Malaria Consortium — SMC in Karamoja, Uganda in 2024 and Nampula, Mozambique in 2024-2025 (November 2023 - January 2024)

Note: This page summarizes the rationale behind a GiveWell-recommended grant to Malaria Consortium. Malaria Consortium staff reviewed this page prior to publication.

Published: November 2024

Summary

Background

Malaria is a large driver of under-5 mortality in Uganda and Mozambique.1 Seasonal malaria chemoprevention (SMC) involves giving children monthly courses of antimalarial medicines for part of the year in places where a high proportion of malaria cases occur during the rainy season, which is true of both Karamoja, Uganda, and Nampula, Mozambique.2

GiveWell previously co-funded Malaria Consortium to conduct SMC implementation and effectiveness studies in Nampula over the 2020/2021 and 2021/2022 seasons (the malaria transmission peak crosses calendar years in this region) and in Karamoja over the 2021 and 2022 seasons.3 SMC had previously been studied and delivered only in the Sahel region of Africa, based on the World Health Organization (WHO)’s recommendation that SMC only be delivered in geographies with low resistance to sulfadoxine–pyrimethamine (SP) and amodiaquine (AQ), the antimalarial medicines used in SMC.4 We detailed the scope of these studies in Mozambique on a previous grant page. The study in Uganda closely mirrored the design outlined there. Our analysis of the preliminary results from these studies suggests that SMC is effective in reducing malaria deaths in children under 5 who receive it in Uganda and Mozambique by about 64% over the period when it's administered.5

GiveWell funding has subsequently supported SMC delivery by Malaria Consortium in 5 of 9 districts in Karamoja in the 2023 season, with the remaining 4 districts expected to be supported by the Global Fund.6 GiveWell also funded Malaria Consortium to deliver SMC in all 23 districts of Nampula over the 2022/2023 and 2023/2024 seasons.

What we think this grant will do

With this grant, Malaria Consortium will provide funding and operational support to an SMC campaign in Karamoja for the 2024 SMC season and in Nampula for the 2024/2025 SMC season. We think this grant will cause children to receive SMC who would not otherwise have received it, which in turn will reduce under-5 malaria cases and deaths.

Malaria Consortium's role in SMC programs is described in more detail in this section of our top charity review.

Why we made this grant

Our best guess is that these grants are 10-11x as cost-effective as unconditional cash transfers (GiveWell’s benchmark for comparing different programs). At the time of writing this page, GiveWell’s funding bar is to fund grants to our top charities that we estimate to be 8x or more as cost-effective as cash transfers.

We detail why we think this grant is cost-effective below. In simple terms, we think these grants are cost-effective because:

• SMC is effective at preventing malaria. We estimate that SMC reduces malaria incidence in children who receive it in Uganda and Mozambique by about 64% over the period when it's administered, which we estimate accounts for 52-62% of annual malaria mortality. We assume that reduced malaria cases translate 1:1 into reduced malaria deaths.7 This is somewhat less pronounced than in Sahelian countries, where we estimate a 79% reduction.
• SMC is a highly targeted program. It is delivered to a group at high risk of malaria (children under 5 years old) and in a time-limited window during which a high proportion of malaria transmission occurs. While this transmission period is longer in Karamoja and Nampula than in the Sahel, we think it’s concentrated enough to make both locations good candidates for SMC delivery.8
• It is relatively cheap to reach children with SMC. We estimate that it costs Malaria Consortium approximately $6.50-$8 per year to reach a child with all their recommended cycles of SMC in Karamoja and Nampula. More below.
• GiveWell funding increases the proportion of people protected by SMC. Without SMC campaigns, we estimate that virtually no children would get SMC from other sources. We also expect that in the absence of GiveWell funding, it is relatively unlikely that another funder would support campaigns during the upcoming SMC seasons in the areas covered by this grant in Uganda and Mozambique. However, it's an open question whether this will be true in the longer term.

A sketch of our cost-effectiveness analysis for these grants is below, using Karamoja, Uganda as an example:

What we are estimating	Best guess (rounded)	Confidence intervals (25th - 75th percentile)	Implied cost-effectiveness
Donation to Malaria Consortium (arbitrary value)	$1,000,000
Cost per child reached with SMC	$8	$7 – $10	11x – 8x
Number of children receiving SMC	152,000
Percent of children who would have received SMC without mass distribution	0%
Annual mortality rate from malaria and associated causes among children who do not receive SMC	0.54%	0.24% – 0.76%	5x – 14x
Proportion of malaria mortality occurring in SMC season	62%	50% - 78%	8x - 13x
Reduction in malaria mortality from receiving SMC	64%	51% - 77%	8x - 12x
Initial cost-effectiveness estimate
Cost per death averted (child mortality only)	~$3,800
Moral weight for each death averted	116
Initial cost-effectiveness estimate	9x
Summary of primary benefits (% of modeled benefits)
Reduced child mortality	84%
Reduced mortality among older children and adults	2%	1% - 4%	10x - 11x
Income increases in later life	14%	8% - 19%	10x - 11x
Additional adjustments
Adjustment for additional program benefits and downsides	28%	17% – 41%	9x - 11x
Adjustment for grantee-level factors	-8%	-17% - -4%	9x - 11x
Adjustment for diverting other actors’ spending into SMC (“leverage”)	-1%
Adjustment for diverting other actors’ spending away from SMC (“funging”)	-19%	-42% - -11%	7x - 11x
Overall cost-effectiveness(multiples of cash transfers)	10x

You can see our full cost-effectiveness analysis for this grant here and a simple version here. The other factors informing our decision to make this grant are:

• Malaria Consortium as an implementer (more). Malaria Consortium has a strong track record delivering SMC programs in the Sahel with GiveWell support, and our qualitative assessment of Malaria Consortium as an organization is highly positive. In 2020, GiveWell also began funding Malaria Consortium to pilot delivery of its program outside the Sahel in Nampula, Mozambique and Karamoja, Uganda. Malaria Consortium believes that continued SMC deployment in both locations is appropriate based on the effectiveness and drug resistance data they've seen from both locations thus far.
• Stakeholder support for SMC outside the Sahel (more). While we have open questions and concerns about SMC outside of the Sahel (more), support for SMC outside the Sahel from stakeholders like WHO, Global Fund, and the Mozambique and Uganda national malaria control programs (NMCPs) increase our confidence that continued delivery is appropriate.
• Time-sensitivity (more). The funding needs for the 2024 SMC season in Karamoja and the 2024/2025 season in Nampula were both time-sensitive, as Malaria Consortium needs to order SMC drugs in advance to avoid campaign delays.

Main reservations

• How effective is SMC at averting malaria cases outside the Sahel? Outside the Sahel, we estimate that receiving SMC reduces malaria mortality by 64% during the period when it is delivered. This estimate is based on the results of two RCTs from Karamoja and Nampula conducted by Malaria Consortium. Results from these studies were difficult to interpret. (more)
• What is the relationship between SMC effectiveness, efficacy, and drug resistance in Mozambique and Uganda? We think that anti-malarial drug resistance is more prevalent in Mozambique and Uganda than in Sahel countries.9 We don’t yet have a good understanding of whether delivering SMC in high-resistance settings might exacerbate drug resistance and, in turn, what effect this might have on SMC efficacy (its ability to clear malaria parasites from the blood) or its effectiveness in reducing clinical malaria. We currently account for higher resistance to one of the drugs used in SMC by applying a -10% drug resistance adjustment in our cost-effectiveness model to geographies outside the Sahel, including Mozambique and Uganda. We are also unsure how to interpret preliminary results from chemoprevention efficacy studies (CPES) from Mozambique and Uganda, which suggest suboptimal SMC efficacy despite the promising RCT results on reducing malaria incidence. We anticipate that we will learn more about how to interpret these findings and how they compare to SMC efficacy and effectiveness in the Sahel once full CPES results from both locations as well as from Nigeria and Burkina Faso are available. (more)
• What do important stakeholders think about SMC outside of the Sahel, and how is the funding situation changing? Key stakeholders have signaled they are in favor of continuing SMC in Mozambique and Uganda. We think this means there is a moderate risk that we are crowding out future funding from other actors by continuing to support SMC implementation in both locations. We'd also like to better understand how results from CPES studies and SMC effectiveness trials from Mozambique and Uganda are interpreted by key stakeholders in the SMC space. (more)

Other reservations

• What is the mortality rate for children not receiving SMC? In the absence of SMC, we estimate that the chance that a child under five in Uganda and Mozambique will die as a result of malaria per year is ~0.5%. However, our analysis relies on malaria mortality data that is inherently uncertain. (more)
• How seasonal is SMC mortality outside the Sahel? We estimate that 52% and 62% of annual malaria mortality occurs during the SMC seasons in Nampula and Karamoja, respectively. However, we have not deeply investigated malaria transmission seasonality across locations. (more)
• How much does it cost to deliver SMC in Mozambique and Uganda? We are relatively uncertain how much it costs to deliver SMC in Mozambique and Uganda. (more)

Funding for the grant

This funding comes from the following sources:

• $12.3 million is from donations made to GiveWell’s Top Charities Fund.
• $2.3 million is from a grant made by Effektiv Spenden on GiveWell’s recommendation.
• $0.7 million is from a grant made by Giving What We Can on GiveWell’s recommendation.
• $0.3 million is from a grant made by a donor on GiveWell's recommendation.
• $0.3 million is from a grant made by Effective Altruism Australia on GiveWell’s recommendation.
• $0.06 million is from GiveWell's unrestricted funds.
• $0.05 million is from a grant made by Effective Altruism New Zealand on GiveWell’s recommendation.

