PATH — Study of Perennial Malaria Chemoprevention/RTS,S Malaria Vaccine (February 2023)

Note: This page summarizes the rationale behind a GiveWell grant to PATH. PATH staff reviewed this page prior to publication.

Published: October 2023

Implementers

This study will be conducted through PMI Insights, a multidisciplinary malaria partnership which brings together national malaria programs, research institutions, program partners, and donors to prioritize, design, and implement operational research and program evaluation based on malaria-endemic country-driven research priorities.1

PATH, a member of PMI Insights, is a global non-profit launched in 1977 which works in a number of health areas, including malaria, with the goal of promoting health equity.2 In September 2021, GiveWell recommended a $120,000 grant to PATH to scope opportunities for implementing intermittent preventive treatment in infants (IPTi) for malaria, and in January 2022, GiveWell recommended a grant of approximately $5 million to PATH to support ministries of health in Ghana, Kenya, and Malawi in the implementation of the RTS,S malaria vaccine through the end of 2023.

PATH will subcontract to a team of researchers from Kintampo Health Research Centre (Ghana Health Service) and London School of Hygiene and Tropical Medicine (LSHTM) to design and implement the trial.3

The interventions

This trial will measure the relative effect of the RTS,S malaria vaccine administered with chemoprevention compared to the effect of malaria vaccines alone in infants and young children (3 to 24 months of age) in a perennial transmission setting in Ghana.4

Perennial malaria chemoprevention (PMC), previously known as IPTi, is the provision of preventive antimalarial medicine to infants, primarily through routine vaccination visits.5

The RTS,S/AS01 (RTS,S) malaria vaccine protects children against P. falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa. In October 2021, the World Health Organization (WHO) issued a recommendation for the widespread use of the RTS,S vaccine among children in sub-Saharan Africa and in other regions with moderate to high P. falciparum malaria transmission.6 Since 2019, RTS,S has been implemented through routine childhood immunization systems in selected areas of Ghana, Kenya, and Malawi through the Malaria Vaccine Implementation Programme (MVIP).7

Do PMC and RTS,S work?

PMC

Overall, we believe there is strong evidence that PMC reduces clinical malaria, which gives us a moderate level of confidence that it reduces deaths due to malaria. There is evidence from 9 trials included in Esu, Oringanje, and Meremikwu 2019, a Cochrane meta-analysis, that PMC/IPTi reduces cases of clinical malaria by 24%. We have a moderate level of confidence in this estimate; we have not thoroughly vetted the meta-analysis or reviewed component studies.8 The trials in the meta-analysis were not powered to detect an effect on mortality, which is the benefit we model in our cost-effectiveness analysis, but we think it’s likely that reductions in malaria translate to reductions in mortality. We’re also uncertain about the extent to which findings from trials will generalize to future implementation and how much to discount effects based on concerns about resistance to antimalarial medicines. According to PMI, in addition to the published studies we reviewed, there are a large number of ongoing pilot studies of PMC as well as countries that are implementing or planning to implement PMC.9

For more information, see our intervention report on PMC (then called IPTi).

RTS,S

Evidence from a phase-3 clinical trial and a pilot evaluation indicates that RTS,S reduces the rate of clinical malaria and severe malaria in young children. We think that there is strong evidence that children who receive a four-dose schedule are less likely to experience clinical or severe malaria. There is some evidence indicative of “rebound” in severe malaria for children receiving three doses, but we are uncertain as to the magnitude.10 In addition, RTS,S could plausibly avert deaths even given some rebound in risk of severe malaria because it provides higher protection to younger, potentially more vulnerable, children. Results from the ongoing Malaria Vaccine Pilot Evaluation will provide more information about the effects of three or four doses of RTS,S on mortality.

For more information, see our intervention report on malaria vaccination.

