Official Publication of Korean Vaccine Society, Korea
Open Access, Peer-reviewed, Quarterly
pISSN 2287-3651   eISSN 2287-366X
    Clin Exp Vaccine Res. 2023 Jan;12(1):60-69. English.
    Published online Jan 31, 2023.
    https://doi.org/10.7774/cevr.2023.12.1.60
    © Korean Vaccine Society.
    Original Article

    Humoral immune response to SARS-CoV-2 mRNA vaccines is associated with choice of vaccine and systemic adverse reactions

    Hanna Klingel, Alexander Krüttgen, Matthias Imöhl and Michael Kleines
      • Laboratory Diagnostic Center, University Hospital RWTH Aachen, Aachen, Germany.
    • Corresponding author: Michael Kleines, PhD. Laboratory Diagnostic Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074 Aachen, Germany. Tel: +49-241-80-88671, Fax: +49-241-80-82512, Email: mkleines@ukaachen.de
    Received May 07, 2022; Accepted January 10, 2023.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Purpose

    Although the fast development of safe and effective messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 has been a success, waning humoral immunity has led to the recommendation of booster immunization. However, knowledge of the humoral immune response to different booster strategies and the association with adverse reactions is limited.

    Materials and Methods

    We investigated adverse reactions and anti-spike protein immunoglobulin G (IgG) concentrations among health care workers who received primary immunization with mRNA-1273 and booster immunization with mRNA-1273 or BNT162b2.

    Results

    Adverse reactions were reported by 85.1% after the first dose, 94.7% after the second dose, 87.5% after a third dose of BNT162b2, and 86.0% after a third dose of mRNA-1273. They lasted for a median of 1.8, 2.0, 2.5, and 1.8 days, respectively; 6.4%, 43.6%, and 21.0% of the participants were unable to work after the first, second, and third vaccination, respectively, which should be considered when scheduling vaccinations among essential workers. Booster immunization induced a 13.75-fold (interquartile range, 9.30–24.47) increase of anti-spike protein IgG concentrations with significantly higher concentrations after homologous compared to heterologous vaccination. We found an association between fever, chills, and arthralgia after the second vaccination and anti-spike protein IgG concentrations indicating a linkage between adverse reactions, inflammation, and humoral immune response.

    Conclusion

    Further investigations should focus on the possible advantages of homologous and heterologous booster vaccinations and their capability of stimulating memory B-cells. Additionally, understanding inflammatory processes induced by mRNA vaccines might help to improve reactogenicity while maintaining immunogenicity and efficacy.

    Keywords
    SARS-CoV-2; mRNA vaccines; Secondary immunization; Adverse reactions; Humoral immunity

    Introduction

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing pandemic of coronavirus disease 2019 (COVID-19) [1]. A global effort has been made to rapidly develop vaccines that protect against COVID-19 [2].

    The messenger RNA (mRNA) based vaccines mRNA-1273 (Spikevax; Moderna Biotech Spain S.L., Madrid, Spain) and BNT162b2 (Comirnaty; BioNTech Manufacturing GmbH, Mainz, Germany; Pfizer Manufacturing Belgium NV, Puurs-Sint-Amands, Belgium) were the first SARS-CoV-2 vaccines approved in the United States [3, 4] and Europe [5, 6]. Both vaccines’ nucleoside-modified mRNA is encapsulated in lipid nanoparticles and encodes the SARS-CoV-2 spike (S) protein stabilized in its prefusion conformation [7, 8]. Immunity against the spike protein is expected to protect against COVID-19 [9]. Despite their similar composition, mRNA-1273 and BNT162b2 elicit slightly different immune responses. Vaccination with mRNA-1273 induces an antibody and type 1 helper T-cell–mediated immune response against the viral spike protein [7]. BNT162b2 additionally induces a specific cytotoxic T-cell response [10]. Nevertheless, both vaccines have demonstrated a comparable, high efficacy [11, 12].

