key: cord-0911224-uiqsxxbc authors: Kaur, U.; KL, A.; Chauhan, M.; Joshi, A.; Kansal, S.; Jaisawal, V.; Patwardhan, K.; Chakrabarti, S. S. title: A prospective observational study on BBV152 coronavirus vaccine use in adolescents and comparison with adults- first real-world safety analysis date: 2022-04-10 journal: nan DOI: 10.1101/2022.04.08.22273634 sha: 3dc6457e51b46a950f4dc4181c0cd7c7f45a0430 doc_id: 911224 cord_uid: uiqsxxbc Background: The BBV152 COVID-19 vaccine (COVAXIN) has recently been approved for adolescents. We provide the first real world safety data of COVAXIN use in adolescents and compare this with adults. Methods: A prospective observational study is being conducted since January 2022. Enrolled adolescents and adults were contacted telephonically after 14 days of receiving the BBV152 vaccine. Primary outcome was vaccine safety assessed as rates of adverse events following immunization (AEFI). Severity grading of AEFIs was done using the FDA scale. Findings: A total of 698 adolescents and 326 adults were enrolled. AEFIs occurred in 36.3% adolescents after first and in 37.9% after second dose. Systemic involvement was seen in 15-17% adolescents. Injection site pain and fever were the common AEFIs. Majority of AEFIs were mild-moderate. Severe and atypical AEFIs were observed in 0.9% and 0.6% adolescents respectively. Majority of AEFIs recovered in 1-2 days. In >2% adolescents, AEFIs were persisting at 14-day follow-up since the second dose. No difference in AEFI incidence and patterns was observed between adolescents and adults. Regression analysis showed females and those with history of allergy to be respectively at 1.5-times and 3-times increased risk of AEFIs among adolescents. Interpretation: COVAXIN carries an overall favorable short term safety profile in adolescents. The observed AEFI rates in adolescents are much lower than that reported with mRNA vaccines. Female adolescents and those with history of allergy need watchfulness. With some AEFIs persisting at 14 days, a longer follow-up is recommended to strengthen the safety data of these vaccines. Funding: No funding support Background: The BBV152 COVID-19 vaccine (COVAXIN) has recently been approved for adolescents. We provide the first real world safety data of COVAXIN use in adolescents and compare this with adults. Methods: A prospective observational study is being conducted since January 2022. Enrolled adolescents and adults were contacted telephonically after 14 days of receiving the BBV152 vaccine. Primary outcome was vaccine safety assessed as rates of adverse events following immunization (AEFI). Severity grading of AEFIs was done using the FDA scale. Findings: A total of 698 adolescents and 326 adults were enrolled. AEFIs occurred in 36.3% adolescents after first and in 37.9% after second dose. Systemic involvement was seen in 15-17% adolescents. Injection site pain and fever were the common AEFIs. Majority of AEFIs were mild-moderate. Severe and atypical AEFIs were observed in 0.9% and 0.6% adolescents respectively. Majority of AEFIs recovered in 1-2 days. In >2% adolescents, AEFIs were persisting at 14-day follow-up since the second dose. No difference in AEFI incidence and patterns was observed between adolescents and adults. Regression analysis showed females and those with history of allergy to be respectively at 1.5-times and 3-times increased risk of AEFIs among adolescents. Interpretation: COVAXIN carries an overall favorable short term safety profile in adolescents. The observed AEFI rates in adolescents are much lower than that reported with mRNA vaccines. Female adolescents and those with history of allergy need watchfulness. With some AEFIs persisting at 14 days, a longer follow-up is recommended to strengthen the safety data of these vaccines. Vaccines based on novel and pre-existing platforms have been licensed for use to curtail the Coronavirus disease-2019 (COVID-19) pandemic. These include messenger RNA (mRNA) based vaccines, viral vectored vaccines, and inactivated severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines. Initially high-risk groups were prioritized for vaccination, and later on the programme was extended to the general population. The World Health Organization (WHO) recommends extension of vaccination to children [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] years of age once the high-risk population has been adequately vaccinated. 1 Pfizer's mRNA based BNT-162b2 vaccine was the first to get Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for vaccinating children against COVID-19. 2 The inactivated CoronaVac in China has also been granted emergency use approval for children and adolescents. 3 In India, COVISHIELD based on the ChAdOx1-nCoV-19 chimpanzee adenoviral platform and COVAXIN (BBV152), an inactivated SARS-CoV-2 vaccine were mostly used for mass vaccination of the adult population. Of these, COVAXIN has recently been granted emergency use authorization for use in adolescents 15-18 years of age. There is paucity of data on safety profile of inactivated vaccines specific to the adolescent subset. The only evidence available till date is a pre-print of an open label phase 2/3 trial of the BBV152 vaccine by the manufacturer Bharat Biotech which enrolled only 175 adolescents. The vaccine was shown to have a favorable short term safety profile. 