PMC and RTS,S together

The administration of chemoprevention along with malaria vaccines may improve protection against malaria.11 There is evidence demonstrating synergistic improvement in seasonal settings,12 but not from perennial settings where a substantial number of malaria vaccine-eligible children live.13 This study would fill that gap by providing evidence about the efficacy of RTS,S with perennial chemoprevention vs. with a placebo. The study has the potential to impact policy in any setting with perennial malaria transmission and where malaria vaccines are the standard of care.14

The grant

GiveWell is recommending a grant from Open Philanthropy of $1,591,687 to PATH, as the lead grantee for the multi-organizational partnership PMI Insights. PATH will subcontract to a team of researchers from Kintampo Health Research Centre (Ghana Health Service) and LSHTM to conduct an individually randomized placebo-controlled efficacy trial measuring the effects of malaria vaccines and chemoprevention compared to the effects of malaria vaccines alone in perennial transmission settings in Ghana.15 Along with GiveWell, this study will be financed by PMI and another funder.

• PMI’s contribution will fund part of the data collection for the first primary study outcome: efficacy at approximately 18 months of age.16
• GiveWell’s contribution will fill a gap in the first primary outcome and add a second primary outcome: efficacy at 24 months of age with an additional dose of chemoprevention administered at 21 months. It will also fund social science studies on healthcare worker and caregiver acceptability which are expected to inform implementation.17
• Another funder will fund the addition of a third study arm which will use an alternative chemopreventive treatment regimen and immunological analyses.18

At the time of recommending this grant, we expected the trial to include two study arms measuring the effects of RTS,S and SP+AQ compared to RTS,S alone. Shortly after recommending the grant, we learned that the trial would include three study arms to compare the effects of RTS,S and SP+AQ, RTS,S and SP, and RTS,S alone.19 We see this as a positive update to the study design, since it may allow results from the study to be more easily generalized to settings with concerns about SP resistance.

The study is anticipated to start in July 2023 and conclude by March 2026.

Budget for grant activities

GiveWell’s contribution will be added to the contributions of PMI and another funder to cover the full budget for the study. Costs for the full study break down as shown in the table below.20

GiveWell-recommended funding for the grant will be released to PATH by Open Philanthropy in 2024. We recommended this grant well in advance of the disbursement date because PMI needed to secure a funding commitment to cover the full first primary outcome before the research team could move forward with protocol design in order to begin implementation on schedule.

The case for the grant

The primary reasons we are recommending this grant include:

• The results of this study will provide evidence that may allow governments to adopt more effective malaria prevention intervention mixes. More below.
• The study is likely to be well-designed and well-conducted. More below.
• It seems likely that without GiveWell funding, the study wouldn't happen at all or would be delayed. More below.
• It's plausible that the whole of this study could far exceed our bar in cost effectiveness, if the results show that coadministration of vaccines and chemoprevention improves outcomes and if enough children end up being treated through coadministration as a result of this study. More below.

Possibility of adoption of more effective treatment

The results of this study will provide evidence that may inform governments’ decision-making to adopt more effective treatment bundles. If the study demonstrates that RTS,S and chemoprevention are more effective than RTS,S alone, governments in countries with perennial malaria transmission where malaria vaccination alone is the current standard of care may use this data to update their national malaria prevention policies to include both malaria vaccination and chemoprevention as the new standard of care.21 We think that this switch could be highly cost-effective because the drugs used in chemoprevention are relatively cheap and would be leveraged (obtained using government or Global Fund funding) and because the same system (the Expanded Programme on Immunization) could administer both chemoprevention and malaria vaccines.22

While we think it’s likely that governments would be eager to update their policies if malaria vaccination plus chemoprevention was shown to be effective, we have some uncertainties related to how likely it is that this study will be a major contributing factor to governments’ making that shift. See more in our section on reservations.

Expectation of a high quality study

At the time we recommended this grant, the study protocol had not yet been finalized, so there was some chance that the finalized protocol would not be high-quality (see more in our reservations). However, we believed the study would likely be well-designed and well-conducted because:

• The research team has relevant experience, including having successfully conducted a very similar trial of RTS,S with seasonal malaria chemoprevention (Greenwood et al. 2021).23
• The study development process seems likely to draw upon relevant experts. The importance of this research topic seems to be recognized across the malaria community. Technical experts who guided the development of a malaria research learning agenda led by PMI Insights ranked the topic of co-administering vaccines and chemoprevention as the second most important priority across operational research in malaria.24 This leads us to believe that the Kintampo and LSHTM research team will be able to get engagement from relevant experts outside of the core research team. Based on our conversations with the researchers and PMI, the design process seems to draw upon the relevant experts.25 Finally, PMI’s team is conducting technical due diligence of the study protocol.

