Vaccine development is an empirical process, governed by response rates, efficacy studies, side effects and the duration of protection;data gleaned experimentally from large, longitudinal clinical studies. This program develops novel high-resolution molecular metrics that define the mechanisms that mediate long-term protective memory B cell responses after norovirus (NoV) vaccination. Using human vaccine samples, we will: i) characterize broadly protective antibody responses using in vitro and in vivo (mice) models, ii) measure the magnitude of the short and long-term neutralizing antibody response, iii) map key epitopes linked with long- term protective immunity, and iv) deconstruct the B cell memory response associated with homotypic and heterotypic protective immunity after vaccination. As rapidly evolving viruses complicate vaccine development, our technologies and approaches will have wide applicability for global health. NoV are the major cause of acute non-bacterial, epidemic gastroenteritis and cause millions of infections that result in ~200,000 deaths/year, globally. To prevent future NoV outbreaks, we will identify molecular markers for long-term protective immunity after vaccination. Our studies will identify key NoV neutralizing epitopes which mediate type specific and broadly cross reactive short and long-term protective immunity and memory B cell responses following human vaccination and 3) inform second generation NoV vaccine design. The platform technologies developed here are readily portable to other systems. Important outcomes include the identification of key epitopes associated with cross neutralizing, long-term protective immunity across GI and across GII strains, the identification of key barriers to vaccine performance in humans, and the emergence of novel solutions to ameliorate these barriers to effective human NoV vaccine design.
To prevent future norovirus outbreaks, we will identify molecular markers for long-term protective immunity and characterize the breadth of the protective antibody response after vaccination. Our studies will identify key norovirus neutralizing epitopes which mediate type specific and broadly cross reactive short and long-term protective immunity, develop robust platforms for discriminating between short and long-term memory B cell response following human vaccination and inform second generation norovirus vaccine design as certain strains evolve quickly.
|Mallory, Michael L; Lindesmith, Lisa C; Baric, Ralph S (2018) Vaccination-induced herd immunity: Successes and challenges. J Allergy Clin Immunol 142:64-66|
|Johnson, Erik L; Doria-Rose, Nicole A; Gorman, Jason et al. (2018) Sequencing HIV-neutralizing antibody exons and introns reveals detailed aspects of lineage maturation. Nat Commun 9:4136|
|Lindesmith, Lisa C; Brewer-Jensen, Paul D; Mallory, Michael L et al. (2018) Antigenic Characterization of a Novel Recombinant GII.P16-GII.4 Sydney Norovirus Strain With Minor Sequence Variation Leading to Antibody Escape. J Infect Dis 217:1145-1152|
|Wang, Bo; DeKosky, Brandon J; Timm, Morgan R et al. (2018) Functional interrogation and mining of natively paired human VH:VL antibody repertoires. Nat Biotechnol 36:152-155|
|Kocher, Jacob F; Lindesmith, Lisa C; Debbink, Kari et al. (2018) Bat Caliciviruses and Human Noroviruses Are Antigenically Similar and Have Overlapping Histo-Blood Group Antigen Binding Profiles. MBio 9:|
|Lindesmith, Lisa C; Mallory, Michael L; Debbink, Kari et al. (2018) Conformational Occlusion of Blockade Antibody Epitopes, a Novel Mechanism of GII.4 Human Norovirus Immune Evasion. mSphere 3:|
|Lindesmith, Lisa C; Mallory, Michael L; Jones, Taylor A et al. (2017) Impact of Pre-exposure History and Host Genetics on Antibody Avidity Following Norovirus Vaccination. J Infect Dis 215:984-991|
|Lindesmith, Lisa C; Kocher, Jacob F; Donaldson, Eric F et al. (2017) Emergence of Novel Human Norovirus GII.17 Strains Correlates With Changes in Blockade Antibody Epitopes. J Infect Dis 216:1227-1234|
|DeKosky, Brandon J; Lungu, Oana I; Park, Daechan et al. (2016) Large-scale sequence and structural comparisons of human naive and antigen-experienced antibody repertoires. Proc Natl Acad Sci U S A 113:E2636-45|
|Wine, Yariv; Horton, Andrew P; Ippolito, Gregory C et al. (2015) Serology in the 21st century: the molecular-level analysis of the serum antibody repertoire. Curr Opin Immunol 35:89-97|
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