• 1.

    World Health Organization, 2017. World Malaria Report 2017. Geneva, Switzerland: WHO.

  • 2.

    Roberts L, Enserink M, 2007. Did they really say… eradication? Science 318: 15441545.

  • 3.

    Plowe CV, Alonso P, Hoffman SL, 2009. The potential role of vaccines in the elimination of falciparum malaria and the eventual eradication of malaria. J Infect Dis 200: 16461649.

    • Search Google Scholar
    • Export Citation
  • 4.

    Henderson DA, 1999. Lessons from the eradication campaigns. Vaccine 17 (Suppl 3): S53S55.

  • 5.

    Cheng Q, Lawrence G, Reed C, Stowers A, Ranford-Cartwright L, Creasey A, Carter R, Saul A, 1997. Measurement of Plasmodium falciparum growth rates in vivo: a test of malaria vaccines. Am J Trop Med Hyg 57: 495500.

    • Search Google Scholar
    • Export Citation
  • 6.

    Spring M, Polhemus M, Ockenhouse C, 2014. Controlled human malaria infection. J Infect Dis 209 (Suppl 2): S40S45.

  • 7.

    Hoffman SL, 1997. Experimental challenge of volunteers with malaria. Ann Intern Med 127: 233235.

  • 8.

    Epstein JE, Rao S, Williams F, Freilich D, Luke T, Sedegah M, de la Vega P, Sacci J, Richie TL, Hoffman SL, 2007. Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes: an update. J Infect Dis 196: 145154.

    • Search Google Scholar
    • Export Citation
  • 9.

    Church LW et al. 1997. Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge. J Infect Dis 175: 915920.

    • Search Google Scholar
    • Export Citation
  • 10.

    Clyde DF, Most H, McCarthy VC, Vanderberg JP, 1973. Immunization of man against sporozite-induced falciparum malaria. Am J Med Sci 266: 169177.

    • Search Google Scholar
    • Export Citation
  • 11.

    Clyde DF, McCarthy VC, Miller RM, Hornick RB, 1973. Specificity of protection of man immunized against sporozoite-induced falciparum malaria. Am J Med Sci 266: 398401.

    • Search Google Scholar
    • Export Citation
  • 12.

    Clyde DF, Dawkins AT Jr., Heiner GG, McCarthy VC, Hornick RB, 1969. Characteristics of four new drug-resistant strains of Plasmodium falciparum from south-east Asia. Mil Med 134: 787794.

    • Search Google Scholar
    • Export Citation
  • 13.

    Rieckmann KH, Carson PE, Beaudoin RL, Cassells JS, Sell KW, 1974. Letter: sporozoite induced immunity in man against an Ethiopian strain of Plasmodium falciparum. Trans R Soc Trop Med Hyg 68: 258259.

    • Search Google Scholar
    • Export Citation
  • 14.

    Trager W, Jensen JB, 1976. Human malaria parasites in continous culture. Science 193: 673675.

  • 15.

    Vanderberg J, Gwadz R, 1980. The transmission by mosquitoes of plasmodia in the laboratory. Kreier J, ed. Malaria. New York, NY: Academic Press, 154234.

    • Search Google Scholar
    • Export Citation
  • 16.

    Chulay JD, Schneider I, Cosgriff TM, Hoffman SL, Ballou WR, Quakyi IA, Carter R, Trosper JH, Hockmeyer WT, 1986. Malaria transmitted to humans by mosquitoes infected from cultured Plasmodium falciparum. Am J Trop Med Hyg 35: 6668.

    • Search Google Scholar
    • Export Citation
  • 17.

    Herrington DA, Clyde DF, Murphy JR, Baqar S, Levine MM, do Rosario V, Hollingdale MR, 1988. A model for Plasmodium falciparum sporozoite challenge and very early therapy of parasitaemia for efficacy studies of sporozoite vaccines. Trop Geogr Med 40: 124127.

    • Search Google Scholar
    • Export Citation
  • 18.

    Herrington D et al. 1991. Successful immunization of humans with irradiated malaria sporozoites: humoral and cellular responses of the protected individuals. Am J Trop Med Hyg 45: 539547.

    • Search Google Scholar
    • Export Citation
  • 19.

