Longitudinal Analyses after COVID-19 Recovery or Prolonged Infection Reveal Unique Immunological Signatures after Repeated Vaccinations
Abstract
:1. Introduction
2. Methods
2.1. Study Design
2.2. Measurement of Anti-SARS-CoV-2 S-RBD IgM and IgG antibodies
2.3. In Vitro Neutralization Assay
2.4. Cytometric Bead Array
2.5. Isolation of PBMCs
2.6. Single-Cell Sorting by Flow Cytometry
2.7. Single-Cell RT-PCR and Immunoglobulin Gene Sequencing
2.8. Statistical Analyses
3. Results
3.1. Characterization of Serum Antibodies in COVID-19 Patients
3.2. Serum Cytokine Features of COVID-19 Patients Infected with WT and VOC Strains
3.3. Correlation Analysis of Serum Cytokines and Neutralizing Potency in COVID-19 Patients
3.4. Distinct Immune Response in Recovered Patients and Naïve Individuals after mRNA Vaccination
3.5. Antigen-Specific Memory B-Cell Response in a COVID-19 Patient with High Neutralizing Potency after Vaccination
3.6. Longitudinal Cytokine Profiles Reveal a Unique Immune Response after Repeated Vaccination
3.7. Affinity Maturation by the Third Booster Vaccination and the Natural Development That Occurred in Prolonged COVID-19 Patients Are Uniform
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
References
- Mangalmurti, N.; Hunter, C.A. Cytokine Storms: Understanding COVID-19. Immunity 2020, 53, 19–25. [Google Scholar] [CrossRef] [PubMed]
- Waltuch, T.; Gill, P.; Zinns, L.E.; Whitney, R.; Tokarski, J.; Tsung, J.W.; Sanders, J.E. Features of COVID-19 post-infectious cytokine release syndrome in children presenting to the emergency department. Am. J. Emerg. Med. 2020, 38, 2246.e3–2246.e6. [Google Scholar] [CrossRef]
- Liu, Y.; Liu, J.; Plante, K.S.; Plante, J.A.; Xie, X.; Zhang, X.; Ku, Z.; An, Z.; Scharton, D.; Schindewolf, C.; et al. The N501Y spike substitution enhances SARS-CoV-2 infection and transmission. Nature 2022, 602, 294–299. [Google Scholar] [CrossRef]
- Ulrich, L.; Halwe, N.J.; Taddeo, A.; Ebert, N.; Schon, J.; Devisme, C.; Trueb, B.S.; Hoffmann, B.; Wider, M.; Fan, X.; et al. Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta. Nature 2022, 602, 307–313. [Google Scholar] [CrossRef] [PubMed]
- Deng, X.; Garcia-Knight, M.A.; Khalid, M.M.; Servellita, V.; Wang, C.; Morris, M.K.; Sotomayor-Gonzalez, A.; Glasner, D.R.; Reyes, K.R.; Gliwa, A.S.; et al. Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant. Cell 2021, 184, 3426–3437.e3428. [Google Scholar] [CrossRef]
- Motozono, C.; Toyoda, M.; Zahradnik, J.; Saito, A.; Nasser, H.; Tan, T.S.; Ngare, I.; Kimura, I.; Uriu, K.; Kosugi, Y.; et al. SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity. Cell Host Microbe 2021, 29, 1124–1136.e11. [Google Scholar] [CrossRef]
- Twohig, K.A.; Nyberg, T.; Zaidi, A.; Thelwall, S.; Sinnathamby, M.A.; Aliabadi, S.; Seaman, S.R.; Harris, R.J.; Hope, R.; Lopez-Bernal, J.; et al. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: A cohort study. Lancet Infect. Dis. 2022, 22, 35–42. [Google Scholar] [CrossRef]
