Sporozoite immunization of human volunteers under mefloquine prophylaxis is safe, immunogenic and protective: a double-blind randomized controlled clinical trial
Else M Bijker, Remko Schats, Joshua M Obiero, Marije C Behet, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Wouter Graumans, Lisette van Lieshout, Guido J H Bastiaens, Karina Teelen, Cornelus C Hermsen, Anja Scholzen, Leo G Visser, Robert W Sauerwein, Else M Bijker, Remko Schats, Joshua M Obiero, Marije C Behet, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Wouter Graumans, Lisette van Lieshout, Guido J H Bastiaens, Karina Teelen, Cornelus C Hermsen, Anja Scholzen, Leo G Visser, Robert W Sauerwein
Abstract
Immunization of healthy volunteers with chloroquine ChemoProphylaxis and Sporozoites (CPS-CQ) efficiently and reproducibly induces dose-dependent and long-lasting protection against homologous Plasmodium falciparum challenge. Here, we studied whether chloroquine can be replaced by mefloquine, which is the only other licensed anti-malarial chemoprophylactic drug that does not affect pre-erythrocytic stages, exposure to which is considered essential for induction of protection by CPS immunization. In a double blind randomized controlled clinical trial, volunteers under either chloroquine prophylaxis (CPS-CQ, n = 5) or mefloquine prophylaxis (CPS-MQ, n = 10) received three sub-optimal CPS immunizations by bites from eight P. falciparum infected mosquitoes each, at monthly intervals. Four control volunteers received mefloquine prophylaxis and bites from uninfected mosquitoes. CPS-MQ immunization is safe and equally potent compared to CPS-CQ inducing protection in 7/10 (70%) versus 3/5 (60%) volunteers, respectively. Furthermore, specific antibody levels and cellular immune memory responses were comparable between both groups. We therefore conclude that mefloquine and chloroquine are equally effective in CPS-induced immune responses and protection. Trial registration: ClinicalTrials.gov NCT01422954.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
References
- World Health Organization (2013) World malaria report 2013.
- Doolan DL, Dobano C, Baird JK (2009) Acquired immunity to malaria. Clin Microbiol Rev 22: 13–36.
- Tran TM, Li S, Doumbo S, Doumtabe D, Huang CY, et al. (2013) An Intensive Longitudinal Cohort Study of Malian Children and Adults Reveals No Evidence of Acquired Immunity to Plasmodium falciparum Infection. Clin Infect Dis 57: 40–47.
- RTS'S Clinical Trials Partnership, Agnandji ST, Lell B, Fernandes JF, Abossolo BP, et al. (2012) A phase 3 trial of RTS, S/AS01 malaria vaccine in African infants. N Engl J Med 367: 2284–2295.
- Crompton PD, Pierce SK, Miller LH (2010) Advances and challenges in malaria vaccine development. J Clin Invest 120: 4168–4178.
- Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, et al. (2009) Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 361: 468–477.
- Bijker EM, Teirlinck AC, Schats R, van Gemert G-J, van de Vegte-Bolmer M, et al.. (2014) Cytotoxic Markers Associate with Protection against Malaria in Human Volunteers Immunized with Plasmodium falciparum Sporozoites. Journal of Infectious Diseases: jiu293.
- Roestenberg M, Teirlinck AC, McCall MBB, Teelen K, Makamdop KN, et al. (2011) Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study. Lancet 377: 1770–1776.
- Bijker EM, Bastiaens GJ, Teirlinck AC, van Gemert GJ, Graumans W, et al. (2013) Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc Natl Acad Sci U S A 110: 7862–7867.
- Hoffman SL, Goh LM, Luke TC, Schneider I, Le TP, et al. (2002) Protection of humans against malaria by immunization with radiation-attenuated Plasmodium falciparum sporozoites. J Infect Dis 185: 1155–1164.
- Seder RA, Chang LJ, Enama ME, Zephir KL, Sarwar UN, et al.. (2013) Protection Against Malaria by Intravenous Immunization with a Nonreplicating Sporozoite Vaccine. Science.
- Sauerwein RW, Bijker EM, Richie TL (2010) Empowering malaria vaccination by drug administration. Curr Opin Immunol 22: 367–373.
- Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, et al. (2005) Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. J Exp Med 202: 817–828.
- Garulli B, Di Mario G, Sciaraffia E, Accapezzato D, Barnaba V, et al. (2013) Enhancement of T cell-mediated immune responses to whole inactivated influenza virus by chloroquine treatment in vivo. Vaccine 31: 1717–1724.
- Behet MC, Foquet L, van Gemert GJ, Bijker EM, Meuleman P, et al. (2014) Sporozoite immunization of human volunteers under chemoprophylaxis induces functional antibodies against pre-erythrocytic stages of Plasmodium falciparum. Malar J 13: 136.
