Influenza Hemagglutinin Head Domain Mimicry by Rational Design
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Influenza Hemagglutinin Head Domain Mimicry by Rational Design V Vamsee Aditya Mallajosyula1 · Shiv Swaroop1,2 · Raghavan Varadarajan1 Accepted: 9 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Despite diligent vaccination efforts, influenza virus infection remains a major cause for respiratory-related illness across the globe. The less-than-optimal immunity conferred by the currently prescribed seasonal vaccines and protracted production times warrant the development of novel vaccines. Induction of an epitope-focused antibody response targeting known neutralization epitopes is a viable strategy to enhance the breadth of protection against rapidly evolving infectious viruses. We report the development of a design framework to mimic the hemagglutinin (HA) head fragment of H1-subtype viruses by delineating the interaction network of invariant residues lining the receptor binding site (RBS); a site targeted by crossreactive neutralizing antibodies. The incorporation of multiple sequence alignment information in our algorithm to fix the construct termini and engineer rational mutations facilitates the facile extension of the design to heterologous (subtypespecific) influenza strains. We evaluated our design protocol by generating head fragments from divergent influenza A H1N1 A/Puerto Rico/8/34 and pH1N1 A/California/07/2009 strains that share a sequence identity of only 74.4% within the HA1 subunit. The designed immunogens exhibited characteristics of a well-ordered protein, and bound conformation-specific RBS targeting antibodies with high affinity, a desirable feature for putative vaccine candidates. Additionally, the bacterial expression of these immunogens provides a low-cost, rapidly scalable alternative. Keywords Protein engineering · Interaction network · In silico design · Energy minimization · Sequence conservation · Protein stability · Immune focusing · Escherichia coli · Post translation modifications · Subunit vaccine · Hemagglutinin (HA) · HA head · Glycosylation
1 Introduction Influenza virus infections are a global health and economic burden despite concerted efforts towards surveillance and vaccination programs. Currently, a seasonal influenza vaccine is the preferred prophylactic modus operandi. Recommendations for the composition of the trivalent/quadrivalent V Vamsee Aditya Mallajosyula and Shiv Swaroop have contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10930-020-09930-z) contains supplementary material, which is available to authorized users. * Raghavan Varadarajan [email protected] 1
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
Department of Biochemistry, Central University of Rajasthan, Kishangarh, Ajmer 305817, India
2
seasonal influenza vaccine are made by the World Health Organization after elaborate analysis of virological and epidemiological influenza surveillance data across the globe. Development of the seasonal
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