PB,
I am going to annoy V1 again. Here are abstracts of 4 recent research papers on the ts (temperature sensitive) influenza vaccine. They are free of hype and, in my view, present more objective picture.
Papers 1 and 2 address the stability question ("propensity for reversion to virulence"). This makes home vaccination somewhat problematic.
Paper 3 addresses the patent protection problem: other researchers are working on similar attenuated vaccines.
Paper 4 gives a possible explanation on why Ayerst has dropped the development of this particular vaccine: efficacy reported for the described study appears to be marginal.
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1. ARTICLE TITLE: Genetically engineered live attenuated influenza A virus vaccine candidates.
ARTICLE SOURCE: J Virol (United States), Apr 1997, 71(4) p2772-8
AUTHOR(S): Parkin NT; Chiu P; Coelingh K
AUTHOR'S ADDRESS: AVIRON, Mountain View, California 94043, USA.
ABSTRACT: 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 degrees 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 degrees 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.
2. ARTICLE TITLE: Temperature sensitive mutants of influenza A virus generated by reverse genetics and clustered charged to alanine mutagenesis.
ARTICLE SOURCE: Virus Res (Netherlands), Dec 1996, 46(1-2) p31-44
AUTHOR(S): Parkin NT; Chiu P; Coelingh KL
AUTHOR'S ADDRESS: Aviron, Mountain View, CA 94043, USA. nparkin@aviron.com.
ABSTRACT: Temperature sensitive (ts) mutants of influenza A virus have the potential to serve as live attenuated (att) virus vaccines. Previously, ts mutants were isolated by chemical mutagenesis or arose spontaneously, and most likely contained point mutations in one or more genes. While sufficiently attenuated, even the most genetically stable of these viruses was found to revert to a more virulent form in a seronegative vaccinee. Recently developed technology, however, allows the introduction of engineered mutations into the genome of influenza A and B viruses, permitting the rational design of attenuated mutants with the potential for increased genetic stability. To accomplish this goal, we have introduced ts mutations into the PB2 gene of A/Los Angeles/2/87 (H3N2) and rescued the mutated genes into infectious viruses. We have used clustered charged to alanine mutagenesis (substitution of alanine for charged amino acid residues which are present in clusters) of the PB2 gene to generate novel ts mutants. Viruses containing such ts PB2 genes were attenuated in mice and ferrets. This approach has thus yielded several vaccine candidates with ts and attenuated characteristics in animal models. Combination of these mutations with each other or with other ts mutations may lead to a high level of genetic stability.
3. ARTICLE TITLE: [Efficacy of nasal influenza vaccine combined with Escherichia coli heat-labile enterotoxin B subunit containing a trace amount of the holotoxin in healthy volunteers]
ARTICLE SOURCE: Kansenshogaku Zasshi (Japan), Feb 1997, 71(2) p153-61
AUTHOR(S): Hashigucci K; Tamura S; Kurata T; Kamiya H; Ishidate T
AUTHOR'S ADDRESS: E.N.T. Department, Kitasato Institute Hospital.
PUBLICATION TYPE: JOURNAL ARTICLE
ABSTRACT: We conducted a field trial to evaluate the efficacy of nasal influenza vaccine combined with Escherichia coli heat-labile enterotoxin B subunit (LTB) containing a trace amount of the holotoxin (LT) in preventing or attenuating influenza among volunteers during the winter season of 1994-1995. A trivalent inactivated influenza vaccine, composed of A/Yamagata/32/89 (H1N1), A/Kitakyusyu/159/93 (H2N2) and B/Mie/1/93 influenza virus strains, was administered intranasally together with recombinant LTB containing 1% recombinant LT (LTB*). Vaccination was done twice 4 weeks apart. Salivary secretory IgA and serum HI antibodies were measured before and 8 weeks after the primary vaccination. Thirty-two volunteers were enrolled in this study; 18 volunteers (mean age 37.7 +/- 11.3) were given LTB*-combined vaccine and 14 volunteers (mean age 44.1 +/- 11.3) given placebo. Outbreaks of H3N2 subtype and B type virus were observed during this study period. Six (42.9%) of the 14 volunteers in the placebo group and 3 (16.7%) of the 18 receiving the LTB*-combined vaccine contracted influenza. There was no statistically significant difference between the two groups, because the number of subjects was small. Higher percentage of positive IgA and HI antibody responses among vaccines given vaccine with LTB* were observed as compared with those in the placebo group. Positive IgA antibody response to all vaccine strains were observed in 46.7% (7/15) of the vaccine group. On the other hand, none of the placebo group showed positive IgA antibody response to all vaccine strains. These results suggest that nasal influenza vaccine with LTB* appears to be effective in preventing influenza.
LANGUAGE: Japanese
4. ARTICLE TITLE: Evaluation of live attenuated influenza vaccines in children 6-18 months of age: safety, immunogenicity, and efficacy. National Institute of Allergy and Infectious Diseases, Vaccine and Treatment Evaluation Program and the Wyeth-Ayerst ca Influenza Vaccine Investigators Group.
ARTICLE SOURCE: J Infect Dis (United States), Jun 1996, 173(6) p1313-9
AUTHOR(S): Gruber WC; Belshe RB; King JC; Treanor JJ; Piedra PA; Wright PF; Reed GW; Anderson E; Newman F
AUTHOR'S ADDRESS: Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2581, USA,.
ABSTRACT: Live attenuated, cold-adapted (ca) monovalent and bivalent influenza A vaccines were evaluated in seronegative infants (ages 6-18 months) in a double-blind placebo-controlled trial to assess safety and immunogenicity. A total of 182 seronegative subjects received a single intranasal dose (10(6.2) TCID50) of ca A/Kawasaki/9/86 (H1N1) or ca A/Los Angeles/2/87 (H3N2), both as a bivalent vaccine, or placebo. Respiratory and systemic symptoms did not differ between groups after vaccination. Hemagglutination antibody seroconversions to H3N2 exceeded 90%. In contrast, seroconversions to A/Kawasaki/9/86 (H1N1) were significantly less frequent in bivalent ca vaccine recipients (31%) than in monovalent ca H1N1 recipients (83%) (P .002). During a subsequent H3N2 epidemic, nasal washes were cultured for viruses from any subject with respiratory illness. H3N2 infections documented by virus isolation were reduced by 65% in ca H3N2 recipients compared with placebo or ca HIM recipients (P = .01).
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