A Prospective Observational Study on BBV152 Coronavirus Vaccine Use in Adolescents and Comparison with Adults: Interim Results of the First Real-World Safety Analysis

After vaccination for COVID-19, serious AEs 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 [9,10,11]. Myocarditis, though rare, has been observed in adults with mRNA-based COVID-19 vaccines. With recommendations to vaccinate adolescents, myocarditis, as assessed by passive surveillance methods, is being reported in this age group also at an increased frequency [12]. Rates of AEs may be high in adolescents with underlying inflammatory diseases. In adolescents with juvenile rheumatic diseases, an overall favorable short-term safety profile was demonstrated. However, certain complications such as renal failure, pulmonary hemorrhage, and flares of lupus were reported in the vaccine group [13]. Since causality association is not always established in such cases, a longer and disease-specific follow-up is warranted for risk stratification of individuals. The commonly used passive surveillance methods often suffer from underreporting of AEFIs. The actual risk of rare but severe AEs needs evaluation using a prospective cohort-based design. To fill this gap, the present study was planned to generate evidence on the short- and long-term safety profile of COVAXIN in adolescents monitored prospectively at decided intervals. The study is also the first real-world study generating safety data for 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. A higher reactogenicity after the second dose has previously been demonstrated for mRNA-based COVID-19 vaccines [14]. The viral vectored vaccines and inactivated vaccines, on the other hand, have displayed lesser reactogenicity with the second dose [7, 8, 15, 16]. The observation of increased reactogenicity with the second dose in the present study, however, needs a cautious interpretation. Though AEFIs assessed retrospectively were enquired actively from both adolescents and accompanying guardians, the component of recall bias cannot be excluded.

The observed incidence of local and systemic AEFIs in adolescents is higher than reported in the pre-print version of the phase 2/3 trial of COVAXIN by Bharat Biotech (n = 176) [4]. Close to 0.9% of adolescents developed systemic AEFIs of ‘severe’ grade after the first dose. Both local and systemic reactogenicity rates observed in adolescents were higher than those reported previously in adults receiving inactivated COVID-19 vaccines [8, 17]. 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 [7, 8]. Notwithstanding the higher rate of AEFIs, the majority of these were mild-moderate and recovered over a median time of 1–2 days.

Regression analysis showed female adolescents and those with a history of allergy to be at 1.6 times and 3 times higher risk of developing AEFIs, commonly from the SOC of general disorders. These two co-variates have recently been projected as risk factors of AEFI after COVAXIN in adults by a group from eastern India [16]. Female sex, a history of allergy, and presence of hypothyroidism have been proposed as determinants of AEFI after COVISHIELD in adults [15]. 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 [18]. However, AEFI rates with BBV152 were lower compared to mRNA-based vaccines, for which high local (85%) and systemic (55–66%) reactogenicity rates have been observed in adolescents [14]. Whether these differences can also be attributed to variable study designs or ethnic diversity or vaccine types can be verified from head–head comparisons of different vaccines in the same population setting. Among atypical AEs, lymphadenopathy has been reported in 0.8% of adolescent BNT162b2 recipients [14]. In the current study, of the total interviewed adolescents, six atypical AEFIs (0.9%) were reported. Among these, were two cases of increased bleeding, which recovered fully. Abnormal bleeding, though recovered, was also reported by two adult participants. Monitoring of such atypical events along with performance of causality association should be incorporated in future vaccination drives. Among other atypical AEFIs, two were persisting until the time of interview and included a case of disturbing burning sensation in lower limbs and a case of aggravation of pre-vaccination skin allergy. The remaining two cases included recurrence of seizure after both doses in a female with pre-vaccination uncontrolled seizure disorder and hypothyroidism diagnosed within 3 weeks of the first dose in a female with pre-vaccination neck swelling. Both of these participants have been started on the necessary medications by their treating physicians and shall be monitored in the scheduled follow-ups. In all, AEFIs were persistent in > 2% of adolescents at day 14 after the second dose, and also in 3.7% of adults overall, and require further follow-up to predict the course.

Limitations

Before the study was planned, the authors in their clinical practice had observed atypical AEFIs, particularly after BBV152, to be occurring in adults within 7–10 days of vaccination. Based on this and considering the manpower and feasibility issues, one-time telephonic follow-up after 14 days was planned for the present study. Because of administrative issues related to obtaining ethical approval, there was a delay of 7–10 days between the initiation of adolescent vaccination and the start of the study. As a result, nearly half of the adolescents were recruited at the time of their second dose, and AEFIs after the first dose in this subset were assessed retrospectively. Though this was done to reduce time delays in highlighting adolescent-specific safety data in the public domain, an element of recall bias cannot be ruled out in such retrospective evaluation. This bias, to some extent, can also explain a relatively higher rate of AEFIs in adolescents after the second dose of vaccine compared to the first dose. However, the main motive of this retrospective assessment was the timely detection and reporting of adolescent-specific serious, severe, and atypical AEFIs, which are less likely to be affected by recall bias. Though the vaccinees recruited prospectively were informed of the AEFIs expected after vaccine, the need to record them in diaries, and about the telephonic call from the study team, no pre-designed format pertaining to AEFIs was provided to them, mainly because of the varying educational standards of the participants. A pre-designed format could have further reduced errors due to recall bias and improved the overall AEFI reporting. The study was primarily based on telephonic interviews. The telephonic interview is a time-saving tool for obtaining required and sensitive information in detail particularly in resource-limited settings. It is also a practical approach in the time of a pandemic, when travel-related restrictions because of lockdown policies hamper the hospital visit. However, it is inferior to direct observations made by physicians and data retrieval methods based on clinical records. The latter could be arranged in the current study only for a few atypical AEFIs. The study did not involve any physical examinations of the enrolled participants. Further, due to funding issues, no routine blood or radiological investigations could be performed. Therefore, certain AEFIs such as vital sign variations and serious AEFIs such as thrombosis/thrombocytopenia and myocarditis might have been missed, especially when the manifestations were not florid, leading to underestimation of the AEFI incidence. These investigations may be incorporated into future follow-ups with availability of funds.

Some of the AEFIs such as fever, cough, and sore throat overlap with clinical features of COVID-19, the third wave of which was ongoing in the community during the time of adolescent vaccination. Despite the RT-PCR advice given to the vaccinees, the test was not performed by the majority because of the continuous media campaign of common AEFIs expected after vaccination. Further, compared to adolescents, adults were recruited in small numbers. However, nearly a similar number of adolescents and adults recruited prospectively after the first dose were selected to provide unadulterated comparative analysis.

The study design being focused only on a small population of vaccinated individuals is useful for hypothesis generation and detection of early safety signals. However, no conclusions can be drawn on the risk of atypical AEFIs with the vaccine. Future studies with larger sample sizes, involving a comparator arm of unvaccinated adolescents or involving comparisons with the background rate of such events, could provide insights on the possible risk of atypical AEFIs with the BBV152 vaccine.

留言 (0)

沒有登入
gif