Immunization, Vaccines and Biologicals

Questions and answers on RTS,S/ASO1 malaria vaccine

What is RTS,S/AS01?

RTS,S/AS01 (RTS,S) is a malaria vaccine that has been developed through a partnership between GlaxoSmithKline Biologicals (GSK) and the PATH Malaria Vaccine Initiative (MVI), with support from the Bill & Melinda Gates Foundation and from a network of African research centres that performed the studies.

RTS,S acts against Plasmodium falciparum, the most deadly malaria parasite globally, and the most prevalent in Africa. It offers no protection against P. vivax malaria, which predominates in many countries outside of Africa.The vaccine is being considered as a complementary malaria control tool in Africa that could potentially be added to – and not replace – the core package of proven malaria preventive, diagnostic and treatment interventions.

What makes RTS,S different from other malaria candidate vaccines?

RTS,S is the most advanced malaria vaccine candidate the world has seen: the clinical testing of RTS,S is at least 5 to 10 years ahead of other candidate vaccines. RTS,S is also the first malaria vaccine to obtain a positive scientific opinion by the European Medicines Agency, a stringent medicines regulatory authority.

What is the purpose of the WHO malaria vaccine pilot programme?

On 17 November 2016, WHO announced that the RTS,S vaccine would be rolled out in pilot projects in 3 countries in sub-Saharan Africa. The pilot programme, coordinated by WHO, will assess the extent to which the vaccine’s protective effect shown in advanced clinical trials (referred to below as “Phase 3 trials”) can be replicated in real-life settings. Specifically, the programme will evaluate the feasibility of delivering the required 4 doses of the vaccine; the impact of the vaccine on lives saved; and the safety of the vaccine in the context of routine use.

Who will fund this vaccination programme?

WHO has mobilized funding for the first phase of the pilot programme (2017-2020) from the Global Fund to Fight AIDS, Tuberculosis and Malaria, UNITAID and Gavi, the Vaccine Alliance.

What will be the main criteria for country selection?

Countries that participated in the advanced clinical trials for RTS,S will be prioritized for inclusion in the WHO pilot programme. WHO will select three countries with a high malaria burden and well-functioning malaria and immunization programmes. A desire to engage in the vaccine pilots by national stakeholders – particularly the Ministry of Health – is among the key criteria for country selection.

When will countries be selected for the pilots?

Country consultations are ongoing and the names of 3 selected countries will be announced in the coming weeks.

When will the pilot projects be launched?

There is a great deal of preparatory work that will need to be done before the vaccinations begin. WHO and partners will engage in intensive discussions with national stakeholders in the selected countries over the next year. Vaccinations are due to begin in 2018.

In what populations was the Phase 3 trial conducted?

The Phase 3 trial of RTS,S enrolled over 15,000 infants and young children in seven sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and the United Republic of Tanzania). The trial sites within these countries represented a range of malaria transmission settings (low, medium and high) in order to determine the vaccine’s efficacy in these different settings.

There were two target age groups in the trial.

  • Infants who received the malaria vaccine together with other routine childhood vaccines at 6, 10 and 14 weeks of age.
  • Older children who received their first dose of the malaria vaccine between 5 and 17 months of age.

What were the results from the Phase 3 trial?1

Vaccine efficacy

Over the full duration of the trial, vaccine efficacy against clinical malaria in infants was 27% in the group that received four doses of RTS,S (3 doses at 6, 10 and 14 weeks of age, and a fourth dose 18 months later); and 18% in the group that did not receive the fourth dose of the vaccine. In these infants, no significant efficacy was noted against severe malaria, with or without a fourth dose.

Among children aged 5-17 months who received four doses on a 0, 1, 2, 20 month schedule, vaccine efficacy against clinical malaria was 39% over the full duration of the trial. With a four-dose schedule, the overall efficacy against severe malaria among children in this age group was 31.5%, with reductions in severe anaemia, malaria hospitalizations and all-cause hospitalizations also seen.

Among children aged 5-17 months who did not receive a fourth dose of the vaccine, no protection was seen against severe malaria, as cases prevented in the first 18 months occurred later. These results highlight the importance of a fourth dose with this vaccine, as efficacy is short-lived.

Vaccine safety

Among children in the older age group, there was a risk of febrile seizures within 7 days after any of the vaccine doses. Among infants, this risk was only apparent after the fourth dose. There were no long-lasting consequences due to any of the febrile seizures.

Among children in the older age group, an increase in the number of cases of meningitis and cerebral malaria was found in the group receiving the malaria vaccine compared to the control group. The significance of these findings in relation to the vaccination is unclear. An excess of meningitis and cerebral malaria was not seen in infants aged 6–12 weeks.

Why is the efficacy different in the 2 age groups?

