scholarly journals Design and assessment of TRAP-CSP fusion antigens as effective malaria vaccines

2019 ◽  
Author(s):  
Chafen Lu ◽  
Gaojie Song ◽  
Kristin Beale ◽  
Jiabin Yan ◽  
Emma Garst ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Development ◽  
Antibody Responses ◽  
Effective Vaccine ◽  
Repeat Region ◽  
Partial Protection ◽  
Adhesion Protein ◽  
Malaria Vaccines ◽  
Multi Stage ◽  
Antibody Titers

AbstractThe circumsporozoite protein (CSP) and thrombospondin-related adhesion protein (TRAP) are major targets for pre-erythrocytic malaria vaccine development. However, the most advanced CSP-based vaccine RTS,S provides only partial protection, highlighting the need for innovative approaches for vaccine design and development. Here we design and characterize TRAP-CSP fusion antigens, and evaluate their immunogenicity and protection against malaria infection. TRAP N-terminal folded domains were fused to CSP C-terminal fragments consisting of the C-terminal αTSR domain with or without the intervening repeat region. Homogenous, monomeric and properly folded fusion proteins were purified from mammalian transfectants. Notably, fusion improved expression of chimeras relative to the TRAP or CSP components alone. Immunization of BALB/c mice with the P. berghei TRAP-CSP fusion antigens formulated in AddaVax adjuvant elicited antigen-specific antibody responses. Remarkably, fusion antigens containing the CSP repeat region conferred complete sterile protection against P. berghei sporozoite challenge, and furthermore, mice that survived the challenge were completely protected from re-challenge 16 weeks after the first challenge. In contrast, fusion antigens lacking the CSP repeat region were less effective, indicating that the CSP repeat region provided enhanced protection, which correlated with higher antibody titers elicited by fusion antigens containing the CSP repeat region. In addition, we demonstrated that N-linked glycans had no significant effect on antibody elicitation or protection. Our results show that TRAP-CSP fusion antigens could be highly effective vaccine candidates. Our approach provides a platform for designing multi-antigen/multi-stage fusion antigens as next generation more effective malaria vaccines.

scholarly journals A Peptide-BasedPlasmodium falciparumCircumsporozoite Assay To Test for Serum Antibody Responses to Pre-Erythrocyte Malaria Vaccines

2011 ◽  
Vol 18 (5) ◽  
pp. 776-782 ◽  
Author(s):  
Stefan Kostense ◽  
Bregje Mommaas ◽  
Jenny Hendriks ◽  
Mariëlle Verhoeven ◽  
Mariska ter Haak ◽  
...  
Keyword(s):  
High Performance ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Enzyme Linked Immunosorbent Assay ◽  
Repeat Region ◽  
Peptide Antigen ◽  
Content Type ◽  
Good Marker ◽  
Malaria Vaccines ◽  
Antibody Titers

ABSTRACTVarious pre-erythrocyte malaria vaccines are currently in clinical development, and among these is the adenovirus serotype 35-based circumsporozoite (CS) vaccine produced on PER.C6 cells. Although the immunological correlate of protection against malaria remains to be established, the CS antibody titer is a good marker for evaluation of candidate vaccines. Here we describe the validation of an anti-Plasmodium falciparumcircumsporozoite antibody enzyme-linked immunosorbent assay (ELISA) based on the binding of antibodies to a peptide antigen mimicking the CS repeat region. The interassay variability was determined to be below a coefficient of variation (CV) of 15%, and sensitivity was sufficient to detect low antibody titers in subjects from endemic regions. Antibody titers were in agreement with total antibody responses to the whole CS protein. Due to its simplicity and high performance, the ELISA is an easy and rapid method for assessment of pre-erythrocyte malaria vaccines based on CS.

scholarly journals Construction and Immunogenicity of Recombinant Adenovirus Vaccines Expressing the HMW1, HMW2, or Hia Adhesion Protein of Nontypeable Haemophilus influenzae

2010 ◽  
Vol 17 (10) ◽  
pp. 1567-1575 ◽  
Author(s):  
Linda E. Winter ◽  
Stephen J. Barenkamp
Keyword(s):  
Haemophilus Influenzae ◽  
Vaccine Development ◽  
Recombinant Adenovirus ◽  
Serum Antibody ◽  
Nontypeable Haemophilus Influenzae ◽  
Hek 293 ◽  
Adhesion Protein ◽  
Protective Antigens ◽  
Antibody Titers ◽  
Adenoviral Construct

