Assessment of humoral immune response to two mRNA SARS-CoV-2 vaccines (Moderna and Pfizer) in healthcare workers fully vaccinated with and without a history of previous infection

J Appl Microbiol. 2022;133:1969–1974. | 1969 wileyonlinelibrary.com/journal/jam Received: 8 April 2022 | Revised: 1 July 2022 | Accepted: 5 July 2022 DOI: 10.1111/jam.15699 ORIGINAL ARTICLE Assessment of humoral immune response to two mRNA SARSCoV2 vaccines (Moderna and Pfizer) in healthcare workers fully vaccinated with and without a history of previous infection LauraSerrano1,2 | SoniaAlgarate3,4 | BeatrizHerreroCortina2,5,6 | JessicaBueno3 | María T.GonzálezBarriga1 | MaríaDucons3 | JesicaMonteroMarco2,5 | BeatrizAcha1,2 | AnaTaboada1,2 | PilarSanzBurillo1,2 | CristinaYuste1,2 | RafaelBenito2,3,4 | on behalf of the RIPOVAC Study Group This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2022 The Authors. Journal of Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology. Members of the RIPOVAC Study Group are as follows: L. Serrano, T. González, B. Acha, C. Yuste, P. Sanz, A. Taboada, C.I. Ferrández, P. Sahuquillo, E. Zueco, J. MonteroMarco and M. Charlo (Hospital Clínico Universitario Lozano Blesa and IIS Aragón), M. Redondo, L. Fernández, C. Inglés and J. Bueno (Hospital Clínico Universitario Lozano Blesa), R. Benito (Hospital Clínico Universitario Lozano Blesa, Universidad de Zaragoza and IIS Aragón), S. Algarate (Hospital Clínico Universitario Lozano Blesa and Universidad de Zaragoza), B. HerreroCortina (Hospital Clínico Universitario Lozano Blesa, IIS Aragón and Universidad San Jorge). 1Occupational Health Unit, Lozano Blesa University Hospital, Zaragoza, Spain 2Institute for Health Research Aragón, Zaragoza, Spain 3Microbiology Department, Lozano Blesa University Hospital, Zaragoza, Spain 4Microbiology Department, Zaragoza University, Zaragoza, Spain 5Investigation Unit, Lozano Blesa University Hospital, Zaragoza, Spain 6Universidad San Jorge, Villanueva de Gállego, Zaragoza, Spain Correspondence Rafael Benito, Lozano Blesa University Hospital, Zaragoza, Spain. Email: [email protected] Abstract Aims: Presence of antiS1 region of SARSCoV2 spike protein was analysed, at two and eight months, in 477 immunocompetent healthcare workers in Zaragoza, Spain, vaccinated with mRNA1273 (Moderna) or BNT162b2 (Pfizer). Methods and results: Antibody analysis was performed with Alinity i System (Abbott). At 2 months, 100% of vaccinated had antiS1 IgG (mean=13,285 AU ml−1). This value was significantly higher with Moderna (18,192 AU ml−1) than with Pfizer (10,441 AU ml−1). The mean value of antiS1 IgG after vaccination was significantly higher in patients with than without previous infection (18,539 vs. 7919 AU ml−1); in both groups was significantly higher with Moderna than with Pfizer (21,881 vs. 15,733 AU ml−1 and 11,949 vs. 6387 AU ml−1), respectively. At 8 months, 100% of patients were IgG positive, with higher levels with Moderna than with Pfizer. Nevertheless, in ensemble of cases, a mean decrease of antibody levels of 11,025 AU ml−1 was observed. Conclusion: At 2 and 8 months after vaccination, IgG response persists with both vaccines but with important decrease which suggests the need for revaccination. Significance and impact of study: The study contributes to know the immune status after vaccination with two of more used antiSARSCoV2 vaccines. This knowledge is important for establishing the best vaccination strategy KEYWORDS antiS IgG SARSCoV2, healthcare workers, immune response, Moderna, mRNA SARSCoV2 vaccines, Pfizer, postvaccination, RIPOVAC Funding information This research did not receive any specific grant for funding agencies in the public, commercial or not-for-profit sectors. Downloaded from https://academic.oup.com/jambio/article/133/3/1969/6989086 by guest on 29 May 2023 1970 | SERRANO et al. INTRODUCTION The recent rollout of vaccines that induce specific antibodies to SARSCoV2 has provided an important tool in controlling the pandemic. The serology of SARSCoV2, in