Protection of mice against influenza A virus challenge by vaccination with baculovirus-expressed M2 protein

Slepushkin, Vladimir; Katz, Jacqueline M.; Black, Renee A.; Gamble, William C.; Rota, Paul A.; Cox, Nancy J.

doi:10.1016/0264-410x(95)92777-y

Cited by 178 publications

(111 citation statements)

References 15 publications

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Section: Introductionmentioning

confidence: 99%

“…Although the recently emerged pandemic influenza A California strain exhibits four mutations within this domain, the C-terminal 11 amino acid have been completely conserved. In addition, M2e-specific antibodies protect mice [15][16][17][18][19][20], ferrets, and monkeys [21,22] from infection with various different flu strains. Hence, M2e-based vaccines may be promising candidates for pandemics since they could be stockpiled in large amounts prior to the event.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Schmitz¹,

Beerli²,

Bauer³

et al. 2012

Eur J Immunol

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A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7 -/-mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.Keywords: Antibodies r Immunotherapy r Toll like receptors r Vaccination r Virology IntroductionInfection with influenza virus is a major cause of morbidity as well as mortality throughout the world. Influenza virus is a very dynamic pseudo species and constantly avoids immunity at the population level by accumulating mutations in the hemagglutinin (HA) and neuraminidase molecules in a process called genetic drift. In addition, in a rare process called genetic shift, human influenza viruses may reassort with avian or swine influenza viruses [1]. Since under these circumstances, the virus hits an essentially naive population, the epidemic may become a pandemic with potentially millions of people infected and killed by the virus.Correspondence: Dr. Martin F. Bachmann e-mail: martin.bachmann@me.com Induction of protective immunity against influenza virus, not affected by genetic drift or shift, is therefore a major goal in vaccine development [2,3]. T cells are usually more cross-reactive than antibodies [4][5][6] and additionally recognize more conserved, virus-internal proteins [7,8]. Induction of broadly reactive T cells by vaccination may therefore be a potential avenue to follow [9,10]. This, however, may be a difficult task, since protective T-cell responses are usually short lived in mice [11] and humans [12], and it has not been possible so far to induce long-lived T-cell mediated immunity by vaccination. An alternative approach represents the induction of protective antibody responses directed against conserved viral structures. The extracellular domain of M2 (M2e) is a candidate for such a vaccine. M2e is highly conserved in all influenza A strains and has hardly changed over the last 90 years [13,14]. Although the recently emerged pandemic influ...

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Schmitz¹,

Beerli²,

Bauer³

et al. 2012

Eur J Immunol

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“…Monoclonal antibodies to M2e have been shown to be protective in vivo (13)(14)(15)(16)(17), and several groups have demonstrated protection against infection with vaccine strategies based on M2e (18)(19)(20)(21)(22)(23). In these cases, purified M2 protein or peptides derived from M2e sequence have been used as immunogens to generate antiM2e antibodies in animals or as vaccine candidates.…”

mentioning

confidence: 99%

Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses

Grandea

Olsen

Cox

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

120

109

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Influenza remains a serious public health threat throughout the world. Vaccines and antivirals are available that can provide protection from infection. However, new viral strains emerge continuously because of the plasticity of the influenza genome, which necessitates annual reformulation of vaccine antigens, and resistance to antivirals can appear rapidly and become entrenched in circulating virus populations. In addition, the spread of new pandemic strains is difficult to contain because of the time required to engineer and manufacture effective vaccines. Monoclonal antibodies that target highly conserved viral epitopes might offer an alternative protection paradigm. Herein we describe the isolation of a panel of monoclonal antibodies derived from the IgG + memory B cells of healthy, human subjects that recognize a previously unknown conformational epitope within the ectodomain of the influenza matrix 2 protein, M2e. This antibody binding region is highly conserved in influenza A viruses, being present in nearly all strains detected to date, including highly pathogenic viruses that infect primarily birds and swine, and the current 2009 swine-origin H1N1 pandemic strain (S-OIV). Furthermore, these human anti-M2e monoclonal antibodies protect mice from lethal challenges with either H5N1 or H1N1 influenza viruses. These results suggest that viral M2e can elicit broadly cross-reactive and protective antibodies in humans. Accordingly, recombinant forms of these human antibodies may provide useful therapeutic agents to protect against infection from a broad spectrum of influenza A strains.

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“…Vaccination with an M2-containing preparation obtained from a recombinant baculovirus insect cell expression system protected mice against challenge with homologous and heterologous Influenza A strains, as evidenced by decreased morbidity and virus replication, without preventing infection [46]. Although serum antibodies reacting specifically with synthetic M2-derived peptides were present in immunized mice, passive transfer of this M2 immune serum into naive mice did not confer protection against challenge.…”

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

confidence: 96%

“…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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Protection of mice against influenza A virus challenge by vaccination with baculovirus-expressed M2 protein

Cited by 178 publications

References 15 publications

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses

The Influenza Matrix Protein 2 as a Vaccine Target

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