Immunity after COVID-19 vaccinations in immunocompromised patients with psoriasis
Authors: Laura Boekel
Journal: The Lancet Rheumatology (2021)

COVID-19 vaccination is paramount to reduce morbidity and mortality of SARS-CoV-2 infection, but immunosuppressive treatment prescribed to patients with immune-mediated inflammatory diseases might reduce the efficacy of COVID-19 vaccines in these patients. Studies that measure both humoral and cellular immune responses to vaccination are important to fully understand effects of immunosuppressive agents on COVID-19 vaccine immunogenicity. In The Lancet Rheumatology, Satveer Mahil and colleagues1Mahil SK Bechman K Raharja A et al.Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort study.Lancet Rheumatol. 2021; (published online Nov 9.)https://doi.org/10.1016/S2665-9913(21)00333-7Summary Full Text Full Text PDF PubMed Scopus (123) Google Scholar evaluated the development of humoral and cellular immunity against the SARS-CoV-2 spike glycoprotein in 67 patients with psoriasis and 15 healthy controls after the second dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech). All patients had well controlled psoriasis and were receiving monotherapy with methotrexate (n=14), tumour necrosis factor (TNF) inhibitors (n=19), interleukin (IL)-17 inhibitors (n=14), or IL-23 inhibitors (n=20); no patients paused their medication during the vaccination period. A key aspect of the study was that participants received the second BNT162b2 vaccine dose according to an extended interval of up to 12 weeks between doses, compared with the standard 3–4 week interval. After the second dose, patients and controls had similar titres of neutralising antibody against wild-type SARS-CoV-2 and two SARS-CoV-2 variants of concern: the alpha and delta variants. These data are reassuring and important as it is becoming increasing clear that neutralising antibody titres correlate with protection against symptomatic COVID-19,2Castro Dopico X Ols S Loré K Karlsson Hedestam GB Immunity to SARS-CoV-2 induced by infection or vaccination.J Intl Med. 2021; (published online Aug 5.)https://doi:10.1111/joim.13372Crossref Scopus (90) Google Scholar and because breakthrough infections in vaccinated individuals are mainly caused by variants of concern.3Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Annals Rheum Dis. 2021; 80: 1339-1344Crossref PubMed Scopus (206) Google Scholar Another finding of Mahil and colleagues was that total IgG antibody titres against SARS-CoV-2 were numerically lower (albeit not significantly so) in patients treated with methotrexate (median half maximal effective concentration 1751 [IQR 468–4976]) compared with controls (2749 [86–4770]; p=0·20), a trend that has also been observed in other studies.3Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Annals Rheum Dis. 2021; 80: 1339-1344Crossref PubMed Scopus (206) Google Scholar This finding might be important because initial lower antibody titres might reduce the longevity of protection against COVID-19, as antibody titres and cross-neutralising activity to variants of concern decline over time.4Pegu A O'Connell S Schmidt SD et al.Durability of mRNA-1273-induced antibodies against SARS-CoV-2 variants.bioRxiv. 2021; (published online May 16.) (preprint).https://doi:10.1101/2021.05.13.444010Google Scholar However, Frey and colleagues observed that SARS-CoV-2 antibody titres could increase up to 3 months after a second COVID-19 vaccination in a subset of patients, primarily those treated with lymphodepleting therapies (ie, azathioprine, mycophenolate, or methotrexate),5Frey S Connolly CM Chiang TP-Y et al.Antibody kinetics in patients with rheumatic diseases after SARS-CoV-2 mRNA vaccination.Lancet Rheumat. 2021; 3: e753-e754Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar which suggests that some immunosuppressive therapies might delay, rather than fundamentally impair, antibody development. As Mahil and colleagues and others3Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Annals Rheum Dis. 2021; 80: 1339-1344Crossref PubMed Scopus (206) Google Scholar measured the antibody response within the first month after a second vaccination, the lower antibody titres reported in these studies might be an underestimation of the humoral immune response generated in patients receiving methotrexate. Additionally, the magnitude of antibody response after COVID-19 vaccination differs greatly between individuals, regardless of the presence of an underlying autoimmune disease or treatment with immunosuppressive agents, and the quantity of antibodies required to prevent symptomatic infection is still unknown.2Castro Dopico X Ols S Loré K Karlsson Hedestam GB Immunity to SARS-CoV-2 induced by infection or vaccination.J Intl Med. 2021; (published online Aug 5.)https://doi:10.1111/joim.13372Crossref Scopus (90) Google Scholar Studies that assess effects of immunosuppressive agents on clinical outcome measures (ie, symptomatic COVID-19 breakthrough infections) are therefore urgently needed to establish associations between (neutralising) antibody titres and protection against COVID-19, and subsequently, to justify clinical recommendations that are thus far based only on laboratory findings (ie, temporary treatment discontinuation of methotrexate at the time of COVID-19 vaccination). Although neutralising antibodies are reported as the most important surrogate marker for the development of protection against (severe) symptomatic COVID-19,2Castro Dopico X Ols S Loré K Karlsson Hedestam GB Immunity to SARS-CoV-2 induced by infection or vaccination.J Intl Med. 2021; (published online Aug 5.)https://doi:10.1111/joim.13372Crossref Scopus (90) Google Scholar it is increasingly recognised that cellular immunity mediated by T cells also plays an important role in both short-term and long-term protection against the disease.6McMahan K Yu J Mercado NB et al.Correlates of protection against SARS-CoV-2 in rhesus macaques.Nature. 