Immune and behavioral correlates of protection against symptomatic post-vaccination SARS-CoV-2 infection (preprint)

Background: We sought to determine immune and behavioral pre-infection correlates of protection against SARS-CoV-2 post-vaccine infections in a joint analysis of epidemiological and immunological cohort data. Methods: Serum and saliva samples from 176 BNT162b2-vaccinated adults in the Prospective Assessment of SARS-CoV-2 Seroconversion study were collected between October and December 2021 and assessed for serum and saliva levels of Wuhan-1 wild-type (WT) SARS-CoV-2 Spike (S)-specific IgG and IgA binding antibodies (bAb) using a multiplex microsphere-based immunoassay (MMIA). Serum samples were also assessed for WT receptor binding domain (RBD)-specific bAb by two commercial assays, BA.1 S-specific IgG bAb by MMIA, and neutralization activity against D614G, Delta (B.1.617.2), and Omicron BA.1 and BA.1.1 variants using a lentiviral pseudovirus neutralization assay. After the Fall 2021 visit, participants reported all positive PCR and/or antigen tests for SARS-CoV-2. Duration, severity, and type of symptoms, as well as risk exposures and adherence to precautionary measures, were assessed by questionnaires during the Spring 2022 visit. Results: Thirty-two participants (18.2%) developed symptomatic post-vaccination SARS-CoV-2 infections (PVI) between December 7, 2021 and April 1, 2022. Pre-infection WT (geometric mean (GM) of 3,863 vs 2,736 binding antibody unit [BAU]/ml, uninfected vs PVI, p=0.0098) and BA.1 (GM of 276.9 vs 179.9 arbitrary bAb unit [AU]/ml, uninfected vs PVI, p=0.04) anti-S IgG bAb levels measured by MMIA and neutralizing titers (NT) against BA.1 (GM titer [GMT] of 493.6 vs 286.2, uninfected vs PVI, p=0.0313) and BA.1.1 (GMT of 552.0 vs 302.5, uninfected vs PVI, p=0.021) were significantly higher in individuals that did not develop PVIs. WT anti-S bAb levels greater than 5,000 BAU/ml were associated with > 90% protection against symptomatic PVI. In individuals that developed PVI, WT anti-S IgG bAb levels correlated with lower disease severity scores ({rho}= -0.3859, p=0.032) and shorter duration of clinical disease ({rho}= -0.5273, p=0.0023). WT anti-RBD bAb levels measured by commercial assays correlated strongly with bAb levels measured by MMIA ({rho}=0.8239, p<0.0001 and {rho}=0.6929, p<0.0001, Roche and Siemens assays, respectively), but did not reach statistical significance for correlation with protection against PVI. Home risk score, but neither work nor home precautionary measures, correlated strongly with risk of PVI (mean score of 20.77 vs 47.33, uninfected vs PVI respectively, p<0.0001). Conclusions: Anti-S IgG bAb levels (directed against either WT or Omicron BA.1 subvariant) and NTs served as correlates of protection against symptomatic SARS-CoV-2 infection. Anti-S (WT) IgG bAb levels remained a significant correlate of protection against PVIs when adjusting for demography and risk behavior. Results of this study also suggest that commercial assays for anti-S bAb may need to be reformatted to enable detection of higher maximum values for use as predictors of increased susceptibility to SARS-CoV-2 infection.

Assessing Vulnerability to COVID-19 in High-Risk Populations: The Role of SARS-CoV-2 Spike-Targeted Serology (preprint)

