PATH — RTS,S Malaria Vaccines in Pilot Comparison Areas (January 2022)

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

GiveWell spoke with staff members from PATH about updates regarding this grant on September 6, 2022, and March 28, 2023.

Published: April 2022

The organization

PATH 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 GiveWell coordinated with PATH’s Center for Vaccine Innovation and Access in our investigation of this grant. In September 2021, GiveWell recommended a $120,000 grant to PATH to scope opportunities for implementing intermittent preventive treatment in infants (IPTi) for malaria.

The intervention

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.3 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).4

Does it work?

We have not published a program review on RTS,S vaccination for malaria, but we have reviewed WHO’s evidence report on RTS,S as well as the results of phase 3 clinical trials.5

Phase 3 clinical trials found that among children6 receiving a four-dose schedule of the RTS,S/AS01 vaccine, malaria cases were reduced by 36.3% over four years (trials followed the children for a median of 48 months); among children receiving a three-dose schedule, malaria cases were reduced by 28.3%.7 The WHO’s evidence report on RTS,S found that it “has an acceptable safety profile, and its introduction results in a significant reduction in severe malaria, an acceptable surrogate indicator for the likely impact on mortality,” though we have not investigated these estimates beyond reading the report.8

WHO and partners have identified several areas for operational and other research, including work to identify how best to deliver RTS,S/AS01 seasonally or the impacts of RTS,S used in conjunction with intermittent preventive treatment of malaria for infants.9

In our cost-effectiveness analysis, we assume that 70% of children would receive a full four-dose schedule and 30% would receive only three doses.10 This assumption is based on preliminary coverage estimates from the pilot areas.11 After factoring in these dose coverage estimates, adjusting for internal and external validity, and making a simplifying assumption of constant effects over time, we estimate that a four-dose schedule of RTS,S reduces malaria cases an average of about 31% annually, for four years.12

The grant

GiveWell is recommending a grant of approximately $5 million from Open Philanthropy to PATH for the implementation of the RTS,S malaria vaccine through the end of 2023 in portions of three countries. The target areas are those areas of Ghana, Kenya, and Malawi which were used as comparison areas during operational pilots of the vaccine.13 We estimate that this grant will speed up implementation of RTS,S by enabling use of the vaccine in these areas approximately one year earlier compared to the counterfactual.

The grant will build on work begun during the Malaria Vaccine Implementation Programme by the ministries of health in Ghana, Kenya, and Malawi, the WHO, PATH and other partners.14 We expect activities to include:15

• Planning, at the national and subnational levels, for introduction of the vaccine
• Training health care workers on vaccine use
• Forecasting and provision of required vaccine doses and safe injection supplies
• Coordination with GSK, the producer of RTS,S
• Public communication and social mobilization activities

Budget

The budget for the grant is $4,998,769, broken down as follows:16

• $2,415,458 to support in-country activities, especially trainings
• $1,811,571 for PATH and WHO in-country technical support, including staff costs
• $386,280 for vaccine-related supplies and shipping and handling costs for donated doses17
• $385,459 for global support, including global staff costs

The case for the grant

We are recommending this grant for the following primary reasons:

• We believe that financing this opportunity will speed up implementation of RTS,S in the areas covered by the grant by approximately one year compared to what would have happened otherwise, thereby reducing malaria illness and death among vaccinated children. (See more below.)
• We believe the activities funded by the grant will be cost-effective. (See more below.)
• We think it is likely that the activities funded by this grant will be implemented successfully. The Ministries of Health of Ghana, Kenya and Malawi, PATH, and WHO have recently completed very similar work in different areas within the same countries that are targeted by this grant. Thus, we believe that the partners have the relevant relationships and expertise to carry out this work.