    However, antibody levels after complete primary vaccination with mRNA vaccines wane over time [13, 14, 15]. Since neutralizing antibodies are expected to considerably contribute to protection against COVID-19, a decline raises concerns about waning immunity. Additionally, mRNA-1273 and BNT162b2 induced humoral immunity against SARS-CoV-2 variants is reduced [15, 16]. To enhance and broaden immunity [15, 16, 17, 18], booster vaccinations are now being administered. Yet knowledge of the effect of booster immunization on antibody levels particularly in health care workers and possible advantages of homologous and heterologous booster vaccination strategies is still limited.

    Although the new technology and the fast development of mRNA vaccines against SARS-CoV-2 have given rise to safety concerns, several clinical trials have demonstrated acceptable safety with predominately mild to moderate adverse reactions [7, 8, 11, 12, 15, 17, 18, 19, 20, 21, 22]. Whether antibody levels are associated with adverse reactions has not been evaluated in clinical trials. Few studies on BNT162b2 vaccinated individuals [14, 23, 24, 25] and mixed cohorts of mRNA-1273 and BNT162b2 vaccinated health care workers [26, 27] indicate a relationship between antibody levels and adverse reactions. However, further investigations focusing on mRNA-1273 vaccinated individuals and booster immunization are lacking.

    Considering higher COVID-19 mortality in older patients [28], the investigation of the influence of age on vaccine-induced antibody levels is of special interest. Despite immunosenescence immunization with mRNA-1273 has been shown to induce an age-independent humoral immune response [19, 20, 21]. In contrast, BNT162b2 elicits a lower humoral immune response in older individuals when applied as a prime dose [8, 14, 22] but an age-independent humoral immune when used for booster immunization [22, 29]. Interestingly, adverse reactions have been reported to be less common among older people for both vaccines [8, 11, 12, 14, 20, 22]. Evaluation of the association between adverse reactions and immunogenicity might help understand these contradictory observations.

    The present study aims at expanding the knowledge of humoral immune response after primary and booster immunization and of the association between humoral immune response and adverse reactions in health care workers who were vaccinated with mRNA vaccines against SARS-CoV-2.

    Materials and Methods

    Trial design and participants

    The retrospective study’s cohort consisted of 105 health care workers who were primarily vaccinated twice with 100 µg mRNA-1273. In accordance with national recommendations, booster immunization with either 50 µg mRNA-1273 or 30 µg BNT1273 was offered between 6 to 10 months after complete primary immunization. Written informed consent for vacci nation and participation in the study was obtained from each participant. Sample and data acquisition were approved by the Medical Ethics Committee of the University Hospital RWTH Aachen (EK 093/20). Each participant was asked to complete a questionnaire regarding local and systemic adverse reactions and inability to work after the first, second, and third vaccination. Local adverse reactions include pain at the injection site, local swelling, and redness. Fatigue, headache, fever, chills, myalgia, arthralgia, diarrhea, vomiting, rash and pruritus, edema, and being bedridden are summarized as systemic adverse reactions. Participants graded the severity of symptoms as mild, moderate, or severe and stated the approximate beginning and duration of each symptom. Fever was classified as mild, moderate, or severe for temperatures <38.5°C, 38.5°C–39.5°C, and >39.5°C, respectively. Serum was collected at three-time points (TP) to measure anti-S-immunoglobulin G (IgG) concentrations (TP1: 2 to 3 weeks after complete primary immunization, TP2: 5 to 8 months after complete primary immunization but before booster immunization, TP3: at least 2 weeks after booster immunization). Additionally, at TP1 inhibition in a surrogate virus, a neutralization test was measured. According to anti-S-IgG concentrations, the participants were stratified into high-responders (top quartile) and low-responders (bottom quartile). Of the 92 participants who had blood drawn at TP1 and answered the questionnaire 23 were stratified in each quartile. At TP3 BNT162b2 and mRNA-1273 vaccinated participants were evaluated separately to avoid bias. For BNT162b2 vaccinated individuals who had blood drawn at TP3 and completed the questionnaire (n=32), each quartile contained eight participants. Among exclusively mRNA-1273 vaccinated participants who had blood drawn at TP3 and turned in the questionnaire (n=42), 10 were classified as low- and high-responders, respectively. To maximize the sample size mRNA-1273 and BNT162b2 vaccinated participants were also analyzed together. This did not change the findings described below (data not shown).

