scholarly journals Tailoring a Combination Preerythrocytic Malaria Vaccine

2015 ◽  
Vol 84 (3) ◽  
pp. 622-634 ◽  
Author(s):  
Karolis Bauza ◽  
Erwan Atcheson ◽  
Tomas Malinauskas ◽  
Andrew M. Blagborough ◽  
Arturo Reyes-Sandoval
Keyword(s):  
Viral Vectors ◽  
Malaria Vaccine ◽  
Subunit Vaccines ◽  
Content Type ◽  
Adhesive Protein ◽  
Order Of Magnitude ◽  
Antibody Titers ◽  
Malaria Vaccine Candidate ◽  
Low Levels ◽  
Combined Trap

The leading malaria vaccine candidate, RTS,S, based on thePlasmodium falciparumcircumsporozoite protein (CSP), will likely be the first publicly adopted malaria vaccine. However, this and other subunit vaccines, such as virus-vectored thrombospondin-related adhesive protein (TRAP), provide only intermediate to low levels of protection. In this study, thePlasmodium bergheihomologues of antigens CSP and TRAP are combined. TRAP is delivered using adenovirus- and vaccinia virus-based vectors in a prime-boost regime. Initially, CSP is also delivered using these viral vectors; however, a reduction of anti-CSP antibodies is seen when combined with virus-vectored TRAP, and the combination is no more protective than either subunit vaccine alone. Using an adenovirus-CSP prime, protein-CSP boost regime, however, increases anti-CSP antibody titers by an order of magnitude, which is maintained when combined with virus-vectored TRAP. This combination regime using protein CSP provided 100% protection in C57BL/6 mice compared to no protection using virus-vectored TRAP alone and 40% protection using adenovirus-CSP prime and protein-CSP boost alone. This suggests that a combination of CSP and TRAP subunit vaccines could enhance protection against malaria.

scholarly journals Transgenic Parasites Stably Expressing Full-Length Plasmodium falciparum Circumsporozoite Protein as a Model for Vaccine Down-Selection in Mice Using Sterile Protection as an Endpoint

2013 ◽  
Vol 20 (6) ◽  
pp. 803-810 ◽  
Author(s):  
Michael D. Porter ◽  
Jennifer Nicki ◽  
Christopher D. Pool ◽  
Margot DeBot ◽  
Ratish M. Illam ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Vaccine ◽  
Circumsporozoite Protein ◽  
Full Length ◽  
Content Type ◽  
Transmission Cycle ◽  
Degree Of Protection ◽  
Antibody Titers ◽  
Malaria Vaccine Candidate ◽  
Transgenic Parasites

ABSTRACTCircumsporozoite protein (CSP) ofPlasmodium falciparumis a protective human malaria vaccine candidate. There is an urgent need for models that can rapidly down-select novel CSP-based vaccine candidates. In the present study, the mouse-mosquito transmission cycle of a transgenicPlasmodium bergheimalaria parasite stably expressing a functional full-lengthP. falciparumCSP was optimized to consistently produce infective sporozoites for protection studies. A minimal sporozoite challenge dose was established, and protection was defined as the absence of blood-stage parasites 14 days after intravenous challenge. The specificity of protection was confirmed by vaccinating mice with multiple CSP constructs of differing lengths and compositions. Constructs that induced high NANP repeat-specific antibody titers in enzyme-linked immunosorbent assays were protective, and the degree of protection was dependent on the antigen dose. There was a positive correlation between antibody avidity and protection. The antibodies in the protected mice recognized the native CSP on the parasites and showed sporozoite invasion inhibitory activity. Passive transfer of anti-CSP antibodies into naive mice also induced protection. Thus, we have demonstrated the utility of a mouse efficacy model to down-select human CSP-based vaccine formulations.

