Multi-epitope Models Explain How Pre-existing Antibodies Affect the Generation of Broadly Protective Responses to Influenza

• Type of Material: Article
• Authors: Veronika Zarnitsyna, Emory University; Jennie Lavine, Emory University; Ali H. Ellebedy, Emory University; Rafi Ahmed, Emory University; Rustom Antia, Emory University
• Language: English
• Date: 2016-06-23
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2016 Zarnitsyna et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1005692
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 12
• Issue: 6
• Start Page: e1005692
• End Page: e1005692
• Grant/Funding Information: National Institute of Allergy and Infectious Diseases U19 AI1178918 to Rustom Antia.; National Institute of Allergy and Infectious Diseases T32AI074492 to Ali Ellebedy.; National Institute of Allergy and Infectious Diseases HHSN266200700006C to Rafi Ahmed.; National Institute of General Medical Sciences U54 GM111274 to Rustom Antia.; VIZ and RAn were supported by NIH U54 GM111274, AE was supported by training grant NIH T32AI074492, RAh was supported by NIAID HHSN266200700006C, and all authors were supported by U19 AI117891.
• Keywords: Parasitology; HEMAGGLUTININ-STEM; A VIRUS-INFECTION; Life Sciences & Biomedicine; ADAPTIVE IMMUNE-RESPONSE; Virology; Microbiology; CELLS; CONSTRUCTS PROTECT; VACCINATION; SEASONAL INFLUENZA; Science & Technology; CHALLENGE; VACCINES; ESCHERICHIA-COLI
• Research Categories: Biology, Microbiology; Health Sciences, General; Health Sciences, Immunology

Abstract

The development of next-generation influenza vaccines that elicit strain-transcendent immunity against both seasonal and pandemic viruses is a key public health goal. Targeting the evolutionarily conserved epitopes on the stem of influenza’s major surface molecule, hemagglutinin, is an appealing prospect, and novel vaccine formulations show promising results in animal model systems. However, studies in humans indicate that natural infection and vaccination result in limited boosting of antibodies to the stem of HA, and the level of stem-specific antibody elicited is insufficient to provide broad strain-transcendent immunity. Here, we use mathematical models of the humoral immune response to explore how pre-existing immunity affects the ability of vaccines to boost antibodies to the head and stem of HA in humans, and, in particular, how it leads to the apparent lack of boosting of broadly cross-reactive antibodies to the stem epitopes. We consider hypotheses where binding of antibody to an epitope: (i) results in more rapid clearance of the antigen; (ii) leads to the formation of antigen-antibody complexes which inhibit B cell activation through Fcγ receptor-mediated mechanism; and (iii) masks the epitope and prevents the stimulation and proliferation of specific B cells. We find that only epitope masking but not the former two mechanisms to be key in recapitulating patterns in data. We discuss the ramifications of our findings for the development of vaccines against both seasonal and pandemic influenza.