Funding gap and implementation timelines

We estimate that without this grant, Gavi-supported implementation of the RTS,S vaccine would begin in the pilot comparison areas in January 2024. With philanthropic funding, we estimate that implementation would begin in January 2023. These estimates are based on timelines developed by WHO in collaboration with PATH, UNICEF, Gavi, GSK, and the Global Fund for implementation with and without additional philanthropic funding.18 We subjectively adjust those timelines to account for potential overoptimism or delays due to COVID-19 or other factors. PATH told us that there are no other donors who can fund this opportunity.19 We did not triangulate this claim, but it seems plausible to us. Thus, we believe that there is a funding gap to cover approximately one year’s worth of RTS,S implementation in the currently non-vaccinating pilot comparison areas.

Cost-effectiveness

We estimate that the activities funded by the grant are in the range of cost-effectiveness of other programs we would direct funding to. We have completed a very rough cost-effectiveness analysis which preliminarily estimates that the grant activities, averaging across all three countries, are 16 times as cost-effective as unconditional cash-transfers via GiveDirectly.20 We would guess that with deeper investigation, our cost-effectiveness estimate would decrease, but we think it is unlikely to fall below the range of cost-effectiveness that we would direct funding to.21

As discussed above, we estimate that a four-dose schedule of RTS,S reduces malaria cases by an average of approximately 31%, for four years,22 at a cost of roughly $9-$11 per child year of protection.23 To provide an intuitive explanation of the relative cost-effectiveness of this opportunity, we compare the effect and cost of RTS,S in the pilot comparison areas to that of Malaria Consortium’s SMC program in the areas where SMC is implemented. We estimate that SMC reduces malaria cases for one year by approximately 55%,24 at a cost of $5-$8 per child.25 However, we believe this grant opportunity may be more cost-effective than SMC because:

1. This grant opportunity leverages donated vaccine doses and Gavi funds toward future vaccine doses.26
2. We model substantial funging on GiveWell-directed funding to SMC, but we do not believe that this opportunity is likely to be funged.27

Note that the comparison between SMC and this grant is made to assess the cost-effectiveness of the grant opportunity against a similar program that GiveWell has done significant research on, not to identify which program would be more cost-effective for use in the pilot comparison areas (SMC is only recommended for use in areas with highly seasonal transmission of malaria; as such, SMC would not be recommended for use in the majority of the pilot areas.).

Further explanation on our cost-effectiveness analysis of this grant is available here.

Risks and reservations

We have the following primary reservations about this grant:

• It is possible that the COVID-19 pandemic could cause delays. We believe that the biggest threat to the value of this grant is any factor that would cause delays under expedited timelines but not Gavi-supported implementation, since the value of this grant is based on speeding up implementation of RTS,S by approximately one year. However, we believe the risk of COVID-related delays is fairly low, given the successful implementation of the pilot program over the past three years.
• If it takes longer than expected for Gavi to begin funding vaccines for these areas, PATH may require additional funding for implementation to continue. The budget for the current grant covers RTS,S implementation in the pilot comparison areas through the end of 2023, and we expect that Gavi-supported implementation will begin in 2024. In the event that Gavi support is not available at that time, GiveWell may be asked to recommend an additional grant to avoid a discontinuity in implementation. Though we think that a follow-up grant is unlikely to be large,28 it is more likely to crowd out Gavi funding, which could make it less cost-effective.29
• Our understanding is that expansion of RTS,S into the areas covered by this grant is perceived to be a high priority. It is possible that this grant could cause delays in securing Gavi support for implementation in Ghana, Kenya, and Malawi as a whole by relieving pressure to cover these priority areas. WHO told us that it would be unlikely for Gavi to delay its funding.