addition to being a complementary tool in the diagnosis (Fuentes et al.,2021), allows knowing the immune status of the patient after natural infection or after vaccination (Okba et al.,2020). SARSCoV2 induces antibody formation against S (spike) and N (nucleocapsid) proteins. AntiS1 IgG may have neutralizing activity. This activity can be evaluated in vitro with the plate reduction neutralization test, which is difficult to be applied to routine (Santiago et al.,2021). For this reason, diagnostic tests have been manufactured for the quantitative measurement of these antibodies to establish the degree and duration of immunity and, based on them, to develop preventive vaccination strategies. We present data from the observational and prospective RIPOVAC study in a group of healthcare workers in Aragón (Spain). This study aims to quantify the response of IgG against the region of the S1 subunit of the SARSCoV2 spike protein that binds to the receptorbinding domain (RBD) (antiS1 IgG) and of IgM against the spike protein (antiS IgM), two and 8 months after vaccination with two doses of two firstgeneration mRNA vaccines, Moderna (mRNA1273) or PfizerBioNTech (BNT162b2) (with the interval time recommended by the manufacturer, 28 or 21 days, respectively), and the influence on it of prevaccination SARSCoV2 infection. MATERIALS AND METHODS We show data from the RIPOVAC study, conducted at the Lozano Blesa University Clinical Hospital of Zaragoza, Spain, the reference centre of Sector III of the Aragón Health Service (SALUD). Initially, 494 cases were included, belonging to all categories of healthcare workers, but 17 (3.44%) were lost. Finally, 477 voluntary, immunocompetent, nonpregnant healthcare workers (71 male and 406 female, mean age of 45,29 years) vaccinated with Moderna or Pfizer, according to the availability, between February and March 2021 were included. Cases with SARSCoV2 infection between the first dose and the immunogenicity analysis were excluded. The first postvaccine sample was obtained from 477 healthcare workers [Moderna 175 (36.69%) and Pfizer 302 (63.31%)] 2 months after the second dose ±7 days (months of April, May and June 2021), shortly after the peak of antibodies was reached (Montoya et al.,2021). Table1 shows the distribution of 477 healthcare workers by sex, age, type of vaccine and existence or not of previous infection. Women predominate in both groups vaccinated with Moderna and Pfizer, but without significant differences in age. Second sample was obtained from 444 workers, 53 male y 391 female, with mean age of 45,61 years [Moderna 166 (37.39%) and Pfizer 278 (62.61%)] 8 months after the second dose. People with previous positive PCR to SARSCoV2 (Alinity m, Abbott; Viasure, Certest Biotec; or GeneXpert, Cepheid), or with previous positive SARSCoV2 antigen (PanBio COVID19 Ag, Abbott) or with presence of antiN IgG (SARSCoV2 IgG, Abbott) were considered previously infected. The determination of quantitative antiS1 IgG (AU ml−1) and antiS IgM (index) was performed by CMIA (SARSCoV2 IgG II Quant, Abbott and SARSCoV2 IgM, Abbott, respectively) by blinded, trained laboratory staff, using the Abbott Alinity i platform, following the manufacturer's instructions. These reagent kits have a specificity of 100% and sensitivity at 15 days of 98.77%, according to the manufacturer. The analysis was carried out based on the vaccine received, Moderna (175 cases) or Pfizer (302 cases), and the existence or not of a previous SARSCoV2 infection. The protocol was approved by the Clinical Investigation Ethics Committee of Aragón (EPA 21/000) and the recruited healthcare workers gave their written informed TABLE 1 Characteristics of 477 enrolled healthcare workers Vaccine type Sex (%) mean age (SD) Previous infection Yes No Yes No Moderna (175) 28 male (16.00%) 42.14 (13.59) 22 (12.57%) 6 (3.43%) 147 female (84.00%) 43.31 (11.94) 88 (50.29%) 59 (33.71%) Pfizer (302) 43 male (14.24%) Age: 45.71 (SD 12.36) 23 (7.62%) 20 (6.62%) 259 female (85.76%) Age: 46.77 (SD 11.57) 108 (35.76%) 151 (50.00%) Downloaded from https://academic.oup.com/jambio/article/133/3/1969/6989086 by guest on 29 May 2023 | 1971 RESPONSE TO TWO SARSCOV2 VACCINES consent, following the guidelines of the Declaration of Helsinki. Statistical analysis Quantitative variables were described using the mean (standard deviation) and categorical variables were reported using frequencies. Differences in sociodemographic and serological data between the groups were tested using the independent student's ttest or the Mann– Whitney Utest and reported as mean difference (95% confidence interval, CI). Statistical significance was set at p < 0.05 for all calculations. Data analysis was performed using SPSS v.19 (IBM, Chicago, IL, USA). RESULTS All 477 recruited healthcare workers were antiS1 IgG positive at 2 months after vaccination, regardless of the type of vaccine received. The responses ranged from 200 to >40,000 AU ml−1, with a mean of 13,285 AU ml−1 (95% CI: 12,317 to 14,253) (Table2). Only 5 cases (1.05%) had antiS1 IgG values <1000AU ml−1. Nevertheless, antiS IgM was only positive in 110 cases (23.06%), with a mean index of 2.95 (SD 2.45, range 1.00 to 14.93) (Table2). 50% of the antiS IgM positive cases had indexes between 1.00 and 2.00. In Modernavaccinated group (175 cases), the antiS1 IgG mean was 18,192 AU ml−1 (95% CI 16,468 to 19,917), significantly higher than in the group vaccinated with Pfizer (10,441 AU ml−1, 95% CI 9406 to 11,477). Mean difference between Moderna and Pfizer was 7751 (95% CI: 5866 to 9635) (p < 0.001). The same performance was seen for IgM, although without significant differences, showing a higher percentage of positivity and a higher mean index for Moderna than for Pfizer, with percentages of 23.43% and 22.85%, and average indexes of 3.06 (95% CI: 2.18 to 3.83) and 2.89 (95% CI: 2.35 to 3.33), respectively (Table2). In cases without previous infection, antiS1 IgG response was significantly more intense with Moderna (11,949 AU ml−1, 95% CI, 9974 to 13,924) than with Pfizer (6387 AU ml−1, 95% CI: 5579 to 7196). Mean difference between Moderna and Pfizer was 5562 (95% CI: 3787 to 7336) (p < 0.001). AntiS1 IgM response was also greater both in terms of percentage and mean values (Table3), but without significant differences. In cases with history of previous infection, antiS1 IgG response with Moderna vaccine has been significantly more intense, with a mean value of 21,881 AU ml−1 (95% CI: 19,655 to 24,109) versus 15,733 AU ml−1 with Pfizer (95% CI: 13,951 to 17,515). Mean difference between Moderna y Pfizer was 6149 (95% CI: 3344 to 8953) (p < 0.001) (Table4). The response in cases with previous infection is higher than in patients without previous infection. In contrast, the antiS IgM response has been stronger after the Pfizer vaccine, both in percentage and mean terms, but without significant differences (Table4). The 444 healthcare workers analysed 8 months after the second dose also present antiS, with a mean value of 4297 AU ml−1 with Moderna (SD 6289; range 132– >40,000) and of 3449 with Pfizer (SD 6645; range 120– >40,000) (Table5). Antibody levels with Moderna were significantly higher than with Pflzer, also 8 months after vaccination. (p< 0.001). TABLE 2 IgG and IgM response in total population and vaccine type Vaccine Patients IgG ANTIS1 IgM ANTIS Positive Mean AU ml−1 (SD) Range Positive Mean index (SD) Range Moderna 175 175 (100%) 18,192 (11556) 2111– >40,000 41 (23.43%) 3.06 (2.76) 1.03– 12.28 Pfizer 302 302 (100%) 10,441 (9144) 200– >40,000 69 (22.85%) 2.89 (2.27) 1.00– 14.93 Total 477 477 (100%) 13,285 (10755) 200– >40,000 110 (23.06%) 2.95 (2.45) 1.00– 14.93 TABLE 3 IgG and IgM response in total population and vaccine type in noninfected patients Vaccine Patients IgG antiS1 IgM antiS Positive Mean AU ml−1 (SD) Range Positive Mean index (SD) Range Moderna 65 65 (100%) 11,949 (7971) 2111– >40,000 8 (12.30%) 4.83 (4.23) 1.32– 12.28 Pfizer 171 171 (100%) 6387 (5355) 715– 36,122 19 (11.11%) 2.63 (1.95) 1.20– 7.73 Total 236 236 (100%) 7919 (6651) 715– >40,000 27 (11.44%) 3.28 (2.91) 1.20– 12.28 Downloaded from https://academic.oup.com/jambio/article/133/3/1969/6989086 by guest on 29 May 2023 1972 | SERRANO et al. Of the 444 health workers who were analysed at eight months, antibody levels had diminished in 416 (93.69%) and increased in 25 (5.63%). At least four of the latter had been infected after the first extraction (PCR or positive antiN IgG). In the remaining 3 (0.68%), no change could be demonstrated, because both samples presented an antibody level > 40,000 AU ml−1 (Table6). At 8 months, antibody level decreased by a mean of 11,025 AU ml−1, regardless of the type of vaccine administered and 120 cases (72.29%) out of vaccinated with Moderna and 159 cases (57.19%) out of vaccinated with Pfizer showed antibody levels >=1000 AU ml−1. Antibody levels at 8 months after vaccination had decreased to 23.62% and 33.03% in Moderna or Pfizer vaccinated, respectively. In people younger than 30 years, antibody levels are higher compared to older patients (4229 vs. 3699) at 8 months and decrease faster, regardless of the type of vaccine received. DISCUSSION The reagents used for the determination of antiS and antiN antibodies have been evaluated by various authors (Bryan et al.,2020; Narasimhan et al.,2021) with satisfactory results. In the case of IgG, the kit provides quantitative results expressed in AU ml−1. Pfizer vaccine confers 95% protection against COVID19 (Polack et al.,2020). Similar data have been showed by other authors (Vasileiou et al.,2021). Moderna vaccine has a 94.1% efficacy in preventing SARSCoV2 disease, including severe disease (Baden et al., 2021; Mahase,2020). Both vaccines induce the production of antibodies to the spike (S protein) that correlate significantly with neutralizing activity for SARSCoV2 (Wajnberg et al.,2020). Both have been applied to healthcare workers in Sector III of the SALUD in Aragon, Spain. Knowledge of the kinetics of antibodies induced by vaccines against COVID is important to implement a more appropriate preventive strategy, especially when vaccines may be less effective against variants of the virus (Jangra et al.,2021). The Moderna and Pfizer vaccines induced an IgG response in 100% of the studied cases, which is still present 2 months after the second dose, although with different levels of intensity. Moderna vaccine induces a higher response in terms of mean IgG concentration, percentage of positive IgM and average IgM index. This applies to patients without and with previous infection. These data would be consistent with those published by several authors (Krammer et al.,2021; Manisty et al.,2021), who observed a significantly higher IgG response following Pfizer vaccine in patients with previous infection. In addition, Montoya et al.(2021) describe significant differences in IgG indexes in favour of Moderna between 42– 48 and 70– 83 days after the second dose. In five cases, all of them women, from 37 to 55 years old, antiS1 IgG values were less than 1000 AU ml−1, lower than the average value of all the healthcare workers studied. Four of them had not been previously infected and had numbers greater than 700. The fifth had an IgG concentration of 200.7AU ml−1: this case had been previously TABLE 4 IgG and IgM response in total population and vaccine type in exinfected patients Vaccine Patients IgG antiS1 IgM antiS Positive Mean AU ml−1 (SD) Range Positive Mean index (SD) Range Moderna 110 110 (100%) 21,881 (11786) 3335– >40,000 33 (30.00%) 2.62 (2,14) 1.03– 12.13 Pfizer 131 131 (100%) 15,733 (10310) 200– >40,000 50 (38.16%) 2.98 (2.39) 1.00– 14.93 Total 241 241 (100%) 18,539 (11405) 200– >40,000 83 (34.43%) 2.84 (2.29) 1.00– 14.93 TABLE 5 IgG antiS1 response 8 months after the second dose of vaccine Vaccine Patients Positive Mean AU ml−1 (SD) Range Moderna 166 166 (100%) 4297 (6289) 132– >40,000 Pfizer 278 278 (100%) 3449 (6645) 120– >40,000 Total 444 444 (100%) 3766 (6519) 120– >40,000 TABLE 6 Antibody level variation 8 months after the second dose of