- Open Access
Design of a phase III multicenter trial to evaluate the efficacy of the RTS,S/AS01 malaria vaccine in children across diverse transmission settings in Africa
© Leach et al; licensee BioMed Central Ltd. 2011
- Received: 3 March 2011
- Accepted: 4 August 2011
- Published: 4 August 2011
GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative are working in partnership to develop a malaria vaccine to protect infants and children living in malaria endemic regions of sub-Saharan Africa, which can be delivered through the Expanded Programme on Immunization. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and shown to have a favourable safety profile and to be well-tolerated in both adults and children. This paper details the design of the phase III multicentre efficacy trial of the RTS,S/AS01 malaria vaccine candidate, which is pivotal for licensure and policy decision-making.
The phase III trial is a randomized, controlled, multicentre, participant- and observer-blind study on-going in 11 centres associated with different malaria transmission settings in seven countries in sub-Saharan Africa. A minimum of 6,000 children in each of two age categories (6-12 weeks, 5-17 months) have been enrolled. Children were randomized 1:1:1 to one of three study groups: (1) primary vaccination with RTS,S/AS01 and booster dose of RTS,S/AS01; (2) primary vaccination with RTS,S/AS01 and a control vaccine at time of booster; (3) primary vaccination with control vaccine and a control vaccine at time of booster. Primary vaccination comprises three doses at monthly intervals; the booster dose is administered at 18 months post-primary course. Subjects will be followed to study month 32. The co-primary objectives are the evaluation of efficacy over one year post-dose 3 against clinical malaria when primary immunization is delivered at: (1) 6-12 weeks of age, with co-administration of DTPwHepB/Hib antigens and OPV; (2) 5-17 months of age. Secondary objectives include evaluation of vaccine efficacy against severe malaria, anaemia, malaria hospitalization, fatal malaria, all-cause mortality and other serious illnesses including sepsis and pneumonia. Efficacy of the vaccine against clinical malaria under different transmission settings, the evolution of efficacy over time and the potential benefit of a booster will be evaluated. In addition, the effect of RTS,S/AS01 vaccination on growth, and the safety and immunogenicity in HIV-infected and malnourished children will be assessed. Safety of the primary course of immunization and the booster dose will be documented in both age categories.
This pivotal phase III study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study will provide efficacy and safety data to fulfil regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions.
- Severe Malaria
- Indoor Residual Spray
- Vaccine Efficacy
- Clinical Malaria
The past decade has seen unparalleled advances in the fight against malaria, and numerous public and private organizations are contributing hundreds of millions of dollars to malaria infection and disease research [1, 2]. Malaria control interventions, including the use of long-lasting insecticide-treated nets and artemisinin-based combination treatment, have been broadly implemented , with some countries recently reporting an associated fall in malaria incidence . Nevertheless, malaria continues to impose a considerable burden of morbidity and mortality, most significantly in young children, and reducing this burden in this population is, therefore, a public health priority in sub-Saharan Africa [4, 5].
A safe and affordable vaccine would be a valuable addition to existing control measures. GlaxoSmithKline (GSK) Biologicals has been working towards the development of a safe and effective malaria vaccine for more than 20 years and has developed a candidate Plasmodium falciparum malaria vaccine, RTS,S/AS01, which is currently in phase III clinical trials in infants and children living in malaria-endemic regions of sub-Saharan Africa . It is intended that the vaccine will be delivered through the Expanded Programme on Immunization (EPI) to leverage the vaccine delivery systems used to routinely administer immunizations to young children.
The candidate malaria vaccine targets the pre-erythrocytic stage of the P. falciparum parasite. It contains the RTS,S antigen and is formulated with a novel proprietary Adjuvant System (AS). Clinical trials of the vaccine formulated with closely related Adjuvant Systems - AS01 or AS02 - have been conducted, and the RTS,S/AS01 formulation has been selected for phase III development based on comparative clinical studies [7, 8]. AS01 is composed of liposomes and the immunomodulatory molecules, 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and QS21 .
A series of phase II clinical trials have been conducted to determine the safety, immunogenicity and efficacy of the RTS,S/AS vaccine in the target population of children at high risk of the disease. A proof-of-concept study in children aged 1-4 years in Mozambique showed that the RTS,S/AS02 vaccine was well-tolerated, with a vaccine efficacy of 35% against clinical malaria and 49% against severe malaria over 18 months [10, 11]. Subsequent studies in infants have shown that the vaccine is well-tolerated and immunogenic in infants from 6 weeks of age, and can be successfully integrated into the EPI schedule [12, 13]. Phase II studies have estimated the efficacy of the RTS,S/AS01 vaccine against clinical malaria to be 53% over eight months in 5-17 month old children and 59% over 17 months in 6-12 week old infants [14, 15]. At the end of phase II, a pooled analysis of all paediatric safety data was conducted to support the progression of the RTS,S/AS candidate vaccine into large scale phase III clinical testing in Africa. Analysis of the extensive safety database of RTS,S/AS confirmed the favourable safety profile of the vaccine in children and infants living in malaria endemic regions in sub-Saharan Africa [Vekemans, Guerra, Lievens, Benns, Lapierre, Leach, Verstraeten: Pooled safety analysis of paediatric phase II RTS,S/AS malaria candidate vaccine trials, submitted].
The licensure claim of vaccine efficacy will be based principally on a large phase III clinical trial. This paper describes the overall design of the phase III multicentre efficacy study of the candidate RTS,S/AS01 malaria vaccine. The aims of this study are two-fold. Firstly, it will provide pivotal efficacy and safety data to support regulatory approval of the vaccine by the European Medicines Agency (EMA) and African national regulatory authorities and to facilitate pre-qualification by the World Health Organization (WHO). Secondly, it includes a broad range of endpoints that will allow assessment of the full public health impact of the vaccine. This information will be required to support a recommendation by the WHO and implementation decisions by local policy makers, and is key to ensure uptake of the vaccine following licensure . Measures of vaccine efficacy on various disease endpoints in the phase III study may be utilized in an assessment of health economics. Additional data to support the full health economic evaluation are being collected in ancillary studies, such as assessment of quality of life, subject preferences, the measurement of resource utilization and direct and indirect costs, details of which will be described in separate publications.
