Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome

Abstract

Background: Netherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency.

Methods: Vaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls.

Results: None of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls.

Conclusions: Vaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.

Keywords: SPINK5; COVID-19; Immunodeficiency; Netherton syndrome; Vaccination response.

Fig. 1

Vaccination responses to PPV23 and ActHiB. (a) Comparison of antibody concentration (µg/mL) per pneumococcal serotype before and after PPV23 vaccination. Samples exceeding the serotype specific upper limit of detection are marked by a purple symbol. (b) Comparison of antibody concentration (µg/mL) before and after ActHiB vaccination. Symbols show individual data points. Each Netherton syndrome (NS) patient has their own unique symbol as indicated by the legend. Patients 3 and 8 received prior Haemophilus influenza type b vaccination, which was part of the Dutch National Immunisation Programme (DNIP) during their childhood. Patient 5 did not receive PPV23 or ActHiB vaccination, antibody concentrations were thus not determined. The dotted line represents 1.00 µg/mL. PPV23 = Pneumovax 23, polysaccharide vaccine against Streptococcus pneumoniae; ActHiB = conjugate vaccine against Haemophilus influenza type b. Individual patient kinetics pre- and post-vaccination are shown in Supplementary Figure S2

Fig. 2

SARS-CoV-2–specific immune responses after booster vaccination. (a) Comparison of S-specific IgG antibodies (GMT ± 95% CI) after COVID-19 booster vaccination between NS patients and HCW. LLoD is 4.81 BAU/ml, responder (resp) cut-off is 33.8 BAU/ml (dotted line). (b) Comparison of neutralizing antibodies (GMT ± 95% CI) determined by PRNT after COVID-19 booster vaccination between NS patients and HCW. When no neutralization was observed, PRNT50 was given a value of 10. (c, d) Percentage of AIM + T-cells against ancestral SARS-CoV-2, and Omicron sub-lineages BA.1 and BA.5 after COVID-19 booster vaccination. A CEFX peptide pool was included as positive control. Data (GM ± 95% CI) is presented as the percentage of AIM + CD4 (c) and CD8 T-cells (d). LLoD is set at 0.1%. Symbols show individual data points. Individuals with a history of SARS-CoV-2 infection were marked by a red symbol. Each NS patient was given a unique symbol. Bold numbers above the plots represent the respective geometric mean (titer). GMT = geometric mean titer; GM = geometric mean; LLoD = lower limit of detection; S = Spike; BAU = binding arbitrary units; HCW = healthcare workers; PRNT = plaque reduction neutralization test, AIM = activation-induced markers; ANC = ancestral SARS-CoV-2 strain