Serum Neutralization Of SARS Coronavirus 2 Omicron Sublineages BA.1 And BA.2 And Cellular Immune Responses 3 Months After Booster Vaccination
Jun 05, 2023
Abstract
Objectives:
We investigated serum neutralizing activity against BA.1 and BA.2 Omicron sublineages and T cell response before and 3 months after the administration of the booster vaccine in healthcare workers (HCWs).
Methods:
HCWs aged 18e65 years who were vaccinated and received booster doses of the BNT162b2 vaccine were included. AntieSARS coronavirus 2 IgG levels and cellular response (through interferon g ELISpot assay) were evaluated in all participants, and neutralizing antibodies against Delta, BA.1, and BA.2 were evaluated in participants with at least one follow-up visit 1 or 3 months after the administration of the booster dose.
There is a certain relationship between the booster dose of the BNT162b2 vaccine and immunity. According to the results of clinical trials conducted by vaccine manufacturers, two doses of the BNT162b2 vaccine with an interval of 3 weeks can allow more than 90% of the vaccinators to obtain relatively strong immunity and effectively fight against the infection of the new coronavirus. Some researchers believe that boosting doses to a certain extent can enhance the immunity of vaccine recipients, especially for the possible antigenic variation of some new coronavirus variants.
However, booster doses of the vaccine did not lead to better results. Excessive doses may cause some side effects, such as fever, fatigue and other adverse reactions. In addition, the formation of vaccine immunity is also closely related to the innate conditions of the individual immune system and the interaction with the external environment. Therefore, individual vaccination with the BNT162b2 vaccine still needs to be vaccinated according to the recommendations of the vaccine manufacturer, and reasonable vaccinations should be carried out according to the professional advice of doctors. From this point of view, we need to pay special attention to the improvement of immunity. Cistanche can significantly improve immunity. Meat ash contains a variety of biologically active ingredients, such as polysaccharides, two mushrooms, Huang Li, etc. These ingredients can stimulate the immune system. Various types of cells in the system, increase their immune activity.
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Results:
Among 118 HCWs who received the booster dose, 102 and 84 participants attended the 1-month and 3-month visits, respectively. Before the booster vaccine dose, a low serum neutralizing activity against Delta, BA.1, and BA.2 were detectable in only 39/102 (38.2%), 8/102 (7.8%), and 12/102 (11.8%) participants, respectively. At 3 months, neutralizing antibodies against Delta, BA.1, and BA.2 were detected in 84/84 (100%), 79/84 (94%), and 77/84 (92%) participants, respectively. Geometric mean titres of neutralizing antibodies against BA.1 and BA.2 were 2.2-fold and 2.8-fold reduced compared with those for Delta. From 1 to 3 months after the administration of the booster dose, participants with a recent history of SARS coronavirus 2 infections (n ¼ 21/84) had persistent levels of S1 reactive specific T cells and neutralizing antibodies against Delta and BA.2 and 2.2-fold increase in neutralizing antibodies against BA.1 (p 0.014). Conversely, neutralizing antibody titres against Delta (2.5-fold decrease, p < 0.0001), BA.1 (1.5-fold, p 0.02), and BA.2 (2-fold, p < 0.0001) declined from 1 to 3 months after the administration of the booster dose in individuals without any recent infection.
Discussion:
The booster vaccine dose provided a significant and similar response against BA.1 and BA.2.
Omicron sublineages; however, the immune response declined in the absence of a recent infection.
Introduction
The Omicron (B.1.1.529) SARS coronavirus 2 (SARS-CoV-2) variant emerged in late 2021 and rapidly outcompeted the already highly transmissible Delta variant.
The first sublineage of this variant, BA.1, became dominant in Europe between December 2021 and January 2022 and generated serious concern about the efficacy of vaccines owing to the substantial escape from neutralizing antibodies. Indeed, Omicron displayed numerous epitopic modifications of the spike protein, and because the available coronavirus disease 2019 (COVID-19) vaccines were prepared with the original lineage, neutralizing activity against Omicron was absent or very low even in vaccinated people [1,2].