- Saito, A.; Irie, T.; Suzuki, R.; Maemura, T.; Nasser, H.; Uriu, K.; Kosugi, Y.; Shirakawa, K.; Sadamasu, K.; Kimura, I.; et al. Enhanced fusogenicity and pathogenicity of SARS-CoV-2 Delta P681R mutation. Nature 2022, 602, 300–306. [Google Scholar] [CrossRef] [PubMed]
- Lippi, G.; Mattiuzzi, C.; Henry, B.M. Updated picture of SARS-CoV-2 variants and mutations. Diagnosis 2021, 9, 11–17. [Google Scholar] [CrossRef]
- Wei, J.; Pouwels, K.B.; Stoesser, N.; Matthews, P.C.; Diamond, I.; Studley, R.; Rourke, E.; Cook, D.; Bell, J.I.; Newton, J.N.; et al. Antibody responses and correlates of protection in the general population after two doses of the ChAdOx1 or BNT162b2 vaccines. Nat. Med. 2022, 28, 1072–1082. [Google Scholar] [CrossRef]
- Goel, R.R.; Painter, M.M.; Apostolidis, S.A.; Mathew, D.; Meng, W.; Rosenfeld, A.M.; Lundgreen, K.A.; Reynaldi, A.; Khoury, D.S.; Pattekar, A.; et al. mRNA vaccines induce durable immune memory to SARS-CoV-2 and variants of concern. Science 2021, 374, abm0829. [Google Scholar] [CrossRef]
- Barros-Martins, J.; Hammerschmidt, S.I.; Cossmann, A.; Odak, I.; Stankov, M.V.; Morillas Ramos, G.; Dopfer-Jablonka, A.; Heidemann, A.; Ritter, C.; Friedrichsen, M.; et al. Immune responses against SARS-CoV-2 variants after heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination. Nat. Med. 2021, 27, 1525–1529. [Google Scholar] [CrossRef]
- Naito, T.; Tsuchida, N.; Kusunoki, S.; Kaneko, Y.; Tobita, M.; Hori, S.; Ito, S. Reactogenicity and immunogenicity of BNT162b2 or mRNA-1273 COVID-19 booster vaccinations after two doses of BNT162b2 among healthcare workers in Japan: A prospective observational study. Expert Rev. Vaccines 2022, 21, 1319–1329. [Google Scholar] [CrossRef] [PubMed]
- Goel, R.R. Distinct antibody and memory B cell responses in SARS-CoV-2 naïve and recovered individuals after mRNA vaccination. Sci. Immunol. 2021, 6, eabi6950. [Google Scholar] [CrossRef]
- Samanovic, M.I. Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2–experienced individuals. Sci. Transl. Med. 2022, 14, eabi8961. [Google Scholar] [CrossRef] [PubMed]
- Dan, J.M. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 2021, 371, eabf4063. [Google Scholar] [CrossRef]
- Cohen, K.W.; Linderman, S.L.; Moodie, Z.; Czartoski, J.; Lai, L.; Mantus, G.; Norwood, C.; Nyhoff, L.E.; Edara, V.V.; Floyd, K.; et al. Longitudinal analysis shows durable and broad immune memory after SARS-CoV-2 infection with persisting antibody responses and memory B and T cells. Cell Rep. Med. 2021, 2, 100354. [Google Scholar] [CrossRef]
- Bannard, O. Germinal centers: Programmed for affinity maturation and antibody diversification. Curr. Opin. Immunol. 2017, 45, 21–30. [Google Scholar] [CrossRef]
- Wang, Z.; Muecksch, F.; Schaefer-Babajew, D.; Finkin, S.; Viant, C.; Gaebler, C.; Hoffmann, H.H.; Barnes, C.O.; Cipolla, M.; Ramos, V.; et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 2021, 595, 426–431. [Google Scholar] [CrossRef] [PubMed]
- Moriyama, S.; Adachi, Y.; Sato, T.; Tonouchi, K.; Sun, L.; Fukushi, S.; Yamada, S.; Kinoshita, H.; Nojima, K.; Kanno, T.; et al. Temporal maturation of neutralizing antibodies in COVID-19 convalescent individuals improves potency and breadth to circulating SARS-CoV-2 variants. Immunity 2021, 54, 1841–1852.e4. [Google Scholar] [CrossRef]
