Usage and awareness of antiviral medications for COVID-19 (preprint)

We surveyed people that recently tested positive for SARS-CoV-2 to assess the frequency and correlates of early treatment seeking behavior. Among high risk respondents, 66.0% were aware of treatment for COVID-19 and 36.3% had sought treatment, however only 1.7% reported use of an antiviral for SARS-CoV-2 infection. More public outreach is needed to raise awareness of the benefits of treatment for COVID-19.

Association of Increased Fluvoxamine Use with Reports of Benefit for COVID (preprint)

Introduction: Several recent studies have found that fluvoxamine decreases the risk of serious disease progression among people with early COVID-19. In this study, we examined changes in the total number of fluvoxamine tablets dispensed across retail pharmacies in the U.S. Methods: We hypothesized that fluvoxamine prescriptions would increase substantially since March 2021 as an option for the early treatment of COVID-19. We used the IQVIA National Prescription Audit (NPA) Weekly nationally projected data for prescriptions dispensed from retail pharmacies for fluvoxamine from 27 December 2019 to 31 December 2021. We performed an interrupted-time series analyses on frequency of dispensing fluvoxamine tablets. Results: The weekly rate of dispensed tablets of fluvoxamine increased throughout the study period. The weekly number of dispensed tablets of fluvoxamine increased (11.1%) from a baseline of 1,586,154 (95% confidence interval [CI]: 1,563,960 to 1,608,348) to 1,762,381 (95% CI: 1,735,682 to 1,789,080) by December 2021. Conclusion: Our findings are consistent with a modest increase in the use of fluvoxamine for the treatment of COVID-19 associated with the discovery and media dissemination of the potential clinical benefit of fluvoxamine use.

Limited Cross-Variant Immunity after Infection with the SARS-CoV-2 Omicron Variant Without Vaccination (preprint)

SARS-CoV-2 Delta and Omicron strains are the most globally relevant variants of concern (VOCs). While individuals infected with Delta are at risk to develop severe lung disease 1 , Omicron infection causes less severe disease, mostly upper respiratory symptoms 2,3 . The question arises whether rampant spread of Omicron could lead to mass immunization, accelerating the end of the pandemic. Here we show that infection with Delta, but not Omicron, induces broad immunity in mice. While sera from Omicron-infected mice only neutralize Omicron, sera from Delta-infected mice are broadly effective against Delta and other VOCs, including Omicron. This is not observed with the WA1 ancestral strain, although both WA1 and Delta elicited a highly pro-inflammatory cytokine response and replicated to similar titers in the respiratory tracts and lungs of infected mice as well as in human airway organoids. Pulmonary viral replication, pro-inflammatory cytokine expression, and overall disease progression are markedly reduced with Omicron infection. Analysis of human sera from Omicron and Delta breakthrough cases reveals effective cross-variant neutralization induced by both viruses in vaccinated individuals. Together, our results indicate that Omicron infection enhances preexisting immunity elicited by vaccines, but on its own may not induce broad, cross-neutralizing humoral immunity in unvaccinated individuals.

A national survey of early treatment seeking behavior among those with incident SARS-CoV-2 infection (preprint)

