COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection against symptomatic infection after vaccination with mRNA-1273. We fit conditional logistic regression (CLR) models stratified on residential county and calendar date of SARS-CoV-2 PCR testing to assess the association between the time elapsed since vaccination and the odds of symptomatic infection, adjusted for several covariates. There were 2364 symptomatic individuals who had a positive SARS-CoV-2 PCR test after full vaccination with mRNA-1273 (“cases”) and 12949 symptomatic individuals who contributed 15087 negative tests after full vaccination (“controls”). The odds of symptomatic infection were significantly higher 250 days after full vaccination compared to the date of full vaccination (Odds Ratio [OR]: 2.47, 95% confidence interval [CI]: 1.19–5.13). The odds of non-COVID-19 associated hospitalization and non-COVID-19 pneumonia (negative control outcomes) remained relatively stable over the same time interval (Day 250 ORNon-COVID Hospitalization: 0.68, 95% CI: 0.47–1.0; Day 250 ORNon-COVID Pneumonia: 1.11, 95% CI: 0.24–5.2). The odds of symptomatic infection remained significantly lower almost 300 days after the first mRNA-1273 dose as compared to 4 days after the first dose, when immune protection approximates the unvaccinated state (OR: 0.26, 95% CI: 0.17–0.39). Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. In summary, mRNA-1273 robustly protected against symptomatic SARS-CoV-2 infection at least eight months after full vaccination, but the degree of protection waned over this time period.

Durability analysis of the highly effective mRNA-1273 vaccine against COVID-19

The emergence of a heavily mutated SARS-CoV-2 variant (B.1.1.529, Omicron) and it’s spread to 6 continents within a week of initial discovery has set off a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its shared or distinctive clinical phenotypes with other SARS-CoV-2 variants. We compared the mutations of Omicron with prior variants of concern (Alpha, Beta, Gamma, Delta), variants of interest (Lambda, Mu, Eta, Iota and Kappa), and all 1523 SARS-CoV-2 lineages constituting 5.4 million SARS-CoV-2 genomes. Omicron’s Spike protein has 26 amino acid mutations (23 substitutions, two deletions and one insertion) that are distinct compared to other variants of concern. Whereas the substitution and deletion mutations have appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) has not been previously observed in any SARS-CoV-2 lineage other than Omicron. The nucleotide sequence encoding for ins214EPE could have been acquired by template switching involving the genomes of other viruses that infect the same host cells as SARS-CoV-2 or the human transcriptome of host cells infected with SARS-CoV-2. For instance, given recent clinical reports of co-infections in COVID-19 patients with seasonal coronaviruses (e.g. HCoV-229E), single cell RNA-sequencing data showing co-expression of the SARS-CoV-2 and HCoV-229E entry receptors (ACE2 and ANPEP) in respiratory and gastrointestinal cells, and HCoV genomes harboring sequences homologous to the nucleotide sequence that encodes ins214EPE, it is plausible that the Omicron insertion could have evolved in a co-infected individual. There is a need to understand the function of the Omicron insertion and whether human host cells are being exploited by SARS-CoV-2 as an ‘evolutionary sandbox’ for host-virus and inter-viral genomic interplay.

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Omicron variant of SARS-CoV-2 harbors a unique insertion mutation of putative viral or human genomic origin

Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to a MYH6 peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.

Genetic alteration of human MYH6 is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest

Understanding temporal dynamics of COVID-19 symptoms could provide fine-grained resolution to guide clinical decision-making. Here, we use deep neural networks over an institution-wide platform for the augmented curation of clinical notes from 77,167 patients subjected to COVID-19 PCR testing. By contrasting Electronic Health Record (EHR)-derived symptoms of COVID-19-positive (COVIDpos; n = 2,317) versus COVID-19-negative (COVIDneg; n = 74,850) patients for the week preceding the PCR testing date, we identify anosmia/dysgeusia (27.1-fold), fever/chills (2.6-fold), respiratory difficulty (2.2-fold), cough (2.2-fold), myalgia/arthralgia (2-fold), and diarrhea (1.4-fold) as significantly amplified in COVIDpos over COVIDneg patients. The combination of cough and fever/chills has 4.2-fold amplification in COVIDpos patients during the week prior to PCR testing, in addition to anosmia/dysgeusia, constitutes the earliest EHR-derived signature of COVID-19. This study introduces an Augmented Intelligence platform for the real-time synthesis of institutional biomedical knowledge. The platform holds tremendous potential for scaling up curation throughput, thus enabling EHR-powered early disease diagnosis.

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Augmented curation of clinical notes from a massive EHR system reveals symptoms of impending COVID-19 diagnosis

Understanding the relationships between pre-existing conditions and complications of COVID-19 infection is critical to identifying which patients will develop severe disease. Here, we leverage 1.1 million clinical notes from 1,903 hospitalized COVID-19 patients and deep neural network models to characterize associations between 21 pre-existing conditions and the development of 20 complications (e.g. respiratory, cardiovascular, renal, and hematologic) of COVID-19 infection throughout the course of infection (i.e. 0-30 days, 31-60 days, and 61-90 days). Pleural effusion was the most frequent complication of early COVID-19 infection (23% of 383 complications) followed by cardiac arrhythmia (12% of 383 complications). Notably, hypertension was the most significant risk factor associated with 10 different complications including acute respiratory distress syndrome, cardiac arrhythmia and anemia. Furthermore, novel associations between cancer (risk ratio: 3, p=0.02) or immunosuppression (risk ratio: 4.3, p=0.04) with early-onset heart failure have also been identified. Onset of new complications after 30 days is rare and most commonly involves pleural effusion (31-60 days: 24% of 45 patients, 61-90 days: 25% of 36 patients). Overall, the associations between pre-COVID conditions and COVID-associated complications presented here may form the basis for the development of risk assessment scores to guide clinical care pathways.

Times of India · STAT News · Becker's Health IT

Mapping each pre-existing condition’s association to short-term and long-term COVID-19 complications

As of November 29, 2021, booster vaccination against SARS-CoV-2 infection has been recommended for all individuals aged 18 years and older in the United States. A key reason for this recommendation is the expectation that a booster vaccine dose can alleviate observed waning of vaccine effectiveness. Although initial reports of booster effectiveness have been positive, the level of protection from booster vaccination is unclear. We conducted two studies to assess the impact of booster vaccination, with BNT162b2 or mRNA-1273, on the incidence of SARS-CoV-2 infection between August and December 2021. We first compared SARS-CoV-2 infection incidence in cohorts of 3-dose vaccine recipients to incidence in matched cohorts of 2-dose vaccine recipients (cohort size = 24,539 for BNT162b2 and 14,004 for mRNA-1273). Additionally, we applied a test-negative study design to compare the level of protection against symptomatic infection in 3-dose recipients to that observed in recent 2-dose primary vaccine series recipients. 3-dose recipients experienced a significantly lower incidence rate of SARS-CoV-2 infection than the matched 2-dose cohorts (BNT162b2 Incidence Rate Ratio: 0.11, 95% CI: 0.09–0.13 and mRNA-1273 IRR: 0.11, 95% CI: 0.08–0.15). Results from the test-negative study showed the third vaccine dose mitigated waning of vaccine effectiveness, with the risk of symptomatic infection in 3-dose recipients being comparable to that observed 7–73 days after the primary vaccine series. These results show that 3-dose vaccine regimens with BNT162b2 or mRNA-1273 are effective at reducing SARS-CoV-2 infection and support the widespread administration of booster vaccine doses.

As of November 29, 2021, booster vaccination against SARS-CoV-2 infection has been recommended for all individuals aged 18 years and older in the United States. A key reason for this recommendation is the expectation that a booster vaccine dose can alleviate observed waning of vaccine effectiveness. Although initial reports of booster effectiveness have been positive, the level of protection from booster vaccination is unclear. We conducted two studies to assess the impact of booster vaccination, with BNT162b2 or mRNA-1273, on the incidence of SARS-CoV-2 infection between August and December 2021. We first compared SARS-CoV-2 infection incidence in cohorts of 3-dose vaccine recipients to incidence in matched cohorts of 2-dose vaccine recipients (cohort size = 24,539 for BNT162b2 and 14,004 for mRNA-1273). Additionally, we applied a test-negative study design to compare the level of protection against symptomatic infection in 3-dose recipients to that observed in recent 2-dose primary vaccine series recipients. 3-dose recipients experienced a significantly lower incidence rate of SARS-CoV-2 infection than the matched 2-dose cohorts (BNT162b2 Incidence Rate Ratio: 0.11, 95% CI: 0.09–0.13 and mRNA-1273 IRR: 0.11, 95% CI: 0.08–0.15). Results from the test-negative study showed the third vaccine dose mitigated waning of vaccine effectiveness, with the risk of symptomatic infection in 3-dose recipients being comparable to that observed 7–73 days after the primary vaccine series. These results show that 3-dose vaccine regimens with BNT162b2 or mRNA-1273 are effective at reducing SARS-CoV-2 infection and support the widespread administration of booster vaccine doses.

Third dose vaccination with mRNA-1273 or BNT162b2 vaccines improves protection against SARS-CoV-2 infection 

The natural language portions of an electronic health record (EHR) communicate critical information about disease and treatment progression. However, the presence of personally identifying information in this data constrains its broad reuse. In the United States, the Health Insurance Portability and Accountability Act of 1996 (HIPAA) provides a de-identification standard for the removal of protected health information (PHI). Despite continuous improvements in methods for the automated detection of PHI over time, the residual identifiers in clinical notes continue to pose significant challenges – often requiring manual validation and correction that is not scalable to generate the amount of data needed for modern machine learning tools. In this paper, we describe an automated de-identification system that employs an ensemble architecture, incorporating attention-based deep learning models and rule based methods, supported by heuristics for detecting PHI in EHR data. Upon detection of PHI, the system transforms these detected identifiers into plausible, though fictional, surrogates to further obfuscate any leaked identifier. We evaluated the system with a publicly available dataset of 515 notes from the I2B2 2014 de-identification challenge and a dataset of 10,000 notes from the Mayo Clinic. We compared our approach with other existing tools considered best-in-class. The results indicated a recall of 0.992 and 0.994 and a precision of 0.979 and 0.967 on the I2B2 and the Mayo Clinic data, respectively.

