key: cord-0964501-4igjmi3q
authors: Liao, Shu-Yi; Gerber, Anthony N.; Zelarney, Pearlanne; Make, Barry; Wechsler, Michael E.
title: Impaired SARS-CoV-2 mRNA vaccine antibody response in chronic medical conditions: a real-world analysis
date: 2022-01-10
journal: Chest
DOI: 10.1016/j.chest.2021.12.654
sha: d0b00ef033dc9561e34ecf05fe7ece3c1e4f51a9
doc_id: 964501
cord_uid: 4igjmi3q

nan

While vaccines against COVID-19 have led to dramatic decreases in COVID cases and mortality in the US, the majority of patients in the vaccine trials did not have chronic underlying diseases -patients at the highest risk of morbidity and mortality due to COVID-19 1 . Host factors in these high-risk patients may result in reduced responsiveness to vaccines and "breakthrough" COVID cases. As precautionary masking and distancing measures are lifted, individuals who fail to mount an immune response to the vaccines may change their protective behavior without being aware of their potential vulnerability. As of October 12, 2021, there have been at least 31,895 individuals with SARS-CoV-2 breakthrough infections who were hospitalized or died in the US 2,3 . A recent report showed that 39 fully vaccinated health care workers had breakthrough infections and neutralizing antibody titers were lower during the peri-infection period than those in matched uninfected controls 4 . This aligns with data indicating a strong correlation between antibody titers and vaccine efficacy 5 . While a recent study found 46% of transplant patients had no antibody response after two doses of mRNA vaccines 6 , no studies to date have investigated the effects of underlying chronic medical conditions on antibody response. This study used realworld data to evaluate risk factors of impaired antibody response to SARS-CoV-2 mRNA vaccines in individuals with chronic medical conditions evaluated in a respiratory specialty clinic.

Methods: We used National Jewish Health (NJH) electronic medical records to identify patients who received 2 doses of SARS-CoV-2 mRNA vaccines between December 16, 2020-July 24, 2021, and had a spike IgG antibody results at least 14 days after the second dose.

These tests were ordered by individual physicians to evaluate vaccine immunity based on patient request or significant chronic disease. Two different ELISA tests (EUROIMMUN, New Jersey) detecting IgG to spike protein recombinant S1 domain, a surrogate for neutralizing antibodies to COVID vaccinewere used in our clinical laboratory: 1) Anti-SARS-CoV-2 ELISA (qualitative) with the ratio of sample optical density (OD) to calibration OD provided with the kit J o u r n a l P r e -p r o o f was interpreted as positive (≥0.8) or negative (<0.8) prior to July, 2021, and 2) Anti-SARS-CoV-2 QuantiVac ELISA (semi-quantitative) with the relative unit/mL (RU/mL) provided with the kit was interpreted as positive (≥0.8) or negative (<0.8) after July 1, 2021. A negative IgG spike protein from ELISA has been correlated with a lack of neutralizing antibody; this was validated in a recent comparative study 7 and is widely used 6 . Medical conditions were based on physician diagnosis; medications were defined as in a previous study 8 . A multivariate logistic regression model was used to identify clinical characteristics associated with a negative spike IgG protein adjusted for all variables listed in Figure. To minimize confounding by indication, given that patients prescribed medications are more likely to have underlying comorbidities associated with impaired antibody response, overlap propensity score weighting 9 was used. The propensity score was interpreted as the likelihood of receiving the medication of interest. The propensity score was estimated from a multivariate logistic regression model using age, gender, comorbidities, and other medication classes mentioned (except for the medication of interest).

Each patient's weight was the likelihood of being assigned to the opposite medication group.

The propensity score weighting method was then applied to test the association between the medication of interest and impaired antibody response. We did a post hoc power analysis for interstitial lung disease (ILD) as a risk factor for lack of antibody response using G*Power 3.1 10 .

