Early signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas

Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology, clinical severity, and disease course. A genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 4,468 symptomatic patients with infections caused by Omicron from late November 2021 through January 5, 2022. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases, and at the end of the study period caused 98% of new cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with on average decreased disease severity. Two patients with Omicron "stealth" sublineage BA.2 also were identified. The data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and address the lack of information about disease character among US patients.

Delta variants of SARS-CoV-2 cause significantly increased vaccine breakthrough COVID-19 cases in Houston, Texas

Genetic variants of SARS-CoV-2 have repeatedly altered the course of the COVID-19 pandemic. Delta variants of concern are now the focus of intense international attention because they are causing widespread COVID-19 disease globally and are associated with vaccine breakthrough cases. We sequenced the genomes of 16,965 SARS-CoV-2 from samples acquired March 15, 2021 through September 20, 2021 in the Houston Methodist hospital system. This sample represents 91% of all Methodist system COVID-19 patients during the study period. Delta variants increased rapidly from late April onward to cause 99.9% of all COVID-19 cases and spread throughout the Houston metroplex. Compared to all other variants combined, Delta caused a significantly higher rate of vaccine breakthrough cases (23.7% for Delta compared to 6.6% for all other variants combined). Importantly, significantly fewer fully vaccinated individuals required hospitalization. Individuals with vaccine breakthrough cases caused by Delta had a low median PCR cycle threshold (Ct) value (a proxy for high virus load). This value was closely similar to the median Ct value for unvaccinated patients with COVID-19 caused by Delta variants, suggesting that fully vaccinated individuals can transmit SARS-CoV-2 to others. Patients infected with Alpha and Delta variants had several significant differences. Our integrated analysis emphasizes that vaccines used in the United States are highly effective in decreasing severe COVID-19 disease, hospitalizations, and deaths.

Rapid, widespread, and preferential increase of SARS-CoV-2 B.1.1.7 variant in Houston, TX, revealed by 8,857 genome sequences

Genetic variants of the SARS-CoV-2 virus have become of great interest worldwide because they have the potential to detrimentally alter the course of the SARS-CoV-2 pandemic, and disease in individual patients. We recently sequenced 20,453 SARS- CoV-2 genomes from patients with COVID-19 disease in metropolitan Houston (population 7 million), dating from March 2020 to early February 2021. We discovered that all major variants of concern or interest are circulating in the region. To follow up on this discovery, we analyzed 8,857 genome sequences from patients in eight Houston Methodist hospitals dispersed throughout the metroplex diagnosed from January 1, 2021 to March 7, 2021. This sample represents 94% of Houston Methodist cases and 4.8% of all reported cases in metropolitan Houston during this period. We discovered rapid, widespread, and preferential increase of the SARS-CoV-2 UK B.1.1.7 throughout the region. The estimated case doubling time in the Houston area is 6.9 days. None of the 648 UK B.1.1.7 samples identified had the E484K change in spike protein that can cause decreased recognition by antibodies.

Sequence Analysis of 20,453 SARS-CoV-2 Genomes from the Houston Metropolitan Area Identifies the Emergence and Widespread Distribution of Multiple Isolates of All Major Variants of Concern

[Abstract]Since the beginning of the SARS-CoV-2 pandemic, there has been international concern about the emergence of virus variants with mutations that increase transmissibility, enhance escape from the human immune response, or otherwise alter biologically important phenotypes. In late 2020, several "variants of concern" emerged globally, including the UK variant (B.1.1.7), South Africa variant (B.1.351), Brazil variants (P.1 and P.2), and two related California "variants of interest" (B.1.429 and B.1.427). These variants are believed to have enhanced transmissibility capacity. For the South Africa and Brazil variants, there is evidence that mutations in spike protein permit it to escape from some vaccines and therapeutic monoclonal antibodies. Based on our extensive genome sequencing program involving 20,453 virus specimens from COVID-19 patients dating from March 2020, we report identification of all important SARS-CoV-2 variants among Houston Methodist Hospital patients residing in the greater metropolitan area. Although these variants are currently at relatively low frequency in the population, they are geographically widespread. Houston is the first city in the United States to have all variants documented by genome sequencing. As vaccine deployment accelerates worldwide, increased genomic surveillance of SARS-CoV-2 is essential to understanding the presence and frequency of consequential variants and their patterns and trajectory of dissemination. This information is critical for medical and public health efforts to effectively address and mitigate this global crisis.

