key: cord-0934313-tp7wthiv authors: Barchuk, A.; Bulina, A.; Cherkashin, M.; Berezina, N.; Rakova, T.; Kuplevatskaya, D.; Stanevich, O.; Skougarevskiy, D.; Okhotin, A. title: COVID-19 vaccines effectiveness against symptomatic SARS-CoV-2 Delta variant infection: a population-based case-control study in St. Petersburg, Russia date: 2022-01-24 journal: nan DOI: 10.1101/2022.01.24.22269714 sha: d4a477541b1a0d14f3f44827f64cbb2e0cc03ee0 doc_id: 934313 cord_uid: tp7wthiv Background: Studies of mRNA and vector-based vaccines used in different countries report acceptable levels of effectiveness against SARS-CoV-2 infection caused by the Delta variants of SARS-CoV-2. No studies estimated vaccine effectiveness (VE) of Gam-COVID-Vac and other vaccines used in Russia against symptomatic infection with Delta variant. In this population-based case-control study, we aimed to estimate the effectiveness of the Russian COVID-19 vaccines against symptomatic SARS-CoV-2 during the recent outbreak caused by the Delta VOC in October 2021 in St. Petersburg, Russia. Methods: In a population-based case-control study with density sampling of controls, we acquired information on cases and controls from two independent studies conducted in St. Petersburg. Cases were symptomatic patients with confirmed SARS-CoV-2 (using polymerase chain reaction (PCR) test) referred to low-dose computed tomography (LDCT) triage in two outpatient centres between October 6 and 14, 2021 during the Delta variant outbreak. We recruited the controls during the representative survey of the seroprevalence study conducted during the same period in St. Petersburg using random digit dialling. In the primary analysis, we used logistic regression models to estimate the adjusted (age, gender, and history of confirmed COVID-19) VE against symptomatic SARS-CoV-2 resulted in a referral to triage centre for three vaccines used in Russia: Gam-COVID-Vac, EpiVacCorona, and CoviVac. Findings: We included 1,198 cases and 2,747 controls recruited between the 6th and 14th of October in the final analysis. VE was 58% (95% CI: 50; 64) for Gam-COVID-Vac (Sputnik V), 50% (95% CI: 30; 64) for 1-dose Gam-COVID-Vac (Sputnik V) or Sputnik Light, -40% (95% CI: -191; 33) for EpiVacCorona and 38% (95% CI: 0; 62) for CoviVac. Without adjustment for the history of confirmed COVID-19 VE for all vaccines was lower, except for one-dose Gam-COVID-Vac (Sputnik Light). The adjusted VE was slightly lower in women - 52% (95% CI: 41; 62) than men - 66% (95% CI: 55; 74). It was also higher in younger age. However, in the analysis restricted to participants without a history of confirmed COVID-19, the differences in VE by age group were smaller. Interpretation: In contrast to other Russian vaccines, Gam-COVID-Vac is effective against symptomatic SARS-CoV-2 infection caused by Delta VOC. Effectiveness is likely higher than the estimated 58% due to bias arising from high prevalence of the past COVID-19 in St. Petersburg. Funding: Population-based survey in St. Petersburg was funded by Polymetal International, plc. Mounting evidence suggests that vaccines remain effective against new variants of SARSCoV2, the virus that started the COVID19 pandemic. Studies of mRNA and vectorbased vaccines used in different countries report acceptable levels of effectiveness against SARSCoV2 infection caused by the new variants of concern (VOC) [1] [2] [3] [4] [5] [6] [7] . Waning immunity against new VOCs is another emerging concern as the followup time after the start of the vaccination programmes increases [8] . Therefore, timely and ongoing monitoring of the realworld effects for all vaccines used in programmes worldwide is crucial, given the geographical and temporal variation in global vaccine uptake and the spread of the new virus variants [9] . Only several international studies assessed the vaccine effectiveness (VE) of GamCOVIDVac [10] , a vaccine dominating the Russian СOVID19 vaccination programme. A study conducted in Hungary provided data on comparative VE in a national populationbased programme that used several vaccines, including GamCOVIDVac from Russia and HB02 from China [11] . GamCOVIDVac effectiveness against SARSCoV2 infection and COVID19related mortality was comparable to mRNA vaccines and slightly superior to other vectorbased vaccines. However, the Hungary study covers the period before the spread of the Delta VOC. The casecontrol study in St. Petersburg was the first available evidence of vaccine effectiveness (VE) against referral to hospital in patients with symptomatic SARSCoV2 infection in Russia during the spread of the Delta VOC [7] . However, that study had several limitations. The information on the vaccine type was not available, so the estimated VE represented an average effect of three vaccines used in St. Petersburg: GamCOVIDVac, EpiVacCorona [12] , and CoviVac [13] . It was safe to assume that the St. Petersburg study approximated the effectiveness of GamCOVIDVac given that it accounted for 95% of city vaccinations during the period under study. However, the VE for the two other vaccines used in Russia -EpiVacCorona and CoviVac -remained unclear. More importantly, that study did not provide direct evidence on the VE against SARSCoV2 infection and symptomatic disease. Another point of concern in observational studies of VE is the proportion of individuals with natural immunity which protects from reinfection [14, 15] . If casecontrol studies include individuals with immunity after infection as controls, that will likely underestimate the actual VE against SARSCoV2. To illustrate this point, more than 45% of the population have contracted the SARSCoV2 by the end of April, 2021 in St. Petersburg, Russia [16] . Preliminary study results show that seroprevalence in unvaccinated may be more than 75% in October, 2021 [17] . In this populationbased casecontrol study, we aimed to estimate the effectiveness of the Russian COVID19 vaccines against symptomatic SARSCoV2 during the recent outbreak caused by the Delta VOC in October 2021 in St. Petersburg, Russia. two ongoing independent studies in St. Petersburg [7, 16] with populationbased controls sampled at similar points in time when cases have occurred. Our cases were symptomatic patients with confirmed SARSCoV2 (using polymerase chain reaction (PCR) test) referred to lowdose computed tomography (LDCT) triage. Our previous report describes in detail the source and information we collected for the cases [7] . In brief, we collected individuallevel data from two outpatient triage centres of the Medical Institute named after Berezin Sergey (MIBS), a private medical facility contracted by the city government to provide triage service for nearly half of the city districts. Triage centres continuously collected this information from August 2021. In addition to the data collected for our previous casecontrol study, we added information on the vaccine type (GamCOVIDVac (Sputnik V and Sputnik Light), EpiVacCorona, and CoviVac) and the history of confirmed COVID19, which we defined as the positive PCR test at least two months before the current episode. We recruited controls from a survey of the seroprevalence study conducted in the same period in St. Petersburg. Our previous reports described the serosurvey design in detail [16, 18] . It includes a twostep approach: a survey conducted using random digit dial (RDD) and computerassisted telephone interview (CATI) followed by an invitation to a serological test. The survey samples were representative of the population of the city in terms of sociodemographic characteristics. In addition, CATI included questions related to history of confirmed COVID19 and vaccination status in line with information collected from cases. For this study, we extracted information on all SARSCoV2 patients referred to the triage centre between the 6th and 14th of October, 2021 (which was the period when controls data from the survey were available). Vaccination status in our study was selfreported. Both cases and controls were asked about their vaccination status, vaccine type, the number of doses, and dates for the doses. If the exact day was not reported, at least the month and the year of vaccination were collected. Three vaccines were available in St. Petersburg during the pandemic: GamCOVIDVac twodose (Sputnik V) and onedose regimen (Sputnik Light), EpiVacCorona and CoviVac (both twodose regimens). Аll vaccines were approved for primary vaccination, but Sputnik Light was specifically recommended as preferred option for the booster after COVID19 infection. We assigned the full vaccination status to all participants (both cases and controls) who reported the second dose in September 2021 and earlier. We set full vaccination status for participants with uncertain vaccination dates, but this assumption was further addressed in the sensitivity analysis. We assigned partial vaccination status to participants who received only one dose but did not satisfy the criteria for full vaccination status. We have also analysed Sputnik Light vaccines as a distinct group. Participants who received one dose of GamCOVIDVac, but