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PubMed1996

Jennerian and modified Jennerian approach to vaccination against rotavirus diarrhea using a quadrivalent rhesus rotavirus (RRV) and human-RRV reassortant vaccine.

Rotaviruses are the single most important cause of severe diarrhea of infants and young children world-wide. Deaths from rotavirus diarrhea occur infrequently in developed countries; however, in developing countries, rotaviruses are estimated to cause over 870000 deaths in the under five-year age group. There is, therefore, a vital need for a vaccine to prevent severe rotavirus diarrhea in infants and young children. The most extensively evaluated strategy for rotavirus vaccination has been the "Jennerian" approach in which an antigenically related rotavirus strain from an animal host (bovine or simian [rhesus monkey]) is used as the immunogen to induce protection against the four epidemiologically important group A human rotavirus serotypes. These orally administered vaccines were safe and immunogenic but had only limited success because serotype-specific immunity was not induced consistently in the under six-month age group. Therefore, a modified "Jennerian" approach was adopted with the goal of attaining broader antigenic coverage. In this approach four serotypes are combined to form a quadrivalent vaccine comprised of (i) rhesus rotavirus (RRV) which provides coverage for VP7 serotype 3, and (ii) three human-RRV reassortants each with ten RRV genes and a single human rotavirus gene that encodes VP7 serotype 1, 2, or 4 specificity. This modified "Jennerian" approach appears to be quite promising in preventing severe diarrhea in field trials. However, if this approach fails to yield an optimal level of protection consistently, additional modified "Jennerian" strategic, are under development that consider not only human rotavirus VP7 but also human rotavirus VP4, the other outer capsid protein. In addition, a non-"Jennerian" approach includes the development of cold-adapted human rotavirus strains or cold-adapted human rotavirus reassortants as vaccine candidates.

Animals↗

PubMed1991

Molecular evidence for naturally occurring single VP7 gene substitution reassortant between human rotaviruses belonging to two different genogroups.

Twenty four stool rotaviruses that comprised 22 distinct electropherotypes were selected for genome analysis from the collection of diarrheal specimens obtained over an eight-year period. These 22 electropherotypes were found in 46% of the total electropherotypes identified during the previous studies and represented 328 (64%) of rotavirus specimens in the collection. When genomic RNAs from these stool rotaviruses were hybridized to the 32P-labeled transcription probes prepared from prototypes representing three human rotavirus genogroups, Wa, DS-1, and AU-1, any one of the isolates showed a high degree of homology only with one of the three probes, which data confirmed and extended our previous observation on the existence of three distinct genogroups among human rotaviruses. Two stool rotaviruses which had an unusual combination of serotype (G1), subgroup (I) and RNA pattern (an identical short electropherotype), however, yielded the hybridization pattern indicative of an intergenogroupic single VP7 gene substitution reassortant. When they were cell culture adapted and analyzed by RNA-RNA hybridization, molecular evidence was obtained indicating that their VP7 gene derived from viruses belonging to the Wa genogroup whereas the remaining 10 genes hybridized with viruses belonging to the DS-1 genogroup. Interestingly, these natural reassortants emerged in the midst of the rotavirus season in which G1 strains predominated.

Antigens, Viral↗

PubMed1986

Studies on the genetic determinants of influenza virus pathogenicity for mice with the use of reassortants between mouse-adapted and non-adapted variants of the same virus strain.

The original influenza virus strain A/USSR/90/77 (H 1 N 1) and its mouse-adapted variant, differing in their reactivity with anti-hemagglutinin monoclonal antibodies HC 22 and HC 124, were crossed in MDCK cells and in chicken embryos, and 21 clones were isolated by non-selective random cloning. In all the clones the virulence for mice was found to be linked to the antigenic specificity of hemagglutinin (HA). An independent marker, formation of filamentous forms, was reassorted with an expected frequency. In the crosses between UV-irradiated mouse-adapted variant and live non-adapted strain, with selection of clones by a mixture of monoclonal antibodies discriminating between HA of the two variants, virulence also was linked to HA gene. On the contrary, in the experiments with A/Aichi/2/68 (H 3 N 2) strain and its mouse-adapted highly virulent variant these two characteristics--virulence and HA antigenic specificity--could be dissociated. A pathogenic clone having HA of the non-adapted strain was readily obtained; its virulence, however, was weaker than that of the mouse-adapted parent. In the inter-subtypic crosses between A/USSR/90/77 and A/Aichi/2/68 the transfer of the HA gene of the mouse-adapted A/Aichi/2/68 did not confer virulence to the reassortant. The results are discussed in terms of the genetic basis of virulence acquired in the course of influenza virus adaptation to a new host.

