Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1995-06-07
2001-10-16
Minnifield, Nita (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C435S173100, C435S173400, C435S173700, C435S243000
Reexamination Certificate
active
06303129
ABSTRACT:
This invention relates to a process for producing a vaccine from viruses or cells, the vaccine so produced, and the method of use of the vaccine. More particularly, this invention relates to a vaccine against
Borrelia burgdorferi,
the causative agent of Lyme disease in humans.
More particularly, this invention relates to a method wherein viruses or cells, and in particular, the spirochete
Borrelia burgdorferi
in substantially viable form, are disrupted using ultrasound. The resulting preparation can be used as a vaccine (for prevention and/or therapy) for the disease caused by the specific microorganism.
BACKGROUND OF THE INVENTION
Research has been focused for many years on the use of immunotherapy to prevent disease.
The major health problems still to be encountered in non-industrialized environments are those arising from infectious disease. Currently, all types of causative agents, including virus, bacteria and parasites are active sources of infection. The genetic variability of both viruses and parasites and the development of drug resistance in bacteria and parasites has underscored the need for broadly based vaccine development.
Success has been achieved for diseases such as smallpox, measles, tetanus and poliomyelitis but not for Herpes, Hepatitis, AIDS and a number of other major health problems. Approaches that have been successful (e.g., smallpox, polio) have employed attenuated strains of intact organisms that function both as immunogen and adjuvant. Recent strategies focused on defined peptide sequences alone have usually failed to elicit protective responses in vivo suggesting that the presentation of a combination of key antigens to the immune system of the host is the critical element in the overall process. Additional difficulties that have been experienced in the prior art include isolating antigens without modifying them in such a way that they lose the capability to raise protective antibodies or to sensitize cells of the immune system.
The prior art has generally taken two routes to elevate the immune response. One route has been to use immuno-adjuvants which, in a non-specific manner, increase the immune responsiveness of the host, while the second route has been the eliciting of an antibody response using only the antigens.
Attempts to produce a protective immune response by the use of potential antigens isolated from viruses or cells have generally been unsuccessful. One problem is that the products solubilized from the viruses or cells often were found not to be immunogenic. Various theories have been proposed for the failure of the putative antigenic materials to produce a response. One possibility is that the physical or chemical methods employed to release or purify the antigens may be inadequate or resulted in denaturing the antigens. Another possibility is that the problem of producing a suitable solubilized or synthetic vaccine was that antigens either failed to reach the lymphocytes or did so insufficiently to activate them.
The present invention also relates to the production of a vaccine for use against Lyme Disease and the vaccine so produced.
Pathogenic bacteria continue to be a major source of disease in humans and animals. Improvements in minimizing bacterial contamination have made substantial inroads in eradicating or containing the spread of bacterial disease. Many bacterial infections can be effectively treated in the acute phase of infection with antibiotics. There are, however, a large number of diseases that escape early detection and don't respond to antibiotic treatment. Added to this is the possibility of mis-diagnosis, inavailability of medical care, development of antibiotic resistant organisms or asymptmatic primary infection. Many bacterial and parasitic diseases are endemic to certain regions of the world; in particular, the tropics and sub-tropics. The problem is exacerbated in those areas suffering from inadequate water and sewage treatment.
An effective and convenient model for pathogenic bacteria is Lyme Disease caused by the spirochete
Borrelia burgdorferi. Borrelia burgdorferi
is closely related to several other tickborne borne Borrelia which are causative agents for the very serious and debilitating disease, such as Relapsing Fever. Relapsing Fever, although rare in the United States, is endemic in Central America and Africa. Lyme Disease is quite common in the United States; in fact, it is the fastest growing vector-borne disease.
Infection of humans with the spirochete
Borrelia burgdorferi
generally results in the clinical disease more commonly known as Lyme Disease so named after the city in Connecticut where the geographic clustering of juvenile rheumatoid arthritis was first noted. The disease is transmitted by ticks and other major animal hosts are rodents, especially mice, and deer.
Infection by
Borrelia burgdorferi
provides a clinical model for the study of the molecular mechanisms underlying other potentially debilitating human disease.
Borrelia burgdorferi
closely resembles other Borrelia species which are human pathogens, such as
Borrelia hermsi,
and may be used as a model for creating vaccines against general
Borrelia spirochetes.
Moreover,
Borrelia burgdorferia
has been established in rodents isolated from infected ticks and humans, thus establishing an accurate laboratory model of Lyme Disease to be translated to the human system.
Borrelia burgdorferi
is a gram-negative spirochete possessing a linear chromosome about 1,000 kb in size and also several extrachromosomal plasmids of varying size (approximately 8-60 kb).
Borrelia burgdorferi
possesses many kinds of proteins.
The clinical manifestation of the disease follows a multiphasic time course with different symptoms being demonstrated at each disease stage. Infection is initiated by passage through infected ticks. About 70% of human patients demonstrate a characteristic skin rash termed erythema chronica migrans (ECM) whose appearance is sometimes accompanied by fever or regional lymphadenopathy (The approximately 30% of infected patients who do not develop ECM proceed to late Stage 1 disease). Spirochetes, monocytes and neutrophils are present in the ECM lesion. Patient peripheral blood lymphocytes (PBL) are unresponsive to the organism in vitro and there is no circulating antispirochetal antibodies at this stage. Stage 2 infection is characterized by dissemination of the spirochete to many sites in the body including: lymph, heart, neurologic, eyes, liver, respiratory, kidney and musculoskeletal systems. Headache of excruciating intensity is common although cerebrospinal fluid is normal. Patients are often incapacitated for several days with flu-like symptoms. At this stage, the PBL are responsible in vitro to
Borrelia burgdorferi
and serum antibodies are detectable beginning with an IgM response directed against the outer surface components of the spirochete. The temporal development of antibodies to specific antigens of
Borrelia burgdorferi
has been described in detail. With one notable exception, however, identification of protein antigens that are targets for the T cell immune response at any stage of the disease has not been completed.
The immune response in the early stage disease is characterized by infiltration of the ECM lesion by macrophage and neutrophils (PMN). PBL derived T cells are unresponsive to spirochetal antigens and serum does not contain circulating antibodies. Activity of Natural Killer (NK) cells in both the early and late stage Lyme Disease patients is inhibted but NK function is normal in patients that are in remission. Analysis in vitro has shown that NK cells are actually inhibited by spirochetes. There is a characteristic B-cell hyperactivity displayed by patients in various stages of Lyme Disease.
Late stage Lyme Disease is characterized by both circulating anti-spirochetal immunoglobulins and PBL T cell responsiveness to spirochetal antigens. The spirochetal antigens detected by the humoral immune response have been determined and most are cell surface antigens. With few exceptions, the e
Alliger Howard M.
Frey Alan
Coleman Henry D.
Minnifield Nita
Rx Technologies
Sapone William J.
Sudol R. Neil
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