Experimental infection and protection against ... - TI Pharma

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Protection against a Malaria Challenge by Sporozoite Inoculation 183 Figure 3 The proportion of lymphocytes that produced interferon-γ (IFN-γ) and interleukin-2 (Panel A), tumour necrosis factor α (TNF-α) and interleukin-2 (Panel B), or IFN-γ, TNF-α, and interleukin-2 (Panel C) after in vitro stimulation with erythrocytes infected with the homologous strain of P. falciparum (PfRBC), with uninfected erythrocytes (uRBC), or with phytohemagglutinin (PHA) as a positive control are shown before immunization (day I-1) and before malaria challenge (day C-1). Dashed lines represent the proportion of positive cells in unstimulated wells (culture medium only). The geometric mean fluorescence intensity of cells producing IFN-γ (Panel D), TNF-α (Panel E), and interleukin- 2(Panel F) that were isolated from vaccinees on day C-1 is shown after stimulation in vitro with infected erythrocytes. Cells are grouped according to their positivity or negativity for each of the other two cytokines. In Panels G, H, and I, the proportion of lymphocytes that produced IFN-γ and interleukin-2 in response to infected erythrocytes are shown on day I-1 and day C-1 for lymphocyte phenotypes, including naive T cells (CD3+CD45RO−), memory T cells (CD3+CD45RO+), and non-T lymphocytes (CD3−CD45RO−) (Panel G); for T-cell phenotypes, including helper T cells (CD4+CD8−), cytotoxic T cells (CD4−CD8+), and other lymphocytes (CD4−CD8−) (Panel H); and for memory phenotypes, including naive T cells (CD62L+CD45RO−), central memory T cells (CD62L+CD45RO+), effector memory T cells (CD62L−CD45RO+), and other lymphocytes (CD62L−CD45RO−) (Panel I). The proportions of lymphocytes that produced IFN-γ and interleukin-2 after stimulation with uninfected erythrocytes were below 0.005% (not shown). All P values are for the comparison between the vaccine group and the control group and were calculated with the use of the Mann–Whitney test. The T bars represent standard errors..
184 Chapter 9 strain P. falciparum-infected erythrocytes (PfRBC) or controls (Figure 3 and supplementary figures 2+3). Whereas cellular responses to uninfected erythrocytes (uRBC) never differed in any experiment from those to culture medium alone, stimulation with PfRBC elicited small percentages of lymphocytes producing IFNγ or TNFα, but not IL-2, in both groups of volunteers prior to immunization (day I-1, Supplementary figure 2). Although no statistically significant increment was seen in the overall percentage of cells producing individual cytokines (IFNγ+ or TNFα+) in either group following immunization (day C-1), a marked and significant increase was observed in the percentages of cells producing multiple cytokines in response to PfRBC in vera (IFNγ+IL-2+ p=0.026, Figure 3a; TNFα+IL-2+ p=0.046, Figure 3b; IFNγ+TNFα+IL-2+ p=0.032, Figure 3c). The importance of these pluripotent lymphocytes in acquired immune protection is suggested by their higher cytokine content and possibly as a consequence a better effector function (Figure 3d-f). The major contributors to this increase in PfRBC-responding pluripotent lymphocytes were [CD3+CD45RO+) memory-like T cells (p=0.025 vs. day I-1, Figure 3g and supplementary figure 3), in particular CD4+CD8- cells (p=0.005 vs. day I-1, Figure 3h). Most noticeably, these new pluripotent lymphocytes were predominantly of the effector memory (CD62L-CD45RO+) phenotype (p=0.005 vs. day I-1), although there was also a small but significant (p=0.017) increase in the numbers of responding central memory (CD62L+CD45RO+) cells in vera (Figure 3i). Discussion Our study shows that sterile protection to an homologous challenge with P. falciparum malaria can be much more efficiently induced in comparison to irradiation-attenuated sporozoite immunization. In the endemic situation, nonsterile semi-immunity is acquired only after years of repeated natural exposure. The improved efficiency of our approach we believe to be due to a critical balance of exposure to pre- and intra-erythrocytic antigens. In contrast to irradiated sporozoites that arrest early during liver-stage development [4], intact sporozoites under CQ cover mature fully and develop into a first generation of blood-stage parasites [11], thus presenting to the host’s immune system a markedly broader palette of pre-erythrocytic and additionally, albeit at relatively low-dose, erythrocytic-stage antigens. The contribution of intra-erythrocytic antigens to the development of protective immunity is suggested by Pombo et al., who reported that repeated intravenous injection of ultra-low densities of
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Experimental infection and protecti
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Experimental infection and protecti
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Contents Contents 5 Chapter 1 - Int
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Introduction 9 Malaria Malaria is o
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Introduction 11 Preclinical Clinica
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Introduction 13 pipeline of clinica
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Introduction 15 The division of ant
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Introduction 17 Figure 4. Populatio
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Introduction 19 candidates. Initial
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Introduction 21 - to identify param
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Introduction 23 20. Nussenzweig RS,
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Introduction 25 50. Ouedraogo AL, R
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Introduction 27 RTS,S/AS02 in malar
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Chapter 2 Safety and Immunogenicity
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Safety and Immunogenicity of a Reco
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Chapter 3 Humoral immune responses
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Humoral immune responses to a singl
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Chapter 4 82 Abstract The functiona
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84 Chapter 4 Figure 1. Schematic re
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86 Chapter 4 Concentration (mg/ml,
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88 Chapter 4 Figure 4: Correlation
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90 Chapter 4 positively correlated
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92 Chapter 4 Acknowledgements The a
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94 Chapter 4 determinant of subsequ
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Chapter 5 Comparison of clinical an
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Comparison of clinical and parasito
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Chapter 6 Efficacy of pre-erythrocy
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Efficacy of pre-erythrocytic and bl
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Chapter 7 NF135.C10: a new Plasmodi
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NF135.C10: a new Plasmodium falcipa
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Page 199 and 200: 198 Chapter 10 procedures described
Page 201 and 202: 200 Chapter 10 by hand-dissection.
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Page 207 and 208: 206 Chapter 10 temperature (Pearson
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Page 213 and 214: 212 Chapter 10 14. Hermsen CC, Telg
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Page 218 and 219: General Discussion 217 occurrence o
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Page 232 and 233: General Discussion 231 Conclusions
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General Discussion 233 References 1
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General Discussion 235 polymorphonu
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General Discussion 237 57. Church L
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General Discussion 239 85. Beier JC
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General Discussion 241 118. Mueller
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Chapter 12 Summary Samenvatting Lis
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246 Chapter 12 Controlled human mal
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Summary, Samenvatting, List of publ
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254 Chapter 12 Roestenberg M, Teirl
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