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Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

ABSTRACT: Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8⁺ T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo-erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen-specific CD8⁺ T-cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine-induced effector CD8⁺ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen-specific CD8⁺ T-cell killing, which has wide-ranging implications on antigen prioritisation for next-generation pre-erythrocytic malaria vaccines.

SUBMITTER: Muller K

PROVIDER: S-EPMC8033512 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

Müller Katja K Gibbins Matthew P MP Roberts Mark M Reyes-Sandoval Arturo A Hill Adrian V S AVS Draper Simon J SJ Matuschewski Kai K Silvie Olivier O Hafalla Julius Clemence R JCR

EMBO molecular medicine 20210311 4

Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria pre-erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well-characterised epitope for stimulation of CD8<sup>+</sup> T cells, either as an antigen in the sporozoite surface-expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregu ...[more]

PMID: 33709544

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Project description:We previously reported a protective antibody response in mice immunized with synthetic microparticle vaccines made using layer-by-layer fabrication (LbL-MP) and containing the conserved T1BT* epitopes from the P. falciparum circumsporozoite protein. To further optimize the vaccine candidate, a benchtop tangential flow filtration method (LbL-by-TFF) was developed and utilized to produce vaccine candidates that differed in the status of base layer crosslinking, inclusion of a TLR2 ligand in the antigenic peptide, and substitution of serine or alanine for an unpaired cysteine residue in the T* epitope. Studies in mice revealed consistent superiority of the Pam3Cys-modified candidates and a modest benefit of base layer crosslinking, as evidenced by higher and more persistent antibody titers (up to 18 months post-immunization), a qualitative improvement of T-cell responses toward a Th1 phenotype, and greater protection from live parasite challenges compared to the unmodified prototype candidate. Immunogenicity was also tested in a non-human primate model, the rhesus macaque. Base layer-crosslinked LbL-MP loaded with T1BT* peptide with or without covalently linked Pam3Cys elicited T1B-specific antibody responses and T1BT*-specific T-cell responses dominated by IFNγ secretion with lower levels of IL-5 secretion. The Pam3Cys-modified construct was more potent, generating antibody responses that neutralized wild-type P. falciparum in an in vitro hepatocyte invasion assay. IgG purified from individual macaques immunized with Pam3Cys.T1BT* LbL-MP protected naïve mice from challenges with transgenic P. berghei sporozoites that expressed the full-length PfCS protein, with 50-88% of passively immunized mice parasite-free for ≥15 days. Substitution of serine for an unpaired cysteine in the T* region of the T1BT* subunit did not adversely impact immune potency in the mouse while simplifying the manufacture of the antigenic peptide. In a Good Laboratory Practices compliant rabbit toxicology study, the base layer-crosslinked, Pam3Cys-modified, serine-substituted candidate was shown to be safe and immunogenic, eliciting parasite-neutralizing antibody responses and establishing the dose/route/regimen for a clinical evaluation of this novel synthetic microparticle pre-erythrocytic malaria vaccine candidate.

Dataset Information

Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

Publications

Low immunogenicity of malaria pre-erythrocytic stages can be overcome by vaccination.

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