The outcome is a positive antibody response, and the testing variable is ILD. The parameter (Table) . BNT162b2 (Pfizer-BioNTech) was administered to 64% of the patients, and 36% received mRNA-1273 (Moderna). At a mean (standard deviation) of 96 (58) days, range 14-237 days, after dose 2, 21% had no antibody detected. Negative antibody responses were found in 24% of patients receiving the BNT162b2 

Discussion: It is critical to recognize that vaccination may not necessarily confer immunity, at least as assessed by commercially available spike protein antibody tests, in patients with certain chronic medical conditions and certain medication use. In our patients (81% with chronic pulmonary diseases), 21% had no antibody detected > 14 days after the second dose of mRNA vaccines. While these data show that many vaccinated individuals may be at risk for impaired antibody production, we found that ILD (independent of medication use), CHF, and rituximab use are independent risk factors for impaired antibody response. Our study is the first one to identify ILD as an independent risk factor. More studies are needed to identify other potential factors. One possibility is that fibrosis, a common complication seen in ILD, is regulated by interactions between T Cells and cytokines released by relevant immunocompetent cells; ILD patients may have dysregulation or imbalance of this immunoprocess 11 . Reduced influenza vaccine antibody titers have been observed in CHF 12 , which may be due to sympathetic activation in heart failure leading to inhibition of antibody production. For the medications, the effect of rituximab use is consistent with a previous study 13 . In our study, systemic corticosteroid use was not associated with impaired antibody response after controlling for concomitant immunosuppressant use and comorbidities. This finding is different from other recent studies, which showed reduced antibody responses in corticosteroid users; however, the failure to fully control for contributions of potential confounders such as disease-specific factors or concomitant immunosuppressant use was an acknowledged limitation of these studies. 14,15 . While the exact antibody level conferring protection against SARS-CoV-2 is unknown and there are other B cell and T cell-mediated factors involved in protection 16 , a recent study showed that among fully vaccinated health care workers, the occurrence of breakthrough COVID-19 infection was correlated with the titer of antibodies 4 . Limitations of our study include the potential for bias as only those patients specifically chosen by physicians had antibody levels drawn, and only one part of vaccine immune response (i.e., antibodies) was analyzed as opposed to other components such as T cell immunity. We have observed four breakthrough COVID-19 J o u r n a l P r e -p r o o f infections in our study cohort, with a higher rate of 2/77 (2.6%) in negative vs. 2/283 (0.7%) in the positive antibody responses group. However, it is hard to draw any meaningful statistical inference due to low breakthrough rate and relatively small sample size. Our study raises concerns that SARS-CoV-2 vaccination may not result in protective immunity in patients with certain chronic medical conditions. Further studies of immunologic response (including neutralizing antibodies and other measures of B cell and T cell response) and protection in vulnerable populations are needed to define ongoing COVID-19 risk and inform recommendations regarding additional vaccination (i.e., boosters) and behaviors to mitigate risk.

Such studies are particularly important with the predicted seasonal and variant-driven spikes in SARS-CoV-2 infection rates. We are analyzing B and T cell responses to SARS-CoV-2 in our patients and hope this report will stimulate others to further investigate immune responses in patients with chronic medical conditions.

COPD and the risk of poor outcomes in COVID-19: A systematic review and meta-analysis

Hospitalized or fatal COVID-19 vaccine breakthrough cases reported to CDC as of

Breakthrough Covid cases: Data shows how many vaccinated Americans have tested positive

Covid-19 Breakthrough Infections in Vaccinated Health Care Workers

Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

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

Comparative Performance of Five Commercially Available Serologic Assays To Detect Antibodies to SARS-CoV-2 and Identify Individuals with High Neutralizing Titers

Association of inhaled and systemic corticosteroid use with Coronavirus Disease 2019 (COVID-19) test positivity in patients with chronic pulmonary diseases

Overlap Weighting: A Propensity Score Method That Mimics Attributes of a Randomized Clinical Trial

Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses

Immune mechanisms in interstitial lung diseases

Lack of persistence of influenza vaccine antibody titers in patients with heart failure

but not other antirheumatic therapies, is associated with impaired serological response to SARS-CoV-2 vaccination in patients with rheumatic diseases

Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study

High antibody response to two-dose SARS-CoV-2 messenger RNA vaccination in patients with rheumatic and musculoskeletal diseases

The study was approved by the National Jewish Health Institutional Review Board. The authors would like to thank Joy Zimmer for her help with the electronic health record data query.

 (46) 97 (61) a A negative IgG spike protein from ELISA has been correlated with a lack of neutralizing antibody; this was validated in a recent comparative study 7 and is widely used 6