Table 1.

A summary of research needs ranging from basic science to global policy¹

Research need	Practical implications	Likely time to interventions
Basic science
Mechanisms of iron–malaria interactions   Hepatic and/or blood stage effects?   Acute (e.g., NTBI) and/or chronic (e.g., iron loading) effects?   Systemic and/or enteric effects?	Will inform optimization of iron interventions: chemical composition, dose, timing, fortification vs. supplementation, etc.	Short to medium
Mechanisms of iron interactions with other pathogens   Malaria-associated bacteremias   Iron-dependent bacteria (especially TB)   Iron-dependent viral infections (e.g., HIV, hepatitis C)	Will fill extensive knowledge gaps relevant to design of iron-related therapeutic (e.g., iron withholding) and preventive interventions	Medium to long
Hepcidin–iron axis as a mediator of immune responses   Hepcidin as component of innate immunity   Hepcidin–iron axis as potential modulator of adaptive   immune responses, especially vis-à-vis vaccines	Possibility of using hepcidin agonists or antagonists as therapeutic agents and/or vaccine adjuvants	Medium to long
Biology of iron acquisition in an infectious environment   Is ID and/or anemia partly an adaptive response to   infectious threats?   Are there windows of opportunity for safe iron   acquisition between intercurrent infections?	Should definitions of ID and anemia cutoffs be modified in infectious environments? Must infections be reduced before tackling ID?	Short to medium
Clinical science and epidemiology
Risks vs. benefits   Health metrics research on pros and cons of iron   interventions   Further research on iron, brain development, and   cognition	Necessary to balance iron aversion and policy stasis created by Pemba results. Reminder that most interventions (especially vaccines) have risks. Balanced judgment required	Short
Establishing safe modes of iron administration   Very large-scale trials to test safety of iron in malarial   regions (theoretical need but not feasible in practice   to assess serious adverse outcomes and mortality)   Can only be assessed against nominal proxy outcomes   such as malarial infection, NTBI, altered microbiota	The ethics Catch-22 (see text) will prevent any new trials in high-risk environments without malaria surveillance and control. Small trials can never cancel out Pemba	Probably never
Screening   Is the Pemba substudy conclusion that iron is safe in   children with ID secure? Requires replication.   Is the risk vs. benefit equation dependent on markers of   ID?   Would screening ever be a practical option?   Screening implies treatment; is this desirable?	Good clinical practice recommends assessment and diagnosis of a condition before intervention. Pemba data show this to be critical and WHO adopted a screening resolution, but is it practicable?	Short to medium
Supplements vs. fortifiers vs. foods   Wide research agenda exists regarding the efficacy and   safety of supplements vs. fortifiers   Iron as part of multinutrient packages for home-based   fortification (powders or lipid-based pastes) are   currently the favored options but still require validation   Food-based solutions are recognized as difficult to   achieve at present (but see below)	Research in these domains will likely yield the most immediate benefits and help fill the policy/practice void	Immediate and onward
Life-course approaches   Can a life-course approach (e.g., enhancing iron status   of mothers-to-be, cord clamping) reduce the need to   intervene in infancy?	May direct interventions away from pregnancy and young childhood when iron–malaria interactions are most damaging	Short
Technological developments
Formulation of supplements and fortifiers   Further optimization of chemical composition, dose   level, mode of administration, etc.,.   Controlled slow release in duodenum and less residual   unabsorbed iron for intestinal microbiota is the challenge	Much research already completed, but new basic science findings can inform further optimization Efficacy and tolerability (low side-effect profile) tends to correlate with cost; breaking this relationship is critical for low-income settings	Immediate and onward
Crop technology   Accelerated transgenic crop enhancement programs	Can staple foods with enriched iron content (e.g., BioCassava Plus) help bridge the growing gap between flesh food supply and demand ?	Medium and long term
Point-of care diagnostics   Design, optimization, testing, and production of very   low cost point-of-care tests for iron deficiency	Inexpensive, simple, and reliable point-of-care tests will be required if a screening approach is to be endorsed. Even if not endorsed diagnosis of ID is clearly important in tropical medicine	Immediate and onward
Country level planning
Endemicity of malaria and ID   Map regions where malaria and ID overlap   Understand modifying factors such as altitude, season	Governments can make better plans for iron interventions and avoid inaction in nonmalarial areas	Immediate and onward
Integration of programs   How best to integrate intermittent preventive therapy,   bed nets, and iron?	Potential adverse reactions can be avoided if interventions against malaria either precede or accompany iron interventions	Immediate and onward
Global policy
Assessing risks vs. benefits   See above	Necessary to balance iron aversion and policy stasis created by Pemba results. Reminder that most interventions (especially vaccines) have risks. Balanced judgment required	Short
Universal vs. targeted approaches   See above	Resolution and guidance required on whether to adopt screening and a targeted approach to combating ID in malarial areas	Short
Global trends in malaria   Monitor global trends in malaria   Monitor trends in prevention, surveillance, and   treatment	Important to keep iron–malaria issue in an appropriate perspective against rapidly changing patterns of disease	Immediate and onward

¹ID, iron deficiency; NTBI, nontransferrin-bound iron.