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 Assessment of Chimpanzee Adenovirus Serotype 63 Neutralizing Antibodies Prior to Evaluation of a Candidate Malaria Vaccine Regimen Based on Viral Vectors

2014 ◽  
Vol 21 (6) ◽  
pp. 901-903 ◽  
Author(s):  
Issa Nébié ◽  
Nick J. Edwards ◽  
Alfred B. Tiono ◽  
Katie J. Ewer ◽  
Guillaume S. Sanou ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Viral Vectors ◽  
Malaria Vaccine ◽  
Vaccine Trial ◽  
Neutralizing Antibody ◽  
Adenovirus Serotype ◽  
Candidate Malaria Vaccine ◽  
Antibody Titers ◽  
Adults And Children ◽  
Potential Use

ABSTRACTPrior to a chimpanzee adenovirus-based (ChAd63) malarial vaccine trial, sera were collected to assess ChAd63-specific neutralizing antibody titers in Banfora (Burkina Faso). The low neutralizing antibody titers reported in both adults and children (median titers, 139.1 and 35.0, respectively) are encouraging for the potential use of ChAd63 as a malarial vaccine vector.

scholarly journals Tailoring aPlasmodium vivaxVaccine To Enhance Efficacy through a Combination of a CSP Virus-Like Particle and TRAP Viral Vectors

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Erwan Atcheson ◽  
Karolis Bauza ◽  
Ahmed M. Salman ◽  
Eduardo Alves ◽  
Joshua Blight ◽  
...  
Keyword(s):  
Viral Vectors ◽  
Neglected Tropical Diseases ◽  
Content Type ◽  
Adhesion Protein ◽  
Modified Vaccinia Virus Ankara ◽  
Virus Like Particle ◽  
Single Antigen ◽  
Antibody Titers ◽  
Sparing Effect ◽  
Combined Vaccine

ABSTRACTVivax malaria remains one of the most serious and neglected tropical diseases, with 132 to 391 million clinical cases per year and 2.5 billion people at risk of infection. A vaccine againstPlasmodium vivaxcould have more impact than any other intervention, and the use of a vaccine targeting multiple antigens may result in higher efficacy against sporozoite infection than targeting a single antigen. Here, two leadingP. vivaxpreerythrocytic vaccine candidate antigens, theP. vivaxcircumsporozoite protein (PvCSP) and the thrombospondin-related adhesion protein (PvTRAP) were delivered as a combined vaccine. This strategy provided a dose-sparing effect, with 100% sterile protection in mice using doses that individually conferred low or no protection, as with the unadjuvanted antigens PvTRAP (0%) and PvCSP (50%), and reached protection similar to that of adjuvanted components. Efficacy against malaria infection was assessed using a new mouse challenge model consisting of a double-transgenicPlasmodium bergheiparasite simultaneously expressing PvCSP and PvTRAP used in mice immunized with the virus-like particle (VLP) Rv21 previously reported to induce high efficacy in mice using Matrix-M adjuvant, while PvTRAP was concomitantly administered in chimpanzee adenovirus and modified vaccinia virus Ankara (MVA) vectors (viral-vectored TRAP, or vvTRAP) to support effective induction of T cells. We examined immunity elicited by these vaccines in the context of two adjuvants approved for human use (AddaVax and Matrix-M). Matrix-M supported the highest anti-PvCSP antibody titers when combined with Rv21, and, interestingly, mixing PvCSP Rv21 and PvTRAP viral vectors enhanced immunity to malaria over levels provided by single vaccines.

scholarly journals Mother-Newborn Pairs in Malawi Have Similar Antibody Repertoires to Diverse Malaria Antigens

2017 ◽  
Vol 24 (10) ◽  
Author(s):  
Sarah Boudová ◽  
Jenny A. Walldorf ◽  
Jason A. Bailey ◽  
Titus Divala ◽  
Randy Mungwira ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Vaccine Candidate ◽  
Protein Microarray ◽  
Placental Malaria ◽  
Maternal Antibody ◽  
Content Type ◽  
Wide Range ◽  
Malaria Vaccine Candidate ◽  
Antibody Repertoires ◽  
Antibody Levels