Lower immune responses are induced by the vaccine in infants aged 6-12 weeks compared to children aged 5-17 months. Possible factors underlying this difference include interference by co-administration with DTP-containing vaccines, the presence of maternally acquired antibodies to malaria in the 6-12 week olds, and immunological immaturity in the 6-12 week olds compared to the 5-17 month age group.

Licensing, policy recommendations and prequalification

When could the RTS,S/AS01 vaccine be licensed by a regulatory authority?

The European Medicines Agency (EMA), under a process known as article 58, performed a scientific evaluation of this vaccine and issued, in July 2015, what is called "a European scientific opinion", which African regulators may use to help their own regulatory authorities reach a decision on licensure. EMA’s opinion was positive indicating that, in their assessment, the quality of the vaccine and its risk/benefit profile is favourable from a regulatory perspective. This opinion does not take into account contextual elements such as the feasibility of implementation, the value of the vaccine in the context of other malaria control measures, and the likely cost-effectiveness of the intervention in different settings.

The registration of the vaccine will be done by the national regulatory authorities of the African countries that will consider using the vaccine in their jurisdictions. At present, no regulatory authority in the African region has licensed RTS,S for use as a malaria vaccine.

What are WHO’s recommendations related to RTS,S/AS01?

In October 2015, WHO jointly convened the Strategic Advisory Group of Experts (SAGE)2 on Immunization and the Malaria Policy Advisory Committee (MPAC)3 to review all evidence regarding RTS,S relevant for global policy. SAGE/MPAC recommended that pilot implementation of RTS,S occur in parts of 3-5 sub-Saharan African countries, administering 3 doses of the vaccine to children aged 5-9 months of age with a fourth dose 15-18 months later. SAGE and MPAC were not supportive of vaccine use among infants aged 6-14 weeks due to inferior efficacy seen in this age group.

SAGE/MPAC recommended large-scale implementation pilots, to evaluate the extent to which the protection demonstrated in children aged 5–17 months in the Phase 3 trial can be replicated in the context of the routine health system, particularly in view of the need for a 4-dose schedule that requires new immunization contacts. The pilot implementation should also assess the extent to which RTS,S vaccination impacts mortality, which could not be adequately assessed in the Phase 3 trial due to the very low overall mortality in the trial setting, and whether the excess cases of meningitis and cerebral malaria, identified during the Phase 3 trial, are causally related to RTS,S vaccination or not. The pilot implementation programme will generate critical evidence to enable decision-making about the potential wider scale use of this vaccine in 3-5 years’ time.

WHO officially adopted the SAGE/MPAC recommendations in January 2016 and is strongly supportive of the need to proceed with these pilots as the next step for the world’s first malaria vaccine. On 17 November 2016, WHO announced that funding for the first phase of the vaccine pilots (2017-2021) had beensecured and that vaccinations would begin in 2018.

What is the difference between a WHO recommendation for use and WHO prequalification?

A WHO policy recommendation is the global equivalent of a national public health authority's (e.g. Ministry of Health’s) decision on the use of vaccines. Many countries appreciate guidance from the WHO policy recommendation process on which vaccines they should consider for introduction in their national immunization programmes. Similarly, donor agencies, such as the GAVI Alliance, require a WHO recommendation for use before funding procurement of vaccines for developing countries.

WHO prequalification is a separate process and ensures that a specific vaccine from a specific manufacturer meets international standards of quality, safety and efficacy and is appropriate for the target population. Only WHO prequalified vaccines can be supplied to countries through UN agencies.

Malaria control measures

What other interventions exist for malaria control?

There are many effective interventions available that can be used to reduce the burden of malaria in Africa. These include: prevention through mosquito vector control using long-lasting insecticidal bed-nets and, in some settings, indoor residual spraying with insecticides; seasonal malaria chemoprevention in specific settings; intermittent preventive treatment for infants and during pregnancy; prompt diagnostic testing; and treatment of confirmed cases with effective anti-malarial medicines. These measures have dramatically lowered malaria disease burden in many African settings over the years. The malaria disease burden can be lowered further by continuing to scale up existing WHO-recommended control measures. Available malaria control interventions represent some of the most cost-effective measures for public health.

RTS,S is being considered as a complementary intervention, i.e. any use of RTS,S would be in addition to use of the existing non-vaccine malaria preventive measures described.

The need for high quality, safe and effective drugs to treat malaria will continue regardless of any deployment of a first-generation malaria vaccine.

1 In April 2015, the fourth set of results of the Phase 3 trial reported the effect of a fourth dose of the vaccine administered 18 months after the third dose, and provided information on longer term follow-up. Results are now available from an average of 48 months follow-up from dose 1 in the 5-17 month olds, and an average of 38 months follow-up in the 6-12 week old. (RTS,S Clinical Trials Partnership. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet. 2015 Apr 23. pii: S0140-6736(15)60721-8).

Last updated: 22 November 2016

Last update:

22 November 2016 10:50 CET