Infliximab as a potential treatment for COVID-19.

INTRODUCTION: As the third year of the SARS-CoV-2 pandemic approaches, COVID-19 continues to cause substantial morbidity and mortality due to waning vaccine efficacy and the emergence of new, highly contagious subvariants and better therapies are urgently needed. AREAS COVERED: Hospitalized patients who develop hypoxia due to SARS-CoV-2 infection are typically treated with an antiviral agent, remdesivir, as well as an immunomodulator, dexamethasone, but mortality rates for severe COVID-19 remain unacceptably high. Mounting evidence suggests a second immunomodulator added to the standard of care may benefit some hospitalized patients; however, the optimal treatment remains controversial. EXPERT OPINION: On 2 June 2022, the United States National Institutes of Health reported results from a large, randomized placebo-controlled clinical trial known as ACTIV-1. The study found a mortality benefit and substantially improved clinical status for adults hospitalized with COVID-19 who were treated with infliximab, a chimeric monoclonal antibody that binds to and inhibits TNF-α, and is widely used to treat a variety of autoimmune conditions, including rheumatoid arthritis, Crohn's disease, and ulcerative colitis. This manuscript reviews what is known about infliximab as an immunomodulator for patients with COVID-19 and explores how this agent may be used in the future to address the SARS-CoV-2 pandemic.

Geographic disparities in COVID-19 case rates are not reflected in seropositivity rates using a neighborhood survey in Chicago.

To date, COVID-19 case rates are disproportionately higher in Black and Latinx communities across the US, leading to more hospitalizations, and deaths in those communities. These differences in case rates are evident in comparisons of Chicago neighborhoods with differing race and/or ethnicities of their residents. Disparities could be due to neighborhoods with more adverse health outcomes associated with poverty and other social determinants of health experiencing higher prevalence of SARS-CoV-2 infection or due to greater morbidity and mortality resulting from equivalent SARS-CoV-2 infection prevalence. We surveyed five pairs of adjacent ZIP codes in Chicago with disparate COVID-19 case rates for highly specific and quantitative serologic evidence of any prior infection by SARS-CoV-2 to compare with their disparate COVID-19 case rates. Dried blood spot samples were self-collected at home by internet-recruited participants in summer 2020, shortly after Chicago's first wave of the COVID-19 pandemic. Pairs of neighboring ZIP codes with very different COVID-19 case rates had similar seropositivity rates for anti-SARS-CoV-2 receptor binding domain IgG antibodies. Overall, these findings of comparable exposure to SARS-CoV-2 across neighborhoods with very disparate COVID-19 case rates are consistent with social determinants of health, and the co-morbidities related to them, driving differences in COVID-19 rates across neighborhoods.

mRNA intramuscular vaccination produces a robust IgG antibody response in advanced neuromuscular disease.

SARS-CoV-2 vaccines protect against symptomatic and severe COVID-19. The BNT162b2/Pfizer and mRNA-1273/Moderna vaccines represent new vaccine technology relying on administration of mRNA encoding SARS-CoV-2 viral spike protein encased in lipid nanoparticles. The vaccines are administered as two doses into muscle, which elicits a strong response, typically within 14 days after the second dose. Neuromuscular diseases are characterized by the progressive loss of muscle and are often treated with chronic glucocorticoid steroids, both of which may contribute to a blunted immune response to vaccination. Here, we measured IgG antibody content and neutralizing antibody response after mRNA COVID-19 vaccination in non-ambulatory neuromuscular disease patients. After two doses of mRNA COVID-19 vaccine, median anti-receptor binding domain IgG and percent surrogate viral neutralization in non-ambulatory neuromuscular disease samples were significantly elevated similar to healthy vaccinated controls. As in healthy controls, COVID-19 vaccines produce greater antibody levels compared to those with a history of outpatient COVID-19 infection. This data documents that non-ambulatory neuromuscular disease patients respond well to two doses of mRNA COVID-19 vaccine despite low muscle mass and even chronic steroid use.