TechCrunch · EHR Intelligence · Health Leaders Media · Managed Healthcare Executive

Building a best-in-class de-identification tool for electronic medical records through ensemble learning

To assess the association of COVID-19 vaccines and non-COVID-19 vaccines with cerebral venous sinus thrombosis (CVST). Materials and method: We retrospectively analyzed a cohort of 771,805 vaccination events across 266,094 patients in the MayoClinic Health System between 01/01/2017and 03/15/2021. The primary outcome was a positive diagnosis of CVST, identified either by the presence of a corresponding ICD code or by an NLP algorithm which detected positive diagnosis of CVST within free-text clinical notes. For each vaccine we calculated the relative risk by dividing the incidence of CVST in the 30 days following vaccination to that in the 30 days preceding vaccination.

BioWorld · Fierce Biotech · Star Tribune · The Rick Ungar Show · Benzinga

Journal of Stroke and Cerebrovascular Diseases

Cerebral Venous Sinus Thrombosis is not Significantly Linked to COVID-19 Vaccines or Non-COVID Vaccines in a Large Multi-State Health System

Recent reports on waning of COVID-19 vaccine induced immunity have led to the approval and roll-out of additional dose and booster vaccinations. At risk individuals are receiving additional vaccine dose(s), in addition to the regimen that was tested in clinical trials. The risks and the adverse event profiles associated with these additional vaccine doses are currently not well understood. Here, we performed a retrospective study analyzing vaccine-associated adverse events using electronic health records (EHRs) of individuals that have received three doses of mRNA-based COVID-19 vaccines (n = 47,999). By comparing symptoms reported in 2-week time periods after each vaccine dose and in a 2-week period before the 1st vaccine dose, we assessed the risk associated with 3rd dose vaccination, for both BNT162b2 and mRNA-1273. Reporting of severe adverse events remained low after the 3rd vaccine dose, with rates of pericarditis (0.01%, 0%-0.02% 95% CI), anaphylaxis (0.00%, 0%-0.01% 95% CI), myocarditis (0.00%, 0%-0.01% 95% CI), and cerebral venous sinus thrombosis (no cases), consistent with earlier studies. Significantly more individuals (p-value < 0.05) report low-severity adverse events after their 3rd dose compared with after their 2nd dose, including fatigue (4.92% after 3rd dose vs 3.47% after 2nd dose), lymphadenopathy (2.89% vs 2.07%), nausea (2.62% vs 2.04%), headache (2.47% vs 2.07%), arthralgia (2.12% vs 1.70%), myalgia (1.99% vs 1.63%), diarrhea (1.70% vs 1.24%), fever (1.11% vs 0.81%), vomiting (1.10% vs 0.80%), and chills (0.47% vs 0.36%). Our results show that although 3rd dose vaccination against SARS-CoV-2 infection led to increased reporting of low-severity adverse events, risk of severe adverse events remained comparable to the standard 2-dose regime. This study provides support for the safety of 3rd vaccination doses of individuals that are at high-risk of severe COVID-19 and breakthrough infection.

Centers for Disease Control and Prevention (CDC) · U.S. Food and Drug Administration

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Three doses of COVID-19 mRNA vaccination are safe based on adverse events reported in electronic health records

SARS-CoV-2 breakthrough infections have been increasingly reported in fully vaccinated individuals. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2, defined as 14 days after the second dose, against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice between February 1, 2021 and August 22, 2021. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. The primary population included 652 individuals who had a positive symptomatic test after full vaccination with BNT162b2 (cases) and 5,946 individuals with at least one negative symptomatic test after full vaccination (controls). The adjusted odds of symptomatic infection were higher 120 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.21, 95% confidence interval [CI]: 1.33-7.74). Importantly, the odds of infection were still lower 150 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.3, 95% CI: 0.19-0.45), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of experiencing a non-COVID-19 hospitalization decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. Taken together, these data constitute an early signal for waning protection against symptomatic illness while also providing reassurance that BNT162b2 continues to protect against symptomatic SARS-CoV-2 infection several months after full vaccination. Continued surveillance of COVID-19 vaccine durability, particularly against severe disease, is critical to guide effective and equitable strategies to respond to the pandemic, including distribution of booster doses, development of new vaccines, and implementation of both pharmaceutical and nonpharmaceutical interventions.

Durability analysis of the highly effective BNT162b2 vaccine against COVID-19

Highly transmissible or immuno-evasive SARS-CoV-2 variants have intermittently emerged and outcompeted previously circulating strains, resulting in repeated COVID-19 surges, reinfections, and breakthrough infections in vaccinated individuals. With over 6 million SARS-CoV-2 genomes sequenced globally over the last 2 years, there is unprecedented data to decipher how competitive viral evolution results in the emergence of fitter SARS-CoV-2 variants. Much attention has been directed to studying how specific mutations in the Spike protein impact its binding to the ACE2 receptor or viral neutralization by antibodies, but there is limited knowledge of a genomic signature that is shared primarily by the sequential dominant variants. Here we introduce a methodology to quantify the genome-wide distinctiveness of polynucleotide fragments of various lengths (3- to 240-mers) that constitute SARS-CoV-2 sequences (freely available at https://academia.nferx.com/GENI). Compared to standard phylogenetic distance metrics and overall mutational load, the quantification of distinctive 9-mer polynucleotides provides a higher resolution of separation between VOCs (Reference = 89, IQR: 65–108; Alpha = 166, IQR: 149–181; Beta 131, IQR: 114–149; Gamma = 164, IQR: 150–178; Delta = 235, IQR: 217–255; and Omicron = 459, IQR: 395–521). Omicron's exceptionally high genomic distinctiveness may confer a competitive advantage over both prior VOCs (including Delta) and the recently emerged and highly mutated B.1.640.2 (IHU) lineage. Expanding on this analysis, evaluation of genomic distinctiveness weighted by intra-lineage 9-mer conservation for 883 lineages highlights that genomic distinctiveness has increased over time (R2 = 0.37) and that VOCs score significantly higher than contemporary non-VOC lineages, with Omicron among the most distinctive lineages observed till date. This study demonstrates the value of characterizing new SARS-CoV-2 variants by the newly introduced metric of genome-wide polynucleotide distinctiveness and emphasizes the need to go beyond a narrow set of mutations at known functionally or antigenically salient sites on the Spike protein. The consistently higher distinctiveness of each emerging VOC compared to prior VOCs suggests that real-time monitoring of genomic distinctiveness would aid in more rapid assessment of viral fitness.

Continuous genomic diversification of long polynucleotide fragments drives the emergence of new SARS-CoV-2 variants of concern

The COVID-19 pandemic has seen the persistent emergence of fitter Variants of Concern (VOCs) that have successfully out-competed circulating strains, but the determinants of viral fitness remain unknown. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. From the perspective of viral evolution, Distinctiveness captures regional herd exposure and has the advantage over the canonical concept of mutation, which relies foremost on the reference ancestral sequence that is invariant over time. By assessing the correlation between Distinctiveness and change in prevalence for all circulating lineages in each region when a new lineage is introduced, we find that the relative Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness (Pearson r = 0.67). Further, by assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, analysis of Omicron lineages in India and USA shows the BA.1 and BA.2 sub-lineages have comparable distinctiveness, suggesting that they may have similar levels of competitive fitness. Overall, our study proposes that augmenting the ongoing surveillance of highly mutated variants with real-time assessment of Distinctiveness can aid in achieving robust pandemic preparedness.

Competitive fitness of emerging SARS-CoV-2 variants is linked to their Distinctiveness relative to preceding lineages from that region

The highly contagious Delta variant of SARS-CoV-2 has emerged as the new dominant global strain, and reports of reduced effectiveness of COVID-19 vaccines against the Delta variant are highly concerning. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike protein, the mutational landscape of the rest of the SARS-CoV-2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS-CoV-2 proteins from nearly 2 million SARS-CoV-2 genomes from 176 countries/territories. Six highly-prevalent missense mutations in the viral life cycle-associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant (cosine similarity: meanAlpha = 0.94, S.D.Alpha = 0.05; meanDelta = 0.86, S.D.Delta = 0.1; Cohen's dAlpha-Delta = 1.17, p-value < 0.001). Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of targetable amino acid mutations in the Delta variant's proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.

