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Summary: Background: Elicitation of broad immune responses is understood to be required for an efficacious preventative HIV vaccine. This Phase 1 randomized controlled trial evaluated whether administration of vaccine antigens separated at multiple injection sites vs combined, fractional delivery at multiple sites affected T-cell breadth compared to standard, single site vaccination. Methods: We randomized 90 participants to receive recombinant adenovirus 5 (rAd5) vector with HIV inserts gag, pol and env via three different strategies. The Standard group received vaccine at a single anatomic site (n = 30) compared to two polytopic (multisite) vaccination groups: Separated (n = 30), where antigens were separately administered to four anatomical sites, and Fractioned (n = 30), where fractions of each vaccine component were combined and administered at four sites. All groups received the same total dose of vaccine. Findings: CD8 T-cell response rates and magnitudes were significantly higher in the Fractioned group than Standard for several antigen pools tested. CD4 T-cell response magnitudes to Pol were higher in the Separated than Standard group. T-cell epitope mapping demonstrated greatest breadth in the Fractioned group (median 8.0 vs 2.5 for Standard, Wilcoxon p = 0.03; not significant after multiplicity adjustment for co-primary endpoints). IgG binding antibody response rates to Env were higher in the Standard and Fractioned groups vs Separated group. Interpretation: This study shows that the number of anatomic sites for which a vaccine is delivered and distribution of its antigenic components influences immune responses in humans. Funding: National Institute of Allergy and Infectious Diseases, NIH.

In countries with transitional economies such as those found in South Asia, large-scale irrigation systems (LSIS) with a history of public ownership account for about 115 million ha (Mha) or approximately 45% of their total area under irrigation. In terms of the global area of irrigation (320 Mha) for all countries, LSIS are estimated at 130 Mha or 40% of irrigated land. These systems can potentially deliver significant local, regional and global benefits in terms of food, water and energy security, employment, economic growth and ecosystem services. For example, primary crop production is conservatively valued at about US$355 billion. However, efforts to enhance these benefits and reform the sector have been costly and outcomes have been underwhelming and short-lived. We propose the application of a 'theory of change' (ToC) as a foundation for promoting transformational change in large-scale irrigation centred upon a 'global irrigation compact' that promotes new forms of leadership, partnership and ownership (LPO). The compact argues that LSIS can change by switching away from the current channelling of aid finances controlled by government irrigation agencies. Instead it is for irrigators, closely partnered by private, public and NGO advisory and regulatory services, to develop strong leadership models and to find new compensatory partnerships with cities and other river basin neighbours. The paper summarises key assumptions for change in the LSIS sector including the need to initially test this change via a handful of volunteer systems. Our other key purpose is to demonstrate a ToC template by which large-scale irrigation policy can be better elaborated and discussed.