Anti-latent TGFß binding protein 4 antibody improves muscle function and reduces muscle fibrosis in muscular dystrophy.

Duchenne muscular dystrophy, like other muscular dystrophies, is a progressive disorder hallmarked by muscle degeneration, inflammation, and fibrosis. Latent transforming growth factor ß (TGFß) binding protein 4 (LTBP4) is an extracellular matrix protein found in muscle. LTBP4 sequesters and inhibits a precursor form of TGFß. LTBP4 was originally identified from a genome-wide search for genetic modifiers of muscular dystrophy in mice, where there are two different alleles. The protective form of LTBP4, which contains an insertion of 12 amino acids in the protein's hinge region, was linked to increased sequestration of latent TGFß, enhanced muscle membrane stability, and reduced muscle fibrosis. The deleterious form of LTBP4 protein, lacking 12 amino acids, was more susceptible to proteolysis and promoted release of latent TGF-ß, and together, these data underscored the functional role of LTBP4's hinge. Here, we generated a monoclonal human anti-LTBP4 antibody directed toward LTBP4's hinge region. In vitro, anti-LTBP4 bound LTBP4 protein and reduced LTBP4 proteolytic cleavage. In isolated myofibers, the LTBP4 antibody stabilized the sarcolemma from injury. In vivo, anti-LTBP4 treatment of dystrophic mice protected muscle against force loss induced by eccentric contraction. Anti-LTBP4 treatment also reduced muscle fibrosis and enhanced muscle force production, including in the diaphragm muscle, where respiratory function was improved. Moreover, the anti-LTBP4 in combination with prednisone, a standard of care for Duchenne muscular dystrophy, further enhanced muscle function and protected against injury in mdx mice. These data demonstrate the potential of anti-LTBP4 antibodies to treat muscular dystrophy.

Cohabitation With a Known Coronavirus Disease 2019 Case Is Associated With Greater Antibody Concentration and Symptom Severity in a Community-Based Sample of Seropositive Adults.

In a community-based sample of seropositive adults (n = 1101), we found that seropositive individuals who lived with a known coronavirus disease 2019 (COVID-19) case exhibited higher blood anti-severe acute respiratory syndrome coronavirus 2 spike receptor-binding domain immunoglobulin G concentrations and greater symptom severity compared to seropositive individuals who did not live with a known COVID-19 case.

A surrogate virus neutralization test to quantify antibody-mediated inhibition of SARS-CoV-2 in finger stick dried blood spot samples.

The spike protein of SARS-CoV-2 engages the human angiotensin-converting enzyme 2 (ACE2) receptor to enter host cells, and neutralizing antibodies are effective at blocking this interaction to prevent infection. Widespread application of this important marker of protective immunity is limited by logistical and technical challenges associated with live virus methods and venous blood collection. To address this gap, we validated an immunoassay-based method for quantifying neutralization of the spike-ACE2 interaction in a single drop of capillary whole blood, collected on filter paper as a dried blood spot (DBS) sample. Samples are eluted overnight and incubated in the presence of spike antigen and ACE2 in a 96-well solid phase plate. Competitive immunoassay with electrochemiluminescent label is used to quantify neutralizing activity. The following measures of assay performance were evaluated: dilution series of confirmed positive and negative samples, agreement with results from matched DBS-serum samples, analysis of results from DBS samples with known COVID-19 status, and precision (intra-assay percent coefficient of variation; %CV) and reliability (inter-assay; %CV). Dilution series produced the expected pattern of dose-response. Agreement between results from serum and DBS samples was high, with concordance correlation = 0.991. Analysis of three control samples across the measurement range indicated acceptable levels of precision and reliability. Median % surrogate neutralization was 46.9 for PCR confirmed convalescent COVID-19 samples and 0.1 for negative samples. Large-scale testing is important for quantifying neutralizing antibodies that can provide protection against COVID-19 in order to estimate the level of immunity in the general population. DBS provides a minimally-invasive, low cost alternative to venous blood collection, and this scalable immunoassay-based method for quantifying inhibition of the spike-ACE2 interaction can be used as a surrogate for virus-based assays to expand testing across a wide range of settings and populations.