High diversity in Delta variant across countries revealed by genome-wide analysis of SARS-CoV-2 beyond the Spike protein

Although clinical trials and real-world studies have affirmed the effectiveness and safety of the FDA-authorized COVID-19 vaccines, reports of breakthrough infections and persistent emergence of new variants highlight the need to vigilantly monitor the effectiveness of these vaccines. Here we compare the effectiveness of two full-length Spike protein-encoding mRNA vaccines from Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162b2) in the Mayo Clinic Health System over time from January to July 2021, during which either the Alpha or Delta variant was highly prevalent. We defined cohorts of vaccinated and unvaccinated individuals from Minnesota (n = 25,589 each) matched on age, sex, race, history of prior SARS-CoV-2 PCR testing, and date of full vaccination. Both vaccines were highly effective during this study period against SARS-CoV-2 infection (mRNA-1273: 86%, 95%CI: 81-90.6%; BNT162b2: 76%, 95%CI: 69-81%) and COVID-19 associated hospitalization (mRNA-1273: 91.6%, 95% CI: 81-97%; BNT162b2: 85%, 95% CI: 73-93%). However, in July, the effectiveness against infection was considerably lower for mRNA-1273 (76%, 95% CI: 58-87%) with an even more pronounced reduction in effectiveness for BNT162b2 (42%, 95% CI: 13-62%). Notably, the Delta variant prevalence in Minnesota increased from 0.7% in May to over 70% in July whereas the Alpha variant prevalence decreased from 85% to 13% over the same time period. Comparing rates of infection between matched individuals fully vaccinated with mRNA-1273 versus BNT162b2 across Mayo Clinic Health System sites in multiple states (Minnesota, Wisconsin, Arizona, Florida, and Iowa), mRNA-1273 conferred a two-fold risk reduction against breakthrough infection compared to BNT162b2 (IRR = 0.50, 95% CI: 0.39-0.64). In Florida, which is currently experiencing its largest COVID-19 surge to date, the risk of infection in July after full vaccination with mRNA-1273 was about 60% lower than after full vaccination with BNT162b2 (IRR: 0.39, 95% CI: 0.24-0.62). Our observational study highlights that while both mRNA COVID-19 vaccines strongly protect against infection and severe disease, further evaluation of mechanisms underlying differences in their effectiveness such as dosing regimens and vaccine composition are warranted.

The White House · Centers for Disease Control and Prevention (CDC)

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Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence

Efficient and equitable vaccination distribution is a priority for effectively outcompeting the transmission of COVID-19 globally. A recent study from the Centers for Disease Control and Prevention (CDC) identified that US counties with high social vulnerability according to metrics such as poverty, unemployment, low income, and no high school diploma, have significantly lower rates of vaccination compared to the national average. Here, we build upon this analysis to consider associations between county-level vaccination rates and 68 different demographic, socioeconomic, and environmental factors for 1,510 American counties with over 228 million individuals for which vaccination data was also available. Our analysis reveals that counties with high levels of uninsured individuals have significantly lower COVID-19 vaccination rates (Spearman correlation: -0.264), despite the fact that the CDC has mandated that all COVID-19 vaccines are free and cannot be denied to anyone based upon health insurance coverage or immigration status. Furthermore, we find that the counties with high levels of uninsured individuals tend to have the highest COVID-19 incidence rates in March 2021 relative to December 2020 (Spearman correlation: 0.388). Among the 68 factors analyzed, insurance coverage is the only factor which is highly correlated with both vaccination rate and change in COVID-19 incidence during the vaccination period (|Spearman correlation| > 0.25). We also find that counties with higher percentages of Black and Hispanic individuals have significantly lower vaccination rates (Spearman correlations: -0.128, -0.136) and lesser declines of COVID-incidence rates (Spearman correlations: 0.334, 0.330) during the vaccination period. Surprisingly however, after controlling for race, we find that the association between lack of insurance coverage and vaccination rate as well as COVID-19 incidence rates is largely driven by counties with a majority white population. Among the counties with high proportions of white residents (top 10% decile), the association between insurance coverage and vaccination rate is significant (Spearman correlation: -0.210, p-value: 0.002), but among counties with low proportions of white residents (bottom 10% decile) this association is not significant (Spearman correlation: 0.072, p-value: 0.088). Taken together, this study highlights the fact that intricate socioeconomic factors are correlated not just to COVID-19 vaccination rates, but also to COVID-19 incidence fluctuations, underscoring the need to improve COVID-19 vaccination campaigns in marginalized communities. The strong positive correlation between low levels of health insurance coverage and low vaccination rates is particularly concerning, and calls for improved public health messaging to emphasize the fact that health insurance is not required to be eligible for any of the FDA-authorized COVID-19 vaccines in the United States.

Counties with lower insurance coverage are associated with both slower vaccine rollout and higher COVID-19 incidence across the United States

Background: Case reports of patients infected with COVID-19 and influenza virus ("flurona") have raised questions around the prevalence and clinical significance of these reports. Methods: Epidemiological data from the HHS Protect Public Data Hub was analyzed to show trends in SARS-CoV-2 and influenza co-infection-related hospitalizations in the United States in relation to SARS-CoV-2 and influenza strain data from NCBI Virus and FluView. In addition, we retrospectively analyzed all cases of PCR-confirmed SARS-CoV-2 across the Mayo Clinic Enterprise from January 2020 to January 2022 and identified cases of influenza co-infections within two weeks of PCR-positive diagnosis date. Using a cohort from the Mayo Clinic with joint PCR testing data, we estimated the expected number of co-infection cases given the background prevalences of COVID-19 and influenza during the Wuhan (Original), Alpha, Delta, and Omicron waves of the pandemic. Findings: Considering data from all states of the United States using HHS Protect Public Data Hub, hospitalizations due to influenza co-infection with SARS-CoV-2 were seen to be highest in January 2022 compared to all previous months during the COVID-19 pandemic. Among 171,639 SARS-CoV-2-positive cases analyzed at Mayo Clinic between January 2020 and January 2022, only 73 cases of influenza co-infection were observed. Identified coinfected patients were relatively young (mean age: 28.4 years), predominantly male, and had few comorbidities. During the Delta era (June 16, 2021 to December 13, 2021), there were 9 lab-confirmed co-infection cases observed compared to 13.9 expected cases (95% CI: [12.7, 15.2]), and during the Omicron era (December 14, 2021 to January 17, 2022), there were 54 lab-confirmed co-infection cases compared to 80.9 expected cases (95% CI: [76.6, 85.1]). Conclusions: Reported co-infections of SARS-CoV-2 and influenza are rare. These co-infections have occurred throughout the COVID-19 pandemic and their prevalence can be explained by background rates of COVID-19 and influenza infection. Preliminary assessment of longitudinal EHR data suggests that most co-infections so far have been observed among relatively young and healthy patients. Further analysis is needed to assess the outcomes of "flurona" among subpopulations with risk factors for severe COVID-19 such as older age, obesity, and immunocompromised status. Significance Statement: Reports of COVID-19 and influenza co-infections ("flurona") have raised concern in recent months as both COVID-19 and influenza cases have increased to significant levels in the US. Here, we analyze trends in co-infection cases over the course of the pandemic to show that these co-infection cases are expected given the background prevalences of COVID-19 and influenza independently. In addition, from an initial analysis of these co-infection cases which have been observed at the Mayo Clinic, we find that these co-infection cases are extremely rare and have mostly been observed in relatively young, healthy patients.

SARS-CoV-2 and influenza co-infection throughout the COVID-19 pandemic: An assessment of co-infection rates and cohort characterization

Variants of SARS-CoV-2 are evolving under a combination of immune selective pressure in infected hosts and natural genetic drift, raising a global alarm regarding the durability of COVID-19 vaccines. Here, we conducted longitudinal analysis over 1.8 million SARS-CoV-2 genomes from 183 countries or territories to capture vaccination-associated viral evolutionary patterns. To augment this macroscale analysis, we performed viral genome sequencing in 23 vaccine breakthrough COVID-19 patients and 30 unvaccinated COVID-19 patients for whom we also conducted machine-augmented curation of the electronic health records (EHRs). Strikingly, we find the diversity of the SARS-CoV-2 lineages is declining at the country-level with increased rate of mass vaccination (n = 25 countries, mean correlation coefficient = −0.72, S.D. = 0.20). Given that the COVID-19 vaccines leverage B-cell and T-cell epitopes, analysis of mutation rates shows neutralizing B-cell epitopes to be particularly more mutated than comparable amino acid clusters (4.3-fold, p < 0.001). Prospective validation of these macroscale evolutionary patterns using clinically annotated SARS-CoV-2 whole genome sequences confirms that vaccine breakthrough patients indeed harbor viruses with significantly lower diversity in known B cell epitopes compared to unvaccinated COVID-19 patients (2.3-fold, 95% C.I. 1.4-3.7). Incidentally, in these study cohorts, vaccinated breakthrough patients also displayed fewer COVID-associated complications and pre-existing conditions relative to unvaccinated COVID-19 patients. This study presents the first known evidence that COVID-19 vaccines are fundamentally restricting the evolutionary and antigenic escape pathways accessible to SARS-CoV-2. The societal benefit of mass vaccination may consequently go far beyond the widely reported mitigation of SARS-CoV-2 infection risk and amelioration of community transmission, to include stemming of rampant viral evolution.

Reuters · News Medical Life Sciences · 20 Minuten · The Economic Times

COVID-19 vaccines dampen genomic diversity of SARS-CoV-2: Unvaccinated patients exhibit more antigenic mutational variance

IMPORTANCE - Continuous assessment of the effectiveness and safety of the US Food and Drug Administration–authorized SARS-CoV-2 vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes.

OBJECTIVE - To evaluate the effectiveness of the Johnson & Johnson Ad26.COV2.S vaccine for preventing SARS-CoV-2 infection.

DESIGN, SETTING, AND PARTICIPANTS - This comparative effectiveness research study used large - scale longitudinal curation of electronic health records from the multi-state Mayo Clinic Health System (Minnesota, Arizona, Florida, Wisconsin, and Iowa) to identify vaccinated and unvaccinated adults between February 27 and July 22, 2021. The unvaccinated cohort was matched on a propensity score derived from age, sex, zip code, race, ethnicity, and previous number of SARS-CoV-2 polymerase chain reaction tests. The final study cohort consisted of 8889 patients in the vaccinated group and 88,898 unvaccinated matched patients.

EXPOSURE - Single dose of the Ad26.COV2.S vaccine.

MAIN OUTCOMES AND MEASURES - The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts, measured by SARS-CoV-2 polymerase chain reaction testing.

