Methods and reagents for vaccination which generate a CD8 T cell immune response

Abstract

New methods and reagents for vaccination are described which generate a CD8 T cell immune response against malarial and other antigens such as viral and tumour antigens. Novel vaccination regimes are described which employ a priming composition and a boosting composition, the boosting composition comprising a non-replicating or replication-impaired pox virus vector carrying at least one CD8 T cell epitope which is also present in the priming composition.

Description

[0001] This application is a divisional of Ser. No. 09 / 454,204, filed on Dec. 9, 1999, which is a continuation of, and claims priority to International Application No. PCT / GB98 / 01681, filed 9 Jun. 1998 which designates the United States, and which is a continuing application of GB9711957.2 filed 9 Jun. 1997. The entire teachings of U.S. application Ser. No. 09 / 454,204, PCT / GB98 / 01681 and GB9711957.2 are incorporated herein by reference.BACKGROUND OF INVENTION[0002] 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.[0003] 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...

AI Technical Summary

Benefits of technology

[0023] It has now been discovered that non-replicating and replication-impaired strains of poxvirus provide vectors which give an extremely good boosting effect to a primed CTL response. Remarkably, this effect is significantly stronger than a boosting effect by wild type poxviruses. The effect is observed with malarial and other antigens such as viral and tumor antigens, and is protective as shown in mice and non-human primate challenge experiments. Complete rather than partial protection from sporozoite challenge has been observed with the novel immunization regime.

Problems solved by technology

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.

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.

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.

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.

Only low levels of antibody responses were observed with this prime boost regime and the results were considered disappointing.

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.

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.

However, there are two limitations to these findings in terms of their potential usefulness.

Firstly, the immunogenicity induced was only sufficient to achieve partial protection against malaria and even this was dependent on a highly immunogenic priming immunization with an unusual replicating recombinant influenza virus.

Secondly, because of the potential and documented side-effects of using these replicating viruses as immunogens these recombinant vectors are not suitable for general human use as vaccines.

The late block in viral replication does not prevent efficient expression of recombinant genes in MVA.

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