Patterns and persistence of SARS-CoV-2 IgG antibodies in Chicago to monitor COVID-19 exposure.

BACKGROUNDEstimates of seroprevalence to SARS-CoV-2 vary widely and may influence vaccination response. We ascertained IgG levels across a single US metropolitan site, Chicago, from June 2020 through December 2020.METHODSParticipants (n = 7935) were recruited through electronic advertising and received materials for a self-sampled dried-blood spot assay through the mail or a minimal contact in-person method. IgG against the receptor-binding domain of SARS-CoV-2 was measured using an established highly sensitive and highly specific assay.RESULTSOverall seroprevalence was 17.9%, with no significant difference between method of contact. Only 2.5% of participants reported having had a diagnosis of COVID-19 based on virus detection, consistent with a 7-fold greater exposure to SARS-CoV-2 measured by serology than that detected by viral testing. The range of IgG level observed in seropositive participants from this community survey overlapped with the range of IgG levels associated with COVID-19 cases having a documented positive PCR test. From a subset of those who participated in repeat testing, half of seropositive individuals retained detectable antibodies for 3 to 4 months.CONCLUSIONQuantitative IgG measurements with a highly specific and sensitive assay indicated more widespread exposure to SARS-CoV-2 than observed by viral testing. The range of IgG concentrations produced from these asymptomatic exposures was similar to IgG levels occurring after documented nonhospitalized COVID-19, which were considerably lower than those produced from hospitalized COVID-19 cases. The differing ranges of IgG response, coupled with the rate of decay of antibodies, may influence response to subsequent viral exposure and vaccine.FundingNational Science Foundation grant 2035114, NIH grant 3UL1TR001422-06S4, NIH National Center for Advancing Translational Sciences grants UL1 TR001422 and UL1 TR002389, Dixon Family Foundation, Northwestern University Cancer Center (NIH grant P30 CA060553), and Walder Foundation's Chicago Coronavirus Assessment Network.

Exposure to SARS-CoV-2 within the household is associated with greater symptom severity and stronger antibody responses in a community-based sample of seropositive adults.

Magnitude of SARS-CoV-2 virus exposure may contribute to symptom severity. In a sample of seropositive adults (n=1101), we found that individuals who lived with a known COVID-19 case exhibited greater symptom severity and IgG concentrations compared to individuals who were seropositive but did not live with a known case (P<0.0001).

Patterns and persistence of SARS-CoV-2 IgG antibodies in Chicago to monitor COVID-19 exposure.

Background: Estimates of seroprevalence to SARS-CoV-2 vary widely and may influence vaccination response. We ascertained IgG levels across a single US metropolitan site, Chicago, from June 2020 through December 2020. Methods: Participants (n=7935) were recruited through electronic advertising and received materials for a self-sampled dried blood spot assay through the mail or a minimal contact in person method. IgG to the receptor binding domain of SARS-CoV-2 was measured using an established highly sensitive and highly specific assay. Results: Overall seroprevalence was 17.9%, with no significant difference between method of contact. Only 2.5% of participants reported having had a diagnosis of COVID-19 based on virus detection, consistent with a 7-fold greater exposure to SARS-CoV-2 measured by serology than detected by viral testing. The range of IgG level observed in seropositive participants from this community survey overlapped with the range of IgG levels associated with COVID-19 cases having a documented positive PCR positive test. From a subset of those who participated in repeat testing, half of seropositive individuals retained detectable antibodies for 3-4 months. Conclusions: Quantitative IgG measurements with a highly specific and sensitive assay indicate more widespread exposure to SARS-CoV-2 than observed by viral testing. The range of IgG concentration produced from these asymptomatic exposures is similar to IgG levels occurring after documented non-hospitalized COVID-19, which is considerably lower than that produced from hospitalized COVID-19 cases. The differing ranges of IgG response, coupled with the rate of decay of antibodies, may influence response to subsequent viral exposure and vaccine.