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.

scholarly journals Expression and Solubilization of Insect Cell-Based Rabies Virus Glycoprotein and Assessment of Its Immunogenicity and Protective Efficacy in Mice

2011 ◽  
Vol 18 (10) ◽  
pp. 1673-1679 ◽  
Author(s):  
R. Ramya ◽  
B. Mohana Subramanian ◽  
V. Sivakumar ◽  
R. L. Senthilkumar ◽  
K. R. S. Sambasiva Rao ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Insect Cell ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Vector System ◽  
Soluble Form ◽  
Rabies Virus Glycoprotein ◽  
Virus Glycoprotein

ABSTRACTRabies is a fatal zoonotic disease of serious public health and economic significance worldwide. The rabies virus glycoprotein (RVG) has been the major target for subunit vaccine development, since it harbors domains responsible for induction of virus-neutralizing antibodies, infectivity, and neurovirulence. The glycoprotein (G) was cloned using the baculovirus expression vector system (BEVS) and expressed inSpodoptera frugiperda(Sf-9) cells. In order to obtain a soluble form of G suitable for experimentation in mice, 18 different combinations of buffers and detergents were evaluated for their ability to solubilize the insect cell membrane-associated G. The combination that involved 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulfonate (CHAPS) detergent in lysis buffer 1, formulated with Tris, NaCl, 10% dimethyl sulfoxide (DMSO), and EDTA, gave the highest yield of soluble G, as evidenced by the experimental data. Subsequently, several other parameters, such as the concentration of CHAPS and the duration and temperature of the treatment for the effective solubilization of G, were optimized. The CHAPS detergent, buffered at a concentration of 0.4% to 0.7% (wt/vol) at room temperature (23 to 25°C) for 30 min to 1 h using buffer 1, containing 10% DMSO, resulted in consistently high yields. The G solubilized using CHAPS detergent was found to be immunogenic when tested in mice, as evidenced by high virus-neutralizing antibody titers in sera and 100% protection upon virulent intracerebral challenge with the challenge virus standard (CVS) strain of rabies virus. The results of the mice study indicated that G solubilized with CHAPS detergent retained the immunologically relevant domains in the native conformation, thereby paving the way for producing a cell-free and efficacious subunit vaccine.

scholarly journals Identification of a Potent Combination of Key Plasmodium falciparum Merozoite Antigens That Elicit Strain-Transcending Parasite-Neutralizing Antibodies

2012 ◽  
Vol 81 (2) ◽  
pp. 441-451 ◽  
Author(s):  
Alok K. Pandey ◽  
K. Sony Reddy ◽  
Tajali Sahar ◽  
Sonal Gupta ◽  
Hina Singh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Neutralizing Antibodies ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Blood Stage ◽  
Content Type ◽  
Receptor Blocking ◽  
Erythrocyte Invasion ◽  
Invasion Inhibition ◽  
Blood Stage Malaria

ABSTRACTBlood-stage malaria vaccines that target singlePlasmodium falciparumantigens involved in erythrocyte invasion have not induced optimal protection in field trials. Blood-stage malaria vaccine development has faced two major hurdles, antigenic polymorphisms and molecular redundancy, which have led to an inability to demonstrate potent, strain-transcending, invasion-inhibitory antibodies. Vaccines that target multiple invasion-related parasite proteins may inhibit erythrocyte invasion more efficiently. Our approach is to develop a receptor-blocking blood-stage vaccine againstP. falciparumthat targets the erythrocyte binding domains of multiple parasite adhesins, blocking their interaction with their receptors and thus inhibiting erythrocyte invasion. However, with numerous invasion ligands, the challenge is to identify combinations that elicit potent strain-transcending invasion inhibition. We evaluated the invasion-inhibitory activities of 20 different triple combinations of antibodies mixedin vitroagainst a diverse set of six key merozoite ligands, including the novel ligandsP. falciparumapical asparagine-rich protein (PfAARP), EBA-175 (PfF2),P. falciparumreticulocyte binding-like homologous protein 1 (PfRH1), PfRH2, PfRH4, andPlasmodiumthrombospondin apical merozoite protein (PTRAMP), which are localized in different apical organelles and are translocated to the merozoite surface at different time points during invasion. They bind erythrocytes with different specificities and are thus involved in distinct invasion pathways. The antibody combination of EBA-175 (PfF2), PfRH2, and PfAARP produced the most efficacious strain-transcending inhibition of erythrocyte invasion against diverseP. falciparumclones. This potent antigen combination was selected for coimmunization as a mixture that induced balanced antibody responses against each antigen and inhibited erythrocyte invasion efficiently. We have thus demonstrated a novel two-step screening approach to identify a potent antigen combination that elicits strong strain-transcending invasion inhibition, supporting its development as a receptor-blocking malaria vaccine.

