SARS-CoV-2 IgG Spike antibody levels and avidity in natural infection or following vaccination with mRNA-1273 or BNT162b2 vaccines.

Certain aspects of the immunogenicity and effectiveness of the messenger ribonucleic acid (mRNA) vaccines (mRNA-1273 and BNT162b2) developed in response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic are still uncharacterized. Serum or plasma samples from healthy donor recipients of either vaccine (BNT162b2 n = 53, mRNA-1273 n = 49; age 23-67), and individuals naturally infected with SARS-CoV-2 (n = 106; age 18-82) were collected 0-2 months post-infection or 1- and 4 months after second dose of vaccination. Anti-Spike antibody levels and avidity were measured via an enzyme-linked immunosorbent assay (ELISA). Overall, vaccination induced higher circulating anti-Spike protein immunoglobulin G (IgG) antibody levels and avidity compared to infection at similar time intervals. Both vaccines produced similar anti-Spike IgG concentrations at 1 month, while mRNA-1273 demonstrated significantly higher circulating antibody concentrations after 4 months. mRNA-1273 induced significantly higher avidity at month 1 compared to BNT162b2 across all age groups. However, the 23-34 age group was the only group to maintain statistical significance by 4 months. Male BNT162b2 recipients were approaching statistically significant lower anti-Spike IgG avidity compared to females by month 4. These findings demonstrate enhanced anti-Spike IgG levels and avidity following vaccination compared to natural infection. In addition, the mRNA-1273 vaccine induced higher antibody levels by 4 months compared to BNT162b2.

Assay Harmonization Study To Measure Immune Response to SARS-CoV-2 Infection and Vaccines: a Serology Methods Study.

The Coronavirus disease 2019 (COVID-19) pandemic presented the scientific community with an immediate need for accurate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology assays, resulting in an expansion of assay development, some without following a rigorous quality control and validation, and with a wide range of performance characteristics. Vast amounts of data have been gathered on SARS-CoV-2 antibody response; however, performance and ability to compare the results have been challenging. This study seeks to analyze the reliability, sensitivity, specificity, and reproducibility of a set of widely used commercial, in-house, and neutralization serology assays, as well as provide evidence for the feasibility of using the World Health Organization (WHO) International Standard (IS) as a harmonization tool. This study also seeks to demonstrate that binding immunoassays may serve as a practical alternative for the serological study of large sample sets in lieu of expensive, complex, and less reproducible neutralization assays. In this study, commercial assays demonstrated the highest specificity, while in-house assays excelled in antibody sensitivity. As expected, neutralization assays demonstrated high levels of variability but overall good correlations with binding immunoassays, suggesting that binding may be reasonably accurate as well as practical for the study of SARS-CoV-2 serology. All three assay types performed well after WHO IS standardization. The results of this study demonstrate there are high performing serology assays available to the scientific community to rigorously dissect antibody responses to infection and vaccination. IMPORTANCE Previous studies have shown significant variability in SARS-CoV-2 antibody serology assays, highlighting the need for evaluation and comparison of these assays using the same set of samples covering a wide range of antibody responses induced by infection or vaccination. This study demonstrated that there are high performing assays that can be used reliably to evaluate immune responses to SARS-CoV-2 in the context of infection and vaccination. This study also demonstrated the feasibility of harmonizing these assays against the International Standard and provided evidence that the binding immunoassays may have high enough correlation with the neutralization assays to serve as a practical proxy. These results represent an important step in standardizing and harmonizing the many different serological assays used to evaluate COVID-19 immune responses in the population.

The NIH-led research response to COVID-19.

Investment, collaboration, and coordination have been key.

Risk of and duration of protection from SARS-CoV-2 reinfection assessed with real-world data.

This retrospective observational study aimed to gain a better understanding of the protective duration of prior SARS-CoV-2 infection against reinfection. The objectives were two-fold: to assess the durability of immunity to SARS-CoV-2 reinfection among initially unvaccinated individuals with previous SARS-CoV-2 infection, and to evaluate the crude SARS-CoV-2 reinfection rate and associated risk factors. During the pandemic era time period from February 29, 2020, through April 30, 2021, 144,678,382 individuals with SARS-CoV-2 molecular diagnostic or antibody test results were studied. 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. Consistent with prior findings, the risk of reinfection among index-positive individuals was 87% lower than the risk of infection among index-negative individuals. 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. This large US population-based study suggests that infection induced immunity is durable for variants circulating pre-Delta predominance.

Selection, Characterization, Calibration, and Distribution of the U.S. Serology Standard for Anti-SARS-CoV-2 Antibody Detection.

