Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01E and Protection against P falciparum Clinical Malaria
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{"title"=>"Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01E and Protection against P falciparum Clinical Malaria", "type"=>"journal", "authors"=>[{"first_name"=>"Ally", "last_name"=>"Olotu"}, {"first_name"=>"Philippe", "last_name"=>"Moris"}, {"first_name"=>"Jedidah", "last_name"=>"Mwacharo"}, {"first_name"=>"Johan", "last_name"=>"Vekemans"}, {"first_name"=>"Domtila", "last_name"=>"Kimani"}, {"first_name"=>"Michel", "last_name"=>"Janssens"}, {"first_name"=>"Oscar", "last_name"=>"Kai"}, {"first_name"=>"Erik", "last_name"=>"Jongert"}, {"first_name"=>"Marc", "last_name"=>"Lievens"}, {"first_name"=>"Amanda", "last_name"=>"Leach"}, {"first_name"=>"Tonya", "last_name"=>"Villafana"}, {"first_name"=>"Barbara", "last_name"=>"Savarese"}, {"first_name"=>"Kevin", "last_name"=>"Marsh"}, {"first_name"=>"Joe", "last_name"=>"Cohen"}, {"first_name"=>"Philip", "last_name"=>"Bejon"}], "year"=>2011, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"1932-6203", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pmid"=>"21998698", "doi"=>"10.1371/journal.pone.0025786", "sgr"=>"80053602298", "pui"=>"362707308"}, "id"=>"0c7d909e-4a81-3eb2-8336-db5a65316b28", "abstract"=>"BACKGROUND RTS,S/AS01(E) is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%-72%) for protecting children against clinical malaria caused by P. falciparum. We studied CS-specific T cell responses in order to identify correlates of protection. METHODS AND FINDINGS We used intracellular cytokine staining (for IL2, IFNγ, and TNFα), ex-vivo ELISPOTs (IFNγ and IL2) and IFNγ cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5-17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01(E) (NCT00380393). RTS,S/ AS01(E) vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFNγ, TNFα or IL2 compared to control vaccinees. In a multivariable analysis TNFα(+) CD4(+) T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01(E) vaccinees (HR = 0.64, 95%CI 0.49-0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62-1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01(E) vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62-0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or ex vivo ELISPOT data and protection from clinical malaria. The combination of TNFα(+) CD4(+) T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model. CONCLUSIONS RTS,S/AS01(E) induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFα(+) CD4(+) T cells could account for the level of protection conferred by RTS,S/AS01(E). The correlation between CS-specific TNFα(+) CD4(+) T cells and protection needs confirmation in other datasets.", "link"=>"http://www.mendeley.com/research/circumsporozoitespecific-t-cell-responses-children-vaccinated-rtssas01e-protection-against-p-falcipa", "reader_count"=>46, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Researcher"=>13, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>5, "Student > Master"=>7, "Student > Bachelor"=>1, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Researcher"=>13, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>11, "Student > Postgraduate"=>5, "Student > Master"=>7, "Student > Bachelor"=>1, "Lecturer"=>1, "Lecturer > Senior Lecturer"=>1, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Nursing and Health Professions"=>2, "Agricultural and Biological Sciences"=>25, "Medicine and Dentistry"=>8, "Business, Management and Accounting"=>1, "Chemistry"=>1, "Psychology"=>1, "Social Sciences"=>1, "Immunology and Microbiology"=>5}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Chemistry"=>{"Chemistry"=>1}, "Social Sciences"=>{"Social Sciences"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>5}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>25}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>2}, "Business, Management and Accounting"=>{"Business, Management and Accounting"=>1}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Pakistan"=>1, "United Kingdom"=>1, "Kenya"=>2, "Portugal"=>1, "Spain"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/367553"], "description"=>"<div><h3>Background</h3><p>RTS,S/AS01<b><sub>E</sub></b> is the lead candidate pre-erythrocytic malaria vaccine. In Phase IIb field trials the safety profile was acceptable and the efficacy was 53% (95%CI 31%–72%) for protecting children against clinical malaria caused by <em>P. falciparum</em>. We studied CS-specific T cell responses in order to identify correlates of protection.