4 Since the performance and safety of vaccines might differ in larger population samples in the real world and also on long term follow-up, we decided to conduct a prospective observational study of the BBV152 vaccine (COVAXIN) in adolescents aged 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint 15-18 years. Here we provide the first interim real world safety data of COVAXIN in adolescents. A comparative analysis of short-term vaccine safety in adolescents and adults is also presented. This is a prospective observational study conducted in a tertiary hospital of north India. The study started in January 2022 and with a target of one year follow-up of all participants, is expected to be continued till May 2023. Adolescents visiting the vaccination center at the time of either first or second dose were recruited in the study. By the time the study started, a subset of adolescents visiting the centre had already received their first dose, and they were recruited during their second dose. Information regarding AEFIs during first dose received 4 weeks back was obtained from these participants and their accompanying guardians at the time of second dose and was recorded in the pre-designed case report form. Adult participants in the study were recruited while visiting the vaccination center at the time of either their first or second or booster dose. As per the Ministry of Health and Family Welfare (MoHFW) guidelines, adults were eligible for booster if they had received the second dose 9 months back. 5 Some of the adults receiving the second dose had received the first dose more than 3 months back. Because of the significant time lag and the possibility of recall bias, retrospective evaluation of AEFIs was not performed in adults who were enrolled at the time of either second or booster dose. Adult participants were only monitored prospectively to assess the AEFIs. Here we report the first short term safety results of all participants-adolescents or adults who successfully completed at least fourteen days of follow-up post any dose of the BBV152 vaccine (COVAXIN). The authors UK, SSC and VJ had access to the complete data. 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint All individuals who received COVAXIN in the study centre during the period of enrolment were included in the study. Participants were adolescents of 15-18 years age and adults ≥ 19 years of age. Informed consent was taken from the adults. In case of adolescents, informed consent was taken from the accompanying guardian along with written assent of the adolescent. Adolescents who visited the centre without guardians were excluded as were the vaccinees who refused to provide consent/assent. Adverse events following immunization (AEFIs) were recorded at 14-day post vaccination through telephonic interview and the following detailed data for safety analysis were extracted. (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 April 10, 2022. 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint The study started after obtaining permission from the Ethics Committee of the Institute of Medical Sciences, Banaras Hindu University, and written informed consent was taken from the adults. In case of adolescents, informed consent was taken from the guardians along with the written assent of adolescents. Data related to demography and medical history was recorded in a pre-designed case report form. The medical history included history of SARS-CoV-2 positivity at any time in the past, existing co-morbidities, concurrent drug history and history of allergy to any known stimuli. For adolescents visiting the centre for second dose, information regarding AEFIs during the first dose was recorded in the case report form. For all participants, the data recorded included severity of AEFIs, interventions required for the management of AEFIs, outcomes of AEFIs and time to complete recovery. The available safety data from controlled settings shows the AEFI rate to vary from 14-21% in the general population. The primary outcome of the study was to evaluate the safety profile of COVAXIN in adolescents. Considering a 15% rate of occurrence of AEFI, margin of error of 4%, and 10% rate of drop out, the expected sample size for the present study was calculated to be 352. The study also aimed to compare the vaccine safety in adolescents with adult population. Considering the feasibility concerns, it was decided to enrol at least 1000 participants with adolescent:adult ratio of 2:1. The enrolment was stopped after 1024 participants were recruited. 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint For data such as incidence, severity, and outcomes of AEFIs, values were recorded as frequencies as well as percentages. Chi square test was applied for dichotomous variables such as sex, presence of co-morbidities and medications to find association between these potential risk factors and development of AEFIs. Comorbidities in adolescents being quite low in number, were analysed as a single composite variable (comorbidities) rather than separate entities like diabetes, hypertension, hypothyroidism etc. Variables with statistically significant association (P<0.05) on bivariate analysis or deemed to be clinically relevant were incorporated in the final regression model. In addition, a comparative AEFI analysis was done only between adolescents and adults enrolled while receiving the first dose. Others were excluded from this analysis to avoid recall