Early transfusion of a large cohort of COVID-19 patients with high titer anti-SARS-CoV-2 spike protein IgG convalescent plasma confirms a signal of significantly decreased mortality

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 remains a global threat with few proven efficacious treatments. Transfusion of convalescent plasma collected from donors who have recovered from COVID-19 disease has emerged as a promising therapy and has been granted emergency use authorization by the U.S. Food and Drug Administration (FDA). We recently reported results from interim analysis of a propensity-score matched study suggesting that early treatment of COVID-19 patients with convalescent plasma containing high titer anti-spike protein receptor binding domain (RBD) IgG significantly decreases mortality. We here present results from 60-day follow up of our cohort of 351 transfused hospitalized patients. Prospective determination of ELISA anti-RBD IgG titer facilitated selection and transfusion of the highest titer units available. Retrospective analysis by the Ortho VITROS IgG assay revealed a median signal/cutoff (S/C) ratio of 24.0 for transfused units, a value far exceeding the recently FDA-required cutoff of 12.0 for designation of high titer convalescent plasma. With respect to altering mortality, our analysis identified an optimal window of 44 hours post-hospitalization for transfusing COVID-19 patients with high titer convalescent plasma. In the aggregate, the analysis confirms and extends our previous preliminary finding that transfusion of COVID-19 patients soon after hospitalization with high titer anti-spike protein RBD IgG present in convalescent plasma significantly reduces mortality.

Molecular Architecture of Early Disseminationand Massive Second Wave of the SARS-CoV-2 Virus in a Major Metropolitan Area

We sequenced the genomes of 5,085 SARS-CoV-2 strains causing two COVID-19 disease waves in metropolitan Houston, Texas, an ethnically diverse region with seven million residents. The genomes were from viruses recovered in the earliest recognized phase of the pandemic in Houston, and an ongoing massive second wave of infections. The virus was originally introduced into Houston many times independently. Virtually all strains in the second wave have a Gly614 amino acid replacement in the spike protein, a polymorphism that has been linked to increased transmission and infectivity. Patients infected with the Gly614 variant strains had significantly higher virus loads in the nasopharynx on initial diagnosis. We found little evidence of a significant relationship between virus genotypes and altered virulence, stressing the linkage between disease severity, underlying medical conditions, and host genetics. Some regions of the spike protein - the primary target of global vaccine efforts - are replete with amino acid replacements, perhaps indicating the action of selection. We exploited the genomic data to generate defined single amino acid replacements in the receptor binding domain of spike protein that, importantly, produced decreased recognition by the neutralizing monoclonal antibody CR30022. Our study is the first analysis of the molecular architecture of SARS-CoV-2 in two infection waves in a major metropolitan region. The findings will help us to understand the origin, composition, and trajectory of future infection waves, and the potential effect of the host immune response and therapeutic maneuvers on SARS-CoV-2 evolution. IMPORTANCEThere is concern about second and subsequent waves of COVID-19 caused by the SARS-CoV-2 coronavirus occurring in communities globally that had an initial disease wave. Metropolitan Houston, Texas, with a population of 7 million, is experiencing a massive second disease wave that began in late May 2020. To understand SARS-CoV-2 molecular population genomic architecture, evolution, and relationship between virus genotypes and patient features, we sequenced the genomes of 5,085 SARS-CoV-2 strains from these two waves. Our study provides the first molecular characterization of SARS-CoV-2 strains causing two distinct COVID-19 disease waves.

