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US 2005/0100532 A1 Hoffman Et Al US 20050100532A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0100532 A1 Hoffman et al. (43) Pub. Date: May 12, 2005 (54) APPARATUSES AND METHODS FOR THE (60) Provisional application No. 60/370,581, filed on Apr. PRODUCTION OF HAEMATOPHAGOUS 5, 2002. ORGANISMS AND PARASITES SUITABLE FOR WACCNE PRODUCTION Publication Classification (75) Inventors: Stephen L. Hoffman, Gaithersburg, (51) Int. Cl." ............................. A01N 63/04; C12N 1/10 MD (US); Thomas C. Luke, (52) U.S. Cl. ......................... 424/93.4; 424/93.5; 43/107; Brookville, MD (US) 435/258.2 (57) ABSTRACT Correspondence Address: DAVID S. DOLBERG Disclosed are apparatuses and methods for the production of 37 TERRACEAVE. attenuated aseptic parasites in haematophagous insects gen erally, and production of Plasmodium species Sporozoites in RICHMOND, CA 94.801 (US) Anopheles Species mosquitoes specifically; apparatuses and Assignee: SANARIA, INC. methods for the production of Strains of haematophagous (73) insects with desired properties Such as hypoallergenicity or Appl. No.: 10/958,163 hyperinfectivity; methods of producing a parasite Strain that (21) is capable of withstanding cyropreservation at temperatures (22) Filed: Oct. 4, 2004 close to freezing, apparatuses and methods for the injection of an attenuated parasite vaccine, production of parasites and haematophagous insects that are free from contamina Related U.S. Application Data tion by unwanted biological agents, apparatuses for the reconstruction of complex parasitic life cycles aseptically to (63) Continuation-in-part of application No. PCT/US03/ avoid the contamination of the parasite or the insect vector 10797, filed on Apr. 7, 2003. host with unwanted biological agents. Patent Application Publication May 12, 2005 Sheet 1 of 11 US 2005/0100532 A1 On Or y Patent Application Publication May 12, 2005 Sheet 2 of 11 US 2005/0100532 A1 Or 9. CN CN rO O% ) CN CN s s Ox) CN CN Patent Application Publication May 12, 2005 Sheet 3 of 11 US 2005/0100532 A1 r C Or S. / SS s 3 SN S C CN or / \O Cr y O ce O Or CrC) -1 - e op Cad i- O Patent Application Publication May 12, 2005 Sheet 4 of 11 US 2005/0100532 A1 SS. N. ) S Patent Application Publication May 12, 2005 Sheet 5 of 11 US 2005/0100532 A1 J-5.l/ Patent Application Publication May 12, 2005 Sheet 6 of 11 US 2005/0100532 A1 Patent Application Publication May 12, 2005 Sheet 7 of 11 US 2005/0100532 A1 dC -N ) i Patent Application Publication May 12, 2005 Sheet 8 of 11 US 2005/0100532 A1 CO yer- o co S Yes K Patent Application Publication May 12, 2005 Sheet 9 of 11 US 2005/0100532 A1 ( 1 Patent Application Publication May 12, 2005 Sheet 10 of 11 US 2005/0100532 A1 950 901 &Ooot A. RSSSSSSSS8KXXXXXX S&SRSSRSSS&SRSSSSSSSSSSSSSSSSX 906 - FIG. 10 Patent Application Publication May 12, 2005 Sheet 11 of 11 US 2005/0100532 A1 931 FIG. 1 OB US 2005/0100532 A1 May 12, 2005 APPARATUSES AND METHODS FOR THE atovaquone/produanil. However, multiple drug resistant PRODUCTION OF HAEMATOPHAGOUS strains of Plasmodium have recently been observed. In ORGANISMS AND PARASITES SUITABLE FOR addition, the occurrence of drug resistant Strains of malaria WACCINE PRODUCTION is thought to be promoted by the use of these prophylactic antimalarial drugs. Accordingly, Significant efforts have CLAIM OF PRIORITY been undertaken to develop a vaccine for malaria. 0001. This application is a continuation in part of PCT/ 0006 There have been some indications in the scientific US03/10797, which has an International filing date of Apr. literature that a vaccine for malaria could be effective. In 7, 2003 and was published in English on Oct. 23, 2003 (WO regards to a metabolically active non-replicating (attenu 03/087322). This application further claims the benefit ated) whole sporozoite vaccine, Nussenzweig and cowork under 35 U.S.C.S 119(e) of U.S. Provisional Application No. ers (Nature 216: 160-162; 1967) reported that immunizing 60/370,581, filed Apr. 5, 2002. New material is filed under mice with radiation attenuated Plasmodium berghei sporo the provisions of 37 CFRS1.53(b)(2). Zoites. These rodent Studies provided the impetus for human Studies, and during the 1970s, Cylde, Rieckmann, and FIELD OF THE INVENTION colleagues (Clyde et al.; Am. LT Med. Sci. 266:169-177; 0002 The present invention relates to apparatuses and 1973; Cyide et al. Am. LT. Med. Sci. 266:398.401; 1973; methods for the production of parasites in haematophagous Rieckmann et al. Trans. R. Soc. Trop. Med. Hyg. 68:258 insects generally, and to the production of Plasmodium 259; 1974) conducted limited studies that established that Species Sporozoites in Anopheles Species mosquitoes, Spe immunizing human Volunteers with the bites of irradiated cifically. The present invention