Early Drivers of Humoral Immunity to SARS-CoV-2 Infections

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Principal Investigator: Christopher L King
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2022
Award: $679,626
Funding agency: National Cancer Institute

The duration and nature of humoral immunity to SARS-CoV-2 (CoV2) infection is poorly understood. Most
studies have focused on the immune response in patients with clinical illness, but little is known about antibody
response to CoV2 regarding the earliest immunological events immediately after exposure and prior to onset of
illness or in asymptomatic individuals and how this impacts long-term immunological memory. This proposal
addresses these gaps in our knowledge by prospectively following household contacts with clinical cases of
CoV2 to determine innate and adaptive immune events associated with this early viral exposure over a 28 day
period. Detailed evaluation of samples from these patients including RNAseq of peripheral blood cells and
proteomic analysis of oral secretions, the site of initial CoV2 replication. We will determine whether potentially
cross-reactive T cells and secretory IgA may contribute to this early protective immune response and if present
do they enhance the subsequent humoral immune responses by providing greater T cell help to B cells. These
studies will also provide a detailed knowledge of innate immune responses to CoV2 and how this shapes the
nature and duration humoral immunity. Our central hypothesis is that peripheral blood lymphocytes and
oropharyngeal secretions collected from individuals at the time of viral exposure and prior to onset of
symptoms will show innate and adaptive immune responses that correlate with viral clearance and
predict whether or not effective humoral immunity and long-term immunological memory develops.
This hypothesis will be addressed by exploring the following aims; i) evaluating the early immune humoral and
cellular immune responses to CoV2 in close contacts of individuals diagnosed with COVID-19; ii) to assess
early innate immune responses in close contacts of individuals diagnosed with COVID-19 and assess their
relationship with humoral immune responses and viremia; and iii) to examine early drivers of humoral immunity
on the durability of immunological memory and responses to vaccines. This comprehensive evaluation of the
relationships between early infection with innate and adaptive immune on long-term memory and immunity will
provide a rigorous basis for the development of highly informative and scalable serological tests. Our approach
is therefore highly responsive to RFA-CA-20-039, through the development and validation of novel assays that
simultaneously measure innate and adaptive immune responses to CoV2 from early infection; this approach
will help define immune parameters and serological markers associated with asymptomatic vs. symptomatic
infection and disease severity.

Terms: <19S Gamma Globulin><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><ACE2><Address><Affect><Affinity><Age><Animal Model><Animal Models and Related Studies><Antibodies><Antibody Response><Assay><B blood cells><B cell><B cell repertoire><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biologic Assays><Biological Assay><Biology><Blocking Antibodies><Blood><Blood Cells><Blood Circulation><Blood Reticuloendothelial System><Bloodstream><Buccal Cavity><Buccal Cavity Head and Neck><COVID-19><COVID-19 diagnosis><COVID-19 exposure><COVID-19 immunity><COVID-19 infection><COVID-19 outbreak><COVID-19 positive><COVID-19 positivity><COVID-19 virus><COVID19><COVID19 diagnosis><COVID19 immunity><COVID19 infection><COVID19 outbreak><COVID19 positive><COVID19 positivity><COVID19 virus><CV-19><CV19><Cavitas Oris><Cell Body><Cells><Chemotactic Cytokines><Circulation><Clinical><Clinical Trials><CoV-2><CoV2><Communicable Diseases><Coronaviridae Infections><Coronavirus 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