Humoral Immunity to SARS-CoV-2 and Inferred Protection from Infection in a French Longitudinal Community Cohort (preprint)

Population-level immunity to SARS-CoV-2 is growing through vaccination as well as ongoing circulation. Given waning immunity and emergence of new variants, it is important to dynamically determine the risk of re-infection in the population. For estimating immune protection, neutralization titers are most informative, but these assays are difficult to conduct at a population level. Measurement of antibody levels can be implemented at high throughput, but has not been robustly validated as a correlate of protection. Here, we have developed a method that predicts neutralization and protection based on variant-specific antibody measurements to SARS-CoV-2 antigens. This approach allowed us to estimate population-immunity in a longitudinal cohort from France followed for up to 2 years. Participants with a single vaccination or immunity caused by infection only are especially vulnerable to COVID-19 or hospitalization due to SARS-CoV-2. While the median reduced risk to COVID-19 in participants with 3 vaccinations was 96%, the median reduced risk among participants with infection-acquired immunity only was 42%. The results presented here are consistent with data from vaccine-effectiveness studies indicating robustness of our approach. Our multiplex serological assay can be readily optimized and employed to study any new variant and provides a framework for development of an assay that would include protection estimates.

Serological reconstruction of COVID-19 epidemics through analysis of antibody kinetics to SARS-CoV-2 proteins (preprint)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a complex antibody response that varies by orders of magnitude between individuals and over time. Waning antibody levels lead to reduced sensitivity of serological diagnostic tests over time. This undermines the utility of serological surveillance as the SARS-CoV-2 pandemic progresses into its second year. Here we develop a multiplex serological test for measuring antibodies of three isotypes (IgG, IgM, IgA) to five SARS-CoV-2 antigens (Spike (S), receptor binding domain (RBD), Nucleocapsid (N), Spike subunit 2, Membrane-Envelope fusion) and the Spike proteins of four seasonal coronaviruses. We measure antibody responses in several cohorts of French and Irish hospitalized patients and healthcare workers followed for up to eleven months after symptom onset. The data are analysed with a mathematical model of antibody kinetics to quantify the duration of antibody responses accounting for inter-individual variation. One year after symptoms, we estimate that 36% (95% range: 11%, 94%) of anti-S IgG remains, 31% (9%, 89%) anti-RBD IgG remains, and 7% (1%, 31%) anti-N IgG remains. Antibodies of the IgM isotype waned more rapidly, with 9% (2%, 32%) anti-RBD IgM remaining after one year. Antibodies of the IgA isotype also waned rapidly, with 10% (3%, 38%) anti-RBD IgA remaining after one year. Quantitative measurements of antibody responses were used to train machine learning algorithms for classification of previous infection and estimation of time since infection. The resulting diagnostic test classified previous infections with 99% specificity and 98% (95% confidence interval: 94%, 99%) sensitivity, with no evidence for declining sensitivity over the time scale considered. The diagnostic test also provided accurate classification of time since infection into intervals of 0 - 3 months, 3 - 6 months, and 6 - 12 months. Finally, we present a computational method for serological reconstruction of past SARS-CoV-2 transmission using the data from this test when applied to samples from a single cross-sectional sero-prevalence survey.

Outbreak of COVID-19 in Germany Resulting from a Single Travel-Associated Primary Case (preprint)

Background: In December 2019, a newly identified coronavirus (SARS-CoV-2) emerged in Wuhan, China, causing respiratory disease (COVID-19) presenting with fever, cough and frequently pneumonia. WHO has set the strategic objective to interrupt virus spread of SARS-CoV-2 worldwide. An outbreak in Bavaria, Germany, starting end of January 2020, gave the opportunity to study transmission events, incubation period, and attack rates.Methods: A case was defined as a person with SARS-CoV-2-infection confirmed by PCR. Case interviews were conducted to i) describe timing of onset and nature of symptoms, ii) identify and classify contacts. High-risk contacts were actively followed and monitored for symptoms, low-risk contacts were tested upon self-reporting of symptoms. Whole genome sequencing was used to confirm epidemiological links and clarify transmission events where contact histories were ambiguous; integration with epidemiological data enabled precise reconstruction of exposure events and incubation periods.Results: Case #0 was a Chinese person who visited Germany for professional reasons. Sixteen subsequent cases emerged in four transmission generations. Signature mutations occurred upon foundation of generation 2, as well as in one patient pertaining to generation 4. Median incubation period and serial interval were 4.0 days, respectively. Transmissions occurred frequently pre-symptomatic, at day of symptom onset and during prodromal phase (symptoms other than fever and cough for ≥1 day at beginning of illness phase). Attack rates were 75% among members of a household cluster in common isolation, 10% among household contacts only together until isolation of case, and 5% among non-household high-risk contacts.Conclusions: While our cases present with predominately mild, non-specific symptoms, infectiousness before or on the day of symptom onset or during prodromal phase is substantial. Additionally, the incubation period is often very short, false-negative tests may occur. Although the outbreak was apparently controlled, successful long-term and global containment of COVID-19 may be difficult to achieve.Funding Statement: Contributions by C. D. and V. M. C. were funded by the German Ministry of Health (Konsiliarlabor für Coronaviren), as well as the German Center for Infection Research. S.B., T.W., K.P., N.M, and T.S.B. are fellows of the ECDC Fellowship Programme, supported financially by the European Centre for Disease Prevention and Control (ECDC).Declaration of Interests: The authors declared no competing interest. Ethics Approval Statement: The outbreak investigation was conducted as part of the authoritative, official tasks of the county health departments as well as the state health department of the Bavarian Health and Food Safety Authority, supported by the Robert Koch Institute. As conducted in response to a public health emergency, this study was exempt from institutional review board approval.