key: cord-0953035-fp58h1ot
authors: Karampitsakos, Theodoros; Papaioannou, Ourania; Dimeas, Ilias; Tsiri, Panagiota; Sotiropoulou, Vasilina; Tomos, Ioannis; Papanikolaou, Ilias C; Katsaras, Matthaios; Kirgou, Paraskevi; Daniil, Zoe; Gourgoulianis, Konstantinos I; Sampsonas, Fotios; Manali, Effrosyni; Papiris, Spyridon; Bouros, Demosthenes; Tzouvelekis, Argyris
title: Reduced immunogenicity of the mRNA vaccine BNT162b2 in patients with IPF
date: 2022-03-31
journal: ERJ Open Res
DOI: 10.1183/23120541.00082-2022
sha: 36468aa5e48976c2e56522cc48f6dc3711463c73
doc_id: 953035
cord_uid: fp58h1ot

The emergence and spread of 2019 coronavirus disease (COVID-19) are causing a growing global public health crisis. Despite advances in treatment, vaccination remains the best way to contain the pandemic [1]. Vaccines are currently available by means of conditional marketing approval, full approval and emergency use authorization pathways [2]. Evidence suggest that immunocompromised individuals including solid organ transplants recipients and patients under immunosuppressive treatment may have increased mortality from SARS-CoV-2 infection despite double dose messenger RNA (mRNA) vaccine regimens [3]. This is partially attributed to blunted immune responses to vaccination since only 38–54% of kidney and liver transplant recipients developed detectable SARS-CoV-2 antibodies following the second dose of mRNA vaccines [3, 4].

We compared anti-SARS-CoV-2 antibodies three months after the second dose of the mRNA vaccine BNT162b2 in three subgroups: 1) patients with IPF receiving antifibrotics, 2) patients with IPF under no treatment, 3) aged-matched controls.

Patients receiving corticosteroids or steroid sparing agents and patients with malignancies were excluded from the analysis. Subjects with history of prior SARS-CoV-2 infection were also excluded. The recruitment period was between 22/7/2021 and 31/10/2021. All measurements were performed using the authorized Abbott SARS-CoV-2 IgG assay. Positivity cut-off threshold for this assay was 50 AU/ml.

With regards to summary statistics, categorical data were presented as absolute numbers and relative frequencies. Continuous data were demonstrated as mean± standard deviation (SD) or medians with 95% Confidence Interval (95% CI) based on Kolmogorov-Smirnov test for normality. Kruskal-Wallis test was used to detect differences in the aforementioned three subgroups. P-values < 0.05 were considered statistically significant.

Sixty-seven (n=67) subjects were included in the analysis (patients with IPF receiving antifibrotics: 32, patients with IPF under no treatment: 10, controls: 25). Groups The prevalence of anti-SARS-CoV-2 antibodies above the suggested cut-off threshold of 1000 AU/ml was 21.9%, 40% and 72% in the IPF/treatment, IPF/no treatment and control groups, respectively.

To the best of our knowledge, this is the first study showing that patients with IPF did not mount appreciable antispike antibody responses to two doses of SARS-CoV-2 mRNA vaccine compared to general population. Importantly, impaired immunogenicity was observed irrespective of anti-fibrotic treatment further adding to the knowledge that current anti-fibrotics do not cause further immunosuppression but rather confer protection to disease acute exacerbations including those infection-mediated 8, 9 . This is report is of interest given that impaired immune response following vaccination in most diseases has not been attributed to the disease per se but to the compounds used to treat the disease. Limitations of our study include a moderate sample size that may lack generalizability, lack of serial measurements and underpowered arm of patients with IPF under no treatment. However, treatment-naive patients with IPF represent only a small minority in the era of antifibrotics and thus our sample size of non-treated IPF patients is representative of the everyday clinical practice. Moreover, we had not measured anti-SARS-CoV2 antibody levels prior to vaccination; yet, we excluded subjects with history of SARS-CoV-2 infection. Another limitation is that we used Abbott test which quantifies IgG directed against an epitope of the spike protein, but we did not investigate specific immune responses such as specific T cell responses.

We did not also record the exact time of the day that vaccination was performed to adjust for the effect of circadian rhythm. Finally, there is a small age difference between patients with IPF and controls; nonetheless, this is not statistically significant.

Our findings are of important value and should prompt national authorities to prioritize those subgroups of patients for booster doses and stringent precautions at the level of other groups of immunosuppressed individuals considering that reduced levels of anti-SARS-CoV-2 protective antibodies as well as fibrotic lung diseases per se are independent risk factors for increased mortality following SARS-CoV-2 infection 6, 14 . Additional precautionary measures should include personal protective approaches such as protective facial masks and awareness of physical distancing, that played a beneficial role in the early phases of the pandemic 15 ; yet, emergence of highly contagious variants of concerns mandate vaccination approaches to boost effectiveness and encourage fully vaccinated household contacts to offer optimal protection for at risk individuals. 

Tocilizumab improves 28-day survival in hospitalized patients with severe COVID-19: an open label, prospective study. Respiratory research

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients

Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients

Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. The New England journal of medicine

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study

Diagnosis of Idiopathic Pulmonary Fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. American journal of respiratory and critical care medicine

Acute exacerbations in the INPULSIS trials of nintedanib in idiopathic pulmonary fibrosis. The European respiratory journal

Pirfenidone Reduces Respiratory-related Hospitalizations in Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine

50-gene risk profiles in peripheral blood predict COVID-19 outcomes: A retrospective, multicenter cohort study. EBioMedicine

Lymphocyte aggregates persist and accumulate in the lungs of patients with idiopathic pulmonary fibrosis

B cell activating factor is central to bleomycin-and IL-17-mediated experimental pulmonary fibrosis

B lymphocytes are critical for lung fibrosis control and prostaglandin E2 regulation in IL-9 transgenic mice. American journal of respiratory cell and molecular biology

Immune Correlates Analysis of the mRNA-1273 COVID-19 Vaccine Efficacy Trial. medRxiv

Early COVID-19 Lockdown in Greece and IPF: A beneficial "impact" beyond any expectation