Background: Despite effective means to treat SARS-CoV-2 infection, the early treatment seeking behavior of those newly diagnosed with infection is not clear. Methods: We surveyed users of a national SARS-CoV-2 testing company to assess the frequency and correlates of early treatment seeking behavior for a positive test result. We recruited adults (18 years or older) who had tested positive for SARS-CoV-2 by PCR at a large clinical laboratory. To be eligible, individuals had to have a positive test result within 7 days of enrollment. Surveys were anonymous and voluntary. We collected data on demographic characteristics, general health care access and utilization, awareness of treatment for COVID-19, treatment seeking behavior, and treatments received. Descriptive statistics and odds ratios (OR) with 95% confidence intervals (95% CI) were calculated on StataSE. Results: Participants were surveyed from 3-7 January 2022: among the 15,991 who viewed a survey request, 7,647 individuals were eligible and provided responses. The median age of a respondent was 42 years (interquartile range: 32 to 54), 68.9% of respondents were women, and respondents represented 33 different states, districts, and territories. Among respondents, 23.1% reported they had sought treatment or medical advice for their current COVID-19 diagnosis. Of those who were very aware of treatment for COVID-19, 31.0% sought treatment versus 16.7% who were unaware (p-value< 0.001). The odds of treatment seeking behavior were higher for those that were contacted by a medical professional after their diagnosis (OR: 4.57 [95% CI: 3.89 to 5.37]), those with a primary doctor (OR: 2.94 [95% CI: 2.52 to 3.43]), those who self-measured their oxygen saturation (OR: 2.53 [95% CI: 2.25 to 2.84]), and those over 65 years of age (OR: 2.36 [95% CI: 2.02 to 2.76]). There was no difference in those seeking treatment based on heritage, ethnicity, prior COVID-19 diagnosis, state political affiliation, or vaccination status. The odds of seeking treatment were lower among men (OR: 0.88 [95% CI: 0.78 to 0.99]) and those without insurance (OR: 0.62 [95% CI: 0.52 to 0.72]). The most common treatment locations were clinics and most common treatments were Vitamin C, Vitamin D, Zinc, Tylenol, and NSAIDs. Conclusion: More public outreach is needed to raise awareness of the benefits of treatment for COVID-19. We found that people who were more aware about treatment for COVID-19 were more likely to seek medical advice or therapy. Efforts to increase awareness might increase early treatment for SARS-CoV-2 infection. Increased outreach with treatment facilitation from medical professionals and/or public health staff to those with newly detected SARS-CoV-2 infections, particularly among those at higher-risk of complications, might also be helpful.

Omicron mutations enhance infectivity and reduce antibody neutralization of SARS-CoV-2 virus-like particles (preprint)

The Omicron SARS-CoV-2 virus contains extensive sequence changes relative to the earlier arising B.1, B.1.1 and Delta SARS-CoV-2 variants that have unknown effects on viral infectivity and response to existing vaccines. Using SARS-CoV-2 virus-like particles (SC2-VLPs), we examined mutations in all four structural proteins and found that Omicron showed increased infectivity relative to B.1, B.1.1 and similar to Delta, a property conferred by S and N protein mutations. Thirty-eight antisera samples from individuals vaccinated with tozinameran (Pfizer/BioNTech), elasomeran (Moderna), Johnson & Johnson vaccines and convalescent sera from unvaccinated COVID-19 survivors had moderately to dramatically reduced efficacy to prevent cell transduction by VLPs containing the Omicron mutations. The Pfizer/BioNTech and Moderna vaccine antisera showed strong neutralizing activity against VLPs possessing the ancestral spike protein (B.1, B.1.1), with 3-fold reduced efficacy against Delta and 15-fold lower neutralization against Omicron VLPs. Johnson & Johnson antisera showed minimal neutralization of any of the VLPs tested. Furthermore, the monoclonal antibody therapeutics Casirivimab and Imdevimab had robust neutralization activity against B.1, B.1.1 or Delta VLPs but no detectable neutralization of Omicron VLPs. Our results suggest that Omicron is at least as efficient at assembly and cell entry as Delta, and the antibody response triggered by existing vaccines or previous infection, at least prior to boost, will have limited ability to neutralize Omicron. In addition, some currently available monoclonal antibodies will not be useful in treating Omicron-infected patients.

