Outcomes of controlled human malaria infection after BCG vaccination
Jona Walk, L Charlotte J de Bree, Wouter Graumans, Rianne Stoter, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Karina Teelen, Cornelus C Hermsen, Rob J W Arts, Marije C Behet, Farid Keramati, Simone J C F M Moorlag, Annie S P Yang, Reinout van Crevel, Peter Aaby, Quirijn de Mast, André J A M van der Ven, Christine Stabell Benn, Mihai G Netea, Robert W Sauerwein, Jona Walk, L Charlotte J de Bree, Wouter Graumans, Rianne Stoter, Geert-Jan van Gemert, Marga van de Vegte-Bolmer, Karina Teelen, Cornelus C Hermsen, Rob J W Arts, Marije C Behet, Farid Keramati, Simone J C F M Moorlag, Annie S P Yang, Reinout van Crevel, Peter Aaby, Quirijn de Mast, André J A M van der Ven, Christine Stabell Benn, Mihai G Netea, Robert W Sauerwein
Abstract
Recent evidence suggests that certain vaccines, including Bacillus-Calmette Guérin (BCG), can induce changes in the innate immune system with non-specific memory characteristics, termed 'trained immunity'. Here we present the results of a randomised, controlled phase 1 clinical trial in 20 healthy male and female volunteers to evaluate the induction of immunity and protective efficacy of the anti-tuberculosis BCG vaccine against a controlled human malaria infection. After malaria challenge infection, BCG vaccinated volunteers present with earlier and more severe clinical adverse events, and have significantly earlier expression of NK cell activation markers and a trend towards earlier phenotypic monocyte activation. Furthermore, parasitemia in BCG vaccinated volunteers is inversely correlated with increased phenotypic NK cell and monocyte activation. The combined data demonstrate that BCG vaccination alters the clinical and immunological response to malaria, and form an impetus to further explore its potential in strategies for clinical malaria vaccine development.
Conflict of interest statement
The authors declare no competing interests.
Figures
References
- WHO. World Malaria Report 2015. (World Health Organization, Geneva, 2015).
- Olotu A, et al. Seven-year efficacy of RTS,S/AS01 malaria vaccine among young african children. N. Engl. J. Med. 2016;374:2519–2529. doi: 10.1056/NEJMoa1515257.
- Netea MG, Latz E, Mills KH, O’Neill LA. Innate immune memory: a paradigm shift in understanding host defense. Nat. Immunol. 2015;16:675–679. doi: 10.1038/ni.3178.
- Kleinnijenhuis J, et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun. 2014;6:152–158. doi: 10.1159/000355628.
- Kleinnijenhuis J, et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. U.S.A. 2012;109:17537–17542. doi: 10.1073/pnas.1202870109.
- Cheng SC, et al. mTOR− and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014;345:1250684. doi: 10.1126/science.1250684.
- Saeed S, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345:1251086. doi: 10.1126/science.1251086.
- Quintin J, et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe. 2012;12:223–232. doi: 10.1016/j.chom.2012.06.006.
- Clark IA, Allison AC, Cox FE. Protection of mice against Babesia and Plasmodium with BCG. Nature. 1976;259:309–311. doi: 10.1038/259309a0.
- Matsumoto S, et al. Mycobacterium bovis bacillus calmette-guerin induces protective immunity against infection by Plasmodium yoelii at blood-stage depending on shifting immunity toward Th1 type and inducing protective IgG2a after the parasite infection. Vaccine. 2000;19:779–787. doi: 10.1016/S0264-410X(00)00257-7.
- Murphy JR. Host defenses in murine malaria: nonspecific resistance to Plasmodium berghei generated in response to Mycobacterium bovis infection or Corynebacterium parvum stimulation. Infect. Immun. 1981;33:199–211.
- Parra M, et al. Molecular analysis of non-specific protection against murine malaria induced by BCG vaccination. PLoS ONE. 2013;8:e66115. doi: 10.1371/journal.pone.0066115.
- Roth A, et al. BCG vaccination scar associated with better childhood survival in Guinea-Bissau. Int. J. Epidemiol. 2005;34:540–547. doi: 10.1093/ije/dyh392.
- Teirlinck AC, et al. Plasmodium falciparum infection of human volunteers activates monocytes and CD16 + dendritic cells and induces upregulation of CD16 and CD1c expression. Infect. Immun. 2015;83:3732–3739. doi: 10.1128/IAI.00473-15.
- Kleinnijenhuis J, et al. BCG-induced trained immunity in NK cells: Role for non-specific protection to infection. Clin. Immunol. 2014;155:213–219. doi: 10.1016/j.clim.2014.10.005.
- Arts RJW, et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe. 2018;23:89–100 e105. doi: 10.1016/j.chom.2017.12.010.
- Harpaz R, et al. Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge. J. Clin. Investig. 1992;90:515–523. doi: 10.1172/JCI115889.
- Hermsen CC, et al. Circulating concentrations of soluble granzyme A and B increase during natural and experimental Plasmodium falciparum infections. Clin. Exp. Immunol. 2003;132:467–472. doi: 10.1046/j.1365-2249.2003.02160.x.