    Antibody measurements

    To measure total anti-S-IgG concentration, we performed the Liaison SARS-CoV-2 S1/S2 IgG assay (DiaSorin, Saluggia, Italy) as recommended by the manufacturer [30]. For the measurement of neutralizing antibodies, we used a surrogate SARS-CoV-2 neutralization test (SARS-CoV-2 Surrogate Virus Neutralization Test Kit; Genscript Biotech, Piscataway, NJ, USA) according to the manufacturer’s instructions. The method has been described in detail previously [31]. Sera prediluted by 1:20 were used.

    Statistical analysis

    Statistical analysis was performed using IBM SPSS Statistics ver. 27.0 for Windows (IBM Corp., Armonk, NY, USA). Categorical variables are expressed as absolute numbers or frequencies and are compared between groups using Fisher’s exact test. Effect size is reported as odds ratio (OR) and 95% confidence interval (CI). Metric variables are given as median (interquartile range, IQR) or arithmetic mean±standard deviation. We tested for normal distribution by qualitative evaluation of histograms and using the Kolmogorov-Smirnov test. Due to skewed distribution and identification of several outliers, metric variables are compared between two groups using a two-sided Mann-Whitney U test for unpaired variables. Correlation between metric variables was assessed using Spearman’s correlation. All p-values below 0.05 are considered significant.

    Results

    Study population

    The questionnaire was completed by 94 participants after each of the two injections of the primary immunization and by 81 participants after the booster immunization. At TP1, TP2, and TP3 (details: Materials and Methods section), blood for antibody measurements was drawn from 93, 90, and 87 participants, respectively. All participants had two doses of mRNA-1273 administered for primary immunization. Of the participants who had blood drawn at TP3, 51.7% had received mRNA-1273 and 41.4% BNT162b2 as booster vaccination. And 6.9% did not specify the vaccine. The participants’ age ranged from 21 to 73 years with a mean of 49.8±13.1 years and a median of 54 years (IQR, 40.5–59.0 years). Of the participants, 75.2% were older than 40 years, and 45.7% were older than 55 years. And 83.8% of the participants were female.

    Adverse reactions after first, second, and third vaccination

    After the first vaccination, 85.1% of the participants reported symptoms. The symptoms were predominately graded as mild to moderate (Fig. 1). In contrast, 94.7% of the participants stated to have had symptoms after the second vaccination. Symptoms after the second vaccination were characterized as rather moderate to severe (Fig. 2). Most symptoms tended to be more common after the second than after the first immunization. After the booster immunization symptoms were reported by 86.0% of the participants who received mRNA-1273 and by 87.5% of the participants who received BNT162b2. The frequency and intensity of adverse reactions were numerically similar among participants who received mRNA-1273 and BNT162b2 as booster immunization (Fig. 3). The frequency of symptoms after the third immunization tended to be lower than after the second but higher than after the first dose for most symptoms except for local pain, local swelling, diarrhea, and rash. The intensity of symptoms after booster vaccination was comparable to the first immunization.

    Fig. 1
    Frequency and intensity of adverse reactions after the first vaccination with messenger RNA (mRNA)-1273.

    Fig. 2
    Frequency and intensity of adverse reactions after the second vaccination with messenger RNA (mRNA)-1273.

    Fig. 3
    Frequency and intensity of adverse reactions after the third vaccination with messenger RNA (mRNA-1273) or BNT162b2.

