Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

Shekalaghe, Seif; Rutaihwa, Mastidia; Billingsley, Peter F.; Chemba, Mwajuma; Daubenberger, Claudia; James, Eric R.; Mpina, Maximillian; Juma, Omar; Schindler, Tobias; Huber, Eric; Gunasekera, Anusha; Manoj, Anita; Simon, Beatus; Saverino, Elizabeth; Church, L. W. Preston; Hermsen, Cornelus C.; Sauerwein, Robert W.; Plowe, Christopher V.; Venkatesan, Meera; Sasi, Philip; Lweno, Omar; Mutani, Paul; Hamad, Ali; Mohammed, Ali; Urassa, Alwisa; Mzee, Tutu; Padilla, Debbie; Ruben, Adam J.; Sim, B. Kim Lee; Tanner, Marcel; Abdulla, Salim; Hoffman, Stephen L.

doi:10.4269/ajtmh.14-0119

Cited by 118 publications

(143 citation statements)

References 30 publications

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“…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. Our data, however, support antibody control of blood-stage replication only during the initial phase of sub-qPCR-detectable parasitemia: while parasite multiplication based on PCR data could not be directly compared due to the high variability of the amplification dynamics (24), there was no difference between prepatency by TS and qPCR in the two Tanzanian groups.…”

Section: Discussioncontrasting

confidence: 56%

“…In line with such an effect of preexisting antisporozoite immunity would be the observation that those Tanzanian volunteers with a longer prepatancy by qPCR also had higher baseline antibody titers against the sporozoite antigen CSP. However, the first detection by qPCR in both the Dutch and Tanzanians after intradermal PfSPZ injection was uncharacteristically late compared to that for infection by mosquito bite routinely conducted in The Netherlands and elsewhere (11,16,18,19,23,24,35). This is likely due to less efficient liver-stage infection by this route and hence a low initial blood-stage load that reaches the qPCR detection limit only later.…”

Section: Discussionmentioning

confidence: 77%

“…Noteworthy, the differential immune responses described herein may explain why Tanzanian volunteers reported fewer clinical symptoms, such as fever, than their Dutch counterparts during CHMI after PfSPZ injection (24). On the one hand, preexisting antibody responses may reduce the initial parasite load and mediate antidisease immunity.…”

Section: Discussionmentioning

confidence: 82%

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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: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 77%

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

et al. 2015

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“…Other models also exist to support the development of human-infective Plasmodium species, such as P. vivax or P. falciparum, in HepG2 and HC04 hepatoma cell lines, respectively (77,78). However, such studies are more challenging because of the lower infection rates of these parasites (79,80) and the restricted accessibility of these Plasmodium species, requiring access to facilities able to breed mosquitoes infected with these human-infective Plasmodium parasites or cryopreserved Plasmodium species sporozoites (81)(82)(83). Indeed, few research institutes have insectaries that are able to breed human-infective parasites in mosquitoes.…”

Section: Challenges and Current State Of Malaria Drug Developmentmentioning

confidence: 99%

Current therapies and future possibilities for drug development against liver-stage malaria

Raphemot¹,

Posfai²,

Derbyshire³

2016

Journal of Clinical Investigation

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“…Controlled human malaria infection (CHMI) of malaria-naive human volunteers provides an opportunity to investigate this. CHMI can be undertaken by three means: allowing laboratory-reared Plasmodium-infected mosquitoes to feed on study participants (29)(30)(31)(32), injecting cryopreserved sporozoites (33)(34)(35)(36), or injecting PEs (37)(38)(39)(40). We have recently undertaken the current good manufacturing practice production of clinical-grade cultured P. falciparum blood-stage cell banks (41).…”

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Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite

et al. 2016

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j Plasmodium falciparum is the most virulent human malaria parasite because of its ability to cytoadhere in the microvasculature. Nonhuman primate studies demonstrated relationships among knob expression, cytoadherence, and infectivity. This has not been examined in humans. Cultured clinical-grade P. falciparum parasites (NF54, 7G8, and 3D7B) and ex vivo-derived cell banks were characterized. Knob and knob-associated histidine-rich protein expression, CD36 adhesion, and antibody recognition of parasitized erythrocytes (PEs) were evaluated. Parasites from the cell banks were administered to malaria-naive human volunteers to explore infectivity. For the NF54 and 3D7B cell banks, blood was collected from the study participants for in vitro characterization. All parasites were infective in vivo. However, infectivity of NF54 was dramatically reduced. In vitro characterization revealed that unlike other cell bank parasites, NF54 PEs lacked knobs and did not cytoadhere. Recognition of NF54 PEs by immune sera was observed, suggesting P. falciparum erythrocyte membrane protein 1 expression. Subsequent recovery of knob expression and CD36-mediated adhesion were observed in PEs derived from participants infected with NF54. Knobless cell bank parasites have a dramatic reduction in infectivity and the ability to adhere to CD36. Subsequent infection of malaria-naive volunteers restored knob expression and CD36-mediated cytoadherence, thereby showing that the human environment can modulate virulence. P lasmodium falciparum is the most virulent of the six Plasmodium sp. parasites that infect humans. Its ability to cytoadhere and sequester itself in the microvasculature can result in obstruction of blood flow and organ dysfunction, and these are key processes in the development of severe falciparum malaria (1).Parasite cytoadherence and sequestration are facilitated by parasite-encoded knoblike structures that first appear on early trophozoite-stage parasites and are formed beneath the plasma membrane of parasitized erythrocytes (PEs) (2). Cytoadherence to receptors in the deep vasculature prevents removal and destruction of the parasite by the mononuclear phagocytic system, especially the spleen. Higher knob densities have been reported on PEs collected directly from patients than on cultured PEs infected in vitro (3). Following in vitro cultivation of P. falciparum, knob formation on PEs varies in an isolate-dependent manner (3-5), ranging from a mild reduction in density to complete ablation. The major structural protein in knobs is the knob-associated histidinerich protein (KAHRP) (2, 6, 7). Deletion of the gene encoding KAHRP results in the loss of knobs (8, 9).P. falciparum isolates can lose the ability to adhere to tissue receptors in vitro (10). Loss of adherence is isolate dependent and can occur independently of whether the knob phenotype is retained (10). Cytoadherence involves an interaction between parasite ligands and tissue receptors, including CD36, on the vascular endothelium (11, 12). The principal parasite adh...

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Controlled Human Malaria Infection of Tanzanians by Intradermal Injection of Aseptic, Purified, Cryopreserved Plasmodium falciparum Sporozoites

Cited by 118 publications

References 30 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

Current therapies and future possibilities for drug development against liver-stage malaria

Infectivity of Plasmodium falciparum in Malaria-Naive Individuals Is Related to Knob Expression and Cytoadherence of the Parasite

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