Highly conserved influenza A virus epitope sequences as candidates of H3N2 flu vaccine targets

Wu, Ko Wen; Chien, Chih Yi; Li, Shiao Wen; King, Chwan-Chuen; Chang, Chia Hui

doi:10.1016/j.ygeno.2012.06.003

Cited by 16 publications

(11 citation statements)

References 44 publications

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“…Cytotoxic T lymphocytes (CTLs) have been shown to play a significant role in the control of primary IAV infection and to provide cross-protection against different IAV strains in mice and humans (20)(21)(22)(23)(24). New vaccine strategies are increasingly aimed at conserved CTL and B cell epitopes for IAV to overcome seasonal variations in influenza virus antigens (25)(26)(27).…”

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confidence: 99%

Structural and Biochemical Analyses of Swine Major Histocompatibility Complex Class I Complexes and Prediction of the Epitope Map of Important Influenza A Virus Strains

Fan

Wang

et al. 2016

J Virol

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The lack of a peptide-swine leukocyte antigen class I (pSLA I) complex structure presents difficulties for the study of swine cytotoxic T lymphocyte (CTL) immunity and molecule vaccine development to eliminate important swine viral diseases, such as influenza A virus (IAV). Here, after cloning and comparing 28 SLA I allelic genes from Chinese Heishan pigs, pSLA-3*hs0202 was crystalized and solved. SLA-3*hs0202 binding with s␤2m and a KMNTQFTAV (hemagglutinin [HA]-KMN9) peptide from the 2009 pandemic swine H1N1 strain clearly displayed two distinct conformations with HA-KMN9 peptides in the structures, which are believed to be beneficial to stimulate a broad spectrum of CTL immune responses. Notably, we found that different HA-KMN9 conformations are caused, not only by the flexibility of the side chains of residues in the peptide-binding groove (PBG), but also by the skewing of ␣1 and ␣2 helixes forming the PBG. In addition, alanine scanning and circular-dichroism (CD) spectra confirmed that the B, D, and F pockets play critical biochemical roles in determining the peptide-binding motif of SLA-3*hs0202. Based on biochemical parameters and comparisons to similar pockets in other known major histocompatibility complex class I (MHC-I) structures, the fundamental motif for SLA-3*hs0202 was determined to be X-(M/A/R)-(N/Q/R/F)-X-X-X-X-X-(V/I) by refolding in vitro and multiple mutant peptides. Finally, 28 SLA-3*hs0202-restricted epitope candidates were identified from important IAV strains, and two of them have been found in humans as HLA-A*0201-specific IAV epitopes. Structural and biochemical illumination of pSLA-3*hs0202 can benefit vaccine development to control IAV in swine. IMPORTANCEWe crystalized and solved the first SLA-3 structure, SLA-3*hs0202, and found that it could present the same IAV peptide with two distinct conformations. Unlike previous findings showing that variable peptide conformations are caused only by the flexibility of the side chains in the groove, the skewing of the ␣1 and ␣2 helixes is important in the different peptide conformations in SLA-3*hs0202. We also determined the fundamental motif for SLA-3*hs0202 to be X-(M/A/R)-(N/Q/R/F)-X-X-X-X-X-(V/I) based on a series of structural and biochemical analyses, and 28 SLA-3*hs0202-restricted epitope candidates were identified from important IAV strains. We believe our structure and analyses of pSLA-3*hs0202 can benefit vaccine development to control IAV in swine. Influenza A virus (IAV) has always been a major cause of morbidity and mortality throughout history, and new emerging IAVs have posed an increasing threat to human health in recent years (1-3). IAV consists of eight single-stranded-RNA segments encoding 12 proteins: the nucleoprotein (NP), three polymerase proteins (PA, PB1, and PB2), two matrix proteins (M1 and M2), two nonstructural proteins (NS1 and NS2), two surface glycoproteins, hemagglutinin (HA), neuraminidase (NA), and two newly identified proteins (PB1-F2 and PB1-N40) (4-6). Reassortment of the eight gene segments from...