scholarly journals Humoral Responses to Plasmodium falciparum Blood-Stage Antigens and Association with Incidence of Clinical Malaria in Children Living in an Area of Seasonal Malaria Transmission in Burkina Faso, West Africa

2007 ◽  
Vol 76 (2) ◽  
pp. 759-766 ◽  
Author(s):  
Issa Nebie ◽  
Amidou Diarra ◽  
Alphonse Ouedraogo ◽  
Issiaka Soulama ◽  
Edith C. Bougouma ◽  
...  
Keyword(s):  
Malaria Transmission ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Malaria Incidence ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Clinical Malaria ◽  
Blood Stage ◽  
Igg Subclass ◽  
Malaria Surveillance

ABSTRACT There is longstanding evidence that immunoglobulin G (IgG) has a role in protection against clinical malaria, and human antibodies of the cytophilic subclasses are thought to be particularly critical in this respect. In this cohort study, 286 Burkinabè children 6 months to 15 years old were kept under malaria surveillance in order to assess the protective role of antibody responses against four antigens which are currently being evaluated as vaccine candidates: apical membrane antigen 1 (AMA1), merozoite surface protein 1-19 (MSP1-19), MSP3, and glutamate-rich protein (GLURP). Total IgG, IgM, and IgG subclass responses were measured just before the malaria transmission season. The incidence of malaria was 2.4 episodes per child year of risk. After adjusting for the confounding effects of age, the level of total IgG to GLURP was strongly associated with reduced malaria incidence (incidence rate ratio associated with a doubling of total IgG, 0.79; 95% confidence interval, 0.66 to 0.94; P = 0.009.); there was a borderline statistically significant association between the level of total IgG to MSP3 and malaria incidence and no evidence of an association for total IgG to AMA1 and to MSP1-19. Of the IgG subclass responses studied, only IgG3 and IgG4 against GLURP and IgG1 against AMA1 were associated with reduced risk of clinical malaria. There was no evidence of an interaction between responses to AMA1 and baseline parasitemia in their effects on malaria incidence. Currently included in malaria vaccine formulations for clinical trials in humans, these blood-stage antigens, AMA1 and GLURP, offer good prospects for malaria vaccine development.

scholarly journals Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research

2013 ◽  
Vol 2013 ◽  
pp. 1-19 ◽  
Author(s):  
Elena Mata ◽  
Aiala Salvador ◽  
Manoli Igartua ◽  
Rosa María Hernández ◽  
José Luis Pedraz
Keyword(s):  
Protective Immunity ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Memory Cell ◽  
Clinical Malaria ◽  
Vaccine Formulation ◽  
Vaccine Adjuvants ◽  
Cell Responses ◽  
The Status ◽  
Antigenic Targets

There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages.

scholarly journals Identification of four linear B-cell epitopes on the SARS-CoV-2 spike protein able to elicit neutralizing antibodies

2020 ◽  
Author(s):  
Lin Li ◽  
Zhongpeng Zhao ◽  
Xiaolan Yang ◽  
WenDong Li ◽  
Shaolong Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Cell Epitope ◽  
Effective Vaccine ◽  
B Cell Epitopes ◽  
S Protein ◽  
The Public ◽  
B Cell Epitope ◽  
Linear B