Plans for follow up

We plan to ask PATH to report on the following indicators:

• Numbers of district health teams and healthcare workers trained
• Numbers of communities and caregivers reached through information, education and communication (IEC) activities.
• Forecasts of numbers of doses needed, shipped, and used
• Vaccine coverage estimates

Internal forecasts

For this grant, we are recording the following forecasts:

Confidence	Prediction	By time
45%	PATH-supported implementation begins in pilot comparison areas in all three countries	Jan 1, 2023
80%	PATH-supported implementation begins in pilot comparison areas in at least two countries	Jan 1, 2023
90%	PATH-supported implementation begins in pilot comparison areas in at least one country	Jan 1, 2023
12%	Gavi-supported implementation begins in pilot comparison areas in all three countries	Jan 1, 2024
42%	Gavi-supported implementation begins in pilot comparison areas in at least two countries	Jan 1, 2024
80%	Gavi-supported implementation begins in pilot comparison areas in at least one country	Jan 1, 2024

Our process

• We spoke with staff members and reviewed materials from PATH and WHO in order to understand program activities and counterfactual timelines.30
• We spoke with a Gavi staff member to confirm that Gavi wouldn’t be able to offer support before December 2023.31
• We developed a rough cost-effectiveness analysis of the activities funded by this grant and refined it with input from PATH and WHO.
• The case for the grant and cost-effectiveness analysis were reviewed internally by multiple GiveWell staff members.
• We spoke with members of the Ministry of Health in two of the three countries in order to confirm that the program is a priority, that it is feasible, and that PATH would be a good partner.

Sources

Document	Source
Gavi staff member, conversation with GiveWell, January 14, 2022	Unpublished
GiveWell, "Malaria Consortium – Seasonal Malaria Chemoprevention," 2021	Source
GiveWell, "Malaria Consortium and PATH—Scoping Grant to Assess Feasibility of Intermittent Preventive Treatment in Infants (IPTi) for Malaria (September 2021)"	Source
GiveWell, Cost Effectiveness of RTS,S in Pilot Comparison Areas	Source
GiveWell, RTS,S for pilot comparison areas CEA, 2022	Source
GiveWell's non-verbatim summary of a conversation with PATH, July 30, 2021	Source
GiveWell's non-verbatim summary of a conversation with PATH and WHO, January 5, 2022	Source
PATH and WHO, conversation with GiveWell, November 19, 2021	Unpublished
PATH and WHO, responses to GiveWell questions, December 28, 2021	Unpublished
PATH and WHO, responses to GiveWell questions, January 6, 2022	Unpublished
PATH, "About PATH Center for vaccine innovation and access"	Source (archive)
PATH, "About"	Source (archive)
PATH, "Health areas"	Source (archive)
PATH, Budget for 2021-2023 RTS,S implementation grant	Source
RTS,S Clinical Trials Partnership, 2015	Source
WHO, "WHO recommends groundbreaking malaria vaccine for children at risk," 2021	Source (archive)
WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021	Source (archive)
WHO, Timelines to RTS,S malaria vaccine introduction	Unpublished
WHO, WHO Malaria Vaccine Implementation Program Briefing, 2021	Source

• 1Exact grant amount was $4,998,769. PATH, Budget for 2021-2023 RTS,S implementation grant
• 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
  • “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

• 4
  • “PATH is requesting funding to support the rollout of donated doses of the RTS,S vaccine in pilot areas of Ghana, Kenya, and Malawi that have not yet implemented the vaccine. Each of these countries has already implemented a pilot rollout of the vaccine.” GiveWell's non-verbatim summary of a conversation with PATH and WHO, January 5, 2022
  • “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.” WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, p. 7
  • See vaccine coverage estimates for different time periods in Table 1: Vaccine coverage estimates for different time periods according to routine administrative data WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021 pg. 47

• 5 We have reviewed the following:
  • WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021
  • RTS,S Clinical Trials Partnership, 2015

