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Principal Investigator: Galit Alter
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2020
Award: $391,727
Funding agency: National Institute of Allergy and Infectious Diseases
Since 2002, several coronaviruses have emerged able to cause severe respiratory disease, however no vaccine
is available to prevent these rapidly spreading pathogens. Vaccine design has specifically lagged due to our lack
of understanding of the correlates of immunity against these pathogens. Both cellular and humoral immune
responses have been implicated in resolution of disease, but to date only the passive transfer of antibodies has
been shown to confer complete protection in mice. Interestingly, the transfer of both “neutralizing” and non-
neutralizing antibodies have shown protective efficacy, highlighting the role of multiple humoral mechanisms in
limiting viral infection/spread. The precise mechanism of action of these antibodies that have the most profound
impact on limiting disease is currently unclear, but if elucidated could provide critical insights for the development
of effective vaccines against COVID-19 and other coronaviruses. Thus, here we aim to take a systematic
approach to dissect and define both the polyclonal and monoclonal mechanisms by which antibodies confer
protection against COVID-19. Specifically, samples from DNA- and adenovirus 26 (Ad26)- COVID-19 Spike
protein (S) immunized animals, that will be challenged with COVID-19, will be comprehensively profiled using
Systems Serology, to define the functional humoral immune responses linked to protection from infection/disease
in mice, ferrets, and macaques. Machine learning modeling will be employed to discern key immune response
features that translate usefully across these diverse animal contexts. Coupled to a novel systems-Fc-engineering
approach, the COVID-19 CR3022 monoclonal antibody will be engineered to specifically define the Fc-effector
functions that provide the greatest impact on limiting disease. Collectively, these studies will not only define
correlates of immunity across vaccines and species, but also provide mechanistic insights into the precise
mechanisms by which antibodies may confer protection in the context of future vaccines.
Terms: <Adenoviridae><Adenoviruses><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Response><COVID-19><COVID19><Cell Body><Cells><Cessation of life><Clinical Treatment Moab><Complement Activation><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coupled><DNA><Death><Deoxyribonucleic Acid><Development><Disease><Disorder><Engineering><Ferrets><Future><Goals><Human><Immune><Immune response><Immunes><Immunity><Immunize><Immunological response><Immunomodulation><Infection><Infection prevention><Inflammatory><Innate Immune System><Intervention><Intervention Strategies><Lead><Libraries><Link><Lung diseases><M mulatta><M. mulatta><MERS><MERS coronavirus disease><MERS-CoV disease><Macaca><Macaca mulatta><Macaque><Machine Learning><Mediating><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modeling><Modern Man><Molecular><Monkeys><Monoclonal Antibodies><Murine><Mus><Nature><Neutrophil Infiltration><Neutrophil Recruitment><Passive Antibody Transfers><Passive Transfer of Immunity><Pathogenesis><Pb element><Phagocytosis><Phase><Population><Prevent infection><Proteins><Pulmonary Diseases><Pulmonary Disorder><Resolution><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Rhesus Macaque><Rhesus Monkey><Role><SARS><SARS coronavirus disease><SARS-CoV disease><Sampling><Serologic tests><Serological Tests><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><Surface><System><Therapeutic><Translating><Vaccination><Vaccine Design><Vaccines><Viral Diseases><Virus><Virus Diseases><Work><antibody engineering><complement pathway regulation><corona virus><corona virus disease 2019><coronavirus disease 2019><develop a vaccine><development of a vaccine><developmental><disease of the lung><disorder of the lung><heavy metal Pb><heavy metal lead><host response><immune modulation><immune regulation><immune regulator><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><in vivo><insight><interventional strategy><lung disorder><mAbs><machine learned><model of animal><model organism><mutant><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><pathogen><pathogenic virus><prevent><preventing><protective efficacy><serology><social role><vaccine development><vaccine formulation><viral infection><viral pathogen><virus infection><virus-induced disease>