A mutation in the PA protein gene of cold-adapted B/Ann Arbor/1/66 influenza virus associated with reversion of temperature sensitivity and attenuated virulence

Donabedian, Armen M.; DeBorde, Dan C.; Cook, Suzanne M.; Smitka, Curt W.; Maassab, Hunein F.

doi:10.1016/0042-6822(88)90285-1

Cited by 27 publications

(12 citation statements)

References 16 publications

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“…38,39 The 6 internal genes of the LAIV-T parent attenuated strains provide the phenotypic characteristic of attenuation, cold adaptation, and temperature restriction. The polygenic nature and multiple gene mutations contained in the 6 internal genes contribute to the stability of the attenuated phenotype of LAIV-T. 40,41 The formation of new reassortants between LAIV-T and a contemporary interpandemic influenza virus would most likely yield attenuated to wild-type-like variants. Genetic reassortants during interpandemic periods do not seem to have a selective advantage.…”

Section: Discussionmentioning

confidence: 99%

Live Attenuated Influenza Vaccine, Trivalent, Is Safe in Healthy Children 18 Months to 4 Years, 5 to 9 Years, and 10 to 18 Years of Age in a Community-Based, Nonrandomized, Open-Label Trial

Piedra

Gaglani²,

Riggs

et al. 2005

Pediatrics

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ABSTRACT. Objective. Influenza-associated deaths in healthy children that were reported during the 2003-2004 influenza season heightened the public awareness of the seriousness of influenza in children. In 1996 -1998, a pivotal phase III trial was conducted in children who were 15 to 71 months of age. Live attenuated influenza vaccine, trivalent (LAIV-T), was shown to be safe and efficacious. In a subsequent randomized, double-blind, placebo-controlled LAIV-T trial in children who were 1 to 17 years of age, a statistically significant increase in asthma encounters was observed for children who were younger than 59 months. LAIV-T was not licensed to children who were younger than 5 years because of the concern for asthma. We report on the largest safety study to date of the recently licensed LAIV-T in children 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in a 4-year (1998 -2002) community-based trial that was conducted at Scott & White Memorial Hospital and Clinic (Temple, TX).Methods. An open-label, nonrandomized, communitybased trial of LAIV-T was conducted before its licensure. Medical records of all children were surveyed for serious adverse events (SAEs) 6 weeks after vaccination. Health care utilization was evaluated by determining the relative risk (RR) of medically attended acute respiratory illness (MAARI) and asthma rates at 0 to 14 and 15 to 42 days after vaccination compared with the rates before vaccination. Medical charts of all visits coded as asthma were reviewed for appropriate classification of events: acute asthma or other. We evaluated the risk for MAARI (health care utilization for acute respiratory illness) 0 to 14 and 15 to 42 days after LAIV-T by a method similar to the postlicensure safety analysis conducted on measles, mumps, and rubella and on diphtheria, tetanus, and whole-cell pertussis vaccines.Results. All children regardless of age were administered a single intranasal dose of LAIV-T in each vaccine year. In the 4 years of the study, we administered 18 780 doses of LAIV-T to 11 096 children. A total of 4529, 7036, and 7215 doses of LAIV-T were administered to children who were 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age, respectively. In vaccination years 1, 2, 3, and 4, we identified 10, 15, 11, and 6 SAEs, respectively. None of the SAEs was attributed to LAIV-T. In vaccination years 1, 2, 3, and 4, we identified 3, 2, 1, and 0 pregnancies, respectively, among adolescents. All delivered healthy infants. The RR for MAARI from 0 to 14 and 15 to 42 days after LAIV-T was assessed in vaccinees during the 4 vaccine years. Compared with the prevaccination period, there was no significant increase in risk in health care utilization attributed to MAARI from 0 to 14 and 15 to 42 days after vaccination in children who were 18 months to 4 years, 5 to 9 years, and 10 to 18 years of age in the 4 vaccine years. In children who were 18 months to 4 years of age, there was no significant increase in the risk in health care utilization for MAARI, MAARI subcategorie...

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Section: Discussionmentioning

confidence: 99%

Live Attenuated Influenza Vaccine, Trivalent, Is Safe in Healthy Children 18 Months to 4 Years, 5 to 9 Years, and 10 to 18 Years of Age in a Community-Based, Nonrandomized, Open-Label Trial

Piedra

Gaglani²,

Riggs

et al. 2005

Pediatrics

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“…Although the ts phenotype of many experimental ts influenza viruses is unstable in vitro or in vivo (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), the ts phenotype of the caAA60-based vaccines has been very stable following replication in animals and humans (21). Nevertheless, recent studies on the genetic stability of FluMist reported that mutations can occur in the manufacturing process and in the replication of the virus in vaccinated children (40,41).…”

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confidence: 99%

Reversion of Cold-Adapted Live Attenuated Influenza Vaccine into a Pathogenic Virus