- Walther M, et al. Innate immune responses to human malaria: heterogeneous cytokine responses to blood-stage Plasmodium falciparum correlate with parasitological and clinical outcomes. J. Immunol. 2006;177:5736–5745. doi: 10.4049/jimmunol.177.8.5736.
- Church LW, et al. Clinical manifestations of Plasmodium falciparum malaria experimentally induced by mosquito challenge. J. Infect. Dis. 1997;175:915–920. doi: 10.1086/513990.
- Roestenberg M, et al. Comparison of clinical and parasitological data from controlled human malaria infection trials. PLoS ONE. 2012;7:e38434. doi: 10.1371/journal.pone.0038434.
- Walk J, et al. Diagnosis and treatment based on quantitative PCR after controlled human malaria infection. Malar. J. 2016;15:398. doi: 10.1186/s12936-016-1434-z.
- Liehl P, et al. Host-cell sensors for Plasmodium activate innate immunity against liver-stage infection. Nat. Med. 2014;20:47–53. doi: 10.1038/nm.3424.
- Miller JL, Sack BK, Baldwin M, Vaughan AM, Kappe SH. Interferon-mediated innate immune responses against malaria parasite liver stages. Cell Rep. 2014;7:436–447. doi: 10.1016/j.celrep.2014.03.018.
- McCall MB, et al. Memory-like IFN-gamma response by NK cells following malaria infection reveals the crucial role of T cells in NK cell activation by P. falciparum. Eur. J. Immunol. 2010;40:3472–3477. doi: 10.1002/eji.201040587.
- Leentjens J, et al. BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: A randomized, placebo-controlled pilot study. J. Infect. Dis. 2015;212:1930–1938. doi: 10.1093/infdis/jiv332.
- Artavanis-Tsakonas K, et al. Activation of a subset of human NK cells upon contact with Plasmodium falciparum-infected erythrocytes. J. Immunol. 2003;171:5396–5405. doi: 10.4049/jimmunol.171.10.5396.
- Buffen K, et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. 2014;10:e1004485. doi: 10.1371/journal.ppat.1004485.
- Roth A, Garly ML, Jensen H, Nielsen J, Aaby P. Bacillus Calmette-Guerin vaccination and infant mortality. Expert. Rev. Vaccin. 2006;5:277–293. doi: 10.1586/14760584.5.2.277.
- Aaby P, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 2011;204:245–252. doi: 10.1093/infdis/jir240.
- Biering-Sorensen S, et al. Early BCG-denmark and neonatal mortality among infants weighing < 2500 g: A randomized controlled trial. Clin. Infect. Dis. 2017;65:1183–1190. doi: 10.1093/cid/cix525.
- de Bree, L. C. J., et al. Non-specific effects of vaccines: Current evidence and potential implications. Semin. Immunol.39, 35–43 (2018).
- Netea MG, van Crevel R. BCG-induced protection: effects on innate immune memory. Semin. Immunol. 2014;26:512–517. doi: 10.1016/j.smim.2014.09.006.
- Benn CS, Fisker AB, Whittle HC, Aaby P. Revaccination with live attenuated vaccines confer additional beneficial nonspecific effects on overall survival: A review. EBioMedicine. 2016;10:312–317. doi: 10.1016/j.ebiom.2016.07.016.
- Rodrigues A, et al. Revaccination with Bacillus Calmette-Guerin (BCG) vaccine does not reduce morbidity from malaria in African children. Trop. Med. Int. Health.: TM & IH. 2007;12:224–229.
- Roth AE, et al. Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ. 2010;340:c671. doi: 10.1136/bmj.c671.
- Bijker EM, et al. Protection against malaria after immunization by chloroquine prophylaxis and sporozoites is mediated by preerythrocytic immunity. Proc. Natl Acad. Sci. U.S.A. 2013;110:7862–7867. doi: 10.1073/pnas.1220360110.
- Hermsen CC, et al. Detection of Plasmodium falciparum malaria parasites in vivo by real-time quantitative PCR. Mol. Biochem. Parasitol. 2001;118:247–251. doi: 10.1016/S0166-6851(01)00379-6.
- Schats R, et al. Heterologous protection against malaria after immunization with plasmodium falciparum sporozoites. PLoS ONE. 2015;10:e0124243. doi: 10.1371/journal.pone.0124243.
- Roestenberg M, et al. Protection against a malaria challenge by sporozoite inoculation. N. Engl. J. Med. 2009;361:468–477. doi: 10.1056/NEJMoa0805832.
- Nahrendorf W, et al. Memory B-cell and antibody responses induced by Plasmodium falciparum sporozoite immunization. J. Infect. Dis. 2014;210:1981–1990. doi: 10.1093/infdis/jiu354.
- Verhave JP, Leeuwenberg AD, Ponnudurai T, Meuwissen JH, van Druten JA. The biotin-streptavidin system in a two-site ELISA for the detection of plasmodial sporozoite antigen in mosquitoes. Parasite Immunol. 1988;10:17–31. doi: 10.1111/j.1365-3024.1988.tb00200.x.
Source: PubMed