Limited window for donation of convalescent plasma with high live-virus neutralizing antibodies for COVID-19 immunotherapy

The optimal timeframe for donating convalescent plasma to be used for COVID-19 immunotherapy is unknown. To address this important knowledge deficit, we determined in vitro live-virus neutralizing capacity and persistence of IgM and IgG antibody responses against the receptor-binding domain and S1 ectodomain of the SARS-CoV-2 spike glycoprotein in 540 convalescent plasma samples obtained from 175 COVID-19 plasma donors for up to 142 days post-symptom onset. Robust IgM, IgG, and viral neutralization responses to SARS-CoV-2 persist, in the aggregate, for at least 100 days post-symptom onset. However, a notable acceleration in decline in virus neutralization titers [≥]160, a value suitable for convalescent plasma therapy, was observed starting 60 days after first symptom onset. Together, these findings better define the optimal window for donating convalescent plasma useful for immunotherapy of COVID-19 patients and reveal important predictors of an ideal plasma donor, including age and COVID-19 disease severity score. One Sentence SummaryEvaluation of SARS-CoV-2 anti-spike protein IgM, IgG, and live-virus neutralizing titer profiles reveals that the optimal window for donating convalescent plasma for use in immunotherapy is within the first 60 days of symptom onset.

Relationship between Anti-Spike Protein Antibody Titers and SARS-CoV-2 In Vitro Virus Neutralization in Convalescent Plasma

Newly emerged pathogens such as SARS-CoV-2 highlight the urgent need for assays that detect levels of neutralizing antibodies that may be protective. We studied the relationship between anti-spike ectodomain (ECD) and anti-receptor binding domain (RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by two different in vitro assays using convalescent plasma samples obtained from 68 COVID-19 patients, including 13 who donated plasma multiple times. Only 23% (16/68) of donors had been hospitalized. We also studied 16 samples from subjects found to have anti-spike protein IgG during surveillance screening of asymptomatic individuals. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers, and in vitro VN titer. Anti-RBD plasma IgG correlated slightly better than anti-ECD IgG titer with VN titer. The probability of a VN titer [≥]160 was 80% or greater with anti-RBD or anti-ECD titers of [≥]1:1350. Thirty-seven percent (25/68) of convalescent plasma donors lacked VN titers [≥]160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease either VN or IgG titers. Analysis of 2,814 asymptomatic adults found 27 individuals with anti-RBD or anti-ECD IgG titers of [≥]1:1350, and evidence of VN [≥]1:160. Taken together, we conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titer of [≥]1:1350 may provide critical information about protection against COVID-19 disease.

Prevalence of SARS-CoV-2 infection among asymptomatic healthcare workers in greater Houston: a cross-sectional analysis of surveillance data from a large healthcare system

ObjectiveTo determine the prevalence of SARS-CoV-2 infection among asymptomatic COVID-19 facing and non-COVID-19 facing Healthcare Workers (HCWs), with varying job categories across different hospitals. DesignCross-sectional analysis of a healthcare system surveillance program that included asymptomatic clinical (COVID-19 facing and non-COVID-19 facing), and non-clinical HCWs. A convenience sample of asymptomatic community residents (CR) was also tested. Proportions and 95% confidence Intervals (CI) of SARS-CoV-2 positive HCWs are reported. Proportional trend across HCW categories was tested using Chi Square trend test. Logistic regression model-based likelihood estimates of SARS-CoV-2 prevalence among HCWs with varying job functions and across different hospitals are reported as adjusted odds ratios (aOR) and CI. SettingHealthcare system comprising one tertiary care academic medical center and six large community hospitals across Greater Houston and a community sample. Participants2,872 self-reported asymptomatic adult (> 18 years) HCWs and CRs. ExposureClinical HCWs in COVID-19 and non-COVID-19 units, non-Clinical HCWs, and CRs. Job categories of Nursing, Providers, Allied Health, Support, and Administration / Research. Seven hospitals in the healthcare system. Main OutcomesPositive reverse transcriptase polymerized chain reaction (RT-PCR) test for SARS-CoV-2 ResultsAmong 2,872 asymptomatic HCWs and CRs, 3.9% (CI: 3.2 - 4.7) tested positive for SARS-CoV-2. Mean (SD) age was 40.9 (11.7) years and 73% were females. Among COVID-19 facing HCWs 5.4% (CI: 4.5 - 6.5) were positive, whereas 0.6% (CI: 0.2 - 1.7%) of non COVID-19 facing HCWs and none of the non-clinical HCWs or CRs were positive (Ptrend < 0.001). Among COVID-19 facing HCWs, SARS-CoV-2 positivity was similar for all job categories (p = 0.74). However, significant differences in positivity were observed across hospitals. Conclusions and RelevanceAsymptomatic HCWs with COVID-19 patient exposure had a higher rate of SARS-CoV-2 positive testing than those not routinely exposed to COVID-19 patients and those not engaged in patient care. Among HCWs with routine COVID-19 exposure, all job types had relatively similar infection rates. These data can inform hospital surveillance and infection control practices for patient-facing job classifications and suggest that general environmental exposure within hospitals is not a significant source of asymptomatic SARS-CoV-2 infection. What is already known on this topicO_LIA sizeable proportion of individuals who contract the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can remain largely asymptomatic. C_LIO_LIThough such individuals may not develop symptoms, they continue to shed enough viral particles to trigger positive reverse transcriptase polymerized chain reaction (RT PCR) test for SARS-CoV-2 C_LIO_LIPrior reports on proportion of asymptomatic SARS-CoV-2 individuals are highly variable with positivity ranging across < 1% to 36% C_LIO_LIAsymptomatic SARS-CoV-2 infection among healthcare workers is specifically critical to understand C_LI What this study addsO_LIThis study demonstrates that overall rate of SARS-CoV-2 infection among asymptomatic healthcare workers in a large healthcare system of a metropolitan city in the United States was 3.9% C_LIO_LIThe rate of SARS-CoV-2 infection among healthcare workers who provided direct care to COVID-19 patients was 5.4% whereas it was 0.6% among those healthcare workers who did not provide direct care to COVID-19 patients C_LIO_LIThere was no difference in SARS-CoV-2 positivity rate for different job categories of healthcare workers who provided direct care to COVID-19 patients C_LI

