Temperature-sensitive mutants of influenza virus XV. The genetic and biological characterization of a recombinant influenza virus containing two is lesions produced by mating two complementing, single lesion is mutants

Murphy, Brian R.; Wood, Frank T.; Massicot, Judith G.; Spring, Susan B.; Chanock, Robert M.

doi:10.1016/0042-6822(78)90280-5

Cited by 27 publications

(13 citation statements)

References 17 publications

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“…It was shown previously that the Udorn/ 72-ts-t89 virus was genetically stable after replication in the hamster's lung. Furthermore a Vic/75-ts-lA2 38°C ts 133 segregant shared this property as indicated by tests on 44 isolates from lungs (2,3). In the present study, lung isolates from 19 hamsters infected with ts P3 segregants also retained the ts phenotype.…”

Section: Discussionsupporting

confidence: 53%

“…Such t e m p e r a t u r esensitive donor viruses were developed with the e x p e c t a t i o n t h a t a defined gene or set of genes would consistently specify the same level of a t t e n u a t i o n following transfer into each new variant of influenza A virus (1). W e have produced a promising donor virus, the Udorn/72-ts-1 A 2 recombinant, t h a t has a 37 ° C shutoff t e m p e r a t u r e for plaque formation and a ts lesion(s) on the genes coding for the P 1 and P3 proteins (3). This virus was m a d e b y m a t i n g two ts viruses, one t h a t possessed a ts m u t a t i o n on the P 3 gene and the other a ts m u t a t i o n on the P1 gene (3).…”

Section: Introductionmentioning

confidence: 99%

“…W e have produced a promising donor virus, the Udorn/72-ts-1 A 2 recombinant, t h a t has a 37 ° C shutoff t e m p e r a t u r e for plaque formation and a ts lesion(s) on the genes coding for the P 1 and P3 proteins (3). This virus was m a d e b y m a t i n g two ts viruses, one t h a t possessed a ts m u t a t i o n on the P 3 gene and the other a ts m u t a t i o n on the P1 gene (3). To evaluate the ability of this donor virus to a t t e n u a t e new wild t y p e viruses, it was m a t e d with the influenza A/Victoria/3/75 ( H 3 N 2 ) wild t y p e virus, and six ts recombinant viruses bearing the Vic/75 hemagglutinin were isolated (4).…”

Section: Introductionmentioning

confidence: 99%

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Temperature-sensitive mutants of influenza A virus. Transfer of the twots-1 A 2ts lesions present in the Udorn/72-ts-1 A 2 donor virus to the influenza A/Alaska/6/77 (H 3 N 2) wild type virus

Murphy

Wood

Massicot

et al. 1980

Archives of Virology

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The Udorn/72-ts-1A2 temperature-sensitive influenza A virus has a 37 degrees C shutoff temperature and a ts mutation on the genes coding for the P1 and P3 proteins. This ts donor virus was produced with the expectation that the transfer of its two ts genes would regularly and predictably attenuate each new variant of influenza A virus. It had previously been mated with the A/Victoria/75 (H3N2) virus and five Vic/75-ts-1A2 rcombinants were isolated that had both ts-1A2 ts genes and in vitro and in vivo genetic and biological properties similar to their Udorn/72-ts-1A2 parent. The present study was designed to determine if the acquisition of the two ts-1A2 ts genes would also confer a specific level of attenuation on the influenza A/Alaska/6/77 (H3N2) wild type virus. Fifteen recombinant Alaska/77-ts-1A2 viruses were isolated and characterized genetically for the number and location of ts mutations. These clones were also studied for their level of replication and genetic stability in hamsters. Four recombinants possessed both of the ts-1A2 mutations and had a 37 degrees C shutoff temperature for plaque formation. Two recombinants possessed only a ts P1 gene and had either a 38 degrees C or 39 degrees C shutoff temperature. The remaining nine clones had the ts P3 gene and a shutoff temperature of 37 degrees C, 38 degrees C or 39 degrees C. Each of the four 37 degrees C shutoff temperature recombinants that possessed both ts P1 and P3 genes were restricted at least 10,000-fold in replication in the hamster's lung and approximately 100-fold in the nasal turbinates compared to the level of replication of wild type virus in these sites. All isolates from these animals retained the ts phenotype. The level of replication in vivo of the ts P1 and P3 segregants was related to their shutoff temperature of plaque formation in vitro, e.g. the 38 degrees C ts P3 segregant was less restricted in replication in the lungs than a 37 degrees C ts P3 segregant. All isolates from animals infected with the ts P3 segregants were ts, whereas a low level of genetic instability was detected for one of the ts P1 segregants. Since ten independent ts-1A2 recombinants (one Udorn/72, 5 Victoria/75 and 4 Alaska/77) with both ts-1A2 mutations exhibited the same genetic and biologic properties, it is likely that these ts P1 and P3 genes were the prime determinants of attenuation and could effect a similar level of attenuation in other influenza A viruses within the H3N2 subtype.

