Acknowledgement
DE is a senior clinical researcher of the Research Foundation
Flanders/Fonds Wetenschappelijk Onderzoek (FWO: 1800614N). VS is a
senior clinical researcher of the Research Foundation Flanders/Fonds
Wetenschappelijk Onderzoek (FWO: 1804518N).
We would like to thank Mr. T. De Cloet and Mrs. K. Vanbillemont for
their efforts during the COVID-pandemic and their aid in the collection
of this data.
The authors declare no conflict of interest in relation to this work
Informed consent was obtained from the participants of this study
This study was approved by the local Ethics board.
Author contribution: MB: Writing and analyzing of data; AT: critical
review and editing; PVD: critical review and editing; JMD: critical
review and editing; DE: supervision and writing; VS: supervision,
writing and conceptualization
Keywords : COVID-19; vaccine, hypersensitivity, allergy, placebo
To the Editor
Self-limiting mild adverse events (AEs) after COVID-vaccination are
common and should not contraindicate revaccination1.
Unfortunately, these are too often erroneously labeled as
hypersensitivity reactions (HRs), precluding
revaccination2. A patient with a history compatible
with an immediate HR to the vaccine should be offered allergologic
evaluation with the excipients of these vaccines based on the respective
type3,4. In contrast, in the diagnostic work-up of
patients with subjective symptoms or multiple unverified drug
hypersensitivities a placebo-controlled challenge should be
considered5.
In this study, we assessed the reoccurrence rate (RR) of AEs after
vaccination or unrelated to the vaccine in COVID-19-vaccine naïve
patients. We report data on 69 individuals who attended the outpatients’
clinic of the Antwerp University Hospital from April 1 to July 1, 2022,
for risk stratification concerning COVID-19 vaccination. Patient
characteristics are summarized in table 1.
All patients were administered a placebo, either as primary diagnostic
(n=52) or after negative skin testing (n=17). The main reason for
referral was symptoms after previous COVID-19 vaccination (n=41).
Twenty-eight patients were COVID-19-vaccine naïve and reasons for
referral are shown in table 1. Seventeen of the 69 patients were offered
allergologic evaluation including skin tests (STs) with the concerning
excipients or the COVID vaccine, based on clinical suspicion. In 1
patient a polysorbate allergy was diagnosed. She suffered from a so
called 1-1-1-urticaria6 after administration of the
first dose of Vaxzevria®. In all other patients, allergologic evaluation
was negative. All 69 patients were (re)vaccinated in a
placebo-controlled manner. In 11 patients previously vaccinated with
Spikevax® (n=3); Jcovden® (n=3) or Vaxzevria (n=5) a switch was made to
Comirnaty® either due to practical reasons of availability of vaccines
in our center (n=10) or because of confirmed hypersensitivity (n=1).
Out of the 41 patients who reported symptoms after previous dose, 14
reported symptoms after placebo administration and were vaccinated
uneventfully afterwards. Two patients had symptoms after re-exposure to
the vaccine: 1 patient experienced dyspnea with urticaria that was
considered anaphylaxis, 1 patient had urticaria immediately after the
vaccination with Comirnaty®. Both did not meet criteria for mast cell
activation7. Of the 28 COVID-19-vaccine naïve
patients, 5 had symptoms after administration with placebo and were
later vaccinated uneventfully. In total, 19 out of 69 patients (27.54%)
experienced symptoms after placebo. Overall, 67 of 69 patients were
vaccinated uneventfully without premedication and the RR of AEs was 1 in
20 (4.88%). Details regarding allergologic evaluation and vaccination
are shown in table 2.
The aim of this study was dual: first, to evaluate the RR of presumed
AEs after vaccination and second, to evaluate the rate of AEs unrelated
to the vaccine in COVID-19-vaccine naïve patients. A recent
meta-analysis stated that 13.65% of individuals experience reoccurrence
of nonlife-threatening symptoms after a second dose8.
In our cohort, the RR of AEs was 4.88%. The difference might be
explained by the fact that placebo administration enabled to distinguish
the effective reoccurrence of vaccine-induced symptoms from nocebo
effect9,10. Actually, after exposure to placebo 28%
of patients experienced symptoms (similar to the symptoms that occurred
upon previous exposure to the vaccine). Placebo-controlled provocation
is an important part of drug provocation tests (DPTs) but has not been
described before in the context of possible vaccination
hypersensitivity. Previous studies on placebo and nocebo effects in DPTs
demonstrate that patients with symptoms after exposure, anxiety and/or
depression are prone to nocebo effects11.
We conclude that the RR of AEs after COVID-19 vaccination is low. A
thorough history and clinical details regarding symptoms and timing are
essential for correct risk stratification. The use of placebo is of
great value and should be considered in drug provocation tests,
especially in patients with a history of symptoms after previous
exposure and in patients with anxiety or depression.