TNF-α+ CD4+ T cells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4+ T cells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4+ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4+ T cells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing interferon gamma (IFNγ) to tumor necrosis factor alpha (TNF-α) from 5 days to 4 months post-enrollment, with IFNγ-IL-21-TNF-α+ CD4+ T cells the predominant population detected at later time points. Greater percentages of IFNγ-IL-21-TNF-α+ CD4+ T cells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7 months post-infection (⍴ = 0.4, p = 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNγ- and TNF-α-producing, spike-protein-specific CD4+ T cells. These data suggest that SARS-CoV-2-specific, TNF-α-producing CD4+ T cells may play an important role in antibody maintenance following COVID-19.

Dynamics of Respiratory Infectious Diseases in Incarcerated and Free-Living Populations: A Simulation Modeling Study.

BACKGROUND: Historically, correctional facilities have had large outbreaks of respiratory infectious diseases like COVID-19. Hence, importation and exportation of such diseases from correctional facilities raises substantial concern. METHODS: We developed a stochastic simulation model of transmission of respiratory infectious diseases within and between correctional facilities and the community. We investigated the infection dynamics, key governing factors, and relative importance of different infection routes (e.g., incarcerations and releases versus correctional staff). We also developed machine-learning meta-models of the simulation model, which allowed us to examine how our findings depended on different disease, correctional facility, and community characteristics. RESULTS: We find a magnification-reflection dynamic: a small outbreak in the community can cause a larger outbreak in the correction facility, which can then cause a second, larger outbreak in the community. This dynamic is strongest when community size is relatively small as compared with the size of the correctional population, the initial community R-effective is near 1, and initial prevalence of immunity in the correctional population is low. The timing of the correctional magnification and community reflection peaks in infection prevalence are primarily governed by the initial R-effective for each setting. Because the release rates from prisons are low, our model suggests correctional staff may be a more important infection entry route into prisons than incarcerations and releases; in jails, where incarceration and release rates are much higher, our model suggests the opposite. CONCLUSIONS: We find that across many combinations of respiratory pathogens, correctional settings, and communities, there can be substantial magnification-reflection dynamics, which are governed by several key factors. Our goal was to derive theoretical insights relevant to many contexts; our findings should be interpreted accordingly. HIGHLIGHTS: We find a magnification-reflection dynamic: a small outbreak in a community can cause a larger outbreak in a correctional facility, which can then cause a second, larger outbreak in the community.For public health decision makers considering contexts most susceptible to this dynamic, we find that the dynamic is strongest when the community size is relatively small, initial community R-effective is near 1, and the initial prevalence of immunity in the correctional population is low; the timing of the correctional magnification and community reflection peaks in infection prevalence are primarily governed by the initial R-effective for each setting.We find that correctional staff may be a more important infection entry route into prisons than incarcerations and releases; however, for jails, the relative importance of the entry routes may be reversed.For modelers, we combine simulation modeling, machine-learning meta-modeling, and interpretable machine learning to examine how our findings depend on different disease, correctional facility, and community characteristics; we find they are generally robust.

Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference.

Background: The limited variation observed among severe acute respiratory syndrome coronavirus 2 (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, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage. Results: Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0-40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17-208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02-1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28-.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23-1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants. Conclusions: Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

Change in covid-19 risk over time following vaccination with CoronaVac: test negative case-control study.

OBJECTIVE: To estimate the change in odds of covid-19 over time following primary series completion of the inactivated whole virus vaccine CoronaVac (Sinovac Biotech) in São Paulo State, Brazil. DESIGN: Test negative case-control study. SETTING: Community testing for covid-19 in São Paulo State, Brazil. PARTICIPANTS: Adults aged ≥18 years who were residents of São Paulo state, had received two doses of CoronaVac, did not have a laboratory confirmed SARS-CoV-2 infection before vaccination, and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 14 December 2021. Cases were matched to test negative controls by age (in 5 year bands), municipality of residence, healthcare worker status, and epidemiological week of RT-PCR test. MAIN OUTCOME MEASURES: RT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths. Conditional logistic regression was adjusted for sex, number of covid-19 associated comorbidities, race, and previous acute respiratory illness. RESULTS: From 202 741 eligible people, 52 170 cases with symptomatic covid-19 and 69 115 test negative controls with covid-19 symptoms were formed into 43 257 matched sets. Adjusted odds ratios of symptomatic covid-19 increased with time since completion of the vaccination series. The increase in odds was greater in younger people and among healthcare workers, although sensitivity analyses suggested that this was in part due to bias. In addition, the adjusted odds ratios of covid-19 related hospital admission or death significantly increased with time compared with the odds 14-41 days after series completion: from 1.25 (95% confidence interval 1.04 to 1.51) at 70-97 days up to 1.94 (1.41 to 2.67) from 182 days onwards. CONCLUSIONS: Significant increases in the risk of moderate and severe covid-19 outcomes occurred three months after primary vaccination with CoronaVac among people aged 65 and older. These findings provide supportive evidence for the implementation of vaccine boosters in these populations who received this inactivated vaccine. Studies of waning should include analyses designed to uncover common biases.

Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein.

Sero-surveillance can monitor and project disease burden and risk. However, SARS-CoV-2 antibody test results can produce false positive results, limiting their efficacy as a sero-surveillance tool. False positive SARS-CoV-2 antibody results are associated with malaria exposure, and understanding this association is essential to interpret sero-surveillance results from malaria-endemic countries. Here, pre-pandemic samples from eight malaria endemic and non-endemic countries and four continents were tested by ELISA to measure SARS-CoV-2 Spike S1 subunit reactivity. Individuals with acute malaria infection generated substantial SARS-CoV-2 reactivity. Cross-reactivity was not associated with reactivity to other human coronaviruses or other SARS-CoV-2 proteins, as measured by peptide and protein arrays. ELISAs with deglycosylated and desialated Spike S1 subunits revealed that cross-reactive antibodies target sialic acid on N-linked glycans of the Spike protein. The functional activity of cross-reactive antibodies measured by neutralization assays showed that cross-reactive antibodies did not neutralize SARS-CoV-2 in vitro. Since routine use of glycosylated or sialated assays could result in false positive SARS-CoV-2 antibody results in malaria endemic regions, which could overestimate exposure and population-level immunity, we explored methods to increase specificity by reducing cross-reactivity. Overestimating population-level exposure to SARS-CoV-2 could lead to underestimates of risk of continued COVID-19 transmission in sub-Saharan Africa.

Long-Term Accuracy of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Interferon-γ Release Assay and Its Application in Household Investigation.

BACKGROUND: An immunodiagnostic assay that sensitively detects a cell-mediated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed for epidemiological investigation and for clinical assessment of T- cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses. METHODS: The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific T cells was evaluated in coronavirus disease 2019 (COVID-19) convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen. RESULTS: The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI]: 79.0-89.0) and 86.6% (123/142; 95% CI: 80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI: 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI: 64.4-89.2) at 10 months post-infection (P < .01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of + 50% (95% CI: +25.4 to +74.6) and +21.7% (95% CI: +9.23 to +42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts. CONCLUSIONS: The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

Favipiravir for Treatment of Outpatients With Asymptomatic or Uncomplicated Coronavirus Disease 2019: A Double-Blind, Randomized, Placebo-Controlled, Phase 2 Trial.

BACKGROUND: Favipiravir, an oral, RNA-dependent RNA polymerase inhibitor, has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite limited data, favipiravir is administered to patients with coronavirus disease 2019 (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-CoV-2 reverse-transcription polymerase chain reaction assay (RT-PCR) within 72 hours of enrollment. Participants were randomized to receive placebo or favipiravir (1800 mg twice daily [BID] day 1, 800 mg 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 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis. RESULTS: We randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (standard deviation, 12.5 years) and 57 (49%) were women. We found no difference in time to shedding cessation overall (hazard ratio [HR], 0.76 favoring placebo [95% confidence interval {CI}, .48-1.20]) or in subgroups (age, sex, high-risk comorbidities, seropositivity, or symptom duration at enrollment). We detected no difference in time to symptom resolution (initial: HR, 0.84 [95% CI, .54-1.29]; sustained: HR, 0.87 [95% CI, .52-1.45]) and no difference in transition mutation accumulation in the viral genome during treatment. CONCLUSIONS: Our data do not support favipiravir at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher favipiravir doses are effective and safe for patients with COVID-19. CLINICAL TRIALS REGISTRATION: NCT04346628.

Association between primary or booster COVID-19 mRNA vaccination and Omicron lineage BA.1 SARS-CoV-2 infection in people with a prior SARS-CoV-2 infection: A test-negative case-control analysis.