Planned activities and budget

Background

SMC has historically been delivered in the Sahel region of Africa. In the Sahel, malaria transmission is concentrated during the rainy season10 , roughly between July and October. While there are other locations outside the Sahel that experience seasonal malaria, they have historically not received SMC because malaria parasites in those locations have a high level of resistance to one of the antimalarial drugs used during SMC, sulfadoxine-pyrimethamine (SP).11 Because of this, SP is not recommended to treat malaria infections in those locations. However, it was less clear how SP resistance would impact SMC's prophylactic effects in these areas.12

The national malaria control programs (NMCPs) of Mozambique and Uganda recently became interested in piloting SMC and testing its effectiveness in the parts of their countries experiencing seasonal malaria transmission. In 2020, both countries asked Malaria Consortium for support.13 GiveWell funded Malaria Consortium to pilot SMC in Nampula, Mozambique in the SMC seasons in 2020-21 (in two districts) and 2021-22 (at a slightly larger scale)14 and co-funded a two-year implementation study with the Bill & Melinda Gates Foundation (BMGF).15 In Uganda, GiveWell funded Malaria Consortium to pilot SMC in 2021 (two districts) and 2022 (eight districts)16 and co-funded a similar study with BMGF.17 The intervention delivered in these pilots was the same intervention that GiveWell has funded Malaria Consortium to deliver at larger scale in Nigeria, Burkina Faso, Togo, and Chad in the Sahel.

With GiveWell support, Malaria Consortium scaled up SMC delivery to all districts of Nampula province in Mozambique in the 2022-2023 and 2023-2024 SMC seasons. GiveWell also supported SMC delivery in five of Karamoja’s nine districts in the 2023 season, with the Global Fund supporting SMC in the remaining four districts.18 At Malaria Consortium’s recommendation, we made the decision to fund the scale-up in both countries before receiving RCT results on SMC effectiveness. This decision was based on promising results from initial non-randomized trials.19

We have now received the results from the two RCTs we funded in Nampula and Karamoja. Both RCTs found that SMC caused large reductions in malaria cases. Based on our review of this evidence, we think SMC is about 20% less effective in Nampula and Karamoja than in the Sahel region of Africa. Our best guess is that SMC averts about 64% of malaria cases in treated children in high-resistance areas during the high-transmission season.20

While these RCT results demonstrate SMC’s effectiveness in preventing clinical malaria in both Uganda and Mozambique, we are unsure how to interpret additional evidence that Malaria Consortium has generated related to SP resistance in these locations. During the implementation studies in Mozambique and Uganda, Malaria Consortium also conducted resistance marker and chemoprevention efficacy studies21 (CPES) in both locations. Preliminary results from these studies found high levels of SP resistance in both locations22 and a higher than expected number of infections in blood samples collected from children 28 days after receiving SPAQ.23 Although these studies didn’t produce evidence that SMC delivery is contributing to increasing SP resistance in these settings, we remain concerned about the potential impact SMC may have on increasing SP resistance and are unsure how to interpret preliminary CPES results that suggest high malaria infection rates in spite of the reduction of clinical malaria observed in the RCTs. We discuss this in more detail in our risks and reservations below.

What we think this grant will do

The intervention that Malaria Consortium would deliver with these grants is the same intervention that GiveWell funds Malaria Consortium to deliver at large scale in countries in the Sahel. For a description of these activities, see our top charity review of Malaria Consortium’s SMC program.

These one-year grants will enable Malaria Consortium to deliver SMC in Nampula and Karamoja for the upcoming SMC seasons at the same scale it achieved in 2023. $14,574,211 will enable it to deliver SMC in all 23 districts of Nampula province for the 2024/2025 SMC season. $1,427,254 will enable it to deliver SMC to five of Karamoja's nine districts for the 2024 SMC season.24 The size of each grant is based on Malaria Consortium’s estimated 2024/2025 target populations, planned number of cycles, and cost per child per cycle in each setting.

As outlined below, we have several open questions about the continued delivery of SMC outside the Sahel. We have structured this as a one-year grant to ensure Malaria Consortium can continue delivering SMC at its current scale in both countries while we investigate these questions over the coming months.

The case for the grant

High cost-effectiveness

Our best guess is that these grants are 10-11x as cost-effective as unconditional cash transfers (GiveWell’s benchmark for comparing different programs). At the time of writing, GiveWell’s funding bar is to fund grants to our top charities that we estimate to be 8x or more as cost-effective as cash transfers. We expect the grant will avert roughly 4,000 children’s deaths in Uganda and Mozambique.25

We set out the reasons why we think SMC is generally a cost-effective intervention in our SMC intervention report. The main reasons we expect these particular grants to be cost-effective are discussed below.

• Malaria is a major cause of child mortality in these contexts. We estimate that the chance that a 3-59 month old child (the main target group for SMC) will die as a result of malaria is around 0.5% in these contexts.26 We then adjust these estimates upward because we think malaria indirectly causes 0.75 deaths from other causes for every direct malaria death. This is based on evidence that malaria control programs often have larger impacts on mortality than would be expected from their impact on malaria alone.27
• SMC effectiveness — Available evidence suggests that SMC is effective outside the Sahel. In countries in the Sahel subregion, we estimate that SMC reduces malaria incidence by about 79% in children who receive it during the months that SMC is delivered, based on six high-quality trials in the region.28 In Mozambique and Uganda, where antimalarial resistance is more prevalent,29 our estimated effect size relies on two SMC implementation RCTs conducted by Malaria Consortium in those settings.30 We think the preliminary findings from these RCTs suggest that SMC is about 20% less effective in Uganda and Mozambique than in the Sahel region of Africa.31 Based on this, our best guess is that SMC averts about 64% of malaria cases in treated children in Nampula and Karamoja during the high-transmission season. We discuss the evidence base for SMC effectiveness outside the Sahel and our uncertainties in further detail below.
• Seasonality — SMC is delivered in a specific, time-limited window during which a high proportion of malaria transmission occurs.32 The targeted nature of SMC means children are protected during the period of time when the majority of malaria deaths occur. We think that 52% and 62% of malaria deaths occur during the high-transmission seasons in Nampula and Karamoja, respectively. Although this seasonality is not as marked as in the Sahel, where we think 70% of malaria deaths occur during the high-transmission season, we think the relatively high proportion of annual malaria transmission that can be averted by SMC in Nampula and Karamoja makes it a cost-effective intervention in both locations.
• Cost per cycle of SMC — One of the key parameters in GiveWell’s SMC cost-effectiveness model is the average cost per SMC cycle delivered. This estimate is based on (1) previous years’ spending on the program and (2) estimates of the number of children reached from program monitoring data. We typically calculate a cost per SMC cycle administered for each Malaria Consortium-supported country using spending and coverage data from past SMC campaigns conducted in those countries.33 However, because we don't yet have costs and coverage from Malaria Consortium's full-scale implementation of SMC in Mozambique or Uganda, we have roughly estimated that the cost per SMC cycle administered that Malaria Consortium will achieve for this grant will be similar to the cost per SMC cycle administered that it achieved in Chad in 2022 ($1.81).34 While we’re thus somewhat uncertain about the precise cost-effectiveness of each program, our best guess is that they are both roughly around our 8x funding threshold. Cost and coverage reporting from the 2023 and 2024 campaigns in both countries will allow us to improve those estimates.
• Probability that other funders would fill these funding gaps if we did not — After conversations with national malaria programs in Uganda and Mozambique, the Global Fund, and the President’s Malaria Initiative (PMI), we assume a 20% risk of crowding out other potential funders in Mozambique and a 30% risk in Uganda. Our reasoning is outlined below.

