Enhanced T-cell immunity and lower humoral responses following 5-dose SARS-CoV-2 vaccination in patients with inborn errors of immunity compared with healthy controls

Abstract

Objective: Patients with Inborn Errors of Immunity (IEI) are at higher risk of severe SARS-CoV-2 infection. We evaluated humoral and cellular responses to COVID-19 vaccines in Brazilian patients with IEI and healthy controls.

Methods: Fifty-five patients with IEI (13-61 years) and 60 controls (13-71 years) received inactivated SARS-CoV-2 (CoronaVac), non-replicating virus-vectored (ChAdOx1 nCoV-19, AstraZeneca) or monovalent mRNA (Original strain of BNT162b2, Pfizer-BioNTech) and bivalent mRNA (Original/Omicron BA.1, Pfizer-BioNTech) vaccines and were sampled five times. Diagnoses included common variable immunodeficiency (n=25), specific antibody deficiency (n=9), ataxia-telangiectasia (n=5), X-linked agammaglobulinemia (n=4), PIK3CD-related disorders (n=4), hyper-IgM syndrome (n=4), combined immunodeficiency (n=3), and STAT1 gain-of-function (n=1). Humoral immunity was assessed via multiplex microarray for Spike, Nucleocapsid, RBD-Wuhan, RBD-Delta, RBD-BA.1, RBD-BA.2 and RBD-BA.5 neutralizing antibodies. T-cell responses to Spike and Nucleocapsid were assessed using ELISpot.

Results: Patients with IEI exhibited significantly lower levels of Nucleocapsid and RBD-neutralizing antibodies (p < 0.05). Notable differences in RBD-BA.2 (p = 0.008) and IgG-Nucleocapsid (p = 0.010) levels emerged over time. T-cell responses to Spike were stronger in patients with IEI post-booster (405 vs. 149 spot-forming cells/million PBMC; p = 0.002). Both groups showed enhanced Nucleocapsid-specific cellular responses over time (p = 0.017). COVID-19 hospitalization rates among patients with IEI with SARS-CoV-2 diagnosis dropped from 33.3% to zero after the first booster dose.

Conclusions: While humoral responses to SARS-CoV-2 vaccines were weaker in patients with IEI, their cellular immunity was similar to controls. Boosters enhanced both humoral and cellular responses. After completion of the vaccination protocol, none of the patients with IEI were hospitalized with COVID-19. Robust T-cell responses may play a critical role in protecting patients with IEI from severe COVID-19 and mortality.

Keywords: COVID-19 vaccines; ELISpot enzyme-linked immunospot; SARS-CoV-2; booster; immune response; inborn errors of immunity; microarray; primary immunodeficiency disorders.

Figure 1

Study design. Study visits and intervals between study visits or between vaccination and study visits are depicted. The BNT162b2 (Mo Pf) vaccine was used as the third vaccine dose. The 4^th and 5^th vaccine doses were based on local availability. For the control cohort, the 3^rd dose is the first booster and the 4^th dose is the second booster. For the IEI cohort, the 4^th dose is the first booster and the 5^th dose is the second booster. This study compared the immune response after the 1^st and 2^nd booster for both IEI and Control cohorts. AZ = ChAdOx1 nCoV-19, AstraZeneca; CV = CoronaVac; Mo Pf = monovalent mRNA original strain of BNT162b2, Pfizer-BioNTech; Bi Pf = bivalent mRNA Original/Omicron BA.1, Pfizer-BioNTech; Janssen = Ad26.COV2.S.

Figure 2

Humoral response. RBD-Wuhan (A), RBD-Delta (B), Nucleocapsid N-specific IgG (C), RBD-BA.1 (D), RBD-BA.2 (E) and RBD-BA.5 (F) antibodies 1 and 6 months after the 1^st booster and 1 month after the 2^nd booster in IEI and Control. For the control cohort, the 3^rd dose is the first booster and the 4^th dose is the second booster. For the IEI cohort, the 4^th dose is the first booster and the 5^th dose is the second booster. GMT values and 95% Confidence Intervals are shown. The dotted horizontal line is the quantitative cut-offs (NIBSC 21/338) for RBD-Wuhan (9.1 IU/mL), RBD-BA.1 (626.5 IU/mL) and Nucleocapsid (16.4 BAU/mL). No cut-offs are available for RBD-Delta, RBD-BA.2 and RBD-BA.5.

Figure 3

T-cell response. Spike (A) and Nucleocapsid (B) specific T-cell 1 and 6 months after the 1^st booster and 1 month after the 2^nd booster in IEI and Control. For the control cohort, the 3^rd dose is the first booster and the 4^th dose is the second booster. For the IEI cohort, the 4^th dose is the first booster and the 5^th dose is the second booster. Mean values of SFC/10⁶ PBMC with Errors bars are shown. The dotted horizontal line is the responder cut-off of the T-SPOT COVID assay (40 SFC/10⁶ PBMCs).

Figure 4

COVID-19 and hospitalizations. SARS-CoV-2 infection and COVID-19 hospitalization in Control and IEI cohorts before immunization, between 1^st and 3^rd vaccine dose, between 3^rd and 4^th vaccine dose and after 4^th vaccine dose up to 16 months of follow-up. For the control cohort, the 3^rd dose is the first booster and the 4^th dose is the second booster. For the IEI cohort, the 4^th dose is the first booster and the 5^th dose is the second booster.

Figure 5

Humoral vs T-cell responses. Correlation between NAb RBD-Wuhan and Spike T-cell responses 1 and 6 months after the 1^st booster and 1 month after the 2^nd booster in Control [(A–C) respectively] and IEI [(D–F) respectively] cohorts. For the control cohort, the 3^rd dose is the first booster and the 4^th dose is the second booster. For the IEI cohort, the 4^th dose is the first booster and the 5^th dose is the second booster. The dotted horizontal line is the responder cut-off of the NTCHIP^® assay for RBD-Wuhan (9.0 IU/mL). The dotted vertical line is the responder cut-off of the T-SPOT COVID assay (40 SFC/10⁶ PBMCs).