The subsequent sublineage BA.2 rapidly replaced the previous one in Europe around March 2022 to April 2022, and the rates of new sublineages BA.4 and BA.5 increased by June 2022 [3]. BA.2 has shown a selective advantage over BA.1, especially enhanced transmissibility, and can reinfect previously BA.1-infected individuals [4,5].
Recent data have shown that beyond 6 months after the primary vaccination course, neutralizing antibodies against Omicron sublineages were undetectable or at very low levels; however, neutralizing antibody titres increased significantly a few weeks after the administration of booster vaccination (third dose) [6e8].
In this study, we evaluated the neutralizing antibody responses against BA.1 and BA.2 sublineages of the Omicron variant in parallel with the previous Delta variant in a cohort of healthcare workers (HCWs) who were vaccinated and received booster doses of the BNT162b2 mRNA vaccine (PfizereBioNTech). In addition, cellular responses to SARS-CoV-2 were investigated, and the occurrence of infection after the booster dose was analysed.
Methods
This study is part of the MONITOCOV-Aging project (Monitoring the immune response to BNT162b2 mRNA COVID-19 vaccination in older people), in which the protocol amendments concerning the present data were approved by the Ile-De-France V (ID-CRB 2021- A00119-32) ethics committee.
HCWs were consecutively included in the study if they had no significant chronic disease and no medication that could influence their immune responses (including steroids and immunosuppressive therapies), and were aged 18e65 years. All participants initially received two doses of the BNT162b2 vaccine at a 3-week dosing interval. The booster dose was administered to the participants by French national guidelines (at least 6 months after the primary vaccination course). Data from the samples collected before and 3 months after the primary vaccination have been reported previously [9], and data from the samples collected before the administration of the booster as well as at 1 and 3 months after the administration of the booster doses are reported in this study.
AntieSARS-CoV-2 IgG levels and neutralizing antibodies (using a live virus neutralization assay) against Delta variant and BA.1 and BA.2 Omicron sublineages were evaluated. Cellular responses were evaluated through interferon g ELISpot assay.
Please see the supplementary material for detailed methods.
Results
A total of 118 individuals who received the booster dose were included. Samples were collected 1 month after the administration of the booster dose for 102 subjects, and only 84 participants attended the 3-month visit. The median (interquartile range) time between the initial vaccination (second dose) and the booster dose was 254 (248e265) days.
Three months after the primary vaccination course (doses 1 and 2), the median level (interquartile range) of antieSARS-CoV-2 IgG was 1125 (653e1828) BAU/mL. This value declined to 290 (200e534) BAU/mL before the third dose and then peaked at more than 2080 BAU/mL 1 and 3 months after the administration of the booster dose (Fig. 1a). The counts of S1 reactive T cells also increased 1 and 3 months after the administration of the booster dose (Fig. 1a).
As shown in Fig. 1b, before administration of the booster vaccine dose, serum neutralizing activity against Delta, BA.1, and BA.2 were detectable in only 39/102 (38.2%), 8/102 (7.8%), and 12/102 (11.8%) participants, respectively, with low neutralizing antibody titres ranging from 20 to 160. Geometric mean titres (GMTs) were below the limit of detection of 20 for all variants.
One month after administration of the booster dose, a neutralizing activity against Delta, BA.1, and BA.2 was observed in 102/102 (100%), 99/102 (97%), and 101/102 (99%) tested sera, respectively. In addition, the GMTs of neutralizing antibodies (95% CI) significantly increased to 465 (373e579) for Delta, 105 (85e131) for BA.1, and 99 (82e121) for BA.2, indicating that the GMTs against Delta were 4.4- fold and 4.7-fold higher than those against BA.1 (p < 0.0001) and BA.2 (p < 0.0001), respectively.