This grant will crowd out some funding from other funders, but will mostly fill funding gaps that would have remained unfilled

We adjust our cost-effectiveness estimates to account for the extent to which we believe our funding may be crowding out funding that would otherwise have come from other sources. In the case of SMC, this is typically the Global Fund and/or the President’s Malaria Initiative (PMI).

The Global Fund, which has historically been the largest funder of SMC, underwent its latest three-year funding “replenishment” in late 2022 (for interventions to be delivered in 2024-2026). The total value of the replenishment was $15.7 billion, compared to a target of at least $18 billion.35 This represents a fairly stable level of funding compared to the previous replenishment (a 3.3% nominal increase in the overall funding allocated to countries).36 However, in multiple conversations with grantees and other malaria stakeholders, we have heard that funding needs are likely to be higher during the 2024-2026 grant period because of factors including population growth, inflation, and the introduction of new interventions. As a result, we anticipate more funding gaps for higher priority funding needs, including insecticide-treated nets (ITNs), and expect that funding gaps for SMC in the period covered by this grant are unlikely to be filled by the Global Fund.

We also think it’s unlikely that PMI will contribute funding to SMC campaigns in Mozambique or Uganda in the near-term. Funding decisions at PMI are decentralized, made primarily by PMI country offices, and we have been told that no PMI offices outside the Sahel are currently considering funding SMC campaigns due to existing resource constraints.37 However, we think this could change in the medium to long term.

As a result, we think that this grant will crowd out some funding from other funders, but will mostly fill funding gaps that would have remained unfilled. We incorporate this belief in our cost-effectiveness model by assigning a 30% risk of crowding out other potential funders in Karamoja and a 20% risk in Nampula. Beyond our general reasoning above, specific information we used to make these assessments included the following:

• In 2023, Uganda's national malaria program submitted its application to the Global Fund, which includes how it will allocate 2024-2026 funding. Our understanding through conversations with stakeholders is that the application included funding for SMC campaigns in the four Karamoja districts previously supported by the Global Fund. It included the five GiveWell-funded districts in its Prioritized Above Allocation Request (PAAR).38 Our conversations lead us to believe that the chance of SMC being funded in these districts through PAAR is low due to:
  • Higher priority funding gaps in PAAR that are likely to be filled first, including ITNs and integrated community case management.
  • PAAR funding timelines making it unlikely that funding would be available in time for the 2024 campaign.
  • A general expectation of lower available PAAR funding in the 2024-2026 Global Fund funding cycle.

While we think it is possible that the five districts would have been included in Uganda’s Global Fund application in GiveWell’s absence, we do not think it is likely at this point that the Global Fund will fund these districts in 2024 if we had declined to make this grant.

• Through conversations with Mozambique’s national malaria program and the Global Fund, we learned that Mozambique's national malaria program included a new province, Niassa, within its Global Fund 2024-2026 funding application for SMC campaigns alongside Nampula.39 It also included SMC campaigns in Manica Province and six districts in Cabo Delgado Province into PAAR. Through these conversations, we learned that Mozambique did not receive enough funding from the Global Fund for SMC campaigns in both provinces. We also learned that the national malaria program had decided to allocate the funding it did receive from the Global Fund for SMC to the funding gap in Niassa for the 2024/2025 SMC season, possibly in anticipation of GiveWell funding being available to cover Nampula.
• Ultimately, we were not confident that this funding could be reallocated to fully cover SMC delivery in Nampula had we decided not to make this grant. Our best guess is that:
  • Had we decided not to make this grant, funding from the Global Fund would not have been sufficient to fully cover the full funding gap in Nampula.40
  • The inclusion of Niassa in Mozambique’s Global Fund funding application is based on its high malaria disease burden and seasonal transmission patterns, which we expect would mean the program is similarly cost-effective to SMC in Nampula. We did not conduct additional analysis to test this hypothesis prior to making a grant, but we plan to do this in the future. If our analysis suggests that Niassa is not cost-effective, we may consider changing our level of support for SMC in Mozambique in the future.

Malaria Consortium as a grantee

Malaria Consortium has a strong track record delivering SMC programs in the Sahel.41 As discussed above, GiveWell has funded Malaria Consortium to pilot delivery of its program outside the Sahel since 2020.

Malaria Consortium conducts coverage surveys after both individual cycles and full rounds of SMC to estimate the proportion of eligible children its program reached. We have seen results from all SMC rounds that Malaria Consortium has supported with GiveWell-directed funds. Overall, our assessment is that these surveys are methodologically strong and provide evidence that Malaria Consortium’s programs reached a high proportion of targeted children in previous campaigns.42

Our qualitative assessment of Malaria Consortium as an organization is highly positive. We previously rated it as "relatively strong" or higher on seven of eight dimensions included in our qualitative assessments.43 During the grant investigation for our January 2022 renewal grant, we asked several SMC stakeholders for feedback on Malaria Consortium and heard almost exclusively (and often strongly expressed) positive feedback.

Expert support for SMC outside the Sahel

Malaria Consortium believes that continued SMC deployment in Nampula and Karamoja is appropriate based on the effectiveness and drug resistance data they've seen from both locations thus far.44 Because Malaria Consortium has in-house technical malaria expertise, and because we perceive them to be relatively conservative in their position on SMC's promisingness outside of the Sahel, we put significant weight on this recommendation.

While we have open questions and concerns about SMC effectiveness, efficacy, and drug resistance outside of the Sahel (more), buy-in from Malaria Consortium and additional stakeholders increases our confidence that continued delivery is appropriate and we aren’t missing important downsides:

• WHO has signaled support for SMC outside of the Sahel through its revised chemoprevention guidelines.45
• Mozambique and Uganda chose to include SMC in their Global Fund applications and have received permission from the Global Fund to use this funding for SMC46 and the Mozambique national malaria program has indicated that SMC will play an increasingly important role in Mozambique’s national malaria control strategy going forward.47
• In conversations with Medicines for Malaria Venture (MMV), Bill and Melinda Gates Foundation (BMGF), PMI, and Clinton Health Access Initiative (CHAI), we heard general support for continued delivery of SMC outside the Sahel while we learn more about our open questions.

Time-sensitivity

The funding needs for the 2024 SMC season in Karamoja and 2024/2025 season in Nampula were both time-sensitive, as Malaria Consortium needs to order SMC drugs in advance to avoid campaign delays. Given this time sensitivity, we decided to make one-year grants to ensure the programs can continue through the next SMC season while we investigate remaining open questions around SMC delivery outside the Sahel.

Risks and reservations

We discuss our general uncertainties about the cost-effectiveness of SMC in more detail in our SMC intervention report. The main uncertainties we have about these particular grants are discussed below.

What is the malaria mortality rate for children not receiving SMC outside the Sahel?

We estimate an annual malaria-attributable mortality rate among children under age 5 of about 0.5% in both Mozambique and Uganda. This input is based on:

• Baseline mortality estimates from the Institute for Health Metrics and Evaluation (IHME)'s 2019 Global Burden of Disease (GBD) model. Our estimates of annual malaria mortality for children under five are drawn from the Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease (GBD) project.48 We use the 2019 GBD national-level estimate for malaria mortality among 1-59-month-olds. These estimates are a source of significant uncertainty in our analysis. Our understanding is that the GBD estimates rely on a number of modeling assumptions,49 in part because raw data on malaria from health surveillance systems is relatively unreliable in many sub-Saharan countries.50 We have not investigated all the modeling assumptions underlying these estimates in detail, and we think it’s possible that GBD might be underestimating or overestimating malaria deaths. This is the greatest source of uncertainty in our cost-effectiveness estimates for both countries; our 25th to 75th percentile confidence interval for this adjustment implies a ~55% reduction to ~40% increase in cost-effectiveness estimates across Uganda and Mozambique.
• Non-malaria deaths indirectly averted by SMC: Malaria control interventions often have a larger effect on all-cause mortality than would be expected exclusively from declines in malaria-specific mortality.51 Deaths may have several causes, while only being attributed to one cause. For example, malaria may increase the likelihood of death from malnutrition or other infectious diseases.52 We account for this with an estimate that for each death directly caused by malaria, an additional 0.75 deaths are indirectly caused by malaria. However, we are uncertain about what the exact value for this effect should be; our 25th to 75th percentile confidence interval of 0.5 to 1 for this adjustment implies a ~10%% reduction to a ~10% increase in cost-effectiveness estimates across Uganda and Mozambique53 . Our estimate is based on triangulating results from a meta-analysis of the effects of nets on all-cause mortality, conversations with malaria experts, and the effects that other health interventions have on averting indirect deaths.

