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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
3R37AI080289-11S1
Application #
10126673
Study Section
Program Officer
Boggiano, Cesar Augusto
Project Start
2020-01-09
Project End
2022-12-31
Budget Start
2020-04-10
Budget End
2020-12-31
Support Year
11
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
Miller-Novak, Leia K; Das, Jishnu; Musich, Thomas A et al. (2018) Analysis of Complement-Mediated Lysis of Simian Immunodeficiency Virus (SIV) and SIV-Infected Cells Reveals Sex Differences in Vaccine-Induced Immune Responses in Rhesus Macaques. J Virol 92:
Alter, Galit; Barouch, Dan (2018) Immune Correlate-Guided HIV Vaccine Design. Cell Host Microbe 24:25-33
Lofano, Giuseppe; Gorman, Matthew J; Yousif, Ashraf S et al. (2018) Antigen-specific antibody Fc glycosylation enhances humoral immunity via the recruitment of complement. Sci Immunol 3:
Ogunshola, Funsho; Anmole, Gursev; Miller, Rachel L et al. (2018) Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants. Nat Commun 9:5023
Mabuka, Jenniffer M; Dugast, Anne-Sophie; Muema, Daniel M et al. (2017) Plasma CXCL13 but Not B Cell Frequencies in Acute HIV Infection Predicts Emergence of Cross-Neutralizing Antibodies. Front Immunol 8:1104
Ackerman, Margaret E; Barouch, Dan H; Alter, Galit (2017) Systems serology for evaluation of HIV vaccine trials. Immunol Rev 275:262-270
Huang, Yunda; Ferrari, Guido; Alter, Galit et al. (2016) Diversity of Antiviral IgG Effector Activities Observed in HIV-Infected and Vaccinated Subjects. J Immunol 197:4603-4612
Gunn, Bronwyn; Schneider, Jeffrey; Shansab, Maryam et al. (2016) Enhanced binding of antibodies generated during chronic HIV infection to mucus component MUC16. Mucosal Immunol 9:1549-1558
Gunn, Bronwyn M; Alter, Galit (2016) Modulating Antibody Functionality in Infectious Disease and Vaccination. Trends Mol Med 22:969-982
Barouch, Dan H; Alter, Galit; Broge, Thomas et al. (2015) Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349:320-4

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