Modified M2 proteins produce heterotypic immunity against influenza A virus

Frace, A. Michael; Klimov, Alexander; Rowe, Thomas; Black, Renee A.; Katz, Jacqueline M.

doi:10.1016/s0264-410x(99)00005-5

Cited by 127 publications

(72 citation statements)

References 24 publications

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“…In fact, most groups studying heterosubtypic immunity report CTL responses that cross-react with both the priming and challenge viruses (14, 19 -22). Moreover, immunization with conserved proteins, like NP or matrix-2 (M2), leads to demonstrable heterosubtypic immunity (17,21,23,24), as does immunization with peptide Ags that elicit influenza-specific memory CD8 T cells (22,(25)(26)(27). However, CD8 T cells appear to be dispensable for heterosubtypic immunity in some studies (16,28), possibly because CD4, CD8, NK T, and ␥␦T cells play partially redundant roles in heterosubtypic immunity, and elimination of any one of these populations does not substantially impair the response as a whole (4).…”

Section: B Cells Promote Resistance To Heterosubtypic Strains Ofmentioning

confidence: 99%

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

Rangel-Moreno

Carragher

Misra

et al. 2008

The Journal of Immunology

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Immunity to heterosubtypic strains of influenza is thought to be mediated primarily by memory T cells, which recognize epitopes in conserved proteins. However, the involvement of B cells in this process is controversial. We show in this study that influenza-specific memory T cells are insufficient to protect mice against a lethal challenge with a virulent strain of influenza in the absence of B cells. B cells contribute to protection in multiple ways. First, although non-neutralizing Abs by themselves do not provide any protection to challenge infection, they do reduce weight loss, lower viral titers, and promote recovery of mice challenged with a virulent heterosubtypic virus in the presence of memory T cells. Non-neutralizing Abs also facilitate the expansion of responding memory CD8 T cells. Furthermore, in cooperation with memory T cells, naive B cells also promote recovery from infection with a virulent heterosubtypic virus by generating new neutralizing Abs. These data demonstrate that B cells use multiple mechanisms to promote resistance to heterosubtypic strains of influenza and suggest that vaccines that elicit both memory T cells and Abs to conserved epitopes of influenza may be an effective defense against a wide range of influenza serotypes.

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Section: B Cells Promote Resistance To Heterosubtypic Strains Ofmentioning

confidence: 99%

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

Rangel-Moreno

Carragher

Misra

et al. 2008

The Journal of Immunology

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“…It would be advantageous, therefore, to expand vaccine-mediated protection to less variable viral targets. One possible way to achieve this may be through induction of 9,10,14,18,21,24,28).M2 is a 97-amino-acid transmembrane protein of influenza type A virus (15, 16). The mature protein forms homotetramers (12, 29) that have pH-inducible ion channel activity (27,29).…”

mentioning

confidence: 99%

“…It would be advantageous, therefore, to expand vaccine-mediated protection to less variable viral targets. One possible way to achieve this may be through induction of M2e-specific Abs (6,9,10,14,18,21,24,28).…”

mentioning

confidence: 99%

Influenza Type A Virus Escape Mutants Emerge In Vivo in the Presence of Antibodies to the Ectodomain of Matrix Protein 2

Zharikova

Mozdzanowska

Feng

et al. 2005

J Virol

106

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The ectodomain of matrix protein 2 (M2e) of human influenza type A virus strains has remained remarkably conserved since 1918. Because M2e-specific immunity has been shown to decrease morbidity and mortality associated with influenza virus infection in several animal models and because natural infection and current vaccines do not appear to induce a good M2e-specific antibody (Ab) response, M2e has been considered as potential vaccine for inducing cross-reactive protection against influenza type A viruses. The high degree of structural conservation of M2e could in part be the consequence of a poor M2e-specific Ab response and thus the absence of pressure for change. To assess this possibility, we studied the course of infection in SCID mice in the presence or absence of passive M2e-specific monoclonal Abs (MAbs). We found that virus mutants with antigenic changes in M2e emerged in 65% of virus-infected mice treated with M2e-specific but not control MAbs. However, the diversity of escape mutants was highly restricted since only two types were isolated from 22 mice, one with a proline-to-leucine and the other with a proline-to-histidine interchange at amino acid position 10 of M2e. The implications of these findings for the use of M2e as a broadly protective vaccine are discussed.Current influenza virus vaccines aim to induce strong antibody (Ab) responses to the ectodomains of hemagglutinin (HA) and neuraminidase (NA) molecules, since these antibodies (Abs) can provide potent protection against infection and/or disease. The main deficiency of this protection is that it targets highly variable viral determinants. This necessitates not only frequent updating of the vaccine to contemporary circulating virus strains but, given that vaccines have to be produced and applied ahead of exposure to epidemic strains, also a correct prediction of these future epidemic strains. Failure to anticipate the emergence of an epidemic strain with significant antigenic changes compared to the vaccine strain will greatly reduce vaccine-induced protection. It would be advantageous, therefore, to expand vaccine-mediated protection to less variable viral targets. One possible way to achieve this may be through induction of 9,10,14,18,21,24,28).M2 is a 97-amino-acid transmembrane protein of influenza type A virus (15, 16). The mature protein forms homotetramers (12, 29) that have pH-inducible ion channel activity (27,29). M2-tetramers are expressed at high density in the plasma membrane of infected cells but are relatively excluded from sites of virus maturation and therefore incorporated only at low frequency into the membrane of mature virus particles (30,33). Most important in the present context are, first, that the sequence of the 24-amino-acid ectodomain of M2 (M2e) has remained remarkably conserved among human epidemic virus strains (Fig. 1A) (20). Indeed, the majority of human epidemic strains isolated since 1918 share the same M2e protein sequence. Second, several studies in mice have shown that M2e-specific Abs restrict influenz...

