Characterizations of four monoclonal antibodies against M2 protein ectodomain of influenza A virus

Fu, Tong-Ming; Freed, Daniel C.; Horton, Melanie; Fan, Jun; Citron, Michael; Joyce, Joseph G.; Garsky, Victor M.; Casimiro, Danilo R.; Zhao, Qinjian; Shiver, John W.; Liang, Xiaoping

doi:10.1016/j.virol.2008.11.035

Cited by 67 publications

(65 citation statements)

References 29 publications

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“…Hence, the specificity and affinity of the purified subclasses as well as their purity may have been different adding further variables to this published report. In addition, Fu et al [30] also reported some protective capacity of M2e-specific IgG1 antibodies. However, there was no proper comparison between IgG1 and IgG2a/c antibodies made.…”

Section: Resultsmentioning

confidence: 95%

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: Resultsmentioning

confidence: 95%

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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“…In contrast to the apparently uniform antibody response to M2e in naturally infected or vaccinated humans, mice immunized with M2e-derived peptides produced antibodies with a range of specificities within M2e, including the conserved N terminus and also downstream regions (15). It is tempting to speculate that the human immune system has evolved a humoral response that exclusively targets the highly conserved N-terminal segment of M2e rather than the more divergent, and thus less sustainably protective, downstream sites.…”

Section: Resultsmentioning

confidence: 98%

“…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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“…Jegerlehner et al (15) proposed an important role for NK-mediated Ab-dependent cytotoxicity in acquired anti-M2e immunity. However, two recent studies concluded that NK cells are not essential for protection by anti-M2e IgG or following vaccination with M2 expression vectors (16,43). All three studies made use of Ab administration to eliminate NK and NKT cells, either anti-NK1.1 (43) or antiasialo-GM1 (15,16), but used different mouse strains [C57BL/6 (15,43) and BALB/c (16) mice] and different influenza virus challenge strains.…”

Section: Discussionmentioning

confidence: 99%

Universal Vaccine Based on Ectodomain of Matrix Protein 2 of Influenza A: Fc Receptors and Alveolar Macrophages Mediate Protection

Bakkouri

Descamps

Filette

et al. 2011

The Journal of Immunology

294

263

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The ectodomain of matrix protein 2 (M2e) of influenza A virus is an attractive target for a universal influenza A vaccine: the M2e sequence is highly conserved across influenza virus subtypes, and induced humoral anti-M2e immunity protects against a lethal influenza virus challenge in animal models. Clinical phase I studies with M2e vaccine candidates have been completed. However, the in vivo mechanism of immune protection induced by M2e-carrier vaccination is unclear.

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Characterizations of four monoclonal antibodies against M2 protein ectodomain of influenza A virus

Cited by 67 publications

References 29 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

Universal Vaccine Based on Ectodomain of Matrix Protein 2 of Influenza A: Fc Receptors and Alveolar Macrophages Mediate Protection

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