scholarly journals Controlled Human Malaria Infection: Applications, Advances, and Challenges

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Danielle I. Stanisic ◽  
James S. McCarthy ◽  
Michael F. Good
Keyword(s):  
Drug Development ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Blood Stage ◽  
Content Type ◽  
Human Malaria ◽  
Recent Advances ◽  
Blood Stage Infection ◽  
Controlled Human Malaria Infection ◽  
Stage Infection

ABSTRACT Controlled human malaria infection (CHMI) entails deliberate infection with malaria parasites either by mosquito bite or by direct injection of sporozoites or parasitized erythrocytes. When required, the resulting blood-stage infection is curtailed by the administration of antimalarial drugs. Inducing a malaria infection via inoculation with infected blood was first used as a treatment (malariotherapy) for neurosyphilis in Europe and the United States in the early 1900s. More recently, CHMI has been applied to the fields of malaria vaccine and drug development, where it is used to evaluate products in well-controlled early-phase proof-of-concept clinical studies, thus facilitating progression of only the most promising candidates for further evaluation in areas where malaria is endemic. Controlled infections have also been used to immunize against malaria infection. Historically, CHMI studies have been restricted by the need for access to insectaries housing infected mosquitoes or suitable malaria-infected individuals. Evaluation of vaccine and drug candidates has been constrained in these studies by the availability of a limited number of Plasmodium falciparum isolates. Recent advances have included cryopreservation of sporozoites, the manufacture of well-characterized and genetically distinct cultured malaria cell banks for blood-stage infection, and the availability of Plasmodium vivax-specific reagents. These advances will help to accelerate malaria vaccine and drug development by making the reagents for CHMI more widely accessible and also enabling a more rigorous evaluation with multiple parasite strains and species. Here we discuss the different applications of CHMI, recent advances in the use of CHMI, and ongoing challenges for consideration.

scholarly journals Controlled Human Malaria Infection of Healthy Adults With Lifelong Malaria Exposure to Assess Safety, Immunogenicity, and Efficacy of the Asexual Blood Stage Malaria Vaccine Candidate GMZ2

2018 ◽  
Vol 69 (8) ◽  
pp. 1377-1384 ◽  
Author(s):  
Jean Claude Dejon-Agobe ◽  
Ulysse Ateba-Ngoa ◽  
Albert Lalremruata ◽  
Andreas Homoet ◽  
Julie Engelhorn ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Specific Antibody ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Blood Stage ◽  
Control Group ◽  
Asexual Blood Stage ◽  
Human Malaria ◽  
Controlled Human Malaria Infection ◽  
Blood Stage Malaria

AbstractBackgroundGMZ2 is a recombinant malaria vaccine inducing immune responses against Plasmodium falciparum (Pf) merozoite surface protein-3 and glutamate-rich protein. We used standardized controlled human malaria infection (CHMI) to assess the efficacy of this asexual blood-stage vaccine.MethodsWe vaccinated 50 healthy, adult volunteers with lifelong exposure to Pf 3 times, at 4-week intervals, with 30 or 100 µg GMZ2 formulated in CAF01, a liposome-based adjuvant; 100 µg GMZ2, formulated in Alhydrogel; or a control vaccine (Verorab). Approximately 13 weeks after the last vaccination, 35/50 volunteers underwent CHMI by direct venous inoculation of 3200 Pf sporozoites (Sanaria® PfSPZ Challenge).ResultsAdverse events were similarly distributed between GMZ2 and control vaccinees. Baseline-corrected anti-GMZ2 antibody concentrations 4 weeks after the last vaccination were higher in all 3 GMZ2-vaccinated arms, compared to the control group. All GMZ2 formulations induced similar antibody levels. CHMI resulted in 29/34 (85%) volunteers with Pf parasitemia and 15/34 (44%) with malaria (parasitemia and symptoms). The proportion of participants with malaria (2/5 control, 6/10 GMZ2-Alhydrogel, 2/8 30 µg GMZ2-CAF01, and 5/11 100 µg GMZ2-CAF01) and the time it took them to develop malaria were similar in all groups. Baseline, vaccine-specific antibody concentrations were associated with protection against malaria.ConclusionsGMZ2 is well tolerated and immunogenic in lifelong–Pf-exposed adults from Gabon, with similar antibody responses regardless of formulation. CHMI showed no protective effect of prior vaccination with GMZ2, although baseline, vaccine-specific antibody concentrations were associated with protection. CHMI with the PfSPZ Challenge is a potent new tool to validate asexual, blood-stage malaria vaccines in Africa.Clinical Trials RegistrationPan-African Clinical Trials: PACTR201503001038304

