Impaired Memory B-Cell Response to Influenza Immunization in Patients With Common Variable Immunodeficiency (CVID)

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Wei Zhan
Todd Hatchette
Fengyun Yue
Jun Liu
Haihan Song
Hanqi Zhao
Stephen Betschel
Mario Ostrowski


Background: Common variable immunodeficiency (CVID) is a heterogeneous primary immunodeficiency characterized by low serum antibody levels and recurrent infections. The cellular response to immunization in patients with CVID has not been fully investigated. In this study, we aimed to characterize vaccination-induced influenza-specific memory B-cell responses in CVID.

Methods: Eleven individuals affected with CVID and 9 unaffected control individuals were immunized with the 2010-2011 non-adjuvanted seasonal influenza vaccine. Blood samples were collected on the day of vaccination and at week 8 and week 16 after vaccination, and PBMCs were immunophenotyped by flow cytometry. Influenza specific serology was determined using hemagglutination inhibition and microneutralization against vaccine antigens. Influenza-specific memory B-cell responses were determined by ELISpot. 

Results: Individuals with CVID showed wide variability in the frequency of CD19+ B cells in blood. The CVID group had significantly reduced frequencies of CD19+CD27+ memory B cells. Frequencies of circulating T follicular helper (CD4+CXCR5+) cells were similar between those with CVID and healthy controls. In terms of serology, compared to healthy controls, the CVID group overall showed significantly reduced boosting to vaccine antigens by hemagglutination inhibition and microneutralization assays at 8 weeks compared to controls and failed to maintain responses by 16 weeks compared to controls, resulting in a post-vaccination geometric mean titer (GMT) ≥ 40 to strain A/H1N1 in only 27% at 8 weeks, and 22% at 12 weeks for patients with CVID vs 78% and 75%, respectively for healthy controls. In addition, there was a GMT ≥ 40 to A/H3N2 in only 9% at 8 weeks and 22% at 12 weeks for patients with CVID vs 56% and 50%, respectively for healthy controls. Healthy participants showed significant increases in flu-specific IgM-secreting memory B cells after vaccination, whereas patients with CVID showed non-significant mild increases. Before vaccination, patients with CVID had significantly lower frequencies of background level influenza-specific IgG and IgA memory B cells. Half of the patients with CVID showed an increase in influenza-specific IgG-secreting memory B cells post vaccination, whereas the other half showed none. All control participants exhibited an increase in influenza-specific IgG-secreting B cells. None of the patients with CVID developed influenza-specific IgA memory B-cell response post vaccination, compared to 5/8 in healthy controls. At week 16, the frequency of influenza-specific memory B-cell responses decayed but to non-zero baseline in healthy controls and to zero baseline in patients with CVID. 

Conclusions: Together, these data demonstrate that patients with CVID respond heterogeneously, but as a group poorly, to non-adjuvanted influenza vaccine, with a subgroup unable to generate influenza-specific memory B-cell responses. No patient with CVID was able to maintain memory response for prolonged periods. Together, our results suggest a defect in Ig class switching and memory B-cell maintenance in patients with CVID during a de novo vaccine immune response.


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Author Biography

Mario Ostrowski, Department of Immunology, University of Toronto, Toronto, Ontario, M5S1A8, Canada; Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Unity Health, Toronto, Ontario, M5B1W8, Canada

I am full professor of Medicine, Immunology and Pathobiology and Lab medicine at University of Toronto and also is a consultant infectious diseases clinician at St. Michael's Hospital in Toronto, Canada. The research has focused on understanding the immunopathogenesis of chronic persistent virus infections in humans with a focus on two socially important virus infections, HIV (Human Immunodeficiency Virus) and HCV (Hepatitis C Virus) infection. Specific interests include studies on T cell immunoregulation in HIV and HCV infection, molecular adjuvants for vaccination, pDC-virus interactions, and the role of endogenous retroviruses in HIV infection. We bring expertise in T and B cell immunoregulation, serology, pathogenesis and epitope mapping to COVID-19 work


Selenius JS, Martelius T, Pikkarainen S, Siitonen S, Mattila E, Pietikainen R, Suomalainen P, Aalto AH, Saarela J, Einarsdottir E, Jarvinen A, Farkkila M, Kere J, Seppanen M. Unexpectedly High Prevalence of Common Variable Immunodeficiency in Finland. Front Immunol. 2017;8:1190. doi: 10.3389/fimmu.2017.01190. PubMed PMID: 29033928; PMCID: PMC5625003.

Di Renzo M, Pasqui AL, Auteri A. Common variable immunodeficiency: a review. Clin Exp Med. 2004;3(4):211-7. doi: 10.1007/s10238-004-0027-2. PubMed PMID: 15103511.

Jaffe JS, Strober W, Sneller MC. Functional abnormalities of CD8+ T cells define a unique subset of patients with common variable immunodeficiency. Blood. 1993;82(1):192-201. PubMed PMID: 8100719.

Giannouli S, Anagnostou D, Soliotis F, Voulgarelis M. Autoimmune manifestations in common variable immunodeficiency. Clin Rheumatol. 2004;23(5):449-52. doi: 10.1007/s10067-004-0886-7. PubMed PMID: 15278751.

Azizi G, Rezaei N, Kiaee F, Tavakolinia N, Yazdani R, Mirshafiey A, Aghamohammadi A. T-Cell Abnormalities in Common Variable Immunodeficiency. J Investig Allergol

Pathogens and Immunity - Vol 6, No 2 117

Clin Immunol. 2016;26(4):233-43. doi: 10.18176/jiaci.0069. PubMed PMID: 27374799.

