title: Vaccination with M2e-based multiple antigenic peptides: characterization of the B cell response and protection efficacy in inbred and outbred mice.
abstract: BACKGROUND
  The extracellular domain of the influenza A virus protein matrix protein 2 (M2e) is remarkably conserved between various human isolates and thus is a viable target antigen for a universal influenza vaccine. With the goal of inducing protection in multiple mouse haplotypes, M2e-based multiple antigenic peptides (M2e-MAP) were synthesized to contain promiscuous T helper determinants from the Plasmodium falciparum circumsporozoite protein, the hepatitis B virus antigen and the influenza virus hemagglutinin. Here, we investigated the nature of the M2e-MAP-induced B cell response in terms of the distribution of antibody (Ab) secreting cells (ASCs) and Ab isotypes, and tested the protective efficacy in various mouse strains.
  
  
  RESULTS
  Immunization of BALB/c mice with M2e-MAPs together with potent adjuvants, CpG 1826 oligonucleotides (ODN) and cholera toxin (CT) elicited high M2e-specific serum Ab titers that protected mice against viral challenge. Subcutaneous (s.c.) and intranasal (i.n.) delivery of M2e-MAPs resulted in the induction of IgG in serum and airway secretions, however only i.n. immunization induced anti-M2e IgA ASCs locally in the lungs, correlating with M2-specific IgA in the bronchio-alveolar lavage (BAL). Interestingly, both routes of vaccination resulted in equal protection against viral challenge. Moreover, M2e-MAPs induced cross-reactive and protective responses to diverse M2e peptides and variant influenza viruses. However, in contrast to BALB/c mice, immunization of other inbred and outbred mouse strains did not induce protective Abs. This correlated with a defect in T cell but not B cell responsiveness to the M2e-MAPs.
  
  
  CONCLUSIONS
  Anti-M2e Abs induced by M2e-MAPs are highly cross-reactive and can mediate protection to variant viruses. Although synthetic MAPs are promising designs for vaccines, future constructs will need to be optimized for use in the genetically heterogeneous human population.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
authors.forename: Amaya I
authors.initials: AI
authors.lastname: Wolf
authors.forename: Krystyna
authors.initials: K
authors.lastname: Mozdzanowska
authors.forename: Katie L
authors.initials: KL
authors.lastname: Williams
authors.forename: David
authors.initials: D
authors.lastname: Singer
authors.forename: Monique
authors.initials: M
authors.lastname: Richter
authors.forename: Ralf
authors.initials: R
authors.lastname: Hoffmann
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Caton
authors.forename: Laszlo
authors.initials: L
authors.lastname: Otvos
authors.forename: Jan
authors.initials: J
authors.lastname: Erikson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D021461:Animals, Outbred Strains; D000918:Antibody Specificity; D000956:Antigens, Viral / Q000737:chemistry / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology*; D010963:Plasmodium falciparum / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D014763:Viral Matrix Proteins