Adeno-associated virus type 2 in US children with acute severe hepatitis.

As of August 2022, clusters of acute severe hepatitis of unknown aetiology in children have been reported from 35 countries, including the USA1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from patients in Europe and the USA3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment-based sequencing and agnostic metagenomic sequencing to analyse samples from 16 HAdV-positive cases from 1 October 2021 to 22 May 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus type 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P < 0.001) and to 0 of 30 patients with hepatitis of defined aetiology (P < 0.001). In controls, HAdV type 41 was detected in blood from 9 (39.1%) of the 23 patients with acute gastroenteritis (without hepatitis), including 8 of 9 patients with positive stool HAdV testing, but co-infection with AAV2 was observed in only 3 (13.0%) of these 23 patients versus 93% of cases (P < 0.001). Co-infections by Epstein-Barr virus, human herpesvirus 6 and/or enterovirus A71 were also detected in 12 (85.7%) of 14 cases, with higher herpesvirus detection in cases versus controls (P < 0.001). Our findings suggest that the severity of the disease is related to co-infections involving AAV2 and one or more helper viruses.

Nucleic acid biomarkers of immune response and cell and tissue damage in children with COVID-19 and MIS-C

Differential host responses in coronavirus disease 2019 (COVID-19) and multisystem inflammatory syndrome in children (MIS-C) remain poorly characterized. Here we use next-generation sequencing to longitudinally analyze blood samples from pediatric patients with acute COVID-19 (n=70) or MIS-C (n=141) across three hospitals. Profiling of plasma cell-free nucleic acids uncovers distinct signatures of cell injury and death between COVID-19 and MIS-C, with increased multi-organ involvement in MIS-C encompassing diverse cell types including endothelial and neuronal cells, and an enrichment of pyroptosis related genes. Whole blood RNA profiling reveals upregulation of similar pro-inflammatory pathways in COVID-19 and MIS-C, but also MIS-C specific downregulation of T cell-associated pathways. Profiling of plasma cell-free RNA and whole blood RNA in paired samples yields different yet complementary signatures for each disease state. Our work provides a systems-level view of immune responses and tissue damage in COVID-19 and MIS-C and informs the future development of new disease biomarkers. Graphical Loy et al. use cell-free RNA, whole blood RNA, and cell-free DNA sequencing to characterize distinct host response and cellular injury profiles in pediatric patients with MIS-C and/or COVID-19. This study highlights the complementary information from cell-free and whole blood RNA analyses, with broad implications for future liquid biopsy applications.

COVID-19 in vaccinated versus unvaccinated hematologic malignancy patients.

The effect of vaccination on severity of subsequent COVID-19 in patients with hematologic malignancies (HMs) is unknown. In this single-center retrospective cohort study, we found no difference in severity of COVID-19 disease in vaccinated (n = 16) versus unvaccinated (n = 54) HM patients using an adjusted multiple logistic regression model. Recent anti-B-cell therapy was associated with more severe illness.

Association of Culturable-Virus Detection and Household Transmission of SARS-CoV-2, California and Tennessee, 2020-2022.

From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals <6 days, suggesting early transmission. These data examine viral culture as a proxy for infectiousness, reaffirm the need for rapid control measures after infection, and highlight the potential for prolonged infectiousness (≥6 days) in many individuals.

SARS-CoV-2 Spike triggers barrier dysfunction and vascular leak via integrins and TGF-ß signaling.

Severe COVID-19 is associated with epithelial and endothelial barrier dysfunction within the lung as well as in distal organs. While it is appreciated that an exaggerated inflammatory response is associated with barrier dysfunction, the triggers of vascular leak are unclear. Here, we report that cell-intrinsic interactions between the Spike (S) glycoprotein of SARS-CoV-2 and epithelial/endothelial cells are sufficient to induce barrier dysfunction in vitro and vascular leak in vivo, independently of viral replication and the ACE2 receptor. We identify an S-triggered transcriptional response associated with extracellular matrix reorganization and TGF-ß signaling. Using genetic knockouts and specific inhibitors, we demonstrate that glycosaminoglycans, integrins, and the TGF-ß signaling axis are required for S-mediated barrier dysfunction. Notably, we show that SARS-CoV-2 infection caused leak in vivo, which was reduced by inhibiting integrins. Our findings offer mechanistic insight into SARS-CoV-2-triggered vascular leak, providing a starting point for development of therapies targeting COVID-19.

Magnitude and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Household Transmission: A Longitudinal Cohort Study.

BACKGROUND: Households have emerged as important venues for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Little is known, however, regarding the magnitude and determinants of household transmission in increasingly vaccinated populations. METHODS: From September 2020 to January 2022, symptomatic nonhospitalized individuals with SARS-CoV-2 infection by RNA detection were identified within 5 days of symptom onset; all individuals resided with at least 1 other SARS-CoV-2-uninfected household member. These infected persons (cases) and their household members (contacts) were subsequently followed with questionnaire-based measurement and serial nasal specimen collection. The primary outcome was SARS-CoV-2 infection among contacts. RESULTS: We evaluated 42 cases and their 74 household contacts. Among the contacts, 32 (43%) became infected, of whom 5 (16%) were asymptomatic; 81% of transmissions occurred by 5 days after the case's symptom onset. From 21 unvaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection among contacts was 18/40 (45% [95% confidence interval {CI}, 29%-62%]), most of whom were unvaccinated. From 21 vaccinated cases, 14-day cumulative incidence of SARS-CoV-2 infection was 14/34 (41% [95% CI, 25%-59%]) among all contacts and 12/29 (41% [95% CI, 24%-61%]) among vaccinated contacts. At least 1 comorbid condition among cases and 10 or more days of RNA detection in cases were associated with increased risk of infection among contacts. CONCLUSIONS: Among households including individuals with symptomatic SARS-CoV-2 infection, both vaccinated-to-vaccinated and unvaccinated-to-unvaccinated transmission of SARS-CoV-2 to household contacts was common. Because vaccination alone did not notably reduce risk of infection, household contacts will need to employ additional interventions to avoid infection.

Neutralizing Immunity Induced Against the Omicron BA.1 and BA.2 Variants in Vaccine Breakthrough Infections.

BACKGROUND: As of early 2022, the Omicron variants are the predominant circulating lineages globally. Understanding neutralizing antibody responses against Omicron BA.1 and BA.2 after vaccine breakthrough infections will provide insights into BA.2 infectivity and susceptibility to subsequent reinfection. METHODS: Live virus neutralization assays were used to study immunity against Delta and Omicron BA.1 and BA.2 variants in samples from 86 individuals, 24 unvaccinated (27.9%) and 62 vaccinated (72.1%), who were infected with Delta (n = 42, 48.8%) or BA.1 (n = 44, 51.2%). Among the 62 vaccinated individuals, 39 were unboosted (62.9%), whereas 23 were boosted (37.1%). RESULTS: In unvaccinated infections, neutralizing antibodies (nAbs) against the three variants were weak or undetectable, except against Delta for Delta-infected individuals. Both Delta and BA.1 breakthrough infections resulted in strong nAb responses against ancestral wild-type and Delta lineages, but moderate nAb responses against BA.1 and BA.2, with similar titers between unboosted and boosted individuals. Antibody titers against BA.2 were generally higher than those against BA.1 in breakthrough infections. CONCLUSIONS: These results underscore the decreased immunogenicity of BA.1 compared to BA.2, insufficient neutralizing immunity against BA.2 in unvaccinated individuals, and moderate to strong neutralizing immunity induced against BA.2 in Delta and BA.1 breakthrough infections.

Infectious viral shedding of SARS-CoV-2 Delta following vaccination: A longitudinal cohort study.

The impact of vaccination on SARS-CoV-2 infectiousness is not well understood. We compared longitudinal viral shedding dynamics in unvaccinated and fully vaccinated adults. SARS-CoV-2-infected adults were enrolled within 5 days of symptom onset and nasal specimens were self-collected daily for two weeks and intermittently for an additional two weeks. SARS-CoV-2 RNA load and infectious virus were analyzed relative to symptom onset stratified by vaccination status. We tested 1080 nasal specimens from 52 unvaccinated adults enrolled in the pre-Delta period and 32 fully vaccinated adults with predominantly Delta infections. While we observed no differences by vaccination status in maximum RNA levels, maximum infectious titers and the median duration of viral RNA shedding, the rate of decay from the maximum RNA load was faster among vaccinated; maximum infectious titers and maximum RNA levels were highly correlated. Furthermore, amongst participants with infectious virus, median duration of infectious virus detection was reduced from 7.5 days (IQR: 6.0-9.0) in unvaccinated participants to 6 days (IQR: 5.0-8.0) in those vaccinated (P = 0.02). Accordingly, the odds of shedding infectious virus from days 6 to 12 post-onset were lower among vaccinated participants than unvaccinated participants (OR 0.42 95% CI 0.19-0.89). These results indicate that vaccination had reduced the probability of shedding infectious virus after 5 days from symptom onset.

An intranasal ASO therapeutic targeting SARS-CoV-2.

The COVID-19 pandemic is exacting an increasing toll worldwide, with new SARS-CoV-2 variants emerging that exhibit higher infectivity rates and that may partially evade vaccine and antibody immunity. Rapid deployment of non-invasive therapeutic avenues capable of preventing infection by all SARS-CoV-2 variants could complement current vaccination efforts and help turn the tide on the COVID-19 pandemic. Here, we describe a novel therapeutic strategy targeting the SARS-CoV-2 RNA using locked nucleic acid antisense oligonucleotides (LNA ASOs). We identify an LNA ASO binding to the 5' leader sequence of SARS-CoV-2 that disrupts a highly conserved stem-loop structure with nanomolar efficacy in preventing viral replication in human cells. Daily intranasal administration of this LNA ASO in the COVID-19 mouse model potently suppresses viral replication (>80-fold) in the lungs of infected mice. We find that the LNA ASO is efficacious in countering all SARS-CoV-2 "variants of concern" tested both in vitro and in vivo. Hence, inhaled LNA ASOs targeting SARS-CoV-2 represents a promising therapeutic approach to reduce or prevent transmission and decrease severity of COVID-19 in infected individuals. LNA ASOs are chemically stable and can be flexibly modified to target different viral RNA sequences and could be stockpiled for future coronavirus pandemics.

COVID-19 Variant Detection with a High-Fidelity CRISPR-Cas12 Enzyme.

Laboratory tests for the accurate and rapid identification of SARS-CoV-2 variants can potentially guide the treatment of COVID-19 patients and inform infection control and public health surveillance efforts. Here, we present the development and validation of a rapid COVID-19 variant DETECTR assay incorporating loop-mediated isothermal amplification (LAMP) followed by CRISPR-Cas12 based identification of single nucleotide polymorphism (SNP) mutations in the SARS-CoV-2 spike (S) gene. This assay targets the L452R, E484K/Q/A, and N501Y mutations, at least one of which is found in nearly all major variants. In a comparison of three different Cas12 enzymes, only the newly identified enzyme CasDx1 was able to accurately identify all targeted SNP mutations. An analysis pipeline for CRISPR-based SNP identification from 261 clinical samples yielded a SNP concordance of 97.3% and agreement of 98.9% (258 of 261) for SARS-CoV-2 lineage classification, using SARS-CoV-2 whole-genome sequencing and/or real-time RT-PCR as test comparators. We also showed that detection of the single E484A mutation was necessary and sufficient to accurately identify Omicron from other major circulating variants in patient samples. These findings demonstrate the utility of CRISPR-based DETECTR as a faster and simpler diagnostic method compared with sequencing for SARS-CoV-2 variant identification in clinical and public health laboratories.

Limited cross-variant immunity from SARS-CoV-2 Omicron without vaccination.

SARS-CoV-2 Delta and Omicron are globally relevant variants of concern. Although individuals infected with Delta are at risk of developing severe lung disease, infection with Omicron often causes milder symptoms, especially in vaccinated individuals1,2. The question arises of whether widespread Omicron infections could lead to future cross-variant protection, accelerating the end of the pandemic. Here we show that without vaccination, infection with Omicron induces a limited humoral immune response in mice and humans. Sera from mice overexpressing the human ACE2 receptor and infected with Omicron neutralize only Omicron, but not other variants of concern, whereas broader cross-variant neutralization was observed after WA1 and Delta infections. Unlike WA1 and Delta, Omicron replicates to low levels in the lungs and brains of infected animals, leading to mild disease with reduced expression of pro-inflammatory cytokines and diminished activation of lung-resident T cells. Sera from individuals who were unvaccinated and infected with Omicron show the same limited neutralization of only Omicron itself. By contrast, Omicron breakthrough infections induce overall higher neutralization titres against all variants of concern. Our results demonstrate that Omicron infection enhances pre-existing immunity elicited by vaccines but, on its own, may not confer broad protection against non-Omicron variants in unvaccinated individuals.

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19.

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) in some individuals, while the majority remain asymptomatic. Natural killer (NK) cells play an essential role in antiviral defense. NK cell maturation and function are regulated mainly by highly polymorphic killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands. Herein, we tested our hypothesis that the individualized KIR and HLA class I ligand combinations that control NK cell function determine the outcome of SARS-CoV-2 infection. Methods: We characterized KIR and HLA genes in 200 patients hospitalized for COVID-19 and 195 healthy general population controls. Results: The KIR3DL1+HLA-Bw4+ [Odds ratio (OR) = 0.65, p = 0.03] and KIR3DL2+HLA-A3/11+ (OR = 0.6, p = 0.02) combinations were encountered at significantly lower frequency in COVID-19 patients than in the controls. Notably, 40% of the patients lacked both of these KIR+HLA+ combinations compared to 24.6% of the controls (OR = 2.04, p = 0.001). Additionally, activating receptors KIR2DS1+KIR2DS5+ are more frequent in patients with severe COVID-19 than patients with mild disease (OR = 1.8, p = 0.05). Individuals carrying KIR2DS1+KIR2DS5+ genes but missing either KIR3DL1+HLA-Bw4+ combination (OR = 1.73, p = 0.04) or KIR3DL2+HLA-A3/11+ combination (OR = 1.75, p = 0.02) or both KIR3DL1+HLA-Bw4+ and KIR2DL2+HLA-A3/11+ combinations (OR = 1.63, p = 0.03) were more frequent in the COVID-19 cohort compared to controls. Conclusions: The absence of KIR3DL1+HLA-Bw4+ and KIR3DL2+HLA-A3/11+ combinations presumably yields inadequate NK cell maturation and reduces anti-SARS-CoV-2 defense, causing COVID-19. An increased frequency of KIR2DS1+KIR2DS5+ in severe COVID-19 patients suggests vigorous NK cell response triggered via these activating receptors and subsequent production of exuberant inflammatory cytokines responsible for severe COVID-19. Our results demonstrate that specific KIR-HLA combinations that control NK cell maturation and function are underlying immunogenetic variables that determine the dual role of NK cells in mediating beneficial antiviral and detrimental pathologic action. These findings offer a framework for developing potential host genetic biomarkers to distinguish individuals prone to COVID-19.

Neutralizing immunity in vaccine breakthrough infections from the SARS-CoV-2 Omicron and Delta variants.

Virus-like particle (VLP) and live virus assays were used to investigate neutralizing immunity against Delta and Omicron SARS-CoV-2 variants in 259 samples from 128 vaccinated individuals. Following Delta breakthrough infection, titers against WT rose 57-fold and 3.1-fold compared with uninfected boosted and unboosted individuals, respectively, versus only a 5.8-fold increase and 3.1-fold decrease for Omicron breakthrough infection. Among immunocompetent, unboosted patients, Delta breakthrough infections induced 10.8-fold higher titers against WT compared with Omicron (p = 0.037). Decreased antibody responses in Omicron breakthrough infections relative to Delta were potentially related to a higher proportion of asymptomatic or mild breakthrough infections (55.0% versus 28.6%, respectively), which exhibited 12.3-fold lower titers against WT compared with moderate to severe infections (p = 0.020). Following either Delta or Omicron breakthrough infection, limited variant-specific cross-neutralizing immunity was observed. These results suggest that Omicron breakthrough infections are less immunogenic than Delta, thus providing reduced protection against reinfection or infection from future variants.

Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19

Background: The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection causes coronavirus disease-2019 (COVID-19) in some individuals, while the majority remain asymptomatic. Natural killer (NK) cells play an essential role in antiviral defense. NK cell maturation and function are regulated mainly by highly polymorphic killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands. Herein, we tested our hypothesis that the individualized KIR and HLA class I ligand combinations that control NK cell function determine the outcome of SARS-CoV-2 infection. Methods: We characterized KIR and HLA genes in 200 patients hospitalized for COVID-19 and 195 healthy general population controls. Results: The KIR3DL1+HLA-Bw4+ [Odds ratio (OR) = 0.65, p = 0.03] and KIR3DL2+HLA-A3/11+ (OR = 0.6, p = 0.02) combinations were encountered at significantly lower frequency in COVID-19 patients than in the controls. Notably, 40% of the patients lacked both of these KIR+HLA+ combinations compared to 24.6% of the controls (OR = 2.04, p = 0.001). Additionally, activating receptors KIR2DS1+KIR2DS5+ are more frequent in patients with severe COVID-19 than patients with mild disease (OR = 1.8, p = 0.05). Individuals carrying KIR2DS1+KIR2DS5+ genes but missing either KIR3DL1+HLA-Bw4+ combination (OR = 1.73, p = 0.04) or KIR3DL2+HLA-A3/11+ combination (OR = 1.75, p = 0.02) or both KIR3DL1+HLA-Bw4+ and KIR2DL2+HLA-A3/11+ combinations (OR = 1.63, p = 0.03) were more frequent in the COVID-19 cohort compared to controls. Conclusions: The absence of KIR3DL1+HLA-Bw4+ and KIR3DL2+HLA-A3/11+ combinations presumably yields inadequate NK cell maturation and reduces anti-SARS-CoV-2 defense, causing COVID-19. An increased frequency of KIR2DS1+KIR2DS5+ in severe COVID-19 patients suggests vigorous NK cell response triggered via these activating receptors and subsequent production of exuberant inflammatory cytokines responsible for severe COVID-19. Our results demonstrate that specific KIR-HLA combinations that control NK cell maturation and function are underlying immunogenetic variables that determine the dual role of NK cells in mediating beneficial antiviral and detrimental pathologic action. These findings offer a framework for developing potential host genetic biomarkers to distinguish individuals prone to COVID-19.

Contact-Tracing Outcomes Among Household Contacts of Fully Vaccinated Coronavirus Disease 2019 (COVID-19) Patients: San Francisco, California, 29 January-2 July 2021.

BACKGROUND: The extent to which vaccinated persons diagnosed with coronavirus disease 2019 (COVID-19) can transmit to other vaccinated and unvaccinated persons is unclear. METHODS: Using data from the San Francisco Department of Public Health, this report describes outcomes of household contact tracing during 29 January-2 July 2021, where fully vaccinated patients with COVID-19 were the index case in the household. RESULTS: Among 248 fully vaccinated patients with breakthrough infections, 203 (82%) were symptomatic and 105 were identified as the index patient within their household. Among 179 named household contacts, 71 (40%) contacts tested, over half (56%) were fully vaccinated and the secondary attack rate was 28%. Overall transmission from a symptomatic fully vaccinated patient with breakthrough infection to household contacts was suspected in 14 of 105 (13%) of households. Viral genomic sequencing of samples from 44% of fully vaccinated patients showed that 82% of those sequenced were infected by a variant of concern or interest and 77% by a variant carrying mutation(s) associated with resistance to neutralizing antibodies. CONCLUSIONS: Transmission from fully vaccinated symptomatic index patients to vaccinated and unvaccinated household contacts can occur. Indoor face masking and timely testing of all household contacts should be considered when a household member receives a positive test result in order to identify and interrupt transmission chains.

The B.1.427/1.429 (epsilon) SARS-CoV-2 variants are more virulent than ancestral B.1 (614G) in Syrian hamsters.

As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel SARS-CoV-2 variant designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and it was shown to have enhanced infectivity in vitro and decreased antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both variants exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most marked body weight loss among the 3 variants. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three variants. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the oropharynx but not in the lungs. In multi-virus in-vivo competition experiments, we found that B.1. (614G), epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the nasal cavity, B.1. (614G), gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) and WA-1 variants in hamsters. These results demonstrate enhanced virulence and high relative oropharyngeal replication of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) variant.

Predominance of antibody-resistant SARS-CoV-2 variants in vaccine breakthrough cases from the San Francisco Bay Area, California.

Associations between vaccine breakthrough cases and infection by different SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analysed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from 1 February to 30 June 2021, of which 125 (9.1%) were vaccine breakthrough infections. Vaccine breakthrough infections were more commonly associated with circulating antibody-resistant variants carrying ≥1 mutation associated with decreased antibody neutralization (L452R/Q, E484K/Q and/or F490S) than infections in unvaccinated individuals (78% versus 48%, P = 1.96 × 10-8). Differences in viral loads were non-significant between unvaccinated and fully vaccinated cases overall (P = 0.99) and according to lineage (P = 0.09-0.78). Symptomatic vaccine breakthrough infections had comparable viral loads (P = 0.64), whereas asymptomatic breakthrough infections had decreased viral loads (P = 0.023) compared with infections in unvaccinated individuals. In 5 cases with serial samples available for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to an immunocompromised state or infection by an antibody-resistant lineage. Taken together, our results show that vaccine breakthrough infections are overrepresented by antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may be as efficient in spreading COVID-19 as unvaccinated infections, regardless of the infecting lineage.

Community Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Disproportionately Affects the Latinx Population During Shelter-in-Place in San Francisco.

BACKGROUND: There is an urgent need to understand the dynamics and risk factors driving ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission during shelter-in-place mandates. METHODS: We offered SARS-CoV-2 reverse-transcription polymerase chain reaction (PCR) and antibody (Abbott ARCHITECT IgG) testing, regardless of symptoms, to all residents (aged ≥4 years) and workers in a San Francisco census tract (population: 5174) at outdoor, community-mobilized events over 4 days. We estimated SARS-CoV-2 point prevalence (PCR positive) and cumulative incidence (antibody or PCR positive) in the census tract and evaluated risk factors for recent (PCR positive/antibody negative) vs prior infection (antibody positive/PCR negative). SARS-CoV-2 genome recovery and phylogenetics were used to measure viral strain diversity, establish viral lineages present, and estimate number of introductions. RESULTS: We tested 3953 persons (40% Latinx; 41% White; 9% Asian/Pacific Islander; and 2% Black). Overall, 2.1% (83/3871) tested PCR positive: 95% were Latinx and 52% were asymptomatic when tested; 1.7% of census tract residents and 6.0% of workers (non-census tract residents) were PCR positive. Among 2598 tract residents, estimated point prevalence of PCR positives was 2.3% (95% confidence interval [CI], 1.2%-3.8%): 3.9% (95% CI, 2.0%-6.4%) among Latinx persons vs 0.2% (95% CI, .0-.4%) among non-Latinx persons. Estimated cumulative incidence among residents was 6.1% (95% CI, 4.0%-8.6%). Prior infections were 67% Latinx, 16% White, and 17% other ethnicities. Among recent infections, 96% were Latinx. Risk factors for recent infection were Latinx ethnicity, inability to shelter in place and maintain income, frontline service work, unemployment, and household income <$50 000/year. Five SARS-CoV-2 phylogenetic lineages were detected. CONCLUSIONS: SARS-CoV-2 infections from diverse lineages continued circulating among low-income, Latinx persons unable to work from home and maintain income during San Francisco's shelter-in-place ordinance.

SARS-CoV-2 antibody magnitude and detectability are driven by disease severity, timing, and assay.

Interpretation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serosurveillance studies is limited by poorly defined performance of antibody assays over time in individuals with different clinical presentations. We measured antibody responses in plasma samples from 128 individuals over 160 days using 14 assays. We found a consistent and strong effect of disease severity on antibody magnitude, driven by fever, cough, hospitalization, and oxygen requirement. Responses to spike protein versus nucleocapsid had consistently higher correlation with neutralization. Assays varied substantially in sensitivity during early convalescence and time to seroreversion. Variability was dramatic for individuals with mild infection, who had consistently lower antibody titers, with sensitivities at 6 months ranging from 33 to 98% for commercial assays. Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on infection severity, timing, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.