Gathmann B, Mahlaoui N, Ceredih, Gerard L, Oksenhendler E, Warnatz K, Schulze I, Kindle G, Kuijpers TW, Dutch WID, van Beem RT, Guzman D, Workman S, Soler-Palacin P, De Gracia J, Witte T, Schmidt RE, Litzman J, Hlavackova E, Thon V, Borte M, Borte S, Kumararatne D, Feighery C, Longhurst H, Helbert M, Szaflarska A, Sediva A, Belohradsky BH, Jones A, Baumann U, Meyts I, Kutukculer N, Wagstrom P, Galal NM, Roesler J, Farmaki E, Zinovieva N, Ciznar P, Papadopoulou-Alataki E, Bienemann K, Velbri S, Panahloo Z, Grimbacher B, European Society for Immunodeficiencies Registry Working P. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116-26. doi: 10.1016/j.jaci.2013.12.1077. PubMed PMID: 24582312.

Schroeder HW, Jr., Schroeder HW, 3rd, Sheikh SM. The complex genetics of common variable immunodeficiency. J Investig Med. 2004;52(2):90-103. doi: 10.1136/jim-52-02-17. PubMed PMID: 15068224.

Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:301-5. doi: 10.1182/asheducation-2012.1.301. PubMed PMID: 23233596; PMCID: PMC4066657.

Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(1):36-44. doi: 10.1016/S1473-3099(11)70295-X. PubMed PMID: 22032844.

Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621-63. doi: 10.1146/annurev-immunol-031210-101400. PubMed PMID: 21314428.

Wrammert J, Smith K, Miller J, Langley WA, Kokko K, Larsen C, Zheng NY, Mays I, Garman L, Helms C, James J, Air GM, Capra JD, Ahmed R, Wilson PC. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 2008;453(7195):667-71. doi: 10.1038/nature06890. PubMed PMID: 18449194; PMCID: PMC2515609.

Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93(3):190-7. doi: 10.1006/clim.1999.4799. PubMed PMID: 10600329.

Scheifele DW, McNeil SA, Ward BJ, Dionne M, Cooper C, Coleman B, Loeb M, Rubinstein E, McElhaney J, Hatchette T, Li Y, Montomoli E, Schneeberg A, Bettinger JA, Halperin SA, Network PCIR. Safety, immunogenicity, and tolerability of three influenza vaccines in older adults: results of a randomized, controlled comparison. Hum Vaccin Immunother. 2013;9(11):2460-73. doi: 10.4161/hv.25580. PubMed PMID: 23839537; PMCID: PMC3981857.

WHO Global Influenza Surveillance Network. Manual for the laboratory diagnosis and virological surveillance of influenza. World Health Organization. Geneva, Switzerland; 2011.

Zacour M, Ward BJ, Brewer A, Tang P, Boivin G, Li Y, Warhuus M, McNeil SA, LeBlanc JJ, Hatchette TF, Public Health Agency of C, Canadian Institutes of Health Influwww.

Pathogens and Immunity - Vol 6, No 2 118

enza Research N. Standardization of Hemagglutination Inhibition Assay for Influenza Serology Allows for High Reproducibility between Laboratories. Clin Vaccine Immunol. 2016;23(3):236-42. doi: 10.1128/CVI.00613-15. PubMed PMID: 26818953; PMCID: PMC4783428.

Ueno H. Human Circulating T Follicular Helper Cell Subsets in Health and Disease. J Clin Immunol. 2016;36 Suppl 1:34-9. doi: 10.1007/s10875-016-0268-3. PubMed PMID: 26984851.

de Jong JC, Palache AM, Beyer WE, Rimmelzwaan GF, Boon AC, Osterhaus AD. Haemagglutination-inhibiting antibody to influenza virus. Dev Biol (Basel). 2003;115:63-73. PubMed PMID: 15088777.

van Assen S, Holvast A, Telgt DS, Benne CA, de Haan A, Westra J, Kallenberg CG, Bijl M. Patients with humoral primary immunodeficiency do not develop protective anti-influenza antibody titers after vaccination with trivalent subunit influenza vaccine. Clin Immunol. 2010;136(2):228-35. doi: 10.1016/j.clim.2010.03.430. PubMed PMID: 20421178.

Zhao L, Young K, Gemmill I. Summary of the NACI Seasonal Influenza Vaccine Statement for 2019-2020. Can Commun Dis Rep. 2019;45(6):149-55. doi: 10.14745/ccdr.v45i06a01. PubMed PMID: 31285706; PMCID: PMC6587699.

Verschoor CP, Singh P, Russell ML, Bowdish DM, Brewer A, Cyr L, Ward BJ, Loeb M. Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PLoS One. 2015;10(6):e0131531. doi: 10.1371/journal.pone.0131531. PubMed PMID: 26107625; PMCID: PMC4479562.

Sasaki S, Jaimes MC, Holmes TH, Dekker CL, Mahmood K, Kemble GW, Arvin AM, Greenberg HB. Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J Virol. 2007;81(1):215-28. doi: 10.1128/JVI.01957-06. PubMed PMID: 17050593; PMCID: PMC1797237.

Tadount F, Doyon-Plourde P, Rafferty E, MacDonald S, Sadarangani M, Quach C. Is there a difference in the immune response, efficacy, effectiveness and safety of seasonal influenza vaccine in males and females? - A systematic review. Vaccine. 2020;38(3):444-59. doi: 10.1016/j.vaccine.2019.10.091. PubMed PMID: 31711676.

Canada H. Blood products, human immunoglobulin and timing of immunization: Canadian Immunization Guide. In: Canada HCGo, editor.: Government of Canada; January 2020.