Randomized Trial of COVID-19 Booster Vaccinations (Cobovax Study)

Background: The accrual of population immunity to COVID-19 could allow life to return to pre- pandemic normality. Immunity can be acquired through natural infections or, preferably, by vaccination. An unprecedented global effort has succeeded in developing a number of COVID-19 vaccines. All vaccines against COVID-19 approved until now have originally been developed as either a single dose or following a homologous two-dose regimen. Inactivated COVID-19 vaccines have shown inferior immunogenicity compared to mRNA vaccines but there are no studies comparing the advantages of alternative booster doses in individuals who have previously received two doses of an inactivated COVID-19 vaccine or two doses of an mRNA vaccine.

Aims and primary objectives: The aims of this study are: (1) to compare the SARS-CoV-2 antibody responses to one dose of BNT162b2 (mRNA vaccine, Fosun/BioNTech) versus one dose of CoronaVac (inactivated vaccine, Sinovac) in individuals who have previously received two doses of COVID-19 vaccination using BNT162b2 (mRNA vaccine, Fosun/BioNTech) or CoronaVac (inactivated vaccine, Sinovac), and (2) to assess the reactogenicity and safety of one booster dose of BNT162b2 and CoronaVac. The specific primary objective of our study is to assess the vaccine (humoral) immunogenicity, proxied by SARS-CoV-2 serum neutralizing antibody titers, of one booster dose of BNT162b2 or CoronaVac at 28 days after the booster dose in individuals who have previously received two doses of a COVID-19 vaccine.

Study design: Randomized open label trial in adults aged 18 years of age or older (at enrolment). The duration of participation for each participant will be 12 months from the administration of the vaccination booster dose. The immune response and reactogenicity of one dose of BNT162b2 or CoronaVac will be investigated in individuals who previously received two doses of COVID-19 vaccine at least 6 months earlier. Participants will be enrolled shortly before receiving the booster dose of BNT162b2 (day 0), with blood collection at days 0, 28, 182 and 365 days after enrolment for analysis of humoral immune responses. A subset of 25% of participants will provide additional blood samples at day 0, 7 and 30 for assessment of cellular immune responses.

Main outcomes: The primary outcome is the vaccine (humoral) immunogenicity measured as SARS- CoV-2 serum neutralizing antibodies, evaluated as the geometric mean titer (GMT) at 28 days after the booster doses. The secondary outcomes include (1) a comparison of SARS-CoV-2 serum neutralizing antibodies as the geometric mean fold rise from baseline to each post-vaccination timepoint (i.e. at days 28, 182 and 365); (2) a comparison of cellular immune responses at day 7 and 30 compared to day 0; (3) descriptive analysis of the reactogenicity and safety profiles of the booster doses.

Target population: Adults aged 18 years or older

Number of subjects planned: 400 participants to be recruited in 2021-22

Study Duration: 12 months, from September 2021 through to March 2023

Potential implications: This study will provide important evidence into the comparative effects of using a dose of mRNA vaccine or inactivated vaccine to boost the immune response in individuals that had previously received two doses of COVID-19 vaccination. This information together with data collected on reactogenicity and safety could inform COVID-19 vaccination policy locally and internationally.

Inclusion criteria

• Aged 18 years or older at enrolment.
• Have received two doses of BNT162b2 OR two doses of CoronaVac, with the most recent dose at least six months prior to enrolment.
• Currently resident and planning to remain resident in Hong Kong during the duration of the study, i.e. for 12 months after enrolment.
• Agreement to refrain from blood donation during the course of the study.
• Willing to provide blood samples for all the required time points.
• The individual or their caregiver have a home phone or cellular or mobile phone for communications purpose.
• Capable of providing informed consent.

Exclusion criteria

• A history of laboratory-confirmed or clinically confirmed COVID-19 infection prior to enrolment.
• Have previously already received one or two doses of any COVID-19 vaccines except CoronaVac or BNT162b2, for example but not limited to BBIBP-CorV (inactivated vaccine, Sinopharm), AZD1222 (adenovirus vector-based vaccine, Oxford/AstraZeneca), Sputnik V (adenovirus vector-based vaccine, Gamaleya Research Institute) and Ad26.COV2.S (adenovirus vector-based vaccine, Johnson & Johnson).
• Individuals who report any medical condition, or as determined by a clinician, not suitable to receive mRNA or inactivated COVID-19 vaccines, including but not limited to allergies to the active substance or other ingredients of the vaccine.
• Currently with diagnosed medical conditions related to their immune system.
• Use of medication that impairs immune system in the last 6 months, except topical steroids or short-term oral steroids (course lasting ≤ 14 days).
• Administration of immunoglobulins and/or any blood products within 90 days preceding the planned administration of the study vaccines.
• Pregnancy, lactation or intention to become pregnant in the coming 3 months.