title: Attenuation and efficacy of human parainfluenza virus type 1 (HPIV1) vaccine candidates containing stabilized mutations in the P/C and L genes.
abstract: BACKGROUND
  Two recombinant, live attenuated human parainfluenza virus type 1 (rHPIV1) mutant viruses have been developed, using a reverse genetics system, for evaluation as potential intranasal vaccine candidates. These rHPIV1 vaccine candidates have two non-temperature sensitive (non-ts) attenuating (att) mutations primarily in the P/C gene, namely CR84GHNT553A (two point mutations used together as a set) and CDelta170 (a short deletion mutation), and two ts att mutations in the L gene, namely LY942A (a point mutation), and LDelta1710-11 (a short deletion), the last of which has not been previously described. The latter three mutations were specifically designed for increased genetic and phenotypic stability. These mutations were evaluated on the HPIV1 backbone, both individually and in combination, for attenuation, immunogenicity, and protective efficacy in African green monkeys (AGMs).
  
  
  RESULTS
  The rHPIV1 mutant bearing the novel LDelta1710-11 mutation was highly ts and attenuated in AGMs and was immunogenic and efficacious against HPIV1 wt challenge. The rHPIV1-CR84G/Delta170HNT553ALY942A and rHPIV1-CR84G/Delta170HNT553ALDelta1710-11 vaccine candidates were highly ts, with shut-off temperatures of 38 degrees C and 35 degrees C, respectively, and were highly attenuated in AGMs. Immunization with rHPIV1-CR84G/Delta170HNT553ALY942A protected against HPIV1 wt challenge in both the upper and lower respiratory tracts. In contrast, rHPIV1-CR84G/Delta170HNT553ALDelta1710-11 was not protective in AGMs due to over-attenuation, but it is expected to replicate more efficiently and be more immunogenic in the natural human host.
  
  
  CONCLUSIONS
  The rHPIV1-CR84G/Delta170HNT553ALY942A and rHPIV1-CR84G/Delta170HNT553ALDelta1710-11 vaccine candidates are clearly highly attenuated in AGMs and clinical trials are planned to address safety and immunogenicity in humans.
authors.affiliation: Laboratory of Infectious Diseases, Respiratory Viruses Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. ebartlett@niaid.nih.gov
authors.forename: Emmalene J
authors.initials: EJ
authors.lastname: Bartlett
authors.forename: Adam
authors.initials: A
authors.lastname: Castaño
authors.forename: Sonja R
authors.initials: SR
authors.lastname: Surman
authors.forename: Peter L
authors.initials: PL
authors.lastname: Collins
authors.forename: Mario H
authors.initials: MH
authors.lastname: Skiadopoulos
authors.forename: Brian R
authors.initials: BR
authors.lastname: Murphy
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001287:Attachment Sites, Microbiological / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D022241:Parainfluenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D010222:Parainfluenza Virus 1, Human / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology; D010253:Respirovirus Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D016896:Treatment Outcome; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D014779:Virus Replication
chemical_list: D022241:Parainfluenza Vaccines; D010750:Phosphoproteins; D014613:Vaccines, Attenuated; D019444:Vaccines, DNA; D014764:Viral Proteins; C068855:P protein, parainfluenza virus 1