How seasonal is SMC mortality outside the Sahel?

Our analysis is sensitive to our estimate of the proportion of malaria deaths taking place during the high-transmission season when SMC is delivered. This is because we assume that SMC only averts malaria during the period when it is delivered.54 In the Sahel, we estimate that 70% of malaria deaths take place in the high-transmission season when SMC is delivered. However, we think this proportion is lower in Mozambique and Uganda. This is because malaria seasonality tracks rainfall less well in East Africa, as the climate isn't as arid in the non-rainy season, and standing bodies of water ensure continued mosquito presence year-round.55

Our best guess is that 52% and 62% of annual malaria mortality occurs during the SMC seasons in Nampula and Karamoja, respectively. The 52% estimate for Nampula is the average of our 70% estimate for Sahel countries and 33%, which is roughly the proportion of malaria mortality that would occur during the SMC season if there were no seasonality in malaria cases during the four-month period in which SMC is typically delivered in Mozambique.56 For Uganda, we assume the same 52% estimate but add an additional 10% to account for mortalities occurring during the additional, fifth month of SMC delivered there.57

We believe that our cost-effectiveness model would benefit from additional research to inform this parameter, particularly data that would enable us to use location-specific estimates. Malaria Consortium has informed us that it is currently working with malaria modeling groups to review and model seasonality in both Mozambique and Uganda, but we haven’t seen the results of this work yet.58

How effective is SMC at averting malaria cases outside the Sahel?

Outside the Sahel, we estimate that receiving SMC reduces malaria mortality by 64% during the period when it is delivered. This estimate is based on the results of two RCTs from Karamoja and Nampula conducted by Malaria Consortium. Results from these studies were difficult to interpret:59

• The Mozambique RCT found a 67% malaria reduction for treated children. However, we believe this may overestimate the true effect in Mozambique because the trial had high attrition that was imbalanced in a way that under-represented relatively wealthy and educated control group households, which might lead to upward bias in estimates.60 We subjectively discount the effects in Mozambique by 15% to account for this possibility. With this adjustment, our best guess for the RCT effect size estimate in Mozambique is 57%.
• The Uganda RCT found a 95% malaria reduction in the treatment group. While we don’t have specific reasons to suspect upward bias, we think it is implausible that SMC is more effective in high-resistance settings like Uganda than low-resistance ones in the Sahel. As a result, we cap the effect size at 79%, which is our estimated effect size for SMC in the Sahel based on a meta-analysis of nine previous randomized controlled trials conducted in low-resistance settings.61 We view this value as the maximum plausible effect of SMC outside of the Sahel.

To reach an effectiveness estimate based on these uncertain data points, we place 30% weight on our prior assumption that SMC reduces malaria cases by 65% in treated children in Mozambique and Uganda, 50% weight on the adjusted Mozambique RCT effect size, and 20% weight on the capped Uganda RCT effect size.62 Given remaining uncertainty on this key parameter, we may consider seeking more expert feedback on these effect sizes.

What is the relationship between SMC effectiveness, efficacy, and drug resistance?

We don’t yet have a good understanding of whether delivering SMC in high-resistance settings might exacerbate drug resistance and, in turn, what effect this might have on SMC effectiveness in reducing malaria cases over time. Malaria Consortium has generated evidence on drug resistance and SMC efficacy in Karamoja and Nampula over the course of its implementation studies in both settings:

• Drug resistance — Malaria Consortium conducted resistance markers studies to assess how resistant malaria parasites were to SMC drugs before and after the SMC rounds.63 There were two key findings from these studies:
  • As expected,64 they found high levels of genetic markers of SP resistance in both locations, while the prevalence of markers of resistance to AQ (amodiaquine, the other of the two drugs used in SMC) was lower in both locations.65
  • The studies also found small increases in the prevalence of some resistance markers between baseline and endline in intervention areas. Though Malaria Consortium found these changes difficult to interpret,66 it believes that they don’t provide evidence of SMC causing substantial changes in resistance because the magnitude of the changes were small.67 That said, Malaria Consortium does not believe this evidence is sufficient for projecting longer-term trends in resistance and sees a need for ongoing routine monitoring.68

We incorporate an adjustment for higher baseline drug resistance into our estimate of SMC's effectiveness outside of the Sahel: we assume that the risk of SMC campaigns accelerating drug resistance is higher in areas with high baseline resistance (a -10% risk adjustment to our CEA, vs. -4% in the Sahel). However, we do not yet have a good understanding of how resistance is changing over time, particularly in Mozambique and Uganda where SP resistance is higher, and what effect that may have on SMC effectiveness.

• SMC efficacy — Malaria Consortium also conducted chemoprevention efficacy studies69 (CPES) in both locations during the second year of its implementation studies. So far, we have only seen preliminary results from Mozambique, where the study found a concerning number of infections in blood samples collected from children 28 days after receiving SPAQ.70 Malaria Consortium believes that this result indicates suboptimal efficacy and expressed to us that the result is highly surprising given the positive effectiveness results from Mozambique. However, Malaria Consortium has been careful to stress the difficulty of interpreting this result, both because we haven't seen comparator CPES results from other locations (these are forthcoming from Uganda, South Sudan, Burkina Faso, and Nigeria) and, because this is a relatively new data collection protocol, the relationships between chemoprevention efficacy, effectiveness, and resistance markers are not yet well understood.71 GiveWell has not yet thoroughly examined this result nor invested in fully understanding the CPES methodology.

As we do not yet fully understand the seemingly conflicting results between Mozambique’s chemoprevention efficacy study and RCT, this remains a key open question. For its part, Malaria Consortium has told us that it plans to set up ongoing resistance monitoring in places where it delivers SMC outside the Sahel,72 but we don’t yet know the scope and timeline for these plans. Malaria Consortium's high-level position in light of these results is that the effectiveness seen in the trials justifies continuation of SMC in those locations, but that they do not yet recommend a significant expansion of SMC beyond those and similar areas.73 They note that this position may change as new evidence becomes available.

How much does it cost to deliver SMC in these locations?

We calculate the cost per cycle (CPC) of SMC delivered in each country based on the number of SMC cycles delivered by previous Malaria Consortium-supported SMC programs, costs incurred by Malaria Consortium, and costs incurred by other actors. We divide total costs by total cycles delivered to obtain the estimated cost per cycle in each country. This spreadsheet contains our full calculations. We have not yet calculated cost per cycle delivered estimates for Uganda or Mozambique because we don’t yet have data that reflect how expensive the programs will be to implement at full scale.

Our CPC estimates rely on expenditure and SMC coverage data provided by Malaria Consortium.74 However, Malaria Consortium was still operating at a small scale and conducting implementation research in Mozambique and Uganda in 2022, the last year for which we have program data. As a result, we don't expect that this data reflects the costs or coverage that these programs will achieve at full scale.75 We expect that 2023 program reports we receive from Malaria Consortium in 2024 to be more reflective of the coverage and costs these programs will achieve going forward.

Our current analysis uses the $1.81 cost per cycle figure that we estimate for Chad, Malaria Consortium's most expensive Sahelian program.76 We typically use this value for newer geographies—for which we lack country-specific cost per cycle estimates—based on an expectation that early years of a program will be more expensive.

What do important stakeholders think about SMC outside of the Sahel, and how is the funding situation changing?

As above, our sense is that key stakeholders are in favor of continuing SMC in at least some locations outside of the Sahel. However, we’d like to better understand how results from CPES studies and SMC effectiveness trials from Mozambique and Uganda are being interpreted by key stakeholders in the SMC space.

As the global view on SMC outside the Sahel evolves, we anticipate that the funding situation in Mozambique and Uganda may change as well. The Global Fund has already signaled its willingness to fund SMC outside the Sahel, accepting proposals from Mozambique to fund Niassa province in the 2024/2025 SMC season. We think it’s possible that the Global Fund may continue to expand its funding for SMC outside the Sahel going forward and that it may take over all SMC funding in Karamoja in the future. We may be crowding out future funding, if those organizations would be potentially willing to fund this area in the future, by establishing an expectation that GiveWell will fill those funding gaps. We plan to learn more about this and other potential changes to the funding landscape in conversations with key stakeholders.

