Vaccine against lipopolysaccharide core

Details Vaccine against lipopolysaccharide core Vaccine against lipopolysaccharide core

2000-04-25

2004-06-15

Swartz, Rodney P. (Department: 1645)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

Molecular bilayer structure

C424S009321, C424S169100, C424S236100, C424S241100, C424S258100, C427S002140, C530S390100

Reexamination Certificate

active

06749831

ABSTRACT:

FIELD OF THE INVENTION
This invention is in the general field of reducing the adverse effects of endotoxin from Gram-negative bacteria.
BACKGROUND OF THE INVENTION
Endotoxin (also called lipopolysaccharide [LPS]) is thought to exert many of its toxic effects following its entry into the bloodstream. The presence of endotoxin in the blood, endotoxemia, can occur in various situations, e.g., during periods of stress. For example, endotoxemia can occur in patients undergoing certain types of surgery, anti-cancer chemotherapy, radiation therapy, and immunosuppressive treatment, and it can also occur in patients suffering from various trauma, burns, or wounds. It occurs as well in military, police, and fire-fighting personnel as well as in endurance athletes, horses, and in livestock. It can also occur after immunosuppressive treatment, and in patients with sepsis or septic shock as well as in those suffering from stress or trauma as discussed above.
One way that endotoxin may reach the blood is from the patient's intestine because the intestine loses its ability to contain LPS during periods of infection, stress, or trauma. Normally, intestinal flora contain a large amount of endotoxin from Gram-negative microorganisms. It is estimated that the average human colon contains 25 billion nanograms of endotoxin, which is an enormous quantity when one considers that endotoxin concentrations on the order of 10
2
are toxic to humans.
The leakage of live bacterial cells into the bloodstream can result in infection as the bacteria multiply. Many of the bacteria in the intestine are dead, and endotoxin contained within cell membrane fragments of dead bacteria can also enter the bloodstream. In this case infection per se does not develop. Instead, endotoxin from dead bacteria in the blood is thought to initiate a systemic inflammatory response by activating macrophages which release tumor necrosis factor and various interleukins. Endotoxin exposure and the resulting systemic inflammatory response can cause damage to body organs, including the lungs, kidneys, heart, blood vessels, gastrointestinal tract, blood/coagulation system, and nervous system. This proinflammatory response can be severe, causing organs to fail, sometimes resulting in death.
LPS is thought to be a major causative agent of septic shock. It is increasingly recognized that less severe forms of this systemic inflammation cause organ dysfunction as opposed to organ failure. In its mildest form, endotoxemia can cause fever, nausea, and malaise, common symptoms of patients following surgery or patients who are hospitalized for other reasons, and the symptoms even occur, for example in athletes following strenuous activity.
Greater exposure of the host to endotoxin or a greater susceptibility to its effects can result in a larger inflammatory response. For example, many post surgical patients develop pulmonary dysfunction requiring supplemental oxygen. They may also develop hematologic or renal complications. These complications often do not lead to death but instead cause suffering and increase hospital length of stay and thus health care costs. It is estimated that at least 10% of the 28 million United States surgical patients may develop systemic inflammation and possible complications as a result of exposure to endotoxin from Gram-negative microorganisms. See generally, Bennett-Guerrero et al., Crit Care Med, 25:A112, 1997 and Bennett-Guerrero et al., J. Am. Med. Ass. 277:646-650, 1997 discussing certain types of surgical patients at risk.
Among the bacteria and their respective endotoxins which are thought to commonly cause complications are
Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeuruginosa
, Proteus spp., Enterobacter spp., Salmonella spp., Serratia spp, and Shigella spp. These bacteria are Gram-negative bacteria, a class characterized by a specific type of outer membrane which compromises a lipopolysaccharide (LPS) as a major constituent. Although the LPS constituent varies from one bacterial species to another, it may be generally described with reference to
FIG. 1
as consisting of three structural regions: a) Lipid A; b) core; and c) O-polysaccharide outer region. The lipid region of Lipid A is embedded in the outer leaflet of the outer membrane. The oligosaccharide core region is positioned between Lipid A and the O-polysaccharide outer region. Lipid A has the same basic structure in practically all gram negative bacteria and is the main endotoxic determinant. The LPS core region shows a high degree of similarity among bacterial genera. It usually consists of a limited number of sugars. For example, the inner core region is constituted of heptose and 3-deoxy-D-manno-2-octulosonate (KDO) residues, while the outer core region comprises galactose, glucose, or N-acetyl-D-glucosamine residues displayed in various manners depending upon the strain. The O-polysaccharide outer region (also called O-specific antigen or O-specific side chain) is highly variable and is composed of one or more oligosaccharide repeating units characteristic of the serotype.
The presence of the O-polysaccharide side chain confers a smooth aspect to a culture of a wild type bacterium, and, for this reason, wild type bacteria with polysaccharide side chain are usually referred to as smooth bacteria in contrast with mutant cultures which show a rough aspect because they lack the O-polysaccharide side chain and (in some cases) part of the core region. For example, the different chemotypes of rough mutants from Salmonella are conventionally designated by the terms Ra, Rb, Rc, Rd, and Re.
As seen from
FIG. 2
, the LPS of each type comprises the lipid A structure. The Ra chemotype is characterized by a complete core region, the Rb chemotype is characterized by the absence of N-acetyl-D-glucosamine residues, the Rc chemotype is characterized by the absence of N-acetyl-D-glucosamine and galactose residues, the Rd chemotype is characterized by the absence of any residues constituting the outer core, and the Re chemotype is characterized by the sole KDO region attached to lipid A.
FIG. 3
is a diagrammatic representation of the five known complete core chemotypes of
E. coli
as well as the one known complete core chemotype of all Salmonella species.
Not all LPS molecules on the surface of a given cell or in a homogeneous population of cells have the same number of oligosaccharide side chains. For example, a single cell from a population of smooth strain bacteria may include some rough forms of LPS, i.e., LPS that is not substituted with any polysaccharide side chains.
Various treatments for the toxic effect of LPS have been proposed or tried. One of a mammal's defenses against endotoxemia is the presence of antibodies in the blood which can bind to and neutralize blood borne endotoxin, and immunologic methods have been proposed as an alternative or additional treatment to antibiotic therapy to prevent or control such infections or to reduce the toxic effect of endotoxin. For example, conventional polyclonal antisera and hyperimmune sera have been used in an attempt to bolster the native defenses of patients against the adverse effects of bacteria, presumably by enhancing opsonization and phagocytosis of the bacterial cells or by neutralization of the biological activity of LPS. However, the effectiveness of the antisera varies greatly depending upon a large number of factors including, for example, the composition and titer of the specific antibodies, which cannot be easily standardized. The use of these antisera may also carry a risk of transmission of viral infectious diseases.
Patients or potential donors of hyperimmune sera have been vaccinated (i.e. actively immunized) with various immunogens in an attempt to stimulate the host synthesis of cross-reactive anti-endotoxin antibodies. Various vaccine compositions and methods of immunization have been studied over the last two decades. See, e.g., Bhattacharjee A, WO 95/29662; McCabe W R, J Infec Dis 1988; 158:291; Greisman S E, Proc Soc Exp Bio Med 1978; 158:482; Goto

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