BACKGROUND: The benefit of primary and booster vaccination in people who experienced a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains unclear. The objective of this study was to estimate the effectiveness of primary (two-dose series) and booster (third dose) mRNA vaccination against Omicron (lineage BA.1) infection among people with a prior documented infection. METHODS AND FINDINGS: We conducted a test-negative case-control study of reverse transcription PCRs (RT-PCRs) analyzed with the TaqPath (Thermo Fisher Scientific) assay and recorded in the Yale New Haven Health system from November 1, 2021, to April 30, 2022. Overall, 11,307 cases (positive TaqPath analyzed RT-PCRs with S-gene target failure [SGTF]) and 130,041 controls (negative TaqPath analyzed RT-PCRs) were included (median age: cases: 35 years, controls: 39 years). Among cases and controls, 5.9% and 8.1% had a documented prior infection (positive SARS-CoV-2 test record ≥90 days prior to the included test), respectively. We estimated the effectiveness of primary and booster vaccination relative to SGTF-defined Omicron (lineage BA.1) variant infection using a logistic regression adjusted for date of test, age, sex, race/ethnicity, insurance, comorbidities, social venerability index, municipality, and healthcare utilization. The effectiveness of primary vaccination 14 to 149 days after the second dose was 41.0% (95% confidence interval (CI): 14.1% to 59.4%, p 0.006) and 27.1% (95% CI: 18.7% to 34.6%, p < 0.001) for people with and without a documented prior infection, respectively. The effectiveness of booster vaccination (≥14 days after booster dose) was 47.1% (95% CI: 22.4% to 63.9%, p 0.001) and 54.1% (95% CI: 49.2% to 58.4%, p < 0.001) in people with and without a documented prior infection, respectively. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds of infection among boosted (≥14 days after booster dose) and booster-eligible people (≥150 days after second dose). The odds ratio (OR) comparing boosted and booster-eligible people with a documented prior infection was 0.79 (95% CI: 0.54 to 1.16, p 0.222), whereas the OR comparing boosted and booster-eligible people without a documented prior infection was 0.54 (95% CI: 0.49 to 0.59, p < 0.001). This study's limitations include the risk of residual confounding, the use of data from a single system, and the reliance on TaqPath analyzed RT-PCR results. CONCLUSIONS: In this study, we observed that primary vaccination provided significant but limited protection against Omicron (lineage BA.1) infection among people with and without a documented prior infection. While booster vaccination was associated with additional protection against Omicron BA.1 infection in people without a documented prior infection, it was not found to be associated with additional protection among people with a documented prior infection. These findings support primary vaccination in people regardless of documented prior infection status but suggest that infection history may impact the relative benefit of booster doses.

Protection against Omicron from Vaccination and Previous Infection in a Prison System.

BACKGROUND: Information regarding the protection conferred by vaccination and previous infection against infection with the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is limited. METHODS: We evaluated the protection conferred by mRNA vaccines and previous infection against infection with the omicron variant in two high-risk populations: residents and staff in the California state prison system. We used a retrospective cohort design to analyze the risk of infection during the omicron wave using data collected from December 24, 2021, through April 14, 2022. Weighted Cox models were used to compare the effectiveness (measured as 1 minus the hazard ratio) of vaccination and previous infection across combinations of vaccination history (stratified according to the number of mRNA doses received) and infection history (none or infection before or during the period of B.1.617.2 [delta]-variant predominance). A secondary analysis used a rolling matched-cohort design to evaluate the effectiveness of three vaccine doses as compared with two doses. RESULTS: Among 59,794 residents and 16,572 staff, the estimated effectiveness of previous infection against omicron infection among unvaccinated persons who had been infected before or during the period of delta predominance ranged from 16.3% (95% confidence interval [CI], 8.1 to 23.7) to 48.9% (95% CI, 41.6 to 55.3). Depending on previous infection status, the estimated effectiveness of vaccination (relative to being unvaccinated and without previous documented infection) ranged from 18.6% (95% CI, 7.7 to 28.1) to 83.2% (95% CI, 77.7 to 87.4) with two vaccine doses and from 40.9% (95% CI, 31.9 to 48.7) to 87.9% (95% CI, 76.0 to 93.9) with three vaccine doses. Incremental effectiveness estimates of a third (booster) dose (relative to two doses) ranged from 25.0% (95% CI, 16.6 to 32.5) to 57.9% (95% CI, 48.4 to 65.7) among persons who either had not had previous documented infection or had been infected before the period of delta predominance. CONCLUSIONS: Our findings in two high-risk populations suggest that mRNA vaccination and previous infection were effective against omicron infection, with lower estimates among those infected before the period of delta predominance. Three vaccine doses offered significantly more protection than two doses, including among previously infected persons.

Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study.

Background: The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients. Methods: Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial. Results: We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset. Conclusions: Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models. Funding: Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

Effectiveness of an inactivated Covid-19 vaccine with homologous and heterologous boosters against Omicron in Brazil.

The effectiveness of inactivated vaccines (VE) against symptomatic and severe COVID-19 caused by omicron is unknown. We conducted a nationwide, test-negative, case-control study to estimate VE for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac in Brazil in the Omicron context. Analyzing 1,386,544 matched-pairs, VE against symptomatic disease was 8.6% (95% CI, 5.6-11.5) and 56.8% (95% CI, 56.3-57.3) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, VE against severe Covid-19 was 73.6% (95% CI, 63.9-80.7) and 86.0% (95% CI, 84.5-87.4) after receiving a homologous and heterologous booster, respectively. Waning against severe Covid-19 after 120 days was only observed after a homologous booster. Heterologous booster might be preferable to individuals with completed primary series inactivated vaccine.

SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages.

Obesity, characterized by chronic low-grade inflammation of the adipose tissue, is associated with adverse coronavirus disease 2019 (COVID-19) outcomes, yet the underlying mechanism is unknown. To explore whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of adipose tissue contributes to pathogenesis, we evaluated COVID-19 autopsy cases and deeply profiled the response of adipose tissue to SARS-CoV-2 infection in vitro. In COVID-19 autopsy cases, we identified SARS-CoV-2 RNA in adipocytes with an associated inflammatory infiltrate. We identified two distinct cellular targets of infection: adipocytes and a subset of inflammatory adipose tissue-resident macrophages. Mature adipocytes were permissive to SARS-CoV-2 infection; although macrophages were abortively infected, SARS-CoV-2 initiated inflammatory responses within both the infected macrophages and bystander preadipocytes. These data suggest that SARS-CoV-2 infection of adipose tissue could contribute to COVID-19 severity through replication of virus within adipocytes and through induction of local and systemic inflammation driven by infection of adipose tissue-resident macrophages.

Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study.

BACKGROUND: COVID-19 vaccines have proven highly effective among individuals without a previous SARS-CoV-2 infection, but their effectiveness in preventing symptomatic infection and severe outcomes among individuals with previous infection is less clear. We aimed to estimate the effectiveness of four COVID-19 vaccines against symptomatic infection, hospitalisation, and death for individuals with laboratory-confirmed previous SARS-CoV-2 infection. METHODS: Using national COVID-19 notification, hospitalisation, and vaccination datasets from Brazil, we did a test-negative, case-control study to assess the effectiveness of four vaccines (CoronaVac [Sinovac], ChAdOx1 nCoV-19 [AstraZeneca], Ad26.COV2.S [Janssen], and BNT162b2 [Pfizer-BioNtech]) for individuals with laboratory-confirmed previous SARS-CoV-2 infection. We matched cases with RT-PCR positive, symptomatic COVID-19 with up to ten controls with negative RT-PCR tests who presented with symptomatic illnesses, restricting both groups to tests done at least 90 days after an initial infection. We used multivariable conditional logistic regression to compare the odds of test positivity and the odds of hospitalisation or death due to COVID-19, according to vaccination status and time since first or second dose of vaccines. FINDINGS: Between Feb 24, 2020, and Nov 11, 2021, we identified 213 457 individuals who had a subsequent, symptomatic illness with RT-PCR testing done at least 90 days after their initial SARS-CoV-2 infection and after the vaccination programme started. Among these, 30 910 (14·5%) had a positive RT-PCR test consistent with reinfection, and we matched 22 566 of these cases with 145 055 negative RT-PCR tests from 68 426 individuals as controls. Among individuals with previous SARS-CoV-2 infection, vaccine effectiveness against symptomatic infection 14 or more days from vaccine series completion was 39·4% (95% CI 36·1-42·6) for CoronaVac, 56·0% (51·4-60·2) for ChAdOx1 nCoV-19, 44·0% (31·5-54·2) for Ad26.COV2.S, and 64·8% (54·9-72·4) for BNT162b2. For the two-dose vaccine series (CoronaVac, ChAdOx1 nCoV-19, and BNT162b2), effectiveness against symptomatic infection was significantly greater after the second dose than after the first dose. Effectiveness against hospitalisation or death 14 or more days from vaccine series completion was 81·3% (75·3-85·8) for CoronaVac, 89·9% (83·5-93·8) for ChAdOx1 nCoV-19, 57·7% (-2·6 to 82·5) for Ad26.COV2.S, and 89·7% (54·3-97·7) for BNT162b2. INTERPRETATION: All four vaccines conferred additional protection against symptomatic infections and severe outcomes among individuals with previous SARS-CoV-2 infection. The provision of a full vaccine series to individuals after recovery from COVID-19 might reduce morbidity and mortality. FUNDING: Brazilian National Research Council, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Oswaldo Cruz Foundation, JBS, Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Generalitat de Catalunya.