SARS-CoV-2 unprecedentedly threatens the public health at worldwide level. There is an urgent need to develop an effective vaccine within a highly accelerated time. Here, we present the most comprehensive S-protein-based linear B-cell epitope candidate list by combining epitopes predicted by eight widely-used immune-informatics methods with the epitopes curated from literature published between Feb 6, 2020 and July 10, 2020. We find four top prioritized linear B-cell epitopes in the hotspot regions of S protein can specifically bind with serum antibodies from horse, mouse, and monkey inoculated with different SARS-CoV-2 vaccine candidates or a patient recovering from COVID-19. The four linear B-cell epitopes can induce neutralizing antibodies against both pseudo and live SARS-CoV-2 virus in immunized wild-type BALB/c mice. This study suggests that the four linear B-cell epitopes are potentially important candidates for serological assay or vaccine development.

scholarly journals A Plasmodium Promiscuous T Cell Epitope Delivered within the Ad5 Hexon Protein Enhances the Protective Efficacy of a Protein Based Malaria Vaccine

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0154819 ◽  
Author(s):  
Jairo Andres Fonseca ◽  
Monica Cabrera-Mora ◽  
Elena A. Kashentseva ◽  
John Paul Villegas ◽  
Alejandra Fernandez ◽  
...  
Keyword(s):  
T Cell ◽  
Malaria Vaccine ◽  
Protective Efficacy ◽  
Cell Epitope ◽  
T Cell Epitope ◽  
Hexon Protein

scholarly journals Gamma-irradiated SARS-CoV-2 vaccine candidate, OZG-38.61.3, confers protection from SARS-CoV-2 challenge in human ACEII-transgenic mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raife Dilek Turan ◽  
Cihan Tastan ◽  
Derya Dilek Kancagi ◽  
Bulut Yurtsever ◽  
Gozde Sir Karakus ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Vaccine Candidate ◽  
Protective Efficacy ◽  
Phase 1 ◽  
Challenge Test ◽  
Viral Rna ◽  
Viral Vaccine ◽  
Gamma Irradiated

AbstractThe SARS-CoV-2 virus caused the most severe pandemic around the world, and vaccine development for urgent use became a crucial issue. Inactivated virus formulated vaccines such as Hepatitis A and smallpox proved to be reliable approaches for immunization for prolonged periods. In this study, a gamma-irradiated inactivated virus vaccine does not require an extra purification process, unlike the chemically inactivated vaccines. Hence, the novelty of our vaccine candidate (OZG-38.61.3) is that it is a non-adjuvant added, gamma-irradiated, and intradermally applied inactive viral vaccine. Efficiency and safety dose (either 1013 or 1014 viral RNA copy per dose) of OZG-38.61.3 was initially determined in BALB/c mice. This was followed by testing the immunogenicity and protective efficacy of the vaccine. Human ACE2-encoding transgenic mice were immunized and then infected with the SARS-CoV-2 virus for the challenge test. This study shows that vaccinated mice have lowered SARS-CoV-2 viral RNA copy numbers both in oropharyngeal specimens and in the histological analysis of the lung tissues along with humoral and cellular immune responses, including the neutralizing antibodies similar to those shown in BALB/c mice without substantial toxicity. Subsequently, plans are being made for the commencement of Phase 1 clinical trial of the OZG-38.61.3 vaccine for the COVID-19 pandemic.

scholarly journals Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

2016 ◽  
Vol 90 (10) ◽  
pp. 5031-5046 ◽  
Author(s):  
Navid Madani ◽  
Amy M. Princiotto ◽  
David Easterhoff ◽  
Todd Bradley ◽  
Kan Luo ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Effective Vaccine ◽  
Broadly Neutralizing Antibodies ◽  
Variable Regions ◽  
Hiv 1

ABSTRACTThe human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines.IMPORTANCEPreventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus-sensitizing microbicide is combined with a vaccine.

scholarly journals Influence of Respiratory Syncytial Virus F Glycoprotein Conformation on Induction of Protective Immune Responses

2016 ◽  
Vol 90 (11) ◽  
pp. 5485-5498 ◽  
Author(s):  
Concepción Palomo ◽  
Vicente Mas ◽  
Michelle Thom ◽  
Mónica Vázquez ◽  
Olga Cano ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Membrane Fusion ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Protective Antigen ◽  
Protective Efficacy ◽  
Viral Fusion ◽  
Virus Challenge ◽  
Advantages And Disadvantages ◽  
Syncytial Virus

