Randomized Controlled-trial to Evaluate Safety, Immunogenicity and Efficacy of a Vaccine Composed of a Recombinant S1 Antigen for Prevention of Covid-19 in Adults Previously Fully Immunized With Other Vaccines

This is a double-blind, randomized controlled trial to evaluate the safety, immunogenicity and efficacy of an investigational vaccine against Covid-19 in adult volunteers previously fully immunized against Covid-19 with other vaccines [Corona Vac (Sinovac), ChAdOx1 (AZ 1222, Astra Zeneca) or Ad26.Co2.S (Janssen)].

Three different antigen doses of a vaccine composed of a recombinant S1 antigen, a subunit of SARS-CoV-2 virus S protein, will be compared against placebo to evaluate its efficacy, immunogenicity and preliminary efficacy. The study will consist of three cohorts and a total of 360 participants. Each cohort will be consisted of 120 individuals, who will be randomized in a 2:1 fashion for a vaccine composed of a recombinant S1 antigen or placebo. In the first cohort, participants will be randomized to two applications of 10mcg of a vaccine composed of a recombinant S1 antigenor placebo 28 days apart. In the first week of the study, only three volunteers will be enrolled in order to assess the safety of the vaccine after 7 days by an independent Data and Safety Monitoring Board (DSMB). The other 117 participants will be randomized only if there were no safety concerns on these three first enrolled volunteers. After the enrollment of the first 60 participants, 7-day safety data will be reviewed by the DSMB, who will decide on trial continuation sequence. If there were no safety concerns, the second cohort will start. In the second cohort, participants will be randomized to two applications of 25mcg of a vaccine composed of a recombinant S1 antigen or placebo 28 days apart. This cohort will have the same design and evaluation of safety performed on the first cohort. Again, after the enrollment of the first 60 participants, 7-day safety data will be reviewed by the DSMB, who will decide on trial continuation sequence. If there were no safety concerns, the third cohort will start. In the second cohort, participants will be randomized to two applications of 50mcg of a vaccine composed of a recombinant S1 antigen or placebo 28 days apart.

The primary endpoint of safety will be evaluated on day 7 after the first and second application of the vaccine. Therefore, all participants will have this endpoint assessed 36 days after the enrollment. The secondary endpoints will be immunogenicity, evaluated at days 29 (I.e., 28 days after the first dose) and 43 (I.e., 14 days after the second dose), and efficacy, evaluated as the incidence of symptomatic laboratory confirmed cases of Covid-19 from 14 days after the second dose until 12 months after enrollment.

A sample size was calculated based on the probability of adverse events. Assuming a 2.5% incidence of adverse events, a study with 240 participants receiving the active drug would have a probability higher than 99% to recognize at least one adverse event. Assuming a 5% incidence of adverse events, a study with 80 participants receiving the different doses (10, 25 and 50mcg) of the active drug would have a probability of 98% to recognize at least one adverse event.

As mentioned before, an independent DSMB will review safety after the enrollment of the first three participants in each cohort and again after the enrollment of the first 60 participants in each cohort. Pre-specified guidelines will be established to recommend early stopping of the trial for evidence of harm.