Antibody Biomarkers Associated with Sterile Protection Induced by Controlled Human Malaria Infection under Chloroquine Prophylaxis

ABSTRACTImmunization with sporozoites under chloroquine chemoprophylaxis (CPS) induces distinctly preerythrocytic and long-lasting sterile protection against homologous controlled human malaria infection (CHMI). To identify possible humoral immune correlates of protection, plasma samples were collected from 38 CPS-immunized Dutch volunteers for analysis using a wholePlasmodium falciparumproteome microarray with 7,455 full-length or segmented protein features displaying about 91% of the totalP. falciparumproteome. We identified 548 reactive antigens representing 483 unique proteins. Using the breadth of antibody responses for each subject in a mixture-model algorithm, we observed a trimodal pattern, with distinct groups of 16 low responders, 19 medium responders, and 3 high responders. Fifteen out of 16 low responders, 12 of the 19 medium responders, and 3 out of 3 high responders were fully protected from a challenge infection. In the medium-responder group, we identified six novel antigens associated with protection (area under the curve [AUC] value of ≥0.75;P < 0.05) and six other antigens that were specifically increased in nonprotected volunteers (AUC value of ≤0.25;P < 0.05). When used in combination, the multiantigen classifier predicts CPS-induced protective efficacy with 83% sensitivity and 88% specificity. The antibody response patterns characterized in this study represent surrogate markers that may provide rational guidance for clinical vaccine development.IMPORTANCEInfection byPlasmodiumparasites has been a major cause of mortality and morbidity in humans for thousands of years. Despite the considerable reduction of deaths, according to the WHO, over 5 billion people are still at risk, with about 216 million worldwide cases occurring in 2016. More compelling, 15 countries in sub-Saharan Africa bore 80% of the worldwide malaria burden. Complete eradication has been challenging, and the development of an affordable and effective vaccine will go a long way in achieving elimination. However, identifying vaccine candidate targets has been difficult. In the present study, we use a highly effective immunization protocol that confers long-lasting sterile immunity in combination with a wholeP. falciparumproteome microarray to identify antibody responses associated with protection. This study characterizes a novel antibody profile associated with sterile protective immunity and trimodal humoral responses that sheds light on the possible mechanism of CPS-induced immunity againstP. falciparumparasites.

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Immunoprofiles associated with controlled human malaria infection and naturally acquired immunity identify a shared IgA pre-erythrocytic immunoproteome

npj Vaccines ◽

10.1038/s41541-021-00363-y ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Andrea A. Berry ◽

Joshua M. Obiero ◽

Mark A. Travassos ◽

Amed Ouattara ◽

Drissa Coulibaly ◽

...

Keyword(s):

Malaria Infection ◽

Vaccine Development ◽

Protein Microarray ◽

Antibody Responses ◽

Liver Stage ◽

Human Malaria ◽

Controlled Human Malaria Infection ◽

Iga Antibody ◽

Potential Vaccine ◽

Antigen Protein

AbstractKnowledge of the Plasmodium falciparum antigens that comprise the human liver stage immunoproteome is important for pre-erythrocytic vaccine development, but, compared with the erythrocytic stage immunoproteome, more challenging to classify. Previous studies of P. falciparum antibody responses report IgG and rarely IgA responses. We assessed IgG and IgA antibody responses in adult sera collected during two controlled human malaria infection (CHMI) studies in malaria-naïve volunteers and in 1- to 6-year-old malaria-exposed Malian children on a 251 P. falciparum antigen protein microarray. IgG profiles in the two CHMI groups were equivalent and differed from Malian children. IgA profiles were robust in the CHMI groups and a subset of Malian children. We describe immunoproteome differences in naïve vs. exposed individuals and report pre-erythrocytic proteins recognized by the immune system. IgA responses detected in this study expand the list of pre-erythrocytic antigens for further characterization as potential vaccine candidates.

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

Infection and Immunity ◽

10.1128/iai.00541-18 ◽

2018 ◽

Vol 87 (3) ◽

Cited By ~ 7

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.

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Controlled Human Malaria Infection (CHMI) differentially affects cell-mediated and antibody responses to CSP and AMA1 induced by adenovirus vaccines with and without DNA-priming

Human Vaccines & Immunotherapeutics ◽

10.1080/21645515.2015.1019186 ◽

2015 ◽

Vol 11 (11) ◽

pp. 2705-2715 ◽

Cited By ~ 3

Author(s):

Martha Sedegah ◽

Michael R Hollingdale ◽

Fouzia Farooq ◽

Harini Ganeshan ◽

Maria Belmonte ◽

...

Keyword(s):

Malaria Infection ◽

Antibody Responses ◽

Human Malaria ◽

Controlled Human Malaria Infection

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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

Frontiers in Big Data ◽

10.3389/fdata.2021.672460 ◽

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.

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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

10.1101/2021.12.09.21266528 ◽

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.

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Controlled Human Malaria Infection: Applications, Advances, and Challenges

Infection and Immunity ◽

10.1128/iai.00479-17 ◽

2017 ◽

Vol 86 (1) ◽

Cited By ~ 29

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.

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