    Laurens MB et al. Consensus Group on Design of Clinical Trials of Controlled Human Malaria Infection, 2012. A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines. Vaccine 30: 53025304.

    • Search Google Scholar
    • Export Citation
  • 20.

    Clyde DF, McCarthy VC, Miller RM, Woodward WE, 1975. Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg 24: 397401.

    • Search Google Scholar
    • Export Citation
  • 21.

    Institute of Medicine (US), 2007. Committee on ethical considerations for revisions to DHHS regulations for protection of prisoners involved in research. Gostin LO, Vanchieri C, Pope A, eds. Ethical Considerations for Research Involving Prisoners. Washington, DC: National Academies Press (US).

    • Search Google Scholar
    • Export Citation
  • 22.

    Fries LF, Gordon DM, Schneider I, Beier JC, Long GM, Gross M, Que JU, Cryz SJ, Sadoff JC, 1992. Safety, immunogenicity and efficacy of a Plasmodium falciparum vaccine comprising a circumsporozoite protein repeat region peptide conjugated to Pseudomonas aeruginosa toxin A. Infect Immun 328: 257259.

    • Search Google Scholar
    • Export Citation
  • 23.

    Sherwood JA et al. 1996. Plasmodium falciparum circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya. Vaccine 14: 817827.

    • Search Google Scholar
    • Export Citation
  • 24.

    Brown AE et al. 1994. Safety, immunogenicity and limited efficacy study of a recombinant Plasmodium falciparum circumsporozoite vaccine in Thai soldiers. Vaccine 12: 102108.

    • Search Google Scholar
    • Export Citation
  • 25.

    Kester KE et al. RTS,S Vaccine Evaluation Group, 2009. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis 200: 337346.

    • Search Google Scholar
    • Export Citation
  • 26.

    Kester KE et al. RTS,S Malaria Vaccine Evaluation Group, 2001. Efficacy of recombinant circumsporozoite protein vaccine regimens against experimental Plasmodium falciparum malaria. J Infect Dis 183: 640647.

    • Search Google Scholar
    • Export Citation
  • 27.

    Kester KE et al. RTS,S Malaria Vaccine Evaluation Group, 2007. A phase I/IIa safety, immunogenicity, and efficacy bridging randomized study of a two-dose regimen of liquid and lyophilized formulations of the candidate malaria vaccine RTS,S/AS02A in malaria-naive adults. Vaccine 25: 53595366.

    • Search Google Scholar
    • Export Citation
  • 28.

    Kester KE et al. RTS,S Malaria Vaccine Evaluation Group, 2008. Phase 2a trial of 0, 1, and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS,S/AS02 in malaria-naive adults at the Walter Reed Army Institute of Research. Vaccine 26: 21912202.

    • Search Google Scholar
    • Export Citation
  • 29.

    Bojang KA et al. RTS,S Malaria Vaccine Trial Team, 2001. Efficacy of RTS,S/AS02 malaria vaccine against Plasmodium falciparum infection in semi-immune adult men in the Gambia: a randomised trial. Lancet 358: 19271934.

    • Search Google Scholar
    • Export Citation
  • 30.

    Polhemus ME et al. 2009. Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLoS One 4: e6465.

  • 31.

    Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, 2004. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 364: 14111420.

    • Search Google Scholar
    • Export Citation
  • 32.

    RTSS Clinical Trials Partnership, 2015. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 6736: 3145.

    • Search Google Scholar
    • Export Citation
  • 33.

    Chattopadhyay R, Pratt D, 2017. Role of controlled human malaria infection (CHMI) in malaria vaccine development: a U.S. Food & Drug Administration (FDA) perspective. Vaccine 35: 27672769.

    • Search Google Scholar
    • Export Citation
  • 34.

    Teirlinck AC et al. 2013. NF135.C10: a new Plasmodium falciparum clone for controlled human malaria infections. J Infect Dis 207: 656660.

  • 35.

    McCall MBB et al. 2017. Infectivity of Plasmodium falciparum sporozoites determines emerging parasitemia in infected volunteers. Sci Transl Med 9: eaag2490.

    • Search Google Scholar
    • Export Citation
  • 36.

    Herrington DA et al. 1987. Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature 328: 257259.

    • Search Google Scholar
    • Export Citation
  • 37.