The population of the phase III trial mirrors as closely as possible the population of children who usually attend EPI visits. Low-birth-weight infants, malnourished children, and HIV-infected children were eligible. For safety reasons, those that were critically sick were excluded: in particular any child who required hospital admission or had an advanced stage of HIV disease (WHO classification grade 3 or 4). A dedicated phase III study will assess safety and immunogenicity in children exposed to HIV (NCT01148459). Two further studies will evaluate the safety and immunogenicity of RTS,S/AS01: the first in co-administration with rotavirus and Streptococcus pneumoniae vaccines, which are expected to become part of the EPI program in the near future, and the second with three lots of RTS,S/AS01 vaccine in order to demonstrate lot-to-lot consistency.
Clinical development of the RTS,S/AS01 vaccine is undertaken in a public private partnership between GlaxoSmithKline and the PATH Malaria Vaccine Initiative (MVI), which receives funding from the Bill and Melinda Gates Foundation. The trial is also supported by the Malaria Clinical Trials Alliance (MCTA), an African-led organization that aims to build capacity and share best practice for the conduct of clinical trials. This multi-centre efficacy trial was designed by the Clinical Trials Partnership Committee (CTPC), which has membership representing each of the academic institutions participating in trial conduct, GSK Biologicals and MVI.
Treatment groups and vaccination schedule
Primary vaccination: 0, 1, 2 months
Booster vaccination: month 20
Children 5-17 months of age
Control (MCC vaccine)
Control (rabies vaccine)
Control (MCC vaccine)
Children 6-12 weeks of age
RTS,S/AS01 + DTPwHepB/Hib + OPV
RTS,S/AS01 + OPV
RTS,S/AS01 + DTPwHepB/Hib + OPV
Control (MCC vaccine) + OPV
Control (MCC vaccine) + DTPwHepB/Hib + OPV
Control (MCC vaccine) + OPV
Primary immunizations are administered by intramuscular injection into the antero-lateral thigh (children aged 6-12 weeks) or the left deltoid (children aged 5-17 months); all children receive the booster injection in the left deltoid. Neither the study subjects and their parents/guardians nor the study personnel involved in evaluation of the study endpoints are aware of the group allocation of the subjects. Because the study vaccines differ in appearance, the study staff responsible for their preparation and administration is aware of treatment allocation and therefore perform no other role in the trial.
There is no routine testing for HIV infection in this study, HIV tests are performed only if clinically indicated. Voluntary counselling and testing, Highly Active Antiretroviral Therapy (HAART) and Prevention of Mother to Child Transmission (PMCT) are available at all study centres according to national policies.
In accordance with national policies, all centres use artemisinin-based combination therapy (ACT) as first line treatment for malaria cases. The use of insecticide-treated bed nets is optimized at all centres by the close collaboration between research staff and malaria control program managers or through distribution at screening. Other control interventions such as intermittent preventive treatment in infants (IPTi) and indoor residual spraying (IRS) are not currently part of policy in the study areas, but if this changes during the trial, their use will be recorded.
The overall sample size has taken into account the recent description of falling rates of malaria disease in several parts of Africa. To be assured of meeting the primary endpoints, conservative rates of disease were applied in the calculation of sample size and a case driven approach selected . To control for the co-primary endpoint in each of the two age categories, evaluations will be performed at a 2.5% alpha level (Bonferroni correction). Assuming an attack rate in controls of 10/100 children years at risk (cyr), a 12 months follow up period, a true vaccine efficacy of 30% and a drop-out rate of 10% then the sample size of 6000 children in each age category has 90% power to detect a lower limit of the 97.5% CI around estimated VE above 0%. In the event that the attack rate is lower than anticipated, the analysis will be postponed until 450 cases have accumulated. Due to the uncertainty around the rate of severe malaria disease according to the case definitions used in the trial, the total sample size is up to 16000 children and the analysis will be conducted for both age categories pooled when 250 episodes have accumulated. This gives 80% power to detect 30% VE with a lower limit of the 95% CI above 0% or assuming 50% VE 90% power to detect a lower limit of the 95% CI above 25%.
Inclusion and exclusion criteria
Male and female children aged 6-12 weeks or 5-17 months at time of first vaccination
Children in 6-12 week age category must be more than 28 days old at screening and must not have received previous vaccination against diphtheria, tetanus, pertussis or Hemophilus influenzae type B
Acute disease at time of enrolment
Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality
Major congenital defect
Malnutrition requiring hospitalization
Hb ≤8 g/dL with clinical signs of heart failure or severe respiratory distress OR Hb ≤5 g/dL
Currently meeting WHO criteria for stage III or IV severity HIV disease
History of allergic reactions, significant IgE-mediated events or anaphylaxis to previous immunizations
History of allergic disease or reactions likely to exacerbated by any component of the vaccine
History of a neurological disorder or atypical febrile seizure
Concurrently participating in another clinical study of a drug or vaccine unlicensed for that indication, except studies aiming to improve treatment or management of severe malaria
Use of a drug or vaccine unlicensed for that indication other than study vaccines within 30 days preceding the first dose of study vaccine or planned use during the study period
Previous participation in another malaria vaccine trial
Receipt of a vaccine within the preceding 7 days
Other factors that the investigator considers would increase the risk of an adverse outcome or result in incomplete or poor quality data
The candidate malaria vaccine is RTS,S/AS01 (GSK Biologicals, Rixensart, Belgium). The RTS,S antigen is a hybrid recombinant protein consisting of the P. falciparum circumsporozoite (CS) protein central tandem repeat and carboxy-terminal regions fused to the amino-terminus of the S antigen of hepatitis B virus (HBsAg). The vaccine is formulated with the AS01 Adjuvant System.