</p> <h3>Methods and Findings</h3><p>We used intracellular cytokine staining (for IL2, IFNγ, and TNFα), <em>ex-vivo</em> ELISPOTs (IFNγ and IL2) and IFNγ cultured ELISPOT assays to characterize the CS-specific cellular responses in 407 children (5–17 months of age) in a phase IIb randomized controlled trial of RTS,S/AS01<sub>E</sub> (NCT00380393). RTS,S/ AS01<sub>E</sub> vaccinees had higher frequencies of CS-specific CD4+ T cells producing IFNγ, TNFα or IL2 compared to control vaccinees. In a multivariable analysis TNFα<sup>+</sup> CD4<sup>+</sup> T cells were independently associated with a reduced risk for clinical malaria among RTS,S/AS01<sub>E</sub> vaccinees (HR = 0.64, 95%CI 0.49–0.86, p = 0.002). There was a non-significant tendency towards reduced risk among control vaccinees (HR = 0.80, 95%CI 0.62–1.03, p = 0.084), albeit with lower CS-specific T cell frequencies and higher rates of clinical malaria. When data from both RTS,S/AS01<b><sub>E</sub></b> vaccinees and control vaccinees were combined (with adjusting for vaccination group), the HR was 0.74 (95%CI 0.62–0.89, p = 0.001). After a Bonferroni correction for multiple comparisons (n-18), the finding was still significant at p = 0.018. There was no significant correlation between cultured or <em>ex vivo</em> ELISPOT data and protection from clinical malaria. The combination of TNFα<sup>+</sup> CD4<sup>+</sup> T cells and anti-CS antibody statistically accounted for the protective effect of vaccination in a Cox regression model.</p> <h3>Conclusions</h3><p>RTS,S/AS01<b><sub>E</sub></b> induces CS-specific Th1 T cell responses in young children living in a malaria endemic area. The combination of anti-CS antibody concentrations titers and CS-specific TNFα<sup>+</sup> CD4<sup>+</sup> T cells could account for the level of protection conferred by RTS,S/AS01<b><sub>E</sub></b>. The correlation between CS-specific TNFα<sup>+</sup> CD4<sup>+</sup> T cells and protection needs confirmation in other datasets.</p> </div>", "links"=>[], "tags"=>["circumsporozoite-specific", "responses", "children", "vaccinated", "malaria"], "article_id"=>132608, "categories"=>["Biotechnology", "Cancer", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786", "stats"=>{"downloads"=>6, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Circumsporozoite_Specific_T_Cell_Responses_in_Children_Vaccinated_with_RTS_S_AS01_E_and_Protection_against_P_falciparum_Clinical_Malaria/132608", "title"=>"Circumsporozoite-Specific T Cell Responses in Children Vaccinated with RTS,S/AS01<sub>E</sub> and Protection against <em>P falciparum</em> Clinical Malaria", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-06 00:43:28"}
  • {"files"=>["https://ndownloader.figshare.com/files/727808"], "description"=>"<p>All three peptide pools were combined for the ICS assay. The pools were used separately for the <i>ex vivo</i> and plating out of the cultured ELISPOT assay.</p>", "links"=>[], "tags"=>["immunology", "Infectious diseases", "public health and epidemiology", "pediatrics and child health"], "article_id"=>398144, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Peptide_pools_/398144", "title"=>"Peptide pools.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-06 02:15:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/727589"], "description"=>"<p>Where more than one third of responses were at the lower limit of detection, the lower two tertiles are combined (and hence only 2 tertiles are displayed on some plots). For CD4+ TNFα+ responses, the tertiles were 1 to 154 (lower), 155 to 407 (middle) and 408 to 28,840 (upper) cells per million for RTS,S/AS01E vaccinees, and 1 to 26 (lower), 27 to 165 (middle) and 166 to 10,000 (upper) cells per million for control vaccinees. For CD+ IFNγ+ responses the tertiles were 1 to 12 (lower), 13 to 66 (middle) and 67 to 8,320 (upper) cells per million for RTS,S/AS01E vaccinees, and 1 to 40 (lower) and 41 to 5,980 (upper) cells per million for rabies vaccinees. The time point “0 months” refers to the time of a blood draw. Cellular responses were analyzed as time-varying covariates, where the effect of cellular responses from all available blood draws was related to clinical malaria episodes during the period of monitoring after each measurement. Therefore, each RTS,S vaccinee could contribute to 2 periods of monitoring. These three assays were selected for the figure because significant associations on Cox regression were seen (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0025786#pone-0025786-t004\" target=\"_blank\">Table 4</a>).</p>", "links"=>[], "tags"=>["plots", "malaria", "plotted", "vaccinees", "tertile", "responses", "elispot", "peptides"], "article_id"=>397914, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.g004", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Survival_plots_with_time_to_first_episode_of_clinical_malaria_plotted_for_RTS_S_AS01E_left_columns_and_control_vaccinees_left_and_right_columns_according_to_tertile_of_CD4_TNF_responses_top_row_CD4_IFN_responses_middle_row_and_IFN_ex_vivo_ELISPOT_respons/397914", "title"=>"Survival plots with time to first episode of clinical malaria plotted for RTS,S/AS01E (left columns) and control vaccinees (left and right columns) according to tertile of CD4+, TNFα responses (top row), CD4+ IFNγ responses (middle row) and IFNγ <i>ex vivo</i> ELISPOT responses to TH3R/CS.T3T peptides pool (lower row).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:11:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/727741"], "description"=>"<p>HR =  Hazard Ratio for each log (i.e. ten-fold) increase in frequency of T cells. Confidence intervals are 5–95%. HRs are adjusted by anti-CS antibody titre (in 2 groups), age, area of residence, ITN use and distance from the dispensary. NANP = NANP and conserved region peptides pool, TH2R = TH2R region peptides pool, TH3R = TH3R and CS.T3T region peptide pool, Sum =  all three peptide pools summed.</p>", "links"=>[], "tags"=>["cox", "regression", "models", "malaria", "cmi"], "article_id"=>398082, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.t004", "stats"=>{"downloads"=>3, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_hazard_ratio_from_Cox_regression_models_with_95_CI_for_the_outcome_clinical_malaria_by_CMI_assays_/398082", "title"=>"The hazard ratio from Cox regression models (with 95% CI) for the outcome clinical malaria by CMI assays.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-06 02:14:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/727426"], "description"=>"<p>ELISPOT responses are shown for the individual stimulating peptide pools at 1 month post vaccination with RTS,S/AS01<sub>E</sub>.</p>", "links"=>[], "tags"=>["responses", "shown", "stimulating", "peptide", "pools", "vaccination"], "article_id"=>397761, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.g003", "stats"=>{"downloads"=>1, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ELISPOT_responses_are_shown_for_the_individual_stimulating_peptide_pools_at_1_month_post_vaccination_with_RTS_S_AS01_E_/397761", "title"=>"ELISPOT responses are shown for the individual stimulating peptide pools at 1 month post vaccination with RTS,S/AS01<sub>E</sub>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:09:21"}
  • {"files"=>["https://ndownloader.figshare.com/files/727872"], "description"=>"<p>*for p<0.05 or ** for p<0.005 where Mean for Rabies group < Mean for RTS,S/AS01<sub>E</sub> group. # for p<0.05 or ## for p<0.005 where Mean for Rabies group > Mean for RTS,S/AS01<sub>E</sub> group.</p>", "links"=>[], "tags"=>["means", "cmi", "assays", "vaccination"], "article_id"=>398204, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Geometric_means_of_CMI_assays_by_clinic_visit_and_by_vaccination_group_/398204", "title"=>"Geometric means of CMI assays by clinic visit and by vaccination group.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-06 02:16:44"}
  • {"files"=>["https://ndownloader.figshare.com/files/727937"], "description"=>"<p>* = p<0.05.</p><p>** = p<0.001.</p><p>*** = p<0.0001.</p>", "links"=>[], "tags"=>["coefficients", "cmi", "assays", "vaccination"], "article_id"=>398265, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.t003", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inter_assay_Correlation_coefficients_of_CMI_assays_at_1_month_post_vaccination_with_RTS_S_AS01_E_/398265", "title"=>"Inter-assay Correlation coefficients of CMI assays at 1 month post vaccination with RTS,S/AS01<sub>E</sub>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2011-10-06 02:17:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/727292"], "description"=>"<p>* indicates p<0.05 and ** indicates p<0.005.</p>", "links"=>[], "tags"=>["anti-cs", "ics", "responses", "summed", "elispot", "shown", "vaccination"], "article_id"=>397619, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.g002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_time_course_of_anti_CS_CD4_ICS_responses_and_summed_ELISPOT_responses_is_shown_per_time_point_for_RTS_S_AS01_E_and_control_vaccination_groups_/397619", "title"=>"The time course of anti-CS CD4+ ICS responses and summed ELISPOT responses is shown per time point for RTS,S/AS01<sub>E</sub> and control vaccination groups.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:06:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/727113"], "description"=>"<p>An example plot of FACS data acquired following intra-cellular cytokine staining is shown for negative control (medium only), positive control (i.e. staphylococcal enterotoxin B, SEB) and CS peptides.</p>", "links"=>[], "tags"=>["facs", "acquired", "intra-cellular", "cytokine", "staining", "shown", "staphylococcal", "enterotoxin", "cs"], "article_id"=>397441, "categories"=>["Biotechnology", "Infectious Diseases", "Medicine", "Immunology"], "users"=>["Ally Olotu", "Philippe Moris", "Jedidah Mwacharo", "Johan Vekemans", "Domtila Kimani", "Michel Janssens", "Oscar Kai", "Erik Jongert", "Marc Lievens", "Amanda Leach", "Tonya Villafana", "Barbara Savarese", "Kevin Marsh", "Joe Cohen", "Philip Bejon"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0025786.g001", "stats"=>{"downloads"=>5, "page_views"=>114, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_example_plot_of_FACS_data_acquired_following_intra_cellular_cytokine_staining_is_shown_for_negative_control_medium_only_positive_control_i_e_staphylococcal_enterotoxin_B_SEB_and_CS_peptides_/397441", "title"=>"An example plot of FACS data acquired following intra-cellular cytokine staining is shown for negative control (medium only), positive control (i.e. staphylococcal enterotoxin B, SEB) and CS peptides.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2011-10-06 02:04:01"}

PMC Usage Stats | Further Information

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