scholarly journals Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity

2019 ◽  
Author(s):  
Jo-Anne Chan ◽  
David Wetzel ◽  
Linda Reiling ◽  
Kazutoyo Miura ◽  
Damien Drew ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Development ◽  
Transmission Blocking ◽  
Vaccine Candidates ◽  
Virus Like Particles ◽  
Malaria Vaccines ◽  
Membrane Feeding ◽  
B Virus ◽  
Vaccine Antigens ◽  
Novel Virus

ABSTRACTThe development of effective malaria vaccines remains a global health priority. Currently, the most advanced vaccine, known as RTS,S, has only shown modest efficacy in clinical trials. Thus, the development of more efficacious vaccines by improving the formulation of RTS,S for increased efficacy or to interrupt malaria transmission are urgently needed. The RTS,S vaccine is based on the presentation of a fragment of the sporozoite antigen on the surface of virus-like particles (VLPs) based on human hepatitis B virus (HBV). In this study, we have developed and evaluated a novel VLP platform based on duck HBV (known as Metavax) for malaria vaccine development. This platform can incorporate large and complex proteins into VLPs and is produced in a Hansenula cell line compatible with cGMP vaccine production. Here, we have established the expression of leading P. falciparum malaria vaccine candidates as VLPs. This includes Pfs230 and Pfs25, which are candidate transmission-blocking vaccine antigens. We demonstrated that the VLPs effectively induce antibodies to malaria vaccine candidates with minimal induction of antibodies to the duck-HBV scaffold antigen. Antibodies to Pfs230 also recognised native protein on the surface of gametocytes, and antibodies to both Pfs230 and Pfs25 demonstrated transmission-reducing activity in standard membrane feeding assays. These results establish the potential utility of this VLP platform for malaria vaccines, which may be suitable for the development of multi-component vaccines that achieve high vaccine efficacy and transmission-blocking immunity.

scholarly journals Malaria vaccine candidates displayed on novel virus-like particles are immunogenic and induce transmission-blocking activity

PLoS ONE ◽  
2019 ◽  
Vol 14 (9) ◽  
pp. e0221733 ◽  
Author(s):  
Jo-Anne Chan ◽  
David Wetzel ◽  
Linda Reiling ◽  
Kazutoyo Miura ◽  
Damien R. Drew ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Transmission Blocking ◽  
Vaccine Candidates ◽  
Virus Like Particles ◽  
Blocking Activity ◽  
Novel Virus

Plasmodium falciparum Pf77 and male development gene 1 as vaccine antigens that induce potent transmission-reducing antibodies

2021 ◽  
Vol 13 (597) ◽  
pp. eabg2112
Author(s):  
Abhai K. Tripathi ◽  
Miranda S. Oakley ◽  
Nitin Verma ◽  
Godfree Mlambo ◽  
Hong Zheng ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Phase 1 ◽  
Biological Properties ◽  
Natural Immunity ◽  
Specific Expression ◽  
Transmission Blocking ◽  
Male Development ◽  
Malaria Vaccines ◽  
Membrane Feeding ◽  
Vaccine Antigens

Malaria vaccines that disrupt the Plasmodium life cycle in mosquitoes and reduce parasite transmission in endemic areas are termed transmission-blocking vaccines (TBVs). Despite decades of research, there are only a few Plasmodium falciparum antigens that indisputably and reproducibly demonstrate transmission-blocking immunity. So far, only two TBV candidates have advanced to phase 1/2 clinical testing with limited success. By applying an unbiased transcriptomics-based approach, we have identified Pf77 and male development gene 1 (PfMDV-1) as two P. falciparum TBV antigens that, upon immunization, induced antibodies that caused reductions in oocyst counts in Anopheles mosquito midguts in a standard membrane feeding assay. In-depth studies were performed to characterize the genetic diversity of, stage-specific expression by, and natural immunity to these two molecules to evaluate their suitability as TBV candidates. Pf77 and PfMDV-1 display limited antigenic polymorphism, are pan-developmentally expressed within the parasite, and induce naturally occurring antibodies in Ghanaian adults, which raises the prospect of natural boosting of vaccine-induced immune response in endemic regions. Together, these biological properties suggest that Pf77 and PfMDV-1 may warrant further investigation as TBV candidates.

scholarly journals In silico characterisation of putative Plasmodium falciparum vaccine candidates in African malaria populations

