scholarly journals Mapping of safe and early chemo-attenuated live Plasmodium falciparum immunization identifies immune signature of vaccine efficacy

2020 ◽  
Author(s):  
Steffen Borrmann ◽  
Zita Sulyok ◽  
Katja Müller ◽  
Mihaly Sulyok ◽  
Rolf Fendel ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Dose ◽  
Vaccine Efficacy ◽  
Human Subjects ◽  
Vaccine Dose ◽  
Effector Memory ◽  
Liver Stage ◽  
Rodent Malaria ◽  
Immune Signatures ◽  
Malaria Model

AbstractPotent protection against malaria can be induced by attenuated live-immunization with Plasmodium falciparum (Pf) sporozoites (SPZ). However, a better understanding of the critical processes involved in the establishment of protective immunity is needed. We explored the safety and vaccine efficacy of early chemo-attenuation of PfSPZ under atovaquone-proguanil (AP). AP caused early arrest of P. berghei liver stages. Despite the absence of replication, robust protection in mice correlated with parasite-specific effector-memory CD8+ T-cell responses. In a phase I clinical trial a single dose of AP prevented Pf infections in the liver of adult, human subjects who received three doses of 5.12×104 or 1.5×105 PfSPZ by direct venous inoculation combined with oral AP. However, only 2 of 8 (25%) and 2 of 10 (20%), respectively, were protected against controlled human malaria infection (CHMI) 10 weeks after the last vaccine dose, despite levels of IgG antibodies to the Pf circumsporozoite protein (PfCSP) comparable to those achieved in fully protected volunteers after immunization with 5.12×104 PfSPZ with chloroquine chemoprophylaxis active only against subsequent blood stages. We identify lower IgG recognition of the secreted liver stage-specific antigens LISP2 and LSA1 and the multi-stage antigen MSP5 as immune signatures of inferior vaccine efficacy compared to PfSPZ with chloroquine chemoprophylaxis. In conclusion, we show that immune signatures of liver stage antigens, but neither an established rodent malaria model nor concentrations of antibodies against the major surface protein of sporozoites, permit prediction of vaccine efficacy. Thus, this study provides a clear rationale for the development of live sporozoite vaccination protocols that boost exposure to Pf liver stage antigens.Significance StatementOur research demonstrates that attenuation of liver infection of high doses of Plasmodium falciparum sporozoites by concomitant single-dose administration of atovaquone-proguanil is safe in humans. However, vaccine efficacy was modest when compared to an identical protocol using chloroquine that acts only on the subsequent blood infection. Immune signatures of secreted P. falciparum liver stage antigens, but neither an established rodent malaria model nor concentrations of sporozoite antibodies, permit prediction of vaccine efficacy.

scholarly journals In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model

2015 ◽  
Vol 14 (1) ◽  
pp. 48 ◽  
Author(s):  
Drishti Agarwal ◽  
Manish Sharma ◽  
Sandeep K Dixit ◽  
Roshan K Dutta ◽  
Ashok K Singh ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Synergistic Effect ◽  
Rodent Malaria ◽  
Malaria Model

scholarly journals In VitroandIn VivoAntimalarial Activities of T-2307, a Novel Arylamidine

2012 ◽  
Vol 56 (4) ◽  
pp. 2191-2193 ◽  
Author(s):  
Akiko Kimura ◽  
Hiroshi Nishikawa ◽  
Nobuhiko Nomura ◽  
Junichi Mitsuyama ◽  
Shinya Fukumoto ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Body Weight ◽  
Broad Spectrum ◽  
Antimalarial Activity ◽  
Liver Stage ◽  
Rodent Malaria ◽  
Content Type ◽  
Clinically Significant