Treatment of COVID-19 Patients with Convalescent Plasma in Houston, Texas

BackgroundCOVID-19 disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for more than 100 years. MethodsPatients (n=25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28 - April 14, 2020. Patients were transfused with convalescent plasma obtained from donors with confirmed SARS-CoV-2 infection and had been symptom free for 14 days. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 post-transfusion. Clinical improvement was assessed based on a modified World Health Organization 6-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. ResultsAt baseline, all patients were receiving supportive care, including anti-inflammatory and anti-viral treatments, and all patients were on oxygen support. At day 7 post-transfusion with convalescent plasma, nine patients had at least a 1-point improvement in clinical scale, and seven of those were discharged. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged. No adverse events as a result of plasma transfusion were observed. The whole genome sequencing data did not identify a strain genotype-disease severity correlation. ConclusionsThe data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease. Randomized, controlled trials are needed to determine its efficacy.

Molecular Architecture of Early Dissemination and Evolution of the SARS-CoV-2 Virus in Metropolitan Houston, Texas

We sequenced the genomes of 320 SARS-CoV-2 strains from COVID-19 patients in metropolitan Houston, Texas, an ethnically diverse region with seven million residents. These genomes were from the viruses causing infections in the earliest recognized phase of the pandemic affecting Houston. Substantial viral genomic diversity was identified, which we interpret to mean that the virus was introduced into Houston many times independently by individuals who had traveled from different parts of the country and the world. The majority of viruses are apparent progeny of strains derived from Europe and Asia. We found no significant evidence of more virulent viral types, stressing the linkage between severe disease, underlying medical conditions, and perhaps host genetics. We discovered a signal of selection acting on the spike protein, the primary target of massive vaccine efforts worldwide. The data provide a critical resource for assessing virus evolution, the origin of new outbreaks, and the effect of host immune response. SignificanceCOVID-19, the disease caused by the SARS-CoV-2 virus, is a global pandemic. To better understand the first phase of virus spread in metropolitan Houston, Texas, we sequenced the genomes of 320 SARS-CoV-2 strains recovered from COVID-19 patients early in the Houston viral arc. We identified no evidence that a particular strain or its progeny causes more severe disease, underscoring the connection between severe disease, underlying health conditions, and host genetics. Some amino acid replacements in the spike protein suggest positive immune selection is at work in shaping variation in this protein. Our analysis traces the early molecular architecture of SARS-CoV-2 in Houston, and will help us to understand the origin and trajectory of future infection spikes.