Swine influenza matrix 2 (M2) protein contributes to protection against infection with different H1 swine influenza virus (SIV) isolates

College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
Vaccine (Impact Factor: 3.62). 11/2009; 28(2):523-31. DOI: 10.1016/j.vaccine.2009.09.130
Source: PubMed


A swine influenza virus (SIV) vaccine-challenge pig model was used to study the potential of a conserved matrix 2 (M2) protein vaccine alone or in combination with an inactivated H1N1-vaccine to protect against H1N1 and H1N2 viruses. The H1N1-vaccine and heterologous H1N2-challenge virus model has previously been shown to prolong fever and increase SIV-associated pneumonic lesions. The M2 vaccine in combination with the H1N1-vaccine reduced the H1N2 induced fever but not virus shedding. The M2 vaccine alone reduced respiratory signs and pneumonic lesions to levels similar to the negative control pigs following H1N2 infection. This study found that the M2 protein has potential as a vaccine for SIV-associated disease prevention. However, development of an immune response towards the major envelope HA protein was required to reduce SIV shedding.

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    • "Recently it was shown that SIV vaccine associated respiratory problems could be decreased when recombinant M2 was added to the vaccine. However, again M2 alone did not reduce virus shedding [20]. These data suggest that for each species it is necessary to find out whether vaccination with M2 protein or subunits of this protein has a potential. "
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    ABSTRACT: Influenza viruses are characterized by their highly variable surface proteins HA and NA. The third surface protein M2 is a nearly invariant protein in all Influenza A strains. Despite extensive studies in other animal models, this study is the first to describe the use of recombinant M2 protein and a peptide coding for the extracellular part of the M2 protein (M2e) to vaccinate poultry. Four groups of layer chickens received a prime-boost vaccination with recombinant M2 protein, M2e, a tetrameric construct from M2e peptide bound to streptavidin and a control tetrameric construct formulated with Stimune adjuvant. We determined the M2-specific antibody (Ab) responses in the serum before vaccination, three weeks after vaccination and two weeks after booster, at days 21, 42 and 56 of age. The group vaccinated with the M2 protein in combination with Stimune adjuvant showed a significant Ab response to the complete M2 protein as compared to the other groups. In addition an increased Ab response to M2e peptide was found in the group vaccinated with the M2e tetrameric construct. None of the vaccinated animals showed seroconversion to AI in a commercial ELISA. Finally no Ab's were found that bound to M2 expressed on in vitro AI infected MDCK cells. Although Ab's are formed against the M2 protein and to Streptavidin bound M2e peptide in a tetrameric conformation these Ab's do not recognize of M2 on the virus or on infected cells.
    Virology Journal 06/2013; 10(1):206. DOI:10.1186/1743-422X-10-206 · 2.18 Impact Factor
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    • "The search for universal vaccines against influenza viruses is a must. Most efforts have been focussed on driving the immune response against well conserved epitopes or proteins of IV, such as the influenza ion channel M2 protein, and conserved epitopes from the influenza NP and matrix 1 (M1) [12], [13], [14]. More recently, the potential use of highly conserved synthetic peptides from HA2 as an efficient vaccine in mice has also been demonstrated [15]. "
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    ABSTRACT: Outbreaks involving either H5N1 or H1N1 influenza viruses (IV) have recently become an increasing threat to cause potential pandemics. Pigs have an important role in this aspect. As reflected in the 2009 human H1N1 pandemia, they may act as a vehicle for mixing and generating new assortments of viruses potentially pathogenic to animals and humans. Lack of universal vaccines against the highly variable influenza virus forces scientists to continuously design vaccines à la carte, which is an expensive and risky practice overall when dealing with virulent strains. Therefore, we focused our efforts on developing a broadly protective influenza vaccine based on the Informational Spectrum Method (ISM). This theoretical prediction allows the selection of highly conserved peptide sequences from within the hemagglutinin subunit 1 protein (HA1) from either H5 or H1 viruses which are located in the flanking region of the HA binding site and with the potential to elicit broader immune responses than conventional vaccines. Confirming the theoretical predictions, immunization of conventional farm pigs with the synthetic peptides induced humoral responses in every single pig. The fact that the induced antibodies were able to recognize in vitro heterologous influenza viruses such as the pandemic H1N1 virus (pH1N1), two swine influenza field isolates (SwH1N1 and SwH3N2) and a H5N1 highly pathogenic avian virus, confirm the broad recognition of the antibodies induced. Unexpectedly, all pigs also showed T-cell responses that not only recognized the specific peptides, but also the pH1N1 virus. Finally, a partial effect on the kinetics of virus clearance was observed after the intranasal infection with the pH1N1 virus, setting forth the groundwork for the design of peptide-based vaccines against influenza viruses. Further insights into the understanding of the mechanisms involved in the protection afforded will be necessary to optimize future vaccine formulations.
    PLoS ONE 07/2012; 7(7):e40524. DOI:10.1371/journal.pone.0040524 · 3.23 Impact Factor
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    • "Other vaccination strategies targeting M2e have been reported including M2-encoding plasmid DNA [25], M2-expressing recombinant viruses or virus-like particles [26], [27], [28], [29], [30] and several fusion proteins that link M2e peptides to immunogenic proteins [16], [31], [32], [33], [34], [35] or TLR ligands [36]. Most work with M2e-vaccine candidates has been performed in BALB/c mice, but a few studies examined responses in other inbred and outbred mice, ferrets, pigs or monkeys with varying results in terms of induction of anti-M2e Ab titers and protection [24], [27], [30], [37], [38], [39]. Recent results from Phase I clinical trials have raised hopes for applicability in humans (for review see [40], [41]). "
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    ABSTRACT: 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. 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. 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.
    PLoS ONE 12/2011; 6(12):e28445. DOI:10.1371/journal.pone.0028445 · 3.23 Impact Factor
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