The choice of comparator vaccines was guided by the need to offer potential benefit to the control group without compromising the evaluation of study endpoints. The pros and cons of a number of options were debated and consensus reached by the CTPC after taking into account regional epidemiology and EPI programs. Rabies vaccine was chosen as the control for the 5-17 month age category because of the high burden of rabies across all of sub-Saharan Africa, its high fatality rate and the particular risk to children [17–19]. Rabies vaccine has been evaluated according to several different vaccination schedules, and the 0, 1, 2-month schedule used in this trial is expected to produce acceptable antibody titers and provide protection. Rabies vaccine was not appropriate for children in the 6-12 week age category because co-administration with EPI antigens has not been evaluated. For the 6-12 week age group, consideration was given to vaccines against S. pneumoniae, which is a common cause of pneumonia in children in Africa. The reasons for not selecting pneumococcal vaccines were that they were expected to be implemented as policy in some countries prior to the enrolment and so would not provide additional benefit. In addition, there is a poorly understood interaction between malaria and pneumococcal infections. In paediatric hospital admissions, pneumonia and malaria co-occur more often than expected by chance . This may be due to the overlapping clinical symptoms and signs of pneumonia and malaria, or the immunosuppressive effect of malaria infection on pneumococcal pneumonia . The careful characterization of both malaria and pneumonia in this trial will also allow the study of the effect of malaria control on the incidence of pneumococcal disease . Meningococcal disease in Africa is most commonly due to serogroup A, however there currently is no meningococcal A vaccine licensed for use in infants. Meningococcal C conjugate vaccine was chosen because it is acceptably safe and immunogenic when administered according to a 0, 1, 2-month schedule, can be safely co-administered with the other vaccines and will not compromise the analysis of the study endpoints. Although meningitis C is not common in sub-Saharan Africa outbreaks have been reported [23–25] and, therefore, the vaccine may provide some benefit to study subjects.
Endpoint data collection
Clinical malaria cases are detected through passive surveillance at local health facilities. A blood sample for evaluation of malaria parasites is taken from all children with axillary temperature of ≥37.5°C or those reported to have had a fever within 24 hours of presentation. All subjects attending hospital emergency departments in the study areas are evaluated as potential cases of severe malaria following an algorithm, and case assessment is standardized across centers . The algorithm also allows identification of cases of anaemia, sepsis and pneumonia.
Two cross-sectional surveys will be conducted at study months 20 and 32 to assess vaccine efficacy against prevalent parasitaemia and anaemia. Data will be collected on potential covariates which may be included in the analysis of efficacy. These are bed net usage by direct observation, application of IRS, administered doses of IPTi, distance from nearest inpatient health facility, distance from nearest outpatient health facility, pneumococcal/Hib vaccination status, ethnicity, anthropometric measurements and feeding history.
Full quality systems are in place for all laboratory tests in the trial and these are described in a companion paper . Anti-CS and anti-HB antibody titers are measured at all blood sampling time points in a subset of children from both age categories at all sites (See Figure 2 for blood sampling time points). In addition, a nested case control study will evaluate the association between CS-antibody response and protection against malarial disease. In a safety and immunogenicity trial of RTS,S/AS01 co-administered with EPI vaccines, pre-defined non-inferiority criteria compared to control were met for all the DTPwHepB/Hib+OPV, measles and yellow fever antigens, with the exception of polio 3 viruses when RTS,S/AS01 was administered at 0, 1, 2-months . Although a post-hoc analysis showed that differences were explained by pre-vaccination titres, additional data will be collected in this phase III study. Titres will be assessed in a subset of infants in the 6-12 week age category at each site at three time points: study start, one month post primary vaccination, and one month post OPV booster vaccination.
Serious adverse events (SAE) are collected for all subjects for the entire study period. Completeness of SAE reporting is strengthened by monthly visits of field workers to the children's homes. SAEs are defined as AEs resulting in death, which are life-threatening or require hospitalization or prolongation of existing hospitalization or those that result in disability or incapacity. Unsolicited AEs occurring during the 30 days after each vaccine dose and solicited AEs occurring during the seven days after each vaccine dose are collected for the first 200 children enrolled in each age category at each centre. In the remainder of children, only AEs that are considered to be related to vaccination or those resulting in study withdrawal are recorded. Investigators will grade all AEs and SAEs as mild, moderate or severe based on a scale of interference with normal daily activities, and assess the relationship to vaccination.
Seizures occurring within 30 days of vaccination are also required to be reported as SAEs. For seizures occurring within seven days of vaccination, an analysis will be performed based on the Brighton Collaborations guidelines, which captures the features of the seizure and classifies the level of diagnostic certainty . In the first 200 subjects enrolled at each site in the six to 12 weeks age category an analysis of rashes and mucocutaneous diseases within 30 days of vaccination will be performed based on the Brighton Collaboration Guidelines . Due to a theoretical concern that the use of new adjuvanted vaccines may interfere with immunological self-tolerance, regulatory authorities have requested data collection on immune-mediated diseases (IMD). Therefore, all IMDs are reported as SAEs for all subjects over the entire study period. Diagnostic support at a referral laboratory is provided.
Solicited local (injection site) AEs recorded are pain, swelling and redness; grading of symptoms is on a scale of 0-3. Solicited general AEs recorded are drowsiness, fever, irritability/fussiness and loss of appetite; intensity of symptoms (except fever) are graded on a scale of 0-3 based on interference with normal daily activities; fever is defined as axillary temperature ≥37.5°C. Methods have been fully described previously .
