Serologic Markers of Previous Malaria Exposure and Functional Antibodies Inhibiting Parasite Growth Are Associated With Parasite Kinetics Following a Plasmodium falciparum Controlled Human Infection

Jane Achan, Isaie J Reuling, Xi Zen Yap, Edgard Dabira, Abdullahi Ahmad, Momodou Cox, Davis Nwakanma, Kevin Tetteh, Lindsey Wu, Guido J H Bastiaens, Yonas Abebe, Anita Manoj, Harparkash Kaur, Kazutoyo Miura, Carole Long, Peter F Billingsley, B Kim Lee Sim, Stephen L Hoffman, Chris Drakeley, Teun Bousema, Umberto D'Alessandro, Jane Achan, Isaie J Reuling, Xi Zen Yap, Edgard Dabira, Abdullahi Ahmad, Momodou Cox, Davis Nwakanma, Kevin Tetteh, Lindsey Wu, Guido J H Bastiaens, Yonas Abebe, Anita Manoj, Harparkash Kaur, Kazutoyo Miura, Carole Long, Peter F Billingsley, B Kim Lee Sim, Stephen L Hoffman, Chris Drakeley, Teun Bousema, Umberto D'Alessandro

Abstract

Background: We assessed the impact of exposure to Plasmodium falciparum on parasite kinetics, clinical symptoms, and functional immunity after controlled human malaria infection (CHMI) in 2 cohorts with different levels of previous malarial exposure.

Methods: Nine adult males with high (sero-high) and 10 with low (sero-low) previous exposure received 3200 P. falciparum sporozoites (PfSPZ) of PfSPZ Challenge by direct venous inoculation and were followed for 35 days for parasitemia by thick blood smear (TBS) and quantitative polymerase chain reaction. Endpoints were time to parasitemia, adverse events, and immune responses.

Results: Ten of 10 (100%) volunteers in the sero-low and 7 of 9 (77.8%) in the sero-high group developed parasitemia detected by TBS in the first 28 days (P = .125). The median time to parasitemia was significantly shorter in the sero-low group than the sero-high group (9 days [interquartile range {IQR} 7.5-11.0] vs 11.0 days [IQR 7.5-18.0], respectively; log-rank test, P = .005). Antibody recognition of sporozoites was significantly higher in the sero-high (median, 17.93 [IQR 12.95-24] arbitrary units [AU]) than the sero-low volunteers (median, 10.54 [IQR, 8.36-12.12] AU) (P = .006). Growth inhibitory activity was significantly higher in the sero-high (median, 21.8% [IQR, 8.15%-29.65%]) than in the sero-low group (median, 8.3% [IQR, 5.6%-10.23%]) (P = .025).

Conclusions: CHMI was safe and well tolerated in this population. Individuals with serological evidence of higher malaria exposure were able to better control infection and had higher parasite growth inhibitory activity.

Clinical trials registration: NCT03496454.

Keywords: clinical outcomes; controlled human malaria infection; functional antibodies; malaria exposure; parasite kinetics.

© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Antibody histogram plots for screened volunteers in The Gambia controlled human malaria infection study. Light colors are the sero-low group, dark colors are the sero-high group, and gray colors are the other screened volunteers with intermediate immunological profile. Abbreviations: AMA-1, apical membrane antigen 1; Etramp5.Ag1, early transcribed membrane protein; GEXP18, gametocyte exported protein; GLURP.R2, glutamate-rich protein; MSP-1.19, merozoite surface protein 1.19; Rh2.2030, reticulocyte-binding protein homologue.
Figure 2.
Figure 2.
Comparison of parasite kinetics between the 2 exposure groups following controlled human malaria infection. Kaplan–Meier curve for time from inoculation to parasitemia detected by thick blood smear (A) and quantitative polymerase chain reaction (qPCR) (B). Differences in parasite density by qPCR at treatment (C) and peak parasitemia (D).
Figure 3.
Figure 3.
Individual-level kinetics of parasitemia by quantitative polymerase chain reaction (qPCR) following controlled human malaria infection with Plasmodium falciparum (Pf).
Figure 4.
Figure 4.
Differences in clinical outcomes following controlled human malaria infection in the 2 exposure groups, showing proportion of participants without symptoms, number of adverse events (AEs) per participant, and total number of AEs per group.
Figure 5.
Figure 5.
Antibody-mediated responses to Plasmodium falciparum in high- and low-exposure groups. A, The sero-high group had significantly higher (P = .006) titers of antibodies to sporozoite antigens, expressed as arbitrary units (AU). B, There were no significant differences between groups in their ability to block sporozoite invasion of HC04 hepatocytes. C, Plasma from the sero-high group also had significantly higher (P = .0003) levels of antibodies to asexual-stage antigens, also expressed as AU. D, Purified immunoglobulin G from the sero-high exposure group also had significantly higher growth inhibitory activity (P = .025) against blood-stage 3D7 parasites.

