scholarly journals A whole parasite transmission-blocking vaccine for malaria: an ignored strategy

2017 ◽  
Vol 1 (6) ◽  
pp. 547-552 ◽  
Author(s):  
Michael F. Good ◽  
Stephanie K. Yanow
Keyword(s):  
T Cells ◽  
Cellular Immunity ◽  
Vaccine Development ◽  
Mosquito Vector ◽  
Asexual Blood Stage ◽  
Liver Stage ◽  
Transmission Blocking ◽  
Block Transmission ◽  
Immunological Feature ◽  
Transmission Blocking Vaccine

Malaria vaccine approaches can be divided into ‘subunit’ and ‘whole parasite’, and these can be directed at the sporozoite, liver stage, asexual or sexual stages. All combinations of approach and stage are under development with the exception of a whole parasite sexual stage (gametocyte) vaccine. A gametocyte vaccine would aim primarily to block transmission of malaria from the human host to the mosquito vector and as such is referred to as a ‘transmission-blocking vaccine’. An immunological feature of whole parasite vaccines for the sporozoite/liver stage and for the asexual blood stage is the reliance on cellular immunity involving T-cells to control parasite growth. T-cells can also respond vigorously to gametocytes and kill them in the vertebrate host and/or arrest their development. To date, cellular immunity has not been exploited in transmission-blocking vaccine development. Here, the data supporting a gametocyte whole parasite vaccine are reviewed and a strategy for vaccine development and testing is outlined.

scholarly journals Evaluation of the Impact of Codon Optimization and N-Linked Glycosylation on Functional Immunogenicity of Pfs25 DNA Vaccines Delivered byIn VivoElectroporation in Preclinical Studies in Mice

2015 ◽  
Vol 22 (9) ◽  
pp. 1013-1019 ◽  
Author(s):  
Dibyadyuti Datta ◽  
Geetha P. Bansal ◽  
Rajesh Kumar ◽  
Barry Ellefsen ◽  
Drew Hannaman ◽  
...  
Keyword(s):  
Nonhuman Primates ◽  
Vaccine Development ◽  
Dna Vaccines ◽  
Codon Optimization ◽  
Antibody Responses ◽  
Transmission Blocking ◽  
Content Type ◽  
The Impact ◽  
Transmission Blocking Vaccine

ABSTRACTPlasmodium falciparumsexual stage surface antigen Pfs25 is a well-established candidate for malaria transmission-blocking vaccine development. Immunization with DNA vaccines encoding Pfs25 has been shown to elicit potent antibody responses in mice and nonhuman primates. Studies aimed at further optimization have revealed improved immunogenicity through the application ofin vivoelectroporation and by using a heterologous prime-boost approach. The goal of the studies reported here was to systematically evaluate the impact of codon optimization,in vivoelectroporation, and N-linked glycosylation on the immunogenicity of Pfs25 encoded by DNA vaccines. The results from this study demonstrate that while codon optimization andin vivoelectroporation greatly improved functional immunogenicity of Pfs25 DNA vaccines, the presence or absence of N-linked glycosylation did not significantly impact vaccine efficacy. These findings suggest that N-glycosylation of Pfs25 encoded by DNA vaccines is not detrimental to overall transmission-blocking efficacy.

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

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 Use of a Selective Inhibitor To Define the Chemotherapeutic Potential of the Plasmodial Hexose Transporter in Different Stages of the Parasite's Life Cycle

2011 ◽  
Vol 55 (6) ◽  
pp. 2824-2830 ◽  
Author(s):  
Ksenija Slavic ◽  
Michael J. Delves ◽  
Miguel Prudêncio ◽  
Arthur M. Talman ◽  
Ursula Straschil ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Specific Inhibitor ◽  
Parasite Development ◽  
Mosquito Vector ◽  
Hexose Transporter ◽  
Asexual Blood Stage ◽  
Liver Stage ◽  
Content Type ◽  
Green Fluorescent ◽  
Malaria Model

