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Principal Investigator: SABRA L. KLEIN
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2022
Award: $432,172
Funding agency: National Cancer Institute
Research Project 3 Summary
There are insufficient data regarding the long-term humoral immune responses induced after SARS-CoV-2
infection. Our preliminary data indicate that there is variation in the magnitude and duration of antibody
responses following SARS-CoV-2 infection. While IgG and IgA antibodies against spike (S) and the receptor
binding domain of S (S-RBD) appear to remain constant over time, neutralizing antibody (nAb) titers wane and
are not detected in up to 25% of infected individuals who have detectable anti-S and anti-S-RBD antibodies.
We have also observed that during the convalescent phase of SARS-CoV-2 infection, individuals with more
severe COVID-19 (i.e., hospitalized, older, and male patients) have significantly greater serological responses
to SARS-CoV-2. The antibody responses mediating protection from re-infection are not defined, and neither
are responses that may mediate greater pathology. From studies of other viruses, it is clear that a variety of
antibody functions contribute to protection from re-infection and modulate disease severity. Both nAbs and
non-nAbs can mediate a number of different activities, which include complement activation and antibody-
dependent cellular cytotoxicity (ADCC), which may contribute to pathogenesis as well as protections from
SARS-CoV-2. The overarching goal of JH-EPICS Research Project 3 is to analyze the magnitude and duration
of the total as well as functional antibody responses after SARS-CoV-2 infection. We have developed a core
set of serological assays to be applied to a prospective, demographically diverse cohort of hospitalized patients
presenting with mild, moderate, and severe COVID-19 disease. Plasma samples have and will continue to be
collected at multiple timepoints from enrollment through one year post-enrollment. Aim 1 will systematically
evaluate antibody isotype switching and the subclasses and quality of the immunoglobulins (IgG, IgM, and IgA
[monomeric and dimeric]) that recognize the SARS-CoV-2 S and S-RBD. Aim 2 will characterize the kinetics
and duration of the neutralizing antibody response against SARS-CoV-2 and the ability of viruses to escape
from nAbs. Finally, Aim 3 will analyze the function of non-neutralizing SARS-CoV-2-specific serological
response by assessing ADCC, complement-mediated cytotoxicity, and complement fixation activity toward
SARS-CoV-2 virus particles and virus-infected cells. Using linear regression analyses and modeling of these
data in the context of clinical and demographic information, we are uniquely positioned to determine the
modifiers that drive a protective antibody response following SARS-CoV-2 infection or, eventually, vaccination.
Terms: <19S Gamma Globulin><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><Ab-dependent cellular cytotoxicity><Antibodies><Antibody Response><Antibody titer measurement><Autoimmune Status><Autoimmunity><Blood Plasma><Blood Serum><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID survivors><COVID-19 S protein><COVID-19 antibody><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 immune response><COVID-19 infected patient><COVID-19 infection><COVID-19 infection survivors><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 survivors><COVID-19 virus><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 immune response><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cell Body><Cells><Characteristics><Class Switching><Class Switchings><Clinical><CoV-2><CoV2><Complement><Complement Activation><Complement Proteins><Complement-Dependent Cytotoxicity><Data><Disease><Disorder><Enrollment><Fixation><Goals><IgA><IgG><IgM><Immune Globulins><Immune response><Immunity><Immunoglobulin A><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin G><Immunoglobulin M><Immunoglobulins><Immunological response><Individual><Infection><Investigators><Isotype Switching><Isotype Switchings><Kinetics><Linear Regressions><Measures><Mediating><Methods><Modeling><Pathogenesis><Pathology><Patients><Phase><Plasma><Plasma Serum><Population><Position><Positioning Attribute><Prospective cohort><Proteins><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><Regression Analyses><Regression Analysis><Regression Diagnostics><Research Grants><Research Personnel><Research Project Grants><Research Projects><Research Resources><Researchers><Resolution><Resources><Reticuloendothelial System, Serum, Plasma><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 immune response><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 survivors><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 antibody><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serology><Serology test><Serum><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 immune response><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Statistical Regression><Time><Vaccination><Variant><Variation><Virion><Virus><Virus Particle><Work><Wuhan coronavirus><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><antibody against COVID-19><antibody against SARS-CoV-2><antibody against SARS-CoV2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody mediated cellular cytotoxicity><antibody titering><antibody to COVID-19><antibody to SARS-CoV-2><antibody to SARS-CoV2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><cohort><complement pathway regulation><complement-mediated cytotoxicity><convalescent plasma><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 immune response><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 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respiratory syndrome coronavirus 2><influenza infection><influenza virus infection><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><male><nCoV2><neutralizing antibody><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><post SARS-CoV-2 infection><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><prospective><receptor binding><receptor bound><response><sample fixation><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><serology assay><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><survive COVID-19><survive SARS-CoV-2><vaccine development><virology>