DISCUSSION
To the best of our knowledge, this prospective, multicentre, international study is the first to report the long-term safety of the BNT162b2 mRNA COVID-19 vaccine and the immunogenicity over time, induced by two and three doses of the vaccine, in a cohort of adolescents with juvenile-onset AIIRD, treated with a variety of immunomodulating agents.
The safety profile of the second and third vaccine doses was highly favourable, with most participants experiencing either no or mild side-effects and no serious side-effects in either group. Two percent of the AIIRD cohort experienced an exacerbation of the rheumatic disease shortly after the second vaccine dose and none of the patients who received the third vaccine reported subsequent rheumatic disease exacerbation or hospitalization.
The initial 2-dose vaccine was shown to be immunogenic in 91% of the AIIRD adolescents vs. 100% of healthy controls. However, anti-S1/S2 titres were significantly lower in the AIIRD group; similar to reports in adults with AIIRD.
Previous studies have shown waning antibody response to COVID-19 vaccination in the general population and AIIRD. In our patient and control groups, we observed waning of the anti-S1/S2 antibody titres over 6 months, with a faster decline in the control group compared to patients. This finding needs further clarification in larger trials.
Following the third vaccine, the seropositivity rate increased to 100% in adolescents with AIIRD. Furthermore, anti-S1/S2 titres reached a higher level as compared to those measured following the 2-dose vaccine, supporting the recommended booster vaccine dose in adolescents with AIIRD and also consistent with the response observed in adults with AIIRD. Notably, in the largest cohort of AIIRD adults, seropositivity after the third vaccine (82.3%) increased to a rate similar to that documented after the second dose (84.7%). The more vigorous response to the third dose in our adolescent patient cohort compared to adult patients may be explained by a stronger immunogenic response at younger ages and/or the more prevalent use of combination anti-rheumatic therapy in the adult cohort.
A meta-analysis published in 2022 showed that pooled seroconversion rates after a two-dose SARS-CoV-2 vaccination regimen were lower in patients with immune-mediated inflammatory disease compared to healthy controls. Importantly, certain therapies did not impact the seroconversion rates, including anti-TNF, anti-integrin, anti-IL-17, anti-IL6, and anti-12/23, while other therapies resulted in poorer responses including anti-CD20 and anti-CTLA-4. The current study was not large enough to determine the impact of the anti-rheumatic medication on humoral response to vaccination. We reported an adequate humoral response in patients treated with methotrexate and anti-TNF, and a blunted humoral response after the second vaccine dose in a small group of patients treated with MMF, which is consistent with a previous report. According to the literature regarding adults with AIIRD, RTX is a dominant factor for the lack of antibody response to the COVID-19 vaccine at all time points, especially among patients treated with RTX within 6 months prior to vaccination. B-cell depletion also consistently correlates with negative immunological response. Our small cohort of adolescents treated with RTX had a good humoral response. This might be because the vaccines were given at the appropriate times or because of the favourable immunogenic response at young ages.
It is important to note that there is still no consensus regarding the correlation between anti-spike antibody levels and protection from COVID-19 infection. Vaccination against COVID-19 induces both humoral and cellular responses, but it is widely thought that vaccine-induced neutralizing antibodies to the receptor binding domain of the SARS-CoV-2 S protein are a plausible mechanism of protection. A few studies in healthy adults demonstrated a significant correlation between neutralizing antibody titres and vaccine efficacy, with most of the breakthrough infections reported as mild or asymptomatic. Sakir et al. studied 630 patients with AIIRD and reported an association between breakthrough infections and sero-negativity following a COVID-19 vaccination. This provides a basis for exploring postvaccination antibody titres as a potential predictor of breakthrough infection in patients with AIIRD.
The breakthrough infection rate in this study was increased overall, but still comparable between patients with AIIRD and controls. Most of the breakthrough COVID-19 infections occurred either before or after the third vaccine. The median time from last vaccine dose to the COVID-19 infection, was 5 months in both groups. We suggest this as a means to estimate the actual protection from the vaccines. Most cases (88%) were documented during the Omicron surge, which is not surprising, as it is now evident that the original COVID-19 vaccine did not provide enough protection from the Omicron strain. It is notable that during the Delta surge, the breakthrough infection rates were low, similar to a previous report in adolescents with AIIRD. Even though the COVID-19 infection rates during the Delta and Omicron waves were higher among the AIIRD patients as compared to the healthy controls, the differences were not statistically significant.
These data are encouraging to the community of adolescents with juvenile-onset AIIRD and can help reduce hesitancy to vaccinations. The finding that no severe COVID-19 cases were documented can be explained by the effectiveness of the vaccine, that most of the young population experienced a mild form of the disease. In addition, the Omicron variant mostly caused mild illness.
There were several limitations to this study. The number of participants who provided serum samples for humoral response evaluation at 6 months and following the third vaccine decreased significantly, despite the ongoing COVID-19 pandemic. This is probably because the population was less compliant with the third vaccine dose.
In addition, due to the relatively small sample size, and specifically the diversity of rheumatic diseases and medications included in this juvenile-onset cohort, it was not possible to investigate the impact of immunomodulatory medications and type of disease on the anti-S1/S2 titres. In addition, the matching by age was not optimal, as the control group was younger than the patient group, with mean ages of 13.7 and 15.5 years, respectively. However, this might actually strengthen our findings of high seropositivity rates, as younger control children could have more robust immune activity. This study did not include neutralization assays or cellular immunity.
To summarize, this is the first longitudinal study of adolescents with AIIRD to report long-term safety, immunogenicity dynamics and breakthrough COVID-19 infections after the second and third doses of the BNT162b2 mRNA COVID-19 vaccine. We found an excellent safety profile with minimal to no side effects after the vaccinations overall and a minimal risk of rheumatic disease exacerbation. In addition, the rates of breakthrough COVID-19 infections and time from the last vaccination to infection were similar between groups. All the healthy controls and most of the adolescents with AIIRD were seropositive following the second vaccine, followed by a decline in anti-spike S1/S2 antibody titres in both groups over the 6 month period after the second vaccine. The titres were restored in all patients and controls after the third vaccine dose.
The findings of this study can help decrease vaccine hesitancy in adolescents with juvenile-onset AIIRD. Based on our results, it is recommended to booster adolescents with rheumatic disease with the BNT162b2 mRNA COVID-19 vaccine. Additional studies with larger numbers of adolescents with AIIRD are needed to evaluate the impact of anti-rheumatic/immunomodulatory therapies on the long-term immune response to the BNT162B2 vaccine.