Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

Schussek, Sophie; Trieu, Angela; Apte, Simon H.; Sidney, John; Sette, Alessandro; Doolan, Denise L.

doi:10.1128/iai.00544-13

Cited by 17 publications

(23 citation statements)

References 88 publications

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“…A lower first detectable parasitemia in seropositive Tanzanians than in seronegative Tanzanians might therefore additionally be attributed to the control of blood-stage replication prior to qPCR detection. Antibodies directed against AMA-1, for instance, are known to interfere with blood-stage multiplication (36) but can also confer protection against liver-stage infection (37). Since recognition of both crossstage and liver-stage antigens was stronger in the Tanzanian cohort than in the Dutch, and particularly in the seropositive individuals, both possibilities remain open.…”

Section: Discussionmentioning

confidence: 99%

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

et al. 2015

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e To understand the effect of previous malaria exposure on antiparasite immune responses is important for developing successful immunization strategies. Controlled human malaria infections (CHMIs) using cryopreserved Plasmodium falciparum sporozoites provide a unique opportunity to study differences in acquisition or recall of antimalaria immune responses in individuals from different transmission settings and genetic backgrounds. In this study, we compared antiparasite humoral and cellular immune responses in two cohorts of malaria-naive Dutch volunteers and Tanzanians from an area of low malarial endemicity, who were subjected to the identical CHMI protocol by intradermal injection of P. falciparum sporozoites. Samples from both trials were analyzed in parallel in a single center to ensure direct comparability of immunological outcomes. Within the Tanzanian cohort, we distinguished one group with moderate levels of preexisting antibodies to asexual P. falciparum lysate and another that, based on P. falciparum serology, resembled the malaria-naive Dutch cohort. Positive P. falciparum serology at baseline was associated with a lower parasite density at first detection by quantitative PCR (qPCR) after CHMI than that for Tanzanian volunteers with negative serology. Post-CHMI, both Tanzanian groups showed a stronger increase in anti-P. falciparum antibody titers than Dutch volunteers, indicating similar levels of B-cell memory independent of serology. In contrast to the Dutch, Tanzanians failed to increase P. falciparum-specific in vitro recall gamma interferon (IFN-␥) production after CHMI, and innate IFN-␥ responses were lower in P. falciparum lysate-seropositive individuals than in seronegative individuals. In conclusion, positive P. falciparum lysate serology can be used to identify individuals with better parasite control but weaker IFN-␥ responses in circulating lymphocytes, which may help to stratify volunteers in future CHMI trials in areas where malaria is endemic. In 2012, Plasmodium falciparum malaria caused an estimated 207 million cases and 627,000 deaths, of which 90% occurred in children under 5 years of age and in pregnant women in subSaharan Africa (1). Major control efforts have been implemented with some success (2, 3), but malaria eradication will likely require a safe and highly protective vaccine. Subunit vaccines have thus far shown moderate efficacy at best. RTS,S is the only vaccine candidate in phase 3 trials but, despite averting substantial numbers of malaria cases (4), shows only 30 to 50% reduction in clinical disease after 12 months depending on both age and malaria endemicity and even less after 18 months (5-7). These results stress the need for more effective second-generation vaccines. Key requirements are not only the identification of novel immunogens but also a better understanding of protection-related immune responses. This includes the effect of previous malaria exposure on immune responses upon reexposure or vaccination (8,9).During the past 3 decades, controlled human malar...

