We also thank members of the POPVAC programme steering committee (chaired by Professor Richard Hayes) and the Data and Safety Monitoring Board (Dr David Meya, Professor Andrew Prendergast and Dr Elizabeth George). Footnotes Twitter: @GyavN, @I AN, GN and LZ contributed equally. Collaborators: POPVAC trial team: principal investigator: Alison Elliott; project leader: Ludoviko Zirimenya; laboratory staff: Gyaviira Nkurunungi, Stephen Cose, Rebecca Amongin, Beatrice Nassanga, Jacent Nassuuna, Irene Nambuya, Prossy Kabuubi, Emmanuel Niwagaba, Gloria Oduru and Grace Kabami; statisticians and data managers: Emily Webb, Agnes Natukunda, Helen Akurut and Alex Mutebe; clinicians: Anne Wajja, Milly Namutebi, Christopher Zziwa and Joel Serubanja; nurses: Caroline Onen, Esther Nakazibwe, Josephine Tumusiime, Caroline Ninsiima, Susan Amongi and Florence Akello; internal monitor: Mirriam Akello; field workers: Robert Kizindo, Moses Sewankambo, Denis Nsubuga, Samuel Kiwanuka and Fred Kiwudhu; boatman: David Abiriga; administrative management: Moses Kizza and JNK-IN-7 Samsi Nansukusa; internal and external collaborators: Pontiano Kaleebu, Hermelijn Smits, Maria Yazdanbakhsh, Govert van Dam, Paul Corstjens, Sarah Staedke, Henry Luzze, James Kaweesa, Edridah Tukahebwa, Elly Tumushabe and Moses Muwanga. Contributors: AME conceived the study. responses 8?weeks after BCG immunisation and for other vaccines, antibody responses to key vaccine antigens at 4?weeks after immunisation. In secondary analyses, we will determine effects of monthly DP treatment (versus placebo) on correlates of protective immunity, on vaccine response waning, on whether there are differential effects on priming versus boosting immunisations, and on malaria infection prevalence. We will also conduct exploratory immunology assays among subsets of participants to further characterise effects of the intervention on vaccine responses. Ethics and dissemination Ethics approval has been obtained from relevant Ugandan and UK ethics committees. Results will be shared with Uganda Ministry of Health, relevant district councils, community leaders JNK-IN-7 and study participants. Further dissemination will be done through conference proceedings and publications. Trial registration number Current Controlled Trials identifier: ISRCTN62041885. lipopolysaccharide-specific IgG concentration at 4?weeks post Ty21a immunisation. HPV: IgG specific for L1-proteins of HPV-16/18 at 4?weeks post HPV priming immunisation. Td: Td-specific IgG concentration at 4?weeks post Td immunisation. Secondary outcomes These will be assessed in all participants and will further investigate estimates of protective immunity (for vaccines where these are available) and dynamics of the vaccine responses, as well as the impact of the interventions on parasite clearance. Protective immunity Proportions with protective neutralising antibody (YF); protective IgG levels (TT);44 seroconversion rates (Ty21a) at 4?weeks post the corresponding immunisation. Response waning Primary outcome measures (all vaccines) repeated at week 52, and area under the curve analyses. Priming versus boosting Effects on priming versus boosting will be examined for HPV only, comparing outcomes 4?weeks after the first, and 4?weeks after the second vaccine dose. Current malaria infection status and intensity Will be assessed retrospectively by PCR on stored samples collected on immunisation days and at week 52. Furthermore, our sample collection will offer opportunities for an array of exploratory immunological evaluations on stored samples, focussing mainly on vaccine antigen-specific outcomes. Exploratory assessments will provide further detail on JNK-IN-7 JNK-IN-7 immune response characteristics over the study time-course, and on the role of immunological profiles in malaria-mediated modulation of vaccine-specific responses. Additional evaluation of parasite infection Current infection status and intensity will be determined by serum/plasma levels of circulating anodic antigen (CAA). This method is quantitative, highly specific for infection and much more sensitive than the conventional Kato Katz method.45 CAA will be assessed retrospectively on stored samples collected at baseline and at weeks 28 and 52. Prior exposure to schistosomiasis will be evaluated by ELISA for IgG to schistosome egg antigen using stored blood samples collected at baseline. The presence of other helminth infections will JNK-IN-7 be determined retrospectively using stool PCR of samples collected at baseline and at weeks 28 and 52. In accord with national guidelines, all participants will be treated with albendazole or mebendazole after collection of samples for primary endpoints at week 8 and 28, and after collection of samples for secondary endpoints at week 52. Malarial fever: Individuals presenting with fever will be investigated using rapid diagnostic tests for malaria and treated based on the results and according to prevailing national guidelines. Prior malaria exposure will be evaluated by ELISA for IgG to malaria antigen using stored samples collected at baseline. Sample size considerations Based on the literature6 46 47 and preliminary data, we anticipate that SD of primary outcome measures will lie between 0.3 and 0.6 log10; that responses in rural, high-parasite settings may be 0.3 to 0.4 log10 smaller than in the urban setting, and that effective treatment of parasitic infections may restore responses by approximately 0.2 log10 (Tweyongyere em et al /em ).48 We therefore power our study to detect differences of this magnitude (0.2 log10) Rabbit Polyclonal to PDRG1 or (in some cases) smaller. Among 5 to 15?year olds in this study setting, previous studies have reported malaria prevalence of 50% based on microscopy;21 22 we assume malaria prevalence of 60% based on PCR. Based on these assumptions, we plan to include 640 participants in total (320.