Volume 25, Issue 2, Pages (February 2017)

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Volume 25, Issue 2, Pages 547-559 (February 2017) Viral Vector Malaria Vaccines Induce High-Level T Cell and Antibody Responses in West African Children and Infants  Carly M. Bliss, Abdoulie Drammeh, Georgina Bowyer, Guillaume S. Sanou, Ya Jankey Jagne, Oumarou Ouedraogo, Nick J. Edwards, Casimir Tarama, Nicolas Ouedraogo, Mireille Ouedraogo, Jainaba Njie-Jobe, Amidou Diarra, Muhammed O. Afolabi, Alfred B. Tiono, Jean Baptiste Yaro, Uche J. Adetifa, Susanne H. Hodgson, Nicholas A. Anagnostou, Rachel Roberts, Christopher J.A. Duncan, Riccardo Cortese, Nicola K. Viebig, Odile Leroy, Alison M. Lawrie, Katie L. Flanagan, Beate Kampmann, Egeruan B. Imoukhuede, Sodiomon B. Sirima, Kalifa Bojang, Adrian V.S. Hill, Issa Nébié, Katie J. Ewer  Molecular Therapy  Volume 25, Issue 2, Pages 547-559 (February 2017) DOI: 10.1016/j.ymthe.2016.11.003 Copyright © 2017 The Author(s) Terms and Conditions

Figure 1 ELISpot Responses across Trials with Age De-escalation (A) Comparison of peak ELISpot immunogenicity at 7 days post-MVA including data from previously published trials in adults,32,34 expressed as SFC per 106 PBMC (Kruskal-Wallis test with Dunn’s post-test for multiple comparisons between all groups. Dotted lines show lower limit of assay detection (LLD) and positive threshold for ELISpot response. (B) Lymphocyte counts per milliliter of blood for all vaccinated volunteers. (Kruskal-Wallis test with Dunn’s post-test for multiple comparisons between all groups. Adult groups not combined due to difference by 2-tailed Mann-Whitney test, p = 0.0009). (C) ELISpot responses expressed as SFC per milliliter of blood (Kruskal-Wallis test with Dunn’s post-test for multiple comparisons to adult control group denoted by black bars, Kruskal-Wallis test with Dunn’s post-test for multiple comparisons between all pediatric groups denoted by gray bars). Closed circles, UK adults; open circles, Gambian adults; open triangles, all pediatric groups. Numbers in green and group bars represent group medians. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. Molecular Therapy 2017 25, 547-559DOI: (10.1016/j.ymthe.2016.11.003) Copyright © 2017 The Author(s) Terms and Conditions

Figure 2 T Cell Responses by Flow Cytometry Responses were assessed from cryopreserved PBMC for group 2 (5- to 12-month-olds in the Gambia, N = 8) and group 4 (5- to 17-month-olds in Burkina Faso, N = 12). Dotted lines represent the lower limit of detection for CD4+ and CD8+ T cell populations. Bars represent geometric means. Open symbols, group 2; closed symbols, group 4. Molecular Therapy 2017 25, 547-559DOI: (10.1016/j.ymthe.2016.11.003) Copyright © 2017 The Author(s) Terms and Conditions

Figure 3 Antibody Responses to Vaccination (A) Geometric mean time course of anti-TRAP IgG for Gambian 2- to 6-year-olds (group 1) vaccinated with high and low dose ChAd63 ME-TRAP and MVA ME-TRAP. (B) Geometric mean time course of anti-TRAP IgG titer for Gambian 5- to 12-month-olds (group 2), Gambian 10-week-olds (group 3) and Burkinabe 5- to 17-month-olds (group 4). (C) Peak IgG titer at 7 days post-MVA. (D and E) TRAP-specific IgG1 and IgG3 antibodies at day 63 (1 week post-MVA ME-TRAP). (F) TRAP-specific IgA antibodies at day 63. Dashed lines show seropositive threshold (mean + 3 SD of 42 malaria-naive samples tested on each assay). Closed circles UK adults at peak; open circles Gambian adults at peak; open triangles all pediatric groups at peak. All adults boosted with 2 × 108 PFU MVA ME-TRAP, all children and infants boosted with 1 × 108 PFU MVA ME-TRAP. Medians displayed. All comparisons across groups made using Kruskal-Wallis with Dunn’s post-test for multiple comparisons to adult control group. *p < 0.05. **p < 0.01, ***p < 0.001, ****p < 0.0001. Molecular Therapy 2017 25, 547-559DOI: (10.1016/j.ymthe.2016.11.003) Copyright © 2017 The Author(s) Terms and Conditions

Figure 4 Antibody Avidity and Anti-Vector Neutralizing Antibodies (A) Avidity of total IgG (B), IgG1 and (C) IgG3 subtypes in Burkinabe and Gambian younger children and infants (groups 2, 3, and 4) and adults (Kruskal-Wallis test with Dunn’s post-test for multiple comparisons between all groups). (D) Effect of age at first vaccination on IgG1 antibody avidity after boosting in Burkinabe 5- to 17-month-olds (group 4, Spearman’s r = 0.47, p 0.02). (E) Increase in total IgG avidity between 1 and 7 weeks post boost, (p = 0.0015 for 5- to 12-month-olds, p = 0.0010 for 10-week-olds, Wilcoxon matched pairs for comparisons within groups. Mann Whitney test with post-test for multiple comparisons between groups at comparable time points). (F) Change in total IgG avidity between 1 and 7 weeks post boost, expressed as a ratio for each age group (no significant difference by t test). (G and H) Correlations between group 1 neutralizing antibody titers to the ChAd63 vector and peak antibody titers by ELISA and T cell responses by ELISpot, respectively. Spearman’s r = 0.06, p 0.75 for (G) and r = 0.002, p 0.99 for (H). Medians displayed. Kruskal-Wallis tests performed with Dunn’s post-test for multiple comparisons between all groups. *p < 0.05. **p < 0.01, ***p < 0.001, ****p < 0.0001. Molecular Therapy 2017 25, 547-559DOI: (10.1016/j.ymthe.2016.11.003) Copyright © 2017 The Author(s) Terms and Conditions