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Patent Issued for Controlled-Release Immunogenic Formulations to Modulate Immune Response
Staff Writer
July 9, 2012


2012 JUL 9 (NewsRx) -- By a News Reporter-Staff News Editor at AIDS Weekly -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Kipper, Matthew J. (Gaithersburg, MD); Narasimhan, Balaji (Ames, IA); Wilson, Jennifer H. (Ames, IA); Wannemuehler, Michael J. (Gilbert, IA), filed on September 4, 2009, was cleared and issued on May 8, 2012 (see also HIV/AIDS).

The assignee for this patent, patent number 8173104, is Iowa State University Research Foundation, Inc. (Ames, IA).

Reporters obtained the following quote from the background information supplied by the inventors: "While the development of effective single dose vaccines would have major implications for the effectiveness of mass immunization programs, the development of single dose vaccines is fraught with a complex combination of clinical and engineering challenges. Several health organizations have listed the development of single dose vaccines as one of the 'grand challenges' of human health worldwide. Even diseases for which effective vaccines exist remain a threat to public health because patient dropout rates (after initial vaccinations) reach as high as 70% in developing countries (Aguado, M. T.; Lambert, P.-H. (1992) Immunobiology 184, 113-125.). Improved vaccine delivery techniques that require only a single dose to confer protective immunity against childhood diseases would help make mass immunization programs successful. For instance, tetanus is responsible for over 700,000 neonatal deaths annually, half of which could be prevented by immunization alone.

"Induction of the appropriate immune response is essential to the safety and efficacy of vaccines (Woodland, D. L. (2004) Trends Immunol. 25, 98-104). While traditional alum-based vaccines, incorporating tetanus toxoid (TT) in particular, initiate primarily a T helper type 2 (T.sub.H2) response (Singh, M.; O'Hagan, D. T. (2003) Int. J. Parasitology 33, 469-478), a T helper type 1 (T.sub.H1) response may be more effective for protection from or treatment of cancers or infections due to intracellular pathogens (Hanes, J., Cleland, J. L., Langer, R. (1997) Adv. Drug Del. Rev. 28, 97-119). However, the mechanisms governing the type of immune response are complex and not completely understood (Sedlik, C., Deriaud, E., Leclerc, C. (1997) Int. Immunol. 9, 91-103). The T.sub.H2 (humoral) response, characterized by the activation of B cells that differentiate into plasma cells that secrete antibodies, is effective to neutralize extracellular pathogens and toxins, but not to neutralize intracellular pathogens. The T.sub.H1 (cell-mediated) response, involving the activation of interferon-.gamma. producing CD4.sup.+ T cells, CD8.sup.+ cytotoxic ('killer') T cells, and macrophages, is effective against intracellular pathogens (Finkelman, F. D.; Urban, J. F. J. (1992) Parasitol. Today 8, 311-314). The ability to purposefully modulate the immune response to more effectively protect the host from a particular pathogen would improve the effectiveness of vaccines in combating many worldwide diseases.

"A single-dose vaccine would alleviate problems associated with conventional vaccination programs that have high dropout rates. Also, no currently existing formulation can provide a tunable immune response in a single-dose formulation. Accordingly, there is a need for development of improved technologies or regimen that allow for the development of new single-dose vaccines for intracellular pathogens that require a preferential induction of the T.sub.H1 immune response. A need also exists for development of improved technologies or regimen that allow for the development of new single-dose vaccines that induce a balance of both the T.sub.H1 and T.sub.H2 responses for protection from other conditions such as HIV/AIDS and certain types of cancers."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "The present invention provides a single dose immunogenic composition, such as a vaccine, based on biodegradable polymer microparticles. The single dose immunogenic composition, such as a vaccine, contains an effective amount of an immunogen incorporated into a bioerodible polyanhydride copolymer or homopolymer microparticle, such as a microsphere. The microparticles can stabilize proteins and target their delivery to dendritic cells so that the vaccine results in immunity after administration of only a single-dose, by prolonging exposure to the immunogen. The immune response mechanisms (T.sub.H1 vs. T.sub.H2) can be adjusted or 'tuned' by altering the composition of the polyanhydride(s) and of the immunogen(s) in the immunogenic composition, such as a vaccine, formulation.

"The invention provides a single dose immunogenic composition, such as a vaccine, comprising an effective amount of an immunogen incorporated into bioerodible polyanhydride copolymer or homopolymer microparticles so that an amount of immunogen effective to immunize an animal against a pathogen is provided to said animal following administration of a single dose of said microparticles. The invention also provides sustained exposure to an immunogen that can result in maintenance of immuno-regulatory mechanisms. Such therapies could include treatments for autoimmune diseases (e.g. diabetes), allergic reactions, or immune mediated inflammatory diseases (e.g. colitis). The animal can be a human, a domesticated animal such as a companion animal or a farm animal. The immunogenic composition, such as a vaccine, can induce both a primary and secondary immune response in the subject. The immunogenic composition, such as a vaccine, can be derived from any pathogen that elicits a T.sub.H1 or T.sub.H2 response in an animal. The immunogenic composition, such as a vaccine, can induce a balanced immune response, wherein the T.sub.H1 and T.sub.H2 responses are substantially equivalent, in that they both arise and make an effective contribution to immunity.

