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Page #TITLE & ABSTRACT1Participants were randomized, but this is not specified in the title as this is an exploratory analysis performed after the results of the original trial were already published, and there is not enough space in the title to include it. It was included in the title of the two articles reporting the primary analyses ADDIN EN.CITE Alonso PL2004760Alonso PL,Sacarlal J.,Aponte J. J.,Leach A.,Macete E.,Milman J.,Mandomando I.,Spiessens B.,Guinovart C.,Espasa M.,Bassat Q.,Aide P.,Ofori-Anyinam O.,Navia M. M.,Corachan S.,Ceuppens M.,Dubois M. C.,Demoitie M. A.,Dubovsky F.,Menendez C.,Tornieporth N.,Ballou W. R.,Thompson R.,Cohen J.,2004Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trialLancet36494431411-20.Alonso2005750Duration 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 trialAlonso, P. L.Sacarlal, J.Aponte, J. J.Leach, A.Macete, E.Aide, P.Sigauque, B.Milman, J.Mandomando, I.Bassat, Q.Guinovart, C.Espasa, M.Corachan, S.Lievens, M.Navia, M. M.Dubois, M. C.Menendez, C.Dubovsky, F.Cohen, J.Thompson, R.Ballou, W. R.AnimalsAntibodies, Protozoan/bloodChild, PreschoolCross-Sectional StudiesFollow-Up StudiesHumansInfantMalaria Vaccines/immunology/*therapeutic useMalaria, Falciparum/classification/immunology/*prevention & controlMozambiquePlasmodium falciparum/*immunologyResearch Support, Non-U.S. Gov'tSeverity of Illness IndexSingle-Blind MethodLancet.200536695022012-8.(Alonso PL 2004; Alonso 2005).Abstract, Materials and methods (Study design)INTRODUCTIONBackground2Developing a new vaccine is a long and complex process. For example, RTS,S/AS02A (GSK, Rixensart, Belgium), a pre-erythrocytic vaccine based on Plasmodium falciparum circumsporozoite surface protein (CSP) and the candidate malaria vaccine in the most advanced development phase, has been in development for more than two decades. After having demonstrated partial protection against infection in non-immune and semi-immune adults, it underwent proof-of-concept trials in children and infants in Mozambique prior to the planned launch of wider Phase III efficacy trials.
One of the most critical decisions when preparing a vaccines clinical development plan is the proper selection of criteria by which the product will be advanced, re-engineered or terminated. Selection of appropriate study endpoints in the various trials that lead up to definitive Phase III efficacy studies is an important part of this process. Different endpoints can be used to estimate efficacy of a pre-erythrocytic vaccine: P. falciparum asexual-stage infection, clinical malaria, severe malaria or death. Selection of the endpoint depends on several factors, including the type of vaccine, the phase of the trial and the evidence needed for advocacy and policy decision, and it will determine the sample size and have implications in terms of cost and time. Infection is the endpoint closest to the biological target of the vaccine and is the least influenced by local cofactors, such as management of malaria cases and parasite and human genetics. As we go downstream, the clinical and public health relevance increases, but the number of cofactors influencing the risk of malaria is larger, potentially decreasing the generalizability of results.
In 2003, a randomized controlled phase IIb proof-of-concept trial was conducted in Mozambique to provide a preliminary estimate of the efficacy, immunogenicity and safety of RTS,S/AS02A malaria vaccine in an age group (1 to 4 years) that would be close to the ultimate target population (infants). The trial was designed with two cohorts so that it would be possible to estimate vaccine efficacy against two different endpoints: infection and clinical malaria. Cohort 1 was designed to examine efficacy against clinical malaria, because estimation of vaccine efficacy for an endpoint with public health relevance was sought, assessed through health facility-based passive case detection (PCD). During the first six months of follow up (double-blind phase) the vaccine efficacy for the first or only clinical malaria episode was 29.9% (95% CI 11.0-44.9; p=0.004). As an exploratory analysis efficacy against severe malaria was also assessed in this cohort, with an estimate of 57.5% (16.2-80.6; p=0.019). Anti-CSP antibodies were not correlated with the risk of clinical malaria. Cohort 2 enrolled a separate group of children who lived in an area with higher transmission intensity and who contributed to the assessment of the efficacy against first asexual stage P. falciparum parasitemia infection. By enrolling this second cohort it was possible to estimate efficacy for a more upstream endpoint and to evaluate how it correlated with efficacy against clinical malaria in Cohort 1. Participants in Cohort 2 were followed up through both active detection of infection (ADI) and PCD. During the double-blind phase the vaccine efficacy against first infection was 45.0% (31.4-55.9; p<0.0001).
After unblinding data of the first six months of follow up, participants were followed up for an additional 12 months (single-blind phase), during which vaccine efficacy for the first or only clinical malaria episode in cohort 1 was 28.9% (8.4-44.8; p=0.008). Therefore the vaccine efficacy did not wane, showing sustained protection during at least 18 months. In cohort 2 almost all children had already had a P. falciparum infection during the double-blind phase, therefore it was not possible to continue the ADI during the single-blind phase, in which children were only followed up for safety surveillance through health facility-based PCD.
