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 is the first malaria vaccine to have completed pivotal Phase 3 testing and obtained a positive scientific opinion by a stringent medicines regulatory authority.

RTS,S is a vaccine 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. On 29 January 2016, WHO released a position paper on the malaria vaccine. To access this paper, please visit the following link:

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.

The RTS,S vaccine requires the administration of 4 doses—the first 3 doses at monthly intervals and a fourth dose 18 months later.

What are 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 an excess risk of febrile seizures within 7 days after any of the vaccine doses. Among infants, this excess risk was only apparent after the fourth dose. There were no long-lasting sequelae 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 has now issued 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 have 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 has adopted these recommendations and is strongly supportive of the need to proceed with these pilots as the next step for the world’s first malaria vaccine. WHO is now actively working with financing bodies, and the malaria vaccine clinical trials partnership (including PATH and GSK) to mobilize the financial support for the pilots, and to finalize design of the pilot implementation programme.

How are GSK’s planned Phase 4 studies integrated within the pilot implementation programme?

As for any new vaccines approved by EMA, post-approval studies are planned to further characterise the safety and effectiveness of RTS,S. Therefore, GSK is planning Phase 4 studies with a total of 40,000 children to be vaccinated, with a primary objective of further evaluation of safety as part of the Risk Management Plan approved by EMA. The pilot implementation in each of the 3-5 settings is likely to involve 100,000-200,000 children (for a total of 400,000-800,000), in a staged manner. The plan is for the smaller Phase 4 studies to be linked to the larger pilots, with complementary design and objectives.

Which countries will the pilot studies occur in?

If financing is secured from donors, the pilots will occur in moderate to high malaria transmission settings in 3-5 sub-Saharan African countries, with ongoing malaria vector control, and good access to malaria testing and treatment . The choice of sites has not occurred.

Has the vaccine been prequalified by WHO?

RTS,S is currently not prequalified. WHO is awaiting a submission of an application from the manufacturer for prequalification of this vaccine.

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: 23 June 2016


Last update:

23 June 2016 08:59 CEST