/ml (95% CI 230.4, 486.9) in C/Z/Z (D0-D28-M5) regimen, and 441.2 IU/ml (260.8, 746.4) in C/Z/Z (D0-D56-M6) regimen at 14 days after the third dose. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced comparable antibody level comparable with that elicited by three-dose schedules, with the GMTs of 282.9 IU/ml (142.5, 561.8) and 293.9 IU/ml (137.6, 627.9), respectively. Study limitations include the absence of vaccine effectiveness in real-world, and current lack of immune persistence data and the neutralizing antibodies to Omicron. Conclusions Heterologous boosting with ZF001 following primary vaccination of Convidecia is safe and more immunogenic than a single dose of Convidecia. These results support flexibility in cooperating viral vectored vaccines and recombinant protein vaccine. Trial Registration ClinicalTrial.gov NCT04833101