Genuine funding gap

Based on our conversations with PMI and others in the malaria community, it seems likely that without GiveWell funding, this study wouldn't happen at all or would be delayed. The possibility of this study was mentioned to us on multiple occasions in 2022,26 but it has not been conducted yet, giving us more confidence that this is a genuine funding gap despite it being an identified research priority.27

Additionally, staff at PMI Insights told us they needed to secure additional funding in order for the research team to move forward with protocol design and begin implementation on schedule (by May 2023).28

Cost-effectiveness

From GiveWell’s perspective, this study’s main expected impact is through providing evidence that may inform governments’ decisions to adopt coadministration of malaria vaccines and chemoprevention in perennial settings. Assuming that enough children end up being treated through coadministration as a result of this study, it’s plausible that the whole of the study could far exceed our cost-effectiveness threshold for directing funding.

Intuitively, we think that a shift from malaria vaccination alone to coadministration of malaria vaccines and PMC as a standard of care could be very cost-effective because chemoprevention is relatively inexpensive and the costs of its administration through the existing Expanded Programme for Immunization (EPI) platform will be leveraged.29 As a check on this intuition, we prepared a highly speculative BOTEC,30 which suggests that in order for this grant to meet our funding threshold, the study would need to cause implementation of chemoprevention alongside malaria vaccines to occur about 9 months earlier than it would have in the absence of the study. This seems plausible to us.

Risks and reservations

Our primary reservations about this grant are:

• The study protocol has not yet been finalized, so we cannot verify that the finalized design is high quality. Our recommendation rests on the belief that the proposed process will result in a high quality study, which could be wrong. More below.
• The study results may end up being less relevant to governments’ decision making than we expect. More below.
• This study will only employ the RTS,S malaria vaccine, not R21, which may become widely used in the near term. More below.
• We are unsure about the marginal value of the social science acceptability studies, which are about $250,000 of the study's budget. We are relying on the research team’s assertions that these acceptability studies will support government implementation. More below.

Study protocol not yet finalized

Because the study protocol isn’t yet finalized, our recommendation of this grant rests on the belief that the research team’s process for developing the study will result in a high quality study. We have not verified that the finalized design is high quality. We do not see this as a large risk, given what we know about PMI and the research team (see above), but it is possible that the finalized protocol will be less high-quality than we expect.

Uncertain relevance of results to government decision making

It seems likely to us that governments will be eager to implement coadministration of malaria vaccines and chemoprevention if it is shown to be effective, given that both can be administered by routine EPI systems and we’ve seen evidence of governments’ interests in both interventions. However, it’s possible that the study results may end up being less relevant to governments’ decision making than we expect. For example, governments may move ahead with implementing coadministration as the standard of care before study results are available or they may decide not to implement coadministration if there were supply constraints with RTS,S or if a sudden increase in SP resistance limited appetite for chemoprevention.

The trial's results will only be relevant to countries that will have vaccines and not chemoprevention as the standard of care by the time the study’s initial results are available in 2025. We are uncertain how many countries may fit this category.31

Exclusion of R21

This study will only employ the RTS,S malaria vaccine, not the R21 malaria vaccine (which may become widely used in the future).33 As noted above, we’re not certain whether the study’s findings will be interpreted as applying to the R21 vaccine. It’s possible that we should push to add an arm to the study to examine the effectiveness of coadministration of R21 and PMC to address the possibility that findings from RTS,S would not be interpreted as applicable to R21. We’re not doing this because:

• We think it could significantly slow down implementation of the study given increased coordination efforts and added expense.
• We believe there is some chance that the results of the study will be interpreted as applicable to R21, though we are unsure how large that chance is.
• We expect the grant could be cost-effective even if it only affected policy for children expected to be treated by RTS,S.34

Our partners on this grant note that they think results will likely be generalizable to R21.35

Uncertain value of acceptability studies

It’s possible that we shouldn’t fund the acceptability studies because we are uncertain about whether they will be useful to governments’ decision making. The research team told us that the government of Ghana is working with them on designing these and will use their results to guide scale up.36 We attempted to triangulate this claim by speaking with a stakeholder from Ghana, but weren’t able to have this conversation due to the time constraints.

