scholarly journals Chemoprophylaxis Vaccination: Phase I Study to Explore Stage-specific Immunity to Plasmodium falciparum in US Adults

2019 ◽  
Vol 71 (6) ◽  
pp. 1481-1490
Author(s):  
Sara A Healy ◽  
Sean C Murphy ◽  
Jen C C Hume ◽  
Lisa Shelton ◽  
Steve Kuntz ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Phase I ◽  
Malaria Infection ◽  
Blood Smear ◽  
Blood Stage ◽  
Controlled Human Malaria Infection ◽  
Smear Negative ◽  
Parasite Exposure ◽  
Stage Parasite ◽  
Blood Stage Parasite

Abstract Background Chemoprophylaxis vaccination with sporozoites (CVac) with chloroquine induces protection against a homologous Plasmodium falciparum sporozoite (PfSPZ) challenge, but whether blood-stage parasite exposure is required for protection remains unclear. Chloroquine suppresses and clears blood-stage parasitemia, while other antimalarial drugs, such as primaquine, act against liver-stage parasites. Here, we evaluated CVac regimens using primaquine and/or chloroquine as the partner drug to discern whether blood-stage parasite exposure impacts protection against homologous controlled human malaria infection. Methods In a Phase I, randomized, partial double-blind, placebo-controlled study of 36 malaria-naive adults, all CVac subjects received chloroquine prophylaxis and bites from 12–15 P. falciparum–infected mosquitoes (CVac-chloroquine arm) at 3 monthly iterations, and some received postexposure primaquine (CVac-primaquine/chloroquine arm). Drug control subjects received primaquine, chloroquine, and uninfected mosquito bites. After a chloroquine washout, subjects, including treatment-naive infectivity controls, underwent homologous, PfSPZ controlled human malaria infection and were monitored for parasitemia for 21 days. Results No serious adverse events occurred. During CVac, all but 1 subject in the study remained blood-smear negative, while only 1 subject (primaquine/chloroquine arm) remained polymerase chain reaction–negative. Upon challenge, compared to infectivity controls, 3/3 chloroquine arm subjects displayed delayed patent parasitemia (P = .01) but not sterile protection, while 3/11 primaquine/chloroquine subjects remained blood-smear negative. Conclusions CVac-primaquine/chloroquine is safe and induces sterile immunity to P. falciparum in some recipients, but a single 45 mg dose of primaquine postexposure does not completely prevent blood-stage parasitemia. Unlike previous studies, CVac-chloroquine did not produce sterile immunity. Clinical Trials Registration NCT01500980.

scholarly journals Distinct patterns of blood-stage parasite antigens detected by plasma IgG subclasses from individuals with different level of exposure to Plasmodium falciparum infections

2010 ◽  
Vol 9 (1) ◽  
pp. 296 ◽  
Author(s):  
Cathrine Olesen ◽  
Karima Brahimi ◽  
Brian Vandahl ◽  
Susana Lousada-Dietrich ◽  
Prajakta S Jogdand ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Igg Subclasses ◽  
Blood Stage ◽  
Stage Parasite ◽  
Blood Stage Parasite

scholarly journals Identification of the asymptomatic Plasmodium falciparum and Plasmodium vivax gametocyte reservoir under different transmission intensities

2021 ◽  
Vol 15 (8) ◽  
pp. e0009672
Author(s):  
Cristian Koepfli ◽  
Wang Nguitragool ◽  
Anne Cristine Gomes de Almeida ◽  
Andrea Kuehn ◽  
Andreea Waltmann ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Light Microscopy ◽  
Papua New Guinea ◽  
Parasite Density ◽  
Solomon Islands ◽  
Age Groups ◽  
Blood Stage ◽  
Cross Sectional ◽  
Stage Parasite ◽  
Blood Stage Parasite