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confidence: 99%

Structural and Biochemical Analyses of Swine Major Histocompatibility Complex Class I Complexes and Prediction of the Epitope Map of Important Influenza A Virus Strains

Fan

Wang

et al. 2016

J Virol

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“…One approach is to use conserved sequences, such as the stalk region of hemagglutinin (HA) (17)(18)(19) or the internal nucleoprotein (NP) or M1 protein (20,21). Another approach involves consensus sequences that combine many H5N1 hemagglu-tinin sequences into a single gene.…”

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confidence: 99%

Broad Protection against Avian Influenza Virus by Using a Modified Vaccinia Ankara Virus Expressing a Mosaic Hemagglutinin Gene

Kamlangdee

Kingstad-Bakke

Anderson

et al. 2014

J Virol

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A critical failure in our preparedness for an influenza pandemic is the lack of a universal vaccine. Influenza virus strains diverge by 1 to 2% per year, and commercially available vaccines often do not elicit protection from one year to the next, necessitating frequent formulation changes. This represents a major challenge to the development of a cross-protective vaccine that can protect against circulating viral antigenic diversity. We have constructed a recombinant modified vaccinia virus Ankara (MVA) that expresses an H5N1 mosaic hemagglutinin (H5M) (MVA-H5M). This mosaic was generated in silico using 2,145 field-sourced H5N1 isolates. A single dose of MVA-H5M provided 100% protection in mice against clade 0, 1, and 2 avian influenza viruses and also protected against seasonal H1N1 virus (A/Puerto Rico/8/34). It also provided short-term (10 days) and long-term (6 months) protection postvaccination. Both neutralizing antibodies and antigen-specific CD4 ؉ and CD8 ؉ T cells were still detected at 5 months postvaccination, suggesting that MVA-H5M provides long-lasting immunity. IMPORTANCEInfluenza viruses infect a billion people and cause up to 500,000 deaths every year. A major problem in combating influenza is the lack of broadly effective vaccines. One solution from the field of human immunodeficiency virus vaccinology involves a novel in silico mosaic approach that has been shown to provide broad and robust protection against highly variable viruses. Unlike a consensus algorithm which picks the most frequent residue at each position, the mosaic method chooses the most frequent Tcell epitopes and combines them to form a synthetic antigen. These studies demonstrated that a mosaic influenza virus H5 hemagglutinin expressed by a viral vector can elicit full protection against diverse H5N1 challenges as well as induce broader immunity than a wild-type hemagglutinin.

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“…Interestingly, PB1 and NP have been reported earlier to be the most antigenic proteins in ferrets. 27, 28, 29 …”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, PB1 and NP have been reported earlier to be the most antigenic proteins in ferrets. [27][28][29] As pure populations of an ethnic group does not reflect the real world accurately, we hypothetically reconstruct heterogeneous populations and studied the effect of heterogeneity on the total CTL response. Figure 6 illustrates the predicted response for randomly chosen combination of six ethnic groups to the same strain (results for different combinations provided in FluTope).…”

Section: Grouping Populations Into 'Response-types'mentioning

confidence: 99%

Grouping of large populations into few CTL immune ‘response‐types’ from influenza H1N1 genome analysis

Mukherjee

Chandra

2014

Clin & Trans Imm

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Despite extensive work on influenza, a number of questions still remain open about why individuals are differently susceptible to the disease and why only some strains lead to epidemics. Here we study the effect of human leukocyte antigen (HLA) genotype heterogeneity on possible cytotoxic T-lymphocyte (CTL) response to 186 influenza H1N1 genomes. To enable such analysis, we reconstruct HLA genotypes in different populations using a probabilistic method. We find that epidemic strains in general correlate with poor CTL response in populations. Our analysis shows that large populations can be classified into a small number of groups called response-types, specific to a given viral strain. Individuals of a response-type are expected to exhibit similar CTL responses. Extent of CTL responses varies significantly across different populations and increases with increase in genetic heterogeneity. Overall, our analysis presents a conceptual advance towards understanding how genetic heterogeneity influences disease susceptibility in individuals and in populations. We also obtain lists of top-ranking epitopes and proteins, ranked on the basis of conservation, antigenic cross-reactivity and population coverage, which provide ready short-lists for rational vaccine design. Our method is fairly generic and has the potential to be applied for studying other viruses.

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Highly conserved influenza A virus epitope sequences as candidates of H3N2 flu vaccine targets

Cited by 16 publications

References 44 publications

Structural and Biochemical Analyses of Swine Major Histocompatibility Complex Class I Complexes and Prediction of the Epitope Map of Important Influenza A Virus Strains

Structural and Biochemical Analyses of Swine Major Histocompatibility Complex Class I Complexes and Prediction of the Epitope Map of Important Influenza A Virus Strains

Broad Protection against Avian Influenza Virus by Using a Modified Vaccinia Ankara Virus Expressing a Mosaic Hemagglutinin Gene

Grouping of large populations into few CTL immune ‘response‐types’ from influenza H1N1 genome analysis

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