Safety, Immunogenicity and Efficacy of Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine Against Plasmodium Falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali

2019 ◽  
Author(s):  
Keyword(s):  
Plasmodium Falciparum ◽  
Transmission Blocking ◽  
Compound Trial ◽  
Transmission Blocking Vaccine

scholarly journals Engineering a Virus-Like Particle as an Antigenic Platform for a Pfs47-Targeted Malaria Transmission-Blocking Vaccine

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Lampouguin Yenkoidiok-Douti ◽  
Adeline E. Williams ◽  
Gaspar E. Canepa ◽  
Alvaro Molina-Cruz ◽  
Carolina Barillas-Mury
Keyword(s):  
Plasmodium Falciparum ◽  
Amino Acid ◽  
Malaria Transmission ◽  
Transmission Blocking ◽  
High Affinity ◽  
Virus Like Particle ◽  
Antibody Titers ◽  
Reducing Activity ◽  
Sexual Stages ◽  
Transmission Blocking Vaccine

AbstractWe recently characterized Pfs47, a protein expressed on the surface of sexual stages and ookinetes of Plasmodium falciparum, as a malaria transmission-blocking vaccine (TBV) target. Mice immunization induced antibodies that conferred strong transmission-reducing activity (TRA) at a concentration of 200 μg/mL. Here, we sought to optimize the Pfs47 vaccine to elicit higher titers of high-affinity antibodies, capable of inducing strong TRA at a lower concentration. We report the development and evaluation of a Pfs47-based virus-like particle (VLP) vaccine generated by conjugating our 58 amino acid Pfs47 antigen to Acinetobacter phage AP205-VLP using the SpyCatcher:SpyTag adaptor system. AP205-Pfs47 complexes (VLP-P47) formed particles of ~22 nm diameter that reacted with polyclonal anti-Pfs47 antibodies, indicating that the antigen was accessible on the surface of the particle. Mice immunized with VLP-P47 followed by a boost with Pfs47 monomer induced significantly higher antibody titers, with higher binding affinity to Pfs47, than mice that received two immunizations with either VLP-P47 (VLP-P47/VLP-P47) or the Pfs47 monomer (P47/P47). Purified IgG from VLP-P47/P47 mice had strong TRA (83–98%) at concentrations as low as 5 μg/mL. These results indicate that conjugating the Pfs47 antigen to AP205-VLP significantly enhanced antigenicity and confirm the potential of Pfs47 as a TBV candidate.

scholarly journals Global diversity of the gene encoding the Pfs25 protein—a Plasmodium falciparum transmission-blocking vaccine candidate

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Pornpawee Sookpongthai ◽  
Korawich Utayopas ◽  
Thassanai Sitthiyotha ◽  
Theerakamol Pengsakul ◽  
Morakot Kaewthamasorn ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Development ◽  
Protein A ◽  
Distribution Patterns ◽  
Haplotype Network ◽  
Malarial Parasite ◽  
Transmission Blocking ◽  
Global Diversity ◽  
Geographical Populations ◽  
Transmission Blocking Vaccine

Abstract Background Vaccines against the sexual stages of the malarial parasite Plasmodium falciparum are indispensable for controlling malaria and abrogating the spread of drug-resistant parasites. Pfs25, a surface antigen of the sexual stage of P. falciparum, is a leading candidate for transmission-blocking vaccine development. While clinical trials have reported that Pfs25-based vaccines are safe and effective in inducing transmission-blocking antibodies, the extent of the genetic diversity of Pfs25 in malaria endemic populations has rarely been studied. Thus, this study aimed to investigate the global diversity of Pfs25 in P. falciparum populations. Methods A database of 307 Pfs25 sequences of P. falciparum was established. Population genetic analyses were performed to evaluate haplotype and nucleotide diversity, analyze haplotypic distribution patterns of Pfs25 in different geographical populations, and construct a haplotype network. Neutrality tests were conducted to determine evidence of natural selection. Homology models of the Pfs25 haplotypes were constructed, subjected to molecular dynamics (MD), and analyzed in terms of flexibility and percentages of secondary structures. Results The Pfs25 gene of P. falciparum was found to have 11 unique haplotypes. Of these, haplotype 1 (H1) and H2, the major haplotypes, represented 70% and 22% of the population, respectively, and were dominant in Asia, whereas only H1 was dominant in Africa, Central America, and South America. Other haplotypes were rare and region-specific, resulting in unique distribution patterns in different geographical populations. The diversity in Pfs25 originated from ten single-nucleotide polymorphism (SNP) loci located in the epidermal growth factor (EGF)-like domains and anchor domain. Of these, an SNP at position 392 (GGA/GCA), resulting in amino acid substitution 131 (Gly/Ala), defined the two major haplotypes. The MD results showed that the structures of H1 and H2 variants were relatively similar. Limited polymorphism in Pfs25 could likely be due to negative selection. Conclusions The study successfully established a Pfs25 sequence database that can become an essential tool for monitoring vaccine efficacy, designing assays for detecting malaria carriers, and conducting epidemiological studies of P. falciparum. The discovery of the two major haplotypes, H1 and H2, and their conserved structures suggests that the current Pfs25-based vaccines could be used globally for malaria control. Graphical Abstract

