key: cord-0987989-skyiqy4d authors: Kaur, U.; Bala, S.; Joshi, A.; Reddy, N. T. S.; Japur, C.; Chauhan, M.; Pedapanga, N.; Kumar, S.; Mukherjee, A.; Mishra, V.; Talda, D.; Singh, R.; Gupta, R. K.; Yadav, A. K.; Rana, P. J.; Srivastava, J.; Bhat K, S.; Singh, A.; PG, N. K.; Pandey, M.; Patwardhan, K.; Kansal, S.; Chakrabarti, S. S. title: Persistent health issues, adverse events of significant concern, and effectiveness of COVID-19 vaccination- findings from a real-world cohort study of healthcare workers in north India date: 2022-03-30 journal: nan DOI: 10.1101/2022.03.26.22272613 sha: 7b0c3970bcc45f791c1df0e081e69c4cfaddaebe doc_id: 987989 cord_uid: skyiqy4d Background: There is paucity of real-world data on COVID-19 vaccine effectiveness and safety from cohort designs. The current study aimed to evaluate vaccine performance during second wave in India. It also aimed to determine adverse events of significant concern (AESCs), and to ascertain the effect of vaccination on persistent health issues in individuals post COVID-19. Methods: A cohort study was conducted from July-2021 to December-2021 in a tertiary hospital of north India. The primary outcome was vaccine-effectiveness against COVID-19. Secondary outcomes were AESCs, and persistent health issues in those receiving vaccine. Regression analyses were performed to determine risk factors. Results: In 2760 healthcare workers (HCWs) included, 1033 COVID-19 events were reported. Around 6-17% vaccine effectiveness was observed against COVID-19 occurrence. One dose-recipients were at 1.6-times increased risk of COVID-19. Prior SARS-CoV-2 infection was a strong independent protective factor against COVID-19 (aOR 0.66). Full vaccination reduced moderate-severe COVID-19 by 57%. Those with lung disease were at 2.5-times increased risk of moderate-severe COVID-19. AESCs were observed in 1.3% including one case each of myocarditis and severe hypersensitivity. Individuals with hypothyroidism were at 5-times and those receiving vaccine after recovery from COVID-19 were at 3-times higher risk of persistent health issues. Conclusion: COVID-19 vaccination reduced COVID-19 severity but offered marginal protection against occurrence. Relationship of asthma and hypothyroidism with COVID-19 outcomes necessitates focused research. Independent protection of prior SARS-CoV-2 infection was high and persistent health issues were common in individuals receiving vaccine post COVID-19. Recommendations of vaccinating those recovered from COVID-19 need further studies. COVID-19 vaccines have been a major deterrent against the raging pandemic. of these leading vaccines has been predominantly derived from test negative case-control studies. [5] [6] [7] [8] The test negative design can control selection and information bias but does not effectively block the bias due to health seeking behaviour which differs between vaccinated and unvaccinated and is influenced by COVID-19 severity. Further, the appropriate use of this design requires baseline matching of the groups with respect to demographic characteristics, prior SARS-CoV-2 infection, comorbidities, and other variables. 9 It is quite likely that the true estimates of vaccine effectiveness may be better calculated while studying a fixed population with similar exposure levels in a cohort design. 10 Studies done so far have highlighted the effectiveness rates of vaccine at the time when immune protection against COVID-19 is expected to develop i.e 14 days after second dose and 21 days after first dose. Equally important to know however are the epidemiological attributes of COVID-19 and its patterns during early post vaccination period. Worth exploring is the effect of COVID-19 vaccination on persistent post-COVID health events, sometimes referred to as All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; https://doi.org/10.1101/2022.03.26.22272613 doi: medRxiv preprint long COVID. This is particularly relevant in those with a history of natural SARS-CoV-2 infection prior to vaccination. To our knowledge the question of how post-recovery vaccination affects general health of these individuals has not been addressed. Moreover, though short-term safety analysis of COVID-19 vaccines in controlled settings have provided favourable results, the post approval period witnessed numerous case reports and series of serious adverse events and adverse events of special interest. These include reports of adverse cardiac events, thrombosis at atypical sites and new onset autoimmune diseases. [11] [12] [13] The incidence and patterns of such adverse events need to be addressed in the real-world setting with equal emphasis to provide a better understanding of the benefit-risk ratio of COVID-19 vaccines and to stratify patients at risk of developing adverse events. This becomes more relevant owing to the high rates of breakthrough infections being reported from most regions. In this regard, a one year prospective observational safety study in vaccinated priority groups is being carried out by us since