Acute Reactions After Vaccination Against COVID-19 and Long-Term Antibody Levels

In spite of the continuing SARS-CoV-2 pandemic and the confirmed benefits of COVID-19 vaccinations, the vaccination rate in the German population is comparably low. The rate is higher in the healthcare sector, but even here a relevant proportion of workers are unvaccinated (1). The reasons given for not being vaccinated against COVID-19 are diverse, potential adverse effects are mentioned particularly often (2). We wanted to find out which adverse effects occur and whether the occurrence of these is associated with the measured antibody concentrations; to this end we investigated a large population of healthcare workers.

Methods

We analyzed at several time points after the second and third vaccinations the concentration of SARS-CoV spike antibodies in staff members from all professional groups at Ulm University Hospital. We used the Elecsys-Anti-SARS-CoV-2 test (Roche) to determine quantitatively antibody levels against the SARS-CoV-2 spike protein receptor binding domain. We simultaneously used the Elecsys-Anti-SARS-CoV-2 test (Roche) to test for nucleocapsid antibodies. In parallel we administered a standardized questionnaire to record vaccine reactions, on the basis of which we dichotomized the occurrence of vaccine reactions. The statistical evaluation was exploratory and owing to asymmetrically distributed antibody levels we used the Mann-Whitney-U-test. We defined statistical significance at the p<0.05 level. The study was approved by the Ulm ethics committee (No 118/21).

Results

Between May 2021 and March 2022 we undertook a systematic data collection of antibody levels after COVID-19 vaccination. 1842 subjects were included after their second vaccination and 573 after the booster vaccination. Significantly higher antibody levels were seen 14 weeks (±2 weeks) after two doses of Comirnaty (n=1077; 1120 U/mL) and especially after the heterologous sequence of vaccination Vaxzevria-Comirnaty (n=597; 2513 U/mL) than after two doses of Vaxzevria (n = 152, 460.5 U/mL). Antibody levels were significantly higher in people younger than 30 years (n = 354, AS 2307.5 U/mL (71.8–17 033) than in older subjects (n = 1486, AS 1303 U/mL (0.62–16 962); p = 0.001). In 49 subjects (2.6%), nucleocapsid antibodies were confirmed even before their booster vaccination (in the sense of COVID-19 infection having taken place). These subjects also had notably higher antibody levels than nucleocapsid-antibody negative subjects (median antibody count 5473 U/mL (53.9–17 033) versus 1453 U/mL (0.62–12 500). After the third vaccination, 5.8% (n=33) of the subjects tested positive for nucleocapsid antibodies. Over time 24 weeks after the second vaccination, the antibody levels fell to a median of 237 U/mL (0.62–10 257) (n = 403). Only in 54 subjects these remained at the same level or rose by a median of 66.5 U/mL (0–1825). The third vaccination resulted in a pronounced boost to the antibody levels (Table). In most subjects (89%) after the first/second vaccinations, 83% after the third vaccination), acute vaccine side effects were seen that were mostly classified as mild to moderate. The lead symptom were local adverse effects, followed by systemic effects such as fatigue/exhaustion, headache, and musculoskeletal pain. One event that was temporally associated with the third vaccination was categorized as a “severe” potential vaccine reaction (immune thrombocytopenia). An association existed between the occurrence of a vaccine reaction and the antibody levels after the second vaccination (vaccine reaction: n=1641; median antibody level 1563 U/mL [0.62–17 033]; no reaction to the vaccine: n=201; 840 U/mL [28.2–12 500]; p < 0.001), (Figure). This association was also confirmed after the third vaccination (vaccine reaction; n=478, median antibody level 15196 U/mL [769–25 000]; no reaction to the vaccine: n=95, 11 672 U/mL [42–25 000]; p = 0.0012), with high immunogenicity triggered in both groups.

