Functional CVIDs Phenotype Clusters Identified by the Integration of Immune Parameters After BNT162b2 Boosters

Introduction: Assessing the response to vaccinations is one of the diagnostic criteria for Common Variable Immune Deficiencies (CVIDs). Vaccination against SARS-CoV-2 offered the unique opportunity to analyze the immune response to a novel antigen. We identify four CVIDs phenotype clusters by the integration of immune parameters after BTN162b2 boosters.

Methods: We performed a longitudinal study on 47 CVIDs patients who received the 3rd and 4th vaccine dose of the BNT162b2 vaccine measuring the generation of immunological memory. We analyzed specific and neutralizing antibodies, spike-specific memory B cells, and functional T cells.

Results: We found that, depending on the readout of vaccine efficacy, the frequency of responders changes. Although 63.8% of the patients have specific antibodies in the serum, only 30% have high-affinity specific memory B cells and generate recall responses.

Discussion: Thanks to the integration of our data, we identified four functional groups of CVIDs patients with different B cell phenotypes, T cell functions, and clinical diseases. The presence of antibodies alone is not sufficient to demonstrate the establishment of immune memory and the measurement of the in-vivo response to vaccination distinguishes patients with different immunological defects and clinical diseases.

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References

Smith L, Buckley R, Lugar P . Diagnostic Immunization with Bacteriophage ΦX 174 in Patients with Common Variable Immunodeficiency/Hypogammaglobulinemia. Front Immunol. 2014; 5:410. PMC: 4148716. DOI: 10.3389/fimmu.2014.00410. View

Takemori T, Kaji T, Takahashi Y, Shimoda M, Rajewsky K . Generation of memory B cells inside and outside germinal centers. Eur J Immunol. 2014; 44(5):1258-64. DOI: 10.1002/eji.201343716. View

Bergman P, Blennow O, Hansson L, Mielke S, Nowak P, Chen P . Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial. EBioMedicine. 2021; 74:103705. PMC: 8629680. DOI: 10.1016/j.ebiom.2021.103705. View

Romano C, Esposito S, Donnarumma G, Marrone A . Detection of neutralizing anti-severe acute respiratory syndrome coronavirus 2 antibodies in patients with common variable immunodeficiency after immunization with messenger RNA vaccines. Ann Allergy Asthma Immunol. 2021; 127(4):499-501. PMC: 8327608. DOI: 10.1016/j.anai.2021.07.026. View

Capolunghi F, Rosado M, Sinibaldi M, Aranburu A, Carsetti R . Why do we need IgM memory B cells?. Immunol Lett. 2013; 152(2):114-20. DOI: 10.1016/j.imlet.2013.04.007. View

Salinas A, Piano Mortari E, Terreri S, Quintarelli C, Pulvirenti F, Di Cecca S . SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best. J Clin Immunol. 2021; 41(8):1709-1722. PMC: 8527979. DOI: 10.1007/s10875-021-01133-0. View

Inamine A, Takahashi Y, Baba N, Miyake K, Tokuhisa T, Takemori T . Two waves of memory B-cell generation in the primary immune response. Int Immunol. 2005; 17(5):581-9. DOI: 10.1093/intimm/dxh241. View

Pulvirenti F, Di Cecca S, Sinibaldi M, Piano Mortari E, Terreri S, Albano C . T-Cell Defects Associated to Lack of Spike-Specific Antibodies after BNT162b2 Full Immunization Followed by a Booster Dose in Patients with Common Variable Immune Deficiencies. Cells. 2022; 11(12). PMC: 9221747. DOI: 10.3390/cells11121918. View

Aranburu A, Piano Mortari E, Baban A, Giorda E, Cascioli S, Marcellini V . Human B-cell memory is shaped by age- and tissue-specific T-independent and GC-dependent events. Eur J Immunol. 2016; 47(2):327-344. DOI: 10.1002/eji.201646642. View

10.

Taylor J, Pape K, Jenkins M . A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med. 2012; 209(3):597-606. PMC: 3302224. DOI: 10.1084/jem.20111696. View

11.

Muecksch F, Wang Z, Cho A, Gaebler C, Ben Tanfous T, DaSilva J . Increased memory B cell potency and breadth after a SARS-CoV-2 mRNA boost. Nature. 2022; 607(7917):128-134. PMC: 9259484. DOI: 10.1038/s41586-022-04778-y. View

12.

Zou J, Kurhade C, Patel S, Kitchin N, Tompkins K, Cutler M . Neutralization of BA.4-BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine. N Engl J Med. 2023; 388(9):854-857. PMC: 9891359. DOI: 10.1056/NEJMc2214916. View

13.

Arroyo-Sanchez D, Cabrera-Marante O, Laguna-Goya R, Almendro-Vazquez P, Carretero O, Gil-Etayo F . Immunogenicity of Anti-SARS-CoV-2 Vaccines in Common Variable Immunodeficiency. J Clin Immunol. 2021; 42(2):240-252. PMC: 8596355. DOI: 10.1007/s10875-021-01174-5. View

14.

Salinas A, Piano Mortari E, Terreri S, Milito C, Zaffina S, Perno C . Impaired memory B-cell response to the Pfizer-BioNTech COVID-19 vaccine in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2021; 149(1):76-77. PMC: 8523297. DOI: 10.1016/j.jaci.2021.08.031. View

15.

Kubota-Koketsu R, Terada Y, Yunoki M, Sasaki T, Nakayama E, Kamitani W . Neutralizing and binding activities against SARS-CoV-1/2, MERS-CoV, and human coronaviruses 229E and OC43 by normal human intravenous immunoglobulin derived from healthy donors in Japan. Transfusion. 2020; 61(2):356-360. DOI: 10.1111/trf.16161. View

16.

Throsby M, van den Brink E, Jongeneelen M, Poon L, Alard P, Cornelissen L . Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS One. 2008; 3(12):e3942. PMC: 2596486. DOI: 10.1371/journal.pone.0003942. View

17.

Ponsford M, Evans K, Carne E, Jolles S . COVID-19 Vaccine Uptake and Efficacy in a National Immunodeficiency Cohort. J Clin Immunol. 2022; 42(4):728-731. PMC: 8853337. DOI: 10.1007/s10875-022-01223-7. View

18.

Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E . The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2007; 111(1):77-85. DOI: 10.1182/blood-2007-06-091744. View

19.

Carsetti R, Di Sabatino A, Rosado M, Cascioli S, Piano Mortari E, Milito C . Lack of Gut Secretory Immunoglobulin A in Memory B-Cell Dysfunction-Associated Disorders: A Possible Gut-Spleen Axis. Front Immunol. 2020; 10:2937. PMC: 6960143. DOI: 10.3389/fimmu.2019.02937. View

20.

Grimsholm O, Piano Mortari E, Davydov A, Shugay M, Obraztsova A, Bocci C . The Interplay between CD27 and CD27 B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory. Cell Rep. 2020; 30(9):2963-2977.e6. DOI: 10.1016/j.celrep.2020.02.022. View