ABSTRACT Maternal antibodies may play a role in protecting newborns against malaria disease. Plasmodium falciparum parasite surface antigens are diverse, and protection from infection requires allele-specific immunity. Although malaria-specific antibodies have been shown to cross the placenta, the extent to which antibodies that respond to the full repertoire of diverse antigens are transferred from the mother to the infant has not been explored. Understanding the breadth of maternal antibody responses and to what extent these antibodies are transferred to the child can inform vaccine design and evaluation. We probed plasma from cord blood and serum from mothers at delivery using a customized protein microarray that included variants of malaria vaccine target antigens to assess the intensity and breadth of seroreactivity to three malaria vaccine candidate antigens in mother-newborn pairs in Malawi. Among the 33 paired specimens that were assessed, mothers and newborns had similar intensity and repertoire of seroreactivity. Maternal antibody levels against vaccine candidate antigens were the strongest predictors of infant antibody levels. Placental malaria did not significantly impair transplacental antibody transfer. However, mothers with placental malaria had significantly higher antibody levels against these blood-stage antigens than mothers without placental malaria. The repertoire and levels of infant antibodies against a wide range of malaria vaccine candidate antigen variants closely mirror maternal levels in breadth and magnitude regardless of evidence of placental malaria. Vaccinating mothers with an effective malaria vaccine during pregnancy may induce high and potentially protective antibody repertoires in newborns.

Prevalence and Induction of Circulating Antibodies against Recombinant Staphylokinase

1994 ◽  
Vol 71 (01) ◽  
pp. 129-133 ◽  
Author(s):  
P J Declerck ◽  
S Vanderschueren ◽  
J Billiet ◽  
H Moreau ◽  
D Collen
Keyword(s):  
Intravenous Administration ◽  
Human Subjects ◽  
Microtiter Plates ◽  
Staphylococcus Aureus Bacteremia ◽  
Alternative Agent ◽  
Antibody Titers ◽  
Potential Alternative ◽  
Circulating Antibodies ◽  
Low Levels ◽  
Antibody Levels

SummaryStreptokinase (SK) is a routinely used thrombolytic agent but it is immunogenic and allergenic; staphylokinase (STA) is a potential alternative agent which is under early clinical evaluation. The comparative prevalence of antibodies against recombinant STA (STAR) and against SK was studied in healthy subjects and their induction with intravenous administration in small groups of patients.Enzyme-linked immunosorbent assays, using microtiter plates coated with STAR or SK and calibration with affinospecific human antibodies, revealed 2.1 to 65 μg/ml (median 11 μg/ml) anti-STAR antibodies and 0.9 to 370 μg/ml (median 18 μg/ml) anti-SK antibodies (p <0.001 vs anti-STAR antibodies) in plasma from 100 blood donors, with corresponding values of 0.6 to 100 μg/ml (median 7.1 μg/ml) and 0.4 to 120 μg/ml (median 7.3 μg/ml), respectively, in 104 patients with angina pectoris. Three out of 17 patients with Staphylococcus aureus bacteremia had significantly increased anti-STAR antibody levels (150, 75 and 75 μg/ml), and STAR neutralizing activities (2.2, 3.6 and 4.1 μg STAR neutralized per ml plasma, respectively). In 6 patients with acute myocardial infarction, given 10 mg STAR intravenously over 30 min, median anti-STAR antibody levels were 3.5 μg/ml at baseline, 2.9 μg/ml at 6 to 8 days and 1.2 μg/ml at 2 to 9 weeks, with median corresponding titers of STAR neutralizing activity at 2 to 9 weeks of 42 μg/ml plasma. Conversely, in 5 patients treated with 1,500,000 units SK over 60 min, median anti-SK antibodies increased from 2.9 μg/ml at baseline to 360 μg/ml at 5 to 10 days, with corresponding median SK neutralizing activities of 13 μg/ml. Antibodies against STAR did not cross-react with SK and vice versa.Plasma from human subjects contains low levels of circulating antibodies against recombinant staphylokinase, and intravenous administration of this compound boosts antibody titers. These antibodies do however not cross-react with streptokinase, whereby the use of these two immunogenic thrombolytic agents would not be mutually exclusive.

scholarly journals Dectin-2-Targeted Antifungal Liposomes Exhibit Enhanced Efficacy

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Suresh Ambati ◽  
Emma C. Ellis ◽  
Jianfeng Lin ◽  
Xiaorong Lin ◽  
Zachary A. Lewis ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Aspergillus Fumigatus ◽  
Effective Dose ◽  
Cryptococcus Neoformans ◽  
Amphotericin B ◽  
Antifungal Drugs ◽  
Extracellular Matrices ◽  
Content Type ◽  
Order Of Magnitude ◽  
Life Threatening

