Feasibility of reconstructed ancestral H5N1 influenza viruses for cross-clade protective vaccine development

Ducatez, Mariette; Bahl, Justin; Griffin, Yolanda; Stigger-Rosser, Evelyn; Franks, John; Barman, Subrata; Vijaykrishna, Dhanasekaran; Webb, Ashley; Guan, Yi; Webster, Robert G.; Smith, Gavin J. D.; Webby, Richard J.

doi:10.1073/pnas.1012457108

Cited by 57 publications

(61 citation statements)

References 23 publications

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“…Ferret antisera (four ferrets per virus) were raised against the four ancestral strains and against 04-VNM (clade 1), 05-MNG (clade 2.2), 02-CHN (clade 2.1), 06-LAO and 06-HKG (clade 2.3.4), and 06-CHN (clade 4) as previously described (8).…”

Section: Methodsmentioning

confidence: 99%

“…We therefore compared the cross-reactivity of clades 0, 1, 2.1, 2.2, 2.3, 4, and four "ancestral" H5N1 strains to determine that a virus(es) may be a useful diagnostic reagents. The ancestral strains were created from hemagglutinin (HA) and neuraminidase (NA) sequences computationally generated to represent ancestral nodes within the H5 and N1 phylogenetic trees (8).…”

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confidence: 99%

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Extent of Antigenic Cross-Reactivity among Highly Pathogenic H5N1 Influenza Viruses

et al. 2011

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Highly pathogenic H5N1 avian influenza viruses emerged in 1996 and have since evolved so extensively that a single strain can no longer be used as a prepandemic vaccine or diagnostic reagent. We therefore sought to identify the H5N1 strains that may best serve as cross-reactive diagnostic reagents. We compared the crossreactivity of 27 viruses of clades 0, 1, 2.1, 2.2, 2.3, and 4 and of four computationally designed ancestral H5N1 strains by hemagglutination inhibition (HI) and microneutralization (MN) assays. Antigenic cartography was used to analyze the large quantity of resulting data. Cartographs of HI titers with chicken red blood cells were similar to those of MN titers, but HI with horse red blood cells decreased antigenic distances among the H5N1 strains studied. Thus, HI with horse red blood cells seems to be the assay of choice for H5N1 diagnostics. Whereas clade 2.2 antigens were able to detect antibodies raised to most of the tested H5N1 viruses (and clade 2.2-specific antisera detected most of the H5N1 antigens), ancestral strain A exhibited the widest reactivity pattern and hence was the best candidate diagnostic reagent for broad detection of H5N1 strains.

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Extent of Antigenic Cross-Reactivity among Highly Pathogenic H5N1 Influenza Viruses

et al. 2011

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“…In the hemagglutinin inhibition assays (HIAs), a serum dilution of 1:40 is considered protective whereas comparable values were found for an ELISA-based and a colorimetric microneutralization assay; however, these values are not applicable to our assay [13], in particular as it was also shown that ELISA values and HIA values do not correlate, not even within the same subtypes [14]. Moreover, because the majority of heterosubtypic antibodies was found to bind a conserved epitope in the stem of the HA protein and did not interfere with hemagglutination [15,16], they would not be detected by HIAs.…”

Section: Discussionmentioning

confidence: 78%

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Kohler¹,

Scherrer²,

Zagordi³

et al. 2014

Clinical Infectious Diseases

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Background. The effectiveness of trivalent influenza vaccination has been confirmed in several studies. To date, it is not known whether repeated exposure and vaccination to influenza promote production of cross-reactive antibodies. Furthermore, how strains encountered earlier in life imprint the immune response is currently poorly understood.Methods. To determine the prevalence for human homo-and heterosubtypic antibody responses, we scrutinized serum samples from 305 healthy volunteers for hemagglutinin-binding and -neutralizing antibodies against several strains and subtypes of influenza A. Statistical analyses were then performed to establish the association of measured values with potential predictors.Results. It was found that vaccination not only promoted higher binding and neutralizing antibody titers to homosubtypic influenza isolates but also increased heterosubtypic human immune responses. Both binding and neutralizing antibody titers in relation with age of the donors mirrored the course of the different influenza strain circulation during the last century. Advanced age appeared to be of advantage for both binding and neutralizing titers to most subtypes. In contrast, the first virus subtype encountered was found to imprint to some degree subsequent antibody responses. Antibodies to recent strains, however, primarily seemed to be promoted by vaccination.Conclusions. We provide evidence that vaccinations stimulate both homo-and heterosubtypic immune responses in young and middle-aged as well as more senior individuals. Our analyses suggest that influenza vaccinations not only prevent infection against currently circulating strains but can also stimulate broader humoral immune responses that potentially attenuate infections with zoonotic or antigenically shifted strains.

