A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in young infants

Section: Discussionmentioning

confidence: 99%

Parainfluenza Virus Type 3 Expressing the Native or Soluble Fusion (F) Protein of Respiratory Syncytial Virus (RSV) Confers Protection from RSV Infection in African Green Monkeys

Tang¹,

MacPhail²,

Schickli³

et al. 2004

“…RSV-specific cytotoxic cellular responses to natural infection were detected in less than 40% of infants under 5 months of age compared to 65% of children 6 months to 2 years of age (20). Protective responses against respiratory viruses in infancy also are not long lasting (66,76).…”

Section: Rsv Is Not Highly Cytopathic or Invasivementioning

confidence: 99%

Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

Collins¹,

Graham

2008

424

478

Human respiratory syncytial virus (RSV) was first isolated in 1956 from a laboratory chimpanzee with upper respiratory tract disease (for general reviews, see references 21, 57, 102, and 145). RSV was quickly determined to be of human origin and was shown to be the leading worldwide viral agent of serious pediatric respiratory tract disease. In a 13-year prospective study of infants and children in the United States, RSV was detected in 43%, 25%, 11%, and 10% of pediatric hospitalizations for bronchiolitis, pneumonia, bronchitis, and croup, respectively (110). Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. The rate of hospitalization for primary infection is approximately 0.5% but can vary by situation and ethnic group and can be as high as 25% (77).RSV also is a significant cause of morbidity and mortality in the elderly, with an impact approaching that of nonpandemic influenza virus (39). RSV readily infects severely immunocompromised individuals, most notably allogeneic bone marrow transplant recipients, causing high mortality. RSV also makes a substantial contribution to upper respiratory tract disease in individuals of all ages (59,65 Although RSV has a single serotype, reinfection can occur throughout life. RSV in yearly winter/early spring epidemics in temperate regions; elsewhere, the timing of RSV activity can vary widely with the locale. The RSV reservoir in the offseason is unknown. Strains circulate quickly around the earth (150). Neither a vaccine nor an effective antiviral therapy is available, although there is active research in both areas (23,78,138). However, infants at high risk for serious disease can receive passive immunoprophylaxis during the epidemic season by a monthly injection of a commercial RSV-neutralizing monoclonal antibody, palivizumab (Synagis), which provides a 55% reduction in RSV-associated hospitalization (17). THE VIRUSRSV (family Paramyxoviridae, order Mononegavirales) is an enveloped virus with a single-stranded negative-sense RNA genome of 15.2 kb (21). There are animal versions of RSV, including bovine RSV (BRSV) and pneumonia virus of mice (PVM), suggesting that species jumping occurred during the evolution of these viruses. However, there is no animal reservoir for human RSV.Efficient infection by RSV of established cell lines in vitro involves binding to cell-surface glycosaminoglycans (62). However, it is not known how closely this binding models attachment in vivo or whether it is an initial interaction that is followed by a second, higher-affinity step that remains to be identified. The nucleocapsid gains entry to the cytoplasm by membrane fusion; surprisingly, this may involve clathrin-mediated endocytosis rather than surface fusion typical of paramyxoviruses (85). Viral gene expression and RNA replication occur in the cytoplasm, and virions acquire a lipid envelope by budding through the plasmid membrane (Fig. 1). Virions are pleomorphic and include spheres ...

“…This difference may be explained by the greater level of NDV infection in the natural chicken host, thus allowing for detection of subtle differences in viral replication. Successful vaccines or promising vaccine candidates against human influenza, parainfluenza, and respiratory syncytial viruses typically are shed at titers of 10 3 to 10 5 PFU/ml in clinical trials (5,12,13), and it is clear that their immunogenicity depends on replication. In comparison, NDV-HA appears to be highly attenuated, perhaps slightly more attenuated than these other live vaccines.…”

Section: Figmentioning

confidence: 99%

Immunization of Primates with a Newcastle Disease Virus-Vectored Vaccine via the Respiratory Tract Induces a High Titer of Serum Neutralizing Antibodies against Highly Pathogenic Avian Influenza Virus

DiNapoli

Yang

Suguitan

et al. 2007

Self Cite

105

The ongoing outbreak of highly pathogenic avian influenza virus (HPAIV) in birds, the incidence of transmission to humans with a resulting high mortality rate, and the possibility of a human pandemic warrant the development of effective human vaccines against HPAIV. We developed an experimental live-attenuated vaccine for direct inoculation of the respiratory tract based on recombinant avian Newcastle disease virus (NDV) expressing the hemagglutinin (HA) glycoprotein of H5N1 HPAIV (NDV-HA). Expression of the HPAIV HA gene slightly reduced NDV virulence, as evidenced by the increased mean embryo death time and reduced replication in chickens. NDV-HA was administered to African green monkeys in two doses of 2 ؋ 10 7 infectious units each with a 28-day interval to evaluate the systemic and local antibody responses specific to H5N1 HPAIV. The virus was shed only at low titers from the monkeys, indicative of safety. Two doses of NDV-HA induced a high titer of H5N1 HPAIV-neutralizing serum antibodies in all of the immunized monkeys. Moreover, a substantial mucosal immunoglobulin A response was induced in the respiratory tract after one and two doses. The titers of neutralizing antibodies achieved in this study suggest that the vaccine would be likely to prevent mortality and reduce morbidity caused by the H5N1 HPAIV. In addition, induction of a local immune response in the respiratory tract is an important advantage that is likely to reduce or prevent transmission of the virus during an outbreak or a pandemic. This vaccine is a candidate for clinical evaluation in humans.Highly pathogenic avian influenza virus (HPAIV) is widespread in birds and occasionally is transmitted to humans, with a resulting high incidence of mortality. In addition, HPAIV can adapt to humans and create a pandemic. In particular, the H5N1 virus has caused 278 reported human infections and 168 deaths (60% mortality [http://www.who.int/csr/disease/avian _influenza/country/cases_table_2007_03_12/en/index.html, as of 2 April 2007]). The development of vaccines against HPAIV has been impeded by its apparent poor immunogenicity (21,25). In addition, the large-scale production of virus that would be required for a conventional killed vaccine would pose biosafety concerns (19), and a conventional live vaccine would entail risks of genetic exchange with circulating influenza virus strains. We recently evaluated the avian paramyxovirus Newcastle disease virus (NDV) as a vaccine vector administered to the respiratory tract in nonhuman primates and showed that it was highly attenuated and yet induced a substantial immune response against expressed foreign antigens (2). NDV also has the advantage of having a negligible incidence of recombination, which essentially eliminates the concern of genetic exchange with circulating viruses. Here, we have assessed the immunogenicity of recombinant NDV expressing the hemagglutinin (HA) protein of an H5N1 HPAIV virus (NDV-HA) in African green monkeys after respiratory tract mucosal immunization. The vaccine was well to...