COVID-19 Preventive Measures in Northern California Jails: Perceived Deficiencies, Barriers, and Unintended Harms.

Background: Carceral facilities are high-risk settings for COVID-19 transmission. Little is known about the hidden burden of infection or practical barriers to infection control in these settings, especially in jails. There is also limited research on the mental health impacts of the pandemic among people living and working in carceral facilities. Methods: Between July 8, 2020 and April 30, 2021, we performed SARS-CoV-2 rapid antibody testing and administered a questionnaire among residents and staff of four Northern California jails. We utilized multivariable logistic regression, adjusting for demographic and carceral characteristics, to analyze factors associated with prior infection, including perceived likelihood of prior infection and access to new masks. We additionally assessed the implementation of, perceptions toward, and impacts of COVID-19 policies in practice. We engaged stakeholder representatives, including incarcerated individuals, to guide study design, procedures, and results interpretation. Results: We enrolled 788 jail residents and 380 jail staff. Nearly half of residents and two-thirds of staff who were antibody-positive had not previously tested positive for COVID-19. Among residents without a prior COVID-19 diagnosis, antibody positivity was significantly associated with perceived likelihood of prior infection (adjusted OR = 8.9; 95% CI, 3.6-22.0). Residents who had flu-like illness in jail cited inadequate responses to reported illness and deterrents to symptom reporting, including fears of medical isolation and perceptions of medical neglect. Residents also disclosed deficient access to face masks, which was associated with antibody positivity (adjusted OR = 13.8, 95% CI, 1.8-107.0). Worsened mental health was pervasive among residents, attributed not only to fear of COVID-19 and unsanitary jail conditions but also to intensified isolation and deprivation due to pandemic restrictions on in-person visitation, programs, and recreation time. Conclusion: Carceral settings present significant challenges to maintaining infection control and human rights. Custody officials should work diligently to transform the conditions of medical isolation, which could mitigate deterrents to symptom reporting. Furthermore, they should minimize use of restrictive measures like lockdowns and suspension of visitation that exacerbate the mental health harms of incarceration. Instead, custody officials should ensure comprehensive implementation of other preventive strategies like masking, testing, and vaccination, in conjunction with multisector efforts to advance decarceration.

Assessing impact of ventilation on airborne transmission of SARS-CoV-2: a cross-sectional analysis of naturally ventilated healthcare settings in Bangladesh.

OBJECTIVES: To evaluate the risk of exposure to SARS-CoV-2 in naturally ventilated hospital settings by measuring parameters of ventilation and comparing these findings with results of bioaerosol sampling. STUDY DESIGN: Cross-sectional study. STUDY SETTING AND STUDY SAMPLE: The study sample included nine hospitals in Dhaka, Bangladesh. Ventilation characteristics and air samples were collected from 86 healthcare spaces during October 2020 to February 2021. PRIMARY OUTCOME: Risk of cumulative SARS-CoV-2 infection by type of healthcare area. SECONDARY OUTCOMES: Ventilation rates by healthcare space; risk of airborne detection of SARS-CoV-2 across healthcare spaces; impact of room characteristics on absolute ventilation; SARS-CoV-2 detection by naturally ventilated versus mechanically ventilated spaces. RESULTS: The majority (78.7%) of naturally ventilated patient care rooms had ventilation rates that fell short of the recommended ventilation rate of 60 L/s/p. Using a modified Wells-Riley equation and local COVID-19 case numbers, we found that over a 40-hour exposure period, outpatient departments posed the highest median risk for infection (7.7%). SARS-CoV-2 RNA was most frequently detected in air samples from non-COVID wards (50.0%) followed by outpatient departments (42.9%). Naturally ventilated spaces (22.6%) had higher rates of SARS-CoV-2 detection compared with mechanically ventilated spaces (8.3%), though the difference was not statistically significant (p=0.128). In multivariable linear regression with calculated elasticity, open door area and cross-ventilation were found to have a significant impact on ventilation. CONCLUSION: Our findings provide evidence that naturally ventilated healthcare settings may pose a high risk for exposure to SARS-CoV-2, particularly among non-COVID-designated spaces, but improving parameters of ventilation can mitigate this risk.

Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA suggest prolonged gastrointestinal infection.

Background: COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.1, SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in both the lung and intestinal tissue.2, 3, 4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.5. Methods: We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms. Findings: Fecal SARS-CoV-2 RNA is detected in 49.2% [95% confidence interval, 38.2%-60.3%] of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% [8.5%-18.4%] of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% [2.0%-7.3%] shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA. Conclusions: The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19. Funding: This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142.

Use of Recently Vaccinated Individuals to Detect Bias in Test-Negative Case-Control Studies of COVID-19 Vaccine Effectiveness.

Postauthorization observational studies play a key role in understanding COVID-19 vaccine effectiveness following the demonstration of efficacy in clinical trials. Although bias due to confounding, selection bias, and misclassification can be mitigated through careful study design, unmeasured confounding is likely to remain in these observational studies. Phase III trials of COVID-19 vaccines have shown that protection from vaccination does not occur immediately, meaning that COVID-19 risk should be similar in recently vaccinated and unvaccinated individuals, in the absence of confounding or other bias. Several studies have used the estimated effectiveness among recently vaccinated individuals as a negative control exposure to detect bias in vaccine effectiveness estimates. In this paper, we introduce a theoretical framework to describe the interpretation of such a bias indicator in test-negative studies, and outline strong assumptions that would allow vaccine effectiveness among recently vaccinated individuals to serve as a negative control exposure.

Uptake of COVID-19 Vaccination Among Frontline Workers in California State Prisons.

Importance: Prisons and jails are high-risk environments for COVID-19. Vaccination levels among workers in many such settings remain markedly lower than those of residents and members of surrounding communities. The situation is troubling because prison staff are a key vector for COVID-19 transmission. Objective: To assess patterns and timing of staff vaccination in California state prisons and identify individual-level and community-level factors associated with remaining unvaccinated. Design Setting and Participants: This cohort study used data from December 22, 2020, through June 30, 2021, to quantify the fractions of staff and incarcerated residents who remained unvaccinated among 23 472 custody and 7617 health care staff who worked in roles requiring direct contact with residents at 33 of the 35 prisons operated by the California Department of Corrections and Rehabilitation. Multivariable probit regressions assessed demographic, community, and peer factors associated with staff vaccination uptake. Main Outcomes and Measures: Remaining unvaccinated throughout the study period. Results: Of 23 472 custody staff, 3751 (16%) were women, and 1454 (6%) were Asian/Pacific Islander individuals, 1571 (7%) Black individuals, 9008 (38%) Hispanic individuals, and 6666 (28%) White individuals. Of 7617 health care staff, 5434 (71%) were women, and 2148 (28%) were Asian/Pacific Islander individuals, 1201 (16%) Black individuals, 1409 (18%) Hispanic individuals, and 1771 (23%) White individuals. A total of 6103 custody staff (26%) and 3961 health care staff (52%) received 1 or more doses of a COVID-19 vaccine during the first 2 months vaccines were offered, but vaccination rates stagnated thereafter. By June 30, 2021, 14 317 custody staff (61%) and 2819 health care staff (37%) remained unvaccinated. In adjusted analyses, remaining unvaccinated was positively associated with younger age (custody staff: age, 18-29 years vs ≥60 years, 75% [95% CI, 73%-76%] vs 45% [95% CI, 42%-48%]; health care staff: 52% [95% CI, 48%-56%] vs 29% [95% CI, 27%-32%]), prior COVID-19 infection (custody staff: 67% [95% CI, 66%-68%] vs 59% [95% CI, 59%-60%]; health care staff: 44% [95% CI, 42%-47%] vs 36% [95% CI, 36%-36%]), residing in a community with relatively low rates of vaccination (custody staff: 75th vs 25th percentile:, 63% [95% CI, 62%-63%] vs 60% [95% CI, 59%-60%]; health care staff: 40% [95% CI, 39%-41%] vs 34% [95% CI, 33%-35%]), and sharing shifts with coworkers who had relatively low rates of vaccination (custody staff: 75th vs 25th percentile, 64% [95% CI, 62%-66%] vs 59% [95% CI, 57%-61%]; health care staff: 38% [95% CI, 36%-41%] vs 35% [95% CI, 31%-39%]). Conclusions and Relevance: This cohort study of California state prison custody and health care staff found that vaccination uptake plateaued at levels that posed ongoing risks of further outbreaks in the prisons and continuing transmission from prisons to surrounding communities. Prison staff decisions to forgo vaccination appear to be multifactorial, and vaccine mandates may be necessary to achieve adequate levels of immunity in this high-risk setting.