February 2021. With this background, we conducted a cohort study to include the remaining healthcare workers in a major tertiary research and teaching hospital of north India with almost similar degree of exposures to the SARS-CoV-2 due to occupational reasons. The present study centres around two major objectives. It aimed to evaluate vaccine performance during the second wave in India, including in the immediate post-vaccination period. It also aimed to determine the occurrence of adverse events of significant concern in vaccinated individuals. Apart from providing the risk factors of COVID-19 occurrence and severity, for the first time, the study ascertains the real-world effect of vaccination on persistent health issues in individuals who had COVID-19 either prior to or following vaccination. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This retrospective cohort study was conducted during the period of July 2021 to Newly recruited participants were health care workers working in the institute. Broadly, they included consultants (teaching faculty), resident doctors, nursing staff, paramedical staff, laboratory personnel and administrative staff. The participants belonged to modern medical, dental, Ayurvedic (Indian traditional medical), and nursing services. The HCWs available in the institute during working hours were contacted by the study team members as per planned survey schedule for entire institute and relevant medical data was collected in a pre-designed case report form. The HCWs who could not be contacted during three visits made on three different days by study team members due to any reason, or those who refused to participate were not included in the study. Also excluded from the study were those whose COVID-19 related, or COVID-19 vaccination related details were incomplete. The participants were identified as 'confirm' or 'suspect' COVID-19 cases as per Ministry of Health and Family Welfare guidelines (together labelled as COVID-19 cases). 14 These cases were compared to those with no COVID-19 like events for determination of risk factors of incidence. Severity of COVID-19 was also decided as per MoHFW guidelines. 14 Participants with moderate-severe forms of COVID-19 were clubbed in one group and analysed in determining risk factors of COVID-19 severity. HCWs who were symptomatic during the study All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; https://doi.org/10.1101/2022.03.26.22272613 doi: medRxiv preprint period but negative in RT-PCR lab reports were excluded from the analysis. To avoid survival bias, information was collected from each department regarding any deaths of employees during the study period, and family members were contacted to extract the details of vaccination status and mortality of these individuals. The study started after obtaining ethical permission from the Institute Ethics Committee. Written informed consent was obtained from all the study participants. All medical data was collected in a predesigned case report form. The data pertaining to relevant demographics, medical history, concomitant drug history, any history of SARS-CoV-2 infection in the past, COVID-19 vaccination history, adverse events following immunization (AEFIs) and COVID-19 related medical details were collected. For those vaccinated, participants were recruited irrespective of the type of vaccine and centre at which vaccine was received. Case report forms which lacked clarity on COVID-19 or vaccination status were excluded. The primary outcome of the present study was real-world vaccine effectiveness against COVID-19 occurrence and severity during the second wave. We also aimed to predict determinants of both occurrence and severity of disease. To generate more robust data on real-world performance of the vaccines, we used multiple analytic designs, in a departure from previously reported literature. Evaluation was performed at various time points as detailed below. Three strategies were adopted for analysis of vaccine effectiveness-All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Adverse events of significant concern (AESCs) was the main secondary outcome. Events were graded using the FDA adverse event severity grading scale and categorized under AESC if there was occurrence of any of: Other secondary outcomes included health issues in the participants at the time of visit made by study team. These events were studied individually and those All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Overall, medical data was collected successfully from 2765 HCWs. After excluding case report forms of 5 HCWs which lacked essential vaccine related or COVID-19 related information, a total of 2760 HCWs were enrolled in the study. Figure 1 shows flowchart of selection of participants and steps followed in each analysis. Mean age of HCWs was 34.9 (±9.9) years (male=1740, female=1020). After excluding 69 HCWs who were RT-PCR negative suspects, 2691 HCWs were included for main analysis. 