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A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII.

ABSTRACT: Adenovirus (Ad) is thought to be one of the most promising platforms for a malaria vaccine targeted against its liver stages, because of its ability to induce a strong T-cell response against a transgene. However, a further improvement of this platform is needed in order to elicit another arm of the immunity, i.e. humoral response, against malaria. In order to augment immunogenicity and protective efficacy of Ad-based malaria vaccine, we inserted B-cell, as well as CD4+ T-cell, epitopes of Plasmodium falciparum circumsporozoite protein (PfCSP) into the capsid protein, Hexon, and the core protein, VII (pVII), of Ad, respectively, in addition to the PfCSP transgene. Insertion of PfCSP-derived B cell epitope to Hexon significantly enhanced the epitope-specific antibody response compared to AdPfCSP, an Ad vaccine expressing only PfCSP transgene. PfCSP-derived CD4+ T-cell epitope insertion into pVII augmented not only PfCSP-specific CD4+ T-cell response but also anti-PfCSP antibody response. Finally, mice immunized with AdPfCSP having both Hexon and pVII modifications were more protected than AdPfCSP or Hexon-modified AdPfCSP against challenge with transgenic rodent malaria parasites expressing the PfCSP. Overall, this study has demonstrated that Hexon and pVII-modified AdPfCSP vaccine is a promising malaria vaccine which induces strong PfCSP-specific humoral, CD4+ T-cell, and CD8+ T-cell responses and protects against infection with transgenic malaria parasites expressing the PfCSP.

SUBMITTER: Shiratsuchi T

PROVIDER: S-EPMC5709203 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII.

Shiratsuchi Takayuki T Rai Urvashi U Kaneko Izumi I Zhang Min M Iwanaga Shiroh S Yuda Masao M Tsuji Moriya M

Vaccine 20171028 50

Adenovirus (Ad) is thought to be one of the most promising platforms for a malaria vaccine targeted against its liver stages, because of its ability to induce a strong T-cell response against a transgene. However, a further improvement of this platform is needed in order to elicit another arm of the immunity, i.e. humoral response, against malaria. In order to augment immunogenicity and protective efficacy of Ad-based malaria vaccine, we inserted B-cell, as well as CD4+ T-cell, epitopes of Plasm ...[more]

PMID: 29089194

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Project description:A malaria vaccine is a public health priority. In order to produce an effective vaccine, a multistage approach targeting both the blood and the liver stage infection is desirable. The vaccine candidates also need to induce balanced immune responses including antibodies, CD4+ and CD8+ T cells. Protein-based subunit vaccines like RTS,S are able to induce strong antibody response but poor cellular reactivity. Adenoviral vectors have been effective inducing protective CD8+ T cell responses in several models including malaria; nonetheless this vaccine platform exhibits a limited induction of humoral immune responses. Two approaches have been used to improve the humoral immunogenicity of recombinant adenovirus vectors, the use of heterologous prime-boost regimens with recombinant proteins or the genetic modification of the hypervariable regions (HVR) of the capsid protein hexon to express B cell epitopes of interest. In this study, we describe the development of capsid modified Ad5 vectors that express a promiscuous Plasmodium yoelii T helper epitope denominated PyT53 within the hexon HVR2 region. Several regimens were tested in mice to determine the relevance of the hexon modification in enhancing protective immune responses induced by the previously described protein-based multi-stage experimental vaccine PyCMP. A heterologous prime-boost immunization regime that combines a hexon modified vector with transgenic expression of PyCMP followed by protein immunizations resulted in the induction of robust antibody and cellular immune responses in comparison to a similar regimen that includes a vector with unmodified hexon. These differences in immunogenicity translated into a better protective efficacy against both the hepatic and red blood cell stages of P. yoelii. To our knowledge, this is the first time that a hexon modification is used to deliver a promiscuous T cell epitope. Our data support the use of such modification to enhance the immunogenicity and protective efficacy of adenoviral based malaria vaccines.

Dataset Information

A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII.

Publications

A potent malaria vaccine based on adenovirus with dual modifications at Hexon and pVII.

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