RESUMEN
Background & objectives: 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, 28th day. Interpretation & 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.
RESUMEN
To assess the clinical safety of equine rabies immunoglobulin (ERIG) and purified vero cell rabies vaccine (PVRV) administered intradermally in children for post-exposure prophylaxis against rabies, a study was carried out among 1494 children <15 years of age having category III exposure to animal bite at the antirabies clinic of community medicine department of MKCG Medical College Hospital, Berhampur, Orissa from 1st May 2007 to 31st March 2008. The patients received 0.1 ml of PVRV intradermally at two sites on days 0, 3, 7 and 28. The PVRV (Abhayrab) supplied by Government of Orissa had an antigen content of > 2.5 IU per 0.5 ml vial. ERIG (Equirab) was also given on day 0 as per WHO guideline. As much of the immunoglobulin as possible was infiltrated around the wounds after skin test. Side effects were monitored during the follow up visits on days 3, 7 and 28. One hundred & eight children (7.2%) showed positive reaction to the skin test dose of ERIG. These patients could not afford HRIG and were administered ERIG after premedication with oral antihistamine (Levocetrizine). There were no serious systemic side-effects but local side-effects like induration, erythema, pruritus are due to the intradermal rabies vaccination (IDRV) and pain, induration due to ERIG. Low grade fever and malaise were the only systemic side effects observed. None of the children had anaphylaxis or regional lymphadenopathy. Only 3% of children had mild serum sickness like symptoms by days 5 & 7 which subsided with oral analgesics and antihistamines. Our study showed that administration of ERIG & PVRV by intradermal route in children with WHO category-III rabies exposure is safe.