Severe acute infection and chronic pulmonary disease are risk factors for developing post-COVID-19 conditions

Post-COVID-19 conditions, also known as "long COVID", has significantly impacted the lives of many individuals, but the risk factors for this condition are poorly understood. In this study, we performed a retrospective EHR analysis of 89,843 individuals at a multi-state health system in the United States with PCR-confirmed COVID-19, including 1,086 patients diagnosed with long COVID and 1,086 matched controls not diagnosed with long COVID. For these two cohorts, we evaluated a wide range of clinical covariates, including laboratory tests, medication orders, phenotypes recorded in the clinical notes, and outcomes. We found that chronic pulmonary disease (CPD) was significantly more common as a pre-existing condition for the long COVID cohort than the control cohort (odds ratio: 1.9, 95% CI: [1.5, 2.6]). Additionally, long-COVID patients were more likely to have a history of migraine (odds ratio: 2.2, 95% CI: [1.6, 3.1]) and fibromyalgia (odds ratio: 2.3, 95% CI: [1.3, 3.8]). During the acute infection phase, the following lab measurements were abnormal in the long COVID cohort: high triglycerides (meanlongCOVID: 278.5 mg/dL vs. meancontrol: 141.4 mg/dL), low HDL cholesterol levels (meanlongCOVID: 38.4 mg/dL vs. meancontrol: 52.5 mg/dL), and high neutrophil-lymphocyte ratio (meanlongCOVID: 10.7 vs. meancontrol: 7.2). The hospitalization rate during the acute infection phase was also higher in the long COVID cohort compared to the control cohort (ratelongCOVID: 5% vs. ratecontrol: 1%). Overall, this study suggests that the severity of acute infection and a history of CPD, migraine, CFS, or fibromyalgia may be risk factors for long COVID symptoms. Our findings motivate clinical studies to evaluate whether suppressing acute disease severity proactively, especially in patients at high risk, can reduce incidence of long COVID.

Individuals with recent prior SARS-CoV-2 infection are at reduced risk of Omicron infection and associated hospitalization

Omicron sub-lineages such as BA2.12.1 and BA5 have breached prior infection-induced immunity and vaccine-induced immunity. This capacity of Omicron to reinfect patients calls for a characterization of vaccination, infection, and reinfection patterns. We analyzed de-identified longitudinal electronic health records for 389,746 individuals (88,679 fully-vaccinated, 184,205 boosted, 73,184 with prior infection) across multiple US states. Compared to individuals with only full vaccination, the rates of SARS-CoV-2 infections in the Omicron era were reduced for individuals with additional prior infection (1.4 to 1.8-fold reduced, depending on vaccine status) or booster vaccination (1.3 to 2.0-fold reduced). Although prior infection was associated with lower incidence of SARS-CoV-2 infection, we found that the relative risk (RR) of infections for individuals with prior infection has increased during Omicron. During October, 2021, RR was 0.11 [0.10-0.13, 95% CI] while during May, 2022, it increased to 0.57 [0.46-0.68, 95% CI], suggesting an increase in reinfections with Omicron. Furthermore, we found that time since prior infection is associated with risk of reinfection, providing evidence of waning immunity. Prior infections before June, 2021, were associated with marginal reduction in risk of infection (eg., RR = 0.80 [0.68-0.90] for prior infection during January, 2021), while recent prior infections were associated with significant reduction in risk (eg., RR = 0.24 [0.20-0.29, 95% CI] for prior infection during November, 2021). Despite an observed increase in reinfections and vaccine breakthrough infections, our findings emphasize the protective effect of natural and vaccine immunity, with prior infection providing [~]6 months of protection from reinfection.

On the origin of Omicron's unique Spike gene insertion

The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; B.1.1.529/BA.1/BA.2) and its rapid spread globally created public health alarms. 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 [~]1500 SARS-CoV-2 lineages constituting [~]5.8 million SARS-CoV-2 genomes. Omicrons 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 other SARS-CoV-2 lineage. Here, we discuss various mechanisms through which the nucleotide sequence encoding for ins214EPE could have been acquired and highlight the plausibility of template switching via either the human transcriptome or prior viral genomes. Analysis of homology of the inserted nucleotide sequence and flanking regions suggests that this template switching event could have involved the genomes of SARS-CoV-2 variants (e.g. B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g. HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor. Whether ins214EPE impacts the epidemiological or clinical properties of Omicron (e.g. transmissibility) warrants further investigation. There is also a need to understand whether human host cells are being exploited by SARS-CoV-2 as an evolutionary sandbox for inter-viral or host-virus genomic interplay to produce new SARS-CoV-2 variants.

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

The COVID-19 pandemic has seen the persistent emergence of immune-evasive SARS-CoV-2 variants under the selection pressure of natural and vaccination-acquired immunity. However, it is currently challenging to quantify how immunologically distinct a new variant is compared to all the prior variants to which a population has been exposed. Here we define Distinctiveness of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. We observe a correlation between Distinctiveness relative to contemporary sequences and future change in prevalence of a newly circulating lineage (Pearson r = 0.75), suggesting that the Distinctiveness of emergent SARS-CoV-2 lineages is associated with their competitive fitness. We further show that the average Distinctiveness of sequences belonging to a lineage, relative to the Distinctiveness of other sequences that occur at the same place and time (n = 944 location/time data points), is predictive of future increases in prevalence (AUC = 0.88, 0.86-0.90 95% confidence interval). 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, we find that positions that constitute epitopes contribute disproportionately (20-fold higher than the average position) to Distinctiveness. Overall, this study suggests that real-time assessment of new SARS-CoV-2 variants in the context of prior regional herd exposure via Distinctiveness can augment genomic surveillance efforts.