    Symptoms started 5 hours (IQR, 2–8 hours) after the first vaccination, 4 hours (IQR, 2–7 hours) after the second vaccination, 6 hours (IQR, 2–12 hours) after the third vaccination with BNT162b2, and 4 hours (IQR, 1–8 hours) after the third vaccination with mRNA-1273, lasting for 44 hours (IQR, 25–67 hours), 47 hours (IQR, 36–71 hours), 60 hours (IQR, 25–74 hours), and 44 hours (IQR, 34–64 hours), respectively. After the first, second, and third vaccination 6.4%, 43.6%, and 21.0% of the health care workers were temporarily unable to work. Inability to work lasted a median of 1 day (IQR, 1–2 days) after each vaccination.

    Humoral immune response

    At TP1 all participants had anti-S-IgG concentrations above the test-specific cut-off of 39 BAU/mL with a mean of 3,373±1,410 BAU/mL. Inhibition in the surrogate neutralization test exceeded the test-specific cut-off of 20% for all participants with a mean of 70.45%±18,80%. At TP2 and TP3 mean anti-S-IgG concentrations were 645±514 BAU/mL and 9,949±7,950 BAU/mL, respectively. At both time points, all participants far exceeded the test-specific cut-off (Fig. 4). At TP2 anti-S-IgG concentrations had decreased to 0.16 times (IQR, 0.13–0.23 times) the concentrations at TP1. At TP3 anti-S-IgG concentrations were 13.75 times (IQR, 9.30–24.47 times) higher than at TP2 and 2.28 times (IQR, 1.84–3.63 times) higher than at TP1.

    Fig. 4
    Box plots of anti-S-immunoglobulin G (IgG) concentrations 2 to 3 weeks after primary immunization (TP1), 5 to 8 months after primary immunization (TP2) and at least 2 weeks after booster immunization (TP3). Horizonal bars and boxes denote median and interquartile range. Whiskers equal lower and upper quartile±1.5 times the interquartile range. Circles depict outliers outside the lower and upper quartile±1.5 times the interquartile range. Asterisks represent extreme outliers outside the lower and upper quartile±3 times the interquartile range. TP, time points.

    Spearman’s correlation indicated a strong positive correlation between anti-S-IgG concentrations at TP1 and TP2 (r=0.620, p<0.001) (Fig. 5) and a weak, but significant correlation between anti-S-IgG concentrations at TP1 and TP3 (r=0.295, p=0.008) (Fig. 6). There was no significant correlation between anti-S-IgG concentrations at TP2 and TP3 (p=0.057) (Fig. 7).

    Fig. 5
    Scatter plot of anti-S-immunoglobulin G (IgG) concentrations at TP1 and TP2 expressed in BAU/mL. Correlation was assessed by Spearman’s correlation coefficient (r=0.620, p<0.001). TP, time points.

    Fig. 6
    Scatter plot of anti-S-immunoglobulin G (IgG) concentrations at TP1 and TP3 expressed in BAU/mL. Correlation was assessed by Spearman’s correlation coefficient (r=0.295, p=0.008). TP, time points.

    Fig. 7
    Scatter plot of anti-S-immunoglobulin G (IgG) concentrations at TP2 and TP3 expressed in BAU/mL. Correlation was assessed by Spearman’s correlation coefficient (r=0.209, p=0.057). TP, time points.

    At TP3 mRNA-1273 vaccinated individuals had significantly higher anti-S-IgG concentrations than BNT162b2 vaccinated participants (p=0.021). Age, sex distribution, and anti-S-IgG concentrations at TP2 were comparable between participants booster vaccinated with mRNA-1273 or BNT162b2 (Table 1).

    Table 1
    Age, sex, and anti-S-IgG concentrations before (TP2) and after (TP3) booster immunization with BNT162b2 or mRNA-1273

    Association of antibody levels with adverse reactions and age

    Comparison of low- and high-responders at TP1 showed a significantly higher frequency of fever (p=0.023; OR, 6.11; 95% CI, 1.41–26.41), chills (p=0.002; OR, 8.91; 95% CI, 2.25–35.33), and arthralgia (p=0.007; OR, 9.63; 95% CI, 1.82–50.89) after the second immunization among high-responders (Table 2). All other adverse reactions and inability to work after the second vaccination were not significantly associated with high and low anti-S-IgG concentrations at TP1. There was no significant association between adverse reactions and inability to work after the first immunization and low- and high-responders at TP1 (data not shown).