Local monitoring of SARS-CoV-2 Variants in Two Large California Counties in 2021 (preprint)

Introduction: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to persist due to mutations resulting in newer, more infectious variants of concern. The initial government response to COVID-19 failed to engage the private sector. Engaging the private sector could have bolstered the national capacity to process diagnostic tests and track variants of concern for disease for public health surveillance. We aimed to leverage an ongoing private SARS-CoV-2 testing laboratory’s infrastructure to monitor SARS-CoV-2 variants in two large California counties.Methods: Study enrollment was offered to adults aged 18 years or older in Los Angeles County and Riverside County in California who recently tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) with a cycle threshold value less than or equal to 30 cycles. Trained healthcare workers directly observed self-collection of oral fluid or anterior nares specimens within 5 days of study enrollment. Specimens were transported and stored at 8°C or cooler. RNA was extracted from samples. Samples underwent library preparation and were sequenced. Sequencing data were filtered by quality criteria. High-quality genomic data were analyzed to identify SARS-CoV-2 lineages. Participant and genomic data were analyzed using statistical tools and visualized with toolkits. The study was approved by Advarra Institutional Review Board (Pro00053729).Results: From May 27, 2021 to September 9, 2021, 503 participants were enrolled and underwent specimen collection. Of those enrolled, there were 238 (47.3%) females, 329 (63.6%) vaccinated, and 221 (43.9%) of Hispanic or Spanish origin. Of the cohort, 496 (98.6%) had symptoms at the time of collection. Among the 503 participants, 443 (88.1%) nasal specimens and 353 (70.2%) oral specimens yielded sequencing results. Over our study period, the prevalence of the Alpha variant of SARS-CoV-2 decreased (initially 23.1% [95% confidence interval (95% CI): 0% to 0.49%] to 0% [95% CI: 0.0% to 0.0%]) as the prevalence of the Delta variant of SARS-CoV-2 increased (initially 33.3% [95% CI: 0.0% to 100.0%] to 100.0% [95% CI: 100.0% to 100.0%]). A strain that carried mutations of both Delta and Mu was identified.Conclusion: We found that outpatient SARS-CoV-2 variant surveillance could be conducted in private laboratory in a timely and accurate manner. The prevalence of different variants changed over time. A higher proportion of nasal specimens yielded results when compared to oral specimens. Timely outpatient SARS-CoV-2 variant surveillance could be used for public health efforts to identify changes in SARS-CoV-2 strain epidemiology in local areas. Government agencies should engage private laboratories in the surveillance of diseases that threaten the public’s health to supplement national disease reporting networks.

A Systematic Review of the Protective Effect of Prior SARS-CoV-2 Infection on Repeat Infection (preprint)

IntroductionWe systematically reviewed studies to estimate the risk of SARS-CoV-2 reinfection among those previously infected with SARS-CoV-2. MethodsFor this systematic review, we searched scientific publications on PubMed and, the pre-print server, MedRxiv through August 18, 2021. Eligible studies were retrieved on August 18, 2021. We used the following search term on PubMed: ((("Cohort Studies"[Majr]) AND ("COVID-19"[Mesh] OR "SARS-CoV-2"[Mesh])) OR "Reinfection"[Majr]) OR "Reinfection"[Mesh]. We used the following search term on MedRxiv: "Cohort Studies" AND "COVID-19" OR "SARS-CoV-2" AND "Reinfection". The search terms were broad to encompass all possibilities for applicable studies. There were no restrictions on the date of publication. Studies that did not describe cohorts with estimates of the risk of SARS-CoV-2 reinfection among those with previous infection were excluded. Studies that included vaccinated participants were either excluded or limited to sub-groups of non-vaccinated individuals. To identify relevant studies with appropriate control groups, we developed the following criteria for studies to be included in the systematic analysis: (1) baseline polymerase chain reaction (PCR) testing, (2) a negative comparison group, (3) longitudinal follow-up, (4) a cohort of human participants, i.e., not a case report or case series, and (5) outcome determined by PCR. The review was conducted following PRISMA guidelines. We assessed for selection, information, and analysis bias, per PRISMA guidelines. ResultsWe identified 1,392 reports. Of those, 10 studies were eligible for our systematic review. The weighted average risk reduction against reinfection was 90.4% with a standard deviation of 7.7%. Protection against SARS-CoV-2 reinfection was observed for up to 10 months. Studies had potential information, selection, and analysis biases. ConclusionsThe protective effect of prior SARS-CoV-2 infection on re-infection is high and similar to the protective effect of vaccination. More research is needed to characterize the duration of protection and the impact of different SARS-CoV-2 variants.

