Pre-Erythrocytic Vaccine Candidates in Malaria

Tucker, K. M.; Noe, Amy R.; Kotraiah, Vinayaka; Phares, Moriya Tsuji Timothy W.; Nardin, Elizabeth; Gutierrez, Gabriel M.

doi:10.5772/65592

Cited by 6 publications

(7 citation statements)

References 215 publications

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“…While a wide variety of liver-stage malaria vaccine strategies have induced strong CD8 + T cell responses and provided sterile immunity in healthy adults, these vaccines have been less effective in field evaluations in endemic regions (39,40). Indeed, volunteers in malaria-endemic regions are often cleared of parasites before vaccine delivery by drug administration to eliminate the confounding of vaccine efficacy through the parasite's effects on the host's immune state (41).…”

Section: Discussionmentioning

confidence: 99%

A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model

et al. 2020

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The blockade of programmed cell death-1 (PD1) and its ligand PDL1 has been proven to be a successful immunotherapy against several cancers. Similar to cancer, PD1 contributes to the establishment of several chronic infectious diseases, including malaria. While monoclonal antibodies (mAbs) targeting checkpoint receptors are revolutionary in cancer treatment, the immune-related adverse events (irAEs) may prevent their utilization in prophylactic and therapeutic treatments of infectious diseases. The irAEs are, in part, due to the prolonged half-life of mAbs resulting in prolonged activation of the immune system. As an alternative modality to mAbs, peptides represent a viable option because they possess a shorter pharmacokinetic half-life and offer more formulation and delivery options. Here, we report on a 22-amino acid immunomodulatory peptide, LD01, derived from a Bacillus bacteria. When combined prophylactically with an adenovirus-based or irradiated sporozoite-based malaria vaccine, LD01 significantly enhanced antigen-specific CD8 + T cell expansion. Therapeutically, LD01 treatment of mice infected with a lethal malaria strain resulted in survival that was associated with lower numbers of FOXP3 + Tbet + CD4 + regulatory T cells. Taken together, our results demonstrate that LD01 is a potent immunomodulator that acts upon the adaptive immune system to stimulate T cell responses both prophylactically and therapeutically.

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Section: Discussionmentioning

confidence: 99%

A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model

et al. 2020

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“…Plasmodium antigens that have been explored as vaccines/antigens, by parasitic stage Adapted with permission from ref. [87] Copyright 2007 Bentham Science Publishers and [88] Copyright 2016 Intech OpenAbbreviations: CSP, circumsporozoite protein; TRAP, thrombospondin-related adhesive protein; ME-TRAP, multiple epitope-thrombospondin-related adhesive protein; STARP, sporozoite threonine-and asparagine-rich protein; SALSA, sporozoite-and liver-stage antigen; SSP, sporozoite surface protein; SPf66, synthetic P. falciparum 66; MSP, merozoite surface protein; RESA, ring-infected erythrocyte surface antigen; GLURP, glutamine-rich protein; AMA, apical membrane antigen; SERA, serine-repeat antigen; EBA, erythrocyte-binding antigen; HRH5 reticulocyte-binding protein homologue 5, EMP, erythrocyte membrane protein; RAP, rhoptry-associated protein; LSA-1/3, Liver-stage antigen-1/3; CelTOS, Cell-traversal protein for ookinetes and sporozoites; DBP, Duffy binding protein, EXP-1, Exported protein-1; Ripr, RH5-interacting protein; CyPRA, Cysteine-rich protective antigen; Pf, Plasmodium falciparum protein; Pv, Plasmodium vivax protein.…”

Section: Targeting the Sporozoitementioning

confidence: 99%

Development of New Strategies for Malaria Chemoprophylaxis: From Monoclonal Antibodies to Long-Acting Injectable Drugs

Moehrle

2022

TropicalMed

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Drug discovery for malaria has traditionally focused on orally available drugs that kill the abundant, parasitic blood stage. Recently, there has also been an interest in injectable medicines, in the form of monoclonal antibodies (mAbs) with long-lasting plasma half-lives or long-lasting depot formulations of small molecules. These could act as prophylactic drugs, targeting the sporozoites and other earlier parasitic stages in the liver, when the parasites are less numerous, or as another intervention strategy targeting the formation of infectious gametocytes. Generally speaking, the development of mAbs is less risky (costly) than small-molecule drugs, and they have an excellent safety profile with few or no off-target effects. Therefore, populations who are the most vulnerable to malaria, i.e., pregnant women and young children would have access to such new treatments much faster than is presently the case for new antimalarials. An analysis of mAbs that were successfully developed for oncology illustrates some of the feasibility aspects, and their potential as affordable drugs in low- and middle-income countries.

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“…Analysis was performed on a subset of 100 proteins expressed in the preerythrocytic stage of malaria (Supplementary Table 1). This subset included proteins previously evaluated for T cell responses in volunteers vaccinated with irradiated sporozoites (14,39) and as potential subunit vaccines in animal models or clinical trials (40). Also included were thirty-six proteins that were expressed in both the liver stage (41) and blood stage of malaria (42), and were indicated to be conserved and uncharacterized in PlasmoDB (31).…”

Section: Identification Of the Liver Stage Proteins For Analysis And Overview Of The Experimental Frameworkmentioning

confidence: 99%

Identification, Selection and Immune Assessment of Liver Stage CD8 T Cell Epitopes From Plasmodium falciparum

et al. 2021

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Immunization with radiation-attenuated sporozoites (RAS) has been shown to protect against malaria infection, primarily through CD8 T cell responses, but protection is limited based on parasite strain. Therefore, while CD8 T cells are an ideal effector population target for liver stage malaria vaccine development strategies, such strategies must incorporate conserved epitopes that cover a large range of class I human leukocyte antigen (HLA) supertypes to elicit cross-strain immunity across the target population. This approach requires identifying and characterizing a wide range of CD8 T cell epitopes for incorporation into a vaccine such that coverage across a large range of class I HLA alleles is attained. Accordingly, we devised an experimental framework to identify CD8 T cell epitopes from novel and minimally characterized antigens found at the pre-erythrocytic stage of parasite development. Through in silico analysis we selected conserved P. falciparum proteins, using P. vivax orthologues to establish stringent conservation parameters, predicted to have a high number of T cell epitopes across a set of six class I HLA alleles representative of major supertypes. Using the decision framework, five proteins were selected based on the density and number of predicted epitopes. Selected epitopes were synthesized as peptides and evaluated for binding to the class I HLA alleles in vitro to verify in silico binding predictions, and subsequently for stimulation of human T cells using the Modular IMmune In-vitro Construct (MIMIC®) technology to verify immunogenicity. By combining the in silico tools with the ex vivo high throughput MIMIC platform, we identified 15 novel CD8 T cell epitopes capable of stimulating an immune response in alleles across the class I HLA panel. We recommend these epitopes should be evaluated in appropriate in vivo humanized immune system models to determine their protective efficacy for potential inclusion in future vaccines.

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Pre-Erythrocytic Vaccine Candidates in Malaria

Cited by 6 publications

References 215 publications

A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model

A Peptide-Based PD1 Antagonist Enhances T-Cell Priming and Efficacy of a Prophylactic Malaria Vaccine and Promotes Survival in a Lethal Malaria Model

Development of New Strategies for Malaria Chemoprophylaxis: From Monoclonal Antibodies to Long-Acting Injectable Drugs

Identification, Selection and Immune Assessment of Liver Stage CD8 T Cell Epitopes From Plasmodium falciparum

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