key: cord-1014495-yo4k52fc
authors: Abo-helo, Nizar; Muhammad, Emad; Ghaben-amara, Sondus; Panasoff, Josef; Cohen, Shai
title: Specific antibody response of common variable immunodeficiency patients to BNT162b2 COVID-19 vaccination
date: 2021-07-31
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2021.07.021
sha: 6b3497058cc64190139b21a254c67082fbc471cb
doc_id: 1014495
cord_uid: yo4k52fc

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On March 11, 2020, the World Health Organization declared that coronavirus disease 2019 (COVID-19) was a pandemic. 1 Since then, the disease has reached a 1% to 3% estimated overall mortality rate. 2 COVID-19 severity ranges from asymptomatic to acute respiratory distress syndrome and possible death due to multiorgan failure. 2 Therefore, to ameliorate the resultant poor health and social and economic consequences, prophylactic vaccines were developed. On December 11, 2020, the U.S. Food and Drug Administration issued the first emergency use authorization of Pfizer-BioNTech mRNA vaccine (BNT162b2) for COVID-19 prevention. 1 The vaccine was approved following a large randomized, placebo-controlled trial in approximately 44,000 participants aged 16 or older, and showed that a two-dose regimen of BNT162b2 conferred 95% protection against symptomatic COVID-19. 1 This novel lipid nanoparticle-formulated nucleoside-modified RNA vaccine encodes the full length spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which contains the receptor binding domain (RBD) within the S1 subunit. 3 The RBD is a key functional component within the S1 subunit responsible for binding SARS-CoV-2 to angiotensin-converting enzyme 2 receptor, a critical initial step enabling SARS-CoV-2 to penetrate target cells. 4 Among healthy adults, two 30 µg doses of BNT162b2 elicited robust antigen specific CD8+ and Th1-type CD4+ T-cell responses and strong specific antibody responses directed against RBD. 5 However, it is unknown whether patients suffering from primary immunodeficiency disorders of humoral immunity affecting B-cell differentiation and antibody production are able to produce effective specific antibody levels following the two-dose BNT162b2 regimen. Common variable immunodeficiency (CVID) is an antibody deficiency with variable clinical manifestations; while patients mostly suffer from recurrent infections, there is an increased prevalence of autoimmune diseases and malignancy secondary to immunedysregulation. 6 A CVID diagnosis established after the fourth year of life requires a suggestive clinical history, a marked reduced total IgG serum concentration with low IgA or IgM, poor responses to vaccines (and/or absent isohemagglutinins), or low IgD⁻/CD27⁺/CD19⁺ switched memory B (smB) cells, and no evidence of profound T-cell deficiency; additionally, other causes of secondary hypogammaglobulinemia must be excluded. 6 We observed retrospectively the ability of CVID patients to produce SARS-CoV-2 spike-specific IgG in response to the two-dose BNT162b2 regimen as part of Israel's national vaccination program. Additionally, we looked for a correlation with CVID subgroups based on flow cytometry B-cell immunophenotyping. 7 All Patients diagnosed with CVID (n=17) were treated with intravenous immunoglobulin (IVIG) every 4 weeks at Lin, Zuvulon, and Carmel Medical Centers belonging to Clalit Health Services (CHSs), in Haifa, Israel. Revised European Society of Immune Deficiencies (ESID) registry criteria 6 were used for CVID diagnosis. Between December 23, 2020, and March 6, 2021, all CVID patients were vaccinated with the two-dose BNT162b2 regimen. Blood samples were taken at least 14 days after the second dose, before receiving IVIG to measure SARS-CoV-2 S1 IgG levels and obtain and updated flow cytometry analysis. Day 14 was chosen since mRNA vaccine-induced B cell responses typically peak two weeks after the second dose and SARS-COV-2 neutralizing titers appear to follow this pattern. 5 SARS-CoV-2 S1 IgG values above 50 AU/mL were considered protective by the Abbott Architect SARS-CoV-2 S1 IgG assay (manufacturer's data: sensitivity, 98.1% [95% CI 89.9%-99.7%]; specificity, 99.6% [95% CI 99.2%-99.8%]) performed by CHSs serology laboratory. Two patients were excluded: COVID-19 was detected on pre-vaccination PCR testing in one patient, while the second was receiving ongoing immunosuppressive medication (Rituximab). The remaining15 patients were divided into three groups, based on their results, as follows: Group B-, total circulating CD19⁺ B cells ≤1%; Group B+/smB+, total circulating CD19⁺ B cells >1% and smB cells >2%; and Group B+/smB-, total circulating CD19⁺ B cells >1% and smB cells ≤2%. 7 Table 1 provides the cohort characteristics and their serological results. Patients ranged from 22 to 81 years (average, 49.8 years). Blood serology samples were taken 14 to 61 days after the second dose (average, day 31). Four patients (26.67%) did not produce SARS-CoV-2 S1 IgG following both BNT162b2 doses, while 11 (73.33%) had protective titers ranging from 58 AU/mL to 9780.3 AU/mL (average, 1764.00; median, 307.3). Note that while 2/2 Group B-patients had negative serology, all 6/6 Group B+/smB+ patients were seropositive. For Group B+/smB-, 5/7 patients were seropositive. Interestingly, the 2/7 patients with negative serology had a total peripheral CD19⁺ B cell percentage below the lower limit for the normal range (6%-19%), 7 while the 5 seropositive patients were within the normal range. It has been shown that CVID patients with nearly absent total CD19⁺ B cells (≤1%) have severe defects of early B-cell differentiation, whereas severely reduced smB cells (≤2%) indicate defective germinal center (GC) development. 7 Our results suggest that patients with both CD19⁺ B% cells lower than the normal range (6%-19%) and reduced smB cells (≤2%) have prominent GC generation impairment. In line with this idea, the GC has been shown to play a pivotal role on protective antibodies generation for SARS-CoV-2 mRNA vaccines, and that GC responses are strongly correlated with neutralizing antibody production. 8 A possible study limitation may be that patients acquired protective antibodies from the IVIG. However, all CVID patients were on PRIVIGEN® (CSL, Bern, Switzerland; manufacture date: 14.1.2020). Hence, IVIG-stimulated cross-reactive antibodies cannot explain the wide differences between protective antibody levels after vaccination. The presence of significant protective COVID-19 antibody levels in these products is doubtful. In addition, although two patients were receiving steroids, their serological results (Table 1) indicate that steroid use was not responsible for the lack of response to BNT162b2 vaccination.

In conclusion, vaccination of CVID patients with the two-dose BNT162b2 regimen is important, since most of them will produce specific SARS-CoV-2 S1 antibodies in good titers. However, our data indicates that total peripheral CD19⁺ B cells below the normal range (6%-19%) together with smB cells (≤2%), or total peripheral CD19⁺ B cells (≤1%) may predict unresponsiveness to BNT162b2. Our data require further validation in larger CVID populations and subsequent research to detect the rate of postvaccination antibodies decay compared to that of the general population. 

Safety and efficacy of the BNT162b2 mRNA vaccine

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention

Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults

Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein

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30-Year review of pediatric-and adult-onset CVID: Clinical correlates and prognostic indicators

The EUROclass trial defining subgroups in common variable immunodeficiency

SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation