Structural inequalities in the pathway to COVID-19 immunity

BackgroundAs COVID-19 vaccines continue to be rolled-out, the "double burden" of health disparities in both exposure to infection and vaccination coverage intersect to determine the current and future patterns of infection, immunity, and mortality. Serology provides a unique opportunity to measure biomarkers of infection and vaccination simultaneously, and to relate these metrics to demographic and geographic factors. MethodsLeveraging algorithmically selected residual serum samples from two hospital networks in San Francisco, we sampled 1014 individuals during February 2021, capturing transmission during the first 11 months of the epidemic and the early roll out of vaccination. These samples were tested using two serologic assays: one detecting antibodies elicited by infection, and not by vaccines, and one detecting antibodies elicited by both infection and vaccination. We used Bayesian statistical models to estimate the proportion of the population that was naturally infected and the proportion protected due to vaccination. FindingsWe estimated that the risk of prior infection of Latinx residents was 5.3 (95% CI: 3.2 - 10.3) times greater than the risk of white residents aged 18-64 and that white San Francisco residents over the age of 65 were twice as likely (2.0, 95% CI: 1.1 - 4.6) to be vaccinated as Black residents. We also found socioeconomically deprived zipcodes in the city had high probabilities of natural infections and lower vaccination coverage than wealthier zipcodes. InterpretationUsing a platform we created for SARS-CoV-2 serologic data collection in San Francisco, we characterized and quantified the stark disparities in infection rates and vaccine coverage by demographic groups over the first year of the pandemic. While the arrival of the SARS-CoV-2 vaccine has created a light at the end of the tunnel for this pandemic, ongoing challenges in achieving and maintaining equity must also be considered. FundingNIH, NIGMS, Schmidt Science Fellows in partnership with the Rhodes Trust and the Chan Zuckerberg Biohub.

SARS-CoV-2 serology across scales: a framework for unbiased seroprevalence estimation incorporating antibody kinetics and epidemic recency

Serosurveys are a key resource for measuring SARS-CoV-2 cumulative incidence. A growing body of evidence suggests that asymptomatic and mild infections (together making up over 95% of all infections) are associated with lower antibody titers than severe infections. Antibody levels also peak a few weeks after infection and decay gradually. We developed a statistical approach to produce adjusted estimates of seroprevalence from raw serosurvey results that account for these sources of spectrum bias. We incorporate data on antibody responses on multiple assays from a post-infection longitudinal cohort, along with epidemic time series to account for the timing of a serosurvey relative to how recently individuals may have been infected. We applied this method to produce adjusted seroprevalence estimates from five large-scale SARS-CoV-2 serosurveys across different settings and study designs. We identify substantial differences between reported and adjusted estimates of over two-fold in the results of some surveys, and provide a tool for practitioners to generate adjusted estimates with pre-set or custom parameter values. While unprecedented efforts have been launched to generate SARS-CoV-2 seroprevalence estimates over this past year, interpretation of results from these studies requires properly accounting for both population-level epidemiologic context and individual-level immune dynamics.

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

Serosurveillance studies are critical for estimating SARS-CoV-2 transmission and immunity, but interpretation of results is currently limited by poorly defined variability in the performance of antibody assays to detect seroreactivity over time in individuals with different clinical presentations. We measured longitudinal antibody responses to SARS-CoV-2 in plasma samples from a diverse cohort of 128 individuals over 160 days using 14 binding and neutralization assays. For all assays, we found a consistent and strong effect of disease severity on antibody magnitude, with fever, cough, hospitalization, and oxygen requirement explaining much of this variation. We found that binding assays measuring responses to spike protein had consistently higher correlation with neutralization than those measuring responses to nucleocapsid, regardless of assay format and sample timing. However, assays varied substantially with respect to sensitivity during early convalescence and in time to seroreversion. Variations in sensitivity and durability were particularly dramatic for individuals with mild infection, who had consistently lower antibody titers and represent the majority of the infected population, with sensitivities often differing substantially from reported test characteristics (e.g., amongst commercial assays, sensitivity at 6 months ranged from 33% for ARCHITECT IgG to 98% for VITROS Total Ig). Thus, the ability to detect previous infection by SARS-CoV-2 is highly dependent on the severity of the initial infection, timing relative to infection, and the assay used. These findings have important implications for the design and interpretation of SARS-CoV-2 serosurveillance studies.