"The immunogenic composition, such as a vaccine, includes a carrier particle having a polyanhydride matrix, wherein the polyanhydride is a homopolymer or a copolymer of a 1,.omega.-bis(p-carboxyphenoxy)(C.sub.2-C.sub.12)alkane, preferably a (C.sub.4-C.sub.8)alkane with a (C.sub.5-C.sub.20)alkanoic diacid, preferably a (C.sub.8-C.sub.12)alkanoic diacid. The (C.sub.5-C.sub.20)alkanoic diacid can be sebacic acid (SA). The 1,.omega.-bis(p-carboxyphenoxy) (C.sub.1-C.sub.6)alkane can be 1,6-bis(p-carboxyphenoxy) hexane (CPH). The molar ratio of CPH:SA can be less than about 1:1, preferably about 1:1.5-5. The microparticles can be about 100 nm to about 100 .mu.m in diameter, about 100 nm to about 75 .mu.m, or more specifically about 100 nm to about 50 .mu.m in diameter.

"In addition to entrapped immunogen, the immunogenic composition, such as a vaccine, also preferably includes an amount of free immunogen effective to provide a balanced immune response in said animal. Thus, the immunogenic composition, such as a vaccine, can elicit a T.sub.H1 immune response in conjunction with a T.sub.H2 immune response. The immunogenic composition, such as a vaccine, can stimulate the production of interleukin 12 (IL-12). The immunogenic composition, such as a vaccine, can stimulate T.sub.H1 cells that produce interferon .gamma. (INF-.gamma.) in sufficient quantity to suppress IgG1 production.

"A method is provided to induce an immunogenic response in an animal comprising administering to said animal an effective immunogenic amount of the immunogenic composition, such as a vaccine, of the invention, preferably in combination with an aqueous liquid vehicle. The immunogenic composition, such as a vaccine, can be administered by injection or intranasal spray. The immunogenic composition, such as a vaccine, can reduce at least one of the symptoms of infection by a pathogen. The immunogenic composition, such as a vaccine, can be used to vaccinate against a pathogen such as a gram-positive bacterium or bacillus. For example, the pathogen can be C. tetani, C. botulinum, B. anthracis, or C. diphtheriae. The pathogen can also be an acid-fast bacterium such as M. tuberculosis or M. bovis. The vaccine can be used to vaccinate against a pathogen such as a gram-negative bacterium. For example, the bacterium can be a shigellae, salmonellae, bordetellae, francisellae, or yersiniae. The pathogen can also be a spirochete, a chlamydiae, a staphylococci, a streptococci, a pneumococci, or a neisseriae. The pathogen can be a parasite or portion derived from a parasite such as Leishmania, Toxoplasma, Plasmodium (malaria), trypanosomes or Giardia species. The pathogen can be a virus, such as HSV, HIV, EBV, a poliovirus, an influenza virus, a rabies virus, a variola virus, a yellow fever virus or a hepatitis virus. The virus can be a retrovirus, and the retrovirus can be HIV. The pathogen can also be yeast or fungal in nature, including Hitsoplasma, Cryptococcus, or Coccidioides species.

"The immunogen can include a polypeptide or polypeptide subunit of one or more of the pathogens recited herein. The immunogen can be an inactivated polioviruses, rabies virus, vaccinia virus, or yellow fever virus. The immunogen can be a polypeptide or polypeptide subunit of a bacilli, a cocci or other bacterial morphologies. The bacilli can be typhoid, pertussis, or plague. The immunogen can include a polypeptide or polypeptide subunit of a spirochete. The immunogen can include diphtheria toxoids or tetanus toxoids. The immunogen can also include a polypeptide, or polypeptide subunit of a parasite or a virus. The immunogen can also be an oligosaccharide, an oligonucleotide (e.g. DNA), or an allergen.

"The development of a single-dose tetanus toxoid (TT) immunogenic composition, such as a vaccine, based on polyanhydride microspheres composed of 1,6-bis(p-carboxyphenoxy)hexane (CPH) and sebacic acid (SA) is disclosed hereinbelow. Release kinetics can be modulated by altering the copolymer composition, which allows various immunization regimens to be developed. In vivo studies in mice demonstrated that the encapsulation procedure preserves the immunogenicity of TT. The polymer itself can have an adjuvant effect, enhancing the immune response to a small dose of TT, but as the dose of polymer is increased, a localized, dose-dependent inhibition of the immune response may be observed.

"Sustained release of antigenic/immunogenic protein is essential for the efficacy of a single-dose vaccine. TT released from the microspheres maintained its immunogenicity and antigenicity and the microspheres provided a prolonged exposure to TT sufficient to induce the secondary immune response (i.e., isotype switching, high avidity, and high titers were observed) without requiring an additional administration. In addition to providing an immune response with a single immunizing dose, the microsphere delivery vehicle offers the opportunity to select the preferred immune response pathway. While TT administered in buffer alone is known to induce a dominant T.sub.H2 immune response, the TT-loaded microspheres described herein can induce a balanced T.sub.H1 and T.sub.H2 immune response pathways as evidenced by the observed IgG2a and IgG1 antibody responses, respectively, when they are injected intramuscularly."

For more information, see this patent: Kipper, Matthew J.; Narasimhan, Balaji; Wilson, Jennifer H.; Wannemuehler, Michael J.. Controlled-Release Immunogenic Formulations to Modulate Immune Response. U.S. Patent Number 8173104, filed September 4, 2009, and issued May 8, 2012. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&p=80&u=%2Fnetahtml%2FPTO%2Fsearch-bool.html&r=3982&f=G&l=50&co1=AND&d=PTXT&s1=20120508.PD.&OS=ISD/20120508&RS=ISD/20120508

Keywords for this news article include: HIV/AIDS, Virology, Cytokines, Lyssavirus, Salmonella, Lymphokines, RNA Viruses, Rabies Virus, Retroviridae, Tuberculosis, Rhabdoviridae, HIV Infections, Polyanhydrides, Mononegavirales, Interferon-gamma, Biological Factors, Vertebrate Viruses, Yellow Fever Virus, Arbovirus Infections, Primate Lentiviruses.

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