Plans for follow up

• Because of our outstanding questions above, we have structured this as an one-year grant to address a time-sensitive funding need. We plan to learn more on our open questions in discussions with key stakeholders in the coming months, including conversations with Malaria Consortium’s SMC team, as well as stakeholders from the Uganda and Mozambique national malaria programs and at the Global Fund and PMI. Through these conversations, we will seek to understand how evolving views on SMC effectiveness, efficacy, and drug resistance, as well as different funding scenarios, might affect these programs.
• We will conduct a site visit to better understand SMC program implementation practices in Nampula, Mozambique during the 2023/2024 implementation round.
• We plan to roughly model the cost-effectiveness of SMC implementation in Niassa Province of Mozambique in the case that we expect our support is crowding out Global Fund SMC funding away from Nampula and into Niassa.
• We plan to interrogate forthcoming CPES results from Uganda, South Sudan, Burkina Faso, and Nigeria and learn more about CPES methodology. As part of this process, we may also more deeply interrogate our current model for SMC effectiveness and drug resistance outside the Sahel.
• We plan to engage with experts to better inform the seasonality parameter we use for geographies outside the Sahel. As above, we expect seasonality modeling being conducted by malaria modeling groups will better inform this parameter over the next year and will decide on next steps once we have these data on hand.
• Malaria Consortium will report on this campaign's activities, expenditure, and coverage through its annual reporting. We plan to use these results to inform our model for cost per child reached in Mozambique and Uganda.
• We will have monthly calls with Malaria Consortium to discuss its work.

Internal forecasts

Confidence	Prediction	By time
60%	Retrospective analysis of these campaigns will find a cost per cycle delivered of greater than $2.09 in Uganda and Mozambique.77	December 31, 2025
80%	PAAR funding will not become available for SMC in Mozambique or Uganda in 2025.	September 30, 2024
60%	PAAR funding will not become available for SMC in Mozambique or Uganda in 2026	September 30, 2025
70%	We will renew grants to support SMC in Karamoja and Nampula.	October 31, 2024
5%	We learn more about the seasonality of malaria transmission outside the Sahel that pushes these programs below 8x.	December 31, 2024
20%	We learn more about drug resistance / SMC efficacy outside the Sahel that leads us to pause non-Sahel grants	January 31, 2025
25%	We will identify and fund research generation activities relevant to our understanding of next-gen SMC drugs, effectiveness in new demographics, SMC layering, etc.	January 31, 2025
50%	We will identify additional cost-effective regions for SMC delivery in Mozambique	October 31, 2024

Our process

Our process on this grant relied heavily on (a) our prior work on modeling the cost-effectiveness of SMC programs supported by Malaria Consortium, and (b) our relationship with Malaria Consortium and knowledge of its work that has resulted from supporting its SMC program since 2016. Beyond that, as part of the investigation:

• We had several conversations with Malaria Consortium about this opportunity, including a formal presentation about its interpretation of the results from Karamoja and Nampula and its recommendation for continued deployment.
• A Senior Researcher who wasn’t otherwise involved in the grant investigation reviewed the RCT results from Karamoja and Nampula and proposed updated parameter values for effectiveness and drug resistance downside. We shared these with Malaria Consortium for feedback; they didn't offer detailed feedback but said they seemed reasonable at a high level.
• We spoke with stakeholders from BMGF, the Global Fund, MMV, PMI, CHAI, and the Mozambique and Uganda national malaria programs.
• We discussed SMC delivery outside of the Sahel at an internal research workshop. Feedback from that workshop led us to decide to seek more clarity on open questions before recommending a large grant, while conversations with key stakeholders led us to believe that answers to those questions will become clearer as more time passes. As such, we decided to recommend a one-year grant.

Sources

Document	Source
Bhatt et al. 2015	Source (archive)
GiveWell, Analysis of subnational mortality rates for SMC	Source
GiveWell, CEA of SMC outside the Sahel	Source
GiveWell, Global Fund Malaria Funding 2024-2026	Source
GiveWell, Non-Sahel Effect Size Recommendation, analysis	Source
GiveWell, Non-Sahel Effect Size Recommendation, discussion	Source
GiveWell, Seasonal Malaria Chemoprevention	Source
GiveWell's non-verbatim summary of a conversation with Professor Sir Brian Greenwood, January 4, 2017	Source
Jamison et al. 2006	Source
Malaria Consortium, 2022 SMC Coverage Report	Source
Malaria Consortium, 2022 SMC Philanthropy Report	Source
Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)	Unpublished
Malaria Consortium, SMC in East and Southern Africa	Source
Meremikwu et al. 2012	Source (archive)
Nuwa et al. 2023	Source (archive)
Roberts and Matthews 2016	Source (archive)
The Global Fund, "Global Fund Board Hails Record-Breaking Seventh Replenishment Final Outcome of US$15.7 Billion," 2022	Source
The Global Fund, "Seventh Replenishment: Fight for What Counts", 2022	Source (archive)
The Global Fund, Frequently Asked Questions	Source
The Global Fund, Mozambique 2023 Malaria Funding Request	Source
The Global Fund, Uganda 2023 Malaria Funding Request	Source
UNICEF, Mozambique Malaria Data Snapshot, 2020	Source
WHO, SMC field guide, 2013	Source
WHO, Updated WHO Recommendations for malaria chemoprevention, 2022	Source (archive)

• 1
  • 16% of all under-5 deaths in Mozambique were attributable to malaria as of 2018, per UNICEF, Mozambique Malaria Data Snapshot, 2020.
  • “Malaria is the leading cause of morbidity in Uganda with 90–95 % of the population at risk and it contributing to approximately 13% of under-five mortality.” Roberts and Matthews 2016.

• 2
  • “Malaria transmission in the Karamoja sub-region is highest between May and September, with more than 60% of the total annual malaria cases among children under five occurring during this period.” Nuwa et al. 2023, p. 2
  • “While transmission is perennial in the south [of Mozambique], there is a seasonal peak between December or January and March or April in many areas in the northern half of the country.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 41
  • “In 2020, the National Malaria Control Programme — Programa Nacional de Controlo da Malária (PNCM) — approached Malaria Consortium about the possibility of exploring the use of SMC in Nampula province (Figure 9), where under‐five mortality is high and malaria transmission is seasonal.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 42

• 3
  • “An insight brief summarising lessons learnt from the first phase of the project during the 2020/21 season, when SMC was implemented in two districts of Nampula, targeting 70,000 children, was published on Malaria Consortium’s website....The second phase of the project involved SMC delivery to 110,000 children during the 2021/22 season.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 42
  • “The SMC study in Mozambique was designed as a two‐phase hybrid effectiveness‐

  implementation study. The first phase focused on acceptability and feasibility, followed by
  more rigorous assessments of the effectiveness of the intervention and chemoprevention
  efficacy of SPAQ in phase 2…The study was conducted in collaboration with the PNCM and the Centro de Investigação em Saúde de Manhiça. It was co‐funded by the Bill & Melinda Gates Foundation.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 73

  • "A two‐phase hybrid implementation effectiveness study was conducted in the Karamoja subregion in 2021 and 2022, in collaboration with the NMCD and the Infectious Diseases Research Collaboration. Phase 1 of the study was conducted in two districts, with a third district serving as a control. Phase 2 involved research activities in five districts. The study closely mirrored the design of the Mozambique study described above. In addition to exploring the effectiveness of SMC using SPAQ and the chemoprevention efficacy of SPAQ, phase 2 in Uganda also explored the use of DP as an alternative drug regimen for SMC, including a safety study of the use of DP in children under six months. Phase 2 of the study was co‐funded by a grant from the Bill & Melinda Gates Foundation.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 75

• 4
  • “In 2012, the World Health Organization (WHO) recommend the scale-up of SMC in areas where malaria transmission is highly seasonal and the therapeutic efficacy of SP and AQ is above 90%. Consequently, the Sahel region was prioritized for SMC, as prevalence of resistance markers for SP is high in much of east and southern Africa.” Nuwa et al. 2023, p. 2

• 5

  Our full analysis of the preliminary results from the Mozambique and Uganda RCTs can be found here. Our discussion of this analysis is here.