RESULTS - The study was composed of 8889 vaccinated patients (4491men[50.5%];mean[SD] age, 52.4 [16.9] years) and 88 898 unvaccinated patients (44 748 men [50.3%]; mean [SD] age, 51.7 [16.7] years). The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts was 0.26 (95% CI, 0.20-0.34) (60 of 8889 vaccinated patients vs 2236 of 88,898 unvaccinated individuals), which corresponds to an effectiveness of 73.6% (95% CI, 65.9%-79.9%) and a 3.73-fold reduction in SARS-CoV-2 infections.

CONCLUSIONS AND RELEVANCE - This study’s findings are consistent with the clinical trial– reported efficacy of Ad26.COV2.S and the first retrospective analysis, suggesting that the vaccine is effective at reducing SARS-CoV-2 infection, even with the spread of variants such as Alpha or Delta that were not present in the original studies, and reaffirm the urgent need to continue mass vaccination efforts globally.

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IMPORTANCE - Continuous assessment of the effectiveness and safety of the US Food and Drug Administration–authorized SARS-CoV-2 vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes.

OBJECTIVE - To evaluate the effectiveness of the Johnson & Johnson Ad26.COV2.S vaccine for preventing SARS-CoV-2 infection.

DESIGN, SETTING, AND PARTICIPANTS - This comparative effectiveness research study used large - scale longitudinal curation of electronic health records from the multi-state Mayo Clinic Health System (Minnesota, Arizona, Florida, Wisconsin, and Iowa) to identify vaccinated and unvaccinated adults between February 27 and July 22, 2021. The unvaccinated cohort was matched on a propensity score derived from age, sex, zip code, race, ethnicity, and previous number of SARS-CoV-2 polymerase chain reaction tests. The final study cohort consisted of 8889 patients in the vaccinated group and 88,898 unvaccinated matched patients.

EXPOSURE - Single dose of the Ad26.COV2.S vaccine.

MAIN OUTCOMES AND MEASURES - The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts, measured by SARS-CoV-2 polymerase chain reaction testing.

RESULTS - The study was composed of 8889 vaccinated patients (4491men[50.5%];mean[SD] age, 52.4 [16.9] years) and 88 898 unvaccinated patients (44 748 men [50.3%]; mean [SD] age, 51.7 [16.7] years). The incidence rate ratio of SARS-CoV-2 infection in the vaccinated vs unvaccinated control cohorts was 0.26 (95% CI, 0.20-0.34) (60 of 8889 vaccinated patients vs 2236 of 88,898 unvaccinated individuals), which corresponds to an effectiveness of 73.6% (95% CI, 65.9%-79.9%) and a 3.73-fold reduction in SARS-CoV-2 infections.

CONCLUSIONS AND RELEVANCE - This study’s findings are consistent with the clinical trial– reported efficacy of Ad26.COV2.S and the first retrospective analysis, suggesting that the vaccine is effective at reducing SARS-CoV-2 infection, even with the spread of variants such as Alpha or Delta that were not present in the original studies, and reaffirm the urgent need to continue mass vaccination efforts globally.

Analysis of Effectiveness of Ad26.COV2.S Adenoviral Vector Vaccine for COVID-19

BACKGROUND. Real-world clinical data to support the use of casirivimab–imdevimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. This study aimed to assess the outcomes of casirivimab–imdevimab treatment of mild to moderate COVID-19.

METHODS. A retrospective cohort of 696 patients who received casirivimab–imdevimab between December 4, 2020 and April 9, 2021 was compared to a propensity-matched control of 696 untreated patients with mild to moderate COVID-19 at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Primary outcome was rate of hospitalization at days 14, 21 and 28 after infusion.

RESULTS. The median age of the antibody-treated cohort was 63 years (interquartile range, 52–71); 45·5% were ≥65 years old; 51.4% were female. High-risk characteristics were hypertension (52.4%), body mass index ≥35 (31.0%), diabetes mellitus (24.6%), chronic lung disease (22.1%), chronic renal disease (11.4%), congestive heart failure (6.6%), and compromised immune function (6.7%). Compared to the propensity-matched untreated control, patients who received casirivimab–imdevimab had significantly lower all-cause hospitalization rates at day 14 (1.3% vs 3.3%; Absolute Difference: 2.0%; 95% confidence interval (CI): 0.5–3.7%), day 21 (1.3% vs 4.2%; Absolute Difference: 2.9%; 95% CI: 1.2–4.7%), and day 28 (1.6% vs 4.8%; Absolute Difference: 3.2%; 95% CI: 1.4–5.1%). Rates of intensive care unit admission and mortality at days 14, 21 and 28 were similarly low for antibody-treated and untreated groups.

CONCLUSIONS. Among high-risk patients with mild to moderate COVID-19, casirivimab–imdevimab treatment was associated with a significantly lower rate of hospitalization.

Centers for Disease Control and Prevention (CDC)

FierceBiotech · Becker's Hospital Review

BACKGROUND. Real-world clinical data to support the use of casirivimab–imdevimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed. This study aimed to assess the outcomes of casirivimab–imdevimab treatment of mild to moderate COVID-19.

METHODS. A retrospective cohort of 696 patients who received casirivimab–imdevimab between December 4, 2020 and April 9, 2021 was compared to a propensity-matched control of 696 untreated patients with mild to moderate COVID-19 at Mayo Clinic sites in Arizona, Florida, Minnesota, and Wisconsin. Primary outcome was rate of hospitalization at days 14, 21 and 28 after infusion.

RESULTS. The median age of the antibody-treated cohort was 63 years (interquartile range, 52–71); 45·5% were ≥65 years old; 51.4% were female. High-risk characteristics were hypertension (52.4%), body mass index ≥35 (31.0%), diabetes mellitus (24.6%), chronic lung disease (22.1%), chronic renal disease (11.4%), congestive heart failure (6.6%), and compromised immune function (6.7%). Compared to the propensity-matched untreated control, patients who received casirivimab–imdevimab had significantly lower all-cause hospitalization rates at day 14 (1.3% vs 3.3%; Absolute Difference: 2.0%; 95% confidence interval (CI): 0.5–3.7%), day 21 (1.3% vs 4.2%; Absolute Difference: 2.9%; 95% CI: 1.2–4.7%), and day 28 (1.6% vs 4.8%; Absolute Difference: 3.2%; 95% CI: 1.4–5.1%). Rates of intensive care unit admission and mortality at days 14, 21 and 28 were similarly low for antibody-treated and untreated groups.

CONCLUSIONS. Among high-risk patients with mild to moderate COVID-19, casirivimab–imdevimab treatment was associated with a significantly lower rate of hospitalization.

Casirivimab-Imdevimab treatment is associated with reduced rates of hospitalization among high-risk patients with mild to moderate coronavirus disease-19

Large Phase 3 clinical trials of the two FDA-authorized COVID-19 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech), have demonstrated efficacies of 94.1% (n = 30,420, 95% CI: 89.3-96.8) and 95% (n = 43,448, 95% CI: 90.3-97.6) in preventing symptomatic COVID-19, respectively. Given the ongoing vaccine rollout to healthcare personnel and residents of long-term care facilities, here we provide a preliminary assessment of real-world vaccination efficacy in 62,138 individuals from the Mayo Clinic and associated health system (Arizona, Florida, Minnesota, Wisconsin) between December 1st 2020 and February 8th 2021. Our retrospective analysis contrasts 31,069 individuals receiving at least one dose of either vaccine with 31,069 unvaccinated individuals who are propensity-matched based on demographics, location (zip code), and number of prior SARS-CoV-2 PCR tests. 8,041 individuals received two doses of a COVID-19 vaccine and were at risk for infection at least 36 days after their first dose. Administration of two COVID-19 vaccine doses was 88.7% effective in preventing SARS-CoV-2 infection (95% CI: 68.4-97.1%) with onset at least 36 days after the first dose. Furthermore, vaccinated patients who were subsequently diagnosed with COVID-19 had significantly lower 14-day hospital admission rates than propensity-matched unvaccinated COVID-19 patients (3.7% vs. 9.2%; Relative Risk: 0.4; p-value: 0.007). Building upon the previous randomized trials of these vaccines, this study demonstrates their real-world effectiveness in reducing the rates of SARS-CoV-2 infection and COVID-19 severity among individuals at highest risk for infection.

Bloomberg (Feb 2021) · Bloomberg (May 2021) · National Geographic · The Washington Post · The Atlantic · Politico · The Verge · USA Today · CNN · Star Tribune

FDA-authorized COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system

In light of the massive and rapid vaccination campaign against COVID-19, continuous real-world effectiveness and safety assessment of the FDA-authorized vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes. In this study, we leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system (MN, AZ, FL, WN, IA). We compared the infection rate of 2,195 individuals who received a single dose of the Ad26.COV2.S vaccine from Johnson & Johnson (J&J) to the infection rate of 21,950 unvaccinated, propensity-matched individuals between February 27th and April
14th 2021. Of the 1,779 vaccinated individuals with at least two weeks of follow-up, only 3 (0.17%) tested positive for SARS-CoV-2 15 days or more after vaccination compared to 128 of 17,744 (0.72%) unvaccinated individuals (4.34 fold reduction rate). This corresponds to
a vaccine effectiveness of 76.7% (95% CI: 30.3-95.3%) in preventing SARS-CoV-2 infection with onset at least two weeks after vaccination. This data is consistent with the clinical trial-reported efficacy of Ad26.COV2.S in preventing moderate to severe COVID-19 with onset at least 14 days after vaccine administration (66.9%; 95% CI: 59.0-73.4%). Due to the recent authorization of the Ad26.COV2.S vaccine, there are not yet enough hospitalizations, ICU admissions, or deaths within this cohort to robustly assess the effect of vaccination on COVID-19 severity, but these outcomes will be continually assessed in near-real-time with our platform. Collectively, this study provides further evidence that a single dose of Ad26.COV2.S is highly effective in preventing SARS-CoV-2 infection and reaffirms the urgent need to continue mass vaccination efforts globally.