Animals↗

PubMed1987

Bovine rotavirus with rearranged genome reassorts with human rotavirus. Brief report.

Bovine rotavirus (brv) possessing a rearranged genome [Hundley et al. (1985), Virology 143: 88-103] was found to reassort with tissue culture-adapted group A human rotavirus carrying a standard genome. The rearranged part of the brv genome containing segment 5-specific sequences was exchanged with the normal RNA segment 5 of the human rotavirus in some of the reassortants.

Animals↗

PubMed1983

Altered tissue tropism of human-avian reassortant influenza viruses.

Avian influenza viruses replicate to high titers in the cells lining the intestinal tract of birds; however, human strains do not. A series of reassortant viruses with all six internal genes from an avian strain and one or both genes for the surface antigens from a human strain failed to transit and infect the intestinal tracts of ducks. However, these reassortants did replicate in the bursa of ducks after rectal inoculation. These studies provide the first evidence that the hemagglutinin and neuraminidase are critical for the enterotropism of avian viruses but are not essential for replication in other avian tissues.

Animals↗

PubMed1985

Perturbation of differentiated functions during viral infection in vivo. II. Viral reassortants map growth hormone defect to the S RNA of the lymphocytic choriomeningitis virus genome.

Lymphocytic choriomeningitis virus (LCMV) Armstrong caused disordered growth and glucose metabolism secondary to growth hormone deficiency in infected C3H/St mice. In contrast, LCMV strain WE replicated in fewer growth hormone-producing cells, failed to disrupt growth hormone synthesis, and did not cause growth hormone-induced disease in infected, matched controls. The generation of genetic reassortant viruses between the virulent strain of LCMV:Armstrong and the avirulent strain, LCMV:WE, is reported. Using such reassortants and both parental strains of virus in C3H/St mice, the perturbation of growth hormone synthesis was clearly mapped to the S RNA segment of LCMV:ARM.

Animals↗

PubMed1986

A reassortant between influenza A viruses (H7N2) synthesizing an enzymatically inactive neuraminidase at 40 degrees which is not incorporated into infectious particles.

Cells infected with a reassortant (113/Ho, H7N2) between A/fowl plague/Rostock/34 (FPV, H7N1) and A/Hong Kong/1/68 (H3N2) carrying RNA segments 1 and 6 of the Hong Kong virus and the residual genes of FPV, synthesized at 40 degrees a neuraminidase (NA) which is enzymatically not active and which is not incorporated into infectious particles. At 40 degrees NA accumulates in the rough endoplasmic reticulum. It contains mainly carbohydrate side chains of the mannose type, and fucose is only scarcely incorporated. At 33 degrees NA of the reassortant is overproduced, and at least some of it is active and is incorporated into viral particles. Under nonreducing conditions during PAGE its NA migrates to the same position as after heating with mercaptoethanol, in contrast to the Hong Kong parent virus. It is speculated that at 40 degrees the tetramerization of the NA in the rough endoplasmic reticulum does not function, and in this way its migration to the cytoplasmic membrane and its incorporation into infectious particles does not occur. Since 113/Ho is as pathogenic for the chicken (body temperature of 41 degrees) as is FPV, the question arises which role the NA plays in virus replication and spread in the infected organism.

Animals↗

PubMed1987

Mutants of an influenza A reassortant which are cold-sensitive (cs) as well as temperature-sensitive (ts): on the role of the neuraminidase activity for influenza virus infection.

Temperature-sensitive (ts) mutants were obtained by undiluted passage of the cold-sensitive (cs) influenza A reassortant 113/Ho. This reassortant produces normal yields of infectious virus with negligible neuraminidase (NA) at 40 degrees. The mutants obtained from it had a narrow temperature optimum for plaque formation in chick embryo cells, since they were cs as well as ts. Such cs/ts mutants have not been described before. In contrast to mutants derived from FPV, most of the mutants derived from 113/Ho carried a ts defect in the NA gene. NA activity was not detectable after infection with these mutants at 40 degrees. The results are interpreted to mean that, although NA activity is not completely dispensible for influenza A virus replication in tissue cultures, the viruses possess a surplus of NA activity. The normally high activity of NA of influenza viruses seems to be necessary only for the natural infection of the respiratory tract.

Animals↗

PubMed1991

Rotavirus temperature-sensitive mutants are genetically stable and participate in reassortment during mixed infection of mice.

