Pre-Erythrocytic Vaccines against Malaria

Marques-da-Silva, Camila; Peissig, Kristen; Kurup, Samarchith P.

doi:10.3390/vaccines8030400

Cited by 32 publications

(24 citation statements)

References 110 publications

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“…Despite numerous challenges, significant progress has been made toward the development of protective vaccines against preerythrocytic malaria infection. Many vaccine approaches have been evaluated in preclinical animal models, with few advancing into the clinic or beyond Phase 1 studies 70 . Encouraged by the successes of mRNA vaccines against other infectious diseases 17 , we applied an analogous approach to the age-old problem of malaria.…”

Section: Discussionmentioning

confidence: 99%

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice

et al. 2021

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Human malaria affects the vast majority of the world’s population with the Plasmodium falciparum species causing the highest rates of morbidity and mortality. With no licensed vaccine and leading candidates achieving suboptimal protection in the field, the need for an effective immunoprophylactic option continues to motivate the malaria research community to explore alternative technologies. Recent advances in the mRNA discipline have elevated the long-neglected platform to the forefront of infectious disease research. As the immunodominant coat protein of the invasive stage of the malaria parasite, circumsporozoite protein (PfCSP) was selected as the antigen of choice to assess the immunogenic and protective potential of an mRNA malaria vaccine. In mammalian cell transfection experiments, PfCSP mRNA was well expressed and cell associated. In the transition to an in vivo murine model, lipid nanoparticle (LNP) encapsulation was applied to protect and deliver the mRNA to the cell translation machinery and supply adjuvant activity. The immunogenic effect of an array of factors was explored, such as formulation, dose, number, and interval of immunizations. PfCSP mRNA-LNP achieved sterile protection against infection with two P. berghei PfCSP transgenic parasite strains, with mRNA dose and vaccination interval having a greater effect on outcome. This investigation serves as the assessment of pre-erythrocytic malaria, PfCSP mRNA vaccine candidate resulting in sterile protection, with numerous factors affecting protective efficacy, making it a compelling candidate for further investigation.

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Section: Discussionmentioning

confidence: 99%

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice

et al. 2021

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“…Thereafter, experimental results have confirmed that homologous or heterologous priming using viral vector approach could induce the CMI [71]. By using this approach, ME-TRAP, CSVAC (encodes PfCSP alongside a truncated C-terminal lacking 14 amino acids of CSP GPI anchor moiety), combination of PfTRAP with liver stage antigen 1 (LSA1) & LSA2 were developed and tested for their efficacy [42]. The enhanced T-cell based response is the major advantage of this approach.…”

Section: History Of Malaria Vaccine Developmentmentioning

confidence: 96%

“…Similarly, to target particularly the infected RBCs containing merozoites and preventing them to infect other RBCs in the blood/ symptomatic stage has been very difficult. Nonetheless, the longest exposure of infected sporozoites towards the host immune system by invading hepatocytes in the liver stage (5.5 to 7 days in humans and 48 hrs in rodents) and releasing of thousands of merozoites which further continue the blood-stage or symptomatic stage of infection makes the LS most promising stage for the target of vaccine development [14,42], though LS-vaccine has its own limitation of tedious and challenging task of sporozoites.…”

Section: Approach Of Vaccine Development: a Ray Of Hopementioning

confidence: 99%

“…Subsequently, a next generation vaccine was developed (R21) and accounted for the improvised version of RTS,S as it incorporates the longer portion of PfCSP C-terminal armed to N-terminal of HBs Ag. The elevated CSP-specific Ab response, higher immunogenicity at the lower doses (in in-vivo challenge study) and formulation with AS01 adjuvant resulted into beginning of clinical trials of phase 1/2a for its efficacy [42].…”

Section: Rtss (A Recombinant Protein Based Vaccine) Was First Developed By Smithklinementioning

confidence: 99%

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T Cell-Based Vaccines: Hope for Malaria Elimination

Tandel¹,

Dalai²

2021

Current Topics and Emerging Issues in Malaria Elimination

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Among the numerous infectious diseases, malaria still remains the main cause of morbidity and mortality across the world. Every year more than 200 million cases are registered and death toll is of around 4,00,000. The emergence of insecticide and drug resistance has surged an alarming situation to find an effective means to tackle it. From various approaches used for reducing the damage created by malaria to the society, developing effective vaccine has gained the attention of scientific community. The large genome size (24 MB), heterogeneity of the genes, complex life cycle in two different hosts, and expression of wide range of these genes are claimed to hinder the malaria vaccine development. It requires good understanding of the host-pathogen interaction and its correlation with the sterile protection. Recently, subunit vaccine have shown certain promising responses; however, the currently in use of RTS,S vaccine has failed to generate the long-term sterile protection as well as effector memory CD8+T cells. However, the success of sterile protection through vaccination has been proven long back by experimental approaches, where it could be achieved using irradiated sporozoites (RAS) in rodents and humans. Similarly, GAP (genetically attenuated parasite) and CPS (chloroquine chemoprophylaxis with Plasmodium sporozoites) have been shown to induce sterile immunity. Despite all the developments, generation of species and stage specific-CD8+ T cell responses has been modest. In order to generate long-lasting immune response, particularly, liver-stage specific-CD8+ T cells, it is indeed required to study the CD8+ T cell epitope repertoire and its implications on the host immune system. In this chapter we will discuss the current status of T cell-based vaccines and the challenges associated with it.

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“…While RAS provides protective immunity against homologous challenge, protection against heterologous challenge has proven problematic (24). In addition, the requirements for a cold chain to maintain the infective irradiated sporozoites and need for repeated immunizations pose significant obstacles to its wide-spread use (25,26). Both CSP and TRAP subunit-based vaccines (RTS,S and ME-TRAP, respectively) have successfully elicited sterile immunity against malaria infection in humans; however, both have demonstrated only modest efficacy (27).…”

Section: Introductionmentioning

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 Vaccines against Malaria

Cited by 32 publications

References 110 publications

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice

Messenger RNA expressing PfCSP induces functional, protective immune responses against malaria in mice

T Cell-Based Vaccines: Hope for Malaria Elimination

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

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