Forbes · Business Insider · Prevention · Reason

In light of the massive and rapid vaccination campaign against COVID-19, continuous real-world effectiveness and safety assessment of the FDA-authorized vaccines is critical to amplify transparency, build public trust, and ultimately improve overall health outcomes. In this study, we leveraged large-scale longitudinal curation of electronic health records (EHRs) from the multi-state Mayo Clinic health system (MN, AZ, FL, WN, IA). We compared the infection rate of 2,195 individuals who received a single dose of the Ad26.COV2.S vaccine from Johnson & Johnson (J&J) to the infection rate of 21,950 unvaccinated, propensity-matched individuals between February 27th and April 14th 2021. Of the 1,779 vaccinated individuals with at least two weeks of follow-up, only 3 (0.17%) tested positive for SARS-CoV-2 15 days or more after vaccination compared to 128 of 17,744 (0.72%) unvaccinated individuals (4.34 fold reduction rate). This corresponds to a vaccine effectiveness of 76.7% (95% CI: 30.3-95.3%) in preventing SARS-CoV-2 infection with onset at least two weeks after vaccination. This data is consistent with the clinical trial-reported efficacy of Ad26.COV2.S in preventing moderate to severe COVID-19 with onset at least 14 days after vaccine administration (66.9%; 95% CI: 59.0-73.4%). Due to the recent authorization of the Ad26.COV2.S vaccine, there are not yet enough hospitalizations, ICU admissions, or deaths within this cohort to robustly assess the effect of vaccination on COVID-19 severity, but these outcomes will be continually assessed in near-real-time with our platform. Collectively, this study provides further evidence that a single dose of Ad26.COV2.S is highly effective in preventing SARS-CoV-2 infection and reaffirms the urgent need to continue mass vaccination efforts globally.

Analysis of the Effectiveness of the Ad26.COV2.S Adenoviral Vector Vaccine for Preventing COVID-19

Several recent surges in COVID-19 cases due to newly emerging variant strains of SARS-CoV-2 with greater transmissibility have highlighted the virus’s capability to directly modulate spike-ACE2 interactions and promote immune evasion by sterically masking the immunogenic epitopes. Recently, there have also been reports of the bidirectional transfer of coronavirus between different animal species and humans. The ability of coronavirus to infect and adapt to a wide range of hosts can be attributed to new variants that modify the molecular recognition profile of the spike protein (S protein). The receptor-binding domain of the spike protein specifically interacts with key host receptor molecules present on the host cell membranes to gain entry into the host and begin the infection cycle. In this review, we discuss the molecular, structural, and functional diversity associated with the coronavirus receptors across their different phylogenetic lineages and its relevance to various symptomatology in the rapid human-to-human infection in COVID-19 patients, tropism, and zoonosis. Despite this seeming diversity of host receptors, there may be some common underlying mechanisms that influence the host range, virus transmissibility, and pathogenicity. Understanding these mechanisms may be crucial in not only controlling the ongoing pandemic but also help in stopping the resurgence of such virus threats in the future.

Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus
disease-19 (COVID-19) are needed.

2335 Patients who received single-dose bamlanivimab infusion between November 12, 2020, and February 17, 2021,
were compared with a propensity-matched control of 2335 untreated patients with mild to moderate COVID-19 at Mayo
Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21, and 28.

The median age of the population was 63 years; 47.3% of the bamlanivimab-treated cohort were 65 years or more;
49.3% were female and 50.7% were male. High-risk characteristics included hypertension (54.2%), BMI greater than or
equal to 35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease
(14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs. 3.5%; risk
ratio [RR], 0.41), 21 (1.9% vs. 3.9%; RR, 0.49), and 28 (2.5% vs. 3.9%; RR, 0.63).

Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus

2335 Patients who received single-dose bamlanivimab infusion between November 12, 2020, and February 17, 2021,

were compared with a propensity-matched control of 2335 untreated patients with mild to moderate COVID-19 at Mayo

Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21, and 28.

The median age of the population was 63 years; 47.3% of the bamlanivimab-treated cohort were 65 years or more;

49.3% were female and 50.7% were male. High-risk characteristics included hypertension (54.2%), BMI greater than or

equal to 35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease

(14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs. 3.5%; risk

ratio [RR], 0.41), 21 (1.9% vs. 3.9%; RR, 0.49), and 28 (2.5% vs. 3.9%; RR, 0.63).

Intravenous bamlanivimab use associates with reduced hospitalization in high-risk patients with mild to moderate COVID-19

Patients with COVID-19 can experience symptoms and complications after viral clearance. It is important to identify clinical features of patients who are likely to experience these prolonged effects. We conducted a retrospective study to compare longitudinal laboratory test measurements (hemoglobin, hematocrit, estimated glomerular filtration rate, serum creatinine, and blood urea nitrogen) in patients rehospitalized after PCR-confirmed SARS-CoV-2 clearance (n = 104) versus patients not rehospitalized after viral clearance (n = 278). Rehospitalized patients had lower median hemoglobin levels in the year prior to COVID-19 diagnosis (Cohen's D = −0.50; p = 1.2 × 10−3) and during their active SARS-CoV-2 infection (Cohen's D = −0.71; p = 4.6 × 10−8). Rehospitalized patients were also more likely to be diagnosed with moderate or severe anemia during their active infection (Odds Ratio = 4.07; p = 4.99 × 10−9). These findings suggest that anemia-related laboratory tests should be considered in risk stratification algorithms for patients with COVID-19.

Reuters · Business Inside · Philly Voice

Anemia during SARS-CoV-2 infection is associated with rehospitalization after viral clearance

As the COVID-19 vaccination campaign unfolds as one of the most rapid and widespread in history, it is important to continuously assess the real world safety of the FDA-authorized vaccines. Curation from large-scale electronic health records (EHRs) allows for near real-time safety evaluations that were not previously possible. Here, we advance context- and sentiment-aware deep neural networks over the multi-state Mayo Clinic enterprise (Minnesota, Arizona, Florida, Wisconsin) for automatically curating the adverse effects mentioned by physicians in over 108,000 EHR clinical notes between December 1st 2020 to February 8th 2021.We retrospectively compared the clinical notes of 31,069 individuals who received at least one dose of the Pfizer/BioNTech or Moderna vaccine to those of 31,069 unvaccinated individuals who were propensity matched by demographics, residential location, and history of prior SARS-CoV-2 testing. We find that vaccinated and unvaccinated individuals were seen in the the clinic at similar rates within 21 days of the first or second actual or assigned vaccination dose (first dose Odds Ratio = 1.13, 95% CI: 1.09-1.16; second dose Odds Ratio = 0.89, 95% CI: 0.84-0.93). Further, the incidence rates of all surveyed adverse effects were similar or lower in vaccinated individuals compared to unvaccinated individuals after either vaccine dose. Finally, the most frequently documented adverse effects within 7 days of each vaccine dose were arthralgia (Dose 1: 0.59%; Dose 2: 0.39%), diarrhea (Dose 1: 0.58%; Dose 2: 0.33%), erythema (Dose 1: 0.51%; Dose 2: 0.31%), myalgia (Dose 1: 0.40%; Dose 2: 0.34%), and fever (Dose 1: 0.27%; Dose 2: 0.31%). These remarkably low frequencies of adverse effects recorded in EHRs versus those derived from active solicitation during clinical trials (arthralgia: 24-46%; erythema: 9.5-14.7%; myalgia: 38-62%; fever: 14.2-15.5%) emphasize the rarity of vaccine-associated adverse effects requiring clinical attention. This rapid and timely analysis of vaccine-related adverse effects from contextually rich EHR notes of 62,138 individuals, which was enabled through a large scale Artificial Intelligence (AI)-powered platform, reaffirms the safety and tolerability of the FDA-authorized COVID-19 vaccines in practice.

Star Tribune · Becker's Health IT · News Medical Life Sciences

Real-time analysis of a mass vaccination effort via an Artificial Intelligence platform confirms the safety of FDA-authorized COVID-19 vaccines

The current diagnostic gold-standard for SARS-CoV-2 clearance from infected patients is two consecutive negative PCR test results. However, there are anecdotal reports of hospitalization from protracted COVID complications (long-COVID) despite such confirmed viral clearance, presenting a clinical conundrum. We conducted a retrospective analysis of 266 COVID patients to compare those that were admitted/re-admitted post-viral clearance (hospitalized post-clearance cohort, n=93) with those that were hospitalized pre-clearance but were not re-admitted post-viral clearance (non-hospitalized post-clearance cohort, n=173). In order to differentiate these two cohorts, we used neural network models for the augmented curation of comorbidities and complications with positive sentiment in the EHR physician notes. In the year preceding COVID onset, acute kidney injury (n=15 (16.1%), p-value: 0.03), anemia (n=20 (21.5%), p-value: 0.02), and cardiac arrhythmia (n=21 (22.6%), p-value: 0.05) were significantly enriched in the physician notes of the hospitalized post-clearance cohort. This study highlights that these specific pre-existing conditions are associated with amplified hospitalization risk in long-COVID patients, despite their successful SARS-CoV-2 viral clearance. Our findings motivate follow-up prospective research into specific risk factors that predispose some patients towards the long-COVID syndrome.