bias. Results were analysed using SPSS version 16. This study has no funding support. (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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint and AEFI data at 14-days post vaccination was available for the remaining 295. The baseline characteristics of the study participants are mentioned in Table 1 . (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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint Of 340 adolescents interviewed after the second dose, AEFIs were reported by 129 (37.9%). Among these, local site and systemic AEFIs were noticed in 96 (28.2%) and 60 (17.6%) adolescents respectively. Injection site pain was the commonest (28.2%) followed by fever (14.1%) and headache (3.2%). Majority of the local AEFIs were of 'mild' grade and majority of the systemic AEFIs were 'moderate'. No 'severe' or 'serious' AEFIs were observed ( Table 2) . After excluding those lost to follow up, AEFIs after first dose were assessable in 181 adults and after second dose in 102 adults. AEFIs occurred in 93 (51.4%) after first dose and 38 (37.2%) after second dose of the vaccine ( Table 2) . Injection site pain and fever were common adverse events after both doses and majority of the AEFIs were mild-moderate. Only one severe and no serious AEFI was reported in adults. Among atypical AEFIs, epistaxis and heavy menstrual bleed were reported in one case each after the first dose. AEFIs after booster dose were reported in 41.7% and are mentioned in Table 2 . AEFIs till the day of telephonic follow-up were persisting in 11 adults. 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint Direct comparison of AEFI occurrence was performed between adults and adolescents receiving the first dose (n=540). To ensure that the analysis is Bivariate analysis was performed to determine association between AEFIs occurring after first dose and potential risk factors. Variables selected were sex, history of previous COVID-19, presence of co-morbidities and history of allergy. A total of 502 adolescents were selected for analysis of risk factors following any dose, after excluding those who were lost to follow up. In unadjusted analysis, AEFIs occurred commonly in females and those with history of allergy. In adjusted analysis, however, only history of allergy was a significant determinant of AEFI occurrence. Adolescents with history of allergy were at 2.7 times higher risk of developing AEFIs compared to those with no history of allergy. A separate regression analysis was performed to determine risk factors of AEFIs occurring after any dose, in adolescents who had completed their second dose. Those with no history of AEFI after the first dose but lost to follow up after second dose (n=15) were excluded. Thus, 344 adolescents were selected 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint for this analysis. Variables selected for unadjusted analysis were sex, history of COVID-19, presence of co-morbidities and history of allergy. In unadjusted analysis, statistically significant association was observed between the occurrence of AEFIs and female sex, as well as history of allergy. Association of both these factors remained statistically significant even on logistic regression. Females were at 1.6 times and those with history of allergy were at 3 times higher risk of development of AEFIs with respect to respective comparators. Post vaccination, serious adverse events such as the syndrome of thrombosis and thrombocytopenia, acute cardiac events, and new onset as well as flares of autoimmune diseases have been reported in adults. [6] [7] [8] Myocarditis has been commonly observed with mRNA vaccines and was reported initially in adults. With recommendations to vaccinate adolescents, myocarditis, as assessed by passive surveillance methods, is being reported in this age group at an increased frequency. 9 Rates of adverse events may be high in adolescents with underlying inflammatory diseases. In adolescents with juvenile rheumatic diseases, complications such as renal failure, pulmonary hemorrhage and flares of lupus have been reported with the BNT162b2 vaccine, each at the rate of 1 per 91 cases. 10 The passive AEFI surveillance methods often suffer from underreporting. The actual risk of rare but severe adverse events needs evaluation from a prospective cohort-based design. To fill this gap, the present study was planned to generate evidence on short-term and long-term safety profile of COVAXIN in adolescents who are being monitored prospectively at decided intervals. The 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint study is also the first real world study generating safety data of COVAXIN in adolescents. Nearly one third of selected adolescents developed AEFIs. Both local and systemic AEFIs were slightly more common after the second dose in adolescents. This is contrary to the trend observed by us as well as other groups in adults, where AEFIs decrease following the second dose. [11] [12] [13] The observed incidence of local and systemic AEFIs in adolescents is higher than reported in the pre-print version of phase 2/3 trial of COVAXIN by Bharat Biotech (n=175). 4 Close to 0.9% systemic AEFIs were of 'severe' grade compared to none in the phase 2/3 study. Both local and systemic reactogenicity rates observed in adolescents were higher than that reported previously in adults receiving COVAXIN. 