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

Study Design and Setting

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 1 year follow-up of all participants, it is expected to be continued until May 2023. Adolescents visiting the COVID-19 vaccination center of the hospital at the time of either their first or second dose were recruited in the study. As mentioned earlier, COVID-19 vaccination for adolescents began in the country during the first week of January 2022. Since the present study could be started in the second week of January 2022, after obtaining ethical permission, a subset of participants had already received their first dose of vaccine. In the absence of adolescent-specific safety data on COVAXIN, and in order to bring the safety data into the public domain in a timely manner, it was decided that this subset should not be missed out on and would be enrolled while receiving the second dose. In this group, the adverse events following immunization (AEFIs) following the first dose of vaccine were evaluated retrospectively. This was also done to ensure that any serious, severe, or atypical AEFIs, which are less likely to be affected by recall bias, could be identified, and reported in the public domain. The AEFI specific information was obtained from these participants and their accompanying guardians at the time of the 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, second, or booster dose. As per the Ministry of Health and Family Welfare (MoHFW) guidelines, adults at high risk of COVID-19 were eligible for a booster if they had received the second dose at least 9 months (39 weeks) back [6]. Because of the inconsistent availability of COVAXIN and personal health concerns, some of the adults receiving the second dose had received the first dose more than 3 months back, although guidelines mandate a 4- to 6-week gap between the first and second doses for both adults and adolescents. 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. All adult participants were monitored prospectively to assess the AEFIs.

Here, we report the first short-term safety results of all participants—adolescents and adults who successfully completed at least 14 days of follow-up after any dose of the BBV152 vaccine (COVAXIN). The authors UK, SSC, and VJ had access to the complete data.

Study Participants

All individuals who received COVAXIN in the study center during the period of enrolment were included in the study. Participants were adolescents 15–18 years of age and adults ≥ 19 years of age. Informed consent was taken from the adults. In the case of adolescents, informed consent was taken from the accompanying guardian, along with written assent of the adolescent. Adolescents who visited the center without guardians were excluded, as were the vaccinees who refused to provide consent/assent.

Safety Analysis

AEFIs were recorded at 14 days after vaccination through telephonic interview, and the following detailed data for safety analysis were extracted:

• Incidence of AEFIs

• Type and pattern of AEFIs (Medical Dictionary for Regulatory Activities [MedDRA^®] low level terms [LLT] and system organ class [SOC] terminology used)

• Distribution of AEFIs with respect to age and sex

• Outcomes of AEFIs

• Interventions done to manage AEFIs

• Seriousness of AEFIs as per adapted WHO and FDA definitions (Supplementary Table 1, see the electronic supplementary material)

• Severity of AEFIs for local adverse events (AEs) and systemic AEs [these were recorded as per the FDA severity grading scale (Supplementary Table 1)]

• AEFIs requiring hospitalization

• Any vaccine–disease interaction resulting in AEFIs

• Any vaccine–drug interaction resulting in AEFIs

Vaccination Procedure and Enrolment in Study

Participants receiving any dose of COVAXIN were recruited for the present study. COVAXIN is administered intramuscularly in the deltoid at the dose of 0.5 mL as a two-dose schedule, with an interval of 4–6 weeks between the first and second dose. Since mid-January 2022, the booster dose of vaccine was recommended for adults with a gap of 9 months from the second dose [6]. Post vaccination, all participants were routinely monitored at the study site for 30 min. They were informed of the AEs expected after vaccination and of the detailed study procedure, including advice to record AEFIs. They were contacted by phone after 14 days after vaccination. Specifically, they were questioned about local site symptoms such as pain, erythema, swelling, tenderness, and any limitation of physical activity. Also, enquiry was made about the occurrence of systemic events such as fever, fatigability, myalgia, arthralgia, headache, nausea, vomiting, diarrhea, rash, chest tightness, dyspnea, or any other complaint. With the third wave of the COVID-19 pandemic ongoing, individuals were given instructions regarding reverse transcriptase polymerase chain reaction (RT-PCR) based nasal or oropharyngeal swab tests for SARS-CoV-2 in any event of them developing COVID-19 like symptoms.

Data Sources/Measurement

Data related to demography and medical history were 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 including, but not limited to, drugs, vaccines, food products, and dust. For adolescents visiting the center for the 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.