further relates to apparatuses mosquitoes carrying Plasmodium falciparum Sporozoites in a nd methods for the production of Strains of insects (e.g., their Salivary glands could protect Volunteers against a Anopheles mosquitoes) that have desired properties Such as challenge with fully infectious Plasmodium falciparum hypoallergenicity or hyperinfectivity. The present invention sporozoites. Hoffman and Luke (Hoffman et al.; LT. Infect. also relates to methods of producing a Strain of a parasite Dis. 185:1155-1164; 2002) established the full potential of that is capable of withstanding cyropreservation at tempera this approach by reporting the results of 10 years' clinical tures close to freezing. The present invention further relates experience with live mosquito immunizations and chal to apparatuses and methods for the injection of an attenuated lenges, and combined their results with all the published parasite vaccine. The present invention allows for the pro clinical reports of immunizing humans with irradiated Plas duction of parasites and haematophagous insects that are modium sporozoites. free from contamination by unwanted biological agents Such as bacteria and other microorganisms. The apparatuses of 0007. The following 3 points summarize the most impor the present invention provide for the reconstruction of taht findings: 1) Thirteen of 14 volunteers immunized by the complex parasitic life cycles aseptically, So as to avoid the bites of greater than 1000 infected, irradiated mosquitoes contamination of either the parasite or the insect vector host were protected against developing blood-stage Pfalciparum with unwanted biological agents. The present invention also infection when challenged within 10 weeks of their last provides for methods for the production of an attenuated primary immunization; 2) Five of 6 of the 14 volunteers in Plasmodium Sporozoite vaccine that is Stable at relatively (1) above when challenged from 23 to 42 weeks (23, 36,39, shallow cryogenic temperatures. The present invention fur 41, and 42 weeks) after their last primary or Secondary ther provides for apparatuses for the delivery of micro-bolus immunization were protected against experimental chal amounts of vaccine. lenge; and 3) Seven of Seven heterologous challenges (immunized with one strain of Pfalciparum and challenged DESCRIPTION OF THE BACKGROUND with another strain of Pfalciparum) in four individuals were 0.003 Malaria is the most devastating parasitic disease asSociated with complete protection. and, as Such, represents one of the most important public 0008 From this, it was demonstrated that protection was health problems worldwide. According to experts in the achieved in greater than 90% of immunized subjects, lasted field, malaria infects 300 million people a year and kills up for at least 10 months, and demonstrated cross Strain (het to 3 million people per year. A vaccine for malaria would erologous) protection. For the first time, the true efficacy of drastically reduce the impact of this dangerous disease. this experimental vaccine approach was demonstrated. 0004. The causative agents in malaria are various species While this study demonstrated the feasibility of an attenu of the eukaryotic genus Plasmodium, including Plasmodium ated malaria Vaccine, it was considered for many reasons to falciparum, Plasmodium vivax, Piasmodium Ovale, and be impractical to immunize large numbers of Susceptible Plasmodium Malariae. These parasites have a very complex individuals by employing the bites of irradiated infected life cycle that involves both vertebrate and invertebrate mosquitoes. hosts. The vertebrate infective form of the parasite (sporo 0009. One technical hurdle to the development of a Zoites) is present in the Salivary glands of mosquitoes clinically relevant vaccine is the production of aseptic (typically of the genus Anopheles) and the Sporozoites are Sporozoites that are free of contamination by unwanted transferred to humans during feeding by the mosquitoes. In biological agents. Currently, it is not possible to produce the human host, the Sporozoites initially infect the cells of Plasmodium falciparum Sporozoites using an in vitro pro the liver and eventually red blood cells. This infection ceSS. Therefore, Plasmodium falciparum Sporozoites must results in an illness which is potentially fatal to those be obtained from the tissues of infected female Anopheles infected. mosquitoes. However, it is well known that wild and insec 0005 Current prophylactic approaches to malaria include tary reared mosquitoes are highly contaminated with the use of drugs, including chloroquine, mefloquine and unwanted biological agents including bacteria, molds, and US 2005/0100532 A1 May 12, 2005 fungi. This contamination largely
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