The correlation between efficacy against clinical malaria in cohort 1 and efficacy against infection in cohort 2 showed that infection could be consistently used as the primary endpoint for efficacy trials of pre-erythrocytic vaccines, which allows conducting smaller trials with high power, decreasing time and cost. Based on these results, a phase I/IIb randomized controlled trial was recently conducted in infants in the same area to assess the safety, immunogenicity and efficacy of RTS,S/AS02D malaria vaccine, administered at 10, 14 and 18 weeks of age, staggered with the Expanded Program on Immunization vaccines. This infant trial was designed with a single cohort, which was followed up through ADI and PCD, using the same design as for cohort 2 of the previous trial. First or only infection was the main endpoint for evaluation of vaccine efficacy, but further analyses of vaccine efficacy against clinical malaria were explored. During the first three months of follow up, the efficacy against first infection was 65.9% (42.6-79.8; p<0.0001) and that for first or only clinical episode of malaria was 65.8% (25.3-84.4; p=0.007). In this study in young infants anti-CSP antibodies were strongly associated with a reduction in the risk of infection.
In these two trials vaccine efficacy estimates differ for different endpoints, transmission intensities and age groups. To provide more evidence on the factors that may influence vaccine response and its duration, we performed a sub-analysis of cohort 2 data from the study in children, that was not included in the original protocol, to estimate vaccine efficacy for clinical malaria in this cohort, using information collected for safety through the health facility-based PCD system.
IntroductionMETHODSParticipants3Eligibility criteria are not specified in the current manuscript and were summarized in the article presenting the primary study ADDIN EN.CITE Alonso PL2004760Alonso PL,Sacarlal J.,Aponte J. J.,Leach A.,Macete E.,Milman J.,Mandomando I.,Spiessens B.,Guinovart C.,Espasa M.,Bassat Q.,Aide P.,Ofori-Anyinam O.,Navia M. M.,Corachan S.,Ceuppens M.,Dubois M. C.,Demoitie M. A.,Dubovsky F.,Menendez C.,Tornieporth N.,Ballou W. R.,Thompson R.,Cohen J.,2004Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trialLancet36494431411-20.(Alonso PL 2004).
Inclusion criteria:
Healthy male and female children, 1 to 4 years of age at the time of first vaccination (up to but not including 5th birthday).
Written/thumbprinted and witnessed informed consent obtained from the parents or legal guardians, after they have been informed of the risks and benefits of the study in a language, which they clearly understand.
Free of obvious health problems as established by medical history and clinical examination before entering into the study.
Availability for the duration of the immunisation and follow-up period
Exclusion criteria:
Major congenital defects or serious chronic illness. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests (see below). Chronic carriers of the HBsAg will not be excluded from the clinical trial provided they are clinically asymptomatic.
Haematocri t o f l e s s t h a n 2 5 % .
H i s t o r y o f a l l e r g i c r e a c t i o n s t o v a c c i n a t i o n .
H i s t o r y o f a l l e r g i c r e a c t i o n s t o a n y c o m p o n e n t o f t h e H i b e r i x "!, P r e v n a r o r E n g e r i x - B "! v a c c i n e s .
C h r o n i c a d m i n i s t r a t i o n ( d e f i n e d a s m o r e t h a n 1 4 d a y s ) o f i m m u n o - s u p p r e s s a n t s o r o t h e r i m m u n e modifying drugs within six months prior to the first vaccine dose (for corticosteroids, this will mean prednisone, or equivalent, ( 0.5 mg/kg/day. Inhaled and topical steroids are allowed.)
Previous vaccination with an experimental vaccine.
Previous vaccination with hepatitis B vaccine (as documented on health card) in children equal to or more than 24 months of age.
Simultaneous participation in any other clinical trial.
Any other findings which in the opinion of the investigators would increase the risk of having an adverse outcome from participation in the trial.
Severe malnutrition defined as weight for height ( -3z scores.
History of surgical splenectomy.
Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use during the study period.
Planned administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of vaccine. An exception, is the receipt of an EPI or licensed vaccine (measles, oral polio, meningococcal and combined diphtheria/pertussis/tetanus vaccines) which may be given 14 days or more before or after vaccination.
Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period.
Adiagnosis or clinical suspicion of an immunosuppressive or immunodeficient condition of any cause based on a full clinical history and medical examination.
A family history of congenital or hereditary immunodeficiency.
Same-sex twin.
Lack of healthcard (i.e. no previous vaccination record).
Study site
The trial was conducted at the Centro de Investigao em Sade da Manhia (CISM, Manhia Health Research Centre), in Manhia District (Maputo Province), southern Mozambique. The area is under demographic surveillance system (DSS) and has been described in detail elsewhere. Adjacent to CISM is the Manhia District Hospital (110 beds), the main referral hospital in the area. The climate is subtropical with a rainy season from November to April and a cool and dry season during the rest of the year. Malaria transmission, mainly caused by P. falciparum, is perennial with marked seasonality. The trial was conducted in two different areas: Manhia and Maragra, where cohort 1 (n=1605) was recruited, and Ilha Josina, 55 km north of Manhia, where cohort 2 (n=417) was recruited. The estimated entomological inoculation rate for the Manhia area in 2002 was 38 infective bites/person/year, being Anopheles funestus the main vector. In Ilha Josina the transmission is higher than in Manhia, as reflected by a significantly higher geometric mean of antibodies against the whole parasite as assessed by indirect fluorescent antibody test (IFAT) and percentage of splenomegaly at baseline in study participants recruited in that area.