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Section: Discussionmentioning

confidence: 99%

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

et al. 2015

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“…While CSP is a pure pre-erythrocytic antigen expressed during the sporozoite and liver-stage of the parasite [ 19 - 21 ], and MSP-3 can only be detected on blood-stage parasites [ 22 ], AMA-1 [ 23 - 26 ], MSP-1 [ 27 - 29 ] and GLURP [ 30 ] are cross-stage antigens expressed during both the pre-erythrocytic and blood-stage of the parasite.…”

Section: Methodsmentioning

confidence: 99%

Protection of Malian children from clinical malaria is associated with recognition of multiple antigens

Daou

Kouriba

Ouédraogo

et al. 2015

Malar J

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BackgroundNaturally acquired immunity to clinical malaria is thought to be mainly antibody-mediated, but reports on antigen targets are contradictory. Recognition of multiple antigens may be crucial for protection. In this study, the magnitude of antibody responses and their temporal stability was assessed for a panel of malaria antigens in relation to protection against clinical Plasmodium falciparum malaria.MethodsMalian children aged two to 14 years were enrolled in a longitudinal study and followed up by passive and active case detection for seven months. Plasma was collected at enrolment and at the beginning, in the middle and after the end of the transmission season. Antibody titres to the P. falciparum-antigens apical membrane protein (AMA)-1, merozoite surface protein (MSP)-119, MSP-3, glutamine-rich protein (GLURP-R0) and circumsporozoite antigen (CSP) were assessed by enzyme-linked immunosorbent assay (ELISA) for 99 children with plasma available at all time points. Parasite carriage was determined by microscopy and nested PCR.ResultsAntibody titres to all antigens, except MSP-119, and the number of antigens recognized increased with age. After malaria exposure, antibody titres increased in children that had low titres at baseline, but decreased in those with high baseline responses. No significant differences were found between antibody titers for individual antigens between children remaining symptomatic or asymptomatic after exposure, after adjustment for age. Instead, children remaining asymptomatic following parasite exposure had a broader repertoire of antigen recognition.ConclusionsThe present study provides immune-epidemiological evidence from a limited cohort of Malian children that strong recognition of multiple antigens, rather than antibody titres for individual antigens, is associated with protection from clinical malaria.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0567-9) contains supplementary material, which is available to authorized users.

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“…SSP2/TRAP: Sporozoite surface protein 2/Thrombospondin-related anonymous protein (John et al, 2003), UniProt: Q9GTW7, Q9GTW7_PLAFA. AMA-1: Apical membrane antigen 1 (Schussek et al, 2013), UniProt: Q94661, Q94661_PLAFA. Pf332: P. falciparum antigen 332, DBL-like protein (Nilsson et al, 2011), UniProt: Q7JPX6, Q7JPX6_PLAFA.…”

Section: Cd8+ Epitope Frequency Among P Falciparum Antigensmentioning

confidence: 99%

In silico design of knowledge-based Plasmodium falciparum epitope ensemble vaccines

Damfo

Reche

Gatherer

et al. 2017

Journal of Molecular Graphics and Modelling

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Malaria is a global health burden, and a major cause of mortality and morbidity in Africa. Here we designed a putative malaria epitope ensemble vaccine by selecting an optimal set of pathogen epitopes. From the IEDB database, 584 experimentally-verified CD8+ epitopes and 483 experimentally-verified CD4+ epitopes were collected; 89% of which were found in 8 proteins. Using the PVS server, highly conserved epitopes were identified from variability analysis of multiple alignments of Plasmodium falciparum protein sequences. The allele-dependent binding of epitopes was then assessed using IEDB analysis tools, from which the population protection coverage of single and combined epitopes was estimated. Ten conserved epitopes from four well-studied antigens were found to have a coverage of 97.9% of the world population: 7 CD8+ T cell epitopes (LLMDCSGSI, FLIFFDLFLV, LLACAGLAYK, TPYAGEPAPF, LLACAGLAY, SLKKNSRSL, and NEVVVKEEY) and 3 CD4+ T cell epitopes (MRKLAILSVSSFLFV, KSKYKLATSVLAGLL and GLAYKFVVPGAATPYE). The addition of four heteroclitic peptides - single point mutated epitopes - increased HLA binding affinity and raised the predicted world population coverage above 99%.

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Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

Cited by 17 publications

References 88 publications

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

Protection of Malian children from clinical malaria is associated with recognition of multiple antigens

In silico design of knowledge-based Plasmodium falciparum epitope ensemble vaccines

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