Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1997-12-11
2001-07-24
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S234100, C424S093100, C424S093400, C424S823000, C424S824000, C435S243000, C435S822000
Reexamination Certificate
active
06264952
ABSTRACT:
This invention pertains to a method for protecting a mammalian host against infection by Brucella.
A host generally receives the greatest degree of immunity from actual infection by a pathogenic agent. The resulting immunity is specific, long-lasting, and complete—but of course is useful only if the host survives the disease produced by the pathogen. The goal of all vaccinations is to induce the same degree of solid immunity, but without any associated risk of disease; in reality few vaccines meet this ideal standard. Vaccines are often based either on live attenuated pathogenic agents, or on killed agents. The degree of protection provided by both types of vaccines is highly variable.
A facultative intracellular pathogen is a pathogen that is adapted to survive in a host by living within the host's cells, but that can also survive outside host cells at least for a time, depending on the environment it faces. As a general observation, immunity to facultative intracellular pathogens in a vaccinated host is better achieved with a vaccine made from living attenuated agents than with a vaccine made from killed agents. Immunity results from the survival of the living agents within the targeted host tissues for time sufficient to stimulate an appropriate host immune response. See Davis et al.,
Microbiology
, p. 472 (1967); and P. Nicoletti, “Vaccination,” Chapter 11 in K. Nielsen et al.,
Animal Brucellosis
, pp. 283-299 (1990). An appropriate immune response to intracellular pathogens generally depends on the activity of T-lymphocytes. Vaccines made from killed agents frequently produce only humoral immune responses (i.e., antibodies), which are generally less effective in protecting the host against subsequent infection by the virulent intracellular pathogen.
The main risk associated with attenuated live vaccines is that an attenuated vaccine strain can occasionally infect the host and produce disease. Vaccine-induced infection and disease can result from at least three different causes: (1) The vaccine agent may be insufficiently attenuated. (2) The host immune system may be so compromised that it cannot eliminate the attenuated agent. (3) The attenuated agent may spontaneously revert back to a virulent phenotype. For example, it was recently discovered that the genome of the attenuated polio-1 virus used in the Sabin polio vaccine is identical to the wild-type virulent strain in all but two base pairs; thus reversion of this attenuated virus to the wild-type will occur at a statistically predictable frequency.
Even though the medical community recognizes the value of the immunity produced by a variety of living attenuated vaccines, the risk of infection in the vaccinated host has limited their use.
Different intracellular pathogens may gain entrance into host cells by different mechanisms; they may prefer different host cell types; and they may prefer to localize in different cellular compartments. Advantages of an intracellular habitat (for the pathogen) include a degree of protection from the antimicrobial systems of the host, including protection from the host's antibodies, complement, phagocytic white blood cells, and cytotoxic non-phagocytic white blood cells. This shielding from components of the host immune system interferes with the host's ability to mount a specific protective immune response against the agent.
Disadvantages of an intracellular habitat (for the pathogen) include exposure to a wide variety of potential stresses created by the cell, such as altered pH, suboptimal nutrient levels, above-optimal temperatures, membrane damaging enzymes and peptides, and reactive free radicals that can attack both membranes and DNA.
The balance between the advantages of intracellular life and its disadvantages determines not only how long an intracellular pathogen will survive, but also its ability to synthesize virulence factors (factors giving the agent an additional advantage and causing disease in the host), as well as the severity of the resulting disease.
Despite the lack of a general understanding of how a host develops immunity to intracellular pathogens, several typical characteristics of efficacious vaccines to these agents have been identified. The most effective immunity to such agents usually results from infection of the host by the virulent agent itself, resulting in clinical or nonclinical infection, and full stimulation of an appropriate immune response. The most effective immunity to such agents is usually cell-mediated, rather than humoral. Selected subclasses of T-lymphocytes that recognize unique antigenic determinants in the agent, or that recognize determinants associated with the agent, are clonally expanded. Such lymphocytes are then able to activate phagocytic white blood cells to kill the intracellular agents. In some instances the lymphocytes themselves recognize unique antigens associated either with the agent or with a host cell infected with the agent, and synthesize and secrete antimicrobial compounds such as perforins.
Antibodies do not appear to play a large role in protecting the host from intracellular pathogens, or in clearing infections caused by intracellular pathogens. In fact, the antigenic structures recognized by antibody-secreting lymphocytes may have little in common with the antigenic structures responsible for effective cell-mediated immune protection.
Intracellular agents that have been grown on artificial growth media (where possible), collected, washed, and killed (e.g., by heat or chemical denaturation), and then administered to a susceptible host, rarely provide immune protection against the virulent living agent when the host is naturally or experimentally challenged. Agents prepared in this manner do result in the production of specific antibodies by the “vaccinated” host; however, these antibodies do not necessarily confer protection from infection, because the pathogens inhabit intracellular sites not typically reached by antibodies.
It has been previously demonstrated that exposure of a susceptible host to a living, less virulent form of the agent can result in long-lived immunity. The resulting immunity tends to be cell-mediated, as is the immunity resulting from natural infection. The attenuated (nonvirulent) agent must generally spend some time within the host before immunity develops, colonizing the same cells and tissues of the host as does the virulent agent. By contrast, immunity will generally be incomplete or absent if the chosen attenuated agent fails to survive within host tissues for a long enough period of time for a complete immune response to develop, or if the attenuated agent parasitizes a different cell type than does the virulent agent.
M. de Bagues et al., “Vaccination with Live
Brucella abortus
RB51 Provides Protection in Mice against Virulent
B. abortus, B. melitensis
, and
B. ovis
,” Abstracts of Papers Presented at the 73 rd Annual Meeting of the Conference of Research Workers in Animal Diseases, p. 17 (Nov. 9-10, 1992) (which is not prior art to the present application), discloses certain Brucella vaccinations, including Brucella vaccinations with gamma-irradiated cells.
U.S. Pat. No. 3,449,209 discloses an attenuated live Brucella vaccine. U.S. Pat. No. 4,764,370 discloses an attenuated live Salmonella vaccine.
U.S. Pat. Nos. 3,515,708 and 4,340,588 disclose killed Brucella vaccines. U.S. Pat. No. 4,687,666 discloses a killed Leishmania vaccine.
U.S. Pat. No. 4,959,211 discloses viral vaccines prepared by irradiating the virus.
U.S. Pat. No. 4,963,354 discloses a vaccine against a fibrosarcoma in which the fibrosarcoma cells used in the vaccine were gamma-irradiated at a radiation level that ultimately killed the cells, but that left the cells metabolically viable for a time prior to the cells' death.
U.S. Pat. No. 5,190,860 discloses mice immunized with an irradiated
B. abortus
strain for the purpose of raising monoclonal anti-Brucella antibodies. J. G. Howard et al., “Prophylactic Immunization against Experimental Leishmaniasis,” J. Immunology, vol. 129, pp. 2206-2
Enright Frederick M.
Schurig Gerhardt G.
Winter Alexander J.
Wyckoff, III John H.
Board of Supervisors of Louisiana State University and Agricultu
Lee Li
Runnels John H.
Smith Lynette R. F.
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