Verbal autopsies are carried out for all children who die outside a health facility to ascribe the cause of death. The questionnaire used is based on the INDEPTH standard and adapted to be locally appropriate . At study end, all forms will be read by a central panel to attribute cause of death. As a general health indicator, growth is monitored throughout the study according to standardized methods. The length (<2 years of age) and height (≥2 years of age), weight and mid-upper arm circumference are measured at first vaccination and at study months 3, 20 and 32.
Safety and immunogenicity will be described in the special sub-populations of malnourished and HIV-infected children. Weight at enrolment will be used to determine a subset of children who are low weight for age (weight for age z-score ≤-2) and very low weight for age (weight for age z-score ≤-3). HIV infections known at enrolment or diagnosed during the trial are recorded.
Study objectives and case definitions
Primary efficacy objectives
Efficacy against clinical malaria over 1 year in children aged 6-12 weeks at first vaccination (co-administration of DTPwHepB/Hib)1
Efficacy against clinical malaria over 1 year in children aged 5-17 months at first vaccination1
Efficacy against severe malaria
Prevention of anaemia (incident severe anaemia; prevalent moderate and severe anaemia)
Prevention of malaria hospitalization
Evolution over time of efficacy following the primary vaccination course
Additional benefit of a booster dose
Efficacy in different transmission settings
Efficacy against parasite prevalence
Efficacy against other serious illnesses (medical hospitalization, sepsis and pneumonia)
Efficacy against fatal malaria and all-cause mortality
Effect on growth
Immunogenicity of a primary vaccination course
Immunogenicity of a booster dose
Immunological correlates of protection
Immunogenicity of the oral polio vaccine when co-administered with RTS,S/AS01
Safety of a primary vaccination course
Safety of a booster dose
Immunogenicity and safety in HIV-infected children
Immunogenicity and safety in low weight for age children
Case definition of clinical malaria
Secondary definition 1
Secondary definition 2
Secondary definition 3
Threshold of P. falciparum asexual parasitaemia
axillary temperature ≥37.5°C
axillary temperature ≥37.5°Cor history of fever within 24 h of presentation
axillary temperature ≥37.5°C
axillary temperature ≥37.5°C)
Child is unwell and brought to healthcare facility
Child is unwell and brought to healthcare facility
Child is unwell and brought to healthcare facility
Child is unwell and brought to healthcare facility
Meets primary case definition of severe malaria1
Another criterion of the definition is a parasite density threshold. This has been added to increase the specificity of the case definition. Achieving a balance between specificity and sensitivity is a major challenge in defining endpoints in malaria vaccine trials. Low specificity means that vaccine efficacy is likely to be underestimated, whereas low sensitivity means that the power of the study will be reduced . Achieving adequate specificity in the case definition of clinical malaria is difficult, as the symptoms of malaria overlap with those of many other common febrile childhood illnesses. It is well recognized that as parasite density increases, the likelihood that symptoms are caused by P. falciparum infection also increases. A widely-used methodology in malaria research is applied to calculate the specificity and sensitivity of clinical case definitions according to parasite density threshold values . A single parasite density threshold of 5,000 parasites/μL is employed across all centres for the primary endpoint to support pooling of data. This threshold was based on data from previous studies [35–40], and provides a minimum specificity of 80% for all transmission settings and age categories in this trial. By adding the requirement for fever and a parasite density threshold we adhere to the accepted practice to evaluate malaria disease interventions. However, in the evaluation of IPTi, using case definitions with varying parasite density thresholds has not yielded the expected increase in specificity reflected in the estimate of effect . In the case of an intervention that is equally protective against symptomatic parasitaemia and asymptomatic parasitaemia less specific definitions for malaria disease may not significantly impact efficacy estimates. This appears to be the case for this pre-erythrocytic vaccine [14, 42].
The principal analysis for the determination of the primary endpoint is protection against first or only episodes of malaria using a hazard ratio estimated from Cox regression model. This will be adjusted for centres to control for differences in malaria transmission between centres. The statistical methodology is further discussed in the companion paper .
Secondary efficacy objectives
Case definitions of secondary efficacy endpoints
Incident severe anaemia 1
Hb <5.0 g/dL identified on morbidity surveillance in association with P falciparum parasitaemia >5000 parasites/μL
Hb <5.0 g/dL identified on morbidity surveillance
1. P falciparum parasitaemia >0 parasites/μL
2. No parasitaemia
Prevalent anaemia 1
Hb <5.0 g/dL identified at cross sectional survey
Hb <8.0 g/dL identified at cross sectional survey
Medical hospitalisation2 in association with P falciparum parasitaemia >5000 parasites/μL
P falciparum infection is sole or major cause of hospitalization on investigators' clinical judgement
Positive blood culture7
Cough or difficulty breathing (on history)
Tachypnoea (≥50 breaths per minute in children <1 year, ≥40 breaths per minute in children ≥1 year)
Lower chest wall in-drawing
As definition 1, PLUS
1. Chest X-ray consolidation or pleural effusion on a chest X-ray taken within 72 h of admission
2. Chest X-ray consolidation or pleural effusion or other infiltrates on a chest X-ray taken within 72 h of admission
3. Oxygen saturation <90%
Fatal case of severe malaria according to primary case definition 3,4
Fatal case of severe malaria according to secondary definitions 3,4
Death due to any cause5
Death due to medical cause5,6
The case definitions have been selected to be consistent with usual practice wherever possible to allow generalizability of trial findings and comparability with other interventions. Where applicable for fuller interpretation of the data, multiple case definitions for a given endpoint have been used. For example, three secondary definitions of clinical malaria will be analysed (Table 4). The first is highly sensitive and includes detection of any parasite level, plus a history of fever, and is not limited to measured fever at presentation. This definition mirrors the children who are treated under current WHO guidelines and will be important for consideration of the impact of the vaccine on disease burden and in health economic analyses. The second case definition is designed for the analysis of infants; the lower parasite density threshold of >500 parasites/μL may be appropriate for this age group [36, 40]. The third definition, with a high parasite density threshold, is included because it is highly specific.