• 6Children were aged 5-17 months at the time of enrolling in the study. The results we report on are for children, not infants, though both age groups were studied. “From March 27, 2009, until Jan 31, 2011, children (age 5–17 months) and young infants (age 6–12 weeks) were enrolled at 11 centres in seven countries in sub-Saharan Africa.” RTS,S Clinical Trials Partnership, 2015, p. 31.
• 7
  • “One group received RTS,S/AS01 at months 0, 1, and 2, followed by a booster dose at month 20 (R3R group); a second group received the RTS,S/AS01 primary vaccination series with meningococcal serogroup C conjugate vaccine (Menjugate, Novartis, Basel, Switzerland) instead of an RTS,S/AS01 booster (R3C group);” RTS,S Clinical Trials Partnership, 2015, p. 32.
  • “In the modified ITT population, from month 0 until study end, compared with 9585 episodes of clinical malaria that met the primary case definition in children in the C3C group, 6616 episodes occurred in the R3R group (VE 36.3%, 95% CI 31.8–40.5) and 7396 occurred in the R3C group (28.3%, 23.3–32.9)." RTS,S Clinical Trials Partnership, 2015, p. 38.
  • “Children were followed up for a median of 48 months (IQR 39–50)” RTS,S Clinical Trials Partnership, 2015, p. 31.

• 8
  • WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, Pg. 83.
  • The full evidence report was reviewed by WHO’s top advisory bodies on immunization and malaria who jointly recommended use of this vaccine, and the MVIP and WHO’s findings continue to be closely monitored by independent experts.
    • WHO staff, comments on a draft of this page, April 13, 2022 (unpublished).

• 9 “The following research are recommended for the following areas, with the PAG noting that none are prerequisite prior to expanded use of RTS,S/AS01.
  (1) areas with moderate to high malaria transmission with perennial transmission
  • Through the MVIP, continued collection and monitoring data on safety and impact through the end of the programme and in the planned case control study, and on the added benefit of the fourth dose.
  • Through the MVIP, collect additional information on how best to achieve coverage of the 4th dose, and its impact on severe malaria and mortality.
  • Added or synergistic effect of RTS,S/AS01 when given in conjunction with expanded IPTi.

  (2) areas with highly seasonal malaria or areas with perennial malaria transmission with seasonal peaks. Operations research around the delivery of seasonal vaccine dosing, including around annual pre-season dosing after a primary series given through the routine health clinics in areas of perennial or seasonal transmission.

  • Further evaluation will be required to determine how best to deliver the combination of SMC and seasonal malaria vaccination in areas of high malaria burden in the Sahel, sub-Sahel, and areas of perennial transmission with seasonal peaks.
  • Safety, immunogenicity, and effectiveness of annual doses beyond dose 5.
  • Planned follow-up of the ongoing seasonal malaria vaccination trial and case-control study, and evaluation of any age shift effect of clinical or severe malaria cases in immunized children (relative to the control group) after ceasing vaccination.

  (3) both areas (1) and (2):

  • Parasite genotype monitoring to detect any emergence of vaccine escape mutants – in context of broader use of RTS,S/AS01
  • Co-administration of RTS,S/AS01 with typhoid conjugate, Meningococcal, and inactivated polio vaccines, and other antigens as appropriate.” WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, Pg. 84-85.

• 10See our cost-effectiveness analysis for this grant, “Main model” sheet. “Coverage of dose 4” row.
• 11Initial coverage estimates from Malawi and Ghana indicated a maximum 30% drop off rate between dose 3 and dose 4.
  • “While it is too early to assess fourth dose coverage, preliminary information suggests drop-out rates between dose 3 and dose 4 have been around 19-30% in Malawi and Ghana (after 9-10 months of implementation). Insufficient time has passed since 4th dose introduction to assess drop-out rates in Kenya." WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, p. 8-9

  Later data indicated drop off rates of 23% in Malawi (after 13 months), 25% in Ghana (after 12 months), and 52% in Kenya (after 7 months). The average of the 3 coverage rates (77%, 73%, and 48%) is 66%. We increase this rate slightly to place less weight on the Kenya results. We place less weight on the results from Kenya because of the shorter follow up period, updating to a coverage rate of 70%. WHO, WHO Malaria Vaccine Implementation Program Briefing, 2021, Slide 12