13, 14 Apart from adolescents, a higher rate of occurrence of AEFIs (37-51%) was observed in adults too, contrary to the published studies showing close to 12-21% rates. 12, 13 Notwithstanding the higher rate of AEFIs, majority of these were mild-moderate and recovered over a median time of 1-2 days. Regression analysis showed female adolescents and those with history of allergy to be at 1.5 times and 3 times higher risk of developing AEFIs. These two co-variates have recently been projected as risk factors of AEFI after COVAXIN in adults by a group from eastern India. 15 Female sex, history of allergy and presence of hypothyroidism have been proposed as determinants of AEFI after COVISHIELD in adults. 11 The association of AEFIs with hypothyroidism could not be examined in the present study because of a small number of individuals with thyroid disorders. Other vaccines approved for adolescents include CoronaVac of Sinovac (China) and the BNT162b2 mRNA vaccine of Pfizer. Compared to what has been previously reported with CoronaVac, both local and systemic AEFIs were higher with COVAXIN in adolescents, particularly after the second dose. 16 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint However, AEFI rates with BBV152 were lower compared to mRNA based vaccines with which high local (85%) and systemic (55-66%) reactogenicity rates have been observed. 17 As in our study, systemic events have been reported to be more common after the second dose of mRNA vaccine. Among atypical adverse events, lymphadenopathy has been reported in 0.8% adolescent BNT162b2 recipients. 17 In the current study, of the total interviewed adolescents six atypical AEFIs (0.9%) were reported. Among these, were two cases of Around half of the adolescent vaccinees were recruited at the time of receiving their second dose. Data of AEFIs following their first dose was collected at this time. The possibility of recall bias exists due to this study design. Telephonic follow-up at 14 days also may have introduced an element of recall bias. Since the study did not involve physical meetings and examinations of the enrolled participants, certain AEFIs such as vital sign variations may have been missed, leading to underestimation of AEFI incidence. Moreover, despite the definite questions asked on telephonic follow-up, individual vaccinee-specific factors 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint may have resulted in minor variations in recording of AEFIs. The study also does not address the effectiveness aspect of the BBV152 vaccine in real world, the follow-up being short. COVAXIN carries an overall favourable short-term safety profile in adolescents. The AEFI rates with COVAXIN are much lower compared to that reported with mRNA vaccines in adolescents. However, unlike in adults, AEFI rates were higher after the second dose which raises early questions on the effect of probable booster doses. Vigilance is needed while vaccinating females and those with a history of allergy. Watchfulness is also advised for bleeding events. A longer follow up as planned in the study may unravel more information about the long-term safety profile of COVAXIN in adolescents. Since this is a preliminary analysis, associated data may be made available by corresponding author on request. 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 April 10, 2022. ; (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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint 8 . 3 ) 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 April 10, 2022. ; https://doi.org/10.1101/2022.04.08.22273634 doi: medRxiv preprint Interim statement on COVID-19 vaccination for children and adolescents COVID-19) Update: FDA Authorizes Pfizer-BioNTech COVID-19 Vaccine for Emergency Use in Adolescents in Another Important Action in Fight Against Pandemic Sinovac COVID-19 vaccine safe for children, adolescents Immunogenicity and safety of an inactivated SARS-CoV-2 vaccine (BBV152) in children from 2 to 18 years of age: an open-label, age-de-escalation phase 2/3 study Guidelines for COVID-19 vaccination of children between 15-18 years and precaution dose to HCWs, FLWs & 60+ population with comorbidities Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination Acute Cardiac Events After ChAdOx1 nCoV-19 Corona Virus Vaccine: Report of Three Cases Refractory hyper-eosinophilia associated with newly diagnosed rheumatoid arthritis following inactivated BBV152 COVID-19 vaccine Safety and effectiveness of BNT162b2 mRNA Covid-19 vaccine in adolescents Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in adolescents with rheumatic diseases treated with immunomodulatory medications A prospective observational safety study on ChAdOx1 nCoV-19 corona virus vaccine (recombinant) use in healthcare workers-first results from India Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine (BBV152): interim results of a randomised, double-blind, controlled, phase 3 trial Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month followup of a double-blind, randomised phase 1 trial Adverse events following immunization of COVID 19 (Covaxin) vaccine at a tertiary care center of India Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy children and adolescents: a double-blind, randomised, controlled, phase 1/2 clinical trial Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents 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.