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“…When formulated with incomplete Freund's adjuvant, these proteins induced high M2e-specific serum antibody titers in mice and reduced lung virus titers following challenge with H3N2, H2N2 and H1N1 viruses [53]. Jegerlehner et al used a chemical fusion approach to couple the M2e peptide to an engineered HBc VLP.…”

Section: M2e-specific Antibodies Protect Against Influenza a Virus Inmentioning

confidence: 99%

“…However, the reduction in virus yield by the 14C2 antibody observed in vitro was strain dependent, whereas the efficacy of M2e-based vaccine candidates has been documented for multiple Influenza A virus subtypes and strains (Table 1). [46] hM2e HBc Genetic Mouse H1N1, H3N2 [47] hM2 deletion constructs -/GST Genetic Mouse H1N1, H2N2, H3N2 [53] hM2e HBc, NP Genetic Pig H1N1 [60] hM2e HBc Genetic, chemical Mouse H1N1 [61] hM2e BSA Chemical H3N2 (in vitro) [36] hM2e Multiantigen peptide Chemical Mouse H3N2 [37] hM2e GST Genetic Mouse H1N1 [55] hM2e KLH, OMPC Chemical Mouse, ferret, rhesus monkey H1N1, H3N1, H1N1, none [57] hM2e Hydrophobic domain Genetic Mouse H1N1, H5N1, H6N2, H9N2 [56] hM2e Protection induced by M2e-based vaccines probably depends mostly on the killing of M2-expressing cells by antibody-dependent cytotoxicity (ADCC). Elimination of infected cells at an early phase of the infection cycle would reduce new virus production, consistent with the reported drop in lung virus titers of M2e-immune mice.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

The Influenza Matrix Protein 2 as a Vaccine Target

Saelens

2008

Future Virol.

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Matrix protein (M)2 is an Influenza A, type III membrane protein with an extracellular domain (ectodomain of M2 [M2e]) of 23 amino acid residues, which is strongly conserved across virus strains. M2 fulfills an important biological function in the life cycle of the Influenza A virus and has been a target of antiviral drugs. M2e has generated much interest as a potential vaccine target, and a clinical M2e vaccine trial was initiated in 2007. The advantage of M2e compared with hemagglutinin, the prime antigen target in conventional influenza vaccines, is that its sequence is conserved. This means that a stable, efficacious and easily produced M2e-based vaccine would provide protection not only against drifting seasonal influenza epidemic strains, but would also make it possible to vaccinate in anticipation of an emerging pandemic. Furthermore, most reported M2e-based vaccines are produced by economical and safe technologies. IgG subtype antibodies directed against M2e can prevent death from influenza and reduce morbidity in animal models for influenza disease. The immunological mechanism that mediates protection by anti-M2e antibodies is not completely understood, but it probably involves antibody-mediated cellular cytotoxicity. This review summarizes the findings on M2e vaccine candidates and addresses some of the key unanswered questions about this promising Influenza A vaccine target: what is its likely mechanism of action? Which measurable parameters correlate with protection? And what can be expected from clinical use of an M2e-based vaccine?

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Modified M2 proteins produce heterotypic immunity against influenza A virus

Cited by 127 publications

References 24 publications

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

Influenza Type A Virus Escape Mutants Emerge In Vivo in the Presence of Antibodies to the Ectodomain of Matrix Protein 2

The Influenza Matrix Protein 2 as a Vaccine Target

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