Background Understanding epidemiological variables affecting gametocyte carriage and density is essential to design interventions that most effectively reduce malaria human-to-mosquito transmission. Methodology/Principal findings Plasmodium falciparum and P. vivax parasites and gametocytes were quantified by qPCR and RT-qPCR assays using the same methodologies in 5 cross-sectional surveys involving 16,493 individuals in Brazil, Thailand, Papua New Guinea, and Solomon Islands. The proportion of infections with detectable gametocytes per survey ranged from 44–94% for P. falciparum and from 23–72% for P. vivax. Blood-stage parasite density was the most important predictor of the probability to detect gametocytes. In moderate transmission settings (prevalence by qPCR>5%), parasite density decreased with age and the majority of gametocyte carriers were children. In low transmission settings (prevalence<5%), >65% of gametocyte carriers were adults. Per survey, 37–100% of all individuals positive for gametocytes by RT-qPCR were positive by light microscopy for asexual stages or gametocytes (overall: P. falciparum 178/348, P. vivax 235/398). Conclusions/Significance Interventions to reduce human-to-mosquito malaria transmission in moderate-high endemicity settings will have the greatest impact when children are targeted. In contrast, all age groups need to be included in control activities in low endemicity settings to achieve elimination. Detection of infections by light microscopy is a valuable tool to identify asymptomatic blood stage infections that likely contribute most to ongoing transmission at the time of sampling.

scholarly journals Evidence for a Common Role for the Serine-Type Plasmodium falciparum Serine Repeat Antigen Proteases: Implications for Vaccine and Drug Design

2007 ◽  
Vol 75 (12) ◽  
pp. 5565-5574 ◽  
Author(s):  
Joanne E. McCoubrie ◽  
Susanne K. Miller ◽  
Tobias Sargeant ◽  
Robert T. Good ◽  
Anthony N. Hodder ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Functional Redundancy ◽  
Blood Stage ◽  
Parasite Development ◽  
Serine Residue ◽  
Human Malaria Parasite ◽  
Knock Out ◽  
Genetic Deletion ◽  
Stage Parasite ◽  
Blood Stage Parasite

ABSTRACT Serine repeat antigens (SERAs) are a family of secreted “cysteine-like” proteases of Plasmodium parasites. Several SERAs possess an atypical active-site serine residue in place of the canonical cysteine. The human malaria parasite Plasmodium falciparum possesses six “serine-type” (SERA1 to SERA5 and SERA9) and three “cysteine-type” (SERA6 to SERA8) SERAs. Here, we investigate the importance of the serine-type SERAs to blood-stage parasite development and examine the extent of functional redundancy among this group. We attempted to knock out the four P. falciparum serine-type SERA genes that have not been disrupted previously. SERA1, SERA4, and SERA9 knockout lines were generated, while only SERA5, the most strongly expressed member of the SERA family, remained refractory to genetic deletion. Interestingly, we discovered that while SERA4-null parasites completed the blood-stage cycle normally, they exhibited a twofold increase in the level of SERA5 mRNA. The inability to disrupt SERA5 and the apparent compensatory increase in SERA5 expression in response to the deletion of SERA4 provides evidence for an important blood-stage function for the serine-type SERAs and supports the notion of functional redundancy among this group. Such redundancy is consistent with our phylogenetic analysis, which reveals a monophyletic grouping of the serine-type SERAs across the genus Plasmodium and a predominance of postspeciation expansion. While SERA5 is to some extent further validated as a target for vaccine and drug development, our data suggest that the expression level of other serine-type SERAs is the only barrier to escape from anti-SERA5-specific interventions.

scholarly journals Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175

PLoS ONE ◽  
2015 ◽  
Vol 10 (4) ◽  
pp. e0117820 ◽  
Author(s):  
Chetan E. Chitnis ◽  
Paushali Mukherjee ◽  
Shantanu Mehta ◽  
Syed Shams Yazdani ◽  
Shikha Dhawan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Plasmodium Falciparum ◽  
Phase I ◽  
Falciparum Malaria ◽  
Vaccine Candidate ◽  
Plasmodium Falciparum Malaria ◽  
Blood Stage ◽  
Phase I Clinical Trial

scholarly journals Safety, Pharmacokinetics, and Causal Prophylactic Efficacy of KAF156 in a Plasmodium falciparum Human Infection Study

2020 ◽  
Author(s):  
James G Kublin ◽  
Sean C Murphy ◽  
Janine Maenza ◽  
Annette M Seilie ◽  
Jay Prakash Jain ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Protective Efficacy ◽  
Human Infection ◽  
Blood Stage ◽  
Response Analysis ◽  
Serious Adverse Events ◽  
Prophylactic Efficacy ◽  
Blood Stage Infection ◽  
Controlled Human Malaria Infection ◽  
Drug Resistant Strains

