key: cord-1030457-lxlmn48n
authors: Abo-Helo, Nizar; Muhammad, Emad; Ghaben-Amara, Sondus; Cohen, Shai
title: Specific antibody response of 14 common variable immunodeficiency patients to three BNT162b2 mRNA COVID-19 vaccinations
date: 2022-04-06
journal: Ann Allergy Asthma Immunol
DOI: 10.1016/j.anai.2022.03.035
sha: 8f9e74c0f80a8626c4c4a2f163b2f99ea2b1b6bc
doc_id: 1030457
cord_uid: lxlmn48n

nan

On December 20 th , 2020 Israel conducted a vaccination campaign against the spread of coronavirus disease 2019 (COVID-19) with a two-dose regimen of Pfizer-BioNTech mRNA vaccine, BNT262b2. By June 1, 2021, 56% of the population was fully vaccinated. 1 The emergence of the highly infectious delta variant and waning vaccine-elicited immunity contributed to a resurgence in both confirmed and severe illness. In June 2021 the number of PCR-confirmed cases increased substantially. Therefore, on July 12, 2021, Israeli authorities decided to administer a third booster dose. Initial studies had indicated that a third BNT162b2 dose increased the antibody neutralization level on average by a factor of 10, and a large-scale real-life study confirmed that a third dose substantially lowered severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and disease. 2 This decision was also supported by an observed continuous decrease of anti-S IgG titers in the overall population and a strong correlation between IgG and neutralizing antibody titers throughout the 6 months following the two-dose BNT162b2 regimen. 3 This raised an important question: would patients suffering from primary immunodeficiency disorders of humoral immunity affecting B-cell differentiation and antibody production are also be able to produce effective levels of specific antibodies after receiving a third BNT162b2 dose.

We recently reported our observation that 11 (75%) of 15 common variable immunodeficiency (CVID) patients produced specific SARS-CoV-2 S1 antibodies in good titers after receiving the second BNT162b2 dose. 4 Those patients were divided into three groups, based on the EUROClass, as follows: Group B-, total circulating CD19⁺ B cells ≤1%; Group B+/smB+, total circulating CD19⁺ B cells >1% and switched memory B (smB) cells >2%; and Group B+/smB-, total circulating CD19⁺ B cells >1%, and smB cells ≤2%. Our data indicated that total circulating 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. We continued to follow the anti-SARS-CoV-2 spike-specific IgG antibody levels of these patients. We report herein our data including the titers following the third booster or post-vaccination infection.

Antibody levels were measured using Abbott Architect SARS-CoV-2 S1 IgG assay. Levels greater than 50 AU/mL were considered protective, as previously described. 5 One patient of B+/smB-group started rituximab immediately after receiving the second dose and was excluded from this study; hence, 14 patients were included in this study As shown in Table 1 , 5-6 months after the second dose; specific antibodies levels remained non-protective in all patients from group B-, and those in group B+/smB-with B% cells below 6%. Of the 10 patients who initially responded to the vaccine, only two (25%) had unprotective levels. In the other 8 patients, the Spike antibody levels ranged between 68.10-2060.30

Au/mL (median, 152.15). These levels were much lower than reported by a recent study that assessed 122 volunteers for the dynamics of antibody response after a two-dose BNT162b2 regimen. 5 Six months after the second dose, all participants were reported to have protective levels ranging from 893-2463 (median, 1383) (Abbott Architect SARS-CoV-2 S1 IgG assay).

Two of our CVID patients were diagnosed by PCR with COVID-19 following the second dose: patient (F,30), from group B-, was diagnosed six months following the second dose and presented with mild headache symptoms for two days. Her specific antibody levels taken two months thereafter remained nonprotective. The second patient (F,38) from group B+/smB-and CD19⁺B% <6% was diagnosed with COVID-19 six months after the second dose and presented with mild headache symptoms and fever for two days, with seroconversion two months after infection (516.10 AU/ML).

Eleven patients received the third dose, 10 of which produced protective antibodies with levels ranging from179-9972 AU/ML when measured 14-85 days post-vaccination.

Interestingly, patient (M,51) from group B-did not initially respond, but developed a protective level after the third dose, whereas patient F,66 (group B+/smB-) with B% <6% remained seronegative after the third dose. Patient (F,62) from group B+/smB-had protective levels after the third dose and was diagnosed by PCR with COVID-19 36 days afterward. She also had mild disease manifestations and her antibody levels increased to 17,289 AU/ML two-months postinfection.

Although this study is limited by the small cohort, it is the only study to date that made correlations between EUROClass classification and the humoral response to vaccination, and it is the first study to monitor the response of CVID patients to the third BNT162b2 dose. Hence, our observations may have implications for the future treatment of CVID patients in the era of COVID-19 pandemic. Patient (F,38) from group B-developed protective specific antibodies only after infection, which confirms the findings of Pulvirenti et al. 6 , that SARS-CoV-2 infection in CVID patients causes a more efficient classical memory B cell response than BNT162b2 vaccine.

After receiving the two-dose BNT262b2 regimen, two patients were infected by SARS-CoV-2; however, despite having unprotective levels of specific antibodies pre-infection, they only developed mild disease. Interestingly, one of our patients (F,30), who maintained negative serology after infection, developed only mild COVID-19 with no post-acute COVID sequalae.

This suggests that although the two-dose BNT162b2 regimen does not increase the humoral response it may still elicit robust antigen-specific CD8+ and Th1-type CD4+ T-cell responses. 7 A recent study supports this theory and showed that two-thirds of their vaccinated CVID patients indeed developed S-peptide-specific T-cell response. 8 

Coronavirus Pandemic (COVID-19). 2020. Published online at the Our World in Data website

Protection of BNT162b2 vaccine booster against Covid-19 in Israel

Waning immune humoral response to BNT162b2 Covid-19 vaccine over 6 months

Specific antibody response of patients with common variable immunodeficiency to BNT162b2 coronavirus disease 2019 vaccination

Dynamics of antibody response to BNT162b2 vaccine after six months: a longitudinal prospective study

B cell response induced by SARS-CoV-2 infection is boosted by the BNT162b2 vaccine in primary antibody deficiencies

COVID-19 vaccine BNT162b1 elicits human antibody and T H 1 T cell responses

Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity

The results of the third BNT162b2 dose suggest that some CVID patients may need a few BNT162b2 doses to achieve antigen exposure that produces or preserves good humoral response. Therefore, we should consider giving booster doses to CVID patients earlier than 5 months after the second dose.