Three months after administration of the booster dose, neutralizing antibodies against Delta, BA.1, and BA.2 were detected in 100% (n ¼ 84/84), 94% (n ¼ 79/84), and 92% (n ¼ 77/84) of the participants, respectively, and the GMTs were 260 (203e334), 102 (76e136), and 69 (54e88), respectively. GMTs against BA.1 and BA.2 were 2.6-fold and 3.8-fold reduced compared with those against Delta 3 months after the administration of the booster dose (p < 0.0001 in both comparisons).
Within 3 months after the administration of the booster dose, a SARS-CoV-2 infection was confirmed or strongly suspected in 21 subjects (presumably Omicron infections because this variant represented >95% of cases during this period). The infection was confirmed by a positive RT-PCR test result in ten individuals, with the infection occurring during the first 4 weeks (1 subject) or the next 8 weeks (9 subjects) after administration of the booster vaccination. An asymptomatic infection, not confirmed by RT-PCR for this reason [10] and not detectable by serological tests using antigens from the spike protein, was strongly suspected in the remaining 11 individuals by a significant increase of N reactive specific T cells in the interferon g ELISpot assay because the N protein is not an antigen targeted by BNT162b2 (Fig. 1c).
Subgroup analysis showed that 3 months after the administration of the booster dose, S1 reactive specific T cells (Fig. 1c) and neutralizing antibody levels against all variants were higher in the group with a history of postebooster dose infection than in participants without recent infection (Fig. 1d and Table S1). Indeed, the GMT (95% CI) of neutralizing titres declined from 1 to 3 months after the administration of the booster dose in individuals without any recent infection with the Delta (482 [366e635] vs. 190 [143e252]; 2.5-fold decrease; p < 0.0001), BA.1 (110 [85e142] vs. 74 [85e142]; 1.5-fold decrease; p 0.02), or BA.2 variant (104 [81e133] vs. 52 [39e69]; 2-fold decrease; p < 0.0001). Conversely, participants with a recent history of SARS-CoV-2 infection had persistent levels of S1 reactive specific T cells and neutralizing antibodies against Delta and BA.2, and neutralizing antibodies against BA.1 increased from 128.5 (72e229) to 277 (137e557) (2.2-fold increase; p 0.014). (Fig. 1d and Table S1).
Discussion
In this study, we evaluated the vaccine-induced response against Omicron sub-variants. We found that 8.5 months (median) after the primary vaccination course with two doses of an mRNA vaccine, HCWs showed a minimal neutralization antibody response to the Delta variant and BA.1 and BA.2 Omicron sublineages. After administration of the booster dose, the participants exhibited a stronger neutralizing capacity not only against the Delta variant but also against BA.1 and BA.2. This is consistent with the findings in previous reports regarding BA.1 [2,11e15] and BA.2 [6e8]. However, the median neutralizing antibody titres against BA.1 and BA.2 at 1 and 3 months after the administration of the booster dose were significantly reduced compared with those of the previous Delta variant, indicating reduced effectiveness of booster vaccination against the Omicron variant.
Interestingly, 1 month after administration of the booster dose, we observed similar neutralizing antibody levels against BA.1 and BA.2, highlighting that the immune response induced by the BNT162b2 vaccine was similar for both variants. This finding of the early weeks after administration of the booster dose is in agreement with those in other reports [6,7]. However, the decline over time seemed to be more pronounced for the neutralizing activity against BA.2. This observation, which needs to be confirmed, could partially explain the surge of BA.2 and the replacement of BA.1, which probably depends on several factors.
As expected, the occurrence of a SARS-CoV-2 infection after administration of the booster dose leads to a strong immune response [9]. The maintenance or even increase in the activity of neutralizing antibodies against the Omicron variant in patients with SARS-CoV-2 infection after administration of the booster dose suggests that additional antigen exposure can enhance a memory response. This observation is likely due to expanded B cell repertoire and increased affinity maturation after additional antigen exposure, as previously suggested [16,17].
