Abstract
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.
Highlights
Malaria is the most relevant parasitic disease
We hypothesized that increasing the density of T cell epitopes by incorporation within the hyper variable region 2 (HVR2) adenovirus serotype 5 (Ad5) hexon could increase the immunogenicity of the recombinant Plasmodium yoelii chimeric multistage protein (PyCMP) protein, allowing us to develop a simplified immunization regimen
We initially developed an Ad5 vector that expressed a P. yoelii T cell epitope, orthologous to a well characterized CD4 promiscuous T cell epitope derived from P. vivax [30], and tested it using a co-administration with the recombinant PyCMP protein (Ad5HVR2T53+P regimen)
Summary
Malaria is the most relevant parasitic disease. Worldwide distributed, half of the human population, ~3.2 billion people, is at risk of transmission. The emergence, resurgence and spread of antimalarial drug resistance [2,3,4,5] along with vector resistance to insecticides [6, 7] have the potential of reducing the impact of existing malaria control measures, making a vaccine a public health priority. Several preclinical and clinical trials have been aimed to develop an ideal malaria vaccine formulation [8]. The main challenge in designing an effective malaria vaccine is the complexity of the Plasmodium life cycle, as each of the different stages in the host contains a unique set of antigens that hinders the development of protective immune responses [9, 10]. Developing a multistage vaccine, able to induce strong and balanced cellular and humoral responses, is essential to obtain an effective formulation
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