Summary

Intermittent preventive treatment in infants (IPTi) for malaria provides preventive antimalarial medicine to children under 12 months old. It is among the most promising programs we’ve identified in our active pipeline of new interventions. Not only does IPTi appear to be highly effective at reducing clinical malaria, it’s also underutilized (more below), and the population it targets is especially vulnerable to malaria. That implies potential to open up large amounts of room for more funding if IPTi begins to be used more widely—our crude estimate is between $50 million and $200 million globally once it’s scaled—which is something we’re increasingly thinking about as we aim to direct $1 billion in cost-effective funding by 2025.

In September 2021, we recommended a small grant to Malaria Consortium and PATH to assess the feasibility and cost-effectiveness of implementing IPTi at national scale in two countries. This grant was the result of an atypical process for us: because we don’t know of any organizations currently implementing IPTi, we issued a request for information to several charities that we thought might be good candidates to do so (more below). We’re hopeful that this scoping exercise will answer some of our many open questions about IPTi, and that this intervention continues to look promising as we learn more.

What is IPTi?

Intermittent preventive treatment in infants (IPTi) for malaria is a program that distributes preventive antimalarial medicine (usually sulfadoxine-pyrimethamine, or SP) to infants, regardless of whether they have malaria, during routine immunization services. A Cochrane meta-analysis of 12 randomized controlled trials (RCTs) found that IPTi reduced cases of clinical malaria by 30%.^[1]

IPTi appears effective enough that the World Health Organization (WHO) began recommending it 12 years ago, in 2010.^[2] However, our research has identified only one country, Sierra Leone, that has integrated IPTi into its routine national health care practice.^[3] We think this neglectedness is due in part to potentially surmountable logistical factors, such as the need to coordinate work between national malaria control programs and national immunization programs.^[4] Other barriers to implementation have included the way WHO guidelines identified which settings are appropriate for IPTi^[5] (though we understand from speaking with other organizations in the malaria space that these guidelines are currently under revision), and challenges with administering previously available formulations of SP.^[6]

Why we’re excited about it

• Effectiveness – If the results found by the meta-analysis were mirrored in real-world application, IPTi could be another powerful tool through which to reduce incidence of malaria, which continues to be one of the most deadly diseases among under-five children in sub-Saharan Africa.^[7]
• Room for more funding – With only one country having adopted IPTi, there are currently no charities and no philanthropic funding that we know of supporting its implementation at significant scale. The lack of investment in this intervention indicates that it measures up well on one of the criteria we use to assess programs: room for more funding. If IPTi begins to be used at scale in more countries, implementing organizations will likely be able to absorb a great deal of additional resources.
• Cost-effectiveness – Our preliminary estimate suggested that IPTi may be around 18 times as cost-effective as cash transfers, which is above the range of cost-effectiveness of programs we would consider funding.^[8] However, this estimate is quite rough, given our uncertainties about program costs, feasibility of implementation at scale, and the counterfactual impact of funding we might direct to IPTi. More below.

What we’ve done so far

In August 2020, we published an intervention report on IPTi, noting its efficacy in trials and our plans to explore funding opportunities.

Normally, once we’ve identified a sufficiently promising intervention, our next step is speaking to the organizations running the programs that get it out into the world. This was an unusual case: because we know of no organizations implementing IPTi programs at substantial scale,^[9] we issued a request for information (RFI) from several charities that we thought might be good candidates to implement the program, asking them how they would support governments that wanted to administer IPTi at scale.

The RFI process and scoping grant

The RFI asked applicants to briefly describe how they would approach a hypothetical IPTi program, including what geographies they would focus on, key uncertainties they would prioritize resolving before scaling the program, and their vision of path to scale.

Out of seven applicants, we selected two organizations that we thought had the greatest potential for success—PATH and Malaria Consortium—to collaborate on a “scoping study.”^[10] The study will assess the feasibility and cost-effectiveness of integrating IPTi into national health policy in Nigeria and Democratic Republic of the Congo (DRC), two countries with a high malaria burden.^[11] We recommended a grant of $120,000 to fund the study,^[12] which is expected to take four to six months.

Our hope is that the information gathered by PATH and Malaria Consortium during this process will allow us to build out a more sophisticated and accurate cost-effectiveness analysis of IPTi, develop a better sense of where IPTi could be implemented most successfully, and ultimately make an informed decision about whether we should direct funding toward scaling the program.