This study aims to characterize the potential indirect benefits of malaria control through vaccination using the complete morbidity data set collected. Trials with insecticide-treated bed nets have shown a reduction in all-cause mortality that is not solely accounted for by malaria-specific mortality characterized on verbal autopsy [44, 45]. There was an indication of indirect benefits associated with RTS,S/AS vaccination in phase II trials; in one study, the overall trend of fewer SAEs in vaccine recipients was only partly accounted for by malaria events , and in another study, pneumonia hospitalization was less common in vaccine recipients . Specifically, the possible vaccine benefit on bacteraemia/sepsis and pneumonia will be investigated. The evaluation and definition of pneumonia is based on the extensive methodological and case definition work done to support paediatric pneumococcal conjugate vaccine trials .
How the spectrum of clinical benefits provided by vaccination evolves with time will be critically important for policy decisions. This trial will provide information up to 2.5 years after a primary vaccination course. The evaluation of efficacy over time is complicated; children progressively acquire natural immunity as they age and therefore whilst the biological action of the vaccine may persist unchanged the vaccine efficacy that is measured relative to control will fall. Inclusion of a group that will receive a booster dose allows the potential benefit of a primary course plus booster to be measured against both the comparator and against the primary course alone.
To support extrapolation of trial results to other regions, data will be generated from a number of diverse malaria transmission settings; the participating centers are shown superimposed on the Mapping Malaria Risk in Africa (MARA) map of malaria risk in Africa in Figure 1. Site-specific estimates of efficacy against clinical malaria will be produced (this is further detailed in a companion paper ).
This pivotal phase III efficacy study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study design is in full accord with the conclusions of the WHO expert panel on the measurement of malaria vaccine efficacy in phase III clinical trials . The design described here evolved over approximately five years of planning, through collaboration between, and with input from, scientists, regulators, and policy-makers. The study will provide efficacy and safety data to fulfil regulatory requirements, and will supply data on a broad range of disease endpoints that will allow evaluation of the public health impact of the vaccine. Data from the primary analysis of clinical malaria one year after completion of the primary immunization course of children aged 5-17 months are expected to be available in 2012. At the end of the study in 2015, data will be available on a wide range of disease endpoints, as well as information on the evolution of efficacy over time, the potential added benefit of a booster dose and long-term safety.
The authors would particularly like to acknowledge the consistent support and scientific input in the development of the trial design of these experts: Bernhards Ogutu (Malaria Clinical Trials Alliance), Jessica Milman (Bill and Melinda Gates Foundation), Vasee Moorthy (WHO), Lorenz von-Seidlein, Alice Grasset, Anne Walsh, Didier Lapierre, Patricia Atkinson. Lorenz von-Seidlein, Alice Grasset, Anne Walsh, Didier Lapierre, Patricia Atkinson. Philip Bejon is funded by the NIHR Biomedical research Centre in Oxford. Editorial assistance and manuscript coordination were provided by Julia Donnelly, Jarno Jansen, Mary Greenacre and Sarah Benns on behalf of GlaxoSmithKline Biologicals.
Members of the Clinical Trials Partnership Committee during the period of protocol development (2005-2009):
Kintampo Health Research Centre, Ghana: Seth Owusu-Agyei, Kwaku Poku Asante; Ifakara Health Institute, Tanzania: Salim Abdulla; Centro de Investigação em Saude de Manhiça, Mozambique: Eusebio Macete, Jahit Sacarlal; KEMRI-Wellcome Trust Research Programme, Kenya: Philip Bejon, Trudie Lang, Kevin Marsh, Patricia Njuguna, Ally Olotu;
Institut de Recherche en Science de la Santé, Burkina Faso: Tinto Halidou; Albert Schweitzer Hospital, Gabon: Selidji Todagbe Agnandji, Bertrand Lell; Kumasi Centre for Collaborative Research, Ghana: Jennifer Evans; School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Ghana: Tsiri Agbenyega, Daniel Ansong;
KEMRI/CDC Research and Public Health Collaboration, Kenya: Mary J Hamel, Simon Kariuki; KEMRI-Walter Reed Project, Kenya: David Jones, Walter Otieno; University of North Carolina Project, Malawi: Francis Martinson; Institut de Recherche pour le Development, Senegal: Cheikh Sadibou-Sokhna, Jean-François Trape; National Institute of Medical Research, Tanzania: Samwel Gesase, Martha Lemnge, John Lusingu; Prince Leopold Institute of Tropical Medicine, Belgium: Umberto D'Alessandro; University of Tübingen, Germany: Peter Kremsner, Centre de Recerca en Salut Internacional de Barcelona (CRESIB), Hospital Clínic, Universitat de Barcelona, Spain: John Aponte; Swiss Tropical Institute, Switzerland: Marcel Tanner, London School of Hygiene and Tropical Medicine, UK: Brian Greenwood; Centers for Disease Control and Prevention, USA: Laurence Slutsker; University of North Carolina at Chapel Hill, USA: Irving Hoffman