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 Mosquito Bite-Induced Controlled Human Malaria Infection withPlasmodium vivaxorP. falciparumGenerates Immune Responses to Homologous and Heterologous Preerythrocytic and Erythrocytic Antigens

2018 ◽  
Vol 87 (3) ◽  
Author(s):  
Cysha E. Hall ◽  
Lisa M. Hagan ◽  
Elke Bergmann-Leitner ◽  
Donna M. Tosh ◽  
Jason W. Bennett ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Similar Proportion ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Samples ◽  
Content Type ◽  
Human Malaria ◽  
Before And After ◽  
Controlled Human Malaria Infection

ABSTRACTSeroepidemiological studies on the prevalence of antibodies to malaria antigens are primarily conducted on individuals from regions of endemicity. It is therefore difficult to accurately correlate the antibody responses to the timing and number of prior malaria infections. This study was undertaken to assess the evolution of antibodies to the dominant surface antigens ofPlasmodium vivaxandP. falciparumfollowing controlled human malaria infection (CHMI) in malaria-naive individuals. Serum samples from malaria-naive adults, collected before and after CHMI with eitherP. vivax(n= 18) orP. falciparum(n= 18), were tested for the presence of antibodies to the circumsporozoite protein (CSP) and the 42-kDa fragment of merozoite surface protein 1 (MSP-142) ofP. vivaxandP. falciparumusing an enzyme-linked immunosorbent assay (ELISA). Approximately 1 month following CHMI with eitherP. vivaxorP. falciparum, >60% of subjects seroconverted to homologous CSP and MSP-1. More than 50% of the subjects demonstrated reactivity to heterologous CSP and MSP-142, and a similar proportion of subjects remained seropositive to homologous MSP-142>5 months after CHMI. Computational analysis provides insight into the presence of cross-reactive responses. The presence of long-lived and heterologous reactivity and its functional significance, if any, need to be taken into account while evaluating malaria exposure in field settings.

Merozoite vaccination of rhesus monkeys against plasmodium knowlesi malaria; immunity to sporozoite (mosquito-transmitted) challenge

Parasitology ◽  
1977 ◽  
Vol 74 (2) ◽  
pp. 191-198 ◽  
Author(s):  
W. H. G. Richards ◽  
G. H. Mitchell ◽  
G. A. Butcher ◽  
S. Cohen
Keyword(s):  
Rhesus Monkeys ◽  
Malaria Vaccine ◽  
Plasmodium Knowlesi ◽  
Blood Stage ◽  
Parasite Development ◽  
Post Vaccination ◽  
Challenge Strain ◽  
Freeze Dried ◽  
Blood Stage Infection ◽  
Stage Infection

Five normal rhesus monkeys were infected with Plasmodium knowlesi sporozoites (A-strain); two developed rapidly fatal malaria and three chrinic relapsing infections. Vaccination with P. knowlesi (W-strain) merozoites (unmodified or formol-treated and freeze-dried) in Freund's complete adjuvant (FCA) did not inhibit pre-erythrocytic parasite development after challenge with A-strain sporozoites. However, the subsequent blood-stage infection was terminated in nine out of ten vaccinated monkeys even though the challenge strain was different form that used for vaccination. The degree of parasitaemia (0·01–0·70 %) and brevity of infection (1–12 days) in six animals vaccinated with untreated merzoites was similar to that observed after direct challenge with blood-stage parasites. Monkeys were equally resistant to sporozoite challenge given as the post-vaccination infection or administered 6 months after blood challenge. These results are discussed in relation to the development of a human malaria vaccine.

