Discussion
SAEs, cardiovascular deaths
ADVERSE REACTIONS, EVENTS, RECRUITMENT, RECRUITMENT
We found that the Fakhravac inactivated SARS-CoV-2 vaccine is similar in safety and efficacy to the BBIBP-Corv2 vaccine. All observed local and systemic adverse reactions were generally self-limited and resolved completely. We observed a slightly higher occurrence of solicited local and systemic adverse reactions and a slightly lower rate of MAAEs and SAEs in the Fakhravac compared to BBIBP-Corv2 vaccine groups in the randomized arm. With 81.5% estimated efficacy, the Fakhravac vaccine was non-inferior to the reported 72.8% vaccine efficacy of BBIBP-Corv2 within the 10% non-inferiority margin after taking into account the 35% information fraction achieved during the study. In the non-randomized arm, the results were inconclusive. Overall, non-inferiority of the efficacy of the Fakhravac vaccine was demonstrated after adjusting for all possible confounding.The non-randomized arm is prone to confounding and bias. Recruitment for this trial started in September 2021, when the BBIBP-Corv2 vaccine became available to the general Iranian population as part of the national Covid-19 vaccination program. This seriously impacted the willingness of the people to participate in the study, undergo randomization and remain unaware of the type of vaccine received. To overcome the slow recruitment, a change in design to allow the participants to choose the type of vaccine they receive became inevitable. Non-randomized and unblinded participants had less incentive to fill out the mobile application and inform the follow-up center about any change in the state of their health. The considerably lower incidence of symptomatic PCR + Covid-19 in both groups in the non-randomized arm reflects this less cooperative population, particularly in those receiving the BBIBP-Corv2 vaccine.A changing pattern of the pandemic curve further complicated the recruitment and follow-up in the non-randomized arm [We can draw a non-inferiority efficacy conclusion for the Fakhravac vaccine just from our randomized arm. The number of events of the primary outcome in the calculated sample size was 365. Based on our conservative estimates of Covid-19 incidence in Iran, we needed to recruit 40,000 and follow them for six months to reach this number. However, the actual occurrence rates of Covid-19 were much higher than predicted, and we observed 855 cases, 129 (35% of 365 required by target sample size) of which occurred in the randomized arm. After adjusting the α error to 0.002 and confidence intervals (one-way) to 99.9% for 35% information fraction using the conservative O’Brien Fleming method, we were able to demonstrate the non-inferiority of the Fakhravac vaccine within the 10% margin from the reported 72.8% efficacy of the BBIBP-Corv2 vaccine (Table We found that those who received the Fakhravac vaccine are four times less likely to be hospitalized due to Covid-19 than the BBIBP-Corv2 vaccine, which agrees with our findings about symptomatic PCR + Covid-19 in the randomized arm. Given the telephone follow-up of those who had missed two successive weekly self-reports on their mobile application, we believe that the ascertainment of hospitalization due to Covid-19 is not affected by the degree of cooperation of the study participants and is likely to be valid.We observed higher rates of grade I and II local and systemic adverse reactions in the Fakhravac compared to the BBIBP-Corv2 vaccine groups; however, they were all self-limited and were of little clinical value. The higher rates of solicited local and systemic reactions in the Fakhravac vaccine group could be partly attributed to the underreporting of these reactions in the unblinded, non-random BBIBP-Corv2 vaccine recipients. Furthermore, the figures in our study were generally lower than those reported for the BBIBP-Corv2 vaccine [We observed a slightly lower rate of MAAEs and SAEs in the Fakhravac compared to the BBIBP-Corv2 vaccine groups. The standardized Mortality Ratio (SMR) for cardiovascular deaths was not significantly different from the general Iranian population. The details of all SAEs are included in the Additional file In summary, our study shows that the efficacy of the Fakhravac vaccine is non-inferior to the BBIBP-Corv2 vaccine, and the safety profile of both vaccines is similar. Therefore, Fakhravac is a reliable and safe addition to our global arsenal of vaccines against Covid-19.