    Lyke KE et al. 2010. Plasmodium falciparum malaria challenge by the bite of aseptic Anopheles stephensi mosquitoes: results of a randomized infectivity trial. PLoS One 5: e13490.

    • Search Google Scholar
    • Export Citation
  • 38.

    Beier JC, Davis JR, Vaughan JA, Noden BH, Beier MS, 1991. Quantitation of Plasmodium falciparum sporozoites transmitted in vitro by experimentally infected Anopheles gambiae and Anopheles stephensi. Am J Trop Med Hyg 44: 564570.

    • Search Google Scholar
    • Export Citation
  • 39.

    Lyke KE et al. 2015. Optimizing intradermal administration of cryopreserved Plasmodium falciparum sporozoites in controlled human malaria infection. Am J Trop Med Hyg 93: 12741284.

    • Search Google Scholar
    • Export Citation
  • 40.

    Lyke KE et al. 2017. Attenuated PfSPZ vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection. Proc Natl Acad Sci U S A 114: 27112716.

    • Search Google Scholar
    • Export Citation
  • 41.

    Ishizuka AS et al. 2016. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat Med 22: 614623.

  • 42.

    Adams M et al. 2015. An ultrasensitive reverse transcription polymerase chain reaction assay to detect asymptomatic low-density Plasmodium falciparum and Plasmodium vivax infections in small volume blood samples. Malar J 14: 520.

    • Search Google Scholar
    • Export Citation
  • 43.

    Kamau E, Tolbert LS, Kortepeter L, Pratt M, Nyakoe N, Muringo L, Ogutu B, Waitumbi JN, Ockenhouse CF, 2011. Development of a highly sensitive genus-specific quantitative reverse transcriptase real-time PCR assay for detection and quantitation of Plasmodium by amplifying RNA and DNA of the 18S rRNA genes. J Clin Microbiol 49: 29462953.

    • Search Google Scholar
    • Export Citation
  • 44.

    Edelman R et al. 1993. Long-term persistence of sterile immunity in a volunteer immunized with X-irradiated Plasmodium falciparum sporozoites. J Infect Dis 168: 10661070.

    • Search Google Scholar
    • Export Citation
  • 45.

    Herrington DA et al. 1990. Human studies with synthetic peptide sporozoite vaccine (NANP)3-TT and immunization with irradiated sporozoites. Bull World Health Organ 68 (Suppl): 3337.

    • Search Google Scholar
    • Export Citation
  • 46.

    Hoffman SL et al. 1994. Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant. Am J Trop Med Hyg 51: 603612.

    • Search Google Scholar
    • Export Citation
  • 47.

    Davis JR, Cortese JF, Herrington DA, Murphy JR, Clyde DF, Thomas AW, Baqar S, Cochran MA, Thanassi J, Levine MM, 1992. Plasmodium falciparum: in vitro characterization and human infectivity of a cloned line. Exp Parasitol 74: 159168.

    • Search Google Scholar
    • Export Citation
  • 48.

    Laurens MB et al. 2013. Successful human infection with P. falciparum using three aseptic Anopheles stephensi mosquitoes: a new model for controlled human malaria infection. PLoS One 8: e68969.

    • Search Google Scholar
    • Export Citation
  • 49.

    Epstein JE et al. 2011. Live attenuated malaria vaccine designed to protect through hepatic CD8+ T cell immunity. Science 334: 475480.

  • 50.

    Murphy SC et al. 2012. Real-time quantitative reverse transcription PCR for monitoring of blood-stage Plasmodium falciparum infections in malaria human challenge trials. Am J Trop Med Hyg 86: 383394.

    • Search Google Scholar
    • Export Citation
  • 51.

    Jongo SA et al. 2018. Safety, immunogenicity, and protective efficacy against controlled human malaria infection of Plasmodium falciparum sporozoite vaccine in Tanzanian adults. Am J Trop Med Hyg 99: 338349.

    • Search Google Scholar
    • Export Citation
  • 52.

    Murphy SC et al. 2014. External quality assurance of malaria nucleic acid testing for clinical trials and eradication surveillance. PLoS One 9: e97398.

    • Search Google Scholar
    • Export Citation
  • 53.

    Stanisic DI, McCarthy JS, Good MF, 2018. Controlled human malaria infection: applications, advances, and challenges. Infect Immun 86: e00479-17.

