Reduced risk of SARS-CoV-2 infection among household contacts with recent vaccination and past COVID-19 infection: results from two multi-site case-ascertained household transmission studies (preprint)

Background COVID-19 vaccines reduce the risk of severe disease, but it is less clear what effect vaccines have on reducing the risk of infection in high contact settings like households, alone or in combination with prior infection. Methods Households with an individual who tested positive for SARS-CoV-2 during Sep 2021-May 2023 were screened nationwide and at 7 sentinel sites and enrolled if the index cases illness onset was [≤]6 days prior. Household members had daily self-collected nasal swabs tested by RT-PCR for SARS-CoV-2. COVID-19 vaccination status was assessed by plausible self-report (with date) or vaccination records. Prior infection was assessed by self-reported prior testing and by anti-nucleocapsid antibodies presence at enrollment. The effects of prior immunity, including vaccination, prior infection, or hybrid immunity (both vaccination and prior infection) on SARS-CoV-2 infection risk among household contacts were assessed by robust, clustered multivariable Poisson regression. Findings There were 1,532 contacts from 905 households included in this analysis. Of these, 67% were enrolled May-November 2022, when Omicron BA.4/5 predominated. Most contacts (89%) had some immunity to SARS-CoV-2 at the time of household exposure: 8% had immunity from prior infection alone, 51% from vaccination alone, and 29% had hybrid immunity. Sixty percent of contacts tested SARS-CoV-2-positive during follow-up. The risk of SARS-CoV-2 infection was not significantly reduced by vaccination but was reduced among those with prior infection considering such immunity separately (adjusted relative risk 0.83; 95% confidence interval: 0.77, 0.90); however, when accounting for both sources of immunity, only contacts with vaccination and prior infection had significantly reduced risk of infection (aRR: 0.81, 95% CI: 0.70, 0.93). The risk of infection was lower when the last immunizing event (vaccination or infection) occurred [≤]6 months before COVID-19 affected the household (aRR: 0.69, 95% CI: 0.57, 0.83). Interpretation Immunity from COVID-19 vaccination and prior infection was synergistic in protecting household contacts from SARS-CoV-2 infection. These data support COVID-19 vaccination, even for those who have been previously infected.

Changes in Transmission and Symptoms of SARS-CoV-2 in United States Households, April 2020-September 2022 (preprint)

BackgroundThe natural history of SARS-CoV-2 infection and transmission dynamics may have changed as SARS-CoV-2 has evolved and population immunity has shifted. MethodsHousehold contacts, enrolled from two multi-site case-ascertained household transmission studies (April 2020-April 2021 and September 2021-September 2022), were followed for 10-14 days after enrollment with daily collection of nasal swabs and/or saliva for SARS-CoV-2 testing and symptom diaries. SARS-CoV-2 virus lineage was determined by whole genome sequencing, with multiple imputation where sequences could not be recovered. Adjusted infection risks were estimated using modified Poisson regression. Findings858 primary cases with 1473 household contacts were examined. Among unvaccinated household contacts, the infection risk adjusted for presence of prior infection and age was 58% (95% confidence interval [CI]: 49-68%) in households currently exposed to pre-Delta lineages and 90% (95% CI: 74-100%) among those exposed to Omicron BA.5 (detected May - September 2022). The fraction of infected household contacts reporting any symptom was similarly high between pre-Delta (86%, 95% CI: 81-91%) and Omicron lineages (77%, 70-85%). Among Omicron BA.5-infected contacts, 48% (41-56%) reported fever, 63% (56-71%) cough, 22% (17-28%) shortness of breath, and 20% (15-27%) loss of/change in taste/smell. InterpretationThe risk of infection among household contacts exposed to SARS-CoV-2 is high and increasing with more recent SARS-CoV-2 lineages. This high infection risk highlights the importance of vaccination to prevent severe disease. FundingFunded by the Centers for Disease Control and Prevention and the Food and Drug Administration. Key points- Monitoring the transmissibility and symptomatology of SARS-CoV-2 lineages is important for informing public health practice and understanding the epidemiology of COVID-19; household transmission studies contribute to our understanding of the natural history of SARS-CoV-2 infections and the transmissibility of SARS-CoV-2 variants. - The Omicron BA.5 sub-lineage is highly transmissible, similar to previous Omicron sub-lineages. - Over 80% of infected household contacts reported at least 1 symptom during their infection and the proportion of household contacts with asymptomatic infection did not differ by SARS-CoV-2 variant. The most common symptom was cough. Change in taste or smell was more common in Omicron BA.5 infections, compared to previous Omicron sub-lineages, but less common compared to pre-Delta lineages. - The high infection risk among household contacts supports the recommendations that individuals maintain up-to-date and lineage-specific vaccinations to mitigate further risks of severe disease.