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
O. Ajibola ◽  
M. F. Diop ◽  
A. Ghansah ◽  
L. Amenga-Etego ◽  
L. Golassa ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Transmembrane Domain ◽  
Vaccine Development ◽  
Balancing Selection ◽  
Immune Recognition ◽  
African Countries ◽  
Vaccine Candidates ◽  
D Values ◽  
Tajima’S D

AbstractGenetic diversity of surface exposed and stage specific Plasmodium falciparum immunogenic proteins pose a major roadblock to developing an effective malaria vaccine with broad and long-lasting immunity. We conducted a prospective genetic analysis of candidate antigens (msp1, ama1, rh5, eba175, glurp, celtos, csp, lsa3, Pfsea, trap, conserved chrom3, hyp9, hyp10, phistb, surfin8.2, and surfin14.1) for malaria vaccine development on 2375 P. falciparum sequences from 16 African countries. We described signatures of balancing selection inferred from positive values of Tajima’s D for all antigens across all populations except for glurp. This could be as a result of immune selection on these antigens as positive Tajima’s D values mapped to regions with putative immune epitopes. A less diverse phistb antigen was characterised with a transmembrane domain, glycophosphatidyl anchors between the N and C- terminals, and surface epitopes that could be targets of immune recognition. This study demonstrates the value of population genetic and immunoinformatic analysis for identifying and characterising new putative vaccine candidates towards improving strain transcending immunity, and vaccine efficacy across all endemic populations.

scholarly journals Vaccines against malaria

2011 ◽  
Vol 366 (1579) ◽  
pp. 2806-2814 ◽  
Author(s):  
Adrian V. S. Hill
Keyword(s):  
Life Cycle ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Viral Vector ◽  
Cost Effective ◽  
Life Cycle Stage ◽  
Phase Iii ◽  
Small Scale ◽  
Vaccine Candidates ◽  
Adjuvant Vaccine

There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.

scholarly journals Phase I Testing of a Malaria Vaccine Composed of Hepatitis B Virus Core Particles Expressing Plasmodium falciparum Circumsporozoite Epitopes

2004 ◽  
Vol 72 (11) ◽  
pp. 6519-6527 ◽  
Author(s):  
Elizabeth H. Nardin ◽  
Giane A. Oliveira ◽  
J. Mauricio Calvo-Calle ◽  
Kristiane Wetzel ◽  
Carolin Maier ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Phase I ◽  
Malaria Vaccine ◽  
Vaccine Candidate ◽  
Virus Like Particles ◽  
Virus Core ◽  
B Virus ◽  
Malaria Vaccine Candidate

ABSTRACT We report the first phase I trial to assess the safety and immunogenicity of a malaria vaccine candidate, ICC-1132 (Malarivax), composed of a modified hepatitis B virus core protein (HBc) containing minimal epitopes of the Plasmodium falciparum circumsporozoite (CS) protein. When expressed in Escherichia coli, the recombinant ICC-1132 protein forms virus-like particles that were found to be highly immunogenic in preclinical studies of mice and monkeys. Twenty healthy adult volunteers received a 20- or a 50-μg dose of alum-adsorbed ICC-1132 administered intramuscularly at 0, 2, and 6 months. The majority of volunteers in the group receiving the 50-μg dose developed antibodies to CS repeats as well as to HBc. Malaria-specific T cells that secreted gamma interferon were also detected after a single immunization with ICC-1132-alum. These studies support ICC-1132 as a promising malaria vaccine candidate for further clinical testing using more-potent adjuvant formulations and confirm the potential of modified HBc virus-like particles as a delivery platform for vaccines against other human pathogens.

scholarly journals Malaria vaccines: lessons from field trials

1994 ◽  
Vol 10 (suppl 2) ◽  
pp. S310-S326 ◽  
Author(s):  
Claudio J. Struchiner ◽  
M. Elizabeth Halloran ◽  
Robert C. Brunet ◽  
José M. C. Ribeiro ◽  
Eduardo Massad
Keyword(s):  
Causal Inference ◽  
Vaccine Efficacy ◽  
Malaria Vaccine ◽  
Field Trials ◽  
Final States ◽  
Vaccine Candidates ◽  
Malaria Vaccines ◽  
Epidemiologic Data