Figure

Antibody levels after COVID-19 vaccination and presence of acute vaccination side effects

Table

Description of cohort and results of antibody level measurements

Discussion

Several studies showed “fear of adverse effects” as a crucial determinant for refusing the cavid-19 vaccination, some also testified to a conviction that the vaccine is ineffective (3). Our data collection was done in a representative cohort of workers in a German university hospital. In analogy to previous publications we confirmed a satisfactory vaccine response in all subgroups. Only in two subjects (0.1%) did the antibody levels remain below the reported cut-off value after the second vaccination (≥ 0.8 U/mL). Staff who had had heterologous vaccinations (Vaxzevria-Comirnaty) showed significantly higher antibody levels after the second vaccination than those receiving homologous vaccinations, in analogy to the findings reported by other working groups (4). Antibody levels after the third vaccination with an mRNA vaccine was not affected by the previous vaccination scheme/schedule. We confirmed a substantial age dependency in the immune response after the second and third vaccinations. While older “pre-covid” studies postulated an association between the extent of the acute vaccine reaction (“cytokine release”) and vaccine effectiveness, this aspect is currently barely being addressed. Even though the extent of vaccine effectiveness is vastly more complex than merely antibody formation and a B-cell response, a correlation between antibody levels and risk reduction for covid-19 infection has been described for non-omicron virus variants (5). We confirmed significantly higher antibody levels after the second and third vaccinations in subjects with acute vaccine reaction, compared with the group without acute vaccine reaction. In the context of the third vaccination all subjects reached a vaccine titer that was higher than after the second vaccination. We were pleased to see in non-responders to the first and second vaccinations a rise beyond the cut-off value too. A potential study limitation lies in the fact that the retrospective recollection of adverse effects to vaccination at the time of the antibody measurement is susceptible to a certain recall bias. In sum, we were able to confirm in a population of healthcare workers—in addition to the known high humoral immune response especially in the subjects with acute vaccine reactions—significantly higher antibody levels after the second and third vaccinations, in a setting of good tolerance of the vaccines used.

Lukas Perkhofer, Jana Nägele, Joris Kroschel, Benjamin Mayer, Martin Müller*, Thomas Seufferlein*

Acknowledgment

We thank all the healthcare staff at Ulm University Medical Center who participated in the study and the Corona Task Force at Ulm University Medical Center for initiating the resent study. In particular, we thank the following, who were involved in enabling and implementing the study: Prof. Udo X Kaisers, Dr Thomas Gscheidmeier, Prof. Roman Wennauer, Patrick Schauppel, Steffen Bolek, Will Qian, Annsophie Thies, and all the staff at the Central Facility for Clinical Chemistry.

Conflict of interest statement
The authors declare that no conflict of interests exists.

Manuscript received on 28 January 2022, revised version accepted on 6 April 2022.

Translated from the original German by Birte Twisselmann, PhD.

Cite this as
Perkhofer L, Nägele, Kroschel J, Mayer B, Müller M, Seufferlein T: Acute reactions after vaccination against COVID-19 and long-term antibody levels. Dtsch Arztebl Int 2022; 119: 484–5. DOI: 10.3238/arztebl.m2022.0195

References

1. Robert Koch-Institut: KROCO – die Krankenhausbasierte Online-Befragung zur COVID-19-Impfung Ergebnisbericht zur Dritten Befragungswelle. www.rki.de/DE/Content/InfAZ/N/Neuartiges_Coronavirus/Projekte_RKI/Kroco-Report100122.pdf?_blob=publicationFile ( last accessed on 10 January 2022).

2. forsa: Befragung von nicht geimpften Personen zu den Gründen für die fehlende Inanspruchnahme der Corona-Schutzimpfung. www.bundesgesundheitsministerium.de/fileadmin/Dateien/3_Downloads/C/Coronavirus/Befragung_Nichtgeimpfte_-_Forsa-Umfrage_Okt_21.pdf (last accessed on 16 Dezember 2021).

3. Cerda AA, Garcia LY: Hesitation and refusal factors in individuals’ decision-making processes regarding a coronavirus disease 2019 vaccination. Front Public Health 2021; 9: 626852

4. Stuart ASV, Shaw RH, Liu X, et al.: Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial. Lancet 2022; 399: 36–49

5. Khoury DS, Cromer D, Reynaldi A, et al.: Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med 2021; 27: 1205–11