Chemistry: molecular biology and microbiology – Vector – per se
Reexamination Certificate
1999-06-04
2004-02-24
Scheiner, Laurie (Department: 1648)
Chemistry: molecular biology and microbiology
Vector, per se
C424S188100, C424S208100, C435S235100, C435S236000
Reexamination Certificate
active
06696289
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a vector system useful for developing live viral vaccines. More particularly, it relates to replication-competent recombinant Sabin type 1 strain of poliovirus, which can be used for the development of live viral vaccine capable of inducing mucosal immunity.
2. Description of the Prior Arts
Recently it has been reported that various infectious viral disease, which were well known to be spread by blood-mediated routes such as blood transfusions, homosexual intercourse, or sharing of, syringes, also may be transmitted by heterosexual intercourse. In the case of AIDS (Acquired Immunodeficiency Syndrome), the number of heterosexual transmission is far greater than that of the blood-mediated cases (Stingl et al., J. Am. Aca. Dermatol., 22, 1210, 1988). In Korea, 363 out of 527 HIV-1 positive patients are heterosexuals while 99 are infected via homosexual routes (National Institute of Health, Korea, Communicable Diseases Monthly Report, April of 1996). These reports strongly suggest that the HIV-1 can be transmitted through mucosal tissues around the genital organs without blood mediation.
Several papers have reported that HIV-1 transmission and spreading are likely to be initiated by the infection of Langerhans cells or dendritic cells (DCs) at the mucosal tissues. Infected cells return to lymph node to deliver antigen, well known as homing property, where the viral replication occurs, resulting in viremia and AIDS progression. In other words, those who have heterosexual intercourse with HIV-1 infected patients will have Langerhans cells or DCs infected with HIV-1 in mucosal area of the urogenital organs, and the infected DCs return to lymph nodes, activate CD4
+
T-cells in lymph nodes and propagate HIV, resulting in depletion of CD4
+
T-cells followed by AIDS progression (Tschachler et al., J. Inves., Dermator, 88, 238, 1987; Langhoff et al., Proc. Natl.Acad.Aci. USA, 88, 7998, 1991; Patterson & Knight, J. Gen. Virol., 68, 1177, 1987; Patterson et al., Immnol., 72, 361, 1991; Cameron et al., Science, 257, 383, 1992; Embreston et al., Nature, 362, 369, 1993; Fauci, Science, 262, 1011, 1993; Pantleo et al., Nature, 362, 355, 1993; Adema et al., Nature, 387, 713, 1997). These experimental results were substantiated by in vivo experiments by addressing that the Macaque monkeys treated with SIV (Simian immunodeficiency Virus) on their genital organs became infected and then showed AIDS symptom (Miller & Gardner, J. AIDS, 4, 1169, 1991; Miller et al., 3. Virol, 63, 4277, 1989). Moreover, since most of the infectious viral diseases are spread by first infection of mucosal tissues at respiratory, digestive or urogenital organs, mucosal vaccine development is highly recommended to prevent infectious viral. In particular, the common mucosal immune system—immunization at one locus can induce identical immunity to the other mucosal areas in the living body, special characteristics of mucosal immunity, encourages many researchers to develop mucosal vaccine (Kott, Science, 266, 1335, 1994; Cease & Verzofsky, Ann. Rev. Immunol., 12, 923, 1994).
Since long ago, smallpox virus has been proposed as a live viral vaccine vehicle. Recombinant vaccinia virus produced by introducing a vaccine gene into smallpox viral genome was reported to induce cytotoxic T lymphocyte in the immunized monkey. But has not yet been allowed to apply it to human because it may cause a vaccinia syndrome to the immunized individuals when overpropagated. To avoid the possibility, an attenuated vaccinia virus was suggested as a vaccine vehicle instead of virulent strain, but it failed to induce an effective immuniity (Cooney et al., Lancet, 337, 567, 1991; Tartaglia et al., Virol., 188, 217, 1992).
Adenovirus having a smaller genome (34 kbp) than that of vaccinia virus was also proposed as a vaccine vector (Natuk et al., Proc. Natl. Acad. Sci. USA, 89, 7777, 1992; Gallichar et al., J. Infec. Dis., 168, 622, 1993). But the recombinant adenoviruses still have a limitation of side effects, such as conjuctivitis or corneitis, which should be solved for adenovirus to be used as a mucosal vaccine vector.