Importance: Individuals at increased risk for severe outcomes from COVID-19, due to compromised immunity or other risk factors, would benefit from objective measures of vulnerability to infection based on prior infection and/or vaccination. We reviewed published data to identify a specific role and interpretation of SARS-CoV-2 spike-targeted serology testing for such individuals. We also provide real-world evidence of spike-targeted antibody test results, identifying the seronegativity rate across the United States from March 2021 through June 2022. Analysis of antibody test results were compared between post-transplant (ie, immunocompromised) and all other patients tested in the first half of 2022. Finally, specific recommendations are provided for an evidence-based and clinically useful interpretation of spike-targeted serology to identify vulnerability to infection and potential subsequent adverse outcomes. Observations: Decreased vaccine effectiveness among immunocompromised individuals is linked to correspondingly high rates of breakthrough infections. Evidence indicates that negative results on SARS-CoV-2 antibody tests are associated with increased risk for subsequent infection. Results from widely available, laboratory-based tests do not provide a direct measure of protection but appear to correlate well with the presence of surrogate pseudovirus-neutralizing antibodies. The results of SARS-CoV-2 semiquantitative tests have also been associated with vaccine effectiveness and the likelihood of breakthrough infection. The data suggest that "low-positive" results on semiquantitative SARS-CoV-2 spike-targeted antibody tests may help identify persons at increased relative risk for breakthrough infection leading to adverse outcomes. In an analysis of data from large national laboratories during the COVID-19 Omicron-related surge in 2022, results from SARS-CoV-2 spike-targeted antibody tests were negative in 16.6% (742/4459) of solid organ transplant recipients tested compared to only 11.0% (47,552/432,481) of the remaining tested population. Conclusions and Relevance: Standardized semiquantitative and quantitative SARS-CoV-2 spike-targeted antibody tests may provide objective information on risk of SARS-CoV-2 infection and associated adverse outcomes. This holds especially for high-risk populations, including transplant recipients, who demonstrate a relatively higher rate of seronegativity. The widespread availability of such tests presents an opportunity to refine risk assessment for individuals with suboptimal SARS-CoV-2 antibody levels and to promote effective interventions. Interim federal guidance would support physicians and patients while additional investigations are pursued.

Duration of Protection Against SARS-CoV-2 Reinfection and Associated Risk of Reinfection Assessed with Real-World Data (preprint)

ImportanceBetter understanding of the protective duration of prior SARS-CoV-2 infection against reinfection is needed. ObjectivePrimary: To assess the durability of immunity to SARS-CoV-2 reinfection among initially unvaccinated individuals with previous SARS-CoV-2 infection. Secondary: Evaluate the crude SARS-CoV-2 reinfection rate and associated characteristics. Design and SettingRetrospective observational study of HealthVerity data among 144,678,382 individuals, during the pandemic era through April 2021. ParticipantsIndividuals studied had SARS-CoV-2 molecular diagnostic or antibody index test results from February 29 through December 9, 2020, with [≥]365 days of pre-index continuous closed medical enrollment, claims, or electronic health record activity. Main Outcome(s) and Measure(s)Rates of reinfection among index-positive individuals were compared to rates of infection among index-negative individuals. Factors associated with reinfection were evaluated using multivariable logistic regression. For both objectives, the outcome was a subsequent positive molecular diagnostic test result. ResultsAmong 22,786,982 individuals with index SARS-CoV-2 laboratory test data (2,023,341 index positive), the crude rate of reinfection during follow-up was significantly lower (9.89/1,000-person years) than that of primary infection (78.39/1,000 person years). Consistent with prior findings, the risk of reinfection among index-positive individuals was 87% lower than the risk of infection among index-negative individuals (hazard ratio, 0.13; 95% CI, 0.13, 0.13). The cumulative incidence of reinfection among index-positive individuals and infection among index-negative individuals was 0.85% (95% CI: 0.82%, 0.88%) and 6.2% (95% CI: 6.1%, 6.3%), respectively, over follow-up of 375 days. The duration of protection against reinfection was stable over the median 5 months and up to 1-year follow-up interval. Factors associated with an increased reinfection risk included older age, comorbid immunologic conditions, and living in congregate care settings; healthcare workers had a decreased reinfection risk. Conclusions and RelevanceThis large US population-based study demonstrates that SARS-CoV-2 reinfection is uncommon among individuals with laboratory evidence of a previous infection. Protection from SARS-CoV-2 reinfection is stable up to one year. Reinfection risk was primarily associated with age 85+ years, comorbid immunologic conditions and living in congregate care settings; healthcare workers demonstrated a decreased reinfection risk. These findings suggest that infection induced immunity is durable for variants circulating prior to Delta. Key PointsO_ST_ABSQuestionC_ST_ABSHow long does prior SARS-CoV-2 infection provide protection against SARS-CoV-2 reinfection? FindingAmong >22 million individuals tested February 2020 through April 2021, the relative risk of reinfection among those with prior infection was 87% lower than the risk of infection among individuals without prior infection. This protection was durable for up to a year. Factors associated with increased likelihood of reinfection included older age (85+ years), comorbid immunologic conditions, and living in congregate care settings; healthcare workers had lower risk. MeaningPrior SARS-CoV-2 infection provides a durable, high relative degree of protection against reinfection.

