Potency of cryopreserved, irradiated sporozoite vaccine
DESCRIPTION (provided by applicant): Malaria causes an estimated 500 million clinical cases and up to 2.7 million deaths annually, is responsible for a loss of greater than 1% of GDP in Africa annually, and is a serious concern for travelers and military personnel. Sanada's goal is to develop and commercialize an attenuated Plasmodium falciparum sporozoite vaccine for two primary markets with a potential for > $1 billion annual revenues; 1) Travelers from the developed world and 2) Infants and young children in the developing world. In limited trials, this type of immunization has been shown to protect greater than 90% of human volunteers against experimental P. falciparum challenge, protect for greater than 10 months after last immunization, and protect against heterologous challenge. No other experimental malaria vaccine under development has been shown to approach these performance characteristics. Heretofore it has been considered impractical to develop such a vaccine, in large part because volunteers have been immunized by the bite of infected mosquitoes, and mice by intravenous (IV) administration of sporozoites. All findings in humans with irradiated sporozoites have been anticipated by studies in mice with rodent malaria, and mice have now been shown to be 100% protected by subcutaneous administration (a practical route) of radiation- attenuated P. yoeii sporozoites and, in earlier published reports, by IV administration of cryopreserved (-75 degrees C) P. berghei sporozoites (stable for many months).
The primary goal of this project is to develop a method for cryopreserving and irradiating P. falciparum sporozoites acceptable for the manufacturing process for an investigational new drug (IND) application to the FDA. Studies will be done initially with the rodent malaria parasite, P. yoelii because all findings will be able to be assessed in vitro and in vivo in mice. Findings in the P. yoelii system will be used as the foundation for applying similar methods to the development of a P. falciparum vaccine for humans using techniques that will produce an optimized immunogen that meets all regulatory standards. Work is in progress to optimize the method of administration of radiation attenuated P. yoelii sporozoites and to demonstrate that immunization in the skin or muscle with cryopreserved P. yoelii sporozoites induces protective immunity. However, the methods of radiation attenuation currently in use are the same as those used 30 - 40 years ago. Additionally, there have been no advances in methods of cryopreservation for sporozoites in over 20 years. None of the methods currently in use for radiation attenuation or cryopreservation of sporozoites would be suitable for the manufacture of a vaccine for human use. The optimal time point to administer the irradiating dose to sporozoites would be after they are frozen, but there are no data available regarding this approach to cryopreservation. In this project all aspects of the radiation attenuation process will be optimized, including source of radiation, amount of radiation, length of time of irradiation, container in which the radiation is performed, and documentation of radiation exposure (dosimetry) in order to establish a basis for a cGMP process. In addition, studies will be done to determine if radiation of infected mosquitoes, freshly dissected sporozoites, or frozen sporozoites provides the best immunogen - the latter being preferable from a vaccine production perspective. Furthermore, the methods of cryopreservation and thawing will be optimized so as to ensure that a vaccine is stable for at least 6 months. The goal is to deliver a defined method to produce an optimized immunogen that comprises radiation-attenuated/cryopreserved P. falciparum sporozoites, that meets all regulatory standards. The project will also provide a method for cryopreserving unirradiated sporozoites that could be used to challenge volunteers by injection with P. falciparum in vaccine studies worldwide.
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SANARIA, INC. 12115 PARKLAWN DR, STE L ROCKVILLE, MD 20852
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