- Walls, A.C.; Sprouse, K.R.; Bowen, J.E.; Joshi, A.; Franko, N.; Navarro, M.J.; Stewart, C.; Cameroni, E.; McCallum, M.; Goecker, E.A.; et al. SARS-CoV-2 breakthrough infections elicit potent, broad, and durable neutralizing antibody responses. Cell 2022, 185, 872–880.e3. [Google Scholar] [CrossRef]
- Yasuda, H.; Mori, Y.; Chiba, A.; Bai, J.; Murayama, G.; Matsushita, Y.; Miyake, S.; Komatsu, N. Resolution of One-Year Persisting COVID-19 Pneumonia and Development of Immune Thrombocytopenia in a Follicular Lymphoma Patient With Preceding Rituximab Maintenance Therapy: A follow-up Report and Literature Review of Cases With Prolonged Infections. Clin. Lymphoma Myeloma Leuk. 2021, 21, e810–e816. [Google Scholar] [CrossRef]
- Legros, V.; Denolly, S.; Vogrig, M.; Boson, B.; Siret, E.; Rigaill, J.; Pillet, S.; Grattard, F.; Gonzalo, S.; Verhoeven, P.; et al. A longitudinal study of SARS-CoV-2-infected patients reveals a high correlation between neutralizing antibodies and COVID-19 severity. Cell Mol. Immunol. 2021, 18, 318–327. [Google Scholar] [CrossRef]
- Chen, Y.; Zuiani, A.; Fischinger, S.; Mullur, J.; Atyeo, C.; Travers, M.; Lelis, F.J.N.; Pullen, K.M.; Martin, H.; Tong, P.; et al. Quick COVID-19 Healers Sustain Anti-SARS-CoV-2 Antibody Production. Cell 2020, 183, 1496–1507.e16. [Google Scholar] [CrossRef]
- Collier, D.A.; Ferreira, I.; Kotagiri, P.; Datir, R.P.; Lim, E.Y.; Touizer, E.; Meng, B.; Abdullahi, A.; The CITIID-NIHR BioResource COVID-19 Collaboration; Elmer, A.; et al. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature 2021, 596, 417–422. [Google Scholar] [CrossRef]
- Romero-Olmedo, A.J.; Schulz, A.R.; Hochstatter, S.; Das Gupta, D.; Virta, I.; Hirseland, H.; Staudenraus, D.; Camara, B.; Munch, C.; Hefter, V.; et al. Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adults. Nat. Microbiol. 2022, 7, 195–199. [Google Scholar] [CrossRef]
- Davies, N.G.; Abbott, S.; Barnard, R.C.; Jarvis, C.I.; Kucharski, A.J.; Munday, J.D.; Pearson, C.A.B.; Russell, T.W.; Tully, D.C.; Washburne, A.D.; et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 2021, 372, abg3055. [Google Scholar] [CrossRef]
- Volz, E.; Mishra, S.; Chand, M.; Barrett, J.C.; Johnson, R.; Geidelberg, L.; Hinsley, W.R.; Laydon, D.J.; Dabrera, G.; O’Toole, A.; et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature 2021, 593, 266–269. [Google Scholar] [CrossRef] [PubMed]
- Jensen, B.; Luebke, N.; Feldt, T.; Keitel, V.; Brandenburger, T.; Kindgen-Milles, D.; Lutterbeck, M.; Freise, N.F.; Schoeler, D.; Haas, R.; et al. Emergence of the E484K mutation in SARS-COV-2-infected immunocompromised patients treated with bamlanivimab in Germany. Lancet Reg. Health Eur. 2021, 8, 100164. [Google Scholar] [CrossRef]
- Weigang, S.; Fuchs, J.; Zimmer, G.; Schnepf, D.; Kern, L.; Beer, J.; Luxenburger, H.; Ankerhold, J.; Falcone, V.; Kemming, J.; et al. Within-host evolution of SARS-CoV-2 in an immunosuppressed COVID-19 patient as a source of immune escape variants. Nat. Commun 2021, 12, 6405. [Google Scholar] [CrossRef]
