Abstract
BackgroundThe 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.Methodology/Principal FindingsImmunization 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.Conclusion/SignificanceAnti-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.
Highlights
B cell responses and the generation of protective Ab titers are key determinants for antiviral immunity and the basis for successful vaccination
The first-generation M2 ectodomain (M2e)-based multiple antigenic peptide, termed M2e-based multiple antigenic peptides (M2e-multiple antigenic peptides (MAPs)) G40d, contained four M2e side chains with the peptide sequence from influenza virus A/PR/8 (PR8) and two major PR8 HA T helper epitopes identified in BALB/c mice assembled on a polylysine-glycine scaffold peptide [14,15]
With the aim to simplify the peptide synthesis and to create a construct that might be recognized by multiple haplotypes, new M2e-MAPs were generated
Summary
B cell responses and the generation of protective Ab titers are key determinants for antiviral immunity and the basis for successful vaccination. Current influenza virus vaccines elicit strong Ab responses against the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) and mediate sterile protection against reinfections with similar viral strains. Their efficacy is limited due to the frequent mutations in HA and NA and the ability of viral subtypes to reassort and escape immune protection. A promising target for the generation of cross-reactive immunity to multiple different influenza A viruses is the highly conserved 24amino-acid N-terminal extracellular domain of the influenza virus M2 protein, termed M2 ectodomain (M2e) [1,2]. 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
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