Towards a long-term control of SARS-CoV-2 transmission – Identifying the epidemiological, immunological and viral genetic drivers of SARS-CoV-2 transmission and pathogenesis in a representative population-based cohort

The ongoing SARS-CoV-2 pandemic is an unprecedented global challenge with an enormous impact on public health, economies and societies worldwide. A wide variety in approaches have been taken to mitigate and control the spread of SARS-CoV-2 across countries and along different stages of the pandemic. After the successful response to the first pandemic wave, Switzerland is currently entering a critical transitional phase as the Federal Office of Public Health recently began the gradual easing of lockdown measures. In this phase, testing and tracing strategies and potential immunity conferred either by a previous infection or by a potential future vaccine are key instruments for controlling and eventually ending the spread of SARS-CoV-2. However, key aspects regarding the main determinants of transmission, the characteristics of humoral and cellular immune responses and viral genetic factors and their relation to clinical disease courses remain unknown.

In close collaboration with the Health Directorate of the Canton of Zurich, the Zurich SARS-CoV-2 cohort will enroll individuals infected with SARS-CoV-2 in the canton, in order to characterize clinical outcomes and immunological responses after SARS-CoV-2 infection. Furthermore, it aims to examine transmission between SARS-CoV-2 infected index cases and their close contacts through a combination of routine contact tracing and phylogenetic analyses. Moreover, it will establish a biobank with longitudinally sampled biological material. These objectives are incorporated in the core Work Package (WP 0). Here, we propose to leverage the information and biospecimens from this representative, population-based cohort in order to complement its findings and provide an integrative perspective on transmission, immune responses and viral genetics to address the following key objectives, organized into four additional WPs:

  • Infer the transmission network using SARS-CoV-2 sequences and contact tracing information. In WP 1, we will sequence viral genomes and infer the transmission network of SARS-CoV-2 through a combination of phylogenomic approaches and contact tracing information. By using the two synergistic approaches, we will be able to mutually validate these methods and identify the key determinants of viral transmission in the population. In particular, we will evaluate the concordance between transmission events determined by the two approaches, quantify the relative role of local transmission and imported cases, and determine the impact of demographic subgroups, such as children, for ongoing transmission of SARS-CoV-2. Characterize antibody responses and the development of immunity among SARS-CoV-2 positive individuals.
  • In WP 2, we will characterize the presence, dynamics and persistence of antibodies against SARS-CoV-2 over a time window spanning from 14 days to one year post infection. We will determine the ability of antibodies in neutralizing SARS-CoV-2 and preventing reinfection, and determine the time-scale over which antibodies and their neutralizing ability wane. Furthermore, we will assess the association of antibody responses with disease severity and viral shedding.
    Characterize the breadth and durability of T cell responses to SARS-CoV-2 and evaluate the relationship between T cell responses, antibody responses and disease severity.
  • In WP 3, we will assess SARS-CoV-2 specific T cell responses, determine the antigen specificity of these responses and identify immunodominant SARS-CoV-2 epitopes representing potential vaccine targets. Moreover, we will test whether T cell responses outlast antibody responses, evaluate whether SARS-CoV-2 infection results in a loss of T cells specific to other common pathogens leading to a predisposition for future viral infections, and assess the association of T cell responses with disease severity.
    Determine and identify the impact of SARS-CoV-2 viral genetics on clinical outcomes, immune responses and transmission.
  • In WP 4, we will combine the virus genomes sequenced in WP 1 with clinical outcome data from the cohort and the immunological traits determined in WP 2 and WP 3 to quantify the impact of viral genetics on these traits and identify viral genetic strains or mutations associated with high virulence, transmissibility or strong immune responses.
    This exemplary project offers an integrative perspective by bringing together the expertise of epidemiologists, virologists, clinicians and computational biologists to investigate key aspects of SARS-CoV-2 infection, pathogenesis and transmission. Using an innovative approach by combining viral phylogenetics with complementary information from routine contact tracing, this project will provide insights about the early and current spread of the virus, and provide high-quality epidemiological data on viral transmission routes and factors influencing transmission.

Moreover, the Zurich SARS-CoV-2 cohort will provide a unique and representative setting for the detailed study of humoral and cellular immune responses and their correlation with clinical outcomes and viral genetic factors, which will allow conclusions about the development and duration of protection from SARS-CoV-2 infection. The close collaboration with the Health Directorate of the Canton of Zurich, as well as the active connection to and collaboration with the Corona Immunitas program, will allow timely feedback of information to public health decision-makers for the prevention of future waves of the pandemic, the protection of at-risk population groups and the development of national vaccination strategies for Switzerland.