    Table 2
    Adverse reactions after the second vaccination with mRNA-1273 among low- and high-responders after the second vaccination (TP1)

    The frequencies of adverse reactions and inability to work after the third vaccination were not significantly different in high- and low-responders at TP3, neither among BNT162b2 nor among mRNA-1273 vaccinated participants.

    At TP1 and TP2, there was no significant Spearman’s correlation between age and anti-S-IgG concentration (p=0.238, p=0.971, respectively) (Fig. 8). Neither for BNT162b2 nor for mRNA-1273 vaccinated participants, anti-S-IgG concentrations at TP3 significantly correlated with age (p=0.123, p=0.632, respectively) (Fig. 9).

    Fig. 8
    Scatter plot of age expressed in years and anti-S-immunoglobulin G (IgG) concentrations at TP1 and TP2 expressed in BAU/mL. Correlation was assessed by Spearman’s correlation (TP1: p=0.238, TP2: p=0.971). TP, time points.

    Fig. 9
    Scatter plot of age expressed in years and anti-S-immunoglobulin G (IgG) concentrations at TP3 expressed in BAU/mL. Correlation was assessed by Spearman’s correlation (BNT162b2: p=0.123, messenger RNA [mRNA]-1273: p=0.632). Individuals not specifying booster vaccine were excluded from correlation analysis and are represented by white circles. TP, time points.

    Correlation between inhibition in neutralization test and anti-S-IgG concentration

    For normalization anti-S-IgG concentrations and inhibition in the neutralization test measured at TP1 were divided by the test-specific cut-offs. Normalized inhibition was plotted against normalized anti-S-IgG concentration (Fig. 10). Spearman’s correlation indicated a strong correlation between neutralizing antibodies and anti-S-IgG (r=0.806, p<0.001).

    Fig. 10
    Scatter plot of normalized anti-S-immunoglobulin G (IgG) concentrations and inhibition in a surrogate neutralization test at TP1. Correlation was assessed by Spearman’s correlation coefficient (r=0.806, p<0.001). TP, time points.

    Discussion

    The present study aimed at evaluating the humoral immune response to primary and booster immunization with mRNA vaccines against SARS-CoV-2 in health care workers and the association with adverse reactions.

    The frequency of symptoms observed after the first and second vaccination with mRNA-1273 was as expected from the phase 1 to 3 trials with adverse reactions being more common and severe after the second immunization [7, 11, 19, 20]. However, local pain, fatigue, headache, fever, chills, myalgia, and arthralgia were classified as more severe. Adverse reactions after the booster immunization occurred more commonly than after the first vaccination but did not reach the extent of adverse reactions after the second vaccination. Compared to clinical trials on the booster vaccination [15, 17, 18, 21, 22], we observed lower rates of headache, fatigue, myalgia, arthralgia, and chills but higher rates of local redness and swelling and a higher intensity of local pain, especially after mRNA-1273 booster vaccination. Differences in the clinical trials might be explained by our cohort consisting exclusively of health care workers, who might rate health issues differently than the general population. Notably, adverse reactions after a third dose of mRNA-1273 or BNT162b2 were comparable while previous studies have reported conflicting results [21, 32]. We found symptoms to begin mainly within the day of vaccination. Symptoms after the first and second vaccination lasted shorter than in phase 2 and 3 trials on primary vaccination with mRNA-1273 [11, 20]. Of note, symptoms after booster vaccination with BNT162b2 lasted longer compared to vaccinations with mRNA-1273. While most of our participants were able to work after the first dose, almost half and a quarter of them were temporarily absent from work after the second and third doses, respectively. While one study reported about a quarter of the participants requiring time off work without differentiating between the first and second vaccination [33], another study found slightly more participants temporarily unable to work than in our study, both after the first and the second immunization [34]. Taken together, the observed moderate to high frequency and intensity of adverse reactions, the beginning and duration and the high rate of temporary inability to work after the second and third immunization should be considered when scheduling vaccinations, especially among essential workers.