This RFI process was an experiment—we won’t necessarily be doing this as a matter of course in similar situations without readily identifiable implementing organizations. In this case, we think the process helped us figure out a partnership between two organizations with complementary strengths and experience working together in the past. Additionally, we believe that findings from the scoping study (as well as any funding we might direct as a result) may catalyze interest in IPTi from other funders, other implementers, and other countries in the region.

What we’ll do next

The scoping study is expected to be completed by the end of January 2022, after which we’ll conduct a full investigation and build a cost-effectiveness estimate.

If IPTi still looks like a good use of funds after this stage, we’ll likely recommend an operational research grant to PATH and Malaria Consortium to implement IPTi at a smaller scale. This would be an opportunity to observe what IPTi implementation looks like in practice, learn, and make adjustments to the implementation plan as needed.

If the results of smaller-scale implementation are positive, we expect that could open up as much as $50 million in room for more funding to support expanding IPTi to all subnational areas deemed appropriate for the intervention.^[13]

Major uncertainties

As IPTi has yet to be carried out at scale in most countries, we have a number of open questions about how effective and cost-effective it will turn out to be, though we’re hopeful that the scoping activities will go some way toward answering these questions. Uncertainties include:

• Program costs – The technical assistance activities required to implement a program, such as health care worker training, monitoring, and drug procurement, can significantly increase total costs beyond the costs of the antimalarial medicines themselves. Our current estimate is that IPTi will cost about $4 per child treated, including all technical assistance costs,^[14] but without documented evidence of spending to inform our guess, we have low confidence in this number. If IPTi turns out to be much more expensive than we guess now, it won’t be as cost-effective as we expect.
• Suitability and cost-effectiveness at the subnational level – During scoping, PATH and Malaria Consortium might find that some regions, states, or local government areas have a higher infant malaria burden than others, or have better coverage from insecticide-treated nets or seasonal malaria chemoprevention (SMC). Factors such as these could impact how large of an effect we’d expect to see from IPTi in those locations, which would in turn impact cost-effectiveness.
• Feasibility of implementing IPTi at scale – There are many setting-specific factors that contribute to whether IPTi implementation will be feasible or not, including level of interest from country decision-makers, strength of the supply chain that gets medicines where they’re needed, and quality of monitoring and evaluation systems. We expect all of these will become clearer to us when the scoping study is complete.
• Counterfactual impact of our funding – It might be that another funder would step in to support IPTi implementation in the next few years if we don’t, thus reducing the value of our funding recommendation.
• More specific questions around room for more funding – Although the absence of IPTi programs so far indicates likely room for more funding, this depends heavily on the uncertainties around suitability, feasibility, and cost-effectiveness we’ve listed above.

We also have some uncertainties around the scoping grant specifically, which we’ve described on the grant page.

Why do we direct so much funding to malaria programs?

Two of our top charities, Malaria Consortium’s SMC program and Against Malaria Foundation (AMF), support interventions that protect against malaria, and we direct a lot of funding to them. In 2020, we directed over $60 million to AMF, and $69 million to Malaria Consortium for SMC, which together made up over half of our money moved.^[15] If we were to begin to direct significant funding toward IPTi implementation while maintaining similar levels of funding for AMF and Malaria Consortium, that could weight our support even more heavily toward malaria interventions.

But we’re happy to invest heavily in fighting malaria, because:

• It remains a significant problem: malaria killed over 600,000 people in 2020, most of them children under five.^[16] Though illness and death from malaria have been greatly reduced over the last several decades, that progress has slowed in recent years, and malaria deaths increased between 2019 and 2020.^[17] The anti-malaria interventions we’re already supporting are inexpensive and highly effective,^[18] and we intend to continue supporting them as long as both of those things remain true.
• There is no single tool that can effectively combat malaria everywhere. The success of an intervention can vary considerably from place to place, based on environmental factors such as insecticide or drug resistance among malaria parasites, or seasonal rainfall patterns and how malaria transmission is distributed throughout the year.^[19] For this reason, some antimalarial measures can be used only in certain locations, some contraindicate each other,^[20] and in many places a combination of multiple complementary tools is recommended.^[21] We therefore see value in supporting a diversity of malaria prevention measures, which is why we’re also paying attention to new developments such as WHO’s recent recommendation of the RTS,S vaccine.
• There continues to be a lot of room for more funding in malaria prevention. In 2021, we directed $100 million to Malaria Consortium for SMC and another $97 million for insecticide-treated nets ($31 million to Malaria Consortium and $66 million to AMF).^[22] We expect to identify at least a similar amount of room for more funding for these interventions in 2022. Our very rough calculations, based on countries that have expressed interest in IPTi or been proposed by organizations that responded to our RFI, suggest that the global funding gap for IPTi if scaled in suitable locations could be between $50 million and $200 million, depending on cost per child treated.^[23]