- Felgner PL, Roestenberg M, Liang L, Hung C, Jain A, et al. (2013) Pre-erythrocytic antibody profiles induced by controlled human malaria infections in healthy volunteers under chloroquine prophylaxis. Sci Rep 3: 3549.
- Nahrendorf W, Scholzen A, Bijker EM, Teirlinck AC, Bastiaens GJ, et al.. (2014) Memory B-cell and antibody responses induced by Plasmodium falciparum sporozoite immunization. Journal of Infectious Diseases: jiu354.
- CDC (2014) Accessed 27-OCT-2014.
- Nederlandsche Internisten Vereeniging, Hartstichting N, voor Cardiologie NV, voor Heelkunde NV, voor Neurologie NV, et al.. (2006) Multidisciplinaire Richtlijn Cardiovasculair risicomanagement.
- Verhage DF, Telgt DS, Bousema JT, Hermsen CC, van Gemert GJ, et al. (2005) Clinical outcome of experimental human malaria induced by Plasmodium falciparum-infected mosquitoes. Neth J Med 63: 52–58.
- Lejeune D, Souletie I, Houze S, Le bricon T, Le bras J, et al. (2007) Simultaneous determination of monodesethylchloroquine, chloroquine, cycloguanil and proguanil on dried blood spots by reverse-phase liquid chromatography. J Pharm Biomed Anal 43: 1106–1115.
- Ponnudurai T, Lensen AH, Van Gemert GJ, Bensink MP, Bolmer M, et al. (1989) Infectivity of cultured Plasmodium falciparum gametocytes to mosquitoes. Parasitology 98 Pt 2: 165–173.
- Hermsen CC, Telgt DS, Linders EH, van de Locht LA, Eling WM, et al. (2001) Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR. Mol Biochem Parasitol 118: 247–251.
- Roestenberg M, McCall M, Hopman J, Wiersma J, Luty AJ, et al. (2009) Protection against a malaria challenge by sporozoite inoculation. The New England journal of medicine 361: 468–477.
- GraphPad (Last accessed: 4 Dec 2013) QuickCalcs. Accessed.
- Lobel HO, Miani M, Eng T, Bernard KW, Hightower AW, et al. (1993) Long-term malaria prophylaxis with weekly mefloquine. Lancet 341: 848–851.
- Steffen R, Fuchs E, Schildknecht J, Naef U, Funk M, et al. (1993) Mefloquine compared with other malaria chemoprophylactic regimens in tourists visiting east Africa. Lancet 341: 1299–1303.
- Croft AM, Clayton TC, World MJ (1997) Side effects of mefloquine prophylaxis for malaria: an independent randomized controlled trial. Trans R Soc Trop Med Hyg 91: 199–203.
- Schlagenhauf P, Tschopp A, Johnson R, Nothdurft HD, Beck B, et al. (2003) Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: multicentre, randomised, double blind, four arm study. BMJ 327: 1078.
- Barrett PJ, Emmins PD, Clarke PD, Bradley DJ (1996) Comparison of adverse events associated with use of mefloquine and combination of chloroquine and proguanil as antimalarial prophylaxis: postal and telephone survey of travellers. BMJ 313: 525–528.
- Centers for Disease Control and Prevention . Accessed 27 October 2014.
- Ponnudurai T, Lensen AH, van Gemert GJ, Bolmer MG, Meuwissen JH (1991) Feeding behaviour and sporozoite ejection by infected Anopheles stephensi. Trans R Soc Trop Med Hyg 85: 175–180.
- Duffy PE, Sahu T, Akue A, Milman N, Anderson C (2012) Pre-erythrocytic malaria vaccines: identifying the targets. Expert review of vaccines 11: 1261–1280.
- Roestenberg M, de Vlas SJ, Nieman A-E, Sauerwein RW, Hermsen CC (2012) Efficacy of preerythrocytic and blood-stage malaria vaccines can be assessed in small sporozoite challenge trials in human volunteers. J Infect Dis 206: 319–323.
- Roestenberg M, O'Hara GA, Duncan CJA, Epstein JE, Edwards NJ, et al. (2012) Comparison of clinical and parasitological data from controlled human malaria infection trials. PLoS One 7: e38434.
- Rombo L, Bergqvist Y, Hellgren U (1987) Chloroquine and desethylchloroquine concentrations during regular long-term malaria prophylaxis. Bull World Health Organ 65: 879–883.
- Palmer KJ, Holliday SM, Brogden RN (1993) Mefloquine. Drugs 45: 430–475.
- Nganou-Makamdop K, Sauerwein RW (2013) Liver or blood-stage arrest during malaria sporozoite immunization: the later the better? Trends Parasitol 29: 304–310.
Source: PubMed