4.2. CoviVac Immunogenicity in Phases II (18–60 Years) and IIb (60+ Years)
chronic concomitant diseases
ASYMPTOMATIC SARS-COV-2 INFECTION, SARS-COV-2 INFECTION
The phase I/II study in healthy individuals was conducted from 3 October 2020 to 29 March 2021, during the spread of SARS-CoV-2 variant Alpha in the Russian Federation (with a maximum incidence of 29,935 cases per day) and implementation of restriction measures (isolation, use of PPE, etc.). Phase IIb was carried out in the high-risk group (participants over 60 years of age with chronic concomitant diseases) from 8 November 2021 to 17 June 2022, when variant Delta was substituted by variant Omicron, with the latter prevailing most of the time (maximum incidence of 203,949 people per day) against the background of a stable regress of the restrictive measures [In the phase II study, immunogenicity assessment was performed by NT in 167 volunteers (122 in Vaccine Group and 45 in Placebo Group) separately for the participants who were anti-SARS-CoV-2 nAB negative (69/122 in the Vaccine Group and 28/45 in the Placebo Group) or anti-SARS-CoV-2 nAB positive (53/122 in the Vaccine Group and 17/45 in the Placebo Group) at screening. In the phase IIb study, immunogenicity assessment was performed by NT for all 199 volunteers who received at least one dose of the CoviVac vaccine, although 165 (82.5%) volunteers completed the study according to the Protocol.Study participants from different age cohorts were vaccinated according to different schedules: phase II participants (aged 18–60) received two doses of the vaccine with 14 day intervals, whereas the phase IIb participants (aged 60+) received three doses with 21 day intervals. Changes in vaccination schedules were made to provide the most favorable conditions of anti-SARS-CoV-2 immunity development in 60+ recipients, who are expected to have declined immune response. The results of phase II showed an 81.8% seroconversion rate 21 days after the 2nd vaccination (in seronegative vaccinees). To achieve the same rates in the 60+ cohort, we increased the time between vaccinations and added a 3rd vaccination. This allowed us to achieve seroconversion in 88.5% of participants 21 days after the 3rd vaccination in phase IIb.It is obvious that an increase in time between vaccinations and an additional dose of the vaccine would favor the phase II participants as well. However, CoviVac development and phase II were conducted in 2020 during the rise of the COVID-19 pandemic. The vaccine providing anti-SARS-CoV-2 immunity in a short period of time was extremely needed. Therefore, the shortest appropriate schedule was chosen for phase II and following use. Nevertheless, in the present time a three-vaccinations schedule with 21 days between injections seems appropriate.Both for phase II and phase IIb, ‘seroconversion’ for the participants who were seropositive at screening was defined as a fourfold increase in nAB titers compared to baseline. The seroconversion rate for the participants of phase II who had NT titers in NT below 1:256 at screening was comparable to that for participants who were seronegative at screening (85.2% and 86.9%, respectively), while in the participants with nAB titers over 1:256 the seroconversion rate did not exceed 45%, for the participants who were seropositive at screening, the 2nd vaccination did not lead to a further significant increase in NT titers. Both facts signify that there is a maximum level of antibodies against SARS-CoV-2, which the human immune system can produce, and further antigen addition does not increase immunity. Several studies have shown that antibody responses generated both after vaccination and after SARS-CoV-2 infection can decrease significantly over time [Nevertheless, on Day 42 after the 1st vaccination, the seroconversion rate in participants of phase IIb who were seronegative at screening was 86.9% with an average nAB GMT of 1:20 (or 1:30 for positive samples only). However, these nAB levels are above the estimated levels providing protection from symptomatic SARS-CoV-2 infection [In the phase IIb study, the percentage of participants seropositive at screening (65.5%, Nevertheless, these data indicate pronounced dynamics in nAB development in phases II and IIb participants vaccinated with the vaccine CoviVac, in comparison with the phase II participants injected with a Placebo. Moreover, we did not observe a decline in humoral immunity development in phase IIb with individuals aged 60+: CoviVac vaccination was equally effective in terms of seroconversion (z = 5.180, Moreover, during the phase II study, cellular immune response was assessed based on the production of IFN-γ by the CD4+ and CD8+ lymphocytes after stimulation with SARS-CoV-2 S-protein peptide pools. Compared to baseline levels, we observed a statistically significant (