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Section: Discussionsupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Temperature-sensitive mutants of influenza A virus. Transfer of the twots-1 A 2ts lesions present in the Udorn/72-ts-1 A 2 donor virus to the influenza A/Alaska/6/77 (H 3 N 2) wild type virus

Murphy

Wood

Massicot

et al. 1980

Archives of Virology

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“…I t is implicit in this approach to the development of live influenza A virus vaccine t h a t transfer of the temperature-sensitive genes will regularly a t t e n u a t e each new v a r i a n t of influenza A virus to a specific and desired level. Currently, the U d o r n / 7 2 -t s -l A 2 virus is being evaluated for its suitability as a donor of its two ts genes to new variants of influenza A virus (5,6,7). The Udorn/72-ts-1 A 2 virus has a 37 ° C shutoff t e m p e r a t u r e of plaque formation in vitro, has ts mutations on the genes coding for the P 1 and P 3 polymerase proteins, and exhibits a 10,000 fold and ]00-fold reduction of virus replication in the lungs and nasal turbinates of hamsters, respectively (5).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, the U d o r n / 7 2 -t s -l A 2 virus is being evaluated for its suitability as a donor of its two ts genes to new variants of influenza A virus (5,6,7). The Udorn/72-ts-1 A 2 virus has a 37 ° C shutoff t e m p e r a t u r e of plaque formation in vitro, has ts mutations on the genes coding for the P 1 and P 3 polymerase proteins, and exhibits a 10,000 fold and ]00-fold reduction of virus replication in the lungs and nasal turbinates of hamsters, respectively (5). A Vic/75-ts-1 A 2 recombinant was produced b y transfer of the two t s -l A 2 ts genes from the Udorn/72-ts-1A2 parent to the Victoria/3/75-wild t y p e virus (6).…”

Section: Introductionmentioning

confidence: 99%

Temperature-sensitive mutants of influenza A virus: Evaluation of the Alaska/77-ts-1 A 2 temperature-sensitive recombinant virus in seronegative adult volunteers

Murphy

Chanock

Douglas

et al. 1980

Archives of Virology

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An influenza A virus recombinant bearing the surface antigens of the A/Alaska/6/77 (H3N2) wild type virus ands the two ts genes of the A/Udorn/72-ts-1A2 (H3N2) virus was evaluated for attenuation, antigenicity, and transmissibility in 28 adult volunteers all of whom possessed a preinoculation serum hemagglutination-inhibiting (HAI) antibody titer of less than or equal to 1:8 and 18 of whom also possessed a serum neuraminidase-inhibiting (NI) antibody titer of less than or equal to 1:4. The Alaska/77-ts-1A2 recombinant, which had a 37 degrees C shutoff temperature for plaque formation and ts mutations on the genes thought to code for the P1 and P3 polymerase proteins, infected 71 percent of the vaccinees when administered at a dose of 10(6.5) TCID50. Only 3 percent of the vaccinees developed symptoms in contrast to 50 percent of volunteers who received 10(4.2) TCID50 of wild type virus. Vaccinees shed virus for a shorter interval and at a lower titer than the volunteers who received wild type virus. Each ts-1A2 isolate retained the ts phenotype indicating that the recombinant was stable genetically in seronegative adults. An immunological response, as measured by a rise in serum HAI and/or NI antibody, was detected in 71 percent of the vaccinees and 87 percent of the recipients of wild type virus. Transmission of vaccine virus to susceptible contacts was not observed. The two ts-1A2 ts genes have now been transferred to two variants within the H3N2 subtype, the Vic/75 and Alaska/77 viruses, and have rendered the viruses satisfactorily attenuated for adults. The level of infectivity of the Alaska/77-ts-1A2 virus appeared to be low, however.

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Attenuated influenza virus vaccines

Potter

1994

Reviews in Medical Virology

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Temperature-sensitive mutants of influenza virus XV. The genetic and biological characterization of a recombinant influenza virus containing two is lesions produced by mating two complementing, single lesion is mutants

Cited by 27 publications

References 17 publications

Temperature-sensitive mutants of influenza A virus. Transfer of the twots-1 A 2ts lesions present in the Udorn/72-ts-1 A 2 donor virus to the influenza A/Alaska/6/77 (H 3 N 2) wild type virus

Temperature-sensitive mutants of influenza A virus. Transfer of the twots-1 A 2ts lesions present in the Udorn/72-ts-1 A 2 donor virus to the influenza A/Alaska/6/77 (H 3 N 2) wild type virus

Temperature-sensitive mutants of influenza A virus: Evaluation of the Alaska/77-ts-1 A 2 temperature-sensitive recombinant virus in seronegative adult volunteers

Attenuated influenza virus vaccines

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