Geographical distribution of a variant epitope of Pfs4845, a Plasmodium falciparum transmission-blocking vaccine candidate

1996 ◽  
Vol 81 (2) ◽  
pp. 253-257 ◽  
Author(s):  
Christopher J Drakeley ◽  
Manoj T Duraisingh ◽  
Marinete Póvoa ◽  
David J Conway ◽  
Geoffrey A.T Targett ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Geographical Distribution ◽  
Vaccine Candidate ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccine

Plasmodium falciparum: Immunogenicity of Alum-Adsorbed Clinical-Grade TBV25–28, a Yeast-Secreted Malaria Transmission-Blocking Vaccine Candidate

2001 ◽  
Vol 97 (2) ◽  
pp. 61-69 ◽  
Author(s):  
Mary Margaret G Gozar ◽  
Olga Muratova ◽  
David B Keister ◽  
Charlotte R Kensil ◽  
Virginia L Price ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Transmission ◽  
Vaccine Candidate ◽  
Clinical Grade ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccine

scholarly journals Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes

2015 ◽  
Vol 83 (5) ◽  
pp. 1799-1808 ◽  
Author(s):  
Kailash P. Patra ◽  
Fengwu Li ◽  
Darrick Carter ◽  
James A. Gregory ◽  
Sheyenne Baga ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Water Emulsion ◽  
Transmission Blocking ◽  
Content Type ◽  
Oil In Water ◽  
Oil In Water Emulsion ◽  
Transmission Blocking Vaccine

A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate forPlasmodium falciparumtransmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. HereChlamydomonas reinhardtiimicroalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene–oil-in-water emulsion, and GLA plus squalene–oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene–oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface ofP. falciparummacrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene–oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration.

scholarly journals A Reproducible and Scalable Process for Manufacturing a Pfs48/45 Based Plasmodium falciparum Transmission-Blocking Vaccine

2021 ◽  
Vol 11 ◽  
Author(s):  
Susheel K. Singh ◽  
Jordan Plieskatt ◽  
Bishwanath K. Chourasia ◽  
Amanda Fabra-García ◽  
Asier Garcia-Senosiain ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Clinical Evaluation ◽  
Disulfide Bonds ◽  
Process Development ◽  
Drug Product ◽  
Protein A ◽  
Surface Protein ◽  
Size Exclusion ◽  
Transmission Blocking ◽  
Transmission Blocking Vaccine

The cysteine-rich Pfs48/45 protein, a Plasmodium falciparum sexual stage surface protein, has been advancing as a candidate antigen for a transmission-blocking vaccine (TBV) for malaria. However, Pfs48/45 contains multiple disulfide bonds, that are critical for proper folding and induction of transmission-blocking (TB) antibodies. We have previously shown that R0.6C, a fusion of the 6C domain of Pfs48/45 and a fragment of PfGLURP (R0), expressed in Lactococcus lactis, was properly folded and induced transmission-blocking antibodies. Here we describe the process development and technology transfer of a scalable and reproducible process suitable for R0.6C manufacturing under current Good Manufacturing Practices (cGMP). This process resulted in a final purified yield of 25 mg/L, sufficient for clinical evaluation. A panel of analytical assays for release and stability assessment of R0.6C were developed including HPLC, SDS-PAGE, and immunoblotting with the conformation-dependent TB mAb45.1. Intact mass analysis of R0.6C confirmed the identity of the product including the three disulfide bonds and the absence of post-translational modifications. Multi-Angle Light Scattering (MALS) coupled to size exclusion chromatography (SEC-MALS), further confirmed that R0.6C was monomeric (~70 kDa) in solution. Lastly, preclinical studies demonstrated that the R0.6C Drug Product (adsorbed to Alhydrogel®) elicited functional antibodies in small rodents and that adding Matrix-M™ adjuvant further increased the functional response. Here, building upon our past work, we filled the gap between laboratory and manufacturing to ready R0.6C for production under cGMP and eventual clinical evaluation as a malaria TB vaccine.

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