Q&A: The RTS,S malaria vaccine

by MedAccess

Everything you need to know about the decision by Gavi, the Vaccine Alliance to fund the world’s first mass malaria immunisation programmes using the ground-breaking RTS,S/AS01e vaccine.

On 2 December, 2021, Gavi, the Vaccine Alliance’s board agreed to finance the life-saving vaccine’s rollout at scale in sub-Saharan Africa. Find the answers to prominent questions about the roll out of the RTS,S vaccine.

How does RTS,S work?

Malaria invades and destroys our blood cells to reproduce. The plasmodium falciparum parasite enters the human host’s bloodstream through a mosquito bite and infects liver cells.

RTS,S/AS01e (brand name Mosquirix) is an injectable vaccine which aims to trigger the immune system to fight the first stages of malaria. It needs four doses to be effective – the first three are given at five, six and seven months with a booster at 18 months.

This prevents the parasite from infecting the liver, where it can mature, multiply, re-enter the bloodstream and infect red blood cells, leading to disease symptoms.

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Who created RTS,S?

RTS,S was created in 1987 by scientists working SmithKline Beecham Biologicals (now GSK after its merger with Glaxo Wellcome in 2000).

It was developed in partnership with PATH with financial backing from the Bill & Melinda Gates Foundation among other global funders. This targeted the vaccine’s development on protecting infants and young children living in malaria endemic regions in sub-Saharan Africa.

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When will RTS,S be available?

GSK will donate up to 10m for the pilot programmes in Kenya, Ghana and Malawi. It also committed to 15m annually (at manufacturing cost plus five per cent) once RTS,S following recommendation and funding for wider use. GSK estimates once finance is in place, it could be available for widespread deployment from the end of 2022 or early 2023.

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What was the result of RTS,S’ trial?

RTS,S is the first and only vaccine to show protective effect against malaria among young children in Phase Three trials from 2009 to 2014.

This final Phase Three results published in The Lancet in April 2015 found

  • of five to 17 month old children who received four doses of RTS,S/AS01e, the vaccine prevented approximately four in 10 (39%) cases of malaria over four years of follow-up and about three in 10 (29%) cases of severe malaria.
  • the trial reported significant reductions in overall hospital admissions for malaria. The vaccine also reduced the need for blood transfusions required to treat life-threatening malaria anaemia by 29%.
  • among children receiving four doses of the vaccine, an average of 1,774 cases of clinical malaria were prevented for every 1,000 children vaccinated across the 11 trial sites over an average of 48 months of follow-up. The impact was greater, however, in areas of higher disease burden: one site in Kenya recorded 6,565 cases averted for every 1,000 vaccinees.

The report authors concluded that RTS,S, if used correctly, “has the potential to make a substantial contribution to malaria control when used in combination with other effective control measures, especially in areas of high transmission”.

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When did regulators approve RTS,S?

It was granted positive scientific opinion as safe and effective by the European Medicines Agency in July 2015. The agency concluded the quality of the vaccine and its risk/benefit profile was favourable from a regulatory perspective. The assessment applied the same rigorous standards as for medicines to be marketed within the EU.

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Where were the RTS,S pilots?

The World Health Organization (WHO) in October 2015 recommended a major vaccine pilot in Africa to test the feasibility, impact and safety of a four-dose course for children from five months upwards.

The Malaria Vaccine Implementation Programme has been piloting RTS,S in Kenya, Ghana and Malawi since 2019.

More than 2.3 million doses have been administered and up to 800,000 children have been reached with at least one vaccine dose.

The vaccine is administered in routine immunisation programmes led by the national health ministries in each country. This avoids the need for investing in separate immunisation infrastructure.

The pilot coordinated by WHO and supported by international partners, including PATH and UNICEF. The pilot has had $70m investment by three key global health funding bodies: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.

RTS,S manufacturer GSK is donating up to 10 million doses of the vaccine for the pilot.

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Can RTS,S reduce malaria cases on its own?

No. It is intended to complement existing measures to fight malaria, including mosquito nets, insecticide spraying and antimalarials. The European Medicines Agency; the pilots in Kenya, Ghana and Malawi; and World Health Organization concluded the RTS,S should be ‘layered’ with other interventions.

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Is RTS,S approved by the World Health Organization?

Yes. The World Health Organization (WHO) backed the widespread use of RTS,S vaccine in October 2021.

Its official recommendation reads:

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 four doses in children from five months of age for the reduction of malaria disease and burden.

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What did the three national pilots conclude?

The World Health Organization’s recommendation is based on results from an ongoing malaria vaccine pilot programme in Kenya, Ghana and Malawi that has reached more than 800,000 children with at least one dose since 2019 (as of late September 2021).

