title: Pre-clinical toxicity & immunobiological evaluation of DNA rabies vaccine & combination rabies vaccine in rhesus monkeys (Macaca mulatta).
abstract: OBJECTIVE
  Pre-clinical toxicology evaluation of biotechnology products is a challenge to the toxicologist. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed recombinant DNA anti-rabies vaccine [DRV (100 μg)] and combination rabies vaccine [CRV (100 μg DRV and 1.25 IU of cell culture-derived inactivated rabies virus vaccine)], which are intended for clinical use by intramuscular route in Rhesus monkeys.
  
  
  METHODS
  As per the regulatory requirements, the study was designed for acute (single dose - 14 days), sub-chronic (repeat dose - 28 days) and chronic (intended clinical dose - 120 days) toxicity tests using three dose levels, viz. therapeutic, average (2x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in monkeys. The selection of the model i.e. monkey was based on affinity and rapid higher antibody response during the efficacy studies. An attempt was made to evaluate all parameters which included physical, physiological, clinical, haematological and histopathological profiles of all target organs, as well as Tiers I, II, III immunotoxicity parameters.
  
  
  RESULTS
  In acute toxicity there was no mortality in spite of exposing the monkeys to 10XDRV. In sub chronic and chronic toxicity studies there were no abnormalities in physical, physiological, neurological, clinical parameters, after administration of test compound in intended and 10 times of clinical dosage schedule of DRV and CRV under the experimental conditions. Clinical chemistry, haematology, organ weights and histopathology studies were essentially unremarkable except the presence of residual DNA in femtogram level at site of injection in animal which received 10X DRV in chronic toxicity study. No Observational Adverse Effects Level (NOAEL) of DRV is 1000 ug/dose (10 times of therapeutic dose) if administered on 0, 4, 7, 14, 28 th day.
  
  
  CONCLUSIONS
  The information generated by this study not only draws attention to the need for national and international regulatory agencies in formulating guidelines for pre-clinical safety evaluation of biotech products but also facilitates the development of biopharmaceuticals as safe potential therapeutic agents.
authors.affiliation: National Institute of Nutrition (ICMR), Hyderabad, India. nindineshpct@gmail.com
authors.forename: B Dinesh
authors.initials: BD
authors.lastname: Kumar
authors.forename: P Uday
authors.initials: PU
authors.lastname: Kumar
authors.forename: T Prasanna
authors.initials: TP
authors.lastname: Krishna
authors.forename: S
authors.initials: S
authors.lastname: Kalyanasundaram
authors.forename: P
authors.initials: P
authors.lastname: Suresh
authors.forename: V
authors.initials: V
authors.lastname: Jagadeesan
authors.forename: S
authors.initials: S
authors.lastname: Hariharan
authors.forename: A Nadamuni
authors.initials: AN
authors.lastname: Naidu
authors.forename: Kamala
authors.initials: K
authors.lastname: Krishnaswamy
authors.forename: P N
authors.initials: PN
authors.lastname: Rangarajan
authors.forename: V A
authors.initials: VA
authors.lastname: Srinivasan
authors.forename: G S
authors.initials: GS
authors.lastname: Reddy
authors.forename: B
authors.initials: B
authors.lastname: Sesikeran
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D000917:Antibody Formation; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D008253:Macaca mulatta / Q000276:immunology*; D008297:Male; D011818:Rabies / Q000276:immunology* / Q000517:prevention & control*; D011819:Rabies Vaccines / Q000008:administration & dosage* / Q000276:immunology; D011820:Rabies virus; D018675:Toxicity Tests; D017778:Vaccines, Combined / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000276:immunology; D014709:Vero Cells
chemical_list: D000914:Antibodies, Viral; D011819:Rabies Vaccines; D017778:Vaccines, Combined; D019444:Vaccines, DNA