Malaria vaccine candidates have already been tested and new trials are being carried out. We present a brief description of specific issues of validity that are relevant when assessing vaccine efficacy in the field and illustrate how the application of these principles might improve our interpretation of the data being gathered in actual malaria vaccine field trials. Our discussion assumes that vaccine evaluation shares the same general principles of validity with epidemiologic causal inference, i.e., the process of drawing inferences from epidemiologic data aiming at the identification of causes of diseases. Judicious exercise of these principles indicates that, for meaningful interpretation, measures of vaccine efficacy require definitions based upon arguments conditional on the amount of exposure to infection, and specification of the initial and final states in which one believes the effect of interest takes place.

scholarly journals Antibody Targets and Properties for Complement-Fixation Against the Circumsporozoite Protein in Malaria Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Liriye Kurtovic ◽  
Damien R. Drew ◽  
Arlene E. Dent ◽  
James W. Kazura ◽  
James G. Beeson
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Complement Fixation ◽  
Terminal Region ◽  
Antibody Responses ◽  
Circumsporozoite Protein ◽  
Full Length ◽  
Acquired Immunity ◽  
Vaccine Candidates

The Plasmodium falciparum circumsporozoite protein (CSP) forms the basis of leading subunit malaria vaccine candidates. However, the mechanisms and specific targets of immunity are poorly defined. Recent findings suggest that antibody-mediated complement-fixation and activation play an important role in immunity. Here, we investigated the regions of CSP targeted by functional complement-fixing antibodies and the antibody properties associated with this activity. We quantified IgG, IgM, and functional complement-fixing antibody responses to different regions of CSP among Kenyan adults naturally exposed to malaria (n=102) and using a series of rabbit vaccination studies. Individuals who acquired functional complement-fixing antibodies had higher IgG, IgM and IgG1 and IgG3 to CSP. Acquired complement-fixing antibodies targeted the N-terminal, central-repeat, and C-terminal regions of CSP, and positive responders had greater antibody breadth compared to those who were negative for complement-fixing antibodies (p<0.05). Using rabbit vaccinations as a model, we confirmed that IgG specific to the central-repeat and non-repeat regions of CSP could effectively fix complement. However, vaccination with near full length CSP in rabbits poorly induced antibodies to the N-terminal region compared to naturally-acquired immunity in humans. Poor induction of N-terminal antibodies was also observed in a vaccination study performed in mice. IgG and IgM to all three regions of CSP play a role in mediating complement-fixation, which has important implications for malaria vaccine development.

scholarly journals Progress and Insights Toward an Effective Placental Malaria Vaccine

2021 ◽  
Vol 12 ◽  
Author(s):  
Benoît Gamain ◽  
Arnaud Chêne ◽  
Nicola K. Viebig ◽  
Nicaise Tuikue Ndam ◽  
Morten A. Nielsen
Keyword(s):  
Pregnant Women ◽  
Chondroitin Sulfate ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Placental Malaria ◽  
Premature Delivery ◽  
Phase I Clinical Trials ◽  
Malaria Vaccines ◽  
Clinical Consequences ◽  
Chondroitin Sulfate A

In areas where Plasmodium falciparum transmission is endemic, clinical immunity against malaria is progressively acquired during childhood and adults are usually protected against the severe clinical consequences of the disease. Nevertheless, pregnant women, notably during their first pregnancies, are susceptible to placental malaria and the associated serious clinical outcomes. Placental malaria is characterized by the massive accumulation of P. falciparum infected erythrocytes and monocytes in the placental intervillous spaces leading to maternal anaemia, hypertension, stillbirth and low birth weight due to premature delivery, and foetal growth retardation. Remarkably, the prevalence of placental malaria sharply decreases with successive pregnancies. This protection is associated with the development of antibodies directed towards the surface of P. falciparum-infected erythrocytes from placental origin. Placental sequestration is mediated by the interaction between VAR2CSA, a member of the P. falciparum erythrocyte membrane protein 1 family expressed on the infected erythrocytes surface, and the placental receptor chondroitin sulfate A. VAR2CSA stands today as the leading candidate for a placental malaria vaccine. We recently reported the safety and immunogenicity of two VAR2CSA-derived placental malaria vaccines (PRIMVAC and PAMVAC), spanning the chondroitin sulfate A-binding region of VAR2CSA, in both malaria-naïve and P. falciparum-exposed non-pregnant women in two distinct Phase I clinical trials (ClinicalTrials.gov, NCT02658253 and NCT02647489). This review discusses recent advances in placental malaria vaccine development, with a focus on the recent clinical data, and discusses the next clinical steps to undertake in order to better comprehend vaccine-induced immunity and accelerate vaccine development.

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.

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