• 6

  “In 2023, Malaria Consortium expects to implement SMC with philanthropic support in the same five districts as in 2022, but including children who lived in control or buffer communities and thus did not receive SMC in 2022. The philanthropic SMC target population will be approximately 190,000. We expect that the remaining four districts of Karamoja, with a combined target population of 100,000 children will be reached with support from the Global Fund.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 63

• 7

  See this section of our SMC intervention report for more details.

• 8

  At the time of writing, we estimate that 52-65% of malaria occurs in this period in Nampula, Mozambique and Karamoja, Uganda, compared to 70% in the Sahel. See this section of our SMC intervention report for more details.

• 9

  “In 2012, the World Health Organization (WHO) recommend the scale-up of SMC in areas where malaria transmission is highly seasonal and the therapeutic efficacy of SP and AQ is above 90%. Consequently, the Sahel region was prioritized for SMC, as prevalence of resistance markers for SP is high in much of east and southern Africa.” Nuwa et al. 2023, p. 2

• 10

  “Across the Sahel sub-region, most childhood mortality and morbidity from malaria occurs during the rainy season, which is generally short.” WHO, SMC field guide, 2013, p. 1

• 11

  "SMC was not recommended in areas where the therapeutic efficacy of SPAQ is below 90 percent due to parasite resistance, which is widespread across East and southern Africa. Consequently, the Sahel region of West and Central Africa was prioritised for the scale‐up of SMC." Malaria Consortium, 2022 SMC Philanthropy Report, p. 11

• 12

  Conversation with a researcher at Imperial College London, March 30, 2023 (unpublished)

• 13
  • Mozambique: "A mid‐term review of Mozambique’s Malaria Strategic Plan 2017–2022 recommended SMC as a strategy to accelerate impact in the highest‐burden locations. In 2020, the National Malaria Control Programme — Programa Nacional de Controlo da Malária (PNCM) — approached Malaria Consortium about the possibility of exploring the use of SMC in Nampula province (Figure 9), where under‐five mortality is high and malaria transmission is seasonal." Malaria Consortium, 2022 SMC Philanthropy Report, p. 42
  • Uganda: "In 2020, the National Malaria Control Division (NMCD) approached Malaria Consortium with a request to support an SMC implementation study in Karamoja to investigate the feasibility, acceptability and impact of SMC." Malaria Consortium, 2022 SMC Philanthropy Report, p. 58

• 14

  Unlike in the Sahel, the malaria transmission season in Nampula runs across calendar years.
  "...from the first phase of the project during the 2020/21 season, when SMC was implemented in two districts of Nampula, targeting 70,000 children, was published on Malaria Consortium’s website.[50] A key learning was that the benefits of employing more SMC implementers to strengthen community engagement need to be weighed up against budget implications. The second phase of the project involved SMC delivery to 110,000 children during the 2021/22 season." Malaria Consortium, 2022 SMC Philanthropy Report, p. 42

• 15
  • "Since 2020, Malaria Consortium and the PNCM [Mozambique’s NMCP] have been conducting a two‐phase implementation study to test if SMC can be a viable malaria prevention strategy in northern Mozambique despite high resistance to SP." Malaria Consortium, 2022 SMC Philanthropy Report, p. 42
  • “The study was conducted in collaboration with the PNCM and the Centro de Investigação em Saúde de Manhiça. It was co‐funded by the Bill & Melinda Gates Foundation.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 73

• 16

  "In 2021, the first year of SMC implementation in Uganda, philanthropic funding was used to deliver SMC to 90,000 children in two districts of Karamoja. In 2022, philanthropic funding supported SMC delivery in eight districts of Karamoja, with a total target population of 230,000 children." Malaria Consortium, 2022 SMC Philanthropy Report, p. 59

• 17

  "The study commenced in 2021 and employs a similar two‐phase design as the study Malaria Consortium is conducting in Mozambique." Malaria Consortium, 2022 SMC Philanthropy Report, p. 58

• 18

  "In 2023, Malaria Consortium expects to implement SMC with philanthropic support in the same five districts as in 2022, but including children who lived in control or buffer communities and thus did not receive SMC in 2022. The philanthropic SMC target population will be approximately 190,000. We expect that the remaining four districts of Karamoja, with a combined target population of 100,000 children will be reached with support from the Global Fund." Malaria Consortium, 2022 SMC Philanthropy Report, p. 63

• 19

  “We made this grant because we believe it will be cost-effective. Results from the RCT are not yet available, so we are more uncertain about this cost-effectiveness estimate than we typically are for SMC grants, though we have seen promising effectiveness results from a non-randomized trial conducted during the first year of the Nampula project.” GiveWell, Malaria Consortium – Seasonal Malaria Chemoprevention, Nampula, Mozambique, 2022.

• 20

  For further discussion of this SMC effectiveness parameter, see here.

• 21

  "[Chemoprevention efficacy] studies involve taking blood samples from children who have received a full course of SMC medicines under the supervision of a trained distributor at different time points during the 28‐day period during which SPAQ is assumed to confer protection from malaria. Typically, samples are taken on the day when the first doses of SP and AQ are administered (day 0) and then again on days 7, 14 and 28. The presence of malaria parasites in the blood is determined through microscopy and quantitative polymerase chain reaction. This method allows us to detect the presence of genetic markers commonly associated with parasite resistance to the SMC medicines. In addition, pharmacometric analyses are performed on samples taken on days 7 and 28 to determine drug concentrations, which allows us to understand how well the medicines are metabolised and eliminated over time. Taken together, the results enable us to assess not only if the medicines in the dosage provided are efficacious in clearing existing infections and preventing new ones, but also, where parasites survive and breakthrough infections occur, whether this is a result of parasite resistance or suboptimal dosing. This is an important distinction when considering the deployment of SMC, especially in areas where parasite resistance is high. Without measuring drug levels, breakthrough infections could be erroneously ascribed to parasite resistance and the deployment of SMC might not be recommended; when, in reality, the parasites survived due to suboptimal drug exposure, which could be addressed by increasing drug dosage." Malaria Consortium, 2022 SMC Philanthropy Report, p. 17

• 22

  Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)

• 23
  • “The proposed grading of malaria chemoprevention efficacy determining effectiveness has six levels ranging from fully effective (M1) to completely ineffective (M6). Asexual malaria parasites (pink), if present, should be cleared by the SMC dose and reinfections suppressed for at least 28 days. The proportion of subjects who test qPCR positive for P. falciparum at D28 provides the primary measure.” Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)
  • “Conclusions … According to proposed grading system this constitutes near failure in terms of efficacy – but the situation is complex and more work needs to be done.” Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)

• 24

  GiveWell will only fund five of the nine districts in Karamoja because SMC will be implemented with support from the Global Fund in the remaining four districts: “We expect that the remaining four districts of Karamoja, with a combined target population of 100,000 children will be reached with support from the Global Fund.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 63

• 25

  See this row in our SMC CEA. 3,595 deaths averted in Mozambique + 377 deaths averted in Uganda = ~4,000

• 26

  See this row in our cost-effectiveness analysis.

• 27

  See this section of our SMC intervention report for more details.

• 28

  To estimate the impact of SMC, we rely on a systematic review and Cochrane meta-analysis, Meremikwu et al. 2012. This paper summarizes seven randomized controlled trials (RCTs) of SMC (then known as IPTc, intermittent preventive treatment for malaria in children).

• 29

  “In 2012, the World Health Organization (WHO) recommend the scale-up of SMC in areas where malaria transmission is highly seasonal and the therapeutic efficacy of SP and AQ is above 90%. Consequently, the Sahel region was prioritized for SMC, as prevalence of resistance markers for SP is high in much of east and southern Africa.” Nuwa et al. 2023, p. 2

• 30
  • “The SMC study in Mozambique was designed as a two‐phase hybrid effectiveness‐

  implementation study. The first phase focused on acceptability and feasibility, followed by
  more rigorous assessments of the effectiveness of the intervention and chemoprevention
  efficacy of SPAQ in phase 2…The study was conducted in collaboration with the PNCM and the Centro de Investigação em Saúde de Manhiça. It was co‐funded by the Bill & Melinda Gates Foundation.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 73

  • "A two‐phase hybrid implementation effectiveness study was conducted in the Karamoja subregion in 2021 and 2022, in collaboration with the NMCD and the Infectious Diseases Research Collaboration. Phase 1 of the study was conducted in two districts, with a third district serving as a control. Phase 2 involved research activities in five districts. The study closely mirrored the design of the Mozambique study described above. In addition to exploring the effectiveness of SMC using SPAQ and the chemoprevention efficacy of SPAQ, phase 2 in Uganda also explored the use of DP as an alternative drug regimen for SMC, including a safety study of the use of DP in children under six months. Phase 2 of the study was co‐funded by a grant from the Bill & Melinda Gates Foundation.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 75

• 31

  See our full analysis of the preliminary results from the Mozambique and Uganda RCTs here. Our discussion of this analysis is here.