References

    1. Fowkes FJ, Boeuf P, Beeson JG. Immunity to malaria in an era of declining malaria transmission. Parasitology 2016; 143:139–53.
    1. Doolan DL, Dobaño C, Baird JK. Acquired immunity to malaria. Clin Microbiol Rev 2009; 22:13–36.
    1. Tran TM, Li S, Doumbo S, et al. . An intensive longitudinal cohort study of Malian children and adults reveals no evidence of acquired immunity to Plasmodium falciparum infection. Clin Infect Dis 2013; 57:40–7.
    1. Hoffman SL, Oster CN, Plowe CV, et al. . Naturally acquired antibodies to sporozoites do not prevent malaria: vaccine development implications. Science 1987; 237:639–42.
    1. Lell B, Mordmüller B, Dejon Agobe JC, et al. . Impact of sickle cell trait and naturally acquired immunity on uncomplicated malaria after controlled human malaria infection in adults in Gabon. Am J Trop Med Hyg 2018; 98:508–15.
    1. World Health Organization. World malaria report. 2018. Available at: . Accessed 18 March 2019.
    1. Kalayjian BC, Malhotra I, Mungai P, Holding P, King CL. Marked decline in malaria prevalence among pregnant women and their offspring from 1996 to 2010 on the south Kenyan coast. Am J Trop Med Hyg 2013; 89:1129–34.
    1. Snow RW, Kibuchi E, Karuri SW, et al. . Changing malaria prevalence on the Kenyan coast since 1974: climate, drugs and vector control. PLoS One 2015; 10:e0128792.
    1. Mogeni P, Williams TN, Fegan G, et al. . Age, spatial, and temporal variations in hospital admissions with malaria in Kilifi County, Kenya: a 25-year longitudinal observational study. PLoS Med 2016; 13:e1002047.
    1. Griffin JT, Hollingsworth TD, Reyburn H, Drakeley CJ, Riley EM, Ghani AC. Gradual acquisition of immunity to severe malaria with increasing exposure. Proc Biol Sci 2015; 282:20142657.
    1. Migot F, Chougnet C, Raharimalala L, Astagneau P, Lepers JP, Deloron P. Human immune responses to the Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) after a decrease in malaria transmission in Madagascar. Am J Trop Med Hyg 1993; 48:432–9.
    1. Diop F, Richard V, Diouf B, et al. . Dramatic declines in seropositivity as determined with crude extracts of Plasmodium falciparum schizonts between 2000 and 2010 in Dielmo and Ndiop, Senegal. Malar J 2014; 13:83.
    1. Wong J, Hamel MJ, Drakeley CJ, et al. . Serological markers for monitoring historical changes in malaria transmission intensity in a highly endemic region of western Kenya, 1994-2009. Malar J 2014; 13:451.
    1. Sauerwein RW, Roestenberg M, Moorthy VS. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol 2011; 11:57–64.
    1. Stanisic DI, McCarthy JS, Good MF. Controlled human malaria infection: applications, advances, and challenges. Infect Immun 2018; 86 doi:10.1128/IAI.00479-17.
    1. Mordmüller B, Supan C, Sim KL, et al. . Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres. Malar J 2015; 14:117.
    1. Gómez-Pérez GP, Legarda A, Muñoz J, et al. . Controlled human malaria infection by intramuscular and direct venous inoculation of cryopreserved Plasmodium falciparum sporozoites in malaria-naïve volunteers: effect of injection volume and dose on infectivity rates. Malar J 2015; 14:306.
    1. Shekalaghe S, Rutaihwa M, Billingsley PF, et al. . Controlled human malaria infection of Tanzanians by intradermal injection of aseptic, purified, cryopreserved Plasmodium falciparum sporozoites. Am J Trop Med Hyg 2014; 91:471–80.
    1. Hodgson SH, Juma E, Salim A, et al. . Lessons learnt from the first controlled human malaria infection study conducted in Nairobi, Kenya. Malar J 2015; 14:182.
    1. Jongo SA, Shekalaghe SA, Church LWP, et al. . Safety, immunogenicity, and protective efficacy against controlled human malaria infection of Plasmodium falciparum sporozoite vaccine in Tanzanian adults. Am J Trop Med Hyg 2018; 99:338–49.
    1. Dejon-Agobe JC, Ateba-Ngoa U, Lalremruata A, et al. . Controlled human malaria infection of healthy lifelong malaria-exposed adults to assess safety, immunogenicity and efficacy of the asexual blood stage malaria vaccine candidate GMZ2 [manuscript published online ahead of print 18 December 2018]. Clin Infect Dis 2018. doi:10.1093/cid/ciy1087.