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

BackgroundCase reports of patients infected with COVID-19 and influenza virus ("flurona") have raised questions around the prevalence and clinical significance of these reports. MethodsEpidemiological 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. FindingsConsidering 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]). ConclusionsReported 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 StatementReports 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.

Genomic diversification of long polynucleotide fragments is a signature of emerging SARS-CoV-2 variants of concern

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 5 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: 150-182; Beta 130, IQR: 113-147; Gamma = 165, IQR: 152-180; Delta = 234, IQR: 216-253; and Omicron = 294, IQR: 287-315). Omicrons 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 1,363 lineages annotated in GISAID 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 their 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.

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

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.

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

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.

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

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.

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

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.

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

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%). In July, vaccine effectiveness against hospitalization has remained high (mRNA-1273: 81%, 95% CI: 33-96.3%; BNT162b2: 75%, 95% CI: 24-93.9%), but effectiveness against infection was lower for both vaccines (mRNA-1273: 76%, 95% CI: 58-87%; BNT162b2: 42%, 95% CI: 13-62%), with a more pronounced reduction for BNT162b2. 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.

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

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.

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

The raging COVID-19 pandemic in India and reports of "vaccine breakthrough infections" globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed 1.57 million SARS-CoV-2 genomes from 187 countries/territories and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 89 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-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 = 41.8, 95% CI: 6.36-1758, p-value = 7.7e-05). In the recent COVID-19 surge in India, an NTD deletion ({Delta}F157/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 ({Delta}246-253) 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 ({Delta}156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein 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 SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.

Real-world effectiveness of Ad26.COV2.S adenoviral vector vaccine for COVID-19

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.

Cerebral venous sinus thrombosis (CVST) is not significantly linked to COVID-19 vaccines or non-COVID vaccines in a large multi-state US health system

Cerebral venous sinus thrombosis (CVST) has been reported in a small number of individuals who have received the mRNA vaccines1 or the adenoviral vector vaccines for COVID-19 in the US2 and Europe3. Continued pharmacovigilance is integral to mitigating the risk of rare adverse events that clinical trials are underpowered to detect, however, these anecdotal reports have led to the pause or withdrawal of some vaccines in many jurisdictions and exacerbated vaccine hesitancy at a critical moment in the fight against the COVID-19 pandemic. We investigated the frequencies of CVST seen among individuals who received FDA-authorized COVID-19 vaccines from Pfizer-BioNTech (n = 94,818 doses), Moderna (n = 36,350 doses) and Johnson & Johnson - J&J (n = 1,745 doses), and among individuals receiving one of 10 FDA-approved non-COVID-19 vaccines (n = 771,805 doses). Comparing the incidence rates of CVST in 30-day time windows before and after vaccination, we found no statistically significant differences for the COVID-19 vaccines or any other vaccines studied in this population. In total, we observed 3 cases of CVST within the 30 days following Pfizer-BioNTech vaccination (2 females, 1 male; Ages (years): [79, 80, 84]), including one individual with a prior history of thrombosis and another individual with recent trauma in the past 30 days. We did not observe any cases of CVST among the patients receiving Moderna or J&J vaccines in this study population. We further found the baseline CVST incidence in the study population between 2017 and 2021 to be 45 to 98 per million patient years. Overall, this real-world evidence-based study highlights that CVST is rare and is not significantly associated with COVID-19 vaccination. In addition, there is a need for a concerted international effort to monitor EHR data across diverse patient populations and to investigate the underlying biological mechanisms leading to these rare clotting events.

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

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.

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

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.

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

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.

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

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 average1. 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

Higher COVID-19 vaccination rates are linked to decreased county-level COVID-19 incidence across USA

Real world evidence studies of mass vaccination across health systems have reaffirmed the safety1 and efficacy2,3 of the FDA-authorized mRNA vaccines for COVID-19. However, the impact of vaccination on community transmission remains to be characterized. Here, we compare the cumulative county-level vaccination rates with the corresponding COVID-19 incidence rates among 87 million individuals from 580 counties in the United States, including 12 million individuals who have received at least one vaccine dose. We find that cumulative county-level vaccination rate through March 1, 2021 is significantly associated with a concomitant decline in COVID-19 incidence (Spearman correlation {rho} = -0.22, p-value = 8.3e-8), with stronger negative correlations in the Midwestern counties ({rho} = -0.37, p-value = 1.3e-7) and Southern counties ({rho} = -0.33, p-value = 4.5e-5) studied. Additionally, all examined US regions demonstrate significant negative correlations between cumulative COVID-19 incidence rate prior to the vaccine rollout and the decline in the COVID-19 incidence rate between December 1, 2020 and March 1, 2021, with the US western region being particularly striking ({rho} = -0.66, p-value = 5.3e-37). However, the cumulative vaccination rate and cumulative incidence rate are noted to be statistically independent variables, emphasizing the need to continue the ongoing vaccination roll out at scale. Given confounders such as different coronavirus restrictions and mask mandates, varying population densities, and distinct levels of diagnostic testing and vaccine availabilities across US counties, we are advancing a public health resource to amplify transparency in vaccine efficacy monitoring (https://public.nferx.com/covid-monitor-lab/vaccinationcheck). Application of this resource highlights outliers like Dimmit county (Texas), where infection rates have increased significantly despite higher vaccination rates, ostensibly owing to amplified travel as a "vaccination hub"; as well as Henry county (Ohio) which encountered shipping delays leading to postponement of the vaccine clinics. This study underscores the importance of tying the ongoing vaccine rollout to a real-time monitor of spatio-temporal vaccine efficacy to help turn the tide of the COVID-19 pandemic.