ABSTRACTHuman respiratory syncytial virus (hRSV) vaccine development has received new impetus from structure-based studies of its main protective antigen, the fusion (F) glycoprotein. Three soluble forms of F have been described: monomeric, trimeric prefusion, and trimeric postfusion. Most human neutralizing antibodies recognize epitopes found exclusively in prefusion F. Although prefusion F induces higher levels of neutralizing antibodies than does postfusion F, postfusion F can also induce protection against virus challenge in animals. However, the immunogenicity and protective efficacy of the three forms of F have not hitherto been directly compared. Hence, BALB/c mice were immunized with a single dose of the three proteins adjuvanted with CpG and challenged 4 weeks later with virus. Serum antibodies, lung virus titers, weight loss, and pulmonary pathology were evaluated after challenge. Whereas small amounts of postfusion F were sufficient to protect mice, larger amounts of monomeric and prefusion F proteins were required for protection. However, postfusion and monomeric F proteins were associated with more pathology after challenge than was prefusion F. Antibodies induced by all doses of prefusion F, in contrast to other F protein forms, reacted predominantly with the prefusion F conformation. At high doses, prefusion F also induced the highest titers of neutralizing antibodies, and all mice were protected, yet at low doses of the immunogen, these antibodies neutralized virus poorly, and mice were not protected. These findings should be considered when developing new hRSV vaccine candidates.IMPORTANCEProtection against hRSV infection is afforded mainly by neutralizing antibodies, which recognize mostly epitopes found exclusively in the viral fusion (F) glycoprotein trimer, folded in its prefusion conformation, i.e., before activation for membrane fusion. Although prefusion F is able to induce high levels of neutralizing antibodies, highly stable postfusion F (found after membrane fusion) is also able to induce neutralizing antibodies and protect against infection. In addition, a monomeric form of hRSV F that shares epitopes with prefusion F was recently reported. Since each of the indicated forms of hRSV F may have advantages and disadvantages for the development of safe and efficacious subunit vaccines, a direct comparison of the immunogenic properties and protective efficacies of the different forms of hRSV F was made in a mouse model. The results obtained show important differences between the noted immunogens that should be borne in mind when considering the development of hRSV vaccines.

scholarly journals A yeast expressed RBD-based SARS-CoV-2 vaccine formulated with 3M-052-alum adjuvant promotes protective efficacy in non-human primates

2021 ◽  
Vol 6 (61) ◽  
pp. eabh3634
Author(s):  
Maria Pino ◽  
Talha Abid ◽  
Susan Pereira Ribeiro ◽  
Venkata Viswanadh Edara ◽  
Katharine Floyd ◽  
...  
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Vaccine Development ◽  
Protective Efficacy ◽  
Rhesus Macaques ◽  
Cost Effective ◽  
Blood Monocytes ◽  
Middle Income ◽  
Adjuvanted Vaccine

Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low and middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed SARS-CoV-2 specific receptor-binding domain (RBD) based vaccine in rhesus macaques. We formulated the RBD immunogen in alum, a licensed and an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted vaccine promoted better RBD binding and effector antibodies, higher CoV-2 neutralizing antibodies, improved Th1 biased CD4+T cell reactions, and increased CD8+ T cell responses when compared to the alum-alone adjuvanted vaccine. RBD+3M-052-alum induced a significant reduction of SARS-CoV-2 virus in respiratory tract upon challenge, accompanied by reduced lung inflammation when compared with unvaccinated controls. Anti-RBD antibody responses in vaccinated animals inversely correlated with viral load in nasal secretions and BAL. RBD+3M-052-alum blocked a post SARS-CoV-2 challenge increase in CD14+CD16++ intermediate blood monocytes, and Fractalkine, MCP-1, and TRAIL in the plasma. Decreased plasma analytes and intermediate monocyte frequencies correlated with reduced nasal and BAL viral loads. Lastly, RBD-specific plasma cells accumulated in the draining lymph nodes and not in the bone marrow, contrary to previous findings. Together, these data show that a yeast expressed, RBD-based vaccine+3M-052-alum provides robust immune responses and protection against SARS-CoV-2, making it a strong and scalable vaccine candidate.

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