ABSTRACT Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus cause life-threatening candidiasis, cryptococcosis, and aspergillosis, resulting in several hundred thousand deaths annually. The patients at the greatest risk of developing these life-threatening invasive fungal infections have weakened immune systems. The vulnerable population is increasing due to rising numbers of immunocompromised individuals as a result of HIV infection or immunosuppressed individuals receiving anticancer therapies and/or stem cell or organ transplants. While patients are treated with antifungals such as amphotericin B, all antifungals have serious limitations due to lack of sufficient fungicidal effect and/or host toxicity. Even with treatment, 1-year survival rates are low. We explored methods of increasing drug effectiveness by designing fungicide-loaded liposomes specifically targeted to fungal cells. Most pathogenic fungi are encased in cell walls and exopolysaccharide matrices rich in mannans. Dectin-2 is a mammalian innate immune membrane receptor that binds as a dimer to mannans and signals fungal infection. We coated amphotericin-loaded liposomes with monomers of Dectin-2’s mannan-binding domain, sDectin-2. sDectin monomers were free to float in the lipid membrane and form dimers that bind mannan substrates. sDectin-2-coated liposomes bound orders of magnitude more efficiently to the extracellular matrices of several developmental stages of C. albicans, C. neoformans, and A. fumigatus than untargeted control liposomes. Dectin-2-coated amphotericin B-loaded liposomes reduced the growth and viability of all three species more than an order of magnitude more efficiently than untargeted control liposomes and dramatically decreased the effective dose. Future efforts focus on examining pan-antifungal targeted liposomal drugs in animal models of fungal diseases. IMPORTANCE Invasive fungal diseases caused by Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus have mortality rates ranging from 10 to 95%. Individual patient costs may exceed $100,000 in the United States. All antifungals in current use have serious limitations due to host toxicity and/or insufficient fungal cell killing that results in recurrent infections. Few new antifungal drugs have been introduced in the last 2 decades. Hence, there is a critical need for improved antifungal therapeutics. By targeting antifungal-loaded liposomes to α-mannans in the extracellular matrices secreted by these fungi, we dramatically reduced the effective dose of drug. Dectin-2-coated liposomes loaded with amphotericin B bound 50- to 150-fold more strongly to C. albicans, C. neoformans, and A. fumigatus than untargeted liposomes and killed these fungi more than an order of magnitude more efficiently. Targeting drug-loaded liposomes specifically to fungal cells has the potential to greatly enhance the efficacy of most antifungal drugs.

When do job insecure employees adapt to change?

2019 ◽  
Vol 25 (3) ◽  
pp. 271-286 ◽  
Author(s):  
Kristi N. Lavigne ◽  
Victoria L. Whitaker ◽  
Dustin K. Jundt ◽  
Mindy K. Shoss
Keyword(s):  
Job Insecurity ◽  
Small Sample ◽  
Adaptive Performance ◽  
Work Behaviors ◽  
Content Type ◽  
Work Tasks ◽  
Main Effect ◽  
Low Levels ◽  
The Impact ◽  
The Relationship

Purpose The purpose of this paper is to examine the relationship between job insecurity and adaptive performance (AP), contingent on changes to core work tasks, which we position as a situational cue to employees regarding important work behaviors. Design/methodology/approach Employees and their supervisors were invited to participate in the study. Supervisors were asked to provide ratings of employees’ AP and changes to core tasks; employees reported on job insecurity. Findings As predicted, changes to core tasks moderated the relationship between job insecurity and AP. Job insecurity was negatively related to AP for those experiencing low levels of change, but was not related to AP for those experiencing high levels of change. Counter to expectations, no main effect of job insecurity was found. Research limitations/implications This study employed a fairly small sample of workers from two organizations, which could limit generalizability. Practical implications The study identifies changes to core tasks as a boundary condition for the job insecurity–AP relationship. Findings suggest that organizations may not observe deleterious consequences of job insecurity on AP when changes to core tasks are high. Originality/value Few researchers have examined boundary conditions of the impact of job insecurity on AP. Furthermore, inconsistent findings regarding the link between job insecurity and AP have emerged. This study fills the gap and expands upon previous research by examining changes to core tasks as a condition under which job insecurity does not pose an issue for AP.

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