Safety, Tolerability and  &lt;i&gt;Plasmodium Falciparum&lt;/i&gt; Transmission-Reducing Activity of Monoclonal Antibody TB31F: An Open-Label, First-in-Human, Trial in Healthy Malaria-Naïve Adults

Boor, Saskia C van der; Smit, Merel; Beek, Stijn W van; Ramjith, Jordache; Teelen, Karina; Vegte‐Bolmer, Marga van de; Gemert, Geert-Jan van; Pickkers, Peter; Wu, Yimin; Locke, Emily; Lee, Shwu-Maan; King, C. Richter; Birkett, Ashley; Miura, Kazutoyo; Ayorinde, Morolayo  A.; Sauerwein, Robert W.; Heine, Rob ter; Ockenhouse, Christian F.; Bousema, Teun; Jore, Matthijs M.; McCall, Matthew

doi:10.2139/ssrn.4054462

Cited by 2 publications

(4 citation statements)

References 22 publications

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“…Similarly, we analyzed data of a recent trial using reductions in oocyst density (i.e. transmission reducing activity; TRA) by SMFA as the endpoint (30) in the mixed-effects negative binomial regression model. The number of 41.3 oocysts per mosquito for the average person at baseline was reduced to 10.5 after intervention (Figure 3B), resulting in a TRA of 74.5% (95% CI: 71.3, 77.3), significantly higher than the threshold of 70% (p=0.0035).…”

Section: Resultsmentioning

confidence: 99%

“…Postadministration samples were selected where the mean TRA value was approximately 80% (median 77.1%, range 62.4-86.1%), a TRA value traditionally used as threshold to support further development of transmission-blocking interventions (28,29). This dataset was complemented with 11 independent experiments performed for the abovementioned clinical trial (30) to examine variance in oocyst density for SMFA experiments conducted at the same site (Radboudumc, Nijmegen, the Netherlands). The only entry criterion for SMFA experiments was a proportion of infected mosquitos of >70%, a pre-defined quality control threshold (20).…”

Section: Study Populations and Reference Valuesmentioning

confidence: 99%

“…To show a range of power calculations for TRA and TBA respectively, we allowed different combinations of parameter values for the data simulation and empirical power calculations. For both TBA/TRA we allowed sample sizes n = (10,20,30,40) for participants and m = (20, 40, 60) for mosquitos, based on conventional group sizes (31)(32)(33)(34)(35). We used consensus thresholds of meaningful efficacy (24,28,29,36) to define anticipated TBA/TRA = (70%, 80%, 95%) and thresholds for detecting TBA/TRA larger than t = (50%, 80%, 90%).…”

Section: Simulation Scenariosmentioning

confidence: 99%

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Quantifying Reductions in Plasmodium falciparum Infectivity to Mosquitos: A Sample Size Calculator to Inform Clinical Trials on Transmission-Reducing Interventions

Ramjith

Alkema²,

Bradley³

et al. 2022

Front. Immunol.

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Malaria transmission depends on the presence of mature Plasmodium transmission stages (gametocytes) that may render blood-feeding Anopheles mosquitos infectious. Transmission-blocking antimalarial drugs and vaccines can prevent transmission by reducing gametocyte densities or infectivity to mosquitos. Mosquito infection outcomes are thereby informative biological endpoints of clinical trials with transmission blocking interventions. Nevertheless, trials are often primarily designed to determine intervention safety; transmission blocking efficacy is difficult to incorporate in sample size considerations due to variation in infection outcomes and considerable inter-study variation. Here, we use clinical trial data from studies in malaria naive and naturally exposed study participants to present an online sample size calculator tool. This sample size calculator allows studies to be powered to detect reductions in the proportion of infected mosquitos or infection burden (oocyst density) in mosquitos. The utility of this online tool is illustrated using trial data with transmission blocking malaria drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Study Populations and Reference Valuesmentioning

confidence: 99%

Section: Simulation Scenariosmentioning

confidence: 99%

See 1 more Smart Citation

Quantifying Reductions in Plasmodium falciparum Infectivity to Mosquitos: A Sample Size Calculator to Inform Clinical Trials on Transmission-Reducing Interventions

Ramjith

Alkema²,

Bradley³

et al. 2022

Front. Immunol.

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“…Currently, the passive transfer of monoclonal antibodies (mAbs) as a prevention strategy for malaria infections is gaining traction. The concept of passive immunization against malaria is not new 2 , but only recently it has been demonstrated that it can induce protection in humans against a controlled malaria infection and prevent onward transmission 3,4 . Passive immunization can be a valuable approach to induce short-term protection (up to 6 months) against malaria for e.g.…”

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confidence: 99%

Sporozoite motility as a quantitative readout for anti-CSP antibody inhibition

Korne

Schuijlenburg

Sijtsma

et al. 2022

Sci Rep

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Antibodies can prevent malaria by neutralizing the infectious Plasmodium falciparum sporozoites (SPZ) before they establish an infection in the liver. Circumsporozoite protein (CSP), the most abundant surface protein of SPZ is the leading candidate for passive (and subunit) immunization approaches against malaria. Comprehensive assessment of the parasite-inhibitory capacity of anti-CSP monoclonal antibodies (mAbs) is an important step in advancing CSP-based immunization strategies. In this study, we employed a quantitative imaging-based motility assay to quantify the effect of anti-CSP mAbs on SPZ motility, both in vitro and in human skin.Our assay provided a quantitative measure of mAb parasite-inhibitory capacity through measurement of the half-maximal motility inhibitory concentration (IC50M) value for anti-CSP mAbs (IC50M 2A10: 24 nM, IC50M 3SP2: 71 nM). We found a sevenfold discrepancy between the IC50M and the binding saturation concentration measured by ELISA, possibly related to the observed shedding of CSP-mAb complexes during SPZ movement. In a subset of SPZ (5%), in vitro motility was unaffected by the presence of 2A10 while 3SP2 was able to completely block movement. In our ex vivo skin explant model, SPZ proved less susceptible to anti-CSP mAbs compared to SPZ in an in vitro environment. By quantitatively assessing motility, we created a valuable tool that can be used for comprehensive assessment of anti-CSP mAb potency. Insight that will help deepen our understanding of anti-CSP mAb potency and guide selection of the most promising anti-CSP mAbs for downstream clinical development.

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Safety, Tolerability and <i>Plasmodium Falciparum</i> Transmission-Reducing Activity of Monoclonal Antibody TB31F: An Open-Label, First-in-Human, Trial in Healthy Malaria-Naïve Adults

Cited by 2 publications

References 22 publications

Quantifying Reductions in Plasmodium falciparum Infectivity to Mosquitos: A Sample Size Calculator to Inform Clinical Trials on Transmission-Reducing Interventions

Quantifying Reductions in Plasmodium falciparum Infectivity to Mosquitos: A Sample Size Calculator to Inform Clinical Trials on Transmission-Reducing Interventions

Sporozoite motility as a quantitative readout for anti-CSP antibody inhibition

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