vaccine Variation Number of cases % Decrease 416 93.69 Increase 25 5,53 No change 3 0,68 Downloaded from https://academic.oup.com/jambio/article/133/3/1969/6989086 by guest on 29 May 2023 | 1973 RESPONSE TO TWO SARSCOV2 VACCINES asymptomatically infected and with antiN IgG indexes of 5.13 and 4.97 at 11 and 7months prior to sampling, respectively, and 5.07 at the time of serum extraction for this study. The low percentage of IgM positive cases 2 months after vaccination with both types of vaccines is surprising. It is probably a reproduction of low IgM response after vaccination with rapid negativization or even without IgM response. This is a similar situation to that described in 20% of MERS patients in whom antibodies are not detected at 30 days of evolution (Corman et al.,2016). In other study, all patients formed antibodies, but 28% were IgM negative at 2 months (Shi et al.,2004). In the study by Narasimhan et al.(2021) IgM was detected until day 80, but with oscillating values from day 23 with a downward trend. The IgM response has been stronger with Pfizer, in percentage and mean, in patients who had been infected, but without significant differences. There may be a bias in the classification of cases without prior infection owing to a short persistence of antiN IgG in cases of previous infection with SARSCoV2 (Shang et al.,2021). These differences in the response of the immune system may be related with the different concentration of vaccine antigen and administration regimen, with Moderna 100 micrograms and boosted 4 weeks after and with Pfizer 30 micrograms and boosted 3 weeks later. The stronger response with Moderna vaccine, in patients without previous infection and in previously infected patients, may point to a greater persistence of antibodies induced by it and represents greater immunoprotection. IgG antibody levels antiSARSCoV2 persist at 8 months in all healthcare workers after complete vaccination with Moderna or Pfizer, but decreasing to 23% and 33%, respectively. The faster decrease of antibody levels with Moderna could be related with a more intense initial response. These data suggest a limited persistence of antibodies after vaccination and the need for revaccination. In patients with a mild or moderate disease course, immunological response appears in most individuals and persists for at least 10months, although both IgG antibody levels and IFNγ concentrations decreased to about a half within 300 days (Schiffner et al.,2021). In people under 30 years, the antibody levels were higher after 8 months and diminished faster. It could be explained because the younger produced more antibodies after the first determination compared to the older because the immune system is less effective as age increases. More studies are needed to determine the duration of response and the level of protection, important data to determine the frequency of revaccination, the antigenic formulation and the efficacy of vaccines against the different variants. AUTHOR CONTRIBUTIONS L.S., and R.B. designed and coordinated the research studies, conducted experiments, analysed data, and wrote the first version of the manuscript; S.A., J.B., and M.D. conducted experiments; B.H., MT.G., J.M., B.A., A.T., P.S., and C.Y. vaccinated, got data and registered the subjets and obtained human samples. All authors have read and agreed to the published version of the manuscript. ACKNOWLEDGEMENTS The authors want to particularly acknowledge the recruited healthcare workers for their collaboration. CONFLICT OF INTEREST The authors declare no conflict of interest. DATA AVAILABILITY STATEMENT Data available on request from the authors. ORCID Cristina Yuste https://orcid.org/0000-0003-3667-523X Rafael Benito https://orcid.org/0000-0001-5134-1006 REFERENCES Baden, L.R., El Sahly, H.M., Essink, B., Kotloff, K., Frey, S., Novak, R. et al. (2021) Efficacy and safety of the mRNA1273 SARSCov2 vaccine. New England Journal of Medicine, 384, 403– 416. 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