ABSTRACTDuring blood infection, malarial parasites used-glucose as their main energy source. ThePlasmodium falciparumhexose transporter (PfHT), which mediates the uptake ofd-glucose into parasites, is essential for survival of asexual blood-stage parasites. Recently, genetic studies in the rodent malaria model,Plasmodium berghei, found that the orthologous hexose transporter (PbHT) is expressed throughout the parasite's development within the mosquito vector, in addition to being essential during intraerythrocytic development. Here, using ad-glucose-derived specific inhibitor of plasmodial hexose transporters, compound 3361, we have investigated the importance ofd-glucose uptake during liver and transmission stages ofP. berghei. Initially, we confirmed the expression of PbHT during liver stage development, using a green fluorescent protein (GFP) tagging strategy. Compound 3361 inhibited liver-stage parasite development, with a 50% inhibitory concentration (IC50) of 11 μM. This process was insensitive to the externald-glucose concentration. In addition, compound 3361 inhibited ookinete development and microgametogenesis, with IC50s in the region of 250 μM (the latter in ad-glucose-sensitive manner). Consistent with our findings for the effect of compound 3361 on vector parasite stages, 1 mM compound 3361 demonstrated transmission blocking activity. These data indicate that novel chemotherapeutic interventions that target PfHT may be active against liver and, to a lesser extent, transmission stages, in addition to blood stages.

scholarly journals Predicting the public health impact of a malaria transmission-blocking vaccine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joseph D. Challenger ◽  
Daniela Olivera Mesa ◽  
Dari F. Da ◽  
R. Serge Yerbanga ◽  
Thierry Lefèvre ◽  
...  
Keyword(s):  
Public Health ◽  
Malaria Transmission ◽  
Health Impact ◽  
Public Health Impact ◽  
Substantial Impact ◽  
Transmission Blocking ◽  
Block Transmission ◽  
Membrane Feeding ◽  
Field Efficacy ◽  
Transmission Blocking Vaccine

AbstractTransmission-blocking vaccines that interrupt malaria transmission from humans to mosquitoes are being tested in early clinical trials. The activity of such a vaccine is commonly evaluated using membrane-feeding assays. Understanding the field efficacy of such a vaccine requires knowledge of how heavily infected wild, naturally blood-fed mosquitoes are, as this indicates how difficult it will be to block transmission. Here we use data on naturally infected mosquitoes collected in Burkina Faso to translate the laboratory-estimated activity into an estimated activity in the field. A transmission dynamics model is then utilised to predict a transmission-blocking vaccine’s public health impact alongside existing interventions. The model suggests that school-aged children are an attractive population to target for vaccination. Benefits of vaccination are distributed across the population, averting the greatest number of cases in younger children. Utilising a transmission-blocking vaccine alongside existing interventions could have a substantial impact against malaria.

scholarly journals Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen

2020 ◽  
Author(s):  
Nicole G. Bender ◽  
Prachi Khare ◽  
Juan Martinez ◽  
Rebecca E. Tweedell ◽  
Vincent O. Nyasembe ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Malaria Elimination ◽  
Humoral Response ◽  
Vaccine Antigen ◽  
Mosquito Vector ◽  
Transmission Blocking ◽  
Cd1 Mice ◽  
Alanyl Aminopeptidase ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

AbstractMalaria transmission-blocking vaccines (TBVs) are a critical tool for disease elimination. TBVs prevent completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen and structure-function studies have identified two Class II epitopes that induce potent transmission-blocking (T-B) antibodies. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ was immunogenic and immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity and establishing UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.

scholarly journals Immunofocusing humoral immunity potentiates the functional efficacy of the AnAPN1 malaria transmission-blocking vaccine antigen