In conclusion

We’re tentatively excited by IPTi’s potential to reduce illness and death from malaria, but a lot of work remains to be done before we decide whether to recommend further funding. We expect to learn a lot from the scoping grant we’ve made to PATH and Malaria Consortium, and we’ll update when we have results from those activities. In the meantime, you can read more about IPTi in our intervention report, and more about the scoping grant on this grant page.

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1. “Although the effect size varied over time and between drugs, overall IPTi impacts on the incidence of clinical malaria overall, with a 30% reduction (rate ratio 0.70, 0.62 to 0.80; 10 studies, 10,602 participants).” Esu, Oringanje, and Meremikwu 2021, "Main results." ↩︎

2. "WHO is now recommending a new intervention against Plasmodium falciparum malaria: Intermittent Preventive Treatment for infants (IPTi). Intermittent Preventive Treatment in infancy with SP (SP-IPTi) is the administration of a full therapeutic course of SP delivered through the Expanded Program on Immunization (EPI) at defined intervals corresponding to routine vaccination schedules – usually at 10 weeks, 14 weeks, and ∼9 months of age – to infants at risk of malaria." WHO, Policy recommendation on Intermittent Preventive Treatment during infancy with sulphadoxine-pyrimethamine (SP-IPTi) for Plasmodium falciparum malaria control in Africa, 2010, p. 1 ↩︎

3. “However, to date, only Sierra Leone has implemented IPTi at a national scale. The country adopted the intervention in 2016, piloting it in two then four districts before national roll-out in 2018.” WHO, Technical consultation to review the role of drugs in malaria prevention for people living in endemic settings: meeting report, 2020, p. 10 ↩︎

4. "At the central level, there is support to decrease the burden of malaria in infants, and implementation through routine immunization should ensure access for the target population. Integration of IPTi into immunization services, including outreach sessions, adds a preventive intervention and could increase coverage of both interventions in communities. However, careful coordination is required for training, supply and time management. As with IPTp, coordination is required between the established delivery platform, i.e., the routine immunization services, and the national malaria programme. The success of an IPTi programme will depend on strong leadership within the national and subnational EPI teams.” WHO, Technical consultation to review the role of drugs in malaria prevention for people living in endemic settings: meeting report, 2020, p. 11 ↩︎

5. “The recommendation that IPTi should not be implemented in areas with high prevalence of molecular markers of SP resistance was seen as the primary barrier to its implementation for two reasons. First, the requirement for countries to measure molecular markers to determine the applicability of IPTi in their setting may be a barrier, as markers of SP resistance are no longer routinely monitored. Second, the prevalence of molecular markers of drug resistance may not correlate with the effectiveness of chemoprevention, as has been acknowledged with IPTp. However, caution is required in extrapolating findings from semi-immune pregnant women to nonimmune infants.” WHO, Technical consultation to review the role of drugs in malaria prevention for people living in endemic settings: meeting report, 2020, p. 11 ↩︎

6. “Paediatric drug formulation: The pilot implementation studies found that, although it was possible to cut and crush SP tablets for administration to young infants, this was a cumbersome process. A paediatric formulation has been developed for SMC, which would make for much easier administration. The importance of ensuring adequate dosing and of understanding the pharmacokinetics in the target age group was recognized.” WHO, Technical consultation to review the role of drugs in malaria prevention for people living in endemic settings: meeting report, 2020, p. 12

   In April 2021, a dispersible SP tablet at the appropriate dosage for infants was added to WHO's list of prequalified medicinal products. See the second bullet and accompanying footnotes under "The intervention" on our grant page. ↩︎

7. See our program review on IPTi, "What is the problem?": "Malaria is the fourth largest cause of death for children under 5 in sub-Saharan Africa, accounting for 12% of deaths." ↩︎

8. As of early 2022, we are primarily looking to recommend grants that we estimate are 8 or more times as cost-effective as GiveDirectly's unconditional cash transfer program, and are willing to consider recommending a limited amount of funding to grants that are between 5 and 8 times as cost-effective as GiveDirectly. For examples of the cost-effectiveness of our recommendations, see here. ↩︎

