Four viral genes independently contribute to attenuation of live influenza A/Ann Arbor/6/60 (H2N2) cold-adapted reassortant virus vaccines

Snyder, Marshall L.; Betts, Robert F.; DeBorde, Dan C.; Tierney, E L; Clements, Mary Lou; Herrington, Deirdre A.; Sears, Stephen D.; Dolin, Raphael; Maassab, Hunein F.; Murphy, Brian R.

doi:10.1128/jvi.62.2.488-495.1988

Cited by 149 publications

(75 citation statements)

References 28 publications

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“…An attenuated ca virus was generated by passage of the H2N2 influenza A virus A/AnnArbor/6/60 at progressively lower temperatures, yielding a ca donor virus that exhibited the temperature-sensitive (ts), ca, and attenuation (att) phenotypes (117). Complete sequence analysis identified mutations in the coding regions of six of the viral genes, and the att phenotype has been shown to be the result of five mutations in three different gene segments (32,91,175,188,189). Monovalent, bivalent, and trivalent live attenuated vaccines for human influenza viruses have been tested extensively in humans for safety and efficacy (reviewed in reference 125).…”

Section: Avian Influenza Virus Vaccinesmentioning

confidence: 99%

Emerging Respiratory Viruses: Challenges and Vaccine Strategies

2006

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SUMMARY The current threat of avian influenza to the human population, the potential for the reemergence of severe acute respiratory syndrome (SARS)-associated coronavirus, and the identification of multiple novel respiratory viruses underline the necessity for the development of therapeutic and preventive strategies to combat viral infection. Vaccine development is a key component in the prevention of widespread viral infection and in the reduction of morbidity and mortality associated with many viral infections. In this review we describe the different approaches currently being evaluated in the development of vaccines against SARS-associated coronavirus and avian influenza viruses and also highlight the many obstacles encountered in the development of these vaccines. Lessons learned from current vaccine studies, coupled with our increasing knowledge of the host and viral factors involved in viral pathogenesis, will help to increase the speed with which efficacious vaccines targeting newly emerging viral pathogens can be developed.

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Section: Avian Influenza Virus Vaccinesmentioning

confidence: 99%

Emerging Respiratory Viruses: Challenges and Vaccine Strategies

2006

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“…We chose the PB2 gene as a target for mutagenesis for several reasons: mutations in PB2 have been associated with ts and attenuated (att) phenotypes (29,43,52), several ts mutations in PB2 have been molecularly characterized (6,20,23), and a helper virus for rescue of PB2 into infectious influenza viruses has been described (45). We chose to generate the following mutations: (i) mutations associated with ts phenotypes, for which it was possible to introduce new codons that would require more than one nucleotide change to reencode the wild-type amino acid (E65G, P112S, N265S, or I310T); (i) mutations which are associated with marked attenuation in other ts viruses of particular interest (Y658H, found in the PB2 gene of the ts mutants ts1A2 and ts1E) (23); or (iii) mutations which have potential functional importance by virtue of their location within a region of partial sequence similarity with the cellular cap-binding protein, eIF-4E (7).…”

Section: Rationale For Selection Of Pb2 Mutationsmentioning

confidence: 99%

“…While the vaccine has phenotypes of cold adaptation, temperature sensitivity, and attenuation in ferrets and humans, the mechanism for these phenotypes is not well understood. The stability of the attenuation may be explained by evidence that there are mutations in as many as four genes (6,19,20,43).…”

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confidence: 99%

Genetically engineered live attenuated influenza A virus vaccine candidates

Parkin¹,

Chiu²,

Coelingh³

1997

J Virol

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We have generated new influenza A virus live attenuated vaccine candidates by site-directed mutagenesis and reverse genetics. By mutating specific amino acids in the PB2 polymerase subunit, two temperature-sensitive (ts) attenuated viruses were obtained. Both candidates have 38؇C shutoff temperatures in MDCK cells, are attenuated in the respiratory tracts of mice and ferrets, and have very low reactogenicity in ferrets. Infection of mice or ferrets with either mutant conferred significant protection from challenge with the homologous wild-type virus. Three tests for genetic stability were used to assess the propensity for reversion to virulence: 14 days of replication in nude mice, growth at 37؇C in tissue culture, and serial passage in ferrets. One candidate, which contains mutations intended to reduce the ability of PB2 to bind to cap structures, was stable in all three assays, whereas the second candidate, which contains mutations found only in other ts strains of influenza virus, lost its ts phenotype in the last two assays. This approach has therefore enabled the creation of live attenuated influenza A virus vaccine candidates suitable for human testing.

