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Complement

Complement research in the Rice laboratory involves the identification of unique determinants present on bacterial surfaces that may serve as suitable vaccine candidates to protect against infection in humans. In some cases these determinants may also activate or regulate a series of inflammatory mediators called complement (C), which are made up of a group of proteins that are activated sequentially as part of the innate immune response: (1) to combat invading bacteria that infect humans by killing the bacteria and to also enhance their clearance by phagocytes; (2) to facilitate the development of the adaptive immune response to invading bacteria to protect against future infection caused by these organisms and (3) to amplify this immune response once it has developed. Under certain conditions C works to the disadvantage of the host because it is hijacked by microorganisms to down-regulate the activation and binding of C and to also enhance entry into phagocytes (professional and non-professional) where organisms can gain sanctuary; these areas of study are important to consider when vaccines sometimes don’t work. The laboratory examines C interactions with bacteria, particularly the Neisseria species, having been first to report interactions of Neiseria gonorrhoeae with complement (C) down-regulator molecules (factor H; an alternative pathway of C inhibitor) and C4 binding protein (C4BP; a classical pathway of C inhibitor) but also with the only known complement up-regulator, properdin. C down-regulator molecules are important in enabling Neisseria to escape immune surveillance.

Gonococcal vaccine development

As a prelude to identifying suitable vaccine candidates to protect against gonococcal infection, the laboratory first identified and characterized blocking (or subverting) antibody targets on Neisseria species that interfere with productive killing (in vitro ) by complement (C)-dependent bactericidal antibodies. These antibody responses were elicited in a human vaccination trial that used a complex outer membrane structure as an immunogen that had been derived from Neisseria gonorrhoeae. A potentially protective response (C dependent bactericidal antibodies) that was elicited in men by the vaccine was subverted by the accompanying blocking antibody response directed against small amounts of a reduction modifiable protein (Rmp) present in the vaccine, which caused the vaccine to fail when the men who received it were not protected upon subsequent urethral (experimental) challenge with virulent N. gonorrhoeae (experimental urethral gonorrhea in men is safe and an IRB approved method to study this disease). Removal of Rmp-antibody from vaccine serum that has lost baseline bactericidal activity as a result of immunization, restores killing. These experiments were subsequently repeated (and verified) in the mouse experimental model of gonococcal infection. Blocking antibodies are present in normal human serum and are also elicited by gonococcal infection itself. These antibodies may reverse a protective immune antibody response (--a response that may occur with other bacterial infections) and may explain the lack of protective immunity that occurs after gonococcal infection.

In efforts to identify suitable subunit vaccine candidates against gonorrhea devoid of blocking activity, the laboratory examined the chemistry (and immunochemistry) of gonococcal lipopolysaccharide (also known as lipooligosaccharide [LOS]), having reported the first known conserved gonococcal LOS derived oligosaccharide epitope (called 2C7) that is present on almost all wild-type strains of N. gonorrhoeae. This epitope, located in the core of LOS as lactose substitutions on each of the two core heptose molecules of LOS, elicits complement dependent antibody activity in humans both in natural human infection and as a consequence of experimental animal immunization. The Rice laboratory and its collaborators have performed extensive biochemical, structural and genetic analysis of this carbohydrate epitope and the surrounding structure(s) to define their role in complement (C) binding. The 2C7 epitope is: i) broadly expressed as a gonococcal antigenic target in human infection; ii) a critical requirement for gonococcal colonization in the experimental setting and iii) a virulence determinant that is maintained and expressed by gonococci.

To circumvent inherent limitations of carbohydrate antigens as immunogens when they are used as vaccines, the laboratory also “converted” the 2C7 epitope into peptide mimics, first into an anti-idiotope (protein) and then into a complex peptide mimic for testing as vaccine candidates; both have been shown to be the immunologic counterparts (surrogates) of the oligosaccharide epitope. To formulate a prototype vaccine candidate intended for use in humans that represented the 2C7 epitope in antigenicity and immunogenicity, the lab synthesized the candidate compound to >95% purity.  This vaccine candidate, called TMCP2, when administered to BALB/c mice in combination with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE; a Toll-like receptor 4 and TH1 promoting adjuvant), elicited bactericidal IgG and reduced colonization levels of gonococci in experimentally infected mice while accelerating clearance by each of two different gonococcal strains.

These inventions (prototypes and finalized products) have been issued U.S. and foreign patents and are being configured with appropriate adjuvants for use in: (1) humans and (2) experimental models in mice adapted to stimulate the human complement down-regulator system by creating human FH/C4BP transgenic mice.  A gonococcal vaccine candidate has been developed that can be scaled up and produced economically to a high degree of purity. The candidate elicits bactericidal antibodies and is efficacious in a pre-clinical experimental infection model.


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