scholarly journals Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity

2018 ◽  
Vol 3 ◽  
pp. 155 ◽  
Author(s):  
Melissa C. Kapulu ◽  
Patricia Njuguna ◽  
Mainga M. Hamaluba ◽  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Responses ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Parasite Growth ◽  
Host Immunity ◽  
Human Malaria ◽  
Controlled Human Malaria Infection ◽  
Adult Volunteers

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy.  We will use controlled human malaria infection (CHMI) studies with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo.  Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and extracted DNA will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. Registration: ClinicalTrials.gov identifier NCT02739763.

scholarly journals Extrahepatic Exoerythrocytic Forms of Rodent Malaria Parasites at the Site of Inoculation: Clearance after Immunization, Susceptibility to Primaquine, and Contribution to Blood-Stage Infection

2012 ◽  
Vol 80 (6) ◽  
pp. 2158-2164 ◽  
Author(s):  
Tatiana Voza ◽  
Jessica L. Miller ◽  
Stefan H. I. Kappe ◽  
Photini Sinnis
Keyword(s):  
Common Property ◽  
Adaptive Immune Response ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Mammalian Host ◽  
Malaria Parasites ◽  
Rodent Malaria ◽  
Content Type ◽  
Blood Stage Infection ◽  
Stage Infection

ABSTRACTPlasmodiumsporozoites are inoculated into the skin of the mammalian host as infected mosquitoes probe for blood. A proportion of the inoculum enters the bloodstream and goes to the liver, where the sporozoites invade hepatocytes and develop into the next life cycle stage, the exoerythrocytic, or liver, stage. Here, we show that a small fraction of the inoculum remains in the skin and begins to develop into exoerythrocytic forms that can persist for days. Skin exoerythrocytic forms were observed for bothPlasmodium bergheiandPlasmodium yoelii, two different rodent malaria parasites, suggesting that development in the skin of the mammalian host may be a common property of plasmodia. Our studies demonstrate that skin exoerythrocytic stages are susceptible to destruction in immunized mice, suggesting that their aberrant location does not protect them from the host's adaptive immune response. However, in contrast to their hepatic counterparts, they are not susceptible to primaquine. We took advantage of their resistance to primaquine to test whether they could initiate a blood-stage infection directly from the inoculation site, and our data indicate that these stages are not able to initiate malaria infection.

scholarly journals Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection

2017 ◽  
Vol 114 (10) ◽  
pp. 2711-2716 ◽  
Author(s):  
Kirsten E. Lyke ◽  
Andrew S. Ishizuka ◽  
Andrea A. Berry ◽  
Sumana Chakravarty ◽  
Adam DeZure ◽  
...  
Keyword(s):  
T Cells ◽  
Plasmodium Falciparum ◽  
T Cell ◽  
Vaccine Strain ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Protective Efficacy ◽  
Vaccine Dose ◽  
Human Malaria ◽  
Controlled Human Malaria Infection

A live-attenuated malaria vaccine,Plasmodium falciparumsporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) withPlasmodium falciparum(Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35–87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P= 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36–99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.

scholarly journals Comprehensive Data Integration Approach to Assess Immune Responses and Correlates of RTS,S/AS01-Mediated Protection From Malaria Infection in Controlled Human Malaria Infection Trials

2021 ◽  
Vol 4 ◽  
Author(s):  
William Chad Young ◽  
Lindsay N. Carpp ◽  
Sidhartha Chaudhury ◽  
Jason A. Regules ◽  
Elke S. Bergmann-Leitner ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
Modeling Framework ◽  
Effector Functions ◽  
Human Malaria ◽  
Humoral Immune ◽  
Immune Parameters ◽  
Immune Biomarkers ◽  
Controlled Human Malaria Infection