Sample Size

The available safety data from controlled settings shows the AEFI rate to vary between 12 and 21% in the general population [7, 8]. The primary objective of the study was to evaluate the safety profile of COVAXIN in adolescents. Considering a 15% rate of occurrence of any AEFI, a margin of error of 4%, and a 10% rate of drop out, the expected sample size for the present study was calculated to be 355. The study also aimed to compare the vaccine safety in adolescents with the adult population. Considering the feasibility concerns, it was decided to enroll at least 1000 participants, with an adolescent:adult ratio of around 2:1. The enrolment was stopped after 1024 participants were recruited.

Statistical Analysis

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 prior COVID-19 to find associations between these potential risk factors and the development of AEFIs. Comorbidities in adolescents being quite low in number were analyzed as a single composite variable (comorbidities) rather than separate entities like diabetes, hypertension, hypothyroidism, etc. Variables with a statistically significant association (P < 0.05) on bivariate analysis or those deemed to be clinically relevant were incorporated into the final regression model. In this model, an AEFI occurring after any dose was the composite dependent variable. In addition, a comparative AEFI analysis was done only between adolescents and adults enrolled while receiving the first dose and monitored prospectively. This was done to ensure that the analysis was unadulterated by the dose of vaccine or recall bias. Results were analyzed using SPSS version 16.

AEFIs After First Dose in Adolescents

Among the 670 adolescents for whom data were available, 243 reported systemic or local AEFIs (36.3%). The majority of AEFIs involved the injection site and were reported by 183 adolescents (27.3%). Systemic involvement with or without local site involvement was reported by 102 (15.2%). Individually, injection site pain was the commonest AEFI reported (179, 26.7%) followed by fever (12.2%) and weakness (1.9%). The majority of AEFIs occurred within 24 h of receiving the vaccine (n = 233, 95.9% of all AEFIs). Most local site AEFIs were mild (152/183, 83.1%), and most systemic AEFIs were of ‘moderate’ grade (51/102, 50%). Altogether, six adolescents (0.9% of all adolescents: five females, one male) complained of systemic AEFIs of ‘severe’ grade, and no ‘serious’ AEFIs were noticed. Complete recovery from AEFIs was observed in all adolescents except three (two females, one male), and time to recovery (TTR) varied from 0.5 to 7 days. Four atypical AEFIs were reported in four adolescents (0.6%). These included a case of severe menstrual bleeding with no endocrinal disturbance in the past, a case of disturbing burning sensation in lower limbs in a male with insignificant past history, a case of recurrence of seizure within 5 days of the first dose in a female with pre-vaccination uncontrolled seizure disorder, and a case of hypothyroidism within 3 weeks of the first dose in a female with pre-vaccination neck swelling [Table 2 and Supplementary Table 2 (see the electronic supplementary material)]. The latter two were reported to the study team at the time of the second dose. The MedDRA SOCs of reported AEFIs are shown in Fig. 2. Details of severe, atypical, and persisting AEFIs are provided in Supplementary Table 2.

AEFIs After Second Dose in Adolescents

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 adolescents (17.6%), respectively. Injection site pain was the commonest (28.2%), followed by fever (14.1%) and headache (3.2%). The majority of the local AEFIs were of ‘mild’ grade, and the majority of the systemic AEFIs were ‘moderate.’ No ‘severe’ or ‘serious’ AEFIs were observed (Table 2). The majority of AEFIs occurred within 24 h of the vaccine (122, 94.6%), and recovery was seen in all except eight (2.3%) until the date of interview. TTR varied from 0.5 to 14 days. Eight adolescents (six females, two males) had persisting AEFIs at 14 days; none were of ‘severe’ or ‘serious’ grade. Three atypical AEFIs were reported in three adolescents (0.9%). These included one case each of epistaxis, recurrence of seizures in a female with uncontrolled seizure disorder pre-vaccination (same female, as after the first dose), and aggravation of pre-vaccination skin allergy. The MedDRA SOCs of reported AEFIs are shown in Fig. 3. The details of atypical and persisting AEFIs are described in Supplementary Table 2 (see the electronic supplementary material).