Zhou

Meliopoulos

Wang

et al. 2016

J Virol

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The only licensed live attenuated influenza A virus vaccines (LAIVs) in the United States (FluMist) are created using internal protein-coding gene segments from the cold-adapted temperature-sensitive master donor virus A/Ann Arbor/6/1960 and HA/NA gene segments from circulating viruses. During serial passage of A/Ann Arbor/6/1960 at low temperatures to select the desired attenuating phenotypes, multiple cold-adaptive mutations and temperature-sensitive mutations arose. A substantial amount of scientific and clinical evidence has proven that FluMist is safe and effective. Nevertheless, no study has been conducted specifically to determine if the attenuating temperature-sensitive phenotype can revert and, if so, the types of substitutions that will emerge (i.e., compensatory substitutions versus reversion of existing attenuating mutations). Serial passage of the monovalent FluMist 2009 H1N1 pandemic vaccine at increasing temperatures in vitro generated a variant that replicated efficiently at higher temperatures. Sequencing of the variant identified seven nonsynonymous mutations, PB1-E51K, PB1-I171V, PA-N350K, PA-L366I, NP-N125Y, NP-V186I, and NS2-G63E. None occurred at positions previously reported to affect the temperature sensitivity of influenza A viruses. Synthetic genomics technology was used to synthesize the whole genome of the virus, and the roles of individual mutations were characterized by assessing their effects on RNA polymerase activity and virus replication kinetics at various temperatures. The revertant also regained virulence and caused significant disease in mice, with severity comparable to that caused by a wild-type 2009 H1N1 pandemic virus. IMPORTANCEThe live attenuated influenza vaccine FluMist has been proven safe and effective and is widely used in the United States. The phenotype and genotype of the vaccine virus are believed to be very stable, and mutants that cause disease in animals or humans have never been reported. By propagating the virus under well-controlled laboratory conditions, we found that the FluMist vaccine backbone could regain virulence to cause severe disease in mice. The identification of the responsible substitutions and elucidation of the underlying mechanisms provide unique insights into the attenuation of influenza virus, which is important to basic research on vaccines, attenuation reversion, and replication. In addition, this study suggests that the safety of LAIVs should be closely monitored after mass vaccination and that novel strategies to continue to improve LAIV vaccine safety should be investigated.A nnual influenza epidemics are caused by influenza A (H1N1 and H3N2) and influenza B viruses that infect 5% to 10% of adults and 20% to 30% of children (1). Disease outcomes range from subclinical infections to severe infections that result in very high mortality. The estimated 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths each year, as well as significant socioeconomic losses, warrant continuous improvements in influenza preventi...

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“…Previously, the PA M431 amino acid of MDV-B had been shown to contribute to the control of the ts phenotype, but those studies concluded that other residues were also likely to contribute to expression and reversion of this trait (5,6). The findings reported here show that three amino acid loci of MDV-B-PA M431, NP A114, and NP H410-were the minimal elements that controlled the ts phenotype, and reversion of all three loci in combination was required to revert the ts phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…By using classical reassortment techniques, it was reported that the MDV-B PA gene segment could transfer the ts and att phenotypes to the heterologous B/Hong Kong/1732/76 strain (5,6). Mutation of methionine 431 to isoleucine in this reassortant reverted the ts phenotype (i.e., non-ts) of the virus, demonstrating the critical nature of M431.…”

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confidence: 99%

Multiple Gene Segments Control the Temperature Sensitivity and Attenuation Phenotypes of ca B/Ann Arbor/1/66

Hoffmann¹,

Mahmood²,

Chen³

et al. 2005

J Virol

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Cold-adapted (ca) B/Ann Arbor/1/66 is the influenza B virus strain master donor virus for FluMist, a live, attenuated, influenza virus vaccine licensed in 2003 in the United States. Each FluMist vaccine strain contains six gene segments of the master donor virus; these master donor gene segments control the vaccine's replication and attenuation. These gene segments also express characteristic biological traits in model systems. Unlike most virulent wild-type (wt) influenza B viruses, ca B/Ann Arbor/1/66 is temperature sensitive (ts) at 37°C and attenuated (att) in the ferret model. In order to define the minimal genetic components of these phenotypes, the amino acid sequences of the internal genes of ca B/Ann Arbor/1/66 were aligned to those of other influenza B viruses. These analyses revealed eight unique amino acids in three proteins: two in the polymerase subunit PA, two in the M1 matrix protein, and four in the nucleoprotein (NP). Using reverse genetics, these eight wt amino acids were engineered into a plasmid-derived recombinant of ca B/Ann Arbor/ 1/66, and these changes reverted both the ts and the att phenotypes. A detailed mutational analysis revealed that a combination of two sites in NP (A114 and H410) and one in PA (M431) controlled expression of ts, whereas these same changes plus two additional residues in M1 (Q159 and V183) controlled the att phenotype. Transferring this genetic signature to the divergent wt B/Yamanashi/166/98 strain conferred both the ts and the att phenotypes on the recombinant, demonstrating that this small, complex, genetic signature encoded the essential elements for these traits.

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A mutation in the PA protein gene of cold-adapted B/Ann Arbor/1/66 influenza virus associated with reversion of temperature sensitivity and attenuated virulence

Cited by 27 publications

References 16 publications

Live Attenuated Influenza Vaccine, Trivalent, Is Safe in Healthy Children 18 Months to 4 Years, 5 to 9 Years, and 10 to 18 Years of Age in a Community-Based, Nonrandomized, Open-Label Trial

Live Attenuated Influenza Vaccine, Trivalent, Is Safe in Healthy Children 18 Months to 4 Years, 5 to 9 Years, and 10 to 18 Years of Age in a Community-Based, Nonrandomized, Open-Label Trial

Reversion of Cold-Adapted Live Attenuated Influenza Vaccine into a Pathogenic Virus

Multiple Gene Segments Control the Temperature Sensitivity and Attenuation Phenotypes of ca B/Ann Arbor/1/66

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