- Choi, B. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. New Engl. J. Med. 2020, 383, 2291–2293. [Google Scholar] [CrossRef]
- Kemp, S.A.; Collier, D.A.; Datir, R.P.; Ferreira, I.; Gayed, S.; Jahun, A.; Hosmillo, M.; Rees-Spear, C.; Mlcochova, P.; Lumb, I.U.; et al. SARS-CoV-2 evolution during treatment of chronic infection. Nature 2021, 592, 277–282. [Google Scholar] [CrossRef]
- Clark, S.A.; Clark, L.E.; Pan, J.; Coscia, A.; McKay, L.G.A.; Shankar, S.; Johnson, R.I.; Brusic, V.; Choudhary, M.C.; Regan, J.; et al. SARS-CoV-2 evolution in an immunocompromised host reveals shared neutralization escape mechanisms. Cell 2021, 184, 2605–2617.e18. [Google Scholar] [CrossRef]
- Tiller, T.; Meffre, E.; Yurasov, S.; Tsuiji, M.; Nussenzweig, M.C.; Wardemann, H. Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J. Immunol. Methods 2008, 329, 112–124. [Google Scholar] [CrossRef] [Green Version]
- Chen, Y.; Wang, J.; Liu, C.; Su, L.; Zhang, D.; Fan, J.; Yang, Y.; Xiao, M.; Xie, J.; Xu, Y.; et al. IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19. Mol. Med. 2020, 26, 97. [Google Scholar] [CrossRef]
- Romagnani, S. Cytokines and chemoattractants in allergic inflammation. Molecular Immunology 2002, 38, 881–885. [Google Scholar] [CrossRef]
- Yasuda, H.; Tsukune, Y.; Watanabe, N.; Sugimoto, K.; Uchimura, A.; Tateyama, M.; Miyashita, Y.; Ochi, Y.; Komatsu, N. Persistent COVID-19 Pneumonia and to Develop Anti-SARS-CoV-2 Antibodies During Rituximab Maintenance Therapy for Follicular Lymphoma. Clin. Lymphoma Myeloma Leuk. 2020, 20, 774–776. [Google Scholar] [CrossRef]
- Martonik, D.; Parfieniuk-Kowerda, A.; Rogalska, M.; Flisiak, R. The Role of Th17 Response in COVID-19. Cells 2021, 10, 1550. [Google Scholar] [CrossRef]
- Miyauchi, K.; Adachi, Y.; Tonouchi, K.; Yajima, T.; Harada, Y.; Fukuyama, H.; Deno, S.; Iwakura, Y.; Yoshimura, A.; Hasegawa, H.; et al. Influenza virus infection expands the breadth of antibody responses through IL-4 signalling in B cells. Nat. Commun. 2021, 12, 3789. [Google Scholar] [CrossRef]
- Robbiani, D.F.; Gaebler, C.; Muecksch, F.; Lorenzi, J.C.C.; Wang, Z.; Cho, A.; Agudelo, M.; Barnes, C.O.; Gazumyan, A.; Finkin, S.; et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 2020, 584, 437–442. [Google Scholar] [CrossRef]
- Logtenberg, T. Antibody cocktails: Next-generation biopharmaceuticals with improved potency. Trends Biotechnol. 2007, 25, 390–394. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Soh, W.T.; Kishikawa, J.I.; Hirose, M.; Nakayama, E.E.; Li, S.; Sasai, M.; Suzuki, T.; Tada, A.; Arakawa, A.; et al. An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies. Cell 2021, 184, 3452–3466.e18. [Google Scholar] [CrossRef]
- Sodeifian, F.; Nikfarjam, M.; Kian, N.; Mohamed, K.; Rezaei, N. The role of type I interferon in the treatment of COVID-19. J. Med. Virol. 2022, 94, 63–81. [Google Scholar] [CrossRef]