AEFIs in Adults After First, Second, and Booster Dose of COVAXIN

After excluding those lost to follow-up, AEFIs were assessable in 181 adults after the first dose and in 102 adults after the second dose. AEFIs occurred in 93 (51.4%) after the first dose and 38 (37.3%) after the second dose of the vaccine (Table 2). Injection site pain and fever were common AEs after both doses, and the majority of the AEFIs were mild-moderate. Only one severe and no serious AEFI was reported in adults. Among atypical AEFIs reported in two adults (0.7%), epistaxis and heavy menstrual bleed were reported in one case each after the first dose. AEFIs after a booster dose were reported in 41.7% and are mentioned in Table 2. AEFIs until the day of telephonic follow-up were persisting in 11 (eight females, three males) adults (3.7%). The majority of these AEFIs belonged to the SOC of ‘general disorders and administration site conditions’ and ranged in severity from mild to moderate. Details of severe, atypical, and persisting AEFIs in adults are given in Supplementary Table 2 (see the electronic supplementary material).

Comparative Analysis Between Adolescents Receiving First Dose and Adults Receiving First Dose

Direct comparison of AEFI occurrence was performed between adults and adolescents recruited at the time of receiving the first dose (n = 540). After excluding 48 participants lost to follow-up, this analysis was conducted in the set of 492 participants (311 adolescents and 181 adults). No statistically significant difference was observed in the local (41.8% vs 40.3%, P = 0.75), systemic (19% vs 22.1%, P = 0.40), or overall occurrence (50.8% vs 51.4%, P = 0.90) of AEFIs between adolescents and adults.

Risk Factors of AEFIs in Adolescents

Bivariate analysis (Table 3a) was performed to determine association between AEFIs occurring after any dose and potential risk factors. This was performed only in adolescents for whom there was complete information of AEFIs available following both doses (n = 344). Variables selected were sex, history of previous COVID-19, presence of co-morbidities, and history of allergy. In unadjusted analysis, a statistically significant positive association for occurrence of AEFIs was observed with 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 (Table 3b).

Description of AEFIs in Female Adolescents and Adolescents with History of Allergy

With female sex and history of allergy emerging as determinants of AEFIs in adolescents, a separate descriptive analysis was performed to underscore the type of AEFIs in female adolescents (n = 189) and adolescents with a history of allergy (n = 20) for whom information was available for both doses. Injection site pain and fever were the common AEFIs following the first dose of the vaccine, reported by 39 (20.6%) and 24 (12.7%) in female participants, respectively. The two were also the leading AEFIs following the second dose of the vaccine, developing, respectively, in 66 (34.9%) and 23 (12.2%) in female participants. The majority of the AEFIs belonged to the MedDRA SOC of ‘general disorders and administration site conditions,’ followed by ‘nervous system disorders.’ T cases of atypical AEFIs were reported. One was a case of recurrence of seizure in a female with a history of uncontrolled seizure disorder, and the other was hypothyroidism in a female with pre-vaccination history of neck swelling.

Injection site pain and fever were also common AEFIs in adolescents with a history of allergy. Injection site pain occurred in 30% after the first dose and 40% after the second dose, and fever developed in 20% after the first dose and 25% after the second dose in adolescents. T atypical AEFIs were reported in this risk group, while no anaphylactic events were reported. One was a case of recurrence of convulsions in a female with a history of uncontrolled seizure disorder and allergy to sunlight (same patient as described above), and the other was a case of exaggerated skin allergy and generalized burning sensation in a male with a history of allergy to sunlight. Though the majority of AEFIs were mild-moderate and recovered fully, female adolescents were more likely to develop persistent (2.2% vs 0.9%) and severe (1.3% vs 0.3%) AEFIs compared to males.

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.

Below is the link to the electronic supplementary material.

Funding

No funding support.

Conflict of interest

The authors have no conflicts of interest to declare.

Ethics approval

No human experimentation was performed. All procedures were performed as per the Declaration of Helsinki and its further modifications. Study was conducted after permission from Institute Ethics Committee of the Institute of Medical Sciences, Banaras Hindu University (Ethical Approval number: Dean/2022/EC/3210 and Dean/2021/EC/2526).

Consent to participate

Written informed consent/assent obtained from all participants.

Consent for publication

Written informed consent/assent obtained from all participants.

Availability of data and material

Since this is a preliminary analysis, associated data may be made available by the corresponding author on reasonable request, following applicable regulations.

Code availability

Not applicable.

Author contributions

UK: Planned the study, designed the study methodology, supervised data collection and data verification, conducted the review of the literature, performed the statistical analysis, and drafted the first version of the article. AKL, MC, AJ, AD: Assisted in the review of the literature and data collection and recording. SK: Planned the study and supervised data collection. VJ, KP: Supervised data collection and data verification and assisted in the review of the literature. SSC: Supervised the study, assisted in data verification and visualization, and edited the final version of manuscript. All authors read and approved the final version.