ABSTRACT The objective of the present study was to construct and assess the immunogenicity of recombinant adenovirus vectors expressing the HMW1, HMW2, or Hia protein of nontypeable Haemophilus influenzae (NTHi). These proteins are critical adhesins and potential protective antigens expressed by NTHi. Segments of the hmw1A and hmw2A structural genes that encode the distal one-half of mature HMW1 or HMW2 were cloned into the T7 expression vector pGEMEX-2. These constructs encoded stable HMW1 or HMW2 recombinant fusion protein that expresses B-cell epitopes common to most NTHi strains. A segment of the hia gene that encodes the surface-exposed portion of mature Hia was also cloned into pGEMEX-2. The resulting T7 gene 10 translational fusions were excised from the parent plasmids and cloned into the shuttle plasmid pDC316. Cotransfection of HEK 293 cells with the pDC316 derivatives and pBHGloxΔE1,3Cre resulted in the production of viral plaques from which recombinant adenoviruses expressing fusion proteins were recovered. Chinchillas immunized intraperitoneally with a single 108-PFU dose of either the HMW2 or Hia adenoviral construct developed high anti-HMW2 or anti-Hia serum antibody titers within 4 weeks of immunization. Chinchillas immunized intranasally with a single 107- to 109-PFU dose of the Hia adenoviral construct also developed high anti-Hia serum antibody titers within 8 weeks of immunization. Recombinant adenoviruses represent a promising system to induce mucosal and systemic immunity and protection against mucosal diseases such as otitis media. Recombinant adenoviruses expressing recombinant HMW1, HMW2, or Hia protein will be important new tools in NTHi vaccine development efforts.

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 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 Efficacy of a Plasmodium vivax Malaria Vaccine Using ChAd63 and Modified Vaccinia Ankara Expressing Thrombospondin-Related Anonymous Protein as Assessed with Transgenic Plasmodium berghei Parasites

2013 ◽  
Vol 82 (3) ◽  
pp. 1277-1286 ◽  
Author(s):  
Karolis Bauza ◽  
Tomas Malinauskas ◽  
Claudia Pfander ◽  
Burcu Anar ◽  
E. Yvonne Jones ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Plasmodium Berghei ◽  
Malaria Vaccine ◽  
Protective Mechanisms ◽  
Content Type ◽  
Cell Responses ◽  
Malaria Vaccines ◽  
Modified Vaccinia Virus Ankara ◽  
Plasmodium Vivax Malaria ◽  
Antibody Titers

ABSTRACTPlasmodium vivaxis the world's most widely distributed malaria parasite and a potential cause of morbidity and mortality for approximately 2.85 billion people living mainly in Southeast Asia and Latin America. Despite this dramatic burden, very few vaccines have been assessed in humans. The clinically relevant vectors modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAd63 are promising delivery systems for malaria vaccines due to their safety profiles and proven ability to induce protective immune responses againstPlasmodium falciparumthrombospondin-related anonymous protein (TRAP) in clinical trials. Here, we describe the development of new recombinant ChAd63 and MVA vectors expressingP. vivaxTRAP (PvTRAP) and show their ability to induce high antibody titers and T cell responses in mice. In addition, we report a novel way of assessing the efficacy of new candidate vaccines againstP. vivaxusing a fully infectious transgenicPlasmodium bergheiparasite expressingP. vivaxTRAP to allow studies of vaccine efficacy and protective mechanisms in rodents. Using this model, we found that both CD8+T cells and antibodies mediated protection against malaria using virus-vectored vaccines. Our data indicate that ChAd63 and MVA expressing PvTRAP are good preerythrocytic-stage vaccine candidates with potential for future clinical application.

scholarly journals Innocuousness of conjunctival vaccination with Brucella melitensis strain Rev.1 in pregnant Iranian fat-tailed ewes

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Saeed Alamian ◽  
Ramin Bagheri Nejad ◽  
Hamid Reza Jalali ◽  
Armin Kalantari ◽  
Afshar Etemadi
Keyword(s):  
Vaccine Strain ◽  
Brucella Melitensis ◽  
Late Pregnancy ◽  
Vaginal Swab ◽  
Antibody Responses ◽  
Effective Vaccine ◽  
Post Vaccination ◽  
Excretion In Milk ◽  
Induced Abortions ◽  
Antibody Titers

