Clinical Testing of rBV AB Pichia pastoris Vaccine

The Phase 1 clinical trial represents the first human experience of the rBV A B (Pichia pastoris) vaccine. The primary objective of the 1 clinical trial is to evaluate the safety, tolerability, and immunogenicity of a two-dose regimen (day 0, day 28) of rBV A B (Pichia pastoris) vaccine at three dosage levels. A secondary objective is to evaluate human neutralizing antibody as a correlate of protective immunity. This will be determined by transfer of sera from the clinical trial volunteers into...

Vaccines Produced in Pichia pastoris

Vaccines produced in Pichia pastoris represent the most advanced recombinant vaccines currently under development. These include rBV A B (P. pastoris), designed to provide protection against BoNT A and BoNT B the primary candidate of the U.S. Department of Defense Joint Vaccine Acquisition Program (DoD-JVAP) a pentavalent vaccine comprising antigens designed to protect against BoNT types A, B, C, E, and F and a heptavalent vaccine designed to provide protection against all known forms of BoNT...

References

Weinberg, M. and Goy, P., Recherches sur la toxine botulinque, Compt. Rend. Soc. Biol., 90, 269, 1924. 2. Graham, R. et al., The antigenic value of formalized botulinum toxins, J. Am. Met. Vet. Assoc., 75, 21, 1929. 3. Graham, R. and Thorpe, F., Antigenic value of botulinum toxoids kept one year at ice box temperature, J. Immunol., 20, 305, 1931. 4. Velikanov, I., Experimental immunization of man against botulism, Klin. Med, 12, 1802, 1934. 5 Legroux, R. and Jeramec, C., Etudes sur la toxine et...

New Indications

I will now review selected promising developments and newer indications for treatment with BoNT, concentrating on autonomic disturbances and pain. There are many other indications, some of which are discussed in other chapters of this book. Table 7.1 in Section 7.2.4 provides an indication of the range of benefits. 7.2.1 Autonomic Indications Glandular Hypersecretion BoNT influences autonomic function by blocking sympathetic and parasympathetic ganglion cells and postganglionic parasympathetic...

Development of Pentavalent Botulinum Toxoid Vaccine for Human

In response to adverse events from some of these early toxoid preparations, a more highly processed pentavalent vaccine containing serotype A, B, C, D, and E toxoids was developed at Fort Detrick.31 The neurotoxins were precipitated from C. botu-linum cultures, extracted with calcium chloride and, after further precipitation and extraction steps, sterilized by filtration.32 The neurotoxins were inactivated with 0.6 (v v) formalin over 15 to 25 days at 35 to 37 C and pH 5.5 to 6.5, and...

Nonclinical Testing of rBV AB PlChia Pastoris Vaccine

Before submission of the IND for rBV A B (Pichia pastoris) vaccine, the proposed vaccine formulation was tested in GLP toxicity studies to establish its safety. Three studies were performed repeat dose toxicity, repeat dose neurotoxicity, and repeat dose immunogenicity. The designs of these three studies were identical. Mice (CD1) received one (day 0), two (day 0 and day 28), or three (day 0, day 28, day 56) doses of vaccine formulated with or without 0.2 (w v) Alhydrogel at serotype-specific...

Early Toxoid Development and

In 1924, Weinberg and Goy1 first reported the production of a vaccine using formaldehyde treatment of crude extracts derived from neurotoxin-producing bacteria, a process known as toxoiding. The immunogenicity of such preparations was confirmed in animals by others.2-8 Several groups have developed and used toxoid vaccines to protect domestic animals from disease. In particular, an effective type C toxoid was prepared for controlling botulism in sheep and cattle in Australia.9-10 Sterne and...

Formulation of Final Product rBV AB

The current strategy is for the final adjuvanted vaccine product to be a liquid formulation. It has been shown that an adjuvant is needed for the production of a rapid neutralizing antibody response soon after vaccination. The most commonly used adjuvants in vaccines for human use are aluminum hydroxide and aluminum phosphate. Antigen A is potent independently of the adjuvant used, while the potency of Antigen B is considerably lower when it is formulated with aluminum phosphate. All subsequent...

G

GABA-ergic neurons, 221 Gangliosides perturbants, 223-224 productive uptake process and, 223-224 role in adhering CNTs to nerve cells, 51 Gastrointestinal indications, BoNT treatment, 175-180 achalasia, 176 anal fissure, 177-179 esophageal spasm, 175 gastric and pyloric uses, 176 obesity, 177 overview of, 175 pelvic floor dysfunction, 179 rectal pain, 179-180 spasm of sphincter of Oddi, 177 Gastroparesis, 176 Generalized dystonia defined, 147-148 nonbotulinum treatment for, 150-151 onset in...

Table

In Vitro and In Vivo Neuronal Targeting Using Innocuous BoNT Derivatives3 Targeting Vehicle Cargo or Reporter Molecule In Vitro Binding to Neurons or Synaptosomes Ex Situ or In Vitro Blocks Poisoning by Native Toxin Exhibits Expected In Vitro Neuron Cell Trafficking to neurons Kozaki27 type A Hc reduces native 1251 BoNT A bound to synaptosomes Tsukamota63 BoNT C 1, D bind gangliosides much less efficiently than native toxin doubled time to paralysis by native serotype on nerve diaphragm neurons...