Incidence of Severe Acute Respiratory Syndrome Coronavirus-2 infection among previously infected or vaccinated employees (preprint)

Introduction: The protective effect of previous infection versus vaccination is poorly studied. Among a clinical laboratory that has been conducting routine workforce screening since the beginning of the pandemic, we aimed to assess the relative risk of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection among individuals who were SARS-CoV-2 naive, previously infected, or vaccinated. Methods: Using an electronic laboratory information system, employees were divided into three groups: (1) SARS-CoV-2 naive and unvaccinated, (2) previous SARS-CoV-2 infection, and (3) vaccinated. Person-days were measured from the date of the employee first test and truncated at the end of the observation period. SARS-CoV-2 infection was defined as two positive SARS-CoV-2 PCR tests in a 30-day period. Individuals with fewer than 14 days of follow up were excluded. Incidence estimates and the 95% confidence intervals were calculated using the Poisson Exact equation. The incidence rate ratio (IRR) was used as a measure of association between groups. Analyses were performed on StataSE (StataCorp, College Station, TX). Results: We identified 4313, 254 and 739 employee records for groups 1, 2, and 3, respectively. The median age of employees was 29.0 years (interquartile range: 23.6, 39.9). During the observation period, 254, 0, and 4 infections were identified among groups 1, 2, and 3, respectively. Group 1 had an incidence of 25.9 per 100 person-years (95% CI: 22.8-29.3). Group 2 had an incidence of 0 per 100 person-years (95% CI: 0-5.0). Group 3 had an incidence of 1.6 per 100 person-years (95% CI: 0.04-4.2). The IRR of reinfection among those with previous infection compared to SARS-CoV-2 naive was 0 (95% CI: 0-0.19). The IRR of those vaccinated compared to SARS-CoV-2 naive was 0.06 (95% CI: 0.02-0.16). The IRR of those vaccinated compared to prior SARS-CoV-2 was 0 (95% CI: 0-4.98). Conclusion: Previous SARS-CoV-2 infection and vaccination for SARS-CoV-2 were associated with decreased risk for infection or re-infection with SARS-CoV-2 in a routinely screened workforce. The was no difference in the infection incidence between vaccinated individuals and individuals with previous infection. Further research is needed to determine whether our results are consistent with the emergence of new SARS-CoV-2 variants.

Evaluation of the INDICAID COVID-19 Rapid Antigen Test in symptomatic populations and asymptomatic community testing (preprint)

Background As the COVID-19 pandemic continues to cause substantial morbidity and mortality, there is an increased need for rapid, accessible assays for SARS-CoV-2 detection. Methods Here we present a clinical evaluation and real-world implementation of the INDICAID COVID-19 Rapid Antigen Test (INDICAID Rapid Test). A multi-site clinical evaluation of the INDICAID Rapid Test using prospectively collected samples from symptomatic subjects was performed. The INDICAID Rapid Test was then implemented at COVID-19 outbreak screening centers in Hong Kong to screen individuals for COVID-19 to prioritize confirmatory RT-PCR testing among asymptomatic populations. Results The clinical evaluation in symptomatic patient populations demonstrated a positive percent agreement and negative percent agreement of 85.3% (95% confidence interval [95% CI]: 75.6% - 91.6%) and 94.9% (95% CI: 91.6% - 96.9%), respectively, when compared to laboratory-based RT-PCR testing. When used during outbreak testing of 22,994 asymptomatic patients, the INDICAID Rapid Test demonstrated a positive percent agreement of 84.2% (95% CI: 69.6% - 92.6%) and a negative percent agreement of 99.9% (95% CI: 99.9% - 100%) compared to laboratory-based RT-PCR testing. When incorporated in a testing algorithm, the INDICAID Rapid Test reduced time to confirmatory positive result from an average 10.85 hours (standard RT-PCR only) to 0.84 hours, depending on the algorithm. Conclusion The INDICAID Rapid Test has excellent performance when compared to laboratory-based RT-PCR testing, and when used in tandem with RT-PCR, reduces the time to confirmatory positive result.