Pre-existing conditions are associated with COVID-19 patients' hospitalization, despite confirmed clearance of SARS-CoV-2 virus

Multiple clinical studies are ongoing to assess whether existing vaccines may afford protection against SARS-CoV-2 infection through trained immunity. In this exploratory study, we analyze immunization records from 137,037 individuals who received SARS-CoV-2 PCR tests. We find that polio, Hemophilus influenzae type-B (HIB), measles-mumps-rubella (MMR), varicella, pneumococcal conjugate (PCV13), geriatric flu, and hepatitis A / hepatitis B (HepA-HepB) vaccines administered in the past 1, 2, and 5 years are associated with decreased SARS-CoV-2 infection rates, even after adjusting for geographic SARS-CoV-2 incidence and testing rates, demographics, comorbidities, and number of other vaccinations. Furthermore, age, race/ethnicity, and blood group stratified analyses reveal significantly lower SARS-CoV-2 rate among black individuals who have taken the PCV13 vaccine, with relative risk of 0.45 at the 5 year time horizon (n: 653, 95% CI: (0.32, 0.64), p-value: 6.9e-05). These findings suggest that additional pre-clinical and clinical studies are warranted to assess the protective effects of existing non-COVID-19 vaccines and explore underlying immunologic mechanisms. We note that the findings in this study are preliminary and are subject to change as more data becomes available and as further analysis is conducted.

The New York Times · The Washington Post · Reuters · Discover Magazine · Scientific American · Salon · Deccan Herald

Exploratory analysis of immunization records highlights decreased SARS-CoV-2 rates in individuals with recent non-COVID-19 vaccinations

Tumor mutation burden (TMB) is used to select patients to receive immune checkpoint inhibitors (ICIs) but has mixed predictive capabilities. We hypothesized that inactivation of antigen presenting genes (APGs) that result from increased TMBs would result in inherent resistance to ICIs. We observed that somatic mutations in APGs were associated with increasing TMBs across 9,418 tumors of 33 different types. In adenocarcinomas of the lung, ITGAX and CD1B were some of the most commonly mutated APGs. In 62 patients with non-small cell lung cancers treated with a PD-1 inhibitor in second or later lines of therapy, there was an association of increased TMB with mutations in APGs; however, mutations in one or more APGs were associated with improved progression-free survival. Contrary to our hypothesis, mutations in APGs were associated with improved progression-free survival with nivolumab, possibly due to the involvement of single alleles rather than complete loss.

Effects of tumor mutation burden on the antigen presentation pathway

Technology to generate single cell RNA-sequencing (scRNA-seq) datasets and tools to annotate them have advanced rapidly in the past several years. Such tools generally rely on existing transcriptomic datasets or curated databases of cell type defining genes, while the application of scalable natural language processing (NLP) methods to enhance analysis workflows has not been adequately explored. Here we deployed an NLP framework to objectively quantify associations between a comprehensive set of over 20,000 human protein-coding genes and over 500 cell type terms across over 26 million biomedical documents. The resultant gene-cell type associations (GCAs) are significantly stronger between a curated set of matched cell type-marker pairs than the complementary set of mismatched pairs (Mann Whitney p = 6.15 × 10−76, r = 0.24; cohen’s D = 2.6). Building on this, we developed an augmented annotation algorithm (single cell Annotation via Literature Encoding, or scALE) that leverages GCAs to categorize cell clusters identified in scRNA-seq datasets, and we tested its ability to predict the cellular identity of 133 clusters from nine datasets of human breast, colon, heart, joint, ovary, prostate, skin, and small intestine tissues. With the optimized settings, the true cellular identity matched the top prediction in 59% of tested clusters and was present among the top five predictions for 91% of clusters. scALE slightly outperformed an existing method for reference data driven automated cluster annotation, and we demonstrate that integration of scALE can meaningfully improve the annotations derived from such methods. Further, contextualization of differential expression analyses with these GCAs highlights poorly characterized markers of well-studied cell types, such as CLIC6 and DNASE1L3 in retinal pigment epithelial cells and endothelial cells, respectively. Taken together, this study illustrates for the first time how the systematic application of a literature-derived knowledge graph can expedite and enhance the annotation and interpretation of scRNA-seq data.

A Literature-Derived Knowledge Graph Augments the Interpretation of Single Cell RNA-seq Datasets

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1 = 1.67, pDose 1 <0.001, RRDose 2 = 2.2, pDose 1 < 0.001; vomiting: RRDose 1 = 1.58, pDose 1 < 0.001, RRDose 2 = 1.88, pDose 1 = 3.4x10-2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65x10-3; fatigue RR = 0.86, p = 2.89x10-2; lymphadenopathy RR = 0.61, p = 3.45x10-3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines and also promote better clinical management of vaccine-associated adverse events.

Female-male differences in COVID vaccine adverse events have precedence in seasonal flu shots: a potential link to sex-associated baseline gene expression patterns

Public health concerns are emerging based on reports of new SARS-CoV-2 variant strains purportedly triggering a rise in COVID-associated hospitalizations and ICU admissions, particularly in younger patients and the pediatric population. However, analyzing health records of COVID patients from the electronic health records (EHRs) of a multi-state US healthcare system, we find that there is actually a significant drop in COVID-associated hospitalization rates and ICU admission rates in March 2021 compared to February 2021. We further triangulate these EHR-derived insights with the official US government epidemiological data sets to show that during this same time period, there is no apparent nation-wide spike in pediatric hospitalizations. Our study motivates the need to develop a real-time system that integrates various COVID hospitalization and ICU monitoring efforts from the EHR databases of various health systems together with national epidemiological data sets. By infusing SARS-CoV-2 genomic sequencing data to flag potentially new or emergent viral strains, as well as county-level COVID vaccine rollout rates and shifts in SARS-CoV-2 PCR positivity rates into such a real-time monitoring system, public health policies and media reporting can be more effectively informed through the rigor of holistic biomedical data sciences.

COVID-associated pediatric hospitalization and ICU admission trends across a multi-state health system and the broader US population

The raging COVID-19 pandemic in India and reports of “vaccine breakthrough infections” globally have raised alarm mandating the characterization of the immunoevasive features of SARS-CoV-2. Here, we systematically analyzed over 1.3 million SARSCoV-2 genomes from 178 countries and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 116 Spike protein mutations that increased in prevalence during at least one surge in SARSCoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these ‘surge-associated mutations’ (Odds Ratio = 18.2, 95% CI: 7.53-48.7; p=1.465x10-18). In the recent COVID-19 surge in India, an NTD deletion (ΔF157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion (Δ246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection (Δ156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of NTD deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence viral genomes at a larger scale globally and to mandate that sequences are deposited with more granular and transparent clinical annotations to ensure that therapeutic development keeps pace with the evolution of SARS-CoV-2.

Science,The Scientist,American Society of Microbiology (ASM),The Telegraph,Deccan Herald

Antigenic minimalism of SARS-CoV-2 is linked to surges in COVID-19 community transmission and vaccine breakthrough infections

The hand of molecular mimicry in shaping SARS-CoV-2 evolution and immune evasion remains to be deciphered. Here, we report 33 distinct 8-mer/9-mer peptides that are identical between SARS-CoV-2 and the human reference proteome. We benchmark this observation against other viral–human 8-mer/9-mer peptide identity, which suggests generally similar extents of molecular mimicry for SARS-CoV-2 and many other human viruses. Interestingly, 20 novel human peptides mimicked by SARS-CoV-2 have not been observed in any previous coronavirus strains (HCoV, SARS-CoV, and MERS). Furthermore, four of the human 8-mer/9-mer peptides mimicked by SARS-CoV-2 map onto HLA-B*40:01, HLA-B*40:02, and HLA-B*35:01 binding peptides from human PAM, ANXA7, PGD, and ALOX5AP proteins. This mimicry of multiple human proteins by SARS-CoV-2 is made salient by single-cell RNA-seq (scRNA-seq) analysis that shows the targeted genes significantly expressed in human lungs and arteries; tissues implicated in COVID-19 pathogenesis. Finally, HLA-A*03 restricted 8-mer peptides are found to be shared broadly by human and coronaviridae helicases in functional hotspots, with potential implications for nucleic acid unwinding upon initial infection. This study presents the first scan of human peptide mimicry by SARS-CoV-2, and via its benchmarking against human–viral mimicry more broadly, presents a computational framework for follow-up studies to assay how evolutionary tinkering may relate to zoonosis and herd immunity.

Benchmarking evolutionary tinkering underlying human–viral molecular mimicry shows multiple host pulmonary–arterial peptides mimicked by SARS-CoV-2

The death toll of the COVID-19 pandemic has been unprecedented, due to both the high number of SARS-CoV-2 infections and the seriousness of the disease resulting from these infections. Here, we present mortality rates and case fatality rates for COVID-19 over the past year compared with other historic leading causes of death in the United States. Among the risk categories considered, COVID-19 is the third leading cause of death for individuals 40 years old and over, with an overall annual mortality rate of 325 deaths per 100K individuals, behind only cancer (385 deaths per 100K individuals) and heart disease (412 deaths per 100K individuals). In addition, for individuals 40 years old and over, the case fatality rate for COVID-19 is greater than the case fatality rate for motor vehicle accidents. In particular, for the age group 40-49, the relative case fatality rate of COVID-19 is 1.5 fold (95% CI: [1.3, 1.7]) that of a motor vehicle accident, demonstrating that SARS- CoV-2 infection may be significantly more dangerous than a car crash for this age group. For older adults, COVID-19 is even more dangerous, and the relative case fatality rate of COVID-19 is 29.4 fold (95% CI: [23.2, 35.7]) that of a motor vehicle accident for individuals over 80 years old. On the other hand, motor vehicle accidents have a 4.5 fold (95% CI: [3.9, 5.1]) greater relative case fatality rate compared to COVID-19 for the age group of 20-29 years. These results highlight the severity of the COVID-19 pandemic especially for adults above 40 years of age and underscore the need for large-scale preventative measures to mitigate risks for these populations. Given that FDA-authorized COVID-19 vaccines have now been validated by multiple studies for their outstanding real-world effectiveness and safety, vaccination of all individuals who are over 40 years of age is one of the most pressing public health priorities of our time.

