Each influenza hemagglutinin (HA) is a mosaic of conserved and strain-specific epitopes, some of which are recognized by neutralizing antibodies. An influenza vaccine that preferentially elicits neutralizing antibodies that recognize conserved epitopes will be more broadly protective than those now in use. Understanding how the exposure history of subjects, differences in influenza vaccine antigens, and the addition of adjuvants bias the immune response towards different HA epitopes will enable us to design optimal vaccines. The following three hypotheses will be tested. (1] The B-cell repertoires elicited by non-replicating influenza vaccines and by infection differ in degree of polyclonal activation and breadth of neutralization. The repertoires elicited by adjuvanted and non-adjuvanted vaccines differ because adjuvant broadens the range of recognized epitopes. (2] Broadly reactive antibodies, including those recognizing the heterosubtypic stem epitope, are less frequent after true primary than after secondary influenza immunization due to broadening of the response by multiple HA stimulations. (3) Efficient induction of antibodies against a desired epitope requires: (a] proliferation of a favorable germline antibody and (b) an affinity maturation pathway to a desired final specificity. There are preferred germline precursors and maturation pathways for antibodies targeting particular epitopes. Hypotheses 1 and 2 will be tested by mapping the epitopes recognized by the repertoires of human subjects with different exposure histories to influenza infection and/or immunization with adjuvanted or un-adjuvanted vaccines. We will seek broadly neutralizing antibodies (those we want to elicit) to understand their germline precursors and maturation pathways. We will also map the epitopes of the full range of antibodies that bind HA to determine what the humoral immune system "sees." The insights obtained from this mapping will be used to rationally design superior HA immunogens that will be optimized through an iterative cycle of antigen engineering, mouse immunization, repertoire analysis, and antigen redesign. Antigen design techniques will include selective epitope presentation, epitope masking, and germ-line antibody targetting followed by guided affinity maturation. The principles of antigen design revealed by this work could be applied to protective determinants of multiple pathogens for which vaccines are needed.
Influenza vaccines protect against strains closely related to the vaccine strains but not against more distantly related strains, necessitating repeated immunization with new flu vaccines and a race against time to make vaccines during pandemics. Learning how to design vaccine antigens that elicit antibodies that recognize relevant conserved patches on the influenza could allow more broadly protective vaccines against influenza and other diseases. This study aims to learn how to design these improved vaccine antigens.
|Kuraoka, Masayuki; Schmidt, Aaron G; Nojima, Takuya et al. (2016) Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. Immunity 44:542-52|
|Xu, Huafeng; Schmidt, Aaron G; O'Donnell, Timothy et al. (2015) Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage. Proteins 83:771-80|
|Schmidt, Aaron G; Do, Khoi T; McCarthy, Kevin R et al. (2015) Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site. Cell Rep 13:2842-50|
|Harrison, Stephen C (2015) Viral membrane fusion. Virology 479-480:498-507|
|Schmidt, Aaron G; Therkelsen, Matthew D; Stewart, Shaun et al. (2015) Viral receptor-binding site antibodies with diverse germline origins. Cell 161:1026-34|
|Jackson, Katherine J L; Liu, Yi; Roskin, Krishna M et al. (2014) Human responses to influenza vaccination show seroconversion signatures and convergent antibody rearrangements. Cell Host Microbe 16:105-14|
|Schmidt, Aaron G; Xu, Huafeng; Khan, Amir R et al. (2013) Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc Natl Acad Sci U S A 110:264-9|
|Dormitzer, Philip R; Grandi, Guido; Rappuoli, Rino (2012) Structural vaccinology starts to deliver. Nat Rev Microbiol 10:807-13|
|Whittle, James R R; Zhang, Ruijun; Khurana, Surender et al. (2011) Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci U S A 108:14216-21|