Detection of persistent SARS-CoV-2 IgG antibodies in oral mucosal fluid and upper respiratory tract specimens following COVID-19 mRNA vaccination (preprint)

Previous studies have shown that mRNA COVID-19 vaccines are highly effective at preventing SAR-CoV-2 infection by generating an immune response, which in part produces SARS-CoV-2 IgG antibodies in serum. In this study, we hypothesized that COVID-19 vaccines may elicit production of SARS-CoV-2 IgG antibodies in the upper respiratory tract, such as in oral and nasal mucosal fluid. To test that hypothesis, we enrolled 114 participants within 3-7 days of receiving the first dose of the Moderna mRNA COVID-19 vaccine and collected oral mucosal fluid samples on days 5, 10, 15, and 20 after each vaccine dose. Of participants naive to SARS-CoV-2 (n = 89), 79 (85.4%) tested positive for SARS-CoV-2 IgG antibodies by time point 2 (10 days +/-2 days after first vaccine dose), and 100% tested positive for SARS-CoV-2 IgG by time point 3 (15 days +/-2 days after first vaccine dose). Additionally, we collected paired oral mucosal fluid and anterior nares samples from 10 participants who had received both vaccine doses. We found that participants had an average SARS-CoV-2 IgG antibody concentration of 2496.0 +/-2698.0ng/mL in nasal mucosal fluid versus 153.4 +/-141.0ng/mL in oral mucosal fluid. Here, we demonstrate detection and longitudinal persistence of SARS-CoV-2 IgG antibodies in upper respiratory tract specimens following COVID-19 mRNA vaccination.

Post-Disease Divergence in SARS-CoV-2 RNA Detection between Nasopharyngeal, Anterior Nares and Saliva/Oral Fluid Specimens - Significant Implications for Policy & Public Health (preprint)

Background - Patients have been shown to shed SARS-CoV-2 viral RNA in nasopharyngeal (NP) specimens for over 100 days after resolution of clinical disease (1, 2). How this relates to anterior nares and oral fluid specimens has not previously been investigated. Methods - We prospectively collected oral fluid, anterior nares, NP swab and serum specimens from 1,326 individuals at 2 'drive-through' testing locations. The Curative SARS-CoV-2 Assay (Curative Assay)(3) on oral fluid and anterior nares specimens was compared to the EURORealTime SARS-CoV-2 Assay (EuroRT Assay)(4) on anterior nares and NP specimens. Viral culture and IgG serology were used to assess infectious potential and stage of disease. Additionally we investigated differences in viral RNA detection between specimen types, both early (< 21 days) and late (> 21 days) in SARS-CoV-2 infection, by using an employee surveillance program with daily SARS-CoV-2 testing to precisely determine infection date, even without symptoms. We prospectively collected oral fluid, anterior nares and NP swab specimens from 165 subjects with early infections and 22 subjects with late infections. Specimens were tested using the Curative Assay with the 'high-sensitivity' Hologic Aptima SARS-CoV-2 Assay (Hologic Assay)(5) on an NP swab used as the comparator. Late infection specimens were also tested with EuroRT and Zymo Quick SARS-CoV-2 rRT-PCR Kit (Zymo) (6) Assays. Results - The 'drive-through' study showed similar sensitivities of oral fluid and anterior nares specimens on the Curative Assay to anterior nares specimens tested with the EuroRT Assay. However NP specimens tested with the same EuroRT assay produced 20-30% more positives. Incorporating viral culture and serology data to exclude NP RT-PCR positives that are not infectious or late in the course of disease showed a Positive Percent Agreement (PPA) for of 98.2% and 96.2% and Negative Percent Agreement (NPA) of 97.6% and 98.1% for anterior nares and oral fluid specimens, respectively. Within 21 days of infection, the Curative Assay showed a PPA and NPA of 100% and 100%, respectively for oral fluid; of 100% and 99% respectively for anterior nares; and of 98.2% and 99.0%, respectively in nasopharyngeal specimens compared to an NP specimen on the Hologic Assay. 29 positives were asymptomatic and showed 100% PPA and 100% NPA for all specimen types. After 21 days from infection onset, significant divergence between NP and other specimen types occurred on all 4 assays. Out of 22 paired sample sets, 18, 13, 8 and 4 NP specimens were positive on the Curative, Zymo, Hologic and EuroRT assays, respectively, compared to only 3, 2, 0 and 1 positive anterior nares specimens. Only one oral fluid sample was positive in both the Curative and Zymo assays. Conclusions - We used a unique population to show significant divergence between NP specimens and anterior nares or oral fluid specimens >21 days from SARS-CoV-2 infection, which appears to be biological variation and is independent of assay used. This has significant public health implications for the use of NP specimens in community testing programs and policy implications for evaluation of novel specimen types and tests where the use of NP swabs as a comparator may say more about the study population than the assay or specimen type to be evaluated and may unnecessarily limit access to testing.

