Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2000-05-15
2002-09-24
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C435S005000, C435S069100, C530S300000, C530S350000, C424S184100, C424S185100, C424S186100, C424S187100, C424S188100, C424S207100, C424S208100
Reexamination Certificate
active
06455265
ABSTRACT:
The present invention relates to a method for obtaining vaccines for preventing the pathogenic effects related, in humans and in vertebrate animals, to retroviral infections.
The pathogenic effects related to a retroviral infection are the harmful effects, including possible oncogenic or immunosuppressive effects, induced by the introduction of a retrovirus into the body of a host (mammal, bird or alternatively fish), followed by the penetration and by the replication of said retrovirus in the cells of the host which are target cells for the retrovirus, that is to say cells into which the virus is capable of penetrating.
Retroviruses are thus named because they have the capacity, by virtue of the enzyme called reverse transcriptase, of carrying out transcription of RNA to DNA, whereas in living beings, the genetic information usually goes from the DNA of the chromosomes to proteins, via messenger RNA.
Three subfamilies can be distinguished in the retroviral family: the oncoviruses, the lentiviruses and the spumaviruses.
The oncoviruses are retroviruses thus termed because they can be associated with cancers and malignant infections. There may be mentioned, for example, leukemogenic viruses (such as the avian leukemia virus (ALV), the murine leukemia virus (MULV), also called Moloney virus, the feline leukemia virus (FELV), human leukemia viruses such as HTLV1 and HTLV2, the simian leukemia virus or STLV, the bovine leukemia virus or BLV), the primate type D oncoviruses, the type B oncoviruses which are inducers of mammary tumors, or oncoviruses which cause a rapid cancer (such as the Rous sarcoma virus or RSV); see for example STEHELIN et al., J. Mol. Biol. 101: 349-365 (1976).
The lentiviruses are thus named because they are responsible for slow-progressing pathological conditions which very frequently involve immunosuppressive phenomena, including AIDS.
The appended Table 1 indicates, by way of illustration, the pathological conditions associated with some lentiviruses, as well as the main target cells for these lentiviruses.
The spumaviruses manifest fairly low specificity for a given cell type or a given species, and they are sometimes associated with immunosuppressive phenomena; that is the case, for example, for the simian foamy virus (or SFV).
One of the aims of the present invention is the development of methods and vaccine products intended for effectively preventing the pathogenic effects, including the oncogenic or immunosuppressive effects, related to the infection of a host organism by a retrovirus.
Immunosuppression related to infection has been observed for a large number of retroviruses, and may be considered as a pathogenic constant of retroviral infection; see in particular BENDINELLI et al., Advances in Cancer Research 45: 125-181 (1985). This is the case in particular for lentivirus infections. It is also the case in a good number of oncovirus infections; see for example P. SONIGO in the book “SIDA et infection par VIH” [AIDS and HIV Infection], MONTAGNIER et al. (Médecine Science Flammarion), pages 113-122 (1989).
Many human and animal vaccines have been tested for preventing the pathogenic effects of retrovirus infections but, as a general rule, these vaccines are not very effective or are ineffective. In particular, in the field of human or animal AIDS, it is observed that, 14 years after the discovery of the HIV virus (BARRE-SINOUSSI et al., Science 220: 868-871, 1983), it has not yet been possible to find a vaccine which is able to effectively stop a post-vaccine HIV or SIV infection; see for example LINHART et al., AIDS Research and Human Retroviruses 13: 593-599 (1997); VOGT et al., Vaccine 13: 202-208 (1995); and LETVIN et al., J. Virol. 69: 4569-4571 (1995).
The majority of the vaccine preparations used comprise proteins of the retroviral envelope in various forms, for example inactivated viruses, envelope proteins such as the gp 120 and gp 160 proteins of HIV (see in particular GORSE, G. J., Vaccine 10: 383-388, 1992), virus cores with envelope proteins, or envelope proteins associated with various vectors (chimeric viruses, bacteria); see Levy J. A., Trans. Med. Rev. 2: 265-271, 1988 and Microbiol. Rev. 57: 183-289, 1993, in particular page 247.
Other preparations use fragments of the retroviral envelope or immunodominant peptides derived from the envelope glycoproteins, these peptides being presented in various forms (lipopeptides, peptides bound to a supporting protein), so as to make them immunogenic; see in particular Eriksson et al., Vaccine, 11: 859-865 (1993).
The vaccine strategies conventionally described, for example in the field of human, simian or feline AIDS, recommend not modifying the conserved and immunodominant epitopes of the envelope proteins, which may appear to be completely logical. Indeed, on the one hand, these conserved epitopes are common to different viral strains, which is favorable to the production of a vaccine which has to induce an immune response directed against a majority of strains. On the other hand, these immunodominant epitopes are well recognized by the cellular or humoral immune system during the vaccinal and infectious process and, moreover, they frequently represent neutralization sites; see for example HO et al., J. Virol. 61: 2024-2028 (1987); JOHNSON et al., J. Exp. Med. 175: 961-971 (1992); SHAFFERMAN et al., P.N.A.S. U.S.A. 88: 7126-7130 (1991); and HAMMOND et al., J. Immunol. 146: 1470-1477 (1991).
The method of the invention consists, by contrast, in modifying the conserved and immunodominant epitopes of certain proteins of the viral envelope, in order to obtain an effective vaccine. Indeed, the authors of the present invention have discovered that conserved and immunodominant regions of the retroviral envelope may be responsible for harmful autoimmune phenomena. By way of example, in the case of human AIDS, they have observed that certain conserved and immunodominant regions of the HIV envelope exhibit three-dimensional structural analogies and/or cross-reactions with certain regions of at least one protein of the human immune system, such that the administration, as a vaccine, of a viral protein containing said intact regions induces an immune response which is responsible for harmful autoimmune reactions leading to vaccine failure.
At the origin of the present invention, there is, on the one hand, the observation mentioned above that conserved and immunodominant regions of certain retroviruses, usually present in vaccine preparations, are precisely, in a good number of cases, regions which cause harmful autoimmune reactions because they exhibit three-dimensional structural analogies and/or cross-reactions with certain proteins of the host for the virus. At the origin of the present invention, there is also, on the other hand, the observation that said proteins of the host use the same target cell, or the same target cells, as said retroviruses. All these observations carried out by the authors of the invention have led them to think that the retroviral envelope proteins and the host proteins which exhibit three-dimensional structural analogies and/or cross-reactions bind in many cases to the same target cells and possess, on these target cells, common membrane receptors.
It is said that a protein exhibits cross-reactivity with another protein when it is possible to obtain, by in vivo or in vitro immunization with the aid of one of said proteins, an immune response also directed against the other protein, for example when this immunization induces a (so-called B type) humoral response and makes it possible to obtain and to select at least one monoclonal antibody which is capable of recognizing the other protein, or when the same cellular immune response (that is to say of the T type) induced in vitro by one of the proteins recognizes the two proteins, according to the known tests for detecting a T-type immune response, such as for example the tests for cytotoxicity in vitro. It is known that the term “immunization” denotes the process of induction of an immune response following stimu
Brown Stacy S.
Mymetics S.A.
Park Hankyel T.
Teskin Robin L.
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