Preclinical Safety Assessment of a Recombinant Plague Vaccine (rF1V)

Abstract

A recombinant vaccine (rF1V) is being developed to protect adults 18 to 55 years of age from fatal pneumonic plague caused by aerosolized Yersinia pestis. A comprehensive series of studies was conducted to evaluate the general toxicity and local reactogenicity of the rF1V vaccine prior to first use in humans. Toxicity was evaluated in CD-1 mice vaccinated with control material and three dosage concentrations of rF1V with or without Alhydrogel(®) by intramuscular (IM) injection on Study Days 1, 29, 57 and 71 in a volume of 0.1 mL. Total immunizing protein given in each dose was 0, 20 or 60 μg/animal. Local reactogenicity was evaluated in mice at the dosages given and in New Zealand white (NZW) rabbits using the same injection volume and formulations (40, 80, 160 and 320 μg/mL total antigen and 0.3% (w/v) Alhydrogel(®)) intended for human use (0.5 mL). The rF1V vaccine produced no apparent systemic toxicity and only transient edema and erythema at the injection site. Together these results indicated a favorable safety profile for rF1V and supported its use in a Phase 1 clinical trial.

Repeat-Dose Toxicity Study of a Lyophilized Recombinant Protective Antigen-Based Anthrax Vaccine Adjuvanted With CpG 7909

“…Confirmation of induction of an active immune response was also included since toxicity linked to components of the immune response induced by the vaccine must also be considered. 20,21,41 -43 The current study provides additional safety data and confirms the utility of the rat model in assessing safety of vaccine candidates using CpG 7909 as an adjuvant.…”

Vaccine Potential of a Recombinant Bivalent Fusion Protein LcrV-HSP70 Against Plague and Yersiniosis

“…In the recent past, many reports have been published on F1/LcrV based vaccine formulations. The F1/LcrV vaccine antigens adjuvanted with alum induce robust humoral immune responses and impart 100% protection in a mouse model (16,(21)(22)(23)(24) with no side effects in humans (25). F1/LcrV antigen-based vaccine formulations protect cynomolgus macaques against aerosolized Y. pestis but failed to protect African Green monkeys (26,27).…”

Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant

“…Neutrophilia was not observed in rabbits injected with aluminum hydroxide and aluminum phosphate adjuvants in contrast to several other adjuvants tested (Destexhe et al ., ). No effects on neutrophils or any other leukocytes were reported in two preclinical safety studies of recombinant protein vaccines formulated with aluminum hydroxide adjuvant (Price et al ., ; Shearer et al ., ). The increase of neutrophils after repeated injections of the vaccine, but not the aluminum adjuvant alone, suggests that this increase is associated with the immune response rather than local inflammation at the injection site.…”

“…The acute inflammation in the first few days after injection of aluminum adjuvant or the adjuvanted vaccine in both mice and rabbits is consistent with detailed studies on the kinetics of the inflammatory response at the injection site (Lu & HogenEsch, ). Similar to previous reports, there was no difference in the inflammation observed in the group that received the adjuvant only and the group that received the adjuvanted vaccine suggesting that the local reaction is primarily a response to the aluminum adjuvant (Price et al ., ; Shearer et al ., ). A recent review of repeat dose toxicity studies of vaccines reported a slightly enhanced inflammatory response to adjuvanted vaccines compared with adjuvant only in seven of 12 studies that included both experimental groups, suggesting that the immune response to vaccine antigens can contribute to the inflammation (Baldrick, ).…”