Self-Collected Oral Fluid and Nasal Swabs Demonstrate Comparable Sensitivity to Clinician Collected Nasopharyngeal Swabs for Covid-19 Detection (preprint)

BackgroundCurrently, there is a pandemic caused by the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes Covid-19. We wanted to compare specimen types and collection methods to explore if a simpler to collect specimen type could expand access to testing. MethodsWe recruited individuals recently tested for SARS-CoV-2 infection through a "drive-through" testing program. In participants homes, we assessed the performance of self-collected oral fluid swab specimens with and without clinician supervision, clinician-supervised self-collected mid-turbinate (nasal) swab specimens, and clinician-collected nasopharyngeal swab specimens. We tested specimens with a validated reverse transcription-quantitative polymerase chain reaction assay for the detection of SARS-CoV-2 and measured cycle threshold values. Symptom status and date of onset of symptoms was also recorded for each participant. ResultsWe recruited 45 participants. The median age of study participant was 42 years old (Interquartile range, 31 to 52 years). Of the participants, 29 had at least one specimen test positive for SARS-CoV-2. Of those, 21 (73%) of 29 reported active symptoms. By specimen type and home-based collection method, clinician-supervised self-collected oral fluid swab specimens detected 26 (90%) of 29 infected individuals, clinician-supervised self-collected nasal swab specimens detected 23 (85%) of 27, clinician-collected posterior nasopharyngeal swab specimens detected 23 (79%) of 29, and unmonitored self-collected oral fluid swab specimens detected 19 (66%) of 29. Despite nasopharyngeal swabs being considered the gold standard, 4 participants tested negative by clinician-collected nasopharyngeal swab and positive by the 3 other specimen types. Additionally, false negative results by each sample type were seen to generally not overlap. ConclusionsSupervised self-collected oral fluid and nasal swab specimens performed similarly to, if not better than clinician-collected nasopharyngeal swab specimens for the detection of SARS-CoV-2 infection. No sample type captured all SARS-CoV-2 infections, suggesting potential heterogeneity in the distribution of viral load in different parts of the respiratory tract between individuals. Supervised self-collection performed comparably to clinician collection and would allow for rapid expansion of testing capacity in the United States by reducing the need for trained healthcare workers, reducing exposure of healthcare workers, and reducing the amount of PPE (personal protective equipment) being used for testing during a critical shortage.