Emerging influenza viruses and the prospect of a universal influenza virus vaccine

Krammer, Florian

doi:10.1002/biot.201400393

Cited by 69 publications

(62 citation statements)

References 137 publications

(155 reference statements)

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“…If predictions are wrong and the vaccine and the circulating strains are mismatched, vaccine efficacy drops significantly [2]. In addition pandemics occur at irregular intervals and seasonal vaccines are ineffective against those novel viruses [3, 4]. …”

Section: Introductionmentioning

confidence: 99%

Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses

Wohlbold

Nachbagauer

Margine

et al. 2015

Vaccine

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Current influenza virus vaccines provide solid protection from infection with viruses that are well matched with the vaccine strains. However, they do not protect efficiently against drifted or shifted strains. We developed an antigen based on the conserved stalk domain of the influenza virus hemagglutinin and tested its efficacy as a vaccine in a mouse virus challenge model. Although the antigen lacked the correct conformation of the native stalk domain and was not recognized by a panel of neutralizing stalk-reactive antibodies, it did induce considerable protection against H1N1, H5N1 and H6N1 challenge strains. Protection was enhanced when mice had pre-existing immunity against the stalk domain. Since pre-existing immunity is also present in the human population, we hypothesize that a similar antigen could show efficacy in humans as well.

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Section: Introductionmentioning

confidence: 99%

Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses

Wohlbold

Nachbagauer

Margine

et al. 2015

Vaccine

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“…Three human cases of H10N8 virus have been reported in China so far, two of which were fatal (1)(2)(3). Furthermore, an avian H10N7 strain was found to be the etiological agent responsible for the massive die-off harbor seals in the Baltic Sea, an epidemic that killed more than 10% of the local seal population (4)(5)(6).…”

mentioning

confidence: 99%

Hemagglutinin Stalk- and Neuraminidase-Specific Monoclonal Antibodies Protect against Lethal H10N8 Influenza Virus Infection in Mice

Wohlbold

Chromikova

Tan

et al. 2016

J Virol

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Between November 2013 and February 2014, China reported three human cases of H10N8 influenza virus infection in the Jiangxi province, two of which were fatal. Using hybridoma technology, we isolated a panel of H10-and N8-directed monoclonal antibodies (MAbs) and further characterized the binding reactivity of these antibodies (via enzyme-linked immunosorbent assay) to a range of purified virus and recombinant protein substrates. The H10-directed MAbs displayed functional hemagglutination inhibition (HI) and neutralization activity, and the N8-directed antibodies displayed functional neuraminidase inhibition (NI) activity against H10N8. Surprisingly, the HI-reactive H10 antibodies, as well as a previously generated, group 2 hemagglutinin (HA) stalk-reactive antibody, demonstrated NI activity against H10N8 and an H10N7 strain; this phenomenon was absent when virus was treated with detergent, suggesting the anti-HA antibodies inhibited neuraminidase enzymatic activity through steric hindrance. We tested the prophylactic efficacy of one representative H10-reactive, N8-reactive, and group 2 HA stalk-reactive antibody in vivo using a BALB/c challenge model. All three antibodies were protective at a high dose (5 mg/kg). At a low dose (0.5 mg/kg), only the anti-N8 antibody prevented weight loss. Together, these data suggest that antibody targets other than the globular head domain of the HA may be efficacious in preventing influenza virus-induced morbidity and mortality. IMPORTANCEAvian H10N8 and H10N7 viruses have recently crossed the species barrier, causing morbidity and mortality in humans and other mammals. Although these reports are likely isolated incidents, it is possible that more cases may emerge in future winter seasons, similar to H7N9. Furthermore, regular transmission of avian influenza viruses to humans increases the risk of adaptive mutations and reassortment events, which may result in a novel virus with pandemic potential. Currently, no specific therapeutics or vaccines are available against the H10N8 influenza virus subtype. We generated a panel of H10-and N8-reactive MAbs. Although these antibodies may practically be developed into therapeutic agents, characterizing the protective potential of MAbs that have targets other than the HA globular head domain will provide insight into novel antibody-mediated mechanisms of protection and help to better understand correlates of protection for influenza A virus infection. R ecently, avian influenza A viruses of the H10 subtype have been reported to infect seals and humans and have generated concern over their pandemic potential. Three human cases of H10N8 virus have been reported in China so far, two of which were fatal (1-3). Furthermore, an avian H10N7 strain was found to be the etiological agent responsible for the massive die-off harbor seals in the Baltic Sea, an epidemic that killed more than 10% of the local seal population (4-6). The receptor binding profile of H10 viruses is currently debated (7-12), but the subtype has been proven to cause ...

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“…We found that memory CD4 T cells specific for H5 HA persisted in subjects vaccinated many years earlier and that these could be recruited into a subsequent immune response to vaccination, enabling a greatly enhanced antibody response to a serologically distinct H5N1-derived virus (20). Should avian influenza viruses continue to pose a threat to humans (54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64), such a prepandemic strategy could enhance vaccine responsiveness in "at risk" subjects and enhance early and potentially protective antibody responses in infected individuals.…”

Section: Discussionmentioning

confidence: 93%

Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity

DiPiazza

Richards

Poulton

et al. 2017

Clin Vaccine Immunol

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Avian influenza viruses remain a significant concern due to their pandemic potential. Vaccine trials have suggested that humans respond poorly to avian influenza vaccines relative to seasonal vaccines. It is important to understand, first, if there is a general deficiency in the ability of avian hemagglutinin (HA) proteins to generate immune responses and, if so, what underlies this defect. This question is of particular interest because it has been suggested that in humans, the poor immunogenicity of H7 vaccines may be due to a paucity of CD4 T cell epitopes. Because of the generally high levels of cross-reactive CD4 T cells in humans, it is not possible to compare the inherent immunogenicities of avian and seasonal HA proteins in an unbiased manner. Here, we empirically examine the epitope diversity and abundance of CD4 T cells elicited by seasonal and avian HA proteins. HLA-DR1 and HLA-DR4 transgenic mice were vaccinated with purified HA proteins, and CD4 T cells to specific epitopes were identified and quantified. These studies revealed that the diversity and abundance of CD4 T cells specific for HA do not segregate on the basis of whether the HA was derived from human seasonal or avian influenza viruses. Therefore, we conclude that failure in responses to avian vaccines in humans is likely due to a lack of cross-reactive CD4 T cell memory perhaps coupled with competition with or suppression of naive, HA-specific CD4 T cells by memory CD4 T cells specific for more highly conserved proteins.

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Emerging influenza viruses and the prospect of a universal influenza virus vaccine

Cited by 69 publications

References 137 publications

Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses

Vaccination with soluble headless hemagglutinin protects mice from challenge with divergent influenza viruses

Hemagglutinin Stalk- and Neuraminidase-Specific Monoclonal Antibodies Protect against Lethal H10N8 Influenza Virus Infection in Mice

Avian and Human Seasonal Influenza Hemagglutinin Proteins Elicit CD4 T Cell Responses That Are Comparable in Epitope Abundance and Diversity

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