    • Search Google Scholar
    • Export Citation
  • 54.

    Chen WH et al. 2016. Single-dose live oral cholera vaccine CVD 103-HgR protects against human experimental infection with Vibrio cholerae O1 El Tor. Clin Infect Dis 62: 13291335.

    • Search Google Scholar
    • Export Citation
  • 55.

    Levine MM, Chen WH, Kaper JB, Lock M, Danzig L, Gurwith M, 2017. PaxVax CVD 103-HgR single-dose live oral cholera vaccine. Expert Rev Vaccin 16: 197213.

    • Search Google Scholar
    • Export Citation
  • 56.

    Neafsey DE et al. 2015. Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine. N Engl J Med 373: 20252037.

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The Controlled Human Malaria Infection Experience at the University of Maryland

DeAnna J. Friedman-KlabanoffCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Matthew B. LaurensCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Andrea A. BerryCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Mark A. TravassosCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Matthew AdamsCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Kathy A. StraussCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Biraj ShresthaCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Myron M. LevineCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Robert EdelmanCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Kirsten E. LykeCenter for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Controlled human malaria infection (CHMI) is a powerful tool to evaluate the efficacy of malaria vaccines and pharmacologics. Investigators at the University of Maryland, Baltimore, Center for Vaccine Development (UMB-CVD) pioneered the technique in the 1970s and continue to advance the frontiers of CHMI research. We reviewed the records of 338 malaria-naive volunteers who underwent CHMI at UMB-CVD with Plasmodium falciparum from 1971 until 2017. These 338 volunteers underwent 387 CHMI events, including 60 via intradermal injection or direct venous inoculation (DVI) of purified, cryopreserved sporozoites. No volunteer suffered an unplanned hospitalization or required intravenous therapy related to CHMI. Median prepatency period was longer in challenges using NF54 (9 days) than in those using 7G8 (8 days), P = 0.0006 by the log-rank test. With dose optimization of DVI, the prepatent period did not differ between DVI and mosquito bite challenge (log-rank test, P = 0.66). Polymerase chain reaction (PCR) detected P. falciparum infection 3 days earlier than thick smears (P < 0.001), and diagnosis by ultrasensitive PCR was associated with less severe symptoms than smear-based diagnosis (39% versus 0%, P = 0.0003). Historical studies with NF54 showed a shorter median prepatency period of 10.3 days than more recent studies (median 11.0 days, P = 0.02) despite significantly lower salivary gland scores in earlier studies, P = 0.0001. The 47-year experience of CHMI at UMB-CVD has led to advancements in sporozoite delivery, diagnostics, and use of heterologous challenge. Additional studies on new challenge strains and genomic data to reflect regional heterogeneity will help advance the use of CHMI as supporting data for vaccine licensure.

Author Notes

Address correspondence to DeAnna J. Friedman-Klabanoff, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, 685 W. Baltimore St., Rm. 480, Baltimore, MD 21201. E-mail: defriedman@som.umaryland.edu

Financial support: K. E. L. is supported by the National Institutes of Health (NIH) (U19 AI110820, U01 AI089342, and R01AI110852), the Vaccine Research Center of NIH and the EMMES Corporation (HHSN272201000049I), the Office of the Surgeon General, Department of the Army (W81XWH-15-R-0034), and the Joint Warfighter Medical Research Program and Sanaria, Inc. (W81XWH-JW14843). This publication was made possible by an NIH-funded postdoctoral fellowship to D. J. F. K. (T32 AI007524). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Authors’ addresses: DeAnna J. Friedman-Klabanoff, Matthew B. Laurens, Andrea A. Berry, Mark A. Travassos, Matthew Adams, Kathy A. Strauss, Biraj Shrestha, Myron M. Levine, Robert Edelman, and Kirsten E. Lyke, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, E-mails: defriedman@som.umaryland.edu, mlaurens@som.umaryland.edu, aberry@som.umaryland.edu, mtravass@som.umaryland.edu, madams@som.umaryland.edu, kstrauss@som.umaryland.edu, bshrestha@som.umaryland.edu, mlevine@som.umaryland.edu, redelman@som.umaryland.edu, and klyke@som.umaryland.edu.

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