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“…Mutations at HA residues 222 (alanine to valine) and 228 (glycine to serine) increased the receptor binding preference of H6N6 avian IAVs to SA2,6Gal [17]. In addition to glycan receptor binding preference, genetic constellation of RNP complex and adaptative mutations in RNP genes, including PB1, have been shown to affect the host and tissue tropisms of IAVs [18–21]. It has been suggested that avian RNP complex has defects in its replication ability in human cells, and mutations that occur across PB2, PB1, PA, and NP of RNP complex are demonstrated to facilitate adaptation of avian IAVs in humans and other mammalian species (reviewed in Mänz et al [22]).…”

Section: Introductionmentioning

confidence: 99%

Tissue tropisms of avian influenza A viruses affect their spillovers from wild birds to pigs

Zhang

Cummingham²,

et al. 2020

Preprint

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32Wild aquatic birds maintain a large genetically diverse pool of influenza A viruses (IAVs), which can be 33 transmitted to lower mammals and ultimately humans. Through phenotypic analyses, only a small set of 34 avian IAVs replicated well in the epithelial cells of swine upper respiratory tracts, and these viruses were 35 shown to infect and cause virus shedding in pigs. Such a phenotypic trait appears to emerge randomly and 36 are distributed among IAVs across multiple avian species, geographic and temporal orders, and is 37 determined not by receptor binding preference but other markers across genomic segments, such as those 38 in the ribonucleoprotein complex. This study demonstrates that phenotypic variants exist among avian 39 IAVs, only a few of which may result in viral shedding in pigs upon infection, providing opportunities for 40 these viruses to become pig adapted, thus posing a higher potential risk for creating novel variants or 41 detrimental reassortants within pig populations. 42 43 44 45 46 47 Author Summary 49Having both avian-like receptors and human-like α2,6-linked sialic acid receptors, swine serve as a 50 "mixing vessel" for generating human influenza pandemic strains. All HA subtypes of IAVs can infect 51 swine; however, only sporadic cases of avian IAVs are reported in domestic swine. The molecular 52 mechanisms affecting avian IAVs ability to infect swine are still not fully understood. Through 53 phenotypic analyses, this study suggested that tissue tropisms (i.e., in swine upper respiratory tracts) of 54 avian IAVs affect their spillovers from wild birds to pigs, and this phenotype was determined not by 55 receptor binding preference but by other markers across genomic segments, such as those in the 56 ribonucleoprotein complex. In addition, our results showed that such a phenotypic trait was sporadically 57 and randomly distributed among IAVs across multiple avian species, geographic and temporal orders. 58This study suggested an efficient way for risk assessment of avian IAVs, such as in evaluating their 59 potentials to be transmitted from avian to pigs. 60 61 Influenza A viruses (IAVs), a member in the Orthomyxoviridae family, are a negative single stranded 63 RNA virus with eight gene segments, encoding at least 11 proteins. The nomenclatures of IAVs are 64 determined based on antigenic properties of two surface glycoproteins, Hemagglutinin (HA) and 65 Neuraminidase (NA). To date, 18 HA subtypes and 11 NA subtypes have been identified [1, 2]. Besides 66 humans, pigs, dogs, and horses, IAVs have been recovered from variety of bird species, including at least 67 105 wild bird species of 26 different families [3]. Among wild birds, birds of wetlands and aquatic 68 environments such as the Anseriformes (particularly ducks, geese, and swans) and Charadriiformes 69 (particularly gulls, terns, and waders) constitute the major natural IAV reservoir [4]. They maintain a 70 large IAV genetic pool, which contributes to the appearance of new IAVs in other birds, lower mammals, 71 and ultima...

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Four viral genes independently contribute to attenuation of live influenza A/Ann Arbor/6/60 (H2N2) cold-adapted reassortant virus vaccines

Cited by 149 publications

References 28 publications

Emerging Respiratory Viruses: Challenges and Vaccine Strategies

Emerging Respiratory Viruses: Challenges and Vaccine Strategies

Genetically engineered live attenuated influenza A virus vaccine candidates

Tissue tropisms of avian influenza A viruses affect their spillovers from wild birds to pigs

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