Nonclinical safety assessment of repeated administration and biodistribution of a novel rabies self-amplifying mRNA vaccine in rats
| Autor: | Benoit Laffont, Guillaume Dubois, Alan Stokes, Karine Blouin, Maude Bigras, Julius Haruna, Luis-Alexander Rodriguez, Michael Alan Ringenberg, Nawel Ben Abdeljelil, Jamie K. Young, Johanne Pion, Ornella Binazon |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Biodistribution Spleen 010501 environmental sciences Pharmacology Toxicology 030226 pharmacology & pharmacy 01 natural sciences Injections Intramuscular Risk Assessment Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Antigen Medicine Animals Tissue Distribution RNA Messenger 0105 earth and related environmental sciences business.industry General Medicine medicine.disease Rats medicine.anatomical_structure Rabies Vaccines Toxicity Absolute neutrophil count Rabies Female Lymph business Intramuscular injection |
| Zdroj: | Regulatory toxicology and pharmacology : RTP. 113 |
| ISSN: | 1096-0295 |
| Popis: | The novel self-amplifying mRNA (SAM) technology for vaccines consists of an engineered replication-deficient alphavirus genome encoding an RNA-dependent RNA polymerase and the gene of the target antigen. To validate the concept, the rabies glycoprotein G was chosen as antigen. The delivery system for this vaccine was a cationic nanoemulsion. To characterize the local tolerance, potential systemic toxicity and biodistribution of this vaccine, two nonclinical studies were performed. In the repeated dose toxicity study, the SAM vaccine was administered intramuscularly to rats on four occasions at two-week intervals followed by a four-week recovery period. SAM-related changes consisted of a transient increase in neutrophil count, alpha-2-macroglobulin and fibrinogen levels. Transient aspartate aminotransferase and alanine aminotransferase increases were also noted in females only. At necropsy, observations related to the elicited inflammatory reaction, such as enlargement of the draining lymph nodes were observed that were almost fully reversible by the end of the recovery period. In the biodistribution study, rats received a single intramuscular injection of SAM vaccine and then were followed until Day 60. Rabies RNA was found at the injection sites and in the draining lymph nodes one day after administration, then generally decreased in these tissues but remained detectable up to Day 60. Rabies RNA was also transiently found in blood, lungs, spleen and liver. No microscopic changes in the brain and spinal cord were recorded. In conclusion, these results showed that the rabies SAM vaccine was well-tolerated by the animals and supported the clinical development program. |
| Databáze: | OpenAIRE |
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