1033 COVID-19 events were identified in them from the period of February to December 2021. Six HCWs reported developing COVID-19 twice in this period. A total of 973 events occurred in 969 HCWs in the second wave or analysis period (16 th March to 31 st May 2021). Of these 973 events, 238 were rated as moderatesevere grade. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. In Table 1a) . The risk of occurrence of COVID-19 was nearly 1.5-times for those <40 years of age as compared to participants ≥ 40 years, 1.2-times higher All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. for females compared to males and 1.6-times higher in '1' dose group compared to the unvaccinated. Prior SARS-CoV-2 infection was an independent protective factor with a 34% lower risk of COVID-19 in this group compared to those with no prior history of SARS-CoV-2 (p<0.001). Pre-existing lung disease and vaccination status were found to be associated with moderate-severe forms of COVID-19 with statistical significance. Disease burden as well as time to recovery from COVID-19 were significantly lower in '2' and '1' dose groups compared to '0' dose group. Median time to recovery was 10 (7,18) days in '0' dose group and 7 (5,14) days for '2' dose group (p=0.002). Disease burden expressed as median number of symptoms was 5 (3, 7) in '0' dose group and 3 (2, 5) in '2' dose group (p<0.001). Binary logistic regression analysis showed preexisting lung disease to be associated with 2.5-times higher odds of moderate-severe COVID-19 (Table 1b) . Compared to the unvaccinated, the HCWs in '2' dose group were at 57% lower risk of suffering from moderate-severe COVID-19. A total of 935 COVID-19 events (between February to December 2021) were assessed for relationship between timing of COVID-19 vaccination and health issues persistent for ≥ 2 months. With statistical significance, persistent health issues were common in ≥ 40 years age group. Vaccinated HCWs with a history of hypothyroidism, inflammatory arthritis, diabetes mellitus or allergy were more likely to have persistent health issues. Persistent health issues were also common in recipients of COVAXIN compared to those receiving COVISHIELD (p=0.03). Interestingly, a higher percentage of HCWs who received the vaccine after natural COVID-19 had persistent health issues All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; compared to those who received the vaccine before COVID-19. Table 2 shows results of logistic regression and validates potential risk factors of persistent health issues in HCWs. After adjusting for potential confounders, presence of hypothyroidism was associated with 5-times higher risk of persistent health issues and history of allergy was associated with 2-times higher risk. Receiving the vaccine after natural SARS-CoV-2 infection of second wave was associated with a nearly 3-times higher risk of persistent health events. Out of the total 2544 HCWs receiving any vaccine at any time till date, 33 HCWs HCWs. One HCW had a miscarriage and one died due to a cardiac event. Two All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; HCWs recovered while on new treatment and full recovery was seen in the remaining 16 HCWs. Time to recovery varied from 3-150 days. Of the three deaths reported in our study, one death occurred due to cardiac arrest in a male patient in his 40s with underlying obesity, uncontrolled hypertension, and diabetes. The deceased had received his first dose of vaccine around 1.5 months before the event. The remaining two deaths occurred in unvaccinated individuals, one with underlying hypertension, and the other with underlying diabetes (one confirm COVID-19, one suspect COVID-19). The design and conduct of the present study were preceded and influenced by a These wide variations can be explained to some extent by the study designs All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. vaccines should also be investigated as a potential cause of suboptimal vaccine All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; protection and increased propensity towards COVID-19. Some evidence in this regard is provided by a detailed Chinese study on post-vaccination immune modulation. 15 Among other factors, young individuals <40 years of age, and females were observed to be at higher risk of acquiring COVID-19 with respect to comparators. Since majority of the participants in the present study were young health care workers, the age specific findings cannot be extrapolated to the general population. The regression analysis showed prior history of COVID-19 as a strong independent protective factor associated with lower rates of disease. Nearly 34% lower risk of COVID-19 was observed in individuals with SARS-CoV-2 infection in the past. With respect to severity of COVID-19, vaccine effectiveness of 46-51% and 13-19% were observed with '2' and '1' dose respectively. These rates are lower than the severity benefits claimed in controlled settings and some real-world studies. 