- Koyasu, S. Type 2 innate immune responses and the natural helper cell Th2-type innate immune responses. Immunology 2011, 132, 475–481. [Google Scholar] [CrossRef]
- Pavel, A.B.; Glickman, J.W.; Michels, J.R.; Kim-Schulze, S.; Miller, R.L.; Guttman-Yassky, E. Th2/Th1 Cytokine Imbalance Is Associated With Higher COVID-19 Risk Mortality. Front. Genet. 2021, 12, 706902. [Google Scholar] [CrossRef]
- Liang, Z.; Zhu, H.; Wang, X.; Jing, B.; Li, Z.; Xia, X.; Sun, H.; Yang, Y.; Zhang, W.; Shi, L.; et al. Adjuvants for Coronavirus Vaccines. Front. Immunol. 2020, 11, 589833. [Google Scholar] [CrossRef] [PubMed]
- Ohashi, H.; Hishiki, T.; Akazawa, D.; Kim, K.S.; Woo, J.; Shionoya, K.; Tsuchimoto, K.; Iwanami, S.; Moriyama, S.; Kinoshita, H.; et al. Different efficacies of neutralizing antibodies and antiviral drugs on SARS-CoV-2 Omicron subvariants, BA.1 and BA.2. Antiviral Res. 2022, 205, 105372. [Google Scholar] [CrossRef]
- Uraki, R.; Kiso, M.; Iida, S.; Imai, M.; Takashita, E.; Kuroda, M.; Halfmann, P.J.; Loeber, S.; Maemura, T.; Yamayoshi, S.; et al. Characterization and antiviral susceptibility of SARS-CoV-2 Omicron BA.2. Nature 2022, 607, 119–127. [Google Scholar] [CrossRef]
- Takano, T.; Morikawa, M.; Adachi, Y.; Kabasawa, K.; Sax, N.; Moriyama, S.; Sun, L.; Isogawa, M.; Nishiyama, A.; Onodera, T.; et al. Distinct immune cell dynamics correlate with the immunogenicity and reactogenicity of SARS-CoV-2 mRNA vaccine. Cell Rep. Med. 2022, 3, 100631. [Google Scholar] [CrossRef]
- Li, Z.; Xiang, T.; Liang, B.; Deng, H.; Wang, H.; Feng, X.; Quan, X.; Wang, X.; Li, S.; Lu, S.; et al. Characterization of SARS-CoV-2-Specific Humoral and Cellular Immune Responses Induced by Inactivated COVID-19 Vaccines in a Real-World Setting. Front. Immunol. 2021, 12, 802858. [Google Scholar] [CrossRef]
- Peng, P.; Deng, H.J.; Hu, J.; Wei, X.Y.; Xue, J.J.; Li, T.T.; Fang, L.; Liu, B.Z.; Jin, A.S.; Xu, F.L.; et al. Humoral responses in naive or SARS-CoV-2 experienced individuals vaccinated with an inactivated vaccine. Cell Discov. 2021, 7, 68. [Google Scholar] [CrossRef] [PubMed]
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Hisamatsu, D.; Ikeda, A.; Ito, L.; Matsushita, Y.; Hiki, M.; Mori, H.; Tabe, Y.; Naito, T.; Akazawa, C. Longitudinal Analyses after COVID-19 Recovery or Prolonged Infection Reveal Unique Immunological Signatures after Repeated Vaccinations. Vaccines 2022, 10, 1815. https://doi.org/10.3390/vaccines10111815
Hisamatsu D, Ikeda A, Ito L, Matsushita Y, Hiki M, Mori H, Tabe Y, Naito T, Akazawa C. Longitudinal Analyses after COVID-19 Recovery or Prolonged Infection Reveal Unique Immunological Signatures after Repeated Vaccinations. Vaccines. 2022; 10(11):1815. https://doi.org/10.3390/vaccines10111815
Chicago/Turabian StyleHisamatsu, Daisuke, Akari Ikeda, Lisa Ito, Yasushi Matsushita, Makoto Hiki, Hirotake Mori, Yoko Tabe, Toshio Naito, and Chihiro Akazawa. 2022. "Longitudinal Analyses after COVID-19 Recovery or Prolonged Infection Reveal Unique Immunological Signatures after Repeated Vaccinations" Vaccines 10, no. 11: 1815. https://doi.org/10.3390/vaccines10111815