2021; 590: 630-634Crossref PubMed Scopus (748) Google Scholar, 7Painter MM Mathew D Goel RR et al.Rapid induction of antigen-specific CD4+T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination.Immunity. 2021; 54: 2133-2142Summary Full Text Full Text PDF PubMed Scopus (290) Google Scholar However, due to the functional heterogeneity of T cells, the role of cellular immunity, especially in patients treated with immunosuppressive therapy, is still incompletely understood. Mahil and colleagues sought to improve on this knowledge gap by comparing T-cell responses after the first and second dose of the BNT162b2 vaccine in their cohort of patients with psoriasis treated with methotrexate or biologics and healthy controls. They assessed both T helper (Th)1 cell responses (based on production of interferon-γ and IL-2) and T follicular helper (Tfh) cell responses (IL-21), which is unique compared with other studies that mostly measured only Th1 cell function. These data are an important contribution to the literature because both Th1 and Tfh cells have been shown to contribute to protection against COVID-19. Th1 cells support and enhance cytotoxic (CD8+) T cells that aid in protection against COVID-19 by killing infected cells,6McMahan K Yu J Mercado NB et al.Correlates of protection against SARS-CoV-2 in rhesus macaques.Nature. 2021; 590: 630-634Crossref PubMed Scopus (748) Google Scholar and Tfh cells coordinate and sustain humoral immunity.7Painter MM Mathew D Goel RR et al.Rapid induction of antigen-specific CD4+T cells is associated with coordinated humoral and cellular immunity to SARS-CoV-2 mRNA vaccination.Immunity. 2021; 54: 2133-2142Summary Full Text Full Text PDF PubMed Scopus (290) Google Scholar Mahil and colleagues observed that numerical levels of total T-cell responses and individual Th1 and Tfh responses did not significantly differ between patients and controls after both the first and second vaccination, whereas a significant increase of T-cell responses after a second vaccine dose occurred only in controls. Absence of boosting of cellular immunity has been shown previously, specifically for patients receiving methotrexate,3Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Annals Rheum Dis. 2021; 80: 1339-1344Crossref PubMed Scopus (206) Google Scholar and at a larger scale for patients with immune-mediated inflammatory diseases who received various immunosuppressive agents.8Kearns P Siebert S Willicombe M et al.Examining the immunological effects of COVID-19 vaccination in patients with conditions potentially leading to diminished immune response capacity—the OCTAVE Trial.SSRN. 2021; (published online Aug 23.) (preprint).https://doi:10.2139/ssrn.3910058Crossref Google Scholar Additionally, Picchianti-Diamanti and colleagues9Picchianti-Diamanti A Aiello A Laganà B et al.Immunosuppressive therapies differently modulate humoral- and t-cell-specific responses to COVID-19 mRNA vaccine in rheumatoid arthritis patients.Front Immunol. 2021; 12740249Crossref Scopus (71) Google Scholar reported that patients treated with IL-6 inhibitors or abatacept had diminished T-cell responses compared with healthy controls after two doses of BNT162b2. Therefore, the findings of Mahil and colleagues and others3Haberman RH Herati R Simon D et al.Methotrexate hampers immunogenicity to BNT162b2 mRNA COVID-19 vaccine in immune-mediated inflammatory disease.Annals Rheum Dis. 2021; 80: 1339-1344Crossref PubMed Scopus (206) Google Scholar, 9Picchianti-Diamanti A Aiello A Laganà B et al.Immunosuppressive therapies differently modulate humoral- and t-cell-specific responses to COVID-19 mRNA vaccine in rheumatoid arthritis patients.Front Immunol. 2021; 12740249Crossref Scopus (71) Google Scholar suggest that the longevity of protection against COVID-19 might be impaired in patients treated with targeted immunosuppression, given the fundamental role of T cells in sustaining and promoting both cellular and humoral immunity. However, the exact mechanisms that underly the reported immunoinhibitory effects of individual immunosuppressive agents, especially TNF, IL-23, and IL-17 inhibitors, and how the reported laboratory findings translate to clinical outcome measures, remain unclear and warrant further research. In conclusion, the findings of Mahil and colleagues on antibody development after COVID-19 vaccination in patients treated with methotrexate or targeted immunosuppressive agents are reassuring, whereas their observation of absence of boosting of T-cell responses might indicate that durable cellular and humoral immunity is impaired in some patients receiving these drugs. Studies with clinical outcome measures in immunocompromised patients are needed and are important to warrant clinical decisions regarding additional booster vaccinations or temporary treatment discontinuation at the time of vaccination. I declare no competing interests. Humoral and cellular immunogenicity to a second dose of COVID-19 vaccine BNT162b2 in people receiving methotrexate or targeted immunosuppression: a longitudinal cohort studyFunctional humoral immunity (ie, neutralising antibody responses) at 14 days following a second dose of BNT162b2 was not impaired by methotrexate or targeted biologics. A proportion of patients on immunosuppression did not have detectable T-cell responses following the second dose. The longevity of vaccine-elicited antibody responses is unknown in this population. Full-Text PDF Open Access