Long-Term SARS-CoV-2-Specific Immune and Inflammatory Responses Across a Clinically Diverse Cohort of Individuals Recovering from COVID-19

A detailed understanding of long-term SARS-CoV-2-specific T cell responses and their relationship to humoral immunity and markers of inflammation in diverse groups of individuals representing the spectrum of COVID-19 illness and recovery is urgently needed. Data are also lacking as to whether and how adaptive immune and inflammatory responses differ in individuals that experience persistent symptomatic sequelae months following acute infection compared to those with complete, rapid recovery. We measured SARS-CoV-2-specific T cell responses, soluble markers of inflammation, and antibody levels and neutralization capacity longitudinally up to 9 months following infection in a diverse group of 70 individuals with PCR-confirmed SARS-CoV-2 infection. The participants had varying degrees of initial disease severity and were enrolled in the northern California Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort. Adaptive T cell responses remained remarkably stable in all participants across disease severity during the entire study interval. Whereas the magnitude of the early CD4+ T cell immune response is determined by the severity of initial infection (participants requiring hospitalization or intensive care), pre-existing lung disease was significantly associated with higher long-term SARS-CoV2-specific CD8+ T cell responses, independent of initial disease severity or age. Neutralizing antibody levels were strongly correlated with SARS-CoV-2-specific CD4+ T but not CD8+ T cell responses. Importantly, we did not identify substantial differences in long-term virus-specific T cell or antibody responses between participants with and without COVID-19-related symptoms that persist months after initial infection.

Supervised self-collected SARS-CoV-2 testing in indoor summer camps to inform school reopening

Background and ObjectivesTesting strategies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in school settings are needed to assess the efficacy of infection mitigation strategies and inform school reopening policies. We hypothesized that supervised serial self-collected non-nasopharyngeal testing in summer camp settings would be acceptable and feasible. MethodsWe performed a cohort study at two urban day camps for kindergarten-8th graders in June and July 2020. Eligible participants were campers, up to two adult household contacts, and camp staff. We assessed participation rates for providing, at two time points, supervised, self-collected anterior nares samples for reverse transcription polymerase chain reaction (RT-PCR) and saliva samples for antibody testing. We qualitatively assessed testing feasibility and adherence to stated camp infection mitigation strategies. Results76% (186/246) of eligible participants consented. The cohort completing both rounds of testing (n=163) comprised 67 campers, 76 household contacts, and 20 staff. Among those present, 100% of campers and staff completed test collection at both time points. Testing was feasible to implement, including staff participation supervising camper test collection. No virus was detected by RT-PCR; seven participants had antibodies. Observed adherence to stated camp mitigation policies for masking, physical distancing, and stable cohorting was generally high. ConclusionsSupervised, self-collected serial anterior nasal and saliva-based SARS-CoV-2 testing was acceptable, with successful repeated participation by children ages 5-14. This strategy for testing and the observed infection mitigation practices comprise potential core components for safe school reopening.

Universal PCR and antibody testing demonstrate little to no transmission of SARS-CoV-2 in a rural community

BackgroundThe absence of systematic surveillance for SARS-CoV-2 has curtailed accurate appraisal of transmission intensity. Our objective was to perform case detection of an entire rural community to quantify SARS-CoV-2 transmission using PCR and antibody testing. MethodsWe conducted a cross-sectional survey of the prevalence and cumulative incidence of SARSCoV-2 infection in the rural town of Bolinas, California (population 1,620), four weeks following shelter-in-place orders. Residents and county essential workers were tested between April 20th - 24th, 2020. Prevalence by PCR and seroprevalence combining data from two forms of antibody testing were performed in parallel (Abbott ARCHITECT IgG to nucleocapsid protein and in-house IgG ELISA to the receptor binding domain). ResultsOf 1,891 participants, 1,312 were confirmed Bolinas residents (>80% community ascertainment). Zero participants were PCR positive. Assuming 80% sensitivity, it would have been unlikely to observe these results (p< 0.05) if there were > 3 active infections in the community. Based on antibody results, estimated prevalence of prior infection was 0.16% (95% CrI: 0.02%, 0.46%). Seroprevalence estimates using only one of the two tests would have been higher, with greater uncertainty. The positive predictive value (PPV) of a positive result on both tests was 99.11% (95% CrI: 95.75%, 99.94%), compared to PPV 44.19%-63.32% (95% CrI range 3.25%-98.64%) if only one test was utilized. ConclusionsFour weeks following shelter-in-place, active and prior SARS-CoV-2 infection in a rural Northern California community was extremely rare. In this low prevalence setting, use of two antibody tests increased the PPV and precision of seroprevalence estimates.

SARS-CoV-2 seroprevalence and neutralizing activity in donor and patient blood from the San Francisco Bay Area

We report very low SARS-CoV-2 seroprevalence in two San Francisco Bay Area populations. Seropositivity was 0.26% in 387 hospitalized patients admitted for non-respiratory indications and 0.1% in 1,000 blood donors. We additionally describe the longitudinal dynamics of immunoglobulin-G, immunoglobulin-M, and in vitro neutralizing antibody titers in COVID-19 patients. Neutralizing antibodies rise in tandem with immunoglobulin levels following symptom onset, exhibiting median time to seroconversion within one day of each other, and there is >93% positive percent agreement between detection of immunoglobulin-G and neutralizing titers.