    1. Lindsey Wu TH, Ssewanyana I, Oulton T, et al. . Optimisation and standardisation of a multiplex immunoassay of diverse Plasmodium falciparum antigens to assess changes in malaria transmission using sero-epidemiology. Wellcome Open Research 2019; 4.
    1. Obiero JM, Shekalaghe S, Hermsen CC, et al. . Impact of malaria preexposure on antiparasite cellular and humoral immune responses after controlled human malaria infection. Infect Immun 2015; 83:2185–96.
    1. Helb DA, Tetteh KK, Felgner PL, et al. . Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities. Proc Natl Acad Sci U S A 2015; 112:E4438–47.
    1. Hoffman SL, Billingsley PF, James E, et al. . Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria. Hum Vaccin 2010; 6:97–106.
    1. Walk J, Reuling IJ, Behet MC, et al. . Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial. BMC Med 2017; 15:168.
    1. Khalil IF, Abildrup U, Alifrangis LH, et al. . Measurement of lumefantrine and its metabolite in plasma by high performance liquid chromatography with ultraviolet detection. J Pharm Biomed Anal 2011; 54:168–72.
    1. Laurens MB, Duncan CJ, Epstein JE, et al. . Consensus Group on Design of Clinical Trials of Controlled Human Malaria Infection A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines. Vaccine 2012; 30:5302–4.
    1. Hermsen CC, Telgt DS, Linders EH, et al. . Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR. Mol Biochem Parasitol 2001; 118:247–51.
    1. Kaushansky A, Rezakhani N, Mann H, Kappe SH. Development of a quantitative flow cytometry-based assay to assess infection by Plasmodium falciparum sporozoites. Mol Biochem Parasitol 2012; 183:100–3.
    1. Behet MC, Kurtovic L, van Gemert GJ, et al. . The complement system contributes to functional antibody-mediated responses induced by immunization with Plasmodium falciparum malaria sporozoites. Infect Immun 2018; 86 doi:10.1128/IAI.00920-17.
    1. Bastiaens GJH, van Meer MPA, Scholzen A, et al. . Safety, immunogenicity, and protective efficacy of intradermal immunization with aseptic, purified, cryopreserved Plasmodium falciparum sporozoites in volunteers under chloroquine prophylaxis: a randomized controlled trial. Am J Trop Med Hyg 2016; 94:663–73.
    1. Mwesigwa J, Achan J, Di Tanna GL, et al. . Residual malaria transmission dynamics varies across The Gambia despite high coverage of control interventions. PLoS One 2017; 12:e0187059.
    1. Hodgson SH, Juma E, Salim A, et al. . Evaluating controlled human malaria infection in Kenyan adults with varying degrees of prior exposure to Plasmodium falciparum using sporozoites administered by intramuscular injection. Front Microbiol 2014; 5:686.
    1. Snow RW, Marsh K. New insights into the epidemiology of malaria relevant for disease control. Br Med Bull 1998; 54:293–309.
    1. Rolfes MA, McCarra M, Magak NG, et al. . Development of clinical immunity to malaria in highland areas of low and unstable transmission. Am J Trop Med Hyg 2012; 87:806–12.
    1. Drakeley CJ, Corran PH, Coleman PG, et al. . Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure. Proc Natl Acad Sci U S A 2005; 102:5108–13.
    1. Abdi AI, Hodgson SH, Muthui MK, et al. . Plasmodium falciparum malaria parasite var gene expression is modified by host antibodies: longitudinal evidence from controlled infections of Kenyan adults with varying natural exposure. BMC Infect Dis 2017; 17:585.
    1. Kinyanjui SM, Bejon P, Osier FH, Bull PC, Marsh K. What you see is not what you get: implications of the brevity of antibody responses to malaria antigens and transmission heterogeneity in longitudinal studies of malaria immunity. Malar J 2009; 8:242.
    1. Reuling IJ, van de Schans LA, Coffeng LE, et al. . A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model. Elife 2018; 7 doi:10.7554/eLife.31549.

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