had not received the second dose till October entered the Sputnik Light group. The primary outcome was the referral to LDCT triage with symptomatic infection and the positive PCR for SARSCoV 2. Cases were patients referred to LDCT triage who underwent brief physical examination and computed tomography (CT). We were collecting CTscore (five gradations from 0 to 4), which represents lung segment involvement used in our previous study [7] . The secondary outcome was any lung injury as reported by LDCT in the triage centre (CTscore 1, 2, 3, or 4). We did 3 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 24, 2022. ; not collect or use the hospital referral as an outcome in contrast to our previous study because official criteria for hospitalisation changed in the autumn of 2021 in St. Petersburg. Other variables include age, gender, history of confirmed COVID19. We modelled our study plan following the WHO interim guidance to evaluate COVID19 vaccine effectiveness [19] . We used unconditional logistic regression for our primary and secondary outcomes to estimate odds ratios (ORs) for vaccination status among cases and controls, which approximates ORs for the outcomes among the vaccinated and nonvaccinated patients. In the presence of a density control sampling scheme, it approximates the rate ratio from the respective cohort study [20] . This study design was previously used to assess risk factors for respiratory infections [21] . We corrected VE for the history of confirmed COVID19 infection by perfоrming the analyses in the dataset restricted to participants without the history of confirmed COVID19. In the sensitivity analysis, we explored the possible extent of misclassification. To address the misclassification for the vaccination dates for some participants, we have changed the status of controls with uncertain dates of vaccination to non vaccinated. In addition, in another sensitivity analysis, we assumed that cases with missing vaccine names received Gam COVIDVac. We reported all results of sensitivity analysis in Supplementary Materials. The . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint All analyses were conducted in R, study data and code is available online (https://github.com/eusporg/spb_covid_ study20). Polymetal International plc funded the serological study. The main funder had no role in study design, data collection, data analysis, data interpretation, report writing, or decision to submit the publication. The European University at St. Petersburg and MIBS had access to the study data. The European University at St. Petersburg had the final responsibility to submit for publication. Overall, 1,198 cases and 2,747 controls were included in the final analysis. Study participants characteristics are presented in Table 1 In the primary analysis without accounting for the history of confirmed COVID19, the VE against symptomatic PCR confirmed SARSCoV2 infection adjusted for age and gender was 50% (95% CI: 42-58) for GamCOVIDVac (Sputnik V), 51% (95% CI: 32-64) for 1dose GamCOVIDVac (Sputnik V) or Sputnik Light, 64% (95% CI: 230-19)) for EpiVacCorona, and 33% (95% CI: 6-58) for CoviVac. In the analysis restricted to participants without a history of confirmed COVID19, all point estimates of VE moved upwards, except for the Sputnik Light group. The VE was 58% (95% CI: 50-64) for GamCOVID Vac (Sputnik V), 50% (95% CI: 30-64) for 1dose GamCOVIDVac (Sputnik V) or Sputnik Light, 40% (95% CI: 191-33)) for EpiVacCorona, and 38% (95% CI: 0-62) for CoviVac (Table 2) . Crude and adjusted VE against any lung injury following the LDCT assessment is presented in Table 3 . In the analysis restricted to participants without a history of confirmed COVID19, all point estimates of VE against lung injury also moved upwards. The adjusted VE against symptomatic SARSCoV2 infection was slightly lower in women (52%, 95% CI: 41-62) than men (66%, 95% CI: 55-74). It was also higher in younger age (Table 4 ). However, in the analysis restricted to participants without a history of confirmed COVID19, the differences in VE by age group were smaller. In the sensitivity analysis, misclassification related to vaccine name and vaccination dates did not dramatically change VE estimates. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint This is the first study examining the comparative effectiveness of three COVID19 vaccines used in Russia. Our study results assure that GamCOVIDVac is highly effective against symptomatic SARSCoV2 and severe COVID19 pneumonia during the Delta VOC spread. We have shown that GamCOVIDVac provides at least 58% protection against symptomatic infection caused by the Delta VOC. However, the effectiveness is likely to be higher as it is difficult to account for all past SARSCoV2 infections in the Russian population. Furthermore, past COVID19 is associated with decreased vaccine uptake in Russia. Our study's apparent strength is the attempt to account for past infections in both cases and controls and show the resulting direction of possible bias. Assuming natural immunity is protective against reinfection, failure to account for it in populations with high seroprevalence would bias VE estimates downwards. Another possible representation of this is the change in GamCOVIDVac VE by age group after accounting for the history of confirmed COVID19. We have shown that the bias related to a significant number of unvaccinated individuals with a history of COVID19 will likely lead to underestimating the effectiveness of vaccination from observational data. However, we remain uncertain about the possible magnitude of this bias. The individuallevel data on past asymptomatic infection is challenging to obtain, if possible at all. Preliminary results show that seroprevalence in unvaccinated may be more than 75% in October, 2021 [17] in St. Petersburg. In countries with higher vaccine uptake and lower seroprevalence VE estimated in observational studies is higher [5] , but these 7 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint estimates are not directly comparable with our results. The Omicron VOC spread will likely make the interpretation of the VE studies even more difficult. Direct comparison similar to the Hungarian study will be needed for the new variants [11] . In contrast to GamCOVIDVac, two other vaccines, EpiVacCorona and СoviVac, were not similarly effective against symp tomatic infection caused by Delta VOC of SARSCoV2 in our study. Both vaccines were relatively rare in the population of St. Petersburg, and our study was underpowered for them. However, our study provides reasonable doubts about possible effectiveness of EpiVacCorona against new emerging VOCs. CoviVac usefulness is also doubtful in the presence of highly effective GamCOVIDVac. More studies are needed to assess the VE of EpiVacCorona and CoviVac against new variants of SARSCoV2 for them to be used in the ongoing vaccination programme. Unfortunately, efficacy data is currently available only for GamCOVIDVac [22] . Booster campaigns that are now gaining more scientific support should only utilise vaccines with proven efficacy and effectiveness [23] [24] [25] . It is also worth mentioning that while the VE for CoviVac was beyond the VE for GamCOVIDVac, the estimate for EpiVacCorona VE was negative. The efficacy is not likely to be negative, so our results have two realistic explanations. First, individuals could change their behaviour after vaccination, but more likely negative VE is a marker for the bias arising from the undercounting of past COVID19 in controls. This is our second VE study in St. Petersburg, Russia, and it provides a promising independent and timely framework for assessing COVID19 vaccines in Russia. Populationbased casecontrol studies represent a critical postregistration tool to monitor VE against emerging SARSCoV2 VOCs. The Omicron VOC pandemic has not involved Russia by the end of 2021, but there are few doubts that it will affect the course of the pandemic in Russia as previously the Delta VOC had [16] . The lack of realworld evidence may be one of the reasons behind the modest uptake of vaccination in Russia. The majority in Russia does not deny the idea of vaccination but is hesitant [26] . Despite the wide use of casecontrol studies to assess VE, researchers should be aware of all possible biases arising from this study design. Unfortunately, the golden standard to estimate VE -randomised trials -are not applicable in the rapidly changing epidemiological situation, and we have to rely on observational study design. The varying VE against different SARSCoV2 variants is an example of a lack of generalizability for the results of randomised trials. Our study underlines the biases related to the population under study, but additional biases arise from the misclassification of exposure, e.g., vaccination status [27] . The selfreported vaccination status is an important limitation of our study. Several survey participants included in the control group have not reported the exact date of vaccination. While the overall number of such individuals was low, we assumed that the vaccination