Plans for follow up

Our plans for follow-up on this grant are relatively light-touch given the other stakeholders involved. Prior to the beginning of the trial we plan to request the finalized protocol and to ensure that commitments related to research transparency meet our and Open Philanthropy’s high standards. We will request to receive the same updates that PMI requests over the course of the trial, as to not increase administrative burden. After the trial we will consider the following questions as indication of whether the grant was successful:

• Was the trial begun and completed as indicated by the research team’s timelines?
• Were trial results disseminated?
• Did other trials or data collection speak to the same questions as the trial (which could imply that we overestimate the impact of this grant)?

This grant is not eligible for renewal.

Internal forecasts

For this grant, we are recording the following forecasts:

Our process

• We had multiple conversations with PMI and the study researchers about this trial.
• We reviewed a draft protocol and concept note for the trial.
• We created a BOTEC and updated it based on the researchers’ responses to our questions.
• The BOTEC and case for the grant were reviewed internally by multiple GiveWell staff members.

Sources

• 1Bridget Higginbotham, USAID, comments on a draft of this page, June 9, 2023 (unpublished).
• 2
  • “At PATH, we are a global team of innovators working to accelerate health equity so all people and communities can thrive. We advise and partner with public institutions, businesses, grassroots groups, and investors to solve the world’s most pressing health challenges.” PATH, "About"
  • “Launched in 1977 by three intrepid researchers, PATH was a new kind of health organization: a nonprofit that would deliver the expertise, resources, and innovations of private industry to improve health for all.” PATH, "About"
  • PATH, "Health Areas"

• 3"Mechanism and partners (clearly indicate prime partner and local partners if applicable,
  including NMCP): PMI Insights partnering with the London School of Hygiene & Tropical Medicine, Kintampo Health Research Centre, National Malaria Elimination Program of Ghana, and the Ghana EPI Program." PMI, Operational Research Concept Note, February 21, 2023 (unpublished).
• 4"The primary trial objective is to determine whether the combination of RTS,S/AS01E with PMC-
  SP or with PMC-SPAQ is more effective at reducing the incidence of clinical malaria in children up to 24 months of age than the RTS,S/AS01E vaccine, the new standard of care, given alone." PMI, Operational Research Concept Note, February 21, 2023 (unpublished).
• 5“Perennial malaria chemoprevention (PMC) is the administration of a full treatment course of an antimalarial medicine at predefined intervals, regardless of whether the child is infected with malaria, in order to prevent illness in moderate to high perennial malaria transmission settings. … The Expanded Programme on Immunization (EPI) platform remains important for delivering PMC. Other methods of delivery can be explored to optimize access to PMC and integration with other health interventions.” World Health Organization, “WHO Guidelines for malaria - 14 March 2023”
• 6
  • “The World Health Organization (WHO) is recommending widespread use of the RTS,S/AS01 (RTS,S) malaria vaccine among children in sub-Saharan Africa and in other regions with moderate to high P. falciparum malaria transmission.” WHO, "WHO recommends groundbreaking malaria vaccine for children at risk," 2021
  • “WHO recommends that in the context of comprehensive malaria control the RTS,S/AS01 malaria vaccine be used for the prevention of P. falciparum malaria in children living in regions with moderate to high transmission as defined by WHO. RTS,S/AS01 malaria vaccine should be provided in a schedule of 4 doses in children from 5 months of age for the reduction of malaria disease and burden.” WHO, "WHO recommends groundbreaking malaria vaccine for children at risk," 2021
  • “The malaria vaccine, RTS,S, acts against P. falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa.” WHO, "WHO recommends groundbreaking malaria vaccine for children at risk," 2021

• 7
  • “The MVIP is coordinated by WHO in close collaboration with ministries of health (MoH) in the three participating countries – Ghana, Kenya, Malawi – and a range of in-country and international partners. The MoH of the pilot countries have introduced the RTS,S/AS01 vaccine through their childhood immunization services using routine vaccine introduction strategies and methods.” World Health Organization, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, p. 7.
  • See vaccine coverage estimates for different time periods in World Health Organization, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, p. 47, Table 1: Vaccine coverage estimates for different time periods according to routine administrative data.