• 32

  “SMC is conducted during the high transmission period. The start and end dates depend on the pattern of malaria transmission, which generally correlates with rainfall.” WHO, SMC field guide, 2013, p. 19

• 33

  See this section of our SMC intervention report for more details.

• 34

  Of the countries we support in the Sahel, we estimate that Chad has the highest cost per SMC cycle administered. We use this value for newer geographies—for which we lack country-specific cost per cycle estimates—based on the expectation that early years of a program will be more expensive.
  Ahead of making this grant, we roughly modeled an increase to our cost per SMC cycle administered estimates of ~14-15% in Burkina Faso, Nigeria, and Chad. This update is based on:

  • The inclusion of two new downward adjustments into our calculations: an adjustment for self-report bias in SMC coverage figures and an adjustment for overestimated target population figures.
  • Data from Malaria Consortium on costs and coverage from the 2022 SMC season. Not including the two downward adjustments described above, incorporating new data on costs and coverage led to a lower estimated cost per SMC cycle administered in these three countries.

  This analysis is not yet finalized and remains unpublished, though our checks suggest that grants to support Mozambique and Uganda remain above our funding threshold of 8x even after incorporating the increased cost per child reached.

• 35
  • "The Global Fund’s Seventh Replenishment is the world’s opportunity to rise to the challenge and take bold action to protect everyone, everywhere from the deadliest infectious diseases. Our target is to raise at least US$18 billion. This is the minimum required to get the world back on track toward ending HIV, TB [tuberculosis] and malaria, to build resilient and sustainable systems for health and strengthen pandemic preparedness, making the world more equitable and safer from future threats." The Global Fund, "Seventh Replenishment: Fight for What Counts", April 2022.
  • “The Board of the Global Fund to Fight AIDS, Tuberculosis and Malaria welcomed the Seventh Replenishment outcome of US$15.7 billion during a 3-day meeting this week in Geneva.” The Global Fund, "Global Fund Board Hails Record-Breaking Seventh Replenishment Final Outcome of US$15.7 Billion," November 2022

• 36
  • Of the $15.7 billion replenishment, $13.128 billion has been allocated to countries as country grants for HIV, tuberculosis, and malaria. This reflects a 3.3% increase compared to the previous replenishment ($12.71 billion).
  • “Accordingly, the Board approves that the amount of sources of funds for country allocations for the 2023-2025 allocation period is US$ 12.503 billion, to which US$ 0.625 billion will be added prior to determining the country allocation, for a total of US$ 13.128 billion, to be used in accordance with the Allocation Methodology and decision point GF/B47/DP05.” Global Fund, 2023 – 2025 Allocation Period: Sources and Uses of Funds, 48th Board Meeting, 15-17 November, 2022, p. 2.
  • “For the 2020-2022 allocation period, the Global Fund’s Board approved a total of US$12.71 billion for country allocations and US$890 million for catalytic investments.” Global Fund, Description of the 2020-2022 Allocation Methodology, December 2019, p. 1.
  • $4.0 billion was allocated to countries for malaria interventions compared to $3.2 billion in the previous replenishment. See GiveWell’s summary here.

• 37

  Conversation with PMI, Jan 24, 2024 (unpublished)

• 38

  “Countries are encouraged to include with their funding application a Prioritized Above Allocation Request (PAAR) with priority interventions that are part of the country’s strategic plan, which cannot be funded. … This ensures availability of a pre-approved list of interventions for countries to integrate into grants when savings or efficiencies are found during grant-making, or if additional funding becomes available.” The Global Fund, Frequently Asked Questions, p. 1

• 39

  Conversations with the Mozambique NMCP and the Global Fund (unpublished)

• 40

  Conversations with the Mozambique NMCP and the Global Fund (unpublished)

• 41

  Malaria Consortium has used GiveWell-directed funding to support SMC programs in Burkina Faso and Nigeria since 2017 (and has previously supported SMC programs in both countries with non-GiveWell-directed funding). Malaria Consortium has a more limited track record in Togo, where it began supporting SMC in 2020 to a reduced extent, with greater levels of support beginning in 2021. See this spreadsheet for a more detailed breakdown of the regions supported and children targeted by Malaria Consortium SMC programs from 2017-2021.

• 42

  For a full overview of Malaria Consortium’s monitoring and evaluation methodology, see this section of our Malaria Consortium charity report. For our most up-to-date average coverage estimate across all cycles (from 2017 to present), see here.

• 43

  See here.

• 44

  Malaria Consortium's high-level position in light of these results, discussed in these slides, is that "the high effectiveness measures found in the trials justify continued SMC deployment in those locations" but note that this position may change as new evidence becomes available. They do not yet recommend significant expansion of SMC beyond its current areas of deployment outside of the Sahel.

• 45

  “No more geographic restrictions. The original recommendation restricted SMC use to the Sahel subregion of Africa … The updated recommendation recognizes that countries in other parts of Africa with highly seasonal variation in malaria burden could also benefit from SMC.” WHO, Updated WHO Recommendations for malaria chemoprevention, 2022.

• 46

  See The Global Fund, Mozambique 2023 Malaria Funding Request, p. 17 and The Global Fund, Uganda 2023 Malaria Funding Request, p. 35.

• 47

  Ahead of its Global Fund application, the NMCP engaged in a malaria intervention prioritization exercise in conjunction with CHAI and Swiss TPH in which it categorized regions into seasonal and non-seasonal transmission areas. The NMCP’s stated goal is to deliver SMC in all areas it identifies as seasonal transmission areas and PMC elsewhere. Conversations with staff at CHAI and the Mozambique NMCP (unpublished)

• 48

  See our summary of this data for Mozambique here and for Uganda here.

• 49

  This understanding is based on multiple conversations with IHME researchers. Detailed modeling assumptions for the GBD estimates are available in the GBD 2019 methods appendix.

• 50

  "Despite its importance, current knowledge on the nature and drivers of changing endemicity in sub-Saharan Africa is remarkably weak. National health records in 32 highly endemic countries (together accounting for about 90% of the global malaria burden) are considered inadequate to assess trends in malaria cases. This stems from low care-seeking rates (many malaria cases are not seen at formal health facilities), incomplete record keeping and curation (many recorded cases are never captured in surveillance databases), and historically poor access to parasitological diagnosis (malaria cases were often diagnosed presumptively with poor specificity).” Bhatt et al. 2015, p. 2.

• 51
  • "During randomized controlled intervention trials aimed at reducing the incidence of infection (but not 100 percent protective), the all-cause mortality of children is often reduced more than would be attributed by VA [verbal autopsy] diagnosis of malaria. For example, in Kilifi the proportion of deaths of children under five years attributed to malaria by VA was 34 percent (R. W. Snow, unpublished data). During a randomized controlled trial of insecticide-treated bednets in the same area, the incidence of malaria infection was reduced by 50 percent (Snow et al. 1996), which was sufficient to reduce all-cause mortality by 33 percent (Nevill et al. 1996). More dramatically, in The Gambia, insecticide-treated bednets reduced all-cause mortality by over 60 percent, and yet the VA-diagnosed contribution of malaria to all-cause mortality among control populations was only 16 percent (Alonso et al. 1993). This has led some to speculate that malaria infection is a contributor to broad causes of mortality beyond the direct fatal consequences of infection (Molineaux 1997)." Jamison et al. 2006, p. 204.
  • "Data on all-cause mortality of children under five from DSS studies undertaken across a broad range of malaria transmission settings in Sub-Saharan Africa were analyzed against the prevalence of P. falciparum infection at each site. Weighted least-squares regression was used to model the contiguous relationships between all-cause mortality and parasite prevalence rates, allowing for the square of parasite prevalence (for possible saturation of parasite prevalence), timing, location, and the sampling precision of each study (Snow, Korenromp, and Gouws 2004). The unadjusted median all-cause child mortality rate for low prevalence areas of childhood infection (less than 25 percent) was 10.9 per year per 1,000 children under five (IQR 7.8–17.6). This rose dramatically to 39.1 per year per 1,000 children (IQR 32.8–52.2) among populations exposed to childhood parasite prevalence risks greater than or equal to 25 percent. In the regression model, mortality increased significantly with parasite prevalence, but this effect leveled off at higher prevalence rates. The model suggested that, in rural DSS sites throughout Sub-Saharan Africa, all-cause mortality increases by more than twofold (25–30 deaths per 1,000 children under five years old) over the prevalences of malaria infection covered by the DSS sites, and parasite prevalence explained 64 percent of the variation between sites in all-cause under-five mortality. By contrast, the direct estimation of malaria-specific mortality presented earlier for children living under stable endemic conditions was only 28.2 percent." Jamison et al. 2006, p. 206.