date for such individuals is likely to be several months from the interview date. However, we assigned them a "nonvaccinated" status in our sensitivity analysis, and the estimates were only slightly affected. Our definition for full vaccination status was also very conservative, as we decided to accept a minimum of six days between the second vaccine dose and study inclusion. While our decision was driven by the idea that we should not exclude participants without an exact date of vaccination, we do not think that this assumption would significantly bias the results. However, most of the studies choose 14day period [5] , and that should be taken into account when comparing our results to other studies. We have undertaken additional attempts to identify cases (patients with symptomatic SARSCoV2 in October, 2021) who had the history of confirmed COVID19 more than two months before the current episode. We were able to identify only two 8 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint cases of reinfection. While underreporting may occur, it is also likely that a patient with reinfection that requires additional diagnostic followup is an infrequent event. Absolute risks of reinfection, especially of severe disease, are low for the Alpha, Beta, and Delta VOCs [28, 29] . However, more studies are needed to observe the risk of reinfection with new Omicron VOCs, as it is likely to be higher [30] . Overall, the risks may still be lower in absolute terms than for primary infection. In our study, the VE in the Sputnik Light group was similar to twodose GamCOVIDVac. However, the correction for the history of confirmed COVID19 did not move the Sputnik Light VE upwards. Single GamCOVIDVac vaccination labelled as Sputnik Light was used as a booster after the COVID19, so it is likely that the prevalence of past COVID19 is higher is this group. The VE for Sputnik Light could represent the combination of singledose boosted natural immunity mixed with singledose vaccine. Some of these limitations are inherent to observational study design. Still, other difficulties can be overcome by establishing a preexisting framework for realtime assessment of vaccine effectiveness as a part of epidemiological surveillance. In conclusion, GamCOVIDVac effectiveness against symptomatic SARSCoV2 infection caused by Delta VOC is at least 58%, but is likely to be higher. However, estimating effectiveness is difficult due to the high prevalence of natural immunity in the population. Nevertheless, GamCOVIDVac significantly outperforms two other Russian vaccines whose effectiveness against symptomatic SARSCoV2 infection caused by Delta VOC is yet to be shown. Anton Barchuk reports personal fees from AstraZeneca, MSD, and Biocad outside the submitted work. Other authors have no conflict of interest to declare. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted January 24, 2022. ; https://doi.org/10.1101/2022.01.24.22269714 doi: medRxiv preprint Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa Covid19 Vaccine Effectiveness SARSCoV2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness Effectiveness of mRNA BNT162b2 COVID19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study. 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U 83% peterburzhcev est antitela k koronavirusu; 2021 Seroprevalence of SARSCoV2 antibodies in Saint Petersburg, Russia: a populationbased study Evaluation of COVID19 vaccine effectiveness: interim guidance Casecontrol designs in the study of common diseases: updates on the demise of the rare disease assumption and the choice of sampling scheme for controls Cigarette Smoking and Invasive Pneumococcal Disease Safety and efficacy of an rAd26 and rAd5 vectorbased heterologous primeboost COVID 19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia. The Lancet Protection of BNT162b2 Vaccine Booster against Covid19 in Israel Effectiveness of a third dose of the BNT162b2 mRNA COVID19 vaccine for preventing severe outcomes in Israel: an observational study. The Lancet We acknowledge personal support from Vitaly Nesis (Chief Executive Officer, Polymetal International, plc). We are grateful to Alla Samoletova and Alexandra Vasilieva (European University at St. Petersburg) for science communication and administrative support. We thank the interviewers, nurses, and other personnel of the MIBS. We appreciate Yulia Stepantsova (Chursina) input in coordinating phonebased interviews, Daria Danilenko, Alexei Kouprianov and Daniel Munblit for insightful discussions.We also thank all study participants.