Factors associated with COVID-19 vaccine acceptance and hesitancy among residents of Northern California jails.

Carceral facilities are high-risk settings for COVID-19 transmission. Factors associated with COVID-19 vaccine acceptance and hesitancy among incarcerated individuals are poorly understood, especially among jail residents. Here, we conducted a retrospective review of electronic health record (EHR) data on COVID-19 vaccine uptake in custody and additionally administered a survey to assess reasons for vaccine hesitancy, sources of COVID-19 information, and medical mistrust among residents of four Northern California jails. We performed multivariate logistic regression to determine associations with vaccine acceptance. Of 2,564 jail residents offered a COVID-19 vaccine between March 19, 2021 and June 30, 2021, 1,441 (56.2%) accepted at least one dose. Among vaccinated residents, 497 (34.5%) had initially refused. Vaccine uptake was higher among older individuals, women, those with recent flu vaccination, and those living in shared housing. Among 509 survey respondents, leading reasons for vaccine hesitancy were concerns around side effects and suboptimal efficacy, with cost and the need for an annual booster being other hypothetical deterrents to vaccination. Vaccine hesitancy was also associated with mistrust of medical personnel in and out of jail, although this association varied by race/ethnicity. Television and friends/family were the most common and most trusted sources of COVID-19 information, respectively. Overall, vaccine acceptance was much lower among jail residents than the local and national general population. Interventions to increase vaccination rates in this setting should utilize accessible and trusted sources of information to address concerns about side effects and efficacy, while working to mitigate medical and institutional mistrust among residents.

Effectiveness of Coronavirus Disease 2019 (COVID-19) Vaccines Among Incarcerated People in California State Prisons: Retrospective Cohort Study.

BACKGROUND: Prisons and jails are high-risk settings for coronavirus disease 2019 (COVID-19). Vaccines may substantially reduce these risks, but evidence is needed on COVID-19 vaccine effectiveness for incarcerated people, who are confined in large, risky congregate settings. METHODS: We conducted a retrospective cohort study to estimate effectiveness of messenger RNA (mRNA) vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), against confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections among incarcerated people in California prisons from 22 December 2020 through 1 March 2021. The California Department of Corrections and Rehabilitation provided daily data for all prison residents including demographic, clinical, and carceral characteristics, as well as COVID-19 testing, vaccination, and outcomes. We estimated vaccine effectiveness using multivariable Cox models with time-varying covariates, adjusted for resident characteristics and infection rates across prisons. RESULTS: Among 60 707 cohort members, 49% received at least 1 BNT162b2 or mRNA-1273 dose during the study period. Estimated vaccine effectiveness was 74% (95% confidence interval [CI], 64%-82%) from day 14 after first dose until receipt of second dose and 97% (95% CI, 88%-99%) from day 14 after second dose. Effectiveness was similar among the subset of residents who were medically vulnerable: 74% (95% CI, 62%-82%) and 92% (95% CI, 74%-98%) from 14 days after first and second doses, respectively. CONCLUSIONS: Consistent with results from randomized trials and observational studies in other populations, mRNA vaccines were highly effective in preventing SARS-CoV-2 infections among incarcerated people. Prioritizing incarcerated people for vaccination, redoubling efforts to boost vaccination, and continuing other ongoing mitigation practices are essential in preventing COVID-19 in this disproportionately affected population.