GlaxoSmithKline Biologicals, Belgium: W. Ripley Ballou, Amanda Leach, Johan Vekemans, Laurence Vigneron; Malaria Vaccine Initiative, USA: Alan Brooks, Filip Dubovsky, Santiago Ferro Carol Hooks, Christian Loucq, Melinda Moree, John McNeil, Carolyn Petersen, David Poland, Barbara Savarese, Marla Sillman, Tonya Villafana
Disclaimer: Views expressed in this paper represent those of the authors and do not necessarily reflect those of the US Centers for Disease Control and Prevention
- Breman JG, Alilio MS, White NJ: Defining and defeating the intolerable burden of malaria III. Progress and perspectives. Summary. Am J Trop Med Hyg. 2007, 77 (Suppl 6): vi-xi.Google Scholar
- Anon: Rolling back malaria - the next 10 years. Lancet. 2008, 372: 1193-10.1016/S0140-6736(08)61494-4.View ArticleGoogle Scholar
- O'Meara WP, Mangeni JN, Steketee R, Greenwood B: Changes in the burden of malaria in sub-Saharan Africa. Lancet Inf Dis. 2010, 10: 545-555. 10.1016/S1473-3099(10)70096-7.View ArticleGoogle Scholar
- WHO: World Malaria Report. 2010Google Scholar
- Carneiro I, Roca-Feltrer A, Griffin JT, Smith L, Tanner M, Schellenberg JA, Greenwood B, Schellenberg D: Age-Patterns of malaria vary with severity, transmission intensity and seasonality in sub-Saharan Africa: a systematic review and pooled analysis. PLoS ONE. 2010, 5: e8988-10.1371/journal.pone.0008988.PubMed CentralView ArticlePubMedGoogle Scholar
- ClinicalTrials.gov. [http://clinicaltrials.gov/ct2/results?term=NCT00866619]
- Kester KE, Cummings JF, Ofori-Anyinam O, Ockenhouse CF, Krzych U, Moris P, Schwenk R, Nielsen RA, Debebe Z, Pinelis E, Juompan L, Williams J, Dowler M, Stewart VA, Wirtz RA, Dubois MC, Lievens M, Cohen J, Ballou WR, Heppner DG, S Vaccine Evaluation Group: Randomized, double-blind, phase 2a trial of Falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis. 2009, 200: 337-346. 10.1086/600120.View ArticlePubMedGoogle Scholar
- Polhemus ME, Remich SA, Ogutu BR, Waitumbi JN, Otieno L, Apollo S, Cummings JF, Kester KE, Ockenhouse CF, Stewart A, Ofori-Anyinam O, Ramboer I, Cahill CP, Lievens M, Dubois M, Demoitie M, Leach A, Cohen J, Ballou WR, Heppner DG: Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLoS ONE. 2009, 4: e6465-10.1371/journal.pone.0006465.PubMed CentralView ArticlePubMedGoogle Scholar
- Garçon N, Chomez P, Van Mechelen M: GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives. Expert Rev Vaccines. 2007, 6: 723-39. 10.1586/147605184.108.40.2063.View ArticlePubMedGoogle Scholar
- Sacarlal J, Aponte JJ, Aide P, Mandomando I, Bassat Q, Guinovart C, Leach A, Milman J, Macete E, Espasa M, Ofori-Anyinam O, Thonnard J, Corachan S, Dubois MC, Lievens M, Dubovsky F, Ballou WR, Cohen J, Alonso PL: Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a phase IIb trial. Vaccine. 2008, 26: 174-184. 10.1016/j.vaccine.2007.11.003.View ArticlePubMedGoogle Scholar
- Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Aide P, Sigauque B, Milman J, Mandomando I, Bassat Q, Guinovart C, Espasa M, Corachan S, Lievens M, Navia MM, Dubois MC, Menendez C, Dubovsky F, Cohen J, Thompson R, Ballou WR: Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet. 2005, 366: 2012-2018. 10.1016/S0140-6736(05)67669-6.View ArticlePubMedGoogle Scholar
- Aponte JJ, Aide P, Renom M, Mandomando I, Bassat Q, Sacarlal J, Manaca MN, Lafuente S, Barbosa A, Leach A, Lievens M, Vekemans J, Sigauque B, Dubois MC, Demoitié MA, Sillman M, Savarese B, McNeil JG, Macete E, Ballou WR, Cohen J, Alonso PL: Safety of the RTS,S/AS02D candidate malaria vaccine in infants living in a highly endemic area of Mozambique: a double blind randomised controlled phase I/IIb trial. Lancet. 2007, 370: 1543-1551. 10.1016/S0140-6736(07)61542-6.View ArticlePubMedGoogle Scholar
- Abdulla S, Oberholzer R, Juma O, Kubhoja S, Machera F, Membi C, Omari S, Urassa A, Mshinda H, Jumanne A, Salim N, Shomari M, Aebi T, Schellenberg DM, Carter T, Villafana T, Demoitié MA, Dubois MC, Leach A, Lievens M, Vekemans J, Cohen J, Ballou WR, Tanner M: Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med. 2008, 359: 2533-2544. 10.1056/NEJMoa0807773.View ArticlePubMedGoogle Scholar
- Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, Mshamu S, Lang T, Gould J, Dubois MC, Demoitié MA, Stallaert JF, Vansadia P, Carter T, Njuguna P, Awuondo KO, Malabeja A, Abdul O, Gesase S, Mturi N, Drakeley CJ, Savarese B, Villafana T, Ballou WR, Cohen J, Riley EM, Lemnge MM, Marsh K, von Seidlein L: Efficacy of RTS,S/AS01 vaccine against malaria in children 5 to 17 months of age. N Engl J Med. 2008, 359: 2521-2532. 10.1056/NEJMoa0807381.PubMed CentralView ArticlePubMedGoogle Scholar
- Asante KP, Agnandji ST, Lyimo J, Vekemans J, Soulanoudjingar SS, Owusu R, Shomari M, Leach A, Fernandes J, Dosoo D, Chikawe M, Issifou S, Osei-Kwakye K, Lievens M, Paricek M, Apanga S, Mwangoka G, Okissi B, Kwara E, Minja R, Lange J, Boahen O, Kayan K, Adjei G, Chandramohan D, Jongert E, Demoitié MA, Dubois MC, Carter T, Vansadia P, Villafana T, Sillman M, Savarese B, Loucq C, Lapierre D, Ballou WR, Greenwood B, Tanner M, Cohen J, Kremsner PG, Lell B, Owusu-Agyei S, Abdulla S: Safety and efficacy over 19 months of the RTS,S/AS01E candidate malaria vaccine co-administered with Expanded Program of Immunization vaccines: an open randomized controlled trial. Lancet Infect Dis.Google Scholar
- Milstien J, Cárdenas V, Cheyne J, Brooks A: WHO policy development processes for a new vaccine: case study of malaria vaccines. Malar J. 2010, 9: 182-10.1186/1475-2875-9-182.PubMed CentralView ArticlePubMedGoogle Scholar
- Knobel DL, Cleaveland S, Coleman PG, Fèvre EM, Meltzer MI, Miranda ME, Shaw A, Zinsstag J, Meslin FX: Re-evaluating the burden of rabies in Africa and Asia. Bull World Health Organ. 2005, 83: 360-368.PubMed CentralPubMedGoogle Scholar
- Plotkin SA, Ruprecht CE, Koprowski H: Rabies Vaccine. Vaccines. Edited by: Plotkin SA, Orenstein WA. 2004, Philadelphia, Pennsylvania: WB Saunders Company, 4Google Scholar
- Dodet B: The fight against rabies in Africa: From recognition to action. Vaccine. 2009, 27: 5027-5032. 10.1016/j.vaccine.2009.06.030.View ArticlePubMedGoogle Scholar
- Mulholland K: Commentary: Comorbidity as a factor in child health and child survival in developing countries. Int J Epidemiol. 2005, 34: 375-377. 10.1093/ije/dyi028.View ArticlePubMedGoogle Scholar
- O'Dempsey TJD, McArdle TF, Laurence BE, Lamont AC, Todd JE, Greenwood BM: Overlap in the clinical features of pneumonia and malaria in African children. Trans R Soc Trop Med Hyg. 1993, 87: 662-665. 10.1016/0035-9203(93)90279-Y.View ArticlePubMedGoogle Scholar
- Vekemans J, Marsh K, Greenwood B, Leach A, Kabore W, Soulanoudjingar S, Asante KP, Ansong D, Evans J, Sacarlal J, Bejon P, Kamthunzi P, Salim N, Njuguna P, Hamel M, Otieno W, Gesase S, Schellenberg D: Assessment of severe malaria in a multicentre, phase III, RTS,S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care. Malar J.Google Scholar
- Whittle HC, Greenwood BM: Meningococcal meningitis in the northern savanna of Africa. Trop Doct. 1976, 6: 99-104.PubMedGoogle Scholar
- Broome CV, Rugh MA, Yada AA, Giat L, Giat H, Zeltner JM, Sanborn WR, Fraser DW: Epidemic group C meningococcal meningitis in Upper Volta, 1979. Bull World Health Organ. 1983, 61: 325-330.PubMed CentralPubMedGoogle Scholar
- Kwara A, Adegbola RA, Corrah PT, Weber M, Achtman M, Morelli G, Caugant DA, Greenwood BM: Meningitis caused by a serogroup W135 clone of the ET-37 complex of Neisseria meningitidis in West Africa. Trop Med Int Health. 1998, 3: 742-746. 10.1046/j.1365-3156.1998.00300.x.View ArticlePubMedGoogle Scholar
- Swysen C, Vekemans J, Bruls M, Oyakhirome S, Drakeley C, Kremsner P, Greenwood B, Ofori-Anyinam O, Okech B, Villafana T, Carter T, Savarese B, Duse A, Reijman A, Ingram C, Frean J, Ogutu B: Development of standardized laboratory methods and quality processes for a phase III study of the RTS,S/AS01 candidate malaria vaccine. Malar J.Google Scholar
- Agnandji ST, Asante KP, Lyimo J, Vekemans J, Soulanoudjingar SS, Owusu R, Shomari M, Leach A, Fernandes J, Dosoo D, Chikawe M, Issifou S, Osei-Kwakye K, Lievens M, Paricek M, Apanga S, Mwangoka G, Okissi B, Kwara E, Minja R, Lange J, Boahen O, Kayan K, Adjei G, Chandramohan D, Jongert E, Demoitié MA, Dubois MC, Carter T, Vansadia P, Villafana T, Sillman M, Savarese B, Lapierre D, Ballou WR, Greenwood B, Tanner M, Cohen J, Kremsner PG, Lell B, Owusu-Agyei S, Abdulla S: Evaluation of the safety and immunogenicity of the RTS,S/AS01 malaria candidate vaccine when integrated in the Expanded Program of Immunization. J Infect Dis. 2010, 202: 1076-1087. 10.1086/656190.View ArticlePubMedGoogle Scholar
- Bonhoeffer J, Menkes J, Gold MS, de Souza-Brito G, Fisher MC, Halsey N, Vermeer P, Brighton Collaboration Seizure Working Group: Generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. Vaccine. 2004, 22: 557-562. 10.1016/j.vaccine.2003.09.008.View ArticlePubMedGoogle Scholar
- Beigel J, Kohl KS, Khuri-Bulos N, Bravo L, Nell P, Marcy SM, Warschaw K, Ong-Lim A, Poerschke G, Weston W, Lindstrom JA, Stoltman G, Maurer T, Brighton Collaboration Rash Working Group: Rash including mucosal involvement: Case definition and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine. 2007, 25: 5697-5706. 10.1016/j.vaccine.2007.02.066.View ArticlePubMedGoogle Scholar
- Abdulla S, Oberholzer R, Juma O, Kubhoja S, Machera F, Membi C, Omari S, Urassa A, Mshinda H, Jumanne A, Salim N, Shomari M, Aebi T, Schellenberg DM, Carter T, Villafana T, Demoitié MA, Dubois MC, Leach A, Lievens M, Vekemans J, Cohen J, Ballou WR, Tanner M: Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N Engl J Med. 2008, 359: 2533-2544. 10.1056/NEJMoa0807773. Supplementary Appendix, [http://www.nejm.org/doi/suppl/10.1056/NEJMoa0807773/suppl_file/nejm_abdulla_2533sa1.pdf]View ArticlePubMedGoogle Scholar
- WHO: Verbal autopsy standards: ascertaining and attributing cause of death. 2007, World Health Organization, GenevaGoogle Scholar
- Breman JG: The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden. Am J Trop Med Hyg. 2001, 64 (Suppl 1-2): 1-11.PubMedGoogle Scholar
- Greenwood BM, Bojang K, Whitty CJ, Targett GA: Malaria. Lancet. 2005, 365: 1487-98. 10.1016/S0140-6736(05)66420-3.View ArticlePubMedGoogle Scholar
- Alonso PL, Aponte JJ: Field Trials. Methods in Molecular Medicine. Edited by: Doolan DL. 2002, Malaria Methods and Protocols, Totowa, NJ: Humana Press Inc, 72: 607-616.Google Scholar
- Smith T, Schellenberg JA, Hayes R: Attributable fraction estimates and case definitions for malaria in endemic areas. Stat Med. 1994, 13: 2345-2358. 10.1002/sim.4780132206.View ArticlePubMedGoogle Scholar
- Mwangi TW, Ross A, Snow RW, Marsh K: Case definitions of clinical malaria under different transmission conditions in Kilifi District Kenya. J Infect Dis. 2005, 191: 1932-1939. 10.1086/430006.PubMed CentralView ArticlePubMedGoogle Scholar
- Dicko A, Mantel C, Kouriba B, Sagara I, Thera MA, Doumbia S, Diallo M, Poudiougou B, Diakite M, Doumbo OK: Season, fever prevalence and pyrogenic threshold for malaria disease definition in an endemic area of Malawi. Trop Med Int Health. 2005, 10: 550-556. 10.1111/j.1365-3156.2005.01418.x.View ArticlePubMedGoogle Scholar
- McGuinness D, Koram K, Bennett S, Wagner G, Nkrumah F, Riley E: Clinical case definitions for malaria: clinical malaria associated with very low parasite densities in African infants. Trans R Soc Trop Med Hyg. 1998, 92: 527-531. 10.1016/S0035-9203(98)90902-6.View ArticlePubMedGoogle Scholar
- Greenwood BM, Bradley AK, Greenwood AM, Byass P, Jammeh K, Marsh K, Tulloch S, Oldfield FS, Hayes R: Mortality and morbidity from malaria among children in a rural area of The Gambia. Trans R Soc Trop Med Hyg. 1987, 81: 478-486. 10.1016/0035-9203(87)90170-2.View ArticlePubMedGoogle Scholar
- Saúte F, Aponte J, Almeda J, Ascaso C, Abellana R, Vaz N, Dgedge M, Alonso P: Malaria in southern Mozambique: malariometric indicators and malaria case definition in Manhiça district. Trans R Soc Trop Med Hyg. 2003, 97: 661-666. 10.1016/S0035-9203(03)80098-6.View ArticlePubMedGoogle Scholar
- Aponte JJ, Schellenberg D, Egan A, Breckenridge A, Carneiro I, Critchley J, Danquah I, Dodoo A, Kobbe R, Lell B, May J, Premji Z, Sanz S, Sevene E, Soulaymani-Becheikh R, Winstanley P, Adjei S, Anemana S, Chandramohan D, Issifou S, Mockenhaupt F, Owusu-Agyei S, Greenwood B, Grobusch MP, Kremsner PG, Macete E, Mshinda H, Newman RD, Slutsker L, Tanner M, Alonso P, Menendez C: Efficacy and safety of intermittent preventive treatment with sulfadoxine-pyrimethamine for malaria in African infants: a pooled analysis of six randomised, placebo-controlled trials. Lancet. 2009, 374: 1533-42. 10.1016/S0140-6736(09)61258-7.View ArticlePubMedGoogle Scholar
- Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, Mandomando I, Spiessens B, Guinovart C, Espasa M, Bassat Q, Aide P, Ofori-Anyinam O, Navia MM, Corachan S, Ceuppens M, Dubois MC, Demoitié MA, Dubovsky F, Menéndez C, Tornieporth N, Ballou WR, Thompson R, Cohen J: Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet. 2004, 364: 1411-1420. 10.1016/S0140-6736(04)17223-1.View ArticlePubMedGoogle Scholar
- Lievens M, Aponte J, Williamson J, Mmbando B, Mohamed A, Bejon P, Leach A: Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS,S/AS01 malaria vaccine in African children. Malar J.Google Scholar
- Alonso PL, Lindsay SW, Armstrong JR, Conteh M, Hill AG, David PH, Fegan G, de Francisco A, Hall AJ, Shenton FC, Cham K, Greenwood BM: The effect of insecticide-treated bed nets on mortality of Gambian children. Lancet. 1991, 337: 1499-1502. 10.1016/0140-6736(91)93194-E.View ArticlePubMedGoogle Scholar
- Alonso PL, Lindsay SW, Armstrong Schellenberg JR, Keita K, Gomez P, Shenton FC, Hill AG, David PH, Fegan G, Cham K, Greenwood BG, Keita K: A malaria control trial using insecticide-treated bed nets and targeted chemoprophylaxis in a rural area of The Gambia, West Africa. 6. The impact of the interventions on mortality and morbidity from malaria. Trans R Soc Trop Med Hyg. 1993, 87 (suppl 2): 37-44.View ArticlePubMedGoogle Scholar
- WHO: Standardization of interpretation of chest radiographs for the diagnosis of pneumonia in children. 2001, World Health Organization, GenevaGoogle Scholar
- Moorthy V, Reed Z, Smith PG: Measurement of malaria vaccine efficacy in phase III trials. Report of a WHO consultation. Vaccine. 2007, 25: 5115-5123. 10.1016/j.vaccine.2007.01.085.View ArticlePubMedGoogle Scholar
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