Abstract Background KAF156 is a novel antimalarial drug that is active against both liver- and blood-stage Plasmodium parasites, including drug-resistant strains. Here, we investigated the causal prophylactic efficacy of KAF156 in a controlled human malaria infection (CHMI) model. Methods In part 1, healthy, malaria-naive participants received 800 mg KAF156 or placebo 3 hours before CHMI with P. falciparum–infected mosquitoes. In part 2, KAF156 was administered as single doses of 800, 300, 100, 50, or 20 mg 21 hours post-CHMI. All participants received atovaquone/proguanil treatment if blood-stage infection was detected or on day 29. For each cohort, 7–14 subjects were enrolled to KAF156 treatment and up to 4 subjects to placebo. Results KAF156 at all dose levels was safe and well tolerated. Two serious adverse events were reported—both resolved without sequelae and neither was considered related to KAF156. In part 1, all participants treated with KAF156 and none of those randomized to placebo were protected against malaria infection. In part 2, all participants treated with placebo or 20 mg KAF156 developed malaria infection. In contrast, 50 mg KAF156 protected 3 of 14 participants from infection, and doses of 800, 300, and 100 mg KAF156 protected all subjects against infection. An exposure–response analysis suggested that a 24-hour postdose concentration of KAF156 of 21.5 ng/mL (90% confidence interval, 17.66–25.32 ng/mL) would ensure a 95% chance of protection from malaria parasite infection. Conclusions KAF156 was safe and well tolerated and demonstrated high levels of pre- and post-CHMI protective efficacy. Clinical Trials Registration clinicaltrials.gov; NCT04072302 (https://clinicaltrials.gov/ct2/show/NCT04072302).

scholarly journals Correction: Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175

PLoS ONE ◽  
2015 ◽  
Vol 10 (9) ◽  
pp. e0137816 ◽  
Author(s):  
Chetan E. Chitnis ◽  
Paushali Mukherjee ◽  
Shantanu Mehta ◽  
Syed Shams Yazdani ◽  
Shikha Dhawan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Plasmodium Falciparum ◽  
Phase I ◽  
Falciparum Malaria ◽  
Vaccine Candidate ◽  
Plasmodium Falciparum Malaria ◽  
Blood Stage ◽  
Phase I Clinical Trial ◽  
Correction Phase

scholarly journals Multidose Priming and Delayed Boosting Improve PfSPZ Vaccine Efficacy against Heterologous P. falciparum Controlled Human Malaria Infection

2020 ◽  
Author(s):  
Kirsten E Lyke ◽  
Alexandra Singer ◽  
Andrea A Berry ◽  
Sharina Reyes ◽  
Sumana Chakravarty ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Vaccine Efficacy ◽  
Malaria Infection ◽  
Human Malaria ◽  
Group 4 ◽  
Controlled Human Malaria Infection ◽  
Group 3 ◽  
Group 2 ◽  
The Impact ◽  
Group 1

Abstract Background A live-attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine (PfSPZ Vaccine) has shown up to 100% protection against controlled human malaria infection (CHMI) using homologous parasites (same Pf strain as in the vaccine). Using a more stringent CHMI, with heterologous parasites (different Pf strain), we assessed the impact of higher PfSPZ doses, a novel multi-dose prime regimen, and a delayed vaccine boost upon vaccine efficacy. Methods Four groups of 15 healthy, malaria-naïve adults were immunized. Group (Grp) 1 received five doses of 4.5x10 5 PfSPZ (days 1, 3, 5, 7; week 16). Grps 2, 3 and 4 received three doses (weeks 0, 8, 16) with Gp 2 receiving 9.0×10 5/dose, Grp 3 receiving 18.0×10 5/dose, and Grp 4 receiving 27.0×10 5 for dose 1 and 9.0×10 5 for doses 2 and 3. VE was assessed by heterologous CHMI after 12 or 24 weeks. Volunteers not protected at 12 weeks were boosted prior to repeat CHMI at 24 weeks. Results At 12-week CHMI, 6/15 (40%) Group 1 (P=0.04), 3/15 (20%) Group 2 vs. 0/8 controls remained aparasitemic. At 24-week CHMI, 3/13 (23%) Group 3, 3/14 (21%) Group 4 vs. 0/8 controls remained aparasitemic (Groups 2-4, VE not significant). Post-boost, 9/14 (64%) vs. 0/8 controls remained aparasitemic (3/6 Group 1, P=0.025; 6/8 Group 2, P=0.002). Conclusions Four stacked, priming injections (multi-dose priming) showed 40% VE against heterologous CHMI, while dose escalation of PfSPZ using single dose priming was not significantly protective. Boosting unprotected subjects improved VE at 24 weeks to 64%.

Sign in / Sign up

Export Citation Format

Share Document