• 12See our cost-effectiveness analysis for this grant, “Main model” sheet. “Expected reduction in malaria cases among children treated” row.
• 13 “PATH is requesting funding to support the rollout of donated doses of the RTS,S vaccine in pilot areas of Ghana, Kenya, and Malawi that have not yet implemented the vaccine. Each of these countries has already implemented a pilot rollout of the vaccine. The proposal is for funds that would allow vaccine access to previously non-vaccinating areas, which are neighboring areas that served as comparison areas during the pilots.” GiveWell's non-verbatim summary of a conversation with PATH and WHO, January 5, 2022
• 14“The MVIP is coordinated by WHO in close collaboration with ministries of health in participating countries and a range of in-country and international partners. WHO is working with PATH and GSK on the MVIP through a collaboration agreement. PATH provides technical and project management support and is leading studies on health care utilization and the economics of vaccine implementation. GSK is donating up to 10 million doses of RTS,S/AS01 vaccine for use in the pilot and is leading additional studies to continue monitoring the vaccine’s safety and effectiveness in routine use. UNICEF is supporting the forecasting and deployment of the donated vaccines to pilot countries. The MoH of the pilot countries have introduced the RTS,S/AS01 vaccine using routine vaccine introduction strategies and programmes. In-country research partners are leading the evaluation of the RTS,S/AS01 vaccine pilot implementation.” WHO, Full Evidence Report on the RTS,S/AS01 Malaria Vaccine, 2021, Pg. 22.
• 15
  • PATH and WHO, responses to GiveWell questions, December 28, 2021 (unpublished)
  • PATH staff, comments on a draft of this page, April 13, 2022

• 16
  • PATH, Budget for 2021-2023 RTS,S implementation grant
  • Additional information from PATH and WHO, responses to GiveWell questions, December 28, 2021 (unpublished).

• 17 Note that the grant leverages donated doses of RTS,S, supplied to PATH by GSK; thus the cost of vaccine doses themselves are not included in the budget.
• 18WHO, Timelines to RTS,S malaria vaccine introduction (unpublished)
• 19“Potential alternative funding sources. If GiveWell doesn’t fund the proposed program, there would not be an alternative funding source in the near term.” GiveWell's non-verbatim summary of a conversation with PATH and WHO, January 5, 2022
• 20 See our cost-effectiveness analysis of this grant, “Main model” sheet, “CE” row.
• 21For an example of the cost-effectiveness of our recommendations, see this page.
• 22 See our cost-effectiveness analysis for this grant, “Main model” sheet, “Expected reduction in malaria cases among children treated” row.
• 23See our cost-effectiveness analysis for this grant, “Main model” sheet, “Total cost per child year of protection with RTS,S” row.
• 24
  • Expected reduction in malaria cases among children treated with SMC is 79%. See our cost-effectiveness analysis of SMC.
  • We multiply this by the proportion of cases (70%) that occur during the high-transmission season (since this is when SMC is delivered). See our cost-effectiveness analysis for SMC.
  • 0.79*0.70=0.553

• 25See here in our cost-effectiveness analysis for SMC.
• 26
  • PATH and WHO, responses to GiveWell questions, December 28, 2021 (unpublished)
  • See our leveraging adjustments for donated doses and Gavi funds here.

• 27
  • See this section for more on why we believe this grant is unlikely to be funged.
  • See our cost-effectiveness analysis of SMC for more detail on how we think about the risk of funging for that intervention.

• 28For example, shipping and medical commodity costs make up only about $400,000 of the budget for the current grant. PATH, Budget for 2021-2023 RTS,S implementation grant, "Vaccine-related supplies"
• 29For example, if Gavi funding were not available in January 2024 and GiveWell recommended a bridge grant for six months, but in the counterfactual Gavi support could have been available with an additional three months, we would be crowding out three months worth of Gavi funding.
• 30
  • GiveWell's non-verbatim summary of a conversation with PATH, July 30, 2021
  • PATH and WHO, conversation with GiveWell, November 19, 2021 (unpublished)
  • GiveWell's non-verbatim summary of a conversation with PATH and WHO, January 5, 2022

• 31Gavi staff member, conversation with GiveWell, January 14, 2022 (unpublished)