    We confirmed the decline of antibody levels after complete primary immunization with mRNA-1273 over time [13, 15]. However, anti-S-IgG concentrations 5 to 8 months after the second vaccination still far exceeded the test-specific cut-off in all participants. Booster immunization led to an almost 14-fold increase of anti-S-IgG concentrations with antibody levels about 2 times higher than after the second vaccination. The observed increase is in the range of the previously described increase of binding and neutralizing antibodies [15, 17, 18, 21, 22]. However, previous studies mainly focused on homologous booster vaccination strategies, and studies on heterologous booster vaccination especially with mRNA-1273 as the prime dose are limited. In our study, a heterologous vaccination scheme with mRNA-1273 as prime and BNT162b2 as booster vaccination was also effective but resulted in significantly lower antibody concentrations than homologous mRNA-1273 vaccination. One prospective study found numerically higher neutralizing and binding antibody levels after homologous vaccination with mRNA-1273 compared to heterologous vaccination with mRNA-1273 and BNT162b2 but was not designed for direct inter-group comparison [21]. A stronger humoral immune response to homologous vaccination could be explained by a more effective stimulation of memory B-cells. Nevertheless, heterologous vaccination with mRNA-1273 as prime and BNT162b2 as boost might offer immunological advantages, e.g., by inducing an additional cytotoxic T-cell response [10]. Therefore, further prospective and randomized studies are needed to evaluate the advantages and disadvantages of homologous and heterologous vaccination strategies. Interestingly, antibody levels after booster immunization were only weakly correlated with antibody levels measured directly after primary immunization and not correlated with antibody levels measured before booster immunization. An explanation might be the independency of antibody response and generation of memory B-cells which presumably account for the humoral immune response to booster vaccination [26].

    Previous studies have found an association between adverse reactions and humoral immune response among BNT162b2 vaccinated individuals [14, 23, 24, 25] and in mixed study populations of BNT162b2 and mRNA-1273 vaccinated participants [26, 27]. Particularly systemic adverse reactions after the second vaccination showed to be associated with antibody levels. We observed an association between fever, chills, and arthralgia after the second vaccination and anti-S-IgG concentrations after the complete primary vaccination. Our results support the hypothesis that systemic adverse reactions after the second dose are associated with antibody levels not only in BNT162b2 but also in mRNA-1273 vaccinated individuals. Higher frequencies of systemic adverse reactions likely indicate a stronger inflammation [35] which might either be the triggering factor for antibody induction or the result of a stronger immune response.

    Considering higher COVID-19 mortality in older patients, investigation of the immune response to mRNA-1273 in older individuals is crucial [28]. In our study humoral immune response was independent of age. This is in line with the observation that mRNA-1273 elicits an age-independent immune response [19, 20, 21] but contradictory to trials on BNT162b2 that observed a lower humoral immune response in older individuals [8, 14]. However, previous studies focusing on booster immunization showed no correlation between age and humoral immune response to booster vaccination with BNT162b2 [22, 29]. Possible explanations for an age-independent immune response include the activation of memory B cells either against SARS-CoV-2 or endemic human coronaviruses [19, 36] and improvement of immunogenicity compared to traditional vaccine approaches [37].

    Limitations of this study are the small sample size, the predominance of female participants, and the limited age range. While the composition of our study cohort might be representative of the health care system it does not represent the general population and therefore generalization of our findings is limited. Additionally, national booster vaccination strategies changed over the time course of our study. Due to our retrospective study design, this influenced the choice of vaccine depending on availability, age, and primary vaccination.