• 8Our partners note that the CDC has carefully reviewed this data. Julie Gutman, CDC, Comments on a draft of this page, June 2023 (unpublished).
• 9Rose Zulliger, PMI, comments on a draft of this page, June 8, 2023 (unpublished).
• 10“In addition, among 5–17-month-old-children who only received three doses of RTS,S, the initial reduction in severe malaria was counterbalanced by an increase in severe malaria around 18 months after the initial vaccine course, presumably due to waning immunity. This age shift effect has been noted among recipients of other malaria-control interventions when the intervention is withdrawn. Presumably when the intervention group is then compared to a contemporaneously followed control group in the same population who did not receive the intervention and who develop immunity through repeated episodes of natural infection, the intervention group is at comparatively higher risk of malaria and severe disease for a limited period.
  This age shift in severe malaria was most marked in higher transmission settings, possibly because participants in the control group developed immunity through natural infection more rapidly. Importantly, an age shift in severe malaria was not observed up to the end of the follow-up period among children vaccinated at 5-17 months of age who received a fourth dose.”
  World Health Organization, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, p. 64.
• 11It is hypothesized that combining antimalarial drugs with administration of first generation malaria vaccines is more effective than vaccines alone because the vaccines target a particular phase of the life cycle of the parasites that cause malaria (sporozoites), whereas the drugs are effective against later blood stages of the parasite’s life cycle.
  • “Three of the most advanced Plasmodium falciparum malaria vaccines (RTS,S/AS01E, PfSPZ and R21) are pre-erythrocytic vaccines, which induce an immune response directed at the sporozoite or liver stage of the parasite’s life-cycle. The humoral and cellular immune responses induced by these vaccines are highly effective at preventing in the short term the establishment or full development of liver schizonts, but the persistence and rupture of a single schizont are sufficient to establish a blood-stage infection that could result in a severe episode of malaria or even death. An approach that is currently being explored to overcome this challenge is combining a pre-erythrocytic stage vaccine with one that induces an immune response against blood stages of the parasite, thus aborting the infection. However, the development of an effective blood-stage vaccine has proved challenging because of polymorphism in the key blood-stage antigens, such as AMA1, that have been the initial targets for blood-stage vaccine development. A vaccine based on the conserved Rh5 antigen may overcome this problem, but this candidate vaccine is still only at an early stage of clinical development. In contrast to the immune response induced by the first generation of blood-stage vaccine candidates, antimalarial drugs to which the parasite is sensitive can rapidly kill any blood-stage parasites regardless of the parasite strain and provide protection for several weeks dependent upon the anti-malarial used.” Greenwood et al. 2021, p. 2.

• 12Chandramohan et al. 2021 found reductions of 40% for clinical malaria, 30% for severe malaria hospitalization and 25% reductions in death from seasonal malaria chemoprevention (SMC) + RTS,S vs. RTS,S alone:
  “The hazard ratio for the protective efficacy of RTS,S/AS01E as compared with chemoprevention was 0.92 (95% confidence interval [CI], 0.84 to 1.01), which excluded the prespecified noninferiority margin of 1.20. The protective efficacy of the combination as compared with chemoprevention alone was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against hospital admission with severe malaria according to the World Health Organization definition, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria. The protective efficacy of the combination as compared with the vaccine alone against these outcomes was 59.6% (95% CI, 54.7 to 64.0), 70.6% (95% CI, 42.3 to 85.0), and 75.3% (95% CI, 12.5 to 93.0), respectively.” Chandramohan et al. 2021, p. 1005.
• 13PMI shared a confidential spreadsheet with us containing ballpark estimates for the number of malaria vaccines-eligible children in a number of countries. Approximately 1.6 times as many of these children live in perennial malaria transmission settings than in seasonal transmission settings. We consider this estimate to be indicative rather than precise. PMI, Population and Vaccine Demand Estimates (unpublished).
• 14“Plan for how study outcomes will impact NMCP decision making or strategies: Approximately fifteen countries have applied or will apply for the RTS,S/AS01E vaccine and three countries have already expanded their initial deployment. Some of these countries, including Ghana, have not yet decided whether to include PMC in their national malaria control program. Thus, the results of this study will help Ghana, and other countries with similar epidemiology, to make an evidence-based policy decision as to whether PMC-SP or PMC-SPAQ should be introduced alongside the RTS,S/AS01E vaccine to reduce the burden of malaria in perennial transmission settings.” PMI, Operational Research Concept Note, February 21, 2023 (unpublished).
• 15"Mechanism and partners (clearly indicate prime partner and local partners if applicable, including NMCP): PMI Insights partnering with the London School of Hygiene & Tropical Medicine, Kintampo Health Research Centre, National Malaria Elimination Program of Ghana, and the Ghana EPI Program." PMI, Operational Research Concept Note, February 21, 2023 (unpublished).
• 16PMI, Operational Research Concept Note, February 21, 2023 (unpublished), Table 2: Funding institution contributions.
• 17PMI, Operational Research Concept Note, February 21, 2023 (unpublished)
• 18
  • PMI, Operational Research Concept Note, February 21, 2023 (unpublished), Table 2: Funding institution contributions.
  • Megan Littrell, PATH, email to GiveWell, February 22, 2023 (unpublished).
  • Rose Zulliger, PMI, comments on a draft of this page, June 8, 2023 (unpublished).

