Globular Head-Displayed Conserved Influenza H1 Hemagglutinin Stalk Epitopes Confer Protection against Heterologous H1N1 Virus

• Published in: PloS one 2016-04, Vol.11 (4), p.e0153579-e0153579
• Main Authors: Klausberger, Miriam, Tscheliessnig, Rupert, Neff, Silke, Nachbagauer, Raffael, Wohlbold, Teddy John, Wilde, Monika, Palmberger, Dieter, Krammer, Florian, Jungbauer, Alois, Grabherr, Reingard
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Biology and Life Sciences; Biotechnology; Clinical trials; Cytometry; Development and progression; Drug dosages; Epitope mapping; Epitopes - immunology; Female; Flow Cytometry; Gene mapping; Genetic aspects; Genetic variability; Health aspects; Hemagglutinin Glycoproteins, Influenza Virus - chemistry; Hemagglutinin Glycoproteins, Influenza Virus - genetics; Hemagglutinin Glycoproteins, Influenza Virus - immunology; Hemagglutinins; Humans; Immune serum; Immune system; Immunity; Immunogenicity; Immunoglobulins; Immunologic factors; Infections; Influenza; Influenza A; Influenza A Virus, H1N1 Subtype - immunology; Influenza vaccines; Influenza Vaccines - administration & dosage; Influenza virus; Influenza, Human - immunology; Influenza, Human - prevention & control; Influenza, Human - virology; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Natural resources; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - prevention & control; Orthomyxoviridae Infections - virology; Pandemics; Peptide Fragments - genetics; Peptide Fragments - immunology; Peptide mapping; Peptides; Physiological aspects; Prevention; Prophylaxis; Protein Conformation; Proteins; Research and Analysis Methods; Sequence Homology, Amino Acid; Swine flu; Vaccines; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0153579

Significant genetic variability in the head region of the influenza A hemagglutinin, the main target of current vaccines, makes it challenging to develop a long-lived seasonal influenza prophylaxis. Vaccines based on the conserved hemagglutinin stalk domain might provide broader cross-reactive immunity. However, this region of the hemagglutinin is immunosubdominant to the head region. Peptide-based vaccines have gained much interest as they allow the immune system to focus on relevant but less immunogenic epitopes. We developed a novel influenza A hemagglutinin-based display platform for H1 hemagglutinin stalk peptides that we identified in an epitope mapping assay using human immune sera and synthetic HA peptides. Flow cytometry and competition assays suggest that the identified stalk sequences do not recapitulate the epitopes of already described broadly neutralizing stalk antibodies. Vaccine constructs displaying 25-mer stalk sequences provided up to 75% protection from lethal heterologous virus challenge in BALB/c mice and induced antibody responses against the H1 hemagglutinin. The developed platform based on a vaccine antigen has the potential to be either used as stand-alone or as prime-vaccine in combination with conventional seasonal or pandemic vaccines for the amplification of stalk-based cross-reactive immunity in humans or as platform to evaluate the relevance of viral peptides/epitopes for protection against influenza virus infection.