• 52

  “Indirect consequences of P. falciparum infection include anemia (unless anemia is linked to acute high-density parasitemia as a direct cause), low birthweight, growth retardation, or undernutrition. In addition, malaria infection can increase the severity of other comorbid infectious diseases through immune suppression or enhanced invasive capacities across physical barriers to infection (for example, blood and tissue). Previous approaches to the global burden of disease have assumed that each death must be attributed to a single cause and can be fitted into the fixed disease-mix matrix of all causes (Murray and Lopez 1997).” Jamison et al. 2006, p. 204

• 53

  See this cell note for more information.

• 54

  Consistent with this assumption, a World Health Organization report claims that SMC offers a high level of protection for about four weeks after the last treatment, after which protection appears to decline: “The results of clinical trials indicate that a high level of protection against uncomplicated clinical malaria is likely to be maintained for only 4 weeks after administration of each treatment course of SP+ AQ; thereafter, protection appears to decay rapidly.” WHO, SMC field guide, 2013, p. 4. We have not independently vetted this claim.

• 55

  Conversations with researchers at Imperial College London (unpublished)

• 56

  See this cell note in our CEA for more information about how we estimate this for Mozambique.

• 57

  See this cell note in our CEA for more information about how we estimate this for Uganda.

• 58

  Conversation with Malaria Consortium, April 2022 (unpublished)

• 59

  See our full analysis of the preliminary results from the Mozambique and Uganda RCTs here. Our discussion of this analysis is here.

• 60

  See here for a more detailed discussion of these results.

• 61

  See here for a more detailed discussion of these results.

• 62

  See our full analysis of the preliminary results from the Mozambique and Uganda RCTs here. Our discussion of this analysis is here.

• 63

  “The resistance markers surveys that were carried out [in Uganda] before and after the phase 1 SMC round involved analysis of 300 blood samples, taken as dry blood spots, from symptomatic children 3–59 months who had a positive malaria test in the two study districts and the control district. Five mutations of concern associated with SP resistance (PfDHPS437G, 540E and DHFR 51I, 59R 108N) were prevalent, but remained unchanged between baseline and endline. DHFR 164L and DHPS 581G mutations, which mediate high‐level SP resistance, were rare at both baseline and endline. Mutations associated with AQ resistance (PfCRTand PfMDR1 including copy number) were also rare. The results, presented at the Conference on Public Health in Africa, which was held in Kigali in December 2022,[117] indicate that one round of SMC with SPAQ did not appear to select for an observable change in resistance markers for SP and AQ.” Malaria Consortium, 2022 SMC Philanthropy Report, p. 77

• 64

  “SP has been used alone for intermittent preventive treatment in pregnancy (IPTp) for roughly 20 years. This is likely to have contributed to resistance to SP developing in Tanzania and East Africa, and SP is no longer very effective in those places for IPTp. However, it is still effective in much of the rest of Africa. A mutation associated with a particularly high level of SP resistance that appeared in Southeast Asia (the DHFR 164 mutation) also appeared in Uganda but has not spread in Africa.” GiveWell's non-verbatim summary of a conversation with Professor Sir Brian Greenwood, January 4, 2017.

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  Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)

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  Malaria Consortium, SMC in East and Southern Africa, slides 3-10

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  “There is no evidence of substantial changes in the resistance profiles as a result of SMC implementation." Malaria Consortium, SMC in East and Southern Africa, slide 2

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  Malaria Consortium, Comments on a draft of this page, November 2024.

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  "[Chemoprevention efficacy] studies involve taking blood samples from children who have received a full course of SMC medicines under the supervision of a trained distributor at different time points during the 28‐day period during which SPAQ is assumed to confer protection from malaria. Typically, samples are taken on the day when the first doses of SP and AQ are administered (day 0) and then again on days 7, 14 and 28. The presence of malaria parasites in the blood is determined through microscopy and quantitative polymerase chain reaction. This method allows us to detect the presence of genetic markers commonly associated with parasite resistance to the SMC medicines. In addition, pharmacometric analyses are performed on samples taken on days 7 and 28 to determine drug concentrations, which allows us to understand how well the medicines are metabolised and eliminated over time. Taken together, the results enable us to assess not only if the medicines in the dosage provided are efficacious in clearing existing infections and preventing new ones, but also, where parasites survive and breakthrough infections occur, whether this is a result of parasite resistance or suboptimal dosing. This is an important distinction when considering the deployment of SMC, especially in areas where parasite resistance is high. Without measuring drug levels, breakthrough infections could be erroneously ascribed to parasite resistance and the deployment of SMC might not be recommended; when, in reality, the parasites survived due to suboptimal drug exposure, which could be addressed by increasing drug dosage." Malaria Consortium, 2022 SMC Philanthropy Report, p. 17.

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  • “The proposed grading of malaria chemoprevention efficacy determining effectiveness has six levels ranging from fully effective (M1) to completely ineffective (M6). Asexual malaria parasites (pink), if present, should be cleared by the SMC dose and reinfections suppressed for at least 28 days. The proportion of subjects who test qPCR positive for P. falciparum at D28 provides the primary measure.” Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)
  • “Conclusions … According to proposed grading system this constitutes near failure in terms of efficacy – but the situation is complex and more work needs to be done.” Malaria Consortium, Resistance and Chemoprevention Efficacy Results (unpublished)

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  "We do not yet have a detailed understanding of the relationship between effectiveness, resistance and chemoprevention efficacy, or how this relationship is affected by seasonality, immunity or transmission intensity." Malaria Consortium, SMC in East and Southern Africa, slide 3

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  “Any SMC deployment must be accompanied by a strong surveillance system to monitor resistance, drug efficacy, transmission intensity and impact on other malaria interventions.” Malaria Consortium, SMC in East and Southern Africa, slide 6

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  “The high effectiveness measures found in the trials justify continued SMC deployment in those locations and locations where the epidemiological profile is comparable. … We do not advocate for a blanket approach to scaling up SMC in the region and cannot at this point support the deployment of SMC in areas with substantially different epidemiological profiles compared to the study locations.” Malaria Consortium, SMC in East and Southern Africa, slides 6-7

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  SMC coverage refers to the proportion of targeted children who receive SMC. Malaria Consortium conducts surveys after campaigns to understand what proportion of children in the target population received SMC. See more about these surveys in our review of Malaria Consortium here.

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  • "EoC surveys were conducted after cycles 1 and 3 in Mozambique during 2022. It was not feasible to conduct EoC surveys following cycle 2 due to insufficient internal capacity resulting from the additional workload of Phase 2 implementation study activities during 2022." Malaria Consortium, 2022 SMC Coverage Report, p. 26
  • "[In Uganda] the reasons for missing EoC surveys or districts were mainly operational, due to the added workload of conducting Phase 2 SMC implementation research studies coinciding with routine SMC delivery." Malaria Consortium, 2022 SMC Coverage Report, p. 29

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  Ahead of making this grant, we roughly modeled an increase to our cost per SMC cycle administered estimates of ~14-15% in Burkina Faso, Nigeria, and Chad. This update is based on:

  • The inclusion of two new downward adjustments into our calculations: an adjustment for self-report bias in SMC coverage figures and an adjustment for overestimated target population figures.
  • Data from Malaria Consortium on costs and coverage from the 2022 SMC season. Not including the two downward adjustments described above, incorporating new data on costs and coverage led to a lower estimated cost per SMC cycle administered in these three countries.

  This analysis is not yet finalized and remains unpublished, though our checks suggest that grants to support Mozambique and Uganda remain above our funding threshold of 8x even after incorporating the increased cost per child reached.

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  Note that $1.81 is our preliminary cost per child reached estimate after making a few adjustments that have yet to be finalized. See above for details.