Human vaccines have most often been generated by trial and error with little understanding of molecular mechanisms involved in the protective immunity that they provide. This system of vaccine development has been remarkably effective against pathogens that exhibit little variability over time; however, it has become evident that a much more sophisticated approach is required to develop broadly protective vaccines against pathogens that undergo continuous structural change, such as influenza viruses. Current influenza virus vaccines confer protection by eliciting antibodies that block viral entry by bindin regions of the virus that are highly mutable. In order for antibody-based therapies and vaccines to be effective against a breadth of structurally diverse influenza viruses, protection will clearl have to be gained through alternate routes of blocking viral replication. The identification of broadly neutralizing monoclonal antibodies against the conserved stalk domain of the viral hemagglutinin (HA), by members of our group and by others, was a groundbreaking advance, as many of these antibodies are able to block fusion of viral and endosomal membranes, yet bind epitopes that are relatively resistant to structural change. A second critical finding by members of our group was that protection mediated by anti-stalk antibodies at low concentrations is dependent on Fc-Fc Receptor (FcR) interactions; therefore, antibody isotype determines protective activity of anti-stalk antibodies at lower concentrations. The current proposal is for a multi-center investigation into molecular mechanisms that can be harnessed to provide broad-based protection against influenza viruses. Our projects include: 1) Precise mapping of epitopes on the viral HA and neuraminidase glycoproteins that mediate virus neutralization, and dissection of mechanisms by which they achieve neutralization. 2) Immunization studies using chimeric influenza virus proteins designed to identify structural elements able to mediate broad-spectrum humoral immunity. 3) Delineation of the roles of Fc-FcR interactions in viral neutralization. 4) Investigation in human subjects into how to elicit antibodies with favorable Fc domains during vaccination. 5) Studies on the natural evolution of human B cell specificities against influenza antigens. 6) Identification of specific sequences of influenza antigen exposures that elicit broad-spectrum, anti-influenza humoral immunity. Overall, our intention is to better understand the mechanisms of broadly protective humoral immune responses against the influenza virus surface proteins and thereby create a blueprint for advancing a new generation of broadly protective influenza virus vaccines and antibody-based therapeutics.
The projects we propose are hypothesis-driven, mechanistic studies on immunity against influenza viruses and on the activation and regulation of human immune responses. We are confident that the work we have proposed will result in a deeper understanding of molecular mechanisms that can be exploited for generating broadly protective interventions against influenza viruses and we believe that data from our efforts will advance the general understanding of mechanisms of humoral immunity, which will undoubtedly be of benefit to an audience outside of the influenza virus community. Importantly, the Projects proposed in this application are highly integrated and the success of each relies on expertise, resources and reagents made possible through this collaborative effort.
|Broecker, Felix; Liu, Sean T H; Sun, Weina et al. (2018) Immunodominance of Antigenic Site B in the Hemagglutinin of the Current H3N2 Influenza Virus in Humans and Mice. J Virol 92:|
|Nachbagauer, Raffael; Shore, David; Yang, Hua et al. (2018) Broadly Reactive Human Monoclonal Antibodies Elicited following Pandemic H1N1 Influenza Virus Exposure Protect Mice against Highly Pathogenic H5N1 Challenge. J Virol 92:|
|Pardi, Norbert; Parkhouse, Kaela; Kirkpatrick, Ericka et al. (2018) Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat Commun 9:3361|
|Wang, Taia T; Bournazos, Stylianos; Ravetch, Jeffrey V (2018) Immunological responses to influenza vaccination: lessons for improving vaccine efficacy. Curr Opin Immunol 53:124-129|
|Wilson, Patrick C; Cobey, Sarah (2018) Characterization of the immunologic repertoire: A quick start guide. Immunol Rev 284:5-8|
|Stamper, Christopher T; Wilson, Patrick C (2018) What Are the Primary Limitations in B-Cell Affinity Maturation, and How Much Affinity Maturation Can We Drive with Vaccination? Is Affinity Maturation a Self-Defeating Process for Eliciting Broad Protection? Cold Spring Harb Perspect Biol 10:|
|Fulton, Benjamin O; Sun, Weina; Heaton, Nicholas S et al. (2018) The Influenza B Virus Hemagglutinin Head Domain Is Less Tolerant to Transposon Mutagenesis than That of the Influenza A Virus. J Virol 92:|
|Pardi, Norbert; Hogan, Michael J; Naradikian, Martin S et al. (2018) Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med 215:1571-1588|
|Coughlan, Lynda; Palese, Peter (2018) Overcoming Barriers in the Path to a Universal Influenza Virus Vaccine. Cell Host Microbe 24:18-24|
|Krammer, Florian; Fouchier, Ron A M; Eichelberger, Maryna C et al. (2018) NAction! How Can Neuraminidase-Based Immunity Contribute to Better Influenza Virus Vaccines? MBio 9:|
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