3, 16 However, the protection offered by vaccines remained statistically significant in regression analysis after adjusting for potential confounders. Compared to unvaccinated, fully vaccinated individuals were at 57-60% lower risk of moderate-severe disease. This is similar to reports by another group from North India. 17 Apart from vaccination status, presence of pre-existing lung disease, particularly asthma was associated with 2.5-times higher odds of moderatesevere COVID-19. Majority of participants with asthma enrolled in this study had disease of mild-moderate severity and were controlled either on inhaled corticosteroids or systemic leukotriene antagonists. The evidence associating asthma to COVID-19 is conflicting at present. Contrary to expected, asthma was observed to be an underrepresented co-morbidity in hospitalized COVID-19 individuals. 18 In a large cohort study using electronic health records of patients in England, mild-moderate asthma not requiring systemic steroids was All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; not associated with worse clinical outcomes. 19 Only a modest risk of poor COVID-19 outcomes (aHR 1.13) existed with severe asthma. It has been suggested that the Th phenotype of patients should be explored to delineate the relationship of asthma with COVID- 19. 20 Another important objective of the present study was to predict the determinants (which was not certified by peer review) 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 March 30, 2022. ; A detailed safety analysis was performed in individuals with health issues persistent for ≥ 2 months. Majority (60%) of them had received the vaccine postrecovery from natural SARS-CoV-2 infection. Nearly 27% of persistent health issues were related to developing COVID-19 post vaccination. Adverse events of significant concern (AESCs) developed in 33 participants, giving the AESC rate close to 1.3%. Serious AEFIs occurred in 0.3% of HCWs. Considering AESCs with 'probable' causality association with the vaccine, the incidence of cardiac events following COVID-19 vaccines and that of severe hypersensitivity reactions comes close to 1 per 2544 cases which is much higher than what has been claimed by vaccine manufacturers. Of the three deaths reported, one occurred due to cardiac arrest in a partially vaccinated individual with multiple co-morbidities and the remaining two deaths occurred in unvaccinated comorbid individuals, possibly due to COVID-19. The possibility of recall bias exists in the study due to its retrospective design. However, the participants being healthcare workers, the information may be considered mostly reliable. As the study is based on a predominantly healthy younger population, the results may not be extrapolated to the general Indian population. Because of the small number of death events, and no autopsy details available in this questionnaire-based study, not much interpretation can be made in regard to this either. The study further does not provide virus variant specific information. COVID-19 vaccination provided a marginal protection against the occurrence of COVID-19 and a modest protection against the severity of disease. Compared to the unvaccinated, a high risk of occurrence of COVID-19 was observed in participants receiving '1' dose of vaccine. Previous infection by All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. None of the authors report any conflict of interest. All rights reserved. No reuse allowed without permission. (which was not certified by peer review) 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 March 30, 2022. ; (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study Effectiveness of an inactivated virusbased SARS-CoV-2 vaccine, BBV152, in India: a test-negative, casecontrol study SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness Test-Negative Designs Covid-19 Vaccine Effectiveness and the Test-Negative Design Evaluation of COVID-19 vaccine effectiveness. Interim guidance Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military Acute Cardiac Events After ChAdOx1 nCoV-19 Corona Virus Vaccine Behçet's-like adverse event or inaugural Behçet's disease after SARS-CoV-2 mRNA-1273 vaccination? Rheumatology Occurrence of COVID 19 in priority groups receiving ChAdOx1 nCoV 19 coronavirus vaccine (recombinant): A preliminary analysis from north No reuse allowed without permission. (which was not certified by peer review) 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 Comprehensive investigations revealed consistent pathophysiological alterations after vaccination with COVID-19 vaccines Protective Effect of COVID-19 Vaccine Among Health Care Workers During the Second Wave of the pandemic in India ChAdOx1 nCoV-19 effectiveness during an unprecedented surge in SARS COV-2 infections Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy Factors associated with COVID-19-related death using OpenSAFELY Is asthma a risk factor for COVID-19? Are phenotypes important? No reuse allowed without permission. (which was not certified by peer review) 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