Poliovirus contains a positive sense single-stranded RNA of 7.4 Kb nucleotides, which encodes an unique open-reading frame of a long polyprotein (Kitamura et al., Nature 291, 547, 1981). Recently, several groups are trying to develop a poliovirus as a vaccine vehicle for its well-known and attractive advantages—safe, easy to administration, economy, and above all having capacity to induce effective life-long mucosal immunity, which is strongly recommended for an ideal vaccine.
Followings are summary of the published vaccine researches in association with poliovirus developed as a vaccine vehicle:
(1) It was proposed to substitute some portion of VP1, major outer capsid protein of poliovirus with presumed vaccine epitopes of HIV such as gp41, PND (Principle Neutralizing Domain) or gp120. The chimeric virus produced from the genetic recombination effectively induced antibody depending on the characteristics of the epitopes (Burke et al., Nature, 332, 81, 1988; Burke et al., J.Gen.Virol. 70,2475, 1989; Evans et al., Nature, 385, 1989; Dedieu et al., J. Virol., 66, 3161, 1992; Rose et al., J. Gen. Virol., 75, 969, 1994). However, this chimeric virus has a size limitation for the Morrow and his introduced vaccine gene. Chimeric poliovirus could not be assembled properly in the infected cells when the inserted vaccine epitope is larger than 25 amino acid residues.
(2) Morrow and his colleagues (Porter et al., J. Virol., 69, 1548, 1993; Ansaradi et al., Cancer Res., 54, 6359, 1994, Porter et al., J. Virol. 70, 2643, 1996, Porter et al., Vaccine 15, 257, 1997) have suggested poliovirus minireplicon, in which poliovirus structural genes are replaced by foreign sequences, to develop poliovirus-mediated mucosal vaccines. In case of poliovirus minireplicon, the replication defective recombinant viral genome must be co-transfected with other capsid protein-expressing vector for packaging of chimeric viral genome (Porter et al., J. Virol., 69, 1548, 1995). Moreover, high titer of minireplicon is required for vaccination to induce effective mucosal immunity because it works as replication-defective target-specific immunogen rather than live viral vaccine.
(3) Recently, a new strategy was suggested for expression of foreign antigens in the replication-competent recombinant polioviruses by Mattion et al (J. Virol. 68, 3925, 1994) and Andino et al (Science, 265, 1448, 1994). They have introduced a new polylinker region and 3C protease-recognition site on the N-terminal end of the polyprotein of poliovirus. According to this system, foreign gene, cloned in-frame with the poliovirus open reading frame, is followed by an artificial 3C protease site, to allow proteolytic cleavage of the foreign protein from the poliovirus polyprotein. The exogenous nucleic acid is incorporated directly into the poliovirus genome. The exogenous sequences are expressed during virus replication as part of the virus polyprotein and subsequently processed by virus-encoded proteases to produce free antigen and mature viral protein. The foreign antigen is not packaged in the virion but released into the cytoplasm. The prinicle of this method is based on the characteristics of poliovirus-specific 3C-protease published previously. 3C-protease recognizes specific amino acid sequence and then cleaves it at the junction between Glu(Q)/Gly(G) (Hanecak et al., Proc. Natl. Acad. Sci. USA 79, 3793, 1982), and the proteolysis occurs within the intramolecule of long polyprotein (Palmenberg and Reuckert, J. Virol., 41, 244, 1982; Hanecak et al, Cell 37, 1063, 1984). These phenomena are generally observed in picornavirus family (Palmenberg et al., J. Virol. 32, 770, 1979; Palmenberg and Reuckert, J. Virol., 41, 244, 1982). The alanine(A) residue in the P4 position of the Q/G cleavage site (AXXQG; SEQ ID NO: 21) has been confirmed several times to be essential for effective recognition and cle
Bae Yong Soo
Jung Hye Rhan
CreaGene Inc.
Mathews, Collins Shepherd & McKay, P.A.
Parkin Jeffrey S.
Scheiner Laurie
LandOfFree
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