ABSTRACTT-2307, a novel arylamidine, has been shown to exhibit broad-spectrum antifungal activities against clinically significant pathogens. Here, we evaluated thein vitroandin vivoantimalarial activity of T-2307. The 50% inhibitory concentrations (IC50s) of T-2307 againstPlasmodium falciparumFCR-3 and K-1 strains were 0.47 and 0.17 μM, respectively. T-2307 at 2.5 to 10 mg/kg of body weight/day exhibited activity against blood stage and liver stage parasites in rodent malaria models. In conclusion, T-2307 exhibitedin vitroandin vivoantimalarial activity.

scholarly journals A Plasmodium Actin-depolymerizing Factor That Binds Exclusively to Actin Monomers

2005 ◽  
Vol 16 (9) ◽  
pp. 4013-4023 ◽  
Author(s):  
Herwig Schüler ◽  
Ann-Kristin Mueller ◽  
Kai Matuschewski
Keyword(s):  
Plasmodium Falciparum ◽  
Reverse Genetics ◽  
Biochemical Properties ◽  
Model System ◽  
Actin Binding ◽  
Nucleotide Exchange ◽  
Rodent Malaria ◽  
Vital Functions ◽  
Binding Residues ◽  
Malaria Model

ADF/cofilins (AC) are essential F- and G-actin binding proteins that modulate microfilament turnover. The genome of Plasmodium falciparum, the parasite causing malaria, contains two members of the AC family. Interestingly, P. falciparum ADF1 lacks the F-actin binding residues of the AC consensus. Reverse genetics in the rodent malaria model system suggest that ADF1 performs vital functions during the pathogenic red blood cell stages, whereas ADF2 is not present in these stages. We show that recombinant PfADF1 interacts with monomeric actin but does not bind to actin polymers. Although other AC proteins inhibit nucleotide exchange on monomeric actin, the Plasmodium ortholog stimulates nucleotide exchange. Thus, PfADF1 differs in its biochemical properties from previously known AC proteins and seems to promote turnover exclusively by interaction with actin monomers. These findings provide important insights into the low cytosolic abundance and unique turnover characteristics of actin polymers in parasites of the phylum Apicomplexa.

scholarly journals IMRAS—Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0256396
Author(s):  
Martha Sedegah ◽  
Michael R. Hollingdale ◽  
Harini Ganeshan ◽  
Maria Belmonte ◽  
Jun Huang ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Vaccine Efficacy ◽  
Malaria Infection ◽  
Protective Immunity ◽  
Ex Vivo ◽  
Vaccine Dose ◽  
Vaccine Trials ◽  
Controlled Human Malaria Infection ◽  
Ifn Γ

Background Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides >90% sterile protection against Plasmodium falciparum malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800–1200 infected bites should induce ~50% protective vaccine efficacy (VE) against controlled human malaria infection (CHMI) administered three weeks after the final immunization. Two cohorts were immunized separately. VE was 55% in Cohort 1 but 90% in Cohort 2, the cohort that received a higher first dose and a reduced (fractional) fifth dose. Immune responses were better boosted by the fractional fifth dose in Cohort 2 and suggested the importance of the fractional fifth dose for increased protection in Cohort 2 responses. Three protected subjects were later boosted and were protected suggesting that protection could be extended to at least 67 weeks. Methods The ex vivo FluoroSpot assay was used to measure peripheral IFN-γ, IL2, and IFN-γ+IL2 responses to PfNF54 sporozoites and malaria antigens CSP, AMA1, TRAP, and CelTOS using pools of synthetic overlapping 15mer peptides spanning each antigen. Results There was no correlation between IFN-γ, IL2, and IFN-γ+IL2 responses to sporozoites and protection, but fold-increases between post-4th and post-5th responses greater than 1.0 occurred mostly in protected subjects. IFN-γ and IL2 responses to TRAP, CelTOS and CSP occurred only in protected subjects. Peripheral IFN-γ, IL2, and IFN-γ+IL2 responses were short-lived and low by 27 weeks post-CHMI but were restored by boosting. Conclusions These studies highlight the importance of vaccine dose and schedule for vaccine efficacy, and suggest that CSP, TRAP, AMA1 and CelTOS may be targets of protective immunity. The correlation between fold-increases in responses and protection should be explored in other vaccine trials. Trial registration ClinicalTrials.gov NCT01994525.