<em>Brucella</em> <em>melitensis</em> strain Rev.1 is the most effective vaccine against brucellosis in sheep and goats. In Iran, mass vaccination is carried out all over the country in which adult animals are immunized by subcutaneous injection of reduced doses of the vaccine. However, due to antibody responses elicited by vaccination, concomitant implementation of test-andslaughter is impossible. To overcome the problem, vaccination through conjunctival route is recommended. In this study, serological responses of six pregnant Iranian fat-tailed ewes to conjunctival vaccination with standard doses of the vaccine were evaluated using modified Rose Bengal test, serum agglutination test and indirect ELISA. Besides, vaccine strain excretion in milk and vaginal discharges was also examined by microbiological culture of milk and vaginal swab samples taken one day post-parturition. Animals were vaccinated during the second half of gestation. As the results, antibody titers of five (83.3%) ewes decreased to the levels not detectable by the tests within three months after vaccination. No vaccine-induced abortions occurred and vaccinated ewes delivered healthy lambs 50.33±15.56 (mean ± standard deviation) days post-vaccination. Vaccine strain was not isolated from milk and vaginal swab samples. Generally, our study shows full doses of <em>B. melitensis</em> strain Rev.1 can be used conjunctively to vaccinate pregnant Iranian sheep during late pregnancy without abortifacient effects, prolonged antibody responses and vaccine strain excretion in milk and vaginal discharges. Nevertheless, further studies are required to determine safety and immunogenicity of the vaccine in field conditions.

scholarly journals Malaria vaccines: high-throughput tools for antigens discovery with potential for their development

2013 ◽  
pp. 121-128
Author(s):  
Nora Céspedes ◽  
Andrés Vallejo ◽  
Myriam Arévalo-Herrera ◽  
Sócrates Herrera
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Development ◽  
Plasmodium Species ◽  
Cost Effective ◽  
Control Measures ◽  
Anopheles Mosquitoes ◽  
Malaria Vaccines ◽  
Large Numbers ◽  
Immune Potential ◽  
Selection Of

Malaria is a disease induced by parasites of the Plasmodium genus, which are transmitted by Anopheles mosquitoes and represents a great socio-economic burden worldwide. Plasmodium vivax is the second species of malaria worldwide, but it is the most prevalent in Latin America and other regions of the planet. It is currently considered that vaccines represent a cost-effective strategy for controlling transmissible diseases and could complement other malaria control measures; however, the chemical and immunological complexity of the parasite has hindered development of effective vaccines. Recent availability of several genomes of Plasmodium species, as well as bioinformatics tools are allowing the selection of large numbers of proteins and analysis of their immune potential. Herein, we review recently developed strategies for discovery of novel antigens with potential for malaria vaccine development.

The Promise of a Malaria Vaccine—Are We Closer?

2018 ◽  
Vol 72 (1) ◽  
pp. 273-292 ◽  
Author(s):  
Matthew B. Laurens
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Development ◽  
Phase 3 ◽  
Target Populations ◽  
The Past ◽  
Malaria Vaccines ◽  
Long Duration ◽  
Implementation Studies ◽  
Endemic Areas ◽  
Pilot Implementation

Malaria vaccine development has rapidly advanced in the past decade. The very first phase 3 clinical trial of the RTS,S vaccine was completed with over 15,000 African infants and children, and pilot implementation studies are underway. Next-generation candidate vaccines using novel antigens, platforms, or approaches targeting different and/or multiple stages of the Plasmodium life cycle are being tested. Many candidates, in various stages of development, promise enhanced efficacy of long duration and broad protection against genetically diverse malaria strains, with a few studies under way in target populations in endemic areas. Malaria vaccines together with other interventions promise interruption and eventual elimination of malaria in endemic areas.

scholarly journals A VLP for validation of the Plasmodium falciparum circumsporozoite protein junctional epitope for vaccine development

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Erwan Atcheson ◽  
Adrian V. S. Hill ◽  
Arturo Reyes-Sandoval
Keyword(s):  
Neutralizing Antibodies ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Cell Epitope ◽  
Clinical Malaria ◽  
Repeat Region ◽  
Clinical Level ◽  
Virus Like Particle ◽  
Global Health Issue

AbstractMalaria continues to be a pressing global health issue, causing nearly half a million deaths per year. An effective malaria vaccine could radically improve our ability to control and eliminate this pathogen. The most advanced malaria vaccine, RTS,S, confers only 30% protective efficacy under field conditions, and hence the search continues for improved vaccines. New antigens and formulations are always first developed at a pre-clinical level. This paper describes the development of a platform to supplement existing tools of pre-clinical malaria vaccine development, by displaying linear peptides on a virus-like particle (VLP). Peptides from PfCSP, particularly from outside the normal target of neutralizing antibodies, the central NANP repeat region, are screened for evidence of protective efficacy. One peptide, recently identified as a target of potent neutralizing antibodies and lying at the junction between the N-terminal domain and the central repeat region of PfCSP, is found to confer protective efficacy against malaria sporozoite challenge in mice when presented on the Qβ VLP. The platform is also used to explore the effects of increasing numbers of NANP unit repeats, and including a universal CD4+ T-cell epitope from tetanus toxin, on immunogenicity and protective efficacy. The VLP-peptide platform is shown to be of use in screening malaria peptides for protective efficacy and answering basic vaccinology questions in a pre-clinical setting.

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