    In summary, our study showed that adverse reactions after the second and third doses of SARS-CoV-2 mRNA vaccines are common in health care workers resulting in almost half and a quarter of them being unable to work after the second and third dose, respectively. Furthermore, we found both homologous booster immunization with mRNA-1273 and heterologous booster immunization with mRNA-1273 and BNT162b2 to increase binding antibody concentrations with significantly higher levels after homologous booster vaccination. We did not find a correlation between age and humoral immunogenicity supporting the suitability of mRNA vaccines across age groups. Finally, we have demonstrated an association between the frequency of fever, chills, and arthralgia after the second vaccination with mRNA-1273 and anti-S-IgG concentrations after complete primary immunization indicating a linkage between systemic adverse reactions, inflammation, and humoral immune response. Further understanding of the underlying processes might help to improve vaccine reactogenicity while maintaining immunogenicity.

    Notes

    No potential conflict of interest relevant to this article was reported.

    References

      1. Cucinotta D, Vanelli M. WHO declares COVID-19 a pandemic. Acta Biomed 2020;91:157–160.
      1. Poland GA, Ovsyannikova IG, Kennedy RB. SARS-CoV-2 immunity: review and applications to phase 3 vaccine candidates. Lancet 2020;396:1595–1606.
      1. US Food and Drug Administration. Moderna COVID-19 vaccine [Internet]. Silver Spring (MD): FDA; 2021 [cited 2021 May 4].
        Available from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/moderna-covid-19-vaccine .
      1. US Food and Drug Administration. Comirnaty and Pfizer-BioNTech COVID-19 vaccine [Internet]. Silver Spring (MD): FDA; 2021 [cited 2021 Dec 2021].
        Available from: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/comirnaty-and-pfizer-biontech-covid-19-vaccine .
      1. European Medicines Agency. EMA recommends COVID-19 vaccine Moderna for authorisation in the EU [Internet]. Amsterdam: EMA; 2021 [cited 2021 May 4].
        Available from: https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu .
      1. European Medicines Agency. EMA recommends first COVID-19 vaccine for authorisation in the EU [Internet]. Amsterdam: EMA; 2020 [cited 2021 Dec 27].
        Available from: https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu .
      1. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA vaccine against SARS-CoV-2: preliminary report. N Engl J Med 2020;383:1920–1931.
      1. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N Engl J Med 2020;383:2439–2450.
      1. Teo SP. Review of COVID-19 mRNA vaccines: BNT162b2 and mRNA-1273. J Pharm Pract 2022;35:947–951.
      1. Sahin U, Muik A, Vogler I, et al. BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans. Nature 2021;595:572–577.
      1. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med 2021;384:403–416.
      1. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med 2020;383:2603–2615.
      1. Doria-Rose N, Suthar MS, Makowski M, et al. Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for COVID-19. N Engl J Med 2021;384:2259–2261.
      1. Naaber P, Tserel L, Kangro K, et al. Dynamics of antibody response to BNT162b2 vaccine after six months: a longitudinal prospective study. Lancet Reg Health Eur 2021;10:100208
      1. Choi A, Koch M, Wu K, et al. Safety and immunogenicity of SARS-CoV-2 variant mRNA vaccine boosters in healthy adults: an interim analysis. Nat Med 2021;27:2025–2031.
      1. Nemet I, Kliker L, Lustig Y, et al. Third BNT162b2 vaccination neutralization of SARS-CoV-2 omicron infection. N Engl J Med 2022;386:492–494.
      1. Chu L, Vrbicky K, Montefiori D, et al. Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial. Nat Med 2022;28:1042–1049.
      1. Falsey AR, Frenck RW Jr, Walsh EE, et al. SARS-CoV-2 neutralization with BNT162b2 vaccine dose 3. N Engl J Med 2021;385:1627–1629.