Shared within-host SARS-CoV-2 variation in households (preprint)

Background: The limited variation observed among SARS-CoV-2 consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference. Methods: We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples from four prospective studies and combined sequence data with household membership data, a proxy for transmission linkage. Results: Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 SNPs; range, 0-40). Most (83.1%, 255/307) samples harbored at least one intrahost single nucleotide variant (iSNV; median: 117; IQR: 17-208), when applying a liberal minor allele frequency of 0.5% and prior to filtering. A mean of 15.4% of within-host iSNVs were recovered one day later. Pairs in the same household shared significantly more iSNVs (mean: 1.20 iSNVs; 95% CI: 1.02-1.39) than did pairs in different households infected with the same viral clade (mean: 0.31 iSNVs; 95% CI: 0.28-0.34), a signal that increases with increasingly liberal thresholds. Conclusions: Although only a subset of within-host variation is consistently shared across likely transmission pairs, shared iSNVs may augment the information in consensus sequences for predicting transmission linkages.

Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial (preprint)

Background Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries. Methods We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1:1 to receive placebo or favipiravir (1800 mg BID Day 1, 800mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 deep sequencing, we assessed favipiravir’s impact on mutagenesis. Results From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants’ mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48 – 1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54 – 1.29; sustained: HR 0.87, 95% CI 0.52 – 1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment. Conclusions Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19. Trial registration number NCT04346628 Summary In this phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or uncomplicated patients with COVID-19, we found no difference in time to shedding cessation or time to symptom resolution by treatment arm.

Race-ethnicity and Perceptional Determinants of COVID-19 Vaccination Intentions: A Cross-sectional Study Among Health Workers and the General Population in the San Francisco Bay Area (preprint)

Importance: Surveys in the US have found that Black and Latinx individuals have more reservations than their white counterparts about COVID-19 vaccination. However, little is known about the degree to which racial-ethnic differences in COVID-19 vaccination intentions are explained by differences in beliefs or perceptions about COVID-19 vaccines. Objective: To compare intention to receive COVID-19 vaccination by race-ethnicity, to identify perceptional factors that may mediate the association between race-ethnicity and intention to receive the vaccine, and to identify the demographic and perceptional factors most strongly predictive of intention to receive a vaccine. Design: Cross-sectional survey conducted from November, 2020 to January, 2021, nested within two longitudinal cohort studies of prevalence and incidence of SARS CoV-2 among the general population and healthcare workers. Setting: Six San Francisco Bay Area counties. Study Cohort: 3,161 participants in the Track COVID cohort (a population-based sample of adults) and 1,803 participants in the CHART Study cohort (a cohort of employees at three large medical centers). Results: Rates of high vaccine willingness were significantly lower among Black (45.3%), Latinx (62.5%), Asian (65%), multi-racial (67.2%), and other race (61.0%) respondents than among white respondents (77.6%). Black, Latinx, and Asian respondents were significantly more likely than white respondents to endorse reasons to not get vaccinated, especially lack of trust. Participants' motivations and concerns about COVID-19 vaccination only partially explained racial-ethnic differences in vaccination willingness. Being a health worker in the CHART cohort and concern about a rushed government vaccine approval process were the two most important factors predicting vaccination intention. Conclusions and Relevance: Special efforts are required to reach historically marginalized racial-ethnic communities to support informed decision-making about COVID-19 vaccination. These campaigns must acknowledge the history of racism in biomedical research and health care delivery that has degraded the trustworthiness of health and medical science institutions among non-white population and may continue to undermine confidence in COVID-19 vaccines.