Real-world data suggest antibody positivity to SARS-CoV-2 is associated with a decreased risk of future infection (preprint)

ImportanceThere is limited evidence regarding whether the presence of serum antibodies to SARS-CoV-2 is associated with a decreased risk of future infection. Understanding susceptibility to infection and the role of immune memory is important for identifying at-risk populations and could have implications for vaccine deployment. ObjectiveThe purpose of this study was to evaluate subsequent evidence of SARS-CoV-2 infection based on diagnostic nucleic acid amplification test (NAAT) among individuals who are antibody-positive compared with those who are antibody-negative, using real-world data. DesignThis was an observational descriptive cohort study. ParticipantsThe study utilized a national sample to create cohorts from a de-identified dataset composed of commercial laboratory test results, open and closed medical and pharmacy claims, electronic health records, hospital billing (chargemaster) data, and payer enrollment files from the United States. Patients were indexed as antibody-positive or antibody-negative according to their first SARS-CoV-2 antibody test recorded in the database. Patients with more than 1 antibody test on the index date where results were discordant were excluded. Main Outcomes/MeasuresPrimary endpoints were index antibody test results and post-index diagnostic NAAT results, with infection defined as a positive diagnostic test post-index, as measured in 30-day intervals (0-30, 31-60, 61-90, >90 days). Additional measures included demographic, geographic, and clinical characteristics at the time of the index antibody test, such as recorded signs and symptoms or prior evidence of COVID-19 (diagnoses or NAAT+) and recorded comorbidities. ResultsWe included 3,257,478 unique patients with an index antibody test. Of these, 2,876,773 (88.3%) had a negative index antibody result, 378,606 (11.6%) had a positive index antibody result, and 2,099 (0.1%) had an inconclusive index antibody result. Patients with a negative antibody test were somewhat older at index than those with a positive result (mean of 48 versus 44 years). A fraction (18.4%) of individuals who were initially seropositive converted to seronegative over the follow up period. During the follow-up periods, the ratio (CI) of positive NAAT results among individuals who had a positive antibody test at index versus those with a negative antibody test at index was 2.85 (2.73 - 2.97) at 0-30 days, 0.67 (0.6 - 0.74) at 31-60 days, 0.29 (0.24 - 0.35) at 61-90 days), and 0.10 (0.05 - 0.19) at >90 days. ConclusionsPatients who display positive antibody tests are initially more likely to have a positive NAAT, consistent with prolonged RNA shedding, but over time become markedly less likely to have a positive NAAT. This result suggests seropositivity using commercially available assays is associated with protection from infection. The duration of protection is unknown and may wane over time; this parameter will need to be addressed in a study with extended duration of follow up. Key PointsO_ST_ABSQuestionC_ST_ABSCan real-world data be used to evaluate the comparative risk of SARS-CoV-2 infection for individuals who are antibody-positive versus antibody-negative? FindingOf patients indexed on a positive antibody test, 10 of 3,226 with a NAAT (0.3%) had evidence of a positive NAAT > 90 days after index, compared with 491 of 16,157 (3.0%) indexed on a negative antibody test. MeaningIndividuals who are seropositive for SARS-CoV-2 based on commercial assays may be at decreased future risk of SARS-CoV-2 infection.