Enhancing the efficacy of viral vector blood-stage malaria vaccines
<p>Replication-deficient adenovirus (Ad) and modified vaccinia virus Ankara (MVA) vectors expressing single Plasmodium falciparum antigens can induce potent T cell and antibody responses and have entered clinical testing using a heterologous prime-boost immunisation approach (Ad_MVA). This the...
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| Format: | Thesis |
| Language: | English |
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2011
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| _version_ | 1797086618999324672 |
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| author | Forbes, E |
| author2 | Hill, A |
| author_facet | Hill, A Forbes, E |
| author_sort | Forbes, E |
| collection | OXFORD |
| description | <p>Replication-deficient adenovirus (Ad) and modified vaccinia virus Ankara (MVA) vectors expressing single Plasmodium falciparum antigens can induce potent T cell and antibody responses and have entered clinical testing using a heterologous prime-boost immunisation approach (Ad_MVA). This thesis describes a number of pre-clinical approaches aimed at enhancing the efficacy of these viral vectored vaccines targeting the blood-stage of malaria. First, the development of a highly efficacious malaria vaccine is likely to require a multi-antigen and/or multi-stage subunit vaccine. The utility of an Ad_MVA immunisation regime combining vaccines expressing the 42kDa C-terminus of the blood- stage antigen merozoite surface protein 1 (MSP142) and the pre-erythrocytic antigen circumsporozoite protein (CSP) in the P. yoelii mouse model was investigated. It was found that vaccine co- administration leads to maintained antibody responses and efficacy against blood-stage infection, but reduced secondary CD8+ T cell responses and efficacy against liver-stage infection. CD8+ T cell interference can be minimised by co-administering the MVA vaccines at separate sites, resulting in enhanced liver-stage efficacy. The mechanisms of CD8+ T cell interference were explored. Second, Ad_MVA regimes expressing blood-stage antigens that can protect against P. chabaudi and P. yoelii blood-stage infection were tested against P. berghei, but did not confer protection. Similarly, IgG from rabbits immunised against P. falciparum MSP1 (PfMSP1) could not protect mice from a chimeric P. berghei parasite expressing PfMSP1. Third, two molecular adjuvants, the C4bp α-chain oligomerisation domain (IMX108/313) and the Fc fragment of murine IgG2a, were tested for their ability to enhance immunogenicity of recombinant adenoviruses when fused at the C-terminus of a blood-stage antigen. IMX108/313 was found to adjuvant T cell responses of small (< 80kDa) antigens and this was associated with antigen oligomerisation. However, the Fc fragment did not adjuvant responses. Finally, it was found that using a strong early promoter to drive antigen expression enhances the immunogenicity of single administration MVA vaccines, but that this did not enhance post-boost immunogenicity in an Ad_MVA regime.</p> |
| first_indexed | 2024-03-07T02:24:28Z |
| format | Thesis |
| id | oxford-uuid:a51e20cd-dfdb-45fe-9fe0-7231c77afe1f |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:24:28Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:a51e20cd-dfdb-45fe-9fe0-7231c77afe1f2022-03-27T02:38:17ZEnhancing the efficacy of viral vector blood-stage malaria vaccinesThesishttp://purl.org/coar/resource_type/c_db06uuid:a51e20cd-dfdb-45fe-9fe0-7231c77afe1fClinical laboratory sciencesMalariaImmunologyVaccinologyParasitologyInfectious diseasesEnglishOxford University Research Archive - Valet2011Forbes, EHill, ADraper, S<p>Replication-deficient adenovirus (Ad) and modified vaccinia virus Ankara (MVA) vectors expressing single Plasmodium falciparum antigens can induce potent T cell and antibody responses and have entered clinical testing using a heterologous prime-boost immunisation approach (Ad_MVA). This thesis describes a number of pre-clinical approaches aimed at enhancing the efficacy of these viral vectored vaccines targeting the blood-stage of malaria. First, the development of a highly efficacious malaria vaccine is likely to require a multi-antigen and/or multi-stage subunit vaccine. The utility of an Ad_MVA immunisation regime combining vaccines expressing the 42kDa C-terminus of the blood- stage antigen merozoite surface protein 1 (MSP142) and the pre-erythrocytic antigen circumsporozoite protein (CSP) in the P. yoelii mouse model was investigated. It was found that vaccine co- administration leads to maintained antibody responses and efficacy against blood-stage infection, but reduced secondary CD8+ T cell responses and efficacy against liver-stage infection. CD8+ T cell interference can be minimised by co-administering the MVA vaccines at separate sites, resulting in enhanced liver-stage efficacy. The mechanisms of CD8+ T cell interference were explored. Second, Ad_MVA regimes expressing blood-stage antigens that can protect against P. chabaudi and P. yoelii blood-stage infection were tested against P. berghei, but did not confer protection. Similarly, IgG from rabbits immunised against P. falciparum MSP1 (PfMSP1) could not protect mice from a chimeric P. berghei parasite expressing PfMSP1. Third, two molecular adjuvants, the C4bp α-chain oligomerisation domain (IMX108/313) and the Fc fragment of murine IgG2a, were tested for their ability to enhance immunogenicity of recombinant adenoviruses when fused at the C-terminus of a blood-stage antigen. IMX108/313 was found to adjuvant T cell responses of small (< 80kDa) antigens and this was associated with antigen oligomerisation. However, the Fc fragment did not adjuvant responses. Finally, it was found that using a strong early promoter to drive antigen expression enhances the immunogenicity of single administration MVA vaccines, but that this did not enhance post-boost immunogenicity in an Ad_MVA regime.</p> |
| spellingShingle | Clinical laboratory sciences Malaria Immunology Vaccinology Parasitology Infectious diseases Forbes, E Enhancing the efficacy of viral vector blood-stage malaria vaccines |
| title | Enhancing the efficacy of viral vector blood-stage malaria vaccines |
| title_full | Enhancing the efficacy of viral vector blood-stage malaria vaccines |
| title_fullStr | Enhancing the efficacy of viral vector blood-stage malaria vaccines |
| title_full_unstemmed | Enhancing the efficacy of viral vector blood-stage malaria vaccines |
| title_short | Enhancing the efficacy of viral vector blood-stage malaria vaccines |
| title_sort | enhancing the efficacy of viral vector blood stage malaria vaccines |
| topic | Clinical laboratory sciences Malaria Immunology Vaccinology Parasitology Infectious diseases |
| work_keys_str_mv | AT forbese enhancingtheefficacyofviralvectorbloodstagemalariavaccines |