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

Bakkouri, Karim El; Descamps, Francis J; Filette, Marina De; Smet, A. De; Festjens, Els; Birkett, Ashley; Rooijen, Nico van; Verbeek, Sjef; Fiers, Walter; Saelens, Xavier

doi:10.4049/jimmunol.0902147

Cited by 300 publications

(290 citation statements)

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“…This result directly demonstrates that the antibody isotype is crucial for the protection mediated by M2e specific mAbs. These results are in contrast to previous observations by El Bakkouri et al [25], where M2-specific IgG1 antibodies were reported to at least partially protect WT mice from a lethal challenge. This may have been due to a weaker infection in those experiments.…”

Section: Resultscontrasting

confidence: 99%

“…This may have been due to a weaker infection in those experiments. Moreover, in contrast to the experiments described here, where the IgG2c or IgG1 subtype of the same species and affinity were recombinantly produced, El Bakkouri et al [25] purified the subclasses from serum. 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.…”

Section: Resultsmentioning

confidence: 85%

“…However, M2e is poorly expressed on the viral particle [23] and M2e-specific antibodies fail to neutralize the virus during natural infection. Indeed, protection is dependent on Fcγ-receptor expression on macrophages [24,25] and/or NK cells [17].…”

Section: Introductionmentioning

confidence: 99%

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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: Resultscontrasting

confidence: 99%

Section: Resultsmentioning

confidence: 85%

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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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“…Jegerlehner et al (23) showed that partial protection was afforded by anti-M2 Abs in mice, which was mediated in part by ADCC. FcR knockout mice confirmed the importance of ADCC to M2 (24). There is a need to study influenza ADCC to conserved regions of other surface influenza proteins such as HA in human samples using improved assays.…”

mentioning

confidence: 99%

Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity Antibodies in the Absence of Neutralizing Antibodies

Jegaskanda

Job

Kramski

et al. 2013

The Journal of Immunology

203

202

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A better understanding of immunity to influenza virus is needed to generate cross-protective vaccines. Engagement of Ab-dependent cellular cytotoxicity (ADCC) Abs by NK cells leads to killing of virus-infected cells and secretion of antiviral cytokines and chemokines. ADCC Abs may target more conserved influenza virus Ags compared with neutralizing Abs. There has been minimal interest in influenza-specific ADCC in recent decades. In this study, we developed novel assays to assess the specificity and function of influenza-specific ADCC Abs. We found that healthy influenza-seropositive young adults without detectable neutralizing Abs to the hemagglutinin of the 1968 H3N2 influenza strain (A/Aichi/2/1968) almost always had ADCC Abs that triggered NK cell activation and in vitro elimination of influenza-infected human blood and respiratory epithelial cells. Furthermore, we detected ADCC in the absence of neutralization to both the recent H1N1 pandemic strain (A/California/04/2009) as well as the avian H5N1 influenza hemagglutinin (A/Anhui/01/2005). We conclude that there is a remarkable degree of cross-reactivity of influenza-specific ADCC Abs in seropositive humans. Targeting cross-reactive influenza-specific ADCC epitopes by vaccination could lead to improved influenza vaccines.

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“…Although these proteins are small, they have high capacity in binding to regulatory proteins of host cell to create malignancy in target tissues. [6][7][8][9] Todays, it is believed that a bare protein is not enough immunogenic and should be formulated in adjuvants. Actually adjuvants are some substances that increase vaccine immunogenicity and thereby vaccine potency.…”

Section: Introductionmentioning

confidence: 99%

HPV16E7d Candidate Vaccine Modified Genes Expression in Tumor Environment: Flic as Adjuvant Changed TGF-B Gene Expression

Mahdavi

Rakhshani

Riazi-Rad

2017

ACP

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Cervical cancer is one of the most important venereal disease and leads to mortality in women. Human papilloma virus causes this disease. This virus has three protein zones that includes of Early, Late and None coding areas. The early phase consists of E1 to E7 but E6 and E7 are two early oncoproteins of HPV which are responsible for disordering in cell cycle and tumor induction. In this study, the efficiency of FlicE7d-HPV16 and HPV16-E7d-Flic were investigated in tumor bearing Mice models .Tumor was induced in mice with transplantation method. After tumor growth, the mice were divided into five groups. two groups of C57BL/6 Mice were injected with 20µg of the vaccine Flic-E7d-HPV16 and E7d-HPV16-Flic subcutaneously three times with one week interval. The third group only E7d was injected and for fourth group only Flic was injected and for fifth group PBS was injected. One week after final immunization, tumor was assessed for gene expression and pathologic smear. According to pathological studies on the tumor samples of mice which indicated the tumor was kind of Sarcoma, Necrosis, Apoptosis, Mitosis and vessel generation were evaluated in each group. Apoptosis and angiogenesis in A, B group were not observed. According to investigation of TGF-β and VEGF genes and HPRT control gene using PCR-real-Time, there was a decrease of VEGF and TGF-β genes in group A and B. SO the vaccine of group A, B were potent in the reduction of angiogenesis. As a result, Flic as an adjuvant improved anti-tumor effect of HPV16 E7d vaccine.

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

Cited by 300 publications

References 49 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

Cross-Reactive Influenza-Specific Antibody-Dependent Cellular Cytotoxicity Antibodies in the Absence of Neutralizing Antibodies

HPV16E7d Candidate Vaccine Modified Genes Expression in Tumor Environment: Flic as Adjuvant Changed TGF-B Gene Expression

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