scholarly journals The fate of cyclamate in man and other species

1972 ◽  
Vol 129 (4) ◽  
pp. 869-879 ◽  
Author(s):  
A. G. Renwick ◽  
R. T. Williams
Keyword(s):  
Single Dose ◽  
Gastrointestinal Tract ◽  
Biliary Excretion ◽  
Guinea Pigs ◽  
Human Subjects ◽  
Gut Flora

1. 14C-labelled cyclamate has been administered to guinea pigs, rabbits, rats and humans. When given orally to these species on a cyclamate-free diet, cyclamate is excreted unchanged. In guinea pigs some 65% of a single dose is excreted in the urine and 30% in the faeces, the corresponding values for rats being 40 and 50%, for man, 30–50% and 40–60%, and for rabbits, 90 and 5%, the excretion being over a period of 2–3 days. 2. Cyclamate appears to be readily absorbed by rabbits but less readily by guinea pigs, rats and humans. 3. If these animals, including man, are placed on a diet containing cyclamate they develop the ability to convert orally administered cyclamate into cyclohexylamine and consequently into the metabolites of the latter. The extent to which this ability develops is variable, the development occurring more readily in rats than in rabbits or guinea pigs. In three human subjects, one developed the ability quite markedly in 10 days whereas two others did not in 30 days. Removal of the cyclamate from the diet caused a diminution in the ability to convert cyclamate into the amine. 4. In rats that had developed the ability to metabolize orally administered cyclamate, intraperitoneally injected cyclamate was not metabolized and was excreted unchanged in the urine. The biliary excretion of injected cyclamate in rats was very small, i.e. about 0.3% of the dose. 5. The ability of animals to convert cyclamate into cyclohexylamine appears to depend upon a continuous intake of cyclamate and on some factor in the gastrointestinal tract, probably the gut flora.

scholarly journals How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein

2022 ◽  
Vol 219 (2) ◽  
Author(s):  
Ilka Wahl ◽  
Hedda Wardemann
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Vaccine Efficacy ◽  
Circumsporozoite Protein ◽  
Surface Proteins ◽  
Humoral Immune ◽  
Cell Responses ◽  
Humoral Immune Responses ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum

The induction of protective humoral immune responses against sporozoite surface proteins of the human parasite Plasmodium falciparum (Pf) is a prime goal in the development of a preerythrocytic malaria vaccine. The most promising antibody target is circumsporozoite protein (CSP). Although PfCSP induces strong humoral immune responses upon vaccination, vaccine efficacy is overall limited and not durable. Here, we review recent efforts to gain a better molecular and cellular understanding of anti-PfCSP B cell responses in humans and discuss ways to overcome limitations in the induction of stable titers of high-affinity antibodies that might help to increase vaccine efficacy and promote long-lived protection.

scholarly journals ChAdOx1 nCoV-19 (AZD1222) protects Syrian hamsters against SARS-CoV-2 B.1.351 and B.1.1.7

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Robert J. Fischer ◽  
Neeltje van Doremalen ◽  
Danielle R. Adney ◽  
Claude Kwe Yinda ◽  
Julia R. Port ◽  
...  
Keyword(s):  
Single Dose ◽  
Vaccine Efficacy ◽  
Infectious Virus ◽  
Neutralizing Antibody ◽  
Subgenomic Rna ◽  
Syrian Hamsters ◽  
Fold Reduction ◽  
Histopathological Evaluation ◽  
Gross Lesions ◽  
Pulmonary Pathology

AbstractWe investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observe a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 do not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals do not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus can be detected in lungs of vaccinated animals. Histopathological evaluation shows extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs.

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