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Published on: May 2, 2011
Nonclinical toxicology study of recombinant-plasmid DNA anti-rabies vaccines
P Uday Kumar1, B Dinesh Kumar, V V Annapurna
1National Institute of Nutrition, (Indian Council of Medical Research), Hyderabad, Andhra Pradesh 500007, India.
Abstract:
The absence of standard guidelines from National and International regulatory agencies for the safety evaluation of biotechnology products challenges the ingenuity of toxicologists. At present, the development of standard pre-clinical toxicology protocols for such products is on an individual case basis. The present investigation is an attempt to evaluate the safety profile of the first indigenously developed DNA based anti-rabies vaccine in India. The test compounds were DNA rabies vaccine [DRV (100 microg)] and combination rabies vaccine (CRV (100 microg DRV and 1/50 dose of cell culture vaccine)), intended for clinical use by intramuscular route on 1, 7, 14 and 28 day. As per the regular mandatory requirements, the study has been designed to undertake acute (single dose--10 days), sub-chronic (repeat dose--28 days) and chronic (intended clinical dose--120 days) toxicity tests using three dose levels viz. therapeutic, average (2 x therapeutic dose) and highest dose (10 x therapeutic dose) exposure in Swiss Albino mice. The selection of the rodent model viz. Swiss Albino mice is based on affinity and rapid higher antibody response during the efficacy studies. Apart from physical, physiological, clinical, hematological and histopathology profiles of all target organs, the tier-I immunotoxicity parameters have also been monitored. There were no observational adverse effects even at levels of 10x therapeutic dose administration of DRV and CRV. The procedure also emphasizes on the designing of protocols for the products developed by recombinant technique.
Insights
This study evaluated the safety of India's first DNA rabies vaccine (DRV) and a combination rabies vaccine (CRV). Both vaccines showed no adverse effects in mice, even at high doses, supporting their potential clinical use.
Area of Science:
- Biotechnology
- Toxicology
- Vaccinology
Background:
- Lack of standardized regulatory guidelines for biotechnology product safety evaluation.
- Pre-clinical toxicology protocols are developed on a case-by-case basis.
- Need for safety evaluation of novel vaccines, including DNA-based ones.
Purpose of the Study:
- To evaluate the safety profile of the first indigenously developed DNA-based anti-rabies vaccine (DRV) in India.
- To assess the safety of a combination rabies vaccine (CRV) containing DRV.
- To establish pre-clinical toxicology protocols for recombinant-derived vaccines.
Main Methods:
- Acute, sub-chronic, and chronic toxicity tests were conducted in Swiss Albino mice.
- Three dose levels (therapeutic, 2x, and 10x therapeutic) were administered via intramuscular route.
- Evaluated physical, physiological, clinical, hematological, histopathological, and immunotoxicity parameters.
Main Results:
- No observational adverse effects were noted in mice even at 10x the therapeutic dose of DRV and CRV.
- Swiss Albino mice were selected for their affinity and antibody response.
- The study adhered to mandatory pre-clinical testing requirements.
Conclusions:
- The indigenously developed DNA rabies vaccine (DRV) and combination rabies vaccine (CRV) demonstrate a favorable safety profile.
- These findings support the potential clinical application of DRV and CRV.
- The study provides a framework for designing toxicology protocols for recombinant products.
