Multicomponent vaccines

Details Multicomponent vaccines Multicomponent vaccines

1999-08-31

2004-03-09

Graser, Jennifer E. (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Bacterium or component thereof or substance produced by said...

C424S184100, C424S190100, C424S193100, C424S203100, C424S234100, C424S244100, C530S350000

Reexamination Certificate

active

06703025

ABSTRACT:

The invention is in the field of biological products for the treatment and diagnosis of bacterial infections.
BACKGROUND OF THE INVENTION
Staphylococci are Gram-positive spherical cells, usually arranged in grape-like irregular clusters. Some are members of the normal flora of the skin and mucous membranes of humans, others cause suppuration, abscess formation, a variety of pyogenic infections, and even fatal septicemia. Pathogenic staphylococci often hemolyze blood, coagulate plasma, and produce a variety of extracellular enzymes and toxins. The most common type of food poisoning is caused by a heat-stable staphylococci enterotoxin.
The genus Staphylococcus has at least 30 species. The three main species of clinical importance are
Staphylococcus aureus, Staphylococcus epidermidis,
and
Staphylococcus saprophyticus. Staphylococcus aureus
is coagulase-positive, which differentiates it from the other species.
S. aureus
is a major pathogen for humans. Almost every person has some type of
S. aureus
infection during a lifetime, ranging in severity from food poisoning or minor skin infections to severe life-threatening infections. The coagulase-negative staphylococci are normal human flora which sometimes cause infection, often associated with implanted devices, especially in very young, old and immunocompromised patients. Approximately 75% of the infections caused by coagulase-negative staphylococci are due to
S. epidermidis.
Infections due to
Staphylococcus warneri, Staphylococcus hominis,
and other species are less common.
S. saprophyticus
is a relatively common cause of urinary tract infections in young women. The staphylococci produce catalase, which differentiates them from the streptococci.
S. aureus
colonization of the articular cartilage, of which collagen is a major component, within the joint space appears to be an important factor contributing to the development of septic arthritis. Hematogenously acquired bacterial arthritis remains a serious medical problem. This rapidly progressive and highly destructive joint disease is difficult to eradicate. Typically, less than 50% of the infected patients fail to recover without serious joint damage.
S. aureus
is the predominant pathogen isolated from adult patients with hematogenous and secondary osteomyelitis.
In hospitalized patients, Staphylococcus bacteria such as
S. aureus
are a major cause of infection. Initial localized infections of wounds or indwelling medical devices can lead to more serious invasive infections such as septicemia, osteomyelitis, mastitis and endocarditis. In infections associated with medical devices, plastic and metal surfaces become coated with host plasma and matrix proteins such as fibrinogen and fibronectin shortly after implantation. The ability of
S. aureus
and other staphylococcal bacteria to adhere to these proteins is essential to the initiation of infection. Vascular grafts, intravenous catheters, artificial heart valves, and cardiac assist devices are thrombogenic and prone to bacterial colonization. Of the staphylococcal bacteria,
S. aureus
is generally the most damaging pathogen of such infections.
A significant increase in
S. aureus
isolates that exhibit resistance to most of the antibiotics currently available to treat infections has been observed in hospitals throughout the world. The development of penicillin to combat
S. aureus
was a major advance in infection control and treatment. Unfortunately, penicillin-resistant organisms quickly emerged and the need for new antibiotics was paramount. With the introduction of every new antibiotic,
S. aureus
has been able to counter with &bgr;-lactamases, altered penicillin-binding proteins, and mutated cell membrane proteins allowing the bacterium to persist. Consequently, methicillin-resistant
S. aureus
(MRSA) and multidrug resistant organisms have emerged and established major footholds in hospitals and nursing homes around the world. (Chambers, H. F.,
Clin Microbiol Rev,
1:173, 1988; and Mulligan, M. E., et al.,
Am J Med,
94:313, 1993) Today, almost half of the staphylococcal strains causing nosocomial infections are resistant to all antibiotics except vancomycin, and it appears to be only a matter of time before vancomycin will become ineffective as well.
There is a strong and rapidly growing need for therapeutics to treat infections from staphylococci such as
S. aureus
which are effective against antibiotic resistant strains of the bacteria. The U.S. National Institutes for Health has recently indicated that this goal is now a national priority.
MSCRAMMs
Bacterial adherence to host tissue occurs when specific microbial surface adhesins termed MSCRAMMs (Microbial Surface Components Recognizing Adhesive Matrix Molecules) specifically recognize and bind to extracellular matrix (ECM) components, such as fibronectin, fibrinogen, collagen, and elastin. Many pathogenic bacteria have been shown to specifically recognize and bind to various components of the ECM in an interaction which appears to represent a host tissue colonization mechanism. This adherence involves a group of bacterial proteins termed MSCRAMMs (Patti, J., et al.,
Ann Rev Microbiol,
48:585-617, 1994; Patti, J. and Hook, M.,
Cur Opin Cell Biol.,
6:752-758, 1994).
MSCRAMMs on the bacterial cell surface and ligands within the host tissue interact in a lock and key fashion resulting in the adherence of bacteria to the host. Adhesion is often required for bacterial survival and helps bacteria evade host defense mechanisms and antibiotic challenges. Once the bacteria have successfully adhered and colonized host tissues, their physiology is dramatically altered and damaging components such as toxins and enzymes are secreted. Moreover, the adherent bacteria often produce a biofilm and quickly become resistant to the killing effect of most antibiotics.
A bacterium can express MSCRAMMs that recognize a variety of matrix proteins. Ligand-binding sites in MSCRAMMs appear to be defined by relatively short contiguous stretches of amino acid sequences (motifs). Because a similar motif can be found in several different species of bacteria, it appears as though these functional motifs are subjected to interspecies transfer (Patti and Hook,
Curr Opin Cell Biol,
6:752-758, 1994). In addition, a single MSCRAMM can sometimes bind several ECM ligands.
Vaccination Studies
Historically, studies on bacterial adherence have focused primarily on Gram-negative bacteria, which express a wide variety of fimbrial adhesive proteins (designated adhesins) on their cell surface (Falkow, S.,
Cell,
65:1099-1102, 1991). These adhesins recognize specific glycoconjugates exposed on the surface of host cells (particularly epithelial layers). Employing the lectin-like structures in attachment allows the microorganism to efficiently colonize the epithelial surfaces. This provides the bacteria an excellent location for replication and also the opportunity to disseminate to neighboring host tissues. It has been demonstrated that immunization with pilus adhesins can elicit protection against microbial challenge, such as in
Hemophilus influenza
induced otitis media in a chinchilla model (Sirakova et al.,
Infect Immun,
62(5):2002-2020, 1994),
Moraxella bovis
in experimentally induced infectious bovine keratoconjunctivitis (Lepper et al.,
Vet Microbiol,
45(2-3):129-138, 1995), and
E. coli
induced diarrhea in rabbits (McQueen et al.,
Vaccine,
11:201-206, 1993). In most cases, immunization with adhesins leads to the production of immune antibodies that prevent infection by inhibiting bacterial attachment and colonization, as well as enhancing bacterial opsonophagocytosis and antibody-dependent complement-mediated killing.
The use of molecules that mediate the adhesion of pathogenic microbes to host tissue components as vaccine components is emerging as an important step in the development of future vaccines. Because bacterial adherence is the critical first step in the development of most infections, it is an attractive target for the development of novel vaccines. An increa

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