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“…In addition, a case study conducted by the United States CDC, and based upon clinical samples taken during the H7N9 event in China, indicated that despite multiple challenges, properly applied next-generation sequencing technologies to detect and assess the properties of emerging intrahost genetic variants can lead to improved risk assessment. Studies have also been conducted on the potential of use of reconstructed ancestral A(H5N1) influenza viruses to develop cross-clade protective vaccines [10], and on the utility of reverse genetics techniques to improve H5N1 vaccine virus growth rates [11]. Long-term goals in efforts to detect and respond to zoonotic influenza outbreaks include the routine use of surveillance and risk-assignment activities based upon the use of genetic sequencing data, followed by the use of reverse genetics approaches to rapidly generate suitable candidate vaccine viruses.…”

Section: New Technologies and Tools For Improving Influenza Vaccine Vmentioning

confidence: 99%

Strengthening the influenza vaccine virus selection and development process

Ampofo

Azziz‐Baumgartner

Bashir

et al. 2015

Vaccine

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Despite long-recognized challenges and constraints associated with their updating and manufacture, influenza vaccines remain at the heart of public health preparedness and response efforts against both seasonal and potentially pandemic influenza viruses. Globally coordinated virological and epidemiological surveillance is the foundation of the influenza vaccine virus selection and development process. Although national influenza surveillance and reporting capabilities are being strengthened and expanded, sustaining and building upon recent gains has become a major challenge. Strengthening the vaccine virus selection process additionally requires the continuation of initiatives to improve the timeliness and representativeness of influenza viruses shared by countries for detailed analysis by the WHO Global Influenza Surveillance and Response System (GISRS). Efforts are also continuing at the national, regional, and global levels to better understand the dynamics of influenza transmission in both temperate and tropical regions. Improved understanding of the degree of influenza seasonality in tropical countries of the world should allow for the strengthening of national vaccination policies and use of the most appropriate available vaccines. There remain a number of limitations and difficulties associated with the use of HAI assays for the antigenic characterization and selection of influenza vaccine viruses by WHOCCs. Current approaches to improving the situation include the more-optimal use of HAI and other assays; improved understanding of the data produced by neutralization assays; and increased standardization of serological testing methods. A number of new technologies and associated tools have the potential to revolutionize influenza surveillance and response activities. These include the increasingly routine use of whole genome next-generation sequencing and other high-throughput approaches. Such approaches could not only become key elements in outbreak investigations but could drive a new surveillance paradigm. However, despite the advances made, significant challenges will need to be addressed before next-generation technologies become routine, particularly in low-resource settings. Emerging approaches and techniques such as synthetic genomics, systems genetics, systems biology and mathematical modelling are capable of generating potentially huge volumes of highly complex and diverse datasets. Harnessing the currently theoretical benefits of such bioinformatics ("big data") concepts for the influenza vaccine virus selection and development process will depend upon further advances in data generation, integration, analysis and dissemination. Over the last decade, growing awareness of influenza as an important global public health issue has been coupled to ever-increasing demands from the global community for more-equitable access to effective and affordable influenza vaccines. The current influenza vaccine landscape continues to be dominated by egg-based inactivated and live attenuated vaccines, with a small...

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Feasibility of reconstructed ancestral H5N1 influenza viruses for cross-clade protective vaccine development

Cited by 57 publications

References 23 publications

Extent of Antigenic Cross-Reactivity among Highly Pathogenic H5N1 Influenza Viruses

Extent of Antigenic Cross-Reactivity among Highly Pathogenic H5N1 Influenza Viruses

Prevalence and Predictors for Homo- and Heterosubtypic Antibodies Against Influenza A Virus

Strengthening the influenza vaccine virus selection and development process

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