• 19
  • Megan Littrell, PATH, email to GiveWell, February 22, 2023 (unpublished).
  • "The trial will be an individually randomized, placebo-controlled, double-blind trial conducted in infants and young children (3 to 24 months of age). The trial will have three groups of children who will receive either (i) RTS,S/AS01E and PMC-placebo, (ii) RTS,S/ASO1E and PMC-SP, or (iii) RTS,S/ASO1E and PMC-SPAQ." PMI, Operational Research Concept Note, February 21, 2023 (unpublished)

• 20PMI, Operational Research Concept Note, February 21, 2023 (unpublished)
• 21Ghana is waiting for evidence on the effectiveness of the combined RTS,S–PMC regimen before implementing co-administration, so it is expected that the trial results will be useful for Ghana’s decision making and may be similarly useful to other governments as well. Malaria researchers from PMI, CDC, Kintampo Health Research Center, PATH, and LSHTM; conversation with GiveWell; January 13, 2023 (unpublished)
• 22
  • See “Reference price US$ Per Treatment” for Amodiaquine + Pyrimethamine/Sulfadoxine and Pyrimethamine/Sulfadoxine. Global Fund, Pooled Procurement Mechanism Reference Pricing: Antimalarial medicines, 2023
  • “PMC is generally considered cost-effective or highly cost-effective due to its use of the EPI delivery platform to deliver the inexpensive drug SP. The cost per dose delivered in nearly all studies was less than $0.25 for PMC with SP, but more expensive with alternative drugs.” World Health Organization, WHO Guidelines for Malaria, 2023, p. 100.
  • “The EPI platform remains important for delivering PMC, especially in the first year of life, and it may be possible to make use of the EPI or other routine health visits, or establish new contacts to reach children over 1 year of age.” World Health Organization, WHO Guidelines for Malaria, 2023, p. 98.
  • “Decision making on whether to adopt and implement the malaria vaccine should be in close collaboration between the NMP and the EPI and other relevant ministry of health departments. … The EPI leads the logistics of vaccine roll-out and delivery to relevant health facilities. The EPI manages the planning and activities required for vaccine introduction and programme implementation, such as vaccine and supplies procurement; advocacy; communications and social mobilization; training and supervision of health personnel; logistics and cold chain for vaccine storage; service delivery; and monitoring and evaluation.” World Health Organization, WHO Guidelines for Malaria, 2023, p. 143.
  • “The Global Fund will continue to support Intermittent Preventive Treatment for infants (IPTi) and its updated nomenclature with a broadened spectrum, PMC, to reach a larger number of children with this preventive intervention.” Global Fund, Information Note: Malaria, 2022, p. 16.

• 23
  • The LSHTM team published a widely mentioned RTS,S & SMC trial (Greenwood et al. 2021), which provides a close analogue to this study.
  • Kintampo Health Research Centre was involved in Phase III RTS,S trials and is the evaluation lead partner for the MVIP Evaluation.
  • The social studies acceptability trials will involve Jane Grant, a doctoral student who designed similar components of recent trials of R21 and SMC in Burkina Faso and Mali.

