Dr. Patricia Wambui Njuguna. Photo credit: PATH Malaria Vaccine Initiative/David Poland
1 Jun 2010

Late-stage clinical testing of the PATH Malaria Vaccine Initiative's leading vaccine candidate, GlaxoSmithKline Biologicals' (GSK Bio) RTS,S is underway at 11 sites in seven African countries (Gabon, Mozambique, Tanzania, Ghana, Kenya, Malawi, and Burkina Faso). The Phase 3 trial, which was launched in May 2009 by MVI and GSK Bio along with leading African research institutions, is to involve up to 16,000 infants and young children, the groups who would benefit most from an effective malaria vaccine.

MVI recently spoke with one of the people with a leading role in the trial—Dr. Patricia Wambui Njuguna, who is Principal Investigator for the Kenya Medical Research Institute (KEMRI) Kilifi site in Kenya, Site Pediatrician, and co-chair of the Clinical Trials Partnership Committee (CTPC).

Day of the African Child

Q: June 16 is observed as Day of the African Child.* Can you explain why young children suffer disproportionately from malaria?

A: Young children are most vulnerable to all infections as their immune systems are still quite naive. In malaria especially, they have not had previous exposure, which is the current way persons living in endemic areas develop partial immunity. As they grow older, they suffer fewer and milder episodes of malaria as they build their immunity both by exposure and maturity.

What the Phase 3 study of RTS,S aims to show

Q: What are the primary and secondary objectives of the study?

A: The primary objective is to show that the RTS,S candidate vaccine protects against clinical episodes of malaria. We would like to replicate previous Phase 2 study results—where the vaccine's protection was 50 percent—in this larger study.

The secondary objectives are many. Those of importance are: to show that the RTS,S candidate vaccine protects against severe malaria episodes (by stopping mild malaria) and that the effect is the same when HIV and malnutrition are present, in different malaria transmission areas.

Q: What have previous studies of RTS,S shown with regard to the different age groups?

A: Previous studies have shown vaccine efficacy of 50 percent against episodes of clinical malaria in children 5 to 17 months old and up to 65 percent efficacy against malaria infection (over a six-month period) in infants when co-administered with the Expanded Programme on Immunization (EPI) vaccines. This suggests it can be targeted to infants, where the greatest protection has been observed.

Q: Apart from its sheer size, how is the Phase 3 trial different from previous trials of the RTS,S vaccine candidate?

A: The Phase 3 trial is no longer a proof-of-concept trial, but aims to show that the vaccine can work in a general population. It also will address public health interests such as length of immunity (longer follow-up to 32 months is planned) and vaccine efficacy across different transmission areas (conducted across seven countries, at 11 sites). It has also standardized the definitions of severe malaria under the severe malaria algorithm introduced across all the sites.

Recruiting from local communities

Q: Overall, the study is more than two-thirds into the enrollment of young children. When did actual vaccination begin at your site, and when do you anticipate it will end?

A: At our site, the first child was vaccinated on August 3, 2009. We anticipate completing the primary course of three vaccinations for both age groups by mid-2011. The booster course of vaccines will be completed in mid-2012.

Q: How many children do you expect to recruit at your site?

A: We aim to recruit about 900 children at our site.

Q: Has participation in the RTS,S trials benefited your research center and the local community? In what ways?

A: Staff have been trained in the conduct of the study, and the research center has benefited from resources, such as X-ray machines and bedside lab tests. The local health facilities have had infrastructural development, increased staffing, and staff support that includes more doctors, clinical officers, and nurses. In Phase 2, a vaccination center was built in nearby Junju. There has also been increased support for access to health facilities for study participants, and local persons have been employed where possible.

Q: How has recruitment of the 5 to 17 months cohort differed from recruitment of children 6 to 12 weeks old?

A: Recruitment of the 5 to 17 months cohort was achieved in a short time as the children were already there. Recruitment of the 6 to 12 weeks cohort will be achieved over a longer period because we are recruiting as they are born. The birth rate in our region has fallen over time due to increased family planning uptake and food insecurity. The age group is also more sensitive, since with younger infants, parents may be more cautious to enroll in the study.

Q: What has been the reaction or response of the local community to participating in the RTS,S trials?

A: It has been a positive response. The community is interested in participating and if the vaccine becomes available would be willing to take it up.

Managing a trial this big

Q: This trial is spread across 11 sites in seven countries—a magnitude much greater than the Phase 2 trial. How does one manage an endeavor like this?

A: The partnership (GSK Bio and MVI) has had to marshal resources to support the 11 sites involved in running a study that is compliant with Good Clinical Practices. A clear communication plan was put in place to ensure timely feedback to all parties. An efficient and supportive monitoring team was engaged and this is constantly reviewed. Regular meetings among parties, either in person or by telephone, have helped address any upcoming issues.

Q: What are some of the challenges to hosting and conducting a study of this size and nature?

A: Challenges have been linked to communication breakdowns where messages were late in being communicated to the team. Monitoring visits have been very frequent, thus affecting data management timelines. The magnitude of the data generated was not anticipated.

Q: How did a study center like yours prepare for a study this large?

A: We identified a core study team, which was essential for study preparation and set up. We had to identify the sites for the study, and make the attendant infrastructural input at the sites.

Looking ahead

Q: When will we know how efficacious and safe this vaccine is?

A: Under current plans, the file for the RTS,S vaccine candidate would be submitted to regulatory authorities in 2012 based on efficacy in children 5 to 17 months old. Additional safety and immunogenicity data from the infant population will be submitted soon thereafter, followed by efficacy data for infants once available. It should be noted that many Phase 2 trials examined the safety of RTS,S and to date it has been shown to have a very good safety profile.

Q: Could the varying transmission settings at the sites affect the way the vaccine works?

A: This is one of the questions we will answer from the Phase 3 results. (I anticipate protection will be seen in the moderate to high transmission areas, but we need to see the data before coming to conclusions.)

Q: When will this vaccine be available?

A: If all goes well, general implementation of RTS,S for infants 6 to 12 weeks old is possible within five years or so. The vaccine could be available for targeted use among young children 5 to 17 months old as early as 2013.

Q: What would the development of an efficacious malaria vaccine mean?

A: An efficacious malaria vaccine would mean that we could reduce the burden of sickness and death to affected populations in Kenya. It would mean less anaemia, better cognitive performance (better school performance), and more productivity as parents have more time and resources for development.

*The Day of the African Child was proclaimed in 1991 by the Organization of African Unity. Since then, it has been observed on June 16 every year and places the spotlight on the lives of African children. This year's theme focuses on planning and budgeting for African children as a collective responsibility. To find out more, visit the UNICEF website.

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