Case fatality rates for COVID-19 are higher than case fatality rates for motor vehicle accidents for individuals over 40 years of age

Background: Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed.

Methods: 2,335 patients who received single-dose bamlanivimab infusion between November 12, 2020 to February 17, 2021 were compared with a propensity-matched control of 2,335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21 and 28.

Results: The median age of the population was 63; 47.3% of the bamlanivimab-treated cohort were ≥65 years; 49.3% were female. High-risk characteristics included hypertension (54.2%), body mass index ≥35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs 3.5%; Odds Ratio [OR], 0.38), 21 (1.9% vs 3.9%; OR, 0.46), and 28 (2.5% vs 3.9%; OR, 0.61). Secondary exploratory outcomes included lower intensive care unit admission rates at days 14 (0.14% vs 1%; OR, 0.12), 21 (0.25% vs 1%; OR: 0.24) and 28 (0.56% vs 1.1%; OR: 0.52), and lower all-cause mortality at days 14 (0% vs 0.33%), 21 (0.05% vs 0.4%; OR,0.08) and 28 (0.11% vs 0.44%; OR, 0.01). Adverse events were uncommon with bamlanivimab, occurring in 19/2355, most commonly fever (n=6), nausea (n=5), and lightheadedness (n=3).

Conclusions: Among high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization compared with usual care.

Funding: Mayo Clinic.

Science · The Scientist · American Society of Microbiology (ASM) · The Telegraph · Deccan Herald

Background: Clinical data to support the use of bamlanivimab for the treatment of outpatients with mild to moderate coronavirus disease-19 (COVID-19) is needed.

Methods: 2,335 patients who received single-dose bamlanivimab infusion between November 12, 2020 to February 17, 2021 were compared with a propensity-matched control of 2,335 untreated patients with mild to moderate COVID-19 at Mayo Clinic facilities across 4 states. The primary outcome was the rate of hospitalization at days 14, 21 and 28.

Results: The median age of the population was 63; 47.3% of the bamlanivimab-treated cohort were ≥65 years; 49.3% were female. High-risk characteristics included hypertension (54.2%), body mass index ≥35 (32.4%), diabetes mellitus (26.5%), chronic lung disease (25.1%), malignancy (16.6%), and renal disease (14.5%). Patients who received bamlanivimab had lower all-cause hospitalization rates at days 14 (1.5% vs 3.5%; Odds Ratio [OR], 0.38), 21 (1.9% vs 3.9%; OR, 0.46), and 28 (2.5% vs 3.9%; OR, 0.61). Secondary exploratory outcomes included lower intensive care unit admission rates at days 14 (0.14% vs 1%; OR, 0.12), 21 (0.25% vs 1%; OR: 0.24) and 28 (0.56% vs 1.1%; OR: 0.52), and lower all-cause mortality at days 14 (0% vs 0.33%), 21 (0.05% vs 0.4%; OR,0.08) and 28 (0.11% vs 0.44%; OR, 0.01). Adverse events were uncommon with bamlanivimab, occurring in 19/2355, most commonly fever (n=6), nausea (n=5), and lightheadedness (n=3).

Conclusions: Among high-risk patients with mild to moderate COVID-19, treatment with bamlanivimab was associated with a statistically significant lower rate of hospitalization compared with usual care.

Association of Intravenous Bamlanivimab Use with Reduced Hospitalization, Intensive Care Unit Admission, and Mortality in Patients with Mild to Moderate COVID-19

Decoding disease mechanisms for addressing unmet clinical need demands the rapid assimilation of the exponentially growing biomedical knowledge. These are either inherently unstructured and non-conducive to current computing paradigms or siloed into structured databases requiring specialized bioinformatics. Despite the recent renaissance in unsupervised neural networks for deciphering unstructured natural languages and the availability of numerous bioinformatics resources, a holistic platform for real-time synthesis of the scientific literature and seamless triangulation with deep omic insights and real-world evidence has not been advanced. Here, we introduce the nferX platform that makes the highly unstructured biomedical knowledge computable and supports the seamless visual triangulation with statistical inference from diverse structured databases. The nferX platform will accelerate and amplify the research potential of subject-matter experts as well as non-experts across the life science ecosystem (https://academia.nferx.com/).

Real-time biomedical knowledge synthesis of the exponentially growing world wide web using unsupervised neural networks

Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. 

Material and Methods: We used mate-pair (n=22), RNA (n=28) and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. 

Results: We observed that inter- or intra-chromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific MHC molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient’s circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. 

Discussion: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. 

Material and Methods: We used mate-pair (n=22), RNA (n=28) and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. 

Results: We observed that inter- or intra-chromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangement-related junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific MHC molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient’s circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. 

Discussion: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

Neoantigenic potential of complex chromosomal rearrangements in mesothelioma

Molecular mimicry of host proteins is an evolutionary strategy adopted by viruses to evade immune surveillance and exploit host cell systems. We report that SARS-CoV-2 has evolved a unique S1/S2 cleavage site (RRARSVAS), absent in any previous coronavirus sequenced, that results in mimicry of an identical FURIN-cleavable peptide on the human epithelial sodium channel α-subunit (ENaC-α). Genetic truncation at this ENaC-α cleavage site causes aldosterone dysregulation in patients, highlighting the functional importance of the mimicked SARS-CoV-2 peptide. Single cell RNA-seq from 65 studies shows significant overlap between the expression of ENaC-α and ACE2, the putative receptor for the virus, in cell types linked to the cardiovascular-renal-pulmonary pathophysiology of COVID-19. Triangulating this cellular fingerprint with amino acid cleavage signatures of 178 human proteases shows the potential for tissue-specific proteolytic degeneracy wired into the SARS-CoV-2 lifecycle. We extrapolate that the evolution of SARS-CoV-2 into a global coronavirus pandemic may be in part due to its targeted mimicry of human ENaC and hijack of the associated host proteolytic network.

SARS-CoV-2 strategically mimics proteolytic activation of human ENaC

Purpose: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to anti-tumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts anti-tumor immunity. 

Experimental Design: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with immunohistochemistry (IHC) and in situ hybridization (ISH). TRAILshort specific monoclonal antibodies were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. 

Results: As many as 40% of primary human tumors express TRAILshort by both RNAseq and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B cell malignancies killed more autologous tumor cells in the presence compared to the absence of TRAILshort antibody (P<0.05). 

Conclusion: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.

Purpose: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to anti-tumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts anti-tumor immunity. 

Experimental Design: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with immunohistochemistry (IHC) and in situ hybridization (ISH). TRAILshort specific monoclonal antibodies were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. 

Results: As many as 40% of primary human tumors express TRAILshort by both RNAseq and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B cell malignancies killed more autologous tumor cells in the presence compared to the absence of TRAILshort antibody (P<0.05). 

Conclusion: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells.

Human cancers express TRAILshort, a dominant negative TRAIL splice variant, which impairs immune effector cell killing of tumor cells

Although anticoagulants such as unfractionated heparin and low molecular weight heparin (LMWH, e.g. enoxaparin) are both being used for therapeutic mitigation of COVID associated coagulopathy (CAC), differences in their clinical outcomes remain to be investigated. Here, we employ automated neural networks supplemented with expert curation (Augmented Curation) for retrospectively analyzing the complete electronic health records (EHRs) of 671 hospitalized COVID-19 patients administered either enoxaparin or unfractionated heparin, but not both. We find that COVID-19 patients administered unfractionated heparin but not enoxaparin have higher rates of mortality (risk ratio: 2.6; 95% C.I.: [1.2-5.4]; p-value: 0.02; BH adjusted p-value: 0.09), thrombotic events (risk ratio: 5.7, 95% C.I.: [2.1, 33.9], p-value: 0.024), acute kidney injury (risk ratio: 5.5; 95% C.I.: [1.2-17.7]; p-value: 0.02; BH adjusted p-value: 0.10), and bacterial pneumonia (risk ratio undefined; 95% C.I.: [1.0, 292]; p-value:0.02; BH adjusted p-value:0.10), compared to patients administered enoxaparin but not unfractionated heparin. Notably, even after controlling for potential confounding factors such as demographics, comorbidities, admission diagnosis, initial ICU status, and initial level of oxygen support, the above differences between the enoxaparin and unfractionated heparin patient cohorts remain statistically significant. This study emphasizes the need for mechanistically investigating differential modulation of the COVID-associated coagulation cascades by enoxaparin versus unfractionated heparin.

Enoxaparin is associated with lower rates of thrombosis, kidney injury, and mortality than unfractionated heparin in hospitalized COVID patients

Current unbiased approaches to mine the large amounts of patient-level data on mutations, structural variations and gene expression result in an unwieldy amount of interactions and correlations, which cannot be parsed to identify disease drivers. Here we present an approach to encode mutational and structural variant data at a patient level in a semantic association space. This approach transforms the presence of a mutation (or other feature) in each patient into the quantitative semantic association score of the corresponding gene and the phenotype of interest, which we have trained on all publicly available literature using word-embedding neural networks. Using data from The Cancer Genome Atlas (TCGA), we encoded the mutation or structural variant status (incl. copy number, fusion and chromothripsis) of all patients in the Lung Adenocarcinoma and Mesothelioma cohorts into our semantic space. 

