A universal influenza A vaccine based on the extracellular domain of the M2 protein

Neirynck, Sabine; Deroo, Tom; Saelens, Xavier; Vanlandschoot, Peter; Jou, Willy Min; Fiers, Walter

doi:10.1038/13484

Cited by 696 publications

(600 citation statements)

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“…Regarding immune mechanisms of protection by A/NP+A/M DNA vaccination, candidates include CTL specific for NP (17) and antibodies to the N-terminal portion of M2 (18). Containing an infection with the kinetics of HK/483 may be difficult because it reaches near peak titers in as little as 24 hours.…”

Section: Discussionmentioning

confidence: 99%

“…Animal studies have demonstrated potent and long-lasting heterosubtypic immunity, that is, exposure to a virus of one subtype protects against challenge infection with another subtype (10–15). The mechanisms of heterosubtypic immunity are not completely understood but likely include both T-cell immunity, in particular CD8+ cytotoxic T-lymphocytes (CTL) (16,17) and CD4+ T cells (13), as well as antibodies to conserved epitopes (18). Heterosubtypic immunity has been reported in humans (19, 20), but its effectiveness and duration are unknown.…”

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confidence: 99%

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DNA Vaccine Expressing Conserved Influenza Virus Proteins Protective Against H5N1 Challenge Infection in Mice

Epstein

Tumpey

Misplon

et al. 2002

Emerg. Infect. Dis.

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Influenza vaccination practice, which is based on neutralizing antibodies, requires being able to predict which viral strains will be circulating. If an unexpected strain, as in the 1997 H5N1 Hong Kong outbreak, or even a pandemic emerges, appropriate vaccines may take too long to prepare. Therefore, strategies based on conserved influenza antigens should be explored. We studied DNA vaccination in mice with plasmids expressing conserved nucleoprotein (NP) and matrix (M) from an H1N1 virus. After vaccination, mice were challenged with A/H5N1 viruses of low, intermediate, and high lethality. A/NP+A/M DNA vaccination reduced replication of A/Hong Kong/486/97 (HK/486), a nonlethal H5N1 strain, and protected against lethal challenge with more virulent A/Hong Kong/156/97 (HK/156). After HK/156 exposure, mice survived rechallenge with A/Hong Kong/483/97 (HK/483), although the DNA vaccination alone protected poorly against this highly virulent strain. In the absence of antigenically matched hemagglutinin-based vaccines, DNA vaccination with conserved influenza genes may provide a useful first line of defense against a rapidly spreading pandemic virus.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

DNA Vaccine Expressing Conserved Influenza Virus Proteins Protective Against H5N1 Challenge Infection in Mice

Epstein

Tumpey

Misplon

et al. 2002

Emerg. Infect. Dis.

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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%

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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“…However, as the M2 is expressed on the surface of infected cells, it is a relevant target provided such an immune response could be initiated in the first place. To date several promising preclinical studies have been completed demonstrating a heterosubtypic response 38 , 39 . A clinical trial in humans is now underway (Table 1).…”

Section: Pandemic Vaccinesmentioning

confidence: 99%

Vaccines for an influenza pandemic: scientific and political challenges

Haaheim

2007

Influenza Resp Viruses

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So far, most published results from clinical trials using various avian influenza virus vaccine formulations have been disappointing. Should the pandemic strike, we still do not have the ability to provide an efficacious pandemic vaccine in time and in sufficient quantities for the world. The H5N1 enzootic could potentially give rise to a pandemic at any time. Transcontinental air traffic could seed the pandemic virus to most corners of the globe within a few weeks/months. We still have a unique window of opportunity to stimulate and support academia and the pharmaceutical industry to accelerate the urgently needed vaccine research. The political inertia is surprising, particularly as politicians, if and when a pandemic eventuates, will be asked why, despite repeated warnings, they did not take appropriate action in time. It is a governmental obligation – and not that of the WHO or the pharmaceutical industry – to protect their nationals. Moreover, when the poorer nations of this world realize that equitable quantities of the scarce supplies of vaccines, drugs and medical essentials will not come their way, the post‐pandemic international scene will be one of even more deep distrust for many years. This scenario is not acceptable.

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A universal influenza A vaccine based on the extracellular domain of the M2 protein

Cited by 696 publications

References 42 publications

DNA Vaccine Expressing Conserved Influenza Virus Proteins Protective Against H5N1 Challenge Infection in Mice

DNA Vaccine Expressing Conserved Influenza Virus Proteins Protective Against H5N1 Challenge Infection in Mice

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

Vaccines for an influenza pandemic: scientific and political challenges

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