Mixed and single infections of 7-day-old suckling mice with SA11 temperature-sensitive (ts) mutants and RRV wild-type were examined to determine if selection against ts mutations occurred in the suckling mouse model. Single infections with ts mutants indicated that mutant replication was restricted relative to wild-type and that disease was similarly reduced. Revertant (ts+) progeny did not appear to be selected during infection. Mixed infection with ts mutant and RRV wild-type revealed a reduction in the replication of RRV suggesting that the ts mutants displayed an interference phenotype in vivo similar to that observed in vitro. However, reduced replication of the RRV parent in mixed infection did not result in a significant reduction in disease relative to RRV infection. When progeny from the mixed infections were isolated at the permissive temperature both ts and ts+ progeny were observed, and the genome segments of these progeny segregated in a manner consistent with the temperature phenotype of each progeny clone and the location of the ts mutation determined in vitro. Selection of ts+ progeny from mixed infected mice at nonpermissive temperature yielded either the RRV parent or ts+ reassortants. The segregation of genome segments in these ts+ reassortant progeny was consistent with the location of the ts lesion determined previously in vitro. These results indicate the following with respect to infection of suckling mice with ts mutants: (1) ts lesions are genetically stable and are not selected against during in vivo infection, (2) ts mutants cause disease with reduced severity, (3) ts mutants interfere with the replication of wild-type virus in vivo but not with the severity of disease, and (4) mixed infection of suckling mice may be useful in genetic studies with rotaviruses not adapted to growth in cultured cells.

Animals↗

PubMed1991

Reassortants with equine 1 (H7N7) influenza virus hemagglutinin in an avian influenza virus genetic background are pathogenic in chickens.

Reassortants possessing the hemagglutinin (HA) gene from A/Equine/London/1416/73 (H7N7) [Eq/Lond] and five or more genes from A/Chicken/Pennsylvania/1370/83 (H5N2) [Ck/Penn] were lethal in chickens. This result demonstrates that horses can maintain influenza viruses whose HAs are capable of promoting virulence. Thus, reassortment of equine and avian influenza virus genes could generate viruses that might be lethal in domestic poultry.

Amino Acid Sequence↗

PubMed1995

PCR restriction analysis of genome composition and stability of cold-adapted reassortant live influenza vaccines.

Using cold-adapted master donor strains of influenza virus as a model, an approach was developed that exploits unique nucleotide differences between the donor strains and wild-type influenza viruses for rapidly and simply determining the genome composition and genetic stability of live attenuated vaccine reassortants. The approach is based on PCR amplification of approximately 150-300-nucleotide-long regions of individual RNA segments that include the unique nucleotide positions, followed by restriction nuclease treatment of the DNAs obtained with specific restriction endonucleases. Restriction sites recognized by chosen nucleases either existed or were created during PCR in the genome of one (but not the other) parent strain. The technique requires a minimal amount of infectious virus (approx. 100 microliters of allantoic or tissue culture fluid with a haemagglutination titre 1:4-1:8 or less) and allows rapid (within about 10 h) determination of the origin of the RNA segment or the presence of a mutation. The method is beneficial for genome composition analysis of reassortant vaccine strains as well as for investigation of the genetic stability of live attenuated vaccines during replication in vaccinees.

Acclimatization↗

PubMed1992

The attenuation phenotype conferred by the M gene of the influenza A/Ann Arbor/6/60 cold-adapted virus (H2N2) on the A/Korea/82 (H3N2) reassortant virus results from a gene constellation effect.

A single gene reassortant (SGR) virus that derived its M gene from the attenuated influenza A/Ann Arbor/6/60 cold-adapted (CA) donor virus and the remaining genes from the A/Korea/82 (H3N2) wild type (WT) virus (designated A/Korea/82 CA M-SGR) was previously shown to be attenuated in mice, hamsters, ferrets, and humans. The attenuation (ATT) phenotype of this SGR virus could result directly from an altered function of the mutant M gene product of the A/Ann Arbor/6/60 CA virus, which differs from the M gene of the A/Ann Arbor/6/60 WT virus at only one amino acid or, indirectly from a gene constellation effect in which ATT results from an inefficient interaction between the products of the M gene of the A/Ann Arbor/6/60 virus and other genes of the A/Korea/82 virus. Several lines of evidence from the present study are consistent with our interpretation that the ATT phenotype of the A/Korea/82 CA M-SGR results from a gene constellation effect. First, the A/Korea/82 CA M-SGR and an A/Korea/82 SGR containing the A/Ann Arbor/6/60 WT M gene were each restricted in replication in the upper and lower respiratory tract of mice compared with the A/Korea/82 WT virus. Second, an A/Udorn/72 CA M-SGR containing the M gene from the A/Ann Arbor/6/60 CA donor virus in a background of other genes derived from the A/Udorn/72 (H3N2) WT virus was not attenuated in the respiratory tract of mice. These data suggest that the change in the amino acid sequence of the M gene product from the A/Ann Arbor/6/60 WT to CA virus is not responsible for the ATT phenotype of the A/Korea/82 CA M-SGR. In addition, evidence of the genetic instability of the A/Korea/82 CA M-SGR is presented, specifically, an extragenic mutation that results in loss of the ATT phenotype. The implications of these findings for the ATT phenotype of the live attenuated reassortant viruses derived from the A/Ann Arbor/6/60 CA donor virus are discussed.

Adaptation, Physiological↗

PubMed1984

Characterization of the genotype and level of attenuation of an influenza A reassortant virus produced by mating the Xia-ts donor virus with A/Beijing/70 (H1N1) wild type virus.

Two H1N1 progeny viruses derived by mating the attenuated donor virus, the A/Ningxia/72-ts (H3N2), and the A/Beijing/70 (H1N1) wild type virus were characterized for their genotype and their level of attenuation in susceptible adult volunteers. One progeny virus, clone PX62, was not a reassortant since it received each of its eight RNA segments from the H1N1 wild type virus. THis virus caused febrile influenza illness. Another progeny virus, clone PXH107, was a reassortant which received the genes coding for the surface antigens from the H1N1 parent virus but each of the other six RNA segments from the H3N2 parent virus. This clone was satisfactorily attenuated in susceptible adults and induced an immune response in at least 60% of the vaccinees. These results indicate that the genetic determinants of attenuation of the A/Ningxia/72-ts virus reside on one or more of the RNA segments that do not code for the surface antigens.

Adolescent↗

PubMed1990

Laboratory properties of cold-adapted influenza B live vaccine strains developed in the US and USSR, and their B/Ann Arbor/1/86 cold-adapted reassortant vaccine candidates.

The adaptation of two influenza B strains (B/Leningrad/14/55 and B/Ann Arbor/1/66) to replication at 25 degrees C is described. Comparison of the two viruses indicates that both also exhibit temperature sensitive phenotypes, although that of the virus B/Leningrad/14/55 is less pronounced. When inoculated into ferrets both viruses replicate well in the trachea, but only the B/Leningrad/14/55 cold-adapted virus replicates in the lungs. This virus exhibited a moderate level of attenuation in the animals, in contrast to the B/Ann Arbor/1/66 cold-adapted virus, which was fully attenuated. Reassortant viruses deriving the surface antigens of the contemporary wild type virus B/Ann Arbor/1/86 and most or all of their other genes, from one or other cold-adapted parent, were virtually indistinguishable from their respective cold-adapted parents. The B/Leningrad/14/55 reassortant was slightly more attenuated than its cold-adapted parent in ferrets. These studies extend knowledge of the properties of viruses used to prepare experimental live influenza B human vaccines.

Animals↗

PubMed1990

Evaluation of a reassortant rhesus rotavirus vaccine in young children.

A candidate live attenuated rotavirus vaccine representative of serotype 1 was administered orally to 26 children, 14 of whom were undergoing primary exposure to rotavirus. The vaccine was derived by reassortment between rhesus rotavirus strain, MMU 18006, and the human serotype 1 strain Wa. The resultant virus has the gene coding for the major surface glycoprotein VP-7 from the human strain and all other genes from the attenuated rhesus parent which is a serotype 3 strain. Prior natural exposure to rotavirus determined the infectivity and immunogenicity of the vaccine. Only two of 12 seropositive children had evidence of reinfection while all 14 seronegative children were infected. Mild febrile illness was seen in vaccinees, however there was no evidence of gastrointestinal disease. As determined by neutralization of the human strains, the resultant serum antibody was entirely strain specific. However, heterotypic neutralization was seen when the rhesus strains were used, suggesting that neutralizing antibody can be directed to shared components of the donor and reassortant strain presumably VP-4, the other major surface protein.

Age Factors↗

PubMed1995

Lack of correlation between serum rotavirus antibody titers and protection following vaccination with reassortant RRV vaccines. US Rotavirus Vaccine Efficacy Group.

In a large placebo-controlled efficacy trial of the rhesus tetravalent (RRV-TV) and serotype 1 monovalent (RRV-S1) rotavirus vaccines in multiple sites throughout the United States, protection against rotavirus disease over a 2-year period was found to be 57 and 40%, respectively (Bernstein et al., J. Am. Med. Assoc., 1995, 273, 1191-1196). Sera collected from a subset of subjects during this trial were used to determine possible correlations between rotavirus antibody responses after vaccination and protection. Between 82% (RRV-S1) and 92% (RRV-TV) of the vaccinees seroconverted by at least one of the six antibody assays performed (i.e. rotavirus IgA and neutralizing antibody to RRV and serotype 1-4 human rotaviruses). Rises in neutralizing antibody were due primarily to RRV. The seroconversion rate was only 18-22% to each of the four human rotavirus serotypes following RRV-TV vaccination and was only 43% to serotype 1 human rotavirus after RRV-S1 administration. Furthermore, no correlate of immunity against rotavirus infection or disease was identifiable based on seroconversion to any of the antibodies measured. Likewise, no consistent relationship was found between the titers of any of these six antibodies following vaccination and protection against rotavirus, thus suggesting that serum antibody titers will not be useful markers of protection with these reassortant RRV vaccines. In addition, vaccinated subjects did not develop higher titers of neutralizing antibody to human rotaviruses following a subsequent natural rotavirus illness, a further indication that only weak immune responses to human rotaviruses were stimulated by vaccination with the RRV reassortants.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Viral↗

PubMed1994

Serological and genotypic characterization of group A rotavirus reassortants from diarrheic calves born to dams vaccinated against rotavirus.

Two strains of bovine rotavirus (BRV), designated strain Nebraska Scottsbluff-1 (NS-1) and NS-2, were isolated from 2 neighboring cow-calf beef cattle ranches where dams had been vaccinated with a commercial vaccine containing group A BRV strain Neonatal Calf Diarrhea Virus (NCDV)-Lincoln (P1:G6). Northern blot hybridizations using whole genomic RNA probes indicated that strains NS-1 and NS-2 had identical group A RNA electrophoretic patterns and were homologous at all gene segments. Strain NS-1 was compared with reference group A BRV strains using serological and genotypic methods. In vitro virus neutralization assays indicated that strain NS-1 was neutralized by a G6-specific neutralizing monoclonal antibody (mAb) and guinea pig hyperimmune serum (GPHS) raised against BRV strain B641 (P5:G6), but not by G10-specific neutralizing mAb or GPHS raised against BRV strain B223 (P11:G10). Nucleic acid hybridization experiments using whole-genomic RNA probes revealed that gene segment 4 of strain NS-1 differed from BRV strains NCDV-Lincoln and B223, but hybridized with strain B641. Conversely, gene segment 5 of strain NS-1 hybridized with BRV strain B223, but not with BRV strains NCDV-Lincoln and B641. A G-specific cDNA probe produced by reverse transcription polymerase chain reaction (RT-PCR) amplification of strain NS-1 hybridized specifically only with G6 strains NCDV-Lincoln and B641, but not with G10 strain B223. Co-electrophoresis experiments using strains NS-1, B641, and B223 further confirmed these results, suggesting that strain NS-1 was a naturally-occurring reassortant BRV between strains B641 and B223. Taken together these results indicated that a naturally-occurring group A BRV reassortant with a P gene different from the vaccine virus was responsible for the diarrheal syndrome observed on both ranches. Results from this study also indicate the existence of at least 2 different gene segments 5 among group A BRV infecting cattle.

Animals↗

PubMed2004

Nuclear reassortment between vegetative mycelia in natural populations of the basidiomycete Heterobasidion annosum.

Somatic incompatibility is not an absolute block to nuclear exchange between incompatible mycelia of the basidiomycete Heterobasidion annosum in vitro. Under laboratory conditions new heterokaryotic genotypes can be isolated from the gap between incompatible heterokaryons, and nuclear migration between pairs of heterokaryons grown in Petri dishes has been observed. In this study, we test the hypothesis of nuclear transfer and reassortment between heterokaryotic mycelia in natural populations of H. annosum. We developed six microsatellite markers to genotype nuclei populating 21 somatically incompatible mycelia of H. annosum isolated from a single stump of Picea abies, and found that the detected heterokaryons share nuclei; 10 of the nuclear haplotypes were found in more than one mycelium. In one isolate, four nuclear types were found in the same mycelium. These findings indicate that new heterokaryons can be formed as a result of nuclear reassortment between incompatible heterokaryotic mycelia in nature.

Agaricales↗