Its rationale was based on six factors:

  • feasible to deliver: vaccine introduction is feasible, improves health and saves lives, with good and equitable coverage of RTS,S seen through routine immunization systems. This occurred even in the context of the COVID-19 pandemic.
  • reaching the unreached: RTS,S increases equity in access to malaria prevention.
    • data from the pilot programme showed that more than two-thirds of children in the three countries who are not sleeping under a mosquito net are benefitting from the RTS,S vaccine.
    • layering the tools results in over 90% of children benefitting from at least one preventive intervention (insecticide-treated mosquito nets or the malaria vaccine).
  • strong safety profile: to date, more than 2.3 million doses of the vaccine have been administered in three African countries – the vaccine has a favourable safety profile.
  • no negative impact on uptake of mosquito nets, other childhood vaccinations, or health seeking behaviour for febrile illness: in areas where the vaccine has been introduced, there has been no decrease in the use of insecticide-treated nets, uptake of other childhood vaccinations or health seeking behaviour for febrile illness.
  • high impact in real-life childhood vaccination settings: significant reduction (30%) in deadly severe malaria, even when introduced in areas where insecticide-treated nets are widely used and there is good access to diagnosis and treatment.
  • highly cost-effective: modelling estimates that the vaccine is cost effective in areas of moderate to high malaria transmission.

It follows a study of 6000 children by the London School of Hygiene and Tropical Medicine published in the New England Journal of Medicine in August 2021. This showed that after three years the combination of seasonal administration of antimalarials and RTS,S vaccination lowered clinical episodes of malaria, hospital admissions with World Health Organisation-defined severe malaria and deaths from malaria by 70% compared to antimalarials alone.

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What are the next steps for the pilots?

The pilots are ongoing. The World Health Organization has asked the pilots to assess the value of the fourth RTS,S vaccine dose and measure the long-term impact on child deaths.

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What is the financial agreement between Gavi, GSK and MedAccess?

GSK has invested $700 million in the development of RTS,S and is donating up to 10 million doses for the ongoing pilot in Kenya, Ghana and Malawi. It also committed to 15m annually (at production cost plus at least five percents) once RTS,S following recommendation and funding for wider use. GSK is on record stating once finance is in place, it could be available for widespread deployment from the end of 2022 or early 2023.

Gavi agreed to fund GSK’s continued manufacturing of the RTS,S antigen for a period of up to three years. MedAccess’ production guarantee came into force on 1st September 2021, after six months of negotiation.

It meant MedAccess would have replenished Gavi for the majority costs to date, if Gavi’s board did not agree to open a funding window for an immunisation programme.

Now the Gavi Board has approved a programme, GSK will credit the value of the Gavi-funded costs towards procurement of finished doses for the immunisation programme.

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Why was Gavi, GSK and MedAccess’ financial agreement needed?

The agreement between MedAccess, Gavi and GSK ensured RTS,S production would continue in advance of key decisions.

The innovative financing agreement guaranteed ongoing manufacturing of the RTS,S bulk antigen, in advance of critical decisions by World Health Organization and Gavi’s board in autumn 2021.

This will accelerate vaccine rollout to the new mass immunisation programme by avoiding production being scaled back – which require a long production ramp-up phase if GSK had to restart the dedicated antigen production facility.

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What is the impact of the financial agreement between Gavi, GSK and MedAccess?

MedAccess’ original projection was that an additional 7.5 million children could receive the RTS,S/AS01e vaccine as a result of continued production in advance of policy and funding decisions. These children would have missed out on the vaccine if countries had to wait to introduce it into their routine immunisation schedules while production was restarted. We estimated that this would lead to 8.7 million cases of malaria and 36,000 deaths being averted.

We projected impact across various timelines between 2021 and 2028 to ensure we captured the full range of potential impact – dependent on the exact timing WHO’s policy decision and Gavi’s funding decision.

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Will GSK continue to manufacture RTS,S?

In January 2021, PATH, GlaxoSmithKline (GSK), and Bharat Biotech (BBIL) announced the signing of a product transfer agreement for the RTS,S/AS01 malaria vaccine.

BBIL will become the sole supplier of the vaccine by 2029. The antigen technology will transfer from GSK, while it ensures the continuous production of the adjuvant (AS01e).

GSK will continue to meet its existing commitment to malaria vaccine supply, including the donation of 10 million doses for the Malaria Vaccine Implementation Programme in Kenya, Ghana and Malawi.

GSK will also work with partners, funders and governments to ensure the commitment to 15 million annual doses are supplied, at no more than five percent above the cost of production.

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