• 24PMI Insights ran a “stakeholder consultation process to identify pressing evidence gaps in malaria strategy and guidelines and to define a set of country-driven operational research (OR) and program evaluation (PE) priorities to address the gaps.” They ranked research to “Evaluate the effectiveness and cost-effectiveness of different strategies for deploying the RTS,S/AS01 malaria vaccine with chemoprevention” as the second most important research topic in their prioritized list. PMI, Defining country-driven research priorities for malaria control and elimination, pp. 1,4.
• 25
  • PMI and researchers consulted with WHO experts in the discussion around whether to add a third arm to the trial. PMI, conversation with GiveWell, January 31, 2023 (unpublished).
  • At the time of our recommendation, PMI was coordinating talks with an ongoing multi-country working group on expanded dosage regimes for IPTI (PMC) to ensure that findings from the scale up of PMC across countries would inform the decision of the particular PMC drug regimen used in the studies.

• 26
  • Conversation between GiveWell and a Malaria funder on February 24, 2022 (unpublished).
  • Conversation between GiveWell and a Malaria funder on September 9, 2022 (unpublished).

• 27PMI Insights ran a “stakeholder consultation process to identify pressing evidence gaps in malaria strategy and guidelines and to define a set of country-driven operational research (OR) and program evaluation (PE) priorities to address the gaps.” They ranked research to “Evaluate the effectiveness and cost-effectiveness of different strategies for deploying the RTS,S/AS01 malaria vaccine with chemoprevention” as the second most important research topic in their prioritized list. PMI, Defining country-driven research priorities for malaria control and elimination, pp. 1,4.
• 28Malaria researchers from PMI, CDC, Kintampo Health Research Center, PATH, and LSHTM; conversation with GiveWell; January 13, 2023 (unpublished)
• 29
  • See “Reference price US$ Per Treatment” for Amodiaquine + Pyrimethamine/Sulfadoxine and Pyrimethamine/Sulfadoxine. Global Fund, Pooled Procurement Mechanism Reference Pricing: Antimalarial medicines, 2023
  • “PMC is generally considered cost-effective or highly cost-effective due to its use of the EPI delivery platform to deliver the inexpensive drug SP. The cost per dose delivered in nearly all studies was less than $0.25 for PMC with SP, but more expensive with alternative drugs.” World Health Organization, WHO Guidelines for Malaria, 2023, p. 100.
  • “The Global Fund will continue to support Intermittent Preventive Treatment for infants (IPTi) and its updated nomenclature with a broadened spectrum, PMC, to reach a larger number of children with this preventive intervention.” Global Fund, Information Note: Malaria, 2022, p. 16.

• 30GiveWell, PMC RTSS Threshold BOTEC, 2023. Note: The critical assumptions of this BOTEC (in particular, how much more effective chemoprevention + malaria vaccines will be than malaria vaccines alone, the costs of chemoprevention and the assumptions that vaccine supply will be available to cover the eligible population in high burden areas) are speculative. The BOTEC is intended to be illustrative rather than definitive.
• 31We have added a subjective adjustment to our threshold BOTEC to account for this uncertainty.
• 32The trial's results would likely be applicable to the R21 malaria vaccine (not yet recommended for wide use) as RTS,S and R21 are generally viewed as bio-equivalent. Malaria researchers from PMI, CDC, Kintampo Health Research Center, PATH, and LSHTM; conversation with GiveWell; January 13, 2023 (unpublished)
• 33R21 is a malaria vaccine which (as of April 2023) is undergoing a Phase III clinical trial with an estimated study completion date of March 2024. Clinical Trials Study Record, "R21/Matrix-M in African Children Against Clinical Malaria," 2023.
• 34In our illustrative BOTEC, we estimate that the study would need to move up treatment of all vaccine eligible children in high burden areas by 9 months to meet our 10x threshold. This implicitly assumes that vaccine supply can cover the estimated population, which likely would require R21’s availability. When we restrict the population to vaccine-eligible children expected to be covered by RTS,S given current supply projections, the study would need to move up co-administration by approximately 1.75 years to meet GiveWell’s 10x threshold for recommending treatment.
• 35Julie Gutman, CDC, Comments on a draft of this page, June 2023 (unpublished).
• 36PMI, conversation with GiveWell, January 31, 2023 (unpublished).