key: cord-0944889-u9s2cy12
authors: Kim, Alfred H J; Sparks, Jeffrey A
title: Immunosuppression and SARS-CoV-2 breakthrough infections
date: 2022-04-29
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(22)00127-8
sha: 407f27c452f8adf676a43a898b838f0fb070b0af
doc_id: 944889
cord_uid: u9s2cy12

nan

Within a year of the introduction of vaccines against SARS-CoV-2, global research efforts had identified that subsets of patients with immune-mediated inflammatory diseases have suboptimal humoral responses after vaccination. Specifically, B cell-depleting therapies, mycophenolate mofetil, and glucocorticoids were found to confer the greatest risk of poor humoral immunity, 1,2 suggesting that patients on these therapies will have the highest risk and severity of breakthrough infections.

Data has emerged confirming these suspicions in patients with immune-mediated inflammatory diseases. The US National COVID Cohort Collaborative consortium found that those who were fully vaccinated on immunosuppression had a 1·25-2·18 times increased risk of breakthrough infection with SARS-CoV-2 after vacciantion. 3 Several case series identified patients taking B cell-depleting therapies, mycophenolate mofetil, methotrexate, and glucocorticoids and those with interstitial lung disease as comprising a very high proportion of those breakthrough cases. [4] [5] [6] Furthermore, the absence of anti-spike antibodies 4-6 weeks after the second dose of COVID-19 vaccine is associated with a 3·6 times increase in breakthrough infection compared with presence of robust humoral responses. 7 Thus, risk of breakthrough infection after COVID-19 vaccination among people with immune-mediated inflammatory diseases could correlate with poor antibody responses from specific immunosuppressive medications.

In The Lancet Rheumatology, Laura Boekel and colleaguges 8 Boekel and colleagues observed increased crude incidence rates of breakthrough infections among the immunosuppressed patients with immunemediated inflammatory diseases (8·0 per 1000 personmonths) and non-immunosuppressed patients with immune-mediated inflammatory diseases (9·2 per 1000 person-months) compared with healthy controls (6·6 per 1000 person-months). However, in multivariable analyses, no association was seen between immunosuppression and risk of breakthrough infection when compared with the combined controls (odds ratio [OR] 0·88 [95% CI 0·66-1·18). 24 (5%) of 437 participants on B cell-depleting therapies, mycophenolate mofetil, or S1P receptor modulator therapy had a breakthrough infection, compared with 37 (4%) of 992 patients using methotrexate and 49 (5%) of 929 using TNF inhibitors. Interestingly, in post-hoc analyses, specific immunosuppressive class was not associated with risk of breakthrough infection, although the study might have been too small to detect small differences. However, participants with more severe outcomes of breakthrough infections (ie, those who were admitted to hospital vs ambulatory care only) were on average older, more likely to be male, and more frequently had obesity, chronic pulmonary disease, diabetes, and cardiovascular disease. Most of the breakthrough infections occurred more than 3 months after vaccination, suggesting either waning immunity or differences in viral epidemiology related to surges in cases. Seropositive participants had reduced odds of breakthrough infections (OR 0·58 [95% CI 0·34-0·98]), concentrated in those with the highest anti-receptor binding domain titres (OR 0·57 [0·28-1·16]); although this was not significant. Finally, those with hybrid immunity (ie, previous SARS-CoV-2 infection before first dose of vaccine) had a lower odds of breakthrough infection (OR 0·34 [0·18-0·56]) than did those without this immunity. Thus, productive humoral responses appear to confer protection from breakthrough infection. This is the largest prospective study to investigate clinical outcomes related to breakthrough infection and was adequately sized to investigate specific immunosuppressive medications. Few severe outcomes occurred, and these were more common in the immunosuppressed participants with immune-mediated inflammatory diseases, particularly among those on B cell-depleting therapies. These patients remain susceptible to poor outcomes even after vaccination, 9 so strategies such as pre-exposure prophylaxis or additional vaccine doses should be strongly considered for this population.

Although there were some signals for breakthrough infection in specific patient groups (eg, seronegative status and some comorbidities), the findings of Boekel and colleagues are reassuring to patients who are immunosuppressed. After vaccination, overall rates and clinical severity of breakthrough infections among patients with immune-mediated inflammatory diseases was similar to among healthy controls. How subsequent variants, such as omicron (B.1.1.529) that might confer reduced vaccine effectiveness, will affect infection rates remains unknown. Patients with immune-mediated diseases who are immunosuppressed might have accelerated waning immunity, placing them at risk over time after vaccine receipt. Therefore, quantifying the effect of additional vaccine doses on breakthrough infection with contemporary circulating variants is needed. Finally, although the findings here offer some evidence that humoral responses confer clinical protection, the specific threshold that offers protection remains unclear. Those with absent humoral responses remain at risk for breakthrough infection, but we continue to caution clinicians to not overinterpret antispike antibody levels as a surrogate of protection at the individual level.

AHJK reports research support from GlaxoSmithKline and Foghorn Therapeutics, and consultancy fees from Alexion Pharmaceuticals, AstraZeneca, Aurinia Pharmaceuticals, Exagen Diagnostics, GlaxoSmithKline, and Pfizer unrelated to this work. JAS reports consultancy fees from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, and Gilead unrelated to this work.

akim@wustl.edu; @alhkim

USA (AHJK); Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital

Antibody development after COVID-19 vaccination in patients with autoimmune diseases in the Netherlands: a substudy of data from two prospective cohort studies

Effect of immunosuppression on the immunogenicity of mRNA vaccines to SARS-CoV-2: a prospective cohort study

Association between immune dysfunction and COVID-19 breakthrough infection after SARS-CoV-2 vaccination in the US

Clinical characteristics and outcomes of COVID-19 breakthrough infections among vaccinated patients with systemic autoimmune rheumatic diseases

SARS-CoV-2 infection after vaccination in patients with inflammatory rheumatic and musculoskeletal diseases

SARS-CoV-2 breakthrough infections among vaccinated individuals with rheumatic disease: results from the COVID-19 Global Rheumatology Alliance provider registry

Postvaccination antibody titres predict protection against COVID-19 in patients with autoimmune diseases: survival analysis in a prospective cohort

Breakthrough SARS-CoV-2 infections with the delta (B.1.617.2) variant in vaccinated patients with immunemediated inflammatory diseases using immunosuppressants: a substudy of two prospective cohort studies

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry