Questions and answers on malaria vaccines
What is RTS,S/AS01?
RTS,S/AS01 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. The clinical testing of RTS,S/AS01 is at least 5-10 years ahead of other candidate malaria vaccines. RTS,S/AS01 is a vaccine against Plasmodium falciparum, with no protection against P. vivax malaria.
Vaccines currently licensed are against human diseases caused by either viruses or bacteria. Should RTS,S/AS01 be licensed, it will be the first ever licensed vaccine against a parasitic disease in humans.
In what populations was the Phase 3 trial conducted?
The Phase 3 trial of RTS,S/AS01 enrolled 15,460 infants and young children in seven sub-Saharan African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, and the United Republic of Tanzania). These countries represent a range of different malaria transmission settings in order to be able to determine the vaccine’s usefulness in these different settings. There are two age groups in the trial. One of these age groups was infants who received the malaria vaccine together with other routine childhood vaccines at 6, 10 and 14 weeks of age. The other age group was older children aged between 5 and 17 months at first dose of RTS,S/AS01.
What are the results from the Phase 3 trial?
In April 2015, the fourth set of results reported the effect of a fourth dose given 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 olds1.
Vaccine efficacy against clinical malaria in 5-17 month old children who received four doses on a 0, 1, 2, 20 month schedule was 39% over the full duration of the trial. With a four-dose schedule the overall efficacy against severe malaria in 5-17 month old children was 31.5% with reductions in severe anaemia, malaria hospitalizations and all-cause hospitalizations also seen.
Without a fourth dose (i.e., three-dose schedule at 0, 1, 2 months), no protection was seen against severe malaria, as cases prevented in the first 18 months were shifted to older age groups. These results highlight the importance of a fourth dose with this vaccine, as efficacy is short-lived.
Vaccine efficacy against clinical malaria in 6-12 week old children was 27% in the group who received four doses on a 0, 1, 2, 20 month schedule the full duration of the trial, and 18% in the group that did not receive the fourth . In 6-12 week old children, no significant efficacy was noted against severe malaria, with or without a fourth dose.
In children in the older age group there was an excess risk of febrile seizures within 7 days after any of the vaccine doses. In children in the younger age group this excess risk was only apparent after the fourth dose. There were no long-lasting sequelae due to any of the febrile seizures.
In children in the older age group there was an increased number of meningitis cases in malaria vaccine groups compared to the control group. These meningitis cases were not temporally related to the timing of vaccine doses and there were a range of aetiologies in the cases identified. An excess of meningitis was not seen in children vaccinated in the younger age group. The cause of this increase in meningitis is unknown.
In children in the older age group there was an increased number of cerebral malaria cases in malaria vaccine groups compared to the control group. This finding was in a subgroup analysis and its significance in relation to vaccination is unclear.
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 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". This is not licensure, but provides a scientific opinion which African regulators may use to help their own regulatory processes. EMA’s opinion was positive indicating that in their assessment the quality of the vaccine and the risk/benefit is favourable from a regulatory perspective. This 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 vaccine will be done by African national regulatory authorities that will consider licensing the vaccine in their jurisdictions. African regulators will consider this when the manufacturer makes a regulatory submission to them, which has not yet occurred.
Therefore for the time being RTS,S/AS01 remains an unlicensed vaccine.
When will WHO consider a recommendation for the use of RTS,S/AS01 vaccine?
WHO will convene 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/AS01 efficacy and safety, as well as other relevant data for global policy. SAGE/MPAC will propose recommendations to WHO for the use of RTS,S/AS01 in October 2015. It is planned that WHO will make its official policy position available by the end of November 2015.
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 about 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 now 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 some 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. 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/AS01 is being considered as a complementary intervention, i.e. any use of RTS,S/AS01 would be in addition to scaled-up access to and use of non-vaccine malaria preventive measures, prompt diagnostic testing and effective anti-malarial medicines.
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 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.