For each cancer, we first defined the set of genes that are most associated to it according to the literature. To project each patient into this semantic space, we next determined if each patient had a mutation in the genes representing the disease semantic vector (e.g. NSCLC). For TCGA data we only counted non-Silent mutations and represented them as a binary number for each gene, i.e. 0 if the patient had no mutations in that gene and 1 if the patient had a non-Silent mutation in the gene. Each patient was then encoded in a binary vector with each member corresponding to a gene from the disease semantic vector. For example, lung adenocarcinoma was associated to 1,367 genes in our semantic space. A lung adenocarcinoma patient’s vector would them be composed of 1,367 binary numbers dictating if the gene is mutated or not in that patient. We then multiply these binary vectors with the semantic disease vector to obtain the patient’s projection in the disease space, which in effect replaces the binary number with the Semantic Association Score between the gene and the disease. Contrary to clustering patient samples by their mutation or structural variant data alone, our projected patient vectors clustered patients together into 22 groups with high patient-to-patient similarity. These clusters recapitulate canonical knowledge about the disease, e.g. Lung Adenocarcinoma patients form clusters that include EGFR-driven and KRAS-driven cohorts. We also see novel groups of patients driven by genes such as MET, STK11 and MALAT1. These clusters can be further stratified by their survival status and other clinical features. We validated our approach with a non-TCGA Mesothelioma cohort, revealing similarities in patient stratification regardless of the data source. This approach represents a dramatic shift in patient segmentation, delivering real-time grouping of patients and biomarker identification, which can accelerate clinical trial design and therapeutic development strategy.

Current unbiased approaches to mine the large amounts of patient-level data on mutations, structural variations and gene expression result in an unwieldy amount of interactions and correlations, which cannot be parsed to identify disease drivers. Here we present an approach to encode mutational and structural variant data at a patient level in a semantic association space. This approach transforms the presence of a mutation (or other feature) in each patient into the quantitative semantic association score of the corresponding gene and the phenotype of interest, which we have trained on all publicly available literature using word-embedding neural networks. Using data from The Cancer Genome Atlas (TCGA), we encoded the mutation or structural variant status (incl. copy number, fusion and chromothripsis) of all patients in the Lung Adenocarcinoma and Mesothelioma cohorts into our semantic space. 

For each cancer, we first defined the set of genes that are most associated to it according to the literature. To project each patient into this semantic space, we next determined if each patient had a mutation in the genes representing the disease semantic vector (e.g. NSCLC). For TCGA data we only counted non-Silent mutations and represented them as a binary number for each gene, i.e. 0 if the patient had no mutations in that gene and 1 if the patient had a non-Silent mutation in the gene. Each patient was then encoded in a binary vector with each member corresponding to a gene from the disease semantic vector. For example, lung adenocarcinoma was associated to 1,367 genes in our semantic space. A lung adenocarcinoma patient’s vector would them be composed of 1,367 binary numbers dictating if the gene is mutated or not in that patient. We then multiply these binary vectors with the semantic disease vector to obtain the patient’s projection in the disease space, which in effect replaces the binary number with the Semantic Association Score between the gene and the disease. Contrary to clustering patient samples by their mutation or structural variant data alone, our projected patient vectors clustered patients together into 22 groups with high patient-to-patient similarity. These clusters recapitulate canonical knowledge about the disease, e.g. Lung Adenocarcinoma patients form clusters that include EGFR-driven and KRAS-driven cohorts. We also see novel groups of patients driven by genes such as MET, STK11 and MALAT1. These clusters can be further stratified by their survival status and other clinical features. We validated our approach with a non-TCGA Mesothelioma cohort, revealing similarities in patient stratification regardless of the data source. This approach represents a dramatic shift in patient segmentation, delivering real-time grouping of patients and biomarker identification, which can accelerate clinical trial design and therapeutic development strategy.

Patient segmentation using machine-learning based literature and genomic data synthesis uncovers novel cohorts of NSCLC and mesothelioma patients

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVIDpos) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVIDneg) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVIDneg patients at the time of diagnostic testing, COVIDpos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVIDpos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVIDpos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.

Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC)

Intensive Care Unit (ICU) admissions and mortality in severe COVID-19 patients are driven by “cytokine storms” and acute respiratory distress syndrome (ARDS). Interim clinical trial results suggest that the corticosteroid dexamethasone displays superior 28-day survival in severe COVID-19 patients requiring ventilation or oxygen. Among 16 patients with plasma IL-6 measurement post-corticosteroid administration, a higher proportion of patients with an IL-6 value over 10 pg/mL have worse outcomes (i.e. ICU Length of Stay > 15 days or death) when compared to 41 patients treated with non-corticosteroid drugs including antivirals, tocilizumab, azithromycin, and hydroxychloroquine (p-value = 0.0024). Given this unexpected clinical association between post-corticosteroid IL-6 levels and COVID-19 severity, we hypothesized that the Glucocorticoid Receptor (GR or NR3C1) may be coupled to IL-6 expression in specific cell types that govern cytokine release syndrome (CRS). Examining single cell RNA-seq data from bronchoalveolar lavage fluid of severe COVID-19 patients and nearly 2 million human cells from a pan-tissue scan shows that alveolar macrophages, smooth muscle cells, and endothelial cells co-express both NR3C1 and IL-6. The mechanism of Glucocorticoid Receptor (GR) agonists mitigating pulmonary and multi-organ inflammation in some COVID-19 patients with respiratory failure, may be in part due to their successful antagonism of IL-6 production within lung macrophages and vasculature.

Plasma IL-6 levels following corticosteroid therapy as an indicator of ICU length of stay in critically ill COVID-19 patients

Longitudinal characterization of SARS-CoV-2 PCR testing from COVID-19 patient’s nasopharynx and its juxtaposition with blood-based IgG-seroconversion diagnostic assays is critical to understanding SARS-CoV-2 infection durations. Here, we retrospectively analyze 851 SARS-CoV-2-positive patients with at least two positive PCR tests and find that 99 of these patients remain SARS-CoV-2-positive after 4 weeks from their initial diagnosis date. For the 851-patient cohort, the mean lower bound of viral RNA shedding was 17.3 days (SD: 7.8), and the mean upper bound of viral RNA shedding from 668 patients transitioning to confirmed PCR-negative status was 22.7 days (SD: 11.8). Among 104 patients with an IgG test result, 90 patients were seropositive to date, with mean upper bound of time to seropositivity from initial diagnosis being 37.8 days (95% CI: 34.3–41.3). Our findings from juxtaposing IgG and PCR tests thus reveal that some SARS-CoV-2-positive patients are non-hospitalized and seropositive, yet actively shed viral RNA (14 of 90 patients). This study emphasizes the need for monitoring viral loads and neutralizing antibody titers in long-term non-hospitalized shedders as a means of characterizing the SARS-CoV-2 infection lifecycle.

Long-term SARS-CoV-2 RNA shedding and its temporal association to IgG seropositivity

The recent explosion of biomedical knowledge presents both a major opportunity and challenge for scientists tackling complex problems in healthcare. Here we present an approach for synthesizing biomedical knowledge based on a combination of word-embeddings and select cooccurrences. We evaluated our ability to recapitulate and retrospectively predict disease-gene associations from the Online Mendelian Inheritance in Man (OMIM) resource. Our metrics achieved an area under the curve (AUC) value of 0.981 at the recapitulation task for 2,400 disease-gene associations. At the most stringent cutoff, our metrics predicted 13.89% of these associations before their first cooccurrence in the literature, with a median time of 4 years between prediction and first cooccurrence. Finally, our literature metrics can be combined with human genetics data to retrospectively predict disease-gene associations, IL-6 and Giant Cell Arteritis provided as an example. We believe this framework can provide robust biomedical hypotheses at a much faster pace than current standard practices.

Recapitulation and retrospective prediction of biomedical associations using temporally-enabled word embeddings

The efficacy and mechanisms of therapeutic action are largely described by atomic bonds and interactions local to drug binding sites. Here we introduce global connectivity analysis as a high-throughput computational assay of therapeutic action – inspired by the Google page rank algorithm that unearths most “globally connected” websites from the information-dense world wide web (www). We execute short timescale (30 ps) molecular dynamics simulations with high sampling frequency (0.01 ps), to identify amino acid residue hubs whose global connectivity dynamics are characteristic of the ligand or mutation associated with the target protein. We find that unexpected allosteric hubs – up to 20Å from the ATP binding site, but within 5Å of the phosphorylation site – encode the Gibbs free energy of inhibition (ΔGinhibition) for select protein kinase-targeted cancer therapeutics. We further find that clinically relevant somatic cancer mutations implicated in both drug resistance and personalized drug sensitivity can be predicted in a high-throughput fashion. Our results establish global connectivity analysis as a potent assay of protein functional modulation. This sets the stage for unearthing disease-causal exome mutations and motivates forecast of clinical drug response on a patient-by-patient basis. We suggest incorporation of structure-guided genetic inference assays into pharmaceutical and healthcare Oncology workflows.

Global connectivity of hub residues in Oncoprotein structures encodes genetic factors dictating personalized drug response to targeted Cancer therapy

The COVID-19 pandemic demands assimilation of all biomedical knowledge to decode mechanisms of pathogenesis. Despite the recent renaissance in neural networks, a platform for the real-time synthesis of the exponentially growing biomedical literature and deep omics insights is unavailable. Here, we present the nferX platform for dynamic inference from 45 quadrillion+ possible conceptual associations from unstructured text and triangulation with insights from Single Cell RNA-sequencing, bulk RNAseq and proteomics from diverse tissue types. A hypothesis-free profiling of ACE2 suggests tongue keratinocytes, olfactory epithelial cells, airway club cells and respiratory ciliated cells as potential reservoirs of the SARS-CoV-2 receptor. We find the gut as the putative hotspot of COVID-19, where a maturation correlated transcriptional signature is shared in small intestine enterocytes among coronavirus receptors(ACE2, DPP4, ANPEP). A holistic data science platform triangulating insights from structured and unstructured data holds potential for accelerating the generation of impactful biological insights and hypotheses.

Knowledge synthesis of 100 million biomedical documents augments the deep expression profiling of coronavirus receptors