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nicole G. Bender ◽  
Prachi Khare ◽  
Juan Martinez ◽  
Rebecca E. Tweedell ◽  
Vincent O. Nyasembe ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Humoral Response ◽  
Vaccine Antigen ◽  
Mosquito Vector ◽  
Transmission Blocking ◽  
Cd1 Mice ◽  
Alanyl Aminopeptidase ◽  
Antigen Structure ◽  
Transmission Blocking Vaccines ◽  
Transmission Blocking Vaccine

AbstractMalaria transmission-blocking vaccines (TBVs) prevent the completion of the developmental lifecycle of malarial parasites within the mosquito vector, effectively blocking subsequent infections. The mosquito midgut protein Anopheline alanyl aminopeptidase N (AnAPN1) is the leading, mosquito-based TBV antigen. Structure-function studies identified two Class II epitopes that can induce potent transmission-blocking (T-B) antibodies, informing the design of the next-generation AnAPN1. Here, we functionally screened new immunogens and down-selected to the UF6b construct that has two glycine-linked copies of the T-B epitopes. We then established a process for manufacturing UF6b and evaluated in outbred female CD1 mice the immunogenicity of the preclinical product with the human-safe adjuvant Glucopyranosyl Lipid Adjuvant in a liposomal formulation with saponin QS21 (GLA-LSQ). UF6b:GLA-LSQ effectively immunofocused the humoral response to one of the key T-B epitopes resulting in potent T-B activity, underscoring UF6b as a prime TBV candidate to aid in malaria elimination and eradication efforts.

scholarly journals Global Diversity of the Gene Encoding the Pfs25 Protein - A Plasmodium Falciparum Transmission-Blocking Vaccine Candidate

2021 ◽  
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 been rarely 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: Pfs25 of P. falciparum comprised 11 unique haplotypes. Of these, haplotype 1 (H1) and H2, the major haplotypes, represented 70% and 22% of the population, respectively. H1 and H2 were dominant in Asia, whereas 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 10 single nucleotide polymorphism (SNP) loci located in 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. MD results showed that structures of H1 and H2 variants were relatively similar. Limited polymorphism in Pfs25 could be likely 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 globally used for malaria control.

scholarly journals Prime and target immunization protects against liver-stage malaria in mice

2018 ◽  
Vol 10 (460) ◽  
pp. eaap9128 ◽  
Author(s):  
Anita Gola ◽  
Daniel Silman ◽  
Adam A. Walters ◽  
Saranya Sridhar ◽  
Stefan Uderhardt ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Vectors ◽  
Viral Vector ◽  
Vaccination Strategy ◽  
Feasibility Trial ◽  
Effective Vaccine ◽  
Mosquito Vector ◽  
Erythrocytic Stage ◽  
Liver Stage ◽  
Circulating T Cells

Despite recent advances in treatment and vector control, malaria is still a leading cause of death, emphasizing the need for an effective vaccine. The malaria life cycle can be subdivided into three stages: the invasion and growth within liver hepatocytes (pre-erythrocytic stage), the blood stage (erythrocytic stage), and, finally, the sexual stage (occurring within the mosquito vector). Antigen (Ag)-specific CD8+ T cells are effectively induced by heterologous prime-boost viral vector immunization and known to correlate with liver-stage protection. However, liver-stage malaria vaccines have struggled to generate and maintain the high numbers of Plasmodium-specific circulating T cells necessary to confer sterile protection. We describe an alternative “prime and target” vaccination strategy aimed specifically at inducing high numbers of tissue-resident memory T cells present in the liver at the time of hepatic infection. This approach bypasses the need for very high numbers of circulating T cells and markedly increases the efficacy of subunit immunization against liver-stage malaria with clinically relevant Ags and clinically tested viral vectors in murine challenge models. Translation to clinical use has begun, with encouraging results from a pilot safety and feasibility trial of intravenous chimpanzee adenovirus vaccination in humans. This work highlights the value of a prime-target approach for immunization against malaria and suggests that this strategy may represent a more general approach for prophylaxis or immunotherapy of other liver infections and diseases.

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