The SARS-CoV-2 pandemic resulted in a demand for highly specific and sensitive serological testing to evaluate seroprevalence and antiviral immune responses to infection and vaccines. Hence, there was an urgent need for a serology standard to harmonize results across different natural history and vaccine studies. The Frederick National Laboratory for Cancer Research (FNLCR) generated a U.S. serology standard for SARS-CoV-2 serology assays and subsequently calibrated it to the WHO international standard (National Institute for Biological Standards and Control [NIBSC] code 20/136) (WHO IS). The development included a collaborative study to evaluate the suitability of the U.S. serology standard as a calibrator for SARS-CoV-2 serology assays. The eight laboratories participating in the study tested a total of 17 assays, which included commercial and in-house-derived binding antibody assays, as well as neutralization assays. Notably, the use of the U.S. serology standard to normalize results led to a reduction in the inter-assay coefficient of variation (CV) for IgM levels (pre-normalization range, 370.6% to 1,026.7%, and post-normalization range, 52.8% to 242.3%) and a reduction in the inter-assay CV for IgG levels (pre-normalization range, 3,416.3% to 6,160.8%, and post-normalization range, 41.6% to 134.6%). The following results were assigned to the U.S. serology standard following calibration against the WHO IS: 246 binding antibody units (BAU)/mL for Spike IgM, 764 BAU/mL for Spike IgG, 1,037 BAU/mL for Nucleocapsid IgM, 681 BAU/mL for Nucleocapsid IgG assays, and 813 neutralizing international units (IU)/mL for neutralization assays. The U.S. serology standard has been made publicly available as a resource to the scientific community around the globe to help harmonize results between laboratories.

Cancer vaccines.

Given the renewed interest in vaccine development sparked by the COVID-19 pandemic, we are revisiting the current state of vaccine development for cancer prevention and treatment. Experts discuss different vaccine types, their antigens and modes of action, and where we stand on their clinical development, plus the challenges we need to overcome for their broad implementation.

Clinical Evidence Generation During a Pandemic: Lessons Learned for Sustaining Progress.

ABSTRACT: Because of significant adaptations forced by the COVID-19 pandemic, resultant changes within health care delivery and clinical research introduced the potential for evaluation of novel evidence generation approaches in oncology. On July 26 and 27, 2021, the National Academies of Science, Engineering, and Medicine, National Cancer Policy Forum hosted a virtual workshop entitled "Cancer Care and Cancer Research in the Context of the COVID-19 Pandemic: A Workshop on Lessons Learned." This workshop examined changes in cancer care and cancer research that occurred in response to the COVID-19 pandemic and considered lessons learned from that experience. The goal was to identify what changes could improve the delivery of high-quality cancer care and the conduct of cancer clinical trials in the postpandemic era, with an emphasis on health equity. How can we sustain the valuable lessons learned that might accelerate progress and enhance clinical evidence generation for patients and clinicians? In this overview, we discuss ways in which the COVID-19 experience has catalyzed research efficiencies as well as fostered a broader array of trial design and research methods that may facilitate improved cancer drug development during the pandemic and beyond.

Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in All of Us Research Program Participants, 2 January to 18 March 2020.

BACKGROUND: With limited severe acute respiratory syndrome coronavirus (SARS-CoV-2) testing capacity in the United States at the start of the epidemic (January-March 2020), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic. METHODS: All of Us study participants in all 50 US states provided blood specimens during study visits from 2 January to 18 March 2020. Participants were considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies with the Abbott Architect SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. The sensitivity and specificity of these ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated, along with 95% confidence intervals (CIs). RESULTS: The estimated sensitivities of the Abbott and EUROIMMUN assays were 100% (107 of 107 [95% CI: 96.6%-100%]) and 90.7% (97 of 107 [83.5%-95.4%]), respectively, and the estimated specificities were 99.5% (995 of 1000 [98.8%-99.8%]) and 99.7% (997 of 1000 [99.1%-99.9%]), respectively. The net sensitivity and specificity of our sequential testing algorithm were 90.7% (97 of 107 [95% CI: 83.5%-95.4%]) and 100.0% (1000 of 1000 [99.6%-100%]), respectively. Of the 24 079 study participants with blood specimens from 2 January to 18 March 2020, 9 were seropositive, 7 before the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi. CONCLUSIONS: Our findings identified SARS-CoV-2 infections weeks before the first recognized cases in 5 US states.

A Trans-Governmental Collaboration to Independently Evaluate SARS-CoV-2 Serology Assays.