The main strength of our study is the evaluation of cellular responses along with the humoral response 3 months after the administration of the booster dose and the positive effect of an early postebooster dose infection on the persistence of the immune response. The main weakness of our study is that we are not able to compare the effectiveness of BNT162b2 with that of other mRNA vaccines or COVID-19 vaccine combinations.
In conclusion, booster doses of COVID-19 vaccines, as additional antigen exposure, provided a strong response against BA.1 and BA.2 Omicron sublineages. Nevertheless, the response will likely decline over time, and this is one of the factors to consider for the future of SARS-CoV-2 vaccine strategies. The public health implication of these findings is that an additional boost might be needed to maintain a consistent immune response in individuals who are at risk of severe COVID-19 with the recent emergence of new sublineages (BA.4 and BA.5).
Author contributions
EKA, JD, BCS, ML, and GL conceptualized and designed the study, collected the data, performed the data analysis, and wrote and revised the manuscript. EKA, JD, BCS, ML, and GL take full responsibility for the integrity of the data and the accuracy of the data analysis. JL, AG, JT, DL, SM, FV, ArD, DHG, JP, DaD, KF, DoD, LB, AlD, AS, DH, MH, FP, BA, and YY participated in the data analysis and revision of the manuscript. ML and GL contributed equally to this work and share similar authorship. All authors gave final approval for the version to be submitted.
Transparency declaration
The authors declare that they have no conflicts of interest. This study received the Label of COVID-19 National Research Priority, awarded by the National Steering Committee on Therapeutic Trials and Other COVID-19 Research (CAPNET). This work was supported by the French government through the Programme Investissement d’Avenir (I-SITE ULNE/ANR-16-IDEX-0004 ULNE) managed by the Agence Nationale de la Recherche and was also supported by a sponsorship from GMF under the aegis of the ANRS-MIE (Agence Nationale de recherche sur le sida et les hepatites, Maladies Infectie uses Emergentes).
Acknowledgements
We are grateful to Veronique Betancourt, Virginie Dutriez, Anne Guigo, Coralie Lefebvre, Veronique Lekeux, Marie-Th er ese Meleszka, Catherine Mortka, and Anthony Rabat for their technical support and Bertrand Accart for his contribution (Centre de Ressources Biologiques, BRIF number BB 0033-00030). We are also grateful to Severine Du Flos, Marie Broyez, Peggy Bouquet, Clementine Rolland, Marion Lecorche, Abeer Shaikh Al Arab, Isa- belle Tonnerre, Floriane Mirgot, Japhete Elenga Koanga, Laurent Schwarb, Emilie Rambaut, and all the nurses implicated in patient sampling and Mathieu Tronchon for data collection.
References
[1] Garcia-Beltran WF, St Denis KJ, Hoelzemer A, Lam EC, Nitido AD, Sheehan ML, et al. mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant. Cell 2022;185:457e66.
[2] Planas D, Saunders N, Maes P, Guivel-Benhassine F, Planchais C, Buchrieser J, et al. Considerable escape of SARS-CoV-2 Omicron to antibody neutralization. Nature 2022;602:671e5. https://doi.org/10.1038/s41586-021-04389-z.
[3] SARS-CoV-2 variants of concern as of 25 August 2022. European Centre for Disease Prevention and Control. Accessed 31 August 2022. https://www.ecdc. europa.eu/en/covid-19/variants-concern.
[4] Lyngse FP, Kirkeby CT, Denwood M, Christiansen LE, Mølbak K, Møller CH, et al. Transmission of SARS-CoV-2 Omicron VOC subvariants BA.1 and BA.2: evidence from Danish households. medRxiv [Preprint] Posted 30 January 2022https://doi.org/10.1101/2022.01.28.22270044.
[5] Stegger M, Edslev SM, Sieber RN, Ingham AC, Ng KL, Tang MHE, et al. Occurrence and significance of Omicron BA.1 infection followed by BA.2 reinfection. medRxiv [Preprint]. Posted 22 February 2022https://doi.org/10. 1101/2022.02.19.22271112.
[6] Yu J, Collier AY, Rowe M, Mardas F, Ventura JD, Wan H, et al. Neutralization of the SARS-CoV-2 Omicron BA.1 and BA.2 variants. N Engl J Med 2022;386: 1579e80. https://doi.org/10.1056/NEJMc2201849.
[7] Pedersen RM, Bang LL, Madsen LW, Sydenham TV, Johansen IS, Jensen TG, et al. Serum neutralization of SARS-CoV-2 Omicron BA.1 and BA.2 after BNT162b2 booster vaccination. Emerg Infect Dis 2022;28:1274e5. https:// doi.org/10.3201/eid2806.220503.
[8] Evans JP, Zeng C, Qu P, Faraone J, Zheng YM, Carlin C, et al. Neutralization of SARS-CoV-2 Omicron sub-lineages BA.1, BA.1.1, and BA.2. Cell Host Microbe 2022;30:1093e102. https://doi.org/10.1016/j.chom.2022.04.014.
[9] Demaret J, Lefevre G, Vuotto F, Trauet J, Duhamel A, Labreuche J, et al. Severe SARS-CoV-2 patients develop a higher specific T-cell response. Clin Transl Immunol 2020;9:e1217. https://doi.org/10.1002/cti2.1217.
[10] Vimercati L, Stefanizzi P, De Maria L, Caputi A, Cavone D, Quarato M, et al. Large-scale IgM and IgG SARS-CoV-2 serological screening among healthcare workers with a low infection prevalence based on nasopharyngeal swab tests in an Italian university hospital: perspectives for public health. Environ Res 2021;195:110793. https://doi.org/10.1016/j.envres.2021.110793.
[11] Jacobsen H, Strengert M, Maaß H, Durand MAY, Kessel B, Harries M, et al. Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations medRxiv [Preprint]. Posted 21 December 2021https://doi.org/10.1101/2021.12.21.21267898.
[12] Perez-Then E, Lucas C, Monteiro VS, Miric M, Brache V, Cochon L, et al. Neutralizing antibodies against the SARS-CoV-2 Delta and Omicron variants following heterologous CoronaVac plus BNT162b2 booster vaccination. Nat Med 2022;28:481e5. https://doi.org/10.1038/s41591-022-01705-6.
[13] Schmidt F, Muecksch F, Weisblum Y, Da Silva J, Bednarski E, Cho A, et al. Plasma neutralization of the SARS-CoV-2 Omicron variant. N Engl J Med 2022;386:599e601. https://doi.org/10.1056/NEJMc2119641.
[14] Wang X, Zhao X, Song J, Wu J, Zhu Y, Li M, et al. Homologous or heterologous booster of inactivated vaccine reduces SARS-CoV-2 Omicron variant escape from neutralizing antibodies. Emerg Microbe. Infect 2022;11:477e81. https:// doi.org/10.1080/22221751.2022.2030200.
[15] Xia H, Zou J, Kurhade C, Cai H, Yang Q, Cutler M, et al. Neutralization and durability of 2 or 3 doses of the BNT162b2 vaccine against Omicron SARSCoV-2. Cell Host Microbe 2022;30:485e8.
[16] Muecksch F, Weisblum Y, Barnes CO, Schmidt F, Schaefer-Babajew D, Wang Z, et al. Affinity maturation of SARS-CoV-2 neutralizing antibodies confers potency, breadth, and resilience to viral escape mutations. Immunity 2021;54: 1853e68.
[17] Muecksch F, Wang Z, Cho A, Gaebler C, Tanfous TB, DaSilva J, et al. Increased potency and breadth of SARS-CoV-2 neutralizing antibodies after a third mRNA vaccine dose. bioRxiv [Preprint]. Posted 15 February 2022https://doi. org/10.1101/2022.02.14.480394.
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