9. ICAP, a research group at Columbia University, has supported the scale-up of IPTi in Sierra Leone in the past, and other organizations have been funded to implement small-scale IPTi pilot programs for research purposes. See here for more details. ↩︎

10. See the proposal from PATH and Malaria Consortium here. ↩︎

11. "Twenty-nine countries accounted for 96% of malaria cases globally, and six countries – Nigeria (27%), the Democratic Republic of the Congo (12%), Uganda (5%), Mozambique (4%), Angola (3.4%) and Burkina Faso (3.4%) – accounted for about 55% of all cases globally." WHO, World Malaria Report 2021, p. xv ↩︎

12. The funding for this study was provided by an individual donor. For more information about the grant recommendation, see this page. ↩︎

13. We estimate about $34 million in potential room for more funding in Nigeria and $16 million in potential room for more funding in DRC. See our calculations here. ↩︎

14. See here in our preliminary cost-effectiveness analysis. This is substantially higher than the estimates we've seen in the academic literature on IPTi, which we believe may be underestimating costs; see footnote 36 in the cost-effectiveness section of our program review of IPTi. ↩︎

15. In 2020, GiveWell donors contributed over $240 million to our recommended charities. Of that total, about $69 million was directed to Malaria Consortium and about $61 million was directed to AMF. See the tables in the "Money Moved" section of our impact page. ↩︎

16. "Globally, malaria deaths reduced steadily over the period 2000–2019, from 896 000 in 2000 to 562 000 in 2015 and to 558 000 in 2019. In 2020, malaria deaths increased by 12% compared with 2019, to an estimated 627 000.

    "The percentage of total malaria deaths in children aged under 5 years reduced from 87% in 2000 to 77% in 2020." WHO, World Malaria Report 2021, p. xvi. ↩︎

17. "There were an estimated 14 million more malaria cases and 47 000 more deaths in 2020 compared to 2019, due to disruptions to services during the pandemic. However, things could have been far worse if not for the efforts of malaria endemic countries to maintain services.

    "Even before the pandemic, global progress against malaria had levelled off, and countries with a high burden of the disease were losing ground. Since 2015, the baseline of WHO’s global malaria strategy, 24 nations have registered increases in malaria mortality. Now, critical 2020 milestones of WHO’s global malaria strategy have been missed, and without immediate and dramatic action, the 2030 targets will not be met.

    "Compounding the need for urgent action, this report also includes sobering new estimates of malaria’s toll on children under 5 years of age in sub-Saharan Africa, where a vast majority of malaria deaths occur each year. Using better data and more accurate methodology, it suggests the disease has claimed many more young lives over the past two decades than previously reported." WHO, World Malaria Report 2021, p. vi ↩︎

18. See our reviews of the evidence on AMF's program and Malaria Consortium's SMC program. ↩︎

19. See, for instance, the WHO guidelines to determine where SMC should be implemented in the "What is the program?" section of our review of SMC. See also a discussion of drug resistance in the "Possible negative/offsetting impacts" section of that page, and a discussion of insecticide resistance in the same section of our review of insecticide-treated nets. ↩︎

20. For example, WHO doesn't recommend that IPTi and SMC be administered in the same area. See the "What is the program?" section of our review of IPTi. ↩︎

21. For example, WHO recommends using a package of several interventions: "The World Health Organization (WHO) Global Technical Strategy for Malaria 2016–2030 (WHO-GTS) sets the goal of universal access to malaria prevention, treatment and diagnosis. This includes a core package of recommended interventions for reducing malaria-related morbidity and mortality: diagnosis and treatment of clinical and severe malaria, vector control with long-lasting insecticide-treated bed nets (LLINs) or indoor residual spraying (IRS) and chemoprevention for high-risk groups (infants, children in areas of seasonal transmission, pregnant women)." Winskill et al. 2019, p. 1 ↩︎

22. These numbers refer to grants made in GiveWell's "metrics year" 2021, February 2021 through January 2022, not the calendar year 2021. They do not include another $7.5 million in donations earmarked by donors for AMF and Malaria Consortium, or donations made directly to these charities based on GiveWell's recommendation, for which we don't yet have data. We're drawing these numbers from our internal records, since we don't yet have a single, easily interpretable public source for them. ↩︎

23. See this spreadsheet for calculations. ↩︎