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.