SARS-CoV-2 subgenomic RNA kinetics in longitudinal clinical samples (preprint)

BackgroundGiven the persistence of viral RNA in clinically recovered COVID-19 patients, subgenomic RNAs (sgRNA) have been reported as potential molecular viability markers for SARS-CoV-2. However, few data are available on their longitudinal kinetics, compared with genomic RNA (gRNA), in clinical samples. MethodsWe analyzed 536 samples from 205 patients with COVID-19 from placebo-controlled, outpatient trials of Peginterferon Lambda-1a (Lambda; n=177) and favipiravir (n=359). Nasal swabs were collected at three time points in the Lambda (Day 1, 4 and 6) and favipiravir (Day 1, 5, and 10) trials. N-gene gRNA and sgRNA were quantified by RT-qPCR. To investigate the decay kinetics in vitro, we measured gRNA and sgRNA in A549ACE2+ cells infected with SARS-CoV-2, following treatment with remdesivir or DMSO control. ResultsAt six days in the Lambda trial and ten days in the favipiravir trial, sgRNA remained detectable in 51.6% (32/62) and 49.5% (51/106) of the samples, respectively. Cycle threshold (Ct) values for gRNA and sgRNA were highly linearly correlated (Pearsons r=0.87) and the rate of increase did not differ significantly in Lambda (1.36 cycles/day vs 1.36 cycles/day; p = 0.97) or favipiravir (1.03 cycles/day vs 0.94 cycles/day; p=0.26) trials. From samples collected 15-21 days after symptom onset, sgRNA was detectable in 48.1% (40/83) of participants. In SARS-CoV-2 infected A549ACE2+ cells treated with remdesivir, the rate of Ct increase did not differ between gRNA and sgRNA. ConclusionsIn clinical samples and in vitro, sgRNA was highly correlated with gRNA and did not demonstrate different decay patterns to support its application as a viability marker. SummaryWe observed prolonged detection of subgenomic RNA in nasal swabs and equivalent decay rates to genomic RNA in both longitudinal nasal swabs and in remdesivir-treated A549ACE2+ cells infected with SARS-CoV-2. Taken together, these findings suggest that subgenomic RNA from SARS-CoV-2 is comparably stable to genomic RNA and that its detection is therefore not a more reliable indicator of replicating virus.

Healthcare personnel knowledge, motivations, concerns and intentions regarding COVID-19 vaccines: a cross-sectional survey (preprint)

Background: Healthcare personnel (HCP) are prioritized for earliest SARS-CoV-2 vaccine administration, yet relatively few data exist on HCP's knowledge, motivations, concerns, and intentions regarding COVID-19 vaccines. Methods: We conducted a cross-sectional survey Nov.16-Dec.8, 2020 among HCP enrolled in a cohort study at three Northern California medical centers serving diverse roles including COVID-19 patient care. Eligible HCP were adult (age<=18) on-site employees of the University of California, San Francisco, San Francisco General Hospital, and Stanford Healthcare. A one-time electronically-administered survey was sent to cohort HCP on November 16, 2020 and responses analyzed. Results: Overall, among 2,448 HCP invited, 2,135 completed the COVID-19 vaccine survey (87.2% response rate). HCPs had mean age 41 years, were 73% female, and had diverse jobs including COVID-19 patient contact. Enthusiasm for vaccination was overall strong, and more HCP (1,453, 69%) said they would definitely/likely receive vaccine if formally FDA-approved versus if approved via emergency use authorization only (785, 35%). While 541 (25%) respondents wanted to be among the earliest to receive vaccine, more desired vaccination after the first round (777, 36%) or >2 months after vaccinations began (389, 18%). Top factors increasing motivation for vaccination included perceiving risk from COVID-19 to self (1,382, 65%) or to family/friends (1355, 63%). Top concerns were vaccine side effects, cited by 596 (28%), and concerns about political involvement in FDA's approval process (249, 12%). Conclusions: HCP were enthusiastic about COVID-19 vaccination for individual protection and protecting others, but harbored concerns about vaccine side effects. Our data may inform emerging vaccine education campaigns.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial (preprint)

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized placebo-controlled trial in 120 patients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint, NCT04331899). In both the 60 patients receiving Lambda and the 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively (HR 0.94; 95% CI 0.64 to 1.39). At enrollment; 41% of subjects were SARS-CoV-2 IgG seropositive; compared to placebo, lambda tended to delay shedding cessation in seronegatives (aHR 0.66, 95% CI 0.39-1.10) and to hasten shedding cessation in seropositives (aHR 1.58, 95% CI 0.88-2.86; p for interaction = 0.03). Liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.

Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial (preprint)

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized placebo-controlled trial in 120 patients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint, NCT04331899). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively (HR 0.94; 95% CI 0.64 to 1.39). At enrollment; 41% of subjects were SARS-CoV-2 IgG seropositive; compared to placebo, lambda tended to delay shedding cessation in seronegatives (aHR 0.66, 95% CI 0.39-1.10) and to hasten shedding cessation in seropositives (aHR 1.58, 95% CI 0.88-2.86; p for interaction = 0.03). Liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.