Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Utility Patent
1995-04-24
2001-01-02
Wortman, Donna C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S085100, C424S085200, C424S085400, C424S204100, C424S207100, C424S209100, C424S211100, C424S218100, C424S221100, C424S224100, C424S229100
Utility Patent
active
06168787
ABSTRACT:
BACKGROUND OF THE INVENTION
I. Field of the Invention
The field of the invention relates to compositions and methods for the induction of immune responses against enveloped virus in mammals. In particular embodiments, the invention relates to vaccines comprising major and minor histocompatibility complex antigens, blood group antigens and other cell surface antigens exhibiting significant genetic polymorphism in mammalian populations, which may be picked up by enveloped viruses as they bud from the cell membrane and may therefore serve as a target for an immune attack.
II. Description of the Related Art
A. Enveloped Viruses
Eukaryotic viruses are a large and diverse group of infectious agents primarily known for the diseases they cause. These agents can be classified by a number of criteria including genome structure, mode of replication and host specificity. Another manner of grouping eukaryotic viruses is by the structure of the viral particle. “Non-enveloped” viral particles are made up of a proteinaceous capsid that surrounds and protects the viral genome. The capsid is formed by viral structural products encoded by the virus genome and synthesized within the host cell. “Enveloped” viruses also have a capsid structure surrounding the genetic material of the virus but, in addition, have a lipid bilayer “envelope” that surrounds the capsid. The envelope is acquired as the capsid buds through one of the host cell membranes—usually the plasma membrane but sometimes from the nuclear membrane, the Golgi apparatus or endoplasmic reticulum.
Exemplary enveloped virus families include Togaviridae, Flaviviridae, Coronaviridae, Rhabdoviridae, Filoviridae, Parantyxoviridae, Orthontyxoviridae, Bunyaviridae, Arenaviridae, Retroviridae, Herpesviridae, Poxviridae and Iridoviridae. These viruses and others are responsible for such diseases as encephalitis, intestinal infections, immunosuppressive disease, respiratory disease, hepatitis and pox infections.
The make-up of an enveloped virus membrane varies depending on the location in the host cells from which the virus acquired its envelope. In general, the envelope comprises a bilayer of lipids completely surrounding the virus capsid or nucleoprotein. In addition to various lipids, the envelope contains integral and transmembrane proteins. Many transmembrane proteins have sugar residues attached and are referred to as glycoproteins. Virally-encoded transmembrane proteins play important roles in the infectious process by acting as targeting ligands, as enzymes and as membrane fusion activators. Because host cells also express many membrane-bound proteins, it is possible for enveloped virus particles to contain host cell proteins as well as those that are virally-encoded. In some instances, the virus may pick up genes of normal cellular components from the host cell which are useful to its propagation in other hosts.
Considerable efforts have been expended toward the development of suitable vaccines designed to protect against infection by disease-causing enveloped viruses. Though some vaccines have proved successful, many others have failed to live up to expectations. Vaccine failures often are attributed to one or more of the following:
1. Enveloped viruses have a notorious reputation for a phenomenon called “antigenic drift.” When antigenic drift occurs, viral antigens mutate and their antigenic profile is altered. If the drift is extensive enough, the immune response generated against the original antigenic profile is no longer able to recognize the mutated forms and, therefore, escape the protective immune mechanisms within the immunized host.
2. Another type of “variation” problem relates to viruses having multiple strains, such as rhinovirus, which may have more than 50 different antigenic strains. Therefore, it is impractical to develop vaccines against all of these viral strains. Yet another example of antigenic variation is exhibited by influenza viruses, which frequently have seasonal variations in the prevailing strains. Thus, it is necessary to redesign particular influenza vaccines on an annual basis, depending upon the prevalent strain of influenza virus that is infecting the population that particular year.
3. Unfortunately, cell mediated immunity or humoral antibody induced against virus-related envelope or nuclear protein antigens may be short-lived. As a result, most current vaccines are capable of inducing immunity only for a short time following immunization. Thus, to achieve ongoing protection, it often is necessary to immunize repeatedly, especially where the antigen is the inactivated virus or a subunit vaccine.
4. A problem with many viral vaccines is the cost-benefit analysis of choosing a “live” versus a “killed” vaccine. In general, immunization with live, attenuated viruses results in a much stronger immune response than with killed virus. In some instances, such as protection against smallpox maybe life long after immunization with live cowpox virus which induces cross reactive immunity to smallpox. While the mechanism behind this phenomena is not fully understood, it is likely that limited replication of attenuated viruses provides a more potent set of antigens with which to stimulate the immune system. Unfortunately, virus strains with sufficient attenuation levels are difficult to produce. In addition, one always runs a risk that the attenuated virus will revert to a pathogenic form following immunization, thereby causing full-blown infection and disease.
Because of many problems outlined above with respect to viral vaccines, effective vaccines have been developed against only a small minority of the many viruses that are capable of infecting the human population. Efforts have been directed primarily against viral vaccines causing potentially fatal illness, such as smallpox. Consequently, there are but a small number of effective vaccines developed against the large number of enveloped viruses which create diseases in humans and other mammals. Although there have been a few successes, such as vaccines against smallpox, measles, mumps, feline leukemia virus and canine distemper virus, humans and other mammal species remain largely unprotected against the vast majority of enveloped viruses.
B. HIV and MHC Antigens
Because of the devastating consequences of infection, and the rapidly growing number of infected individuals, there have been intense efforts directed at producing a vaccine against human immunodeficiency virus (HIV) infection. Because of the danger in using live retroviruses, these vaccines primarily have involved the use of viral subunits, such as the surface glycoprotein gp120/160, and antibodies thereto. For the most part, the results have been disappointing.
A variety of unique problems are presented when working with HIV vaccines. For example, the antigenic drift seen in HIV antigens virtually is unparalleled in other systems. In addition, the putative identification of the CD4 molecule as a receptor, while constituting a major step towards understanding the virus life cycle, has proved to be a problematic complication. Interactions between host molecules and CD4, as well as those between host molecules and gp120/160, appear to hinder the effects of anti-gp120/160-based vaccines.
Another disadvantages in using specific immunization against HIV is that one of the primary methods for detecting infection is by the presence of serological reactivity with HIV in the serum of the individuals, indicating that infection with HIV has occurred. Consequently, immunization with HIV or antigenic subunits thereof will induce similar antibodies, making it difficult to differentiate infection from protection.
One area of research that has developed in response to these and other problems involves the use of major histocompatibility (MHC) antigens. The general principle behind this work is that an infecting HIV particle, either as free enveloped virus or as virally-infected cells, will be associated with MHC antigens that are potentially distinct from those of the recipient. The literature as a whole is, at best
Brumback Brenda G.
Fulbright & Jaworski
John Wayne Cancer Institute
Wortman Donna C.
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