Efficacy of Preerythrocytic and Blood-Stage Malaria Vaccines Can Be Assessed in Small Sporozoite Challenge Trials in Human Volunteers

Roestenberg, Meta; Vlas, Sake J. de; Nieman, An-Emmie; Sauerwein, Robert W.; Hermsen, Cornelus C.

doi:10.1093/infdis/jis355

Cited by 41 publications

(46 citation statements)

References 12 publications

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“…Furthermore, P. falciparum lysate-seropositive Tanzanians had a lower parasite load at the time of first detection by qPCR and at the time of the first peak of parasite load than seronegative Tanzanians. The first peak of blood-stage parasitemia can be used as a proxy for parasite liver load (16,35). Our results might therefore indicate the emergence of fewer parasites from the liver and hence better control of either initiation or progression of liver-stage infection in preexposed individuals within the Tanzanian cohort and in Tanzanians than in the Dutch cohort.…”

Section: Discussionmentioning

confidence: 84%

“…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: 94%

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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: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 94%

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

et al. 2015

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“…One immunized subject developed parasitemia on day 21 after sporozoite challenge, as retrospectively detected by qPCR. The blood-stage parasite multiplication rate after controlled human malaria infection in malaria-naïve subjects is 10.9 on average, but may be as low as 2 (17). With a multiplication rate of 2, a load of 457 parasites per milliliter on day 21 would be the result of an estimated 9,000 merozoites released from the liver (i.e., one infected hepatocyte).…”

Section: Discussionmentioning

confidence: 99%

Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity

Bijker¹,

Bastiaens²,

Teirlinck³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

176

245

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Volunteers immunized under chloroquine chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) develop complete, longlasting protection against homologous sporozoite challenge. Chloroquine affects neither sporozoites nor liver-stages, but kills only asexual forms in erythrocytes once released from the liver into the circulation. Consequently, CPS immunization exposes the host to antigens from both preerythrocytic and blood stages, and induced immunity might target either of these stages. We therefore explored the life cycle stage specificity of CPS-induced protection. Twenty-five malaria-naïve volunteers were enrolled in a clinical trial, 15 of whom received CPS immunization. Five immunized subjects and five controls received a sporozoite challenge by mosquito bites, whereas nine immunized and five control subjects received an i.v. challenge with P. falciparum-infected erythrocytes. The latter approach completely bypasses preerythrocytic stages, enabling a direct comparison of protection against either life cycle stage. CPS-immunized subjects (13 of 14) developed anticircumsporozoite antibodies, whereas only one volunteer generated minimal titers against typical blood-stage antigens. IgG from CPS-immunized volunteers did not inhibit asexual blood-stage growth in vitro. All CPSimmunized subjects (5 of 5) were protected against sporozoite challenge. In contrast, nine of nine CPS-immunized subjects developed parasitemia after blood-stage challenge, with identical prepatent periods and blood-stage multiplication rates compared with controls. Intravenously challenged CPS-immunized subjects showed earlier fever and increased plasma concentrations of inflammatory markers D-dimer, IFN-γ, and monokine induced by IFN-γ than i.v. challenged controls. The complete lack of protection against blood-stage challenge indicates that CPS-induced protection is mediated by immunity against preerythrocytic stages. However, evidence is presented for immune recognition of P. falciparuminfected erythrocytes, suggesting memory responses unable to generate functional immunity.

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“…In a CHMI study, participants are infected with parasites delivered via three alternative routes: with sporozoites via mosquito bite (Chulay et al 1986;Roestenberg et al 2012); via needle-based inoculation of cryopreserved sporozoites (Epstein 2013); or via thawed cryopreserved, infected red blood cells (Lawrence et al 2000;Pombo et al 2002;Duncan et al 2011). CHMI by mosquito bite challenge has been the most widely adopted, and provides a cost-effective, highly reproducible assessment of vaccine candidates for their efficacy against infection.…”

Section: Innovation For Discovery Of New Targets and Biomarkersmentioning

confidence: 99%

Vaccines to Accelerate Malaria Elimination and Eventual Eradication

Healer

Cowman

Kaslow³

et al. 2017

Cold Spring Harb Perspect Med

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Remarkable progress has been made in coordinated malaria control efforts with substantial reductions in malaria-associated deaths and morbidity achieved through mass administration of drugs and vector control measures including distribution of long-lasting insecticideimpregnated bednets and indoor residual spraying. However, emerging resistance poses a significant threat to the sustainability of these interventions. In this light, the malaria research community has been charged with the development of a highly efficacious vaccine to complement existing malaria elimination measures. As the past 40 years of investment in this goal attests, this is no small feat. The malaria parasite is a highly complex organism, exquisitely adapted for survival under hostile conditions within human and mosquito hosts. Here we review current vaccine strategies to accelerate elimination and the potential for novel and innovative approaches to vaccine design through a better understanding of the host-parasite interaction.

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Efficacy of Preerythrocytic and Blood-Stage Malaria Vaccines Can Be Assessed in Small Sporozoite Challenge Trials in Human Volunteers

Cited by 41 publications

References 12 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 against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity

Vaccines to Accelerate Malaria Elimination and Eventual Eradication

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