      1. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020;383:2427–2438.
      1. Chu L, McPhee R, Huang W, et al. A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine. Vaccine 2021;39:2791–2799.
      1. Atmar RL, Lyke KE, Deming ME, et al. Heterologous SARS-CoV-2 booster vaccinations: preliminary report. medRxiv [Preprint]. 2021 Oct 15; [doi: 10.1101/2021.10.10.21264827]
      1. Munro AP, Janani L, Cornelius V, et al. Safety and immunogenicity of seven COVID-19 vaccines as a third dose (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial. Lancet 2021;398:2258–2276.
      1. Tani N, Chong Y, Kurata Y, et al. Relation of fever intensity and antipyretic use with specific antibody response after two doses of the BNT162b2 mRNA vaccine. Vaccine 2022;40:2062–2067.
      1. Held J, Esse J, Tascilar K, et al. Reactogenicity correlates only weakly with humoral immunogenicity after COVID-19 vaccination with BNT162b2 mRNA (Comirnaty(R)). Vaccines (Basel) 2021;9:1063
      1. Oyebanji OA, Wilson B, Keresztesy D, et al. Does a lack of vaccine side effects correlate with reduced BNT162b2 mRNA vaccine response among healthcare workers and nursing home residents? Aging Clin Exp Res 2021;33:3151–3160.
      1. Goel RR, Apostolidis SA, Painter MM, et al. Longitudinal analysis reveals distinct antibody and memory B cell responses in SARS-CoV2 naive and recovered individuals following mRNA vaccination. medRxiv [Preprint]. 2021 Mar 06; [doi: 10.1101/2021.03.03.21252872]
      1. Debes AK, Xiao S, Colantuoni E, et al. Association of vaccine type and prior SARS-CoV-2 infection with symptoms and antibody measurements following vaccination among health care workers. JAMA Intern Med 2021;181:1660–1662.
      1. Williamson EJ, Walker AJ, Bhaskaran K, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020;584:430–436.
      1. Eliakim-Raz N, Leibovici-Weisman Y, Stemmer A, et al. Antibody titers before and after a third dose of the SARS-CoV-2 BNT162b2 vaccine in adults aged ≥60 years. JAMA 2021;326:2203–2204.
      1. Kruttgen A, Cornelissen CG, Dreher M, Hornef MW, Imohl M, Kleines M. Determination of SARS-CoV-2 antibodies with assays from Diasorin, Roche and IDvet. J Virol Methods 2021;287:113978
      1. Tan CW, Chia WN, Qin X, et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol 2020;38:1073–1078.
      1. Hause AM, Baggs J, Marquez P, et al. Safety monitoring of COVID-19 vaccine booster doses among adults: United States, September 22, 2021-February 6, 2022. MMWR Morb Mortal Wkly Rep 2022;71:249–254.
      1. Kadali RA, Janagama R, Peruru S, et al. Non-life-threatening adverse effects with COVID-19 mRNA-1273 vaccine: a randomized, cross-sectional study on healthcare workers with detailed self-reported symptoms. J Med Virol 2021;93:4420–4429.
      1. Ziemann M, Gorg S. Inability to work after Corona vaccination in medical staff. Dtsch Arztebl Int 2021;118:298–299.
      1. Verbeke R, Lentacker I, De Smedt SC, Dewitte H. The dawn of mRNA vaccines: the COVID-19 case. J Control Release 2021;333:511–520.
      1. Wec AZ, Wrapp D, Herbert AS, et al. Broad neutralization of SARS-related viruses by human monoclonal antibodies. Science 2020;369:731–736.
      1. Pardi N, Hogan MJ, Naradikian MS, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 2018;215:1571–1588.
    MeSH Terms
    2019-nCoV Vaccine mRNA-1273
    Arthralgia
    B-Lymphocytes
    BNT162 Vaccine
    Chills
    Delivery of Health Care
    Fever
    Humans
    Immunity, Humoral*
    Immunization
    Immunization, Secondary
    Immunoglobulin G
    Inflammation
    Memory
    Occupational Groups
    Proteins
    RNA, Messenger*
    Respect
    SARS-CoV-2*
    Vaccination
    Vaccines*
    Metrics
    Share
    Links to
    Figures
    slide
    slide
    slide
    slide
    slide
    slide
    slide
    slide
    slide
    slide

    1 / 10

    Tables
    slide
    slide

    1 / 2

    ORCID IDs
    PERMALINK