Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys

Fan, Jun; Liang, Xiaoping; Horton, Melanie; Perry, Helen C.; Citron, Michael; Heidecker, Gwen; Fu, Tong-Ming; Joyce, Joseph G.; Przysiecki, Craig T.; Keller, Paul M.; Garsky, Victor M.; Ionescu, Roxana; Rippeon, Yvette; Shi, Li; Chastain, Michael; Condra, Jon H.; Davies, Mary‐Ellen; Liao, Jason J. Z.; Emini, Emilio A.; Shiver, John W.

doi:10.1016/j.vaccine.2004.02.021

Cited by 294 publications

(253 citation statements)

References 30 publications

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“…The immune response appeared to be well sustained with little decline in titer out to 27 weeks. These findings agree well with published data for other OMPC-based conjugates (24,25). In contrast, macaque responses yielded equivalent geometric mean titer (GMT) at all three dosing levels, suggesting that maximum titer was elicited with Յ2 g conjugated glycopeptide.…”

Section: Resultssupporting

confidence: 91%

An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions

Joyce¹,

Krauss

Song³

et al. 2008

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

124

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The conserved oligomannose epitope, Man9GlcNAc2, recognized by the broadly neutralizing human mAb 2G12 is an attractive prophylactic vaccine candidate for the prevention of HIV-1 infection. We recently reported total chemical synthesis of a series of glycopeptides incorporating one to three copies of Man 9GlcNAc2 coupled to a cyclic peptide scaffold. Surface plasmon resonance studies showed that divalent and trivalent, but not monovalent, compounds were capable of binding 2G12. To test the efficacy of the divalent glycopeptide as an immunogen capable of inducing a 2G12-like neutralizing antibody response, we covalently coupled the molecule to a powerful immune-stimulating protein carrier and evaluated immunogenicity of the conjugate in two animal species. We used a differential immunoassay to demonstrate induction of high levels of carbohydrate-specific antibodies; however, these antibodies showed poor recognition of recombinant gp160 and failed to neutralize a panel of viral isolates in entry-based neutralization assays. To ascertain whether antibodies produced during natural infection could recognize the mimetics, we screened a panel of HIV-1-positive and -negative sera for binding to gp120 and the synthetic antigens. We present evidence from both direct and competitive binding assays that no significant recognition of the glycopeptides was observed, although certain sera did contain antibodies that could compete with 2G12 for binding to recombinant gp120. molecular mimicry ͉ neutralizing antibody

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Section: Resultssupporting

confidence: 91%

An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions

Joyce¹,

Krauss

Song³

et al. 2008

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

124

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“…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%

“…2012. 42: 863-869 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.…”

mentioning

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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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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“…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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Preclinical study of influenza virus A M2 peptide conjugate vaccines in mice, ferrets, and rhesus monkeys

Cited by 294 publications

References 30 publications

An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions

An oligosaccharide-based HIV-1 2G12 mimotope vaccine induces carbohydrate-specific antibodies that fail to neutralize HIV-1 virions

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

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