Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant virus encoding one or more heterologous proteins...
Reexamination Certificate
1999-12-09
2003-12-16
Housel, James (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant virus encoding one or more heterologous proteins...
C424S185100, C435S320100, C530S300000
Reexamination Certificate
active
06663871
ABSTRACT:
BACKGROUND OF INVENTION
A general problem in vaccinology has been an inability to generate high levels of CD8 T cells by immunization. This has impeded the development of vaccines against several diseases including malaria.
Plasmodium falciparum
malaria causes hundreds of millions of malaria infections each year and is responsible for 1-2 million deaths annually. The development of an effective vaccine against malaria is thus a major priority for global public health. A considerable body of immunological research over the last twenty years had led to the identification both of candidate vaccine antigens from the parasite and immunological mechanisms on the host that are likely to protect against infection and disease. However, despite this progress there is still no means of vaccinating against malaria infection which has been shown to be effective in field trials.
A major problem has been the identification of a means of inducing a sufficiently strong immune response in vaccinated individuals to protect against infection and disease. So, although many malaria antigens are known that might be useful in vaccinating against malaria the problem has been how to deliver such antigens or fragments of them known as epitopes, which are recognized by cells of the immune system, in a way that induces a sufficiently strong immune response of a particular type.
It has been known for many years that it is possible to protect individuals by immunizing them with very large doses of irradiated malaria sporozoite given by bites from infected mosquitoes. Although this is a wholly impractical method of mass vaccination it has provided a model for analyzing the immune responses that might be mediating protective immunity against sporozoite infection (Nardin and Nussenzweig 1993).
A considerable amount of research over the last decade or more has indicated that a major protective immune response against the early pre-erythrocytic stage of
P. falciparum
malaria is mediated by T lymphocytes of the CD8+ ve type (CD8+ T cells). Such cells have been shown to mediate protection directly in mouse models of malaria infection (Nardin and Nussenzweig 1993). Such T cells have also been identified in individuals naturally exposed to malaria and in volunteers immunized with irradiated sporozoite (Hill et al. 1991; Aidoo et al. 1995; Wizel et al. 1995). There is much indirect evidence that such CD8+ T cells are protective against malaria infection and disease in humans (Lalvani et al. 1994).
CD8+ T cells may function in more than one way. The best known function is the killing or lysis of target cells bearing peptide antigen in the context of an MHC class I molecule. Hence these cells are often termed cytotoxic T lymphocytes (CTL). However, another function, perhaps of greater protective relevance in malaria infections is the ability of CD8+ T cells to secrete interferon gamma (IFN-&ggr;). Thus assays of lytic activity and of IFN-&ggr; release are both of value in measuring a CD8+ T cell immune response. In malaria these CD8+ ve cells can protect by killing the parasite at the early intrahepatic stage of malaria infection before any symptoms of disease are produced (Seguin et al. 1994).
The agent of fatal human malaria,
P. falciparum
infects a restricted number of host species: humans, chimpanzees and some species of New World monkey. The best non-human model of malaria is the chimpanzee because this species is closely related to humans and liver-stage infection is observed consistently unlike in the monkey hosts (Thomas et al. 1994). Because of the expense and limited availability of chimpanzees most laboratory studies of malaria are performed in mice, using the rodent malaria species
P. berghei
or
P. yoelii
. These latter two models are well studied and it has been shown in both that CD8+ ve lymphocytes play a key role in protective immunity against sporozoite challenge.
Previous studies have assessed a large variety of means of inducing CD8+ T cell responses against malaria. Several of these have shown some level of CD8+ T cell response and partial protection against malaria infection in the rodent models (e.g. Li et al. 1993; Sedegah et al. 1994; Lanar et al. 1996). However, an effective means of immunizing with subunit vaccines by the induction of sufficiently high levels of CD8+ T lymphocytes to protect effectively against malaria sporozoite infection has not previously been demonstrated.
In recent years improved immune responses generated to potential vaccines have been sought by varying the vectors used to deliver the antigen. There is evidence that in some instances antibody responses are improved by using two different vectors administered sequentially as prime and boost. A variety of combinations of prime and boost have been tested in different potential vaccine regimes.
Leong et al. (Vaccines 1995, 327-331) describe immunizing mice firstly to DNA expressing the influenza haemagglutinin (HA) antigen and then with a recombinant fowlpox vector expressing HA. An enhanced antibody response was obtained following boosting.
Richmond et al. (Virology 1997, 230: 265-274) describe attempts to raise neutralizing antibodies against HIV-1 env using DNA priming and recombinant vaccinia virus boosting. Only low levels of antibody responses were observed with this prime boost regime and the results were considered disappointing.
Fuller et al. (Vaccine 1997, 15:924-926 and Immunol Cell Biol 1997, 75:389-396) describe an enhancement of antibody responses to DNA immunization of macaques by using a booster immunization with replicating recombinant vaccinia viruses. However, this did not translate into enhanced protective efficacy as a greater reduction in viral burden and attenuation of CD4 T cell loss was seen in the DNA primed and boosted animals.
Hodge et al. (Vaccine 1997, 15: 759-768) describe the induction of lymphoproliferative T cell responses in a mouse model for cancer using human carcinoembryonic antigen (CEA) expressed in a recombinant fowl pox virus (ALVAC). The authors primed an immune response with CEA-recombinant replication competent vaccinia viruses of the Wyeth or WR strain and boosted the response with CEA-recombinant ALVAC. This led to an increase in T cell proliferation but did not result in enhanced protective efficacy if compared to three wild type recombinant immunizations (100% protection), three recombinant ALVAC-CEA immunizations (70% protection) or WR prime followed by two ALVAC-CEA immunizations (63% protection).
Thus some studies of heterologous prime-boost combination have found some enhancement of antibody and lymphoproliferative responses but no significant effect on protective efficacy in an animal model. CD8 T cells were not measured in these studies. The limited enhancement of antibody response probably simply reflects the fact that antibodies to the priming immunogen will often reduce the immunogenicity of a second immunization with the same immunogen, while boosting with a different carrier will in part overcome this problem. This mechanism would not be expected to be significantly affected by the order of immunization.
Evidence that a heterologous prime boost immunization regime might affect CD8 T cell responses was provided by Li et al. (1993). They described partial protective efficacy induced in mice against malaria sporozoite challenge by administering two live viral vectors, a recombinant replicating influenza virus followed by a recombinant replicating vaccinia virus encoding a malaria epitope. Reversing the order of immunization led to loss of all protective efficacy and the authors suggested that this might be related to infection of liver cells by vaccinia, resulting in localization of CTLs in the liver to protect against the hepatocytic stages of malaria parasites.
Rodrigues et al. (J. Immunol. 1994, 4636-4648) describe immunizing mice with repeated doses of a recombinant influenza virus expressing an immunodominant B cell epitope of the malarial circumsporozoite (CS) protein followed by a recombinant vacci
Blanchard Tom
Gilbert Sarah C.
Hanke Tomas
Hill Adrian V. S.
McMichael Andrew
Foley Shanon
Hamilton Brook Smith & Reynolds P.C.
Housel James
Oxxon Pharmaccines Ltd.
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