The emergence of SARS-CoV-2 created a crucial need for serology assays to detect anti-SARS-CoV-2 antibodies, which led to many serology assays entering the market. A trans-government collaboration was created in April 2020 to independently evaluate the performance of commercial SARS-CoV-2 serology assays and help inform U.S. Food and Drug Administration (FDA) regulatory decisions. To assess assay performance, three evaluation panels with similar antibody titer distributions were assembled. Each panel consisted of 110 samples with positive (n = 30) serum samples with a wide range of anti-SARS-CoV-2 antibody titers and negative (n = 80) plasma and/or serum samples that were collected before the start of the COVID-19 pandemic. Each sample was characterized for anti-SARS-CoV-2 antibodies against the spike protein using enzyme-linked immunosorbent assays (ELISA). Samples were selected for the panel when there was agreement on seropositivity by laboratories at National Cancer Institute's Frederick National Laboratory for Cancer Research (NCI-FNLCR) and Centers for Disease Control and Prevention (CDC). The sensitivity and specificity of each assay were assessed to determine Emergency Use Authorization (EUA) suitability. As of January 8, 2021, results from 91 evaluations were made publicly available (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html). Sensitivity ranged from 27% to 100% for IgG (n = 81), from 10% to 100% for IgM (n = 74), and from 73% to 100% for total or pan-immunoglobulins (n = 5). The combined specificity ranged from 58% to 100% (n = 91). Approximately one-third (n = 27) of the assays evaluated are now authorized by FDA for emergency use. This collaboration established a framework for assay performance evaluation that could be used for future outbreaks and could serve as a model for other technologies. IMPORTANCE The SARS-CoV-2 pandemic created a crucial need for accurate serology assays to evaluate seroprevalence and antiviral immune responses. The initial flood of serology assays entering the market with inadequate performance emphasized the need for independent evaluation of commercial SARS-CoV-2 antibody assays using performance evaluation panels to determine suitability for use under EUA. Through a government-wide collaborative network, 91 commercial SARS-CoV-2 serology assay evaluations were performed. Three evaluation panels with similar overall antibody titer distributions were assembled to evaluate performance. Nearly one-third of the assays evaluated met acceptable performance recommendations, and two assays had EUAs revoked and were removed from the U.S. market based on inadequate performance. Data for all serology assays evaluated are available at the FDA and CDC websites (https://open.fda.gov/apis/device/covid19serology/, and https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/serology-test-evaluation.html).

Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection.

Importance: Understanding the effect of serum antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on susceptibility to infection is important for identifying at-risk populations and could have implications for vaccine deployment. Objective: The study purpose was to evaluate evidence of SARS-CoV-2 infection based on diagnostic nucleic acid amplification test (NAAT) among patients with positive vs negative test results for antibodies in an observational descriptive cohort study of clinical laboratory and linked claims data. Design, Setting, and Participants: The study created cohorts from a deidentified data set composed of commercial laboratory tests, medical and pharmacy claims, electronic health records, and hospital chargemaster data. Patients were categorized as antibody-positive or antibody-negative according to their first SARS-CoV-2 antibody test in the database. Main Outcomes and Measures: Primary end points were post-index diagnostic NAAT results, with infection defined as a positive diagnostic test post-index, 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, including recorded signs and symptoms or prior evidence of coronavirus 2019 (COVID) diagnoses or positive NAAT results and recorded comorbidities. Results: The cohort included 3 257 478 unique patients with an index antibody test; 56% were female with a median (SD) age of 48 (20) years. Of these, 2 876 773 (88.3%) had a negative index antibody result, and 378 606 (11.6%) had a positive index antibody result. Patients with a negative antibody test result were older than those with a positive result (mean age 48 vs 44 years). Of index-positive patients, 18.4% converted to seronegative over the follow-up period. During the follow-up periods, the ratio (95% CI) of positive NAAT results among individuals who had a positive antibody test at index vs those with a negative antibody test at index was 2.85 (95% CI, 2.73-2.97) at 0 to 30 days, 0.67 (95% CI, 0.6-0.74) at 31 to 60 days, 0.29 (95% CI, 0.24-0.35) at 61 to 90 days, and 0.10 (95% CI, 0.05-0.19) at more than 90 days. Conclusions and Relevance: In this cohort study, patients with positive antibody test results were initially more likely to have positive NAAT results, consistent with prolonged RNA shedding, but became markedly less likely to have positive NAAT results over time, suggesting that seropositivity is associated with protection from infection. The duration of protection is unknown, and protection may wane over time.

The COVID-19 Serology Studies Workshop: Recommendations and Challenges.

The development, validation, and appropriate application of serological assays to detect antibodies to SARS-CoV-2 are essential to determining seroprevalence of this virus in the United States and globally and in guiding government leadership and the private sector on back-to-work policies. An interagency working group of the US Department of Health and Human Services convened a virtual workshop to identify knowledge gaps and key outstanding scientific issues and to develop strategies to fill them. Key outcomes of the workshop included recommendations for (1) advancing serology assays as a tool to better understand SARS-CoV-2 infection and (2) conducting crucial serology field studies to advance an understanding of immunity to SARS-CoV-2, leading to protection and duration of protection, including the correlation between serological test results and risk of reinfection.