RTS,S/AS01 (GSK) is the world’s first malaria vaccine. However, despite initial efficacy of almost 70% over the first 6 months of follow-up, efficacy waned over time. A deeper understanding of the immune features that contribute to RTS,S/AS01-mediated protection could be beneficial for further vaccine development. In two recent controlled human malaria infection (CHMI) trials of the RTS,S/AS01 vaccine in malaria-naïve adults, MAL068 and MAL071, vaccine efficacy against patent parasitemia ranged from 44% to 87% across studies and arms (each study included a standard RTS,S/AS01 arm with three vaccine doses delivered in four-week-intervals, as well as an alternative arm with a modified version of this regimen). In each trial, RTS,S/AS01 immunogenicity was interrogated using a broad range of immunological assays, assessing cellular and humoral immune parameters as well as gene expression. Here, we used a predictive modeling framework to identify immune biomarkers measured at day-of-challenge that could predict sterile protection against malaria infection. Using cross-validation on MAL068 data (either the standard RTS,S/AS01 arm alone, or across both the standard RTS,S/AS01 arm and the alternative arm), top-performing univariate models identified variables related to Fc effector functions and titer of antibodies that bind to the central repeat region (NANP6) of CSP as the most predictive variables; all NANP6-related variables consistently associated with protection. In cross-study prediction analyses of MAL071 outcomes (the standard RTS,S/AS01 arm), top-performing univariate models again identified variables related to Fc effector functions of NANP6-targeting antibodies as highly predictive. We found little benefit–with this dataset–in terms of improved prediction accuracy in bivariate models vs. univariate models. These findings await validation in children living in malaria-endemic regions, and in vaccinees administered a fourth RTS,S/AS01 dose. Our findings support a “quality as well as quantity” hypothesis for RTS,S/AS01-elicited antibodies against NANP6, implying that malaria vaccine clinical trials should assess both titer and Fc effector functions of anti-NANP6 antibodies.

scholarly journals Genome, proteome, and immunome data explain why 6 month controlled human malaria infection with sporozoites of the Pf7G8 clone of Plasmodium falciparum is a rigorous predictor of the efficacy of the PfNF54-based PfSPZ Vaccine in Africa

2021 ◽  
Author(s):  
Joana Carneiro Silva ◽  
Ankit Dwivedi ◽  
Kara A Moser ◽  
Mahamadou S. Sissoko ◽  
Judith E. Epstein ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Malaria Infection ◽  
Malaria Vaccine ◽  
Vaccine Development ◽  
West African ◽  
T Cell Epitopes ◽  
Human Malaria ◽  
The Us ◽  
Controlled Human Malaria Infection ◽  
Better Than

Controlled human malaria infection (CHMI) has supported Plasmodium falciparum (Pf) malaria vaccine development by providing preliminary estimates of vaccine efficacy (VE). Because CHMIs generally use Pf strains similar to vaccine strains, VE against antigenically heterogeneous Pf in the field has been required to establish VE. We increased the stringency of CHMI by selecting a Brazilian isolate, Pf7G8, which is genetically distant from the West African parasite (PfNF54) in our PfSPZ vaccines. Using two regimens to identically immunize US and Malian adults, VE over 24 weeks in the field was as good as or better than against CHMI at 24 weeks in the US. To explain this finding, we quantified differences in the genome, proteome and predicted CD8 T cell epitopes of PfNF54 relative to 709 Pf isolates from Africa and Pf7G8. Pf7G8 is more distant from PfNF54 than any African isolates tested. We propose VE against Pf7G8 CHMI for providing pivotal data for malaria vaccine licensure for travelers to Africa, and potentially for endemic populations, because the genetic distance of Pf7G8 from the Pf vaccine strain makes it a stringent surrogate for Pf parasites in Africa.

Sign in / Sign up

Export Citation Format

Share Document