Antigenic variation underlies a large number of the most critical problems now facing vaccine development. Influenza virus is an ideal subject for tackling this issue: it is the most variable pathogen against which we can effectively vaccinate, but its principal surface antigen varies so rapidly that new vaccines must be introduced almost yearly. We propose to use innovative analyses of B-cell repertoires and new possibilities in structural studies to understand the structural and immunological mechanisms underlying cross reactivity and immunodominance, as a foundation for designing immunogens that will elicit a more broadly neutralizing response than those currently in use. We will test the following three hypotheses, to which the three Aims of each Project correspond. (1) The B-cell repertoires elicited by inactivated vaccines and by infection differ in degree of polyclonal activation and breadth of neutralization;the repertoires elicited by immunization with adjuvanted and non-adjuvanted TIV differ because adjuvant increases the breadth of recognized epitopes. (2) Broadly reactive Abs, including those recognizing the heterosubtypic stem epitope, are less frequent after true primary than after secondary TIV immunization due to broadening of the response by multiple HA stimulations. (3) Efficient induction of Abs against a desired epitope requires: (a) proliferation of a favorable germline Ab and (b) an affinity maturation pathway to a desired final specificity;there are preferred germline precursors and maturation pathways for Abs targeting particular epitopes. The group of investigators that joins in this proposal brings together strengths in immunology, virology, structural biology, and vaccine development. The principal investigators have worked closely and effectively together in past collaborations.

Public Health Relevance

The work will have a significant impact on influenza vaccine development and for immunization against other pathogens with rapid antigenic variation. The project will also lead to a greatly improved understanding of the human immune response to vaccines and to the implementation of novel structural methods in virology and immunology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI089618-03
Application #
8516979
Study Section
Special Emphasis Panel (ZAI1-LR-I (M1))
Program Officer
Leitner, Wolfgang W
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$2,100,193
Indirect Cost
$272,296
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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