More detail was given in the article reporting the primary analysis ADDIN EN.CITE Alonso PL2004760Alonso PL,Sacarlal J.,Aponte J. J.,Leach A.,Macete E.,Milman J.,Mandomando I.,Spiessens B.,Guinovart C.,Espasa M.,Bassat Q.,Aide P.,Ofori-Anyinam O.,Navia M. M.,Corachan S.,Ceuppens M.,Dubois M. C.,Demoitie M. A.,Dubovsky F.,Menendez C.,Tornieporth N.,Ballou W. R.,Thompson R.,Cohen J.,2004Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trialLancet36494431411-20.(Alonso PL 2004).
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Materials and methods (Study design) Interventions4Vaccination procedures are only briefly described in the current manuscript, but were described in detail in the article reporting the primary analysis:
RTS,S consists of a hybrid molecule recombinantly expressed in yeast, in which the circumsporozoite protein, 9 central tandem repeat, and carboxyl-terminal regions are fused to the N terminal of the S antigen of hepatitis B virus (HBsAg) in a particle that also incluyes the unfused S antigen. A full adult dose of RTS,S/AS02A (GSK Biologicals, Rixensart, Belgium) contains 50 _g of lyophilised RTS,S antigen reconstituted in 500 _L of AS02A adjuvant (proprietary oil in water emulsion with the immunostimulants monophosphoryl lipid A [MPL; Corixa, Seattle, WA, USA] and Quillaja saponaria fraction 21 [QS21; Antigenics, New York, NY, USA]). We used half the adult dose in this trialie, a 250 _L dose containing 25 _g of RTS,S antigen in 250 _L AS02A adjuvant. Because routine hepatitis B vaccination was introduced into the EPI schedule of Mozambique in July, 2001, children aged 1224 months had already received hepatitis B immunisation. Accordingly, children younger than 24 months received as control vaccines two doses of the seven-valent pneumococcal conjugate vaccine (Prevnar Wyeth Lederle Vaccines, Madison, NJ, USA) at the first and third vaccination and one dose of Haemophilus influenzae type b vaccine (GSK Biologicals) at the second vaccination. For children older than 24 months, the control vaccine was the paediatric hepatitis B vaccine (GSK Biologicals). We administered both RTS,S/AS02A and control vaccines intramuscularly in the deltoid region of alternating arms according to a 0, 1, 2 month vaccination Schedule ADDIN EN.CITE Alonso PL2004760Alonso PL,Sacarlal J.,Aponte J. J.,Leach A.,Macete E.,Milman J.,Mandomando I.,Spiessens B.,Guinovart C.,Espasa M.,Bassat Q.,Aide P.,Ofori-Anyinam O.,Navia M. M.,Corachan S.,Ceuppens M.,Dubois M. C.,Demoitie M. A.,Dubovsky F.,Menendez C.,Tornieporth N.,Ballou W. R.,Thompson R.,Cohen J.,2004Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trialLancet36494431411-20.(Alonso PL 2004).
Materials and methods (Study design, Procedures)Objectives5
To provide more evidence on the factors that may influence vaccine response and its duration, we performed a sub-analysis of cohort 2 data that was not included in the original protocol, to estimate vaccine efficacy for clinical malaria in this cohort, using information collected for safety through the health facility-based PCD s y s t e m .
A b s t r a c t , I n t r o d u c t i o n O u t c o m e s 6 I n t h i s e x p l o r a t o r y a n a l y s e s , n o t i n c l u d e d i n t h e o r i g i n a l p r o t o c o l , t h e e n d p o i n t s w e r e t h e f o l l o w i n g :
- f i r s t o r o n l y c l i n i c a l m a l a r i a e p i s o d e ( A x i l l a r y t e m p e r a t u r e e" 3 7 . 5 C + P . f a l c i p a r u m a s e x u a l p a r a s i t a e m i a >2500 parasites/l) detected by passive case detection or active detection of infection over a 6 month observation period starting 14 days after dose 3 (study months 2.5 to 8.5) in children in Cohort 2.
-first or only clinical malaria episode (Axillary t e m p e r a t u r e e" 3 7 . 5 C + P . f a l c i p a r u m a s e x u a l p a r a s i t a e m i a > 2 5 0 0 p a r a s i t e s / l ) d e t e c t e d b y p a s s i v e c a s e d e t e c t i o n o r a c t i v e d e t e c t i o n o f i n f e c t i o n o v e r a 1 2 m o n t h o b s e r v a t i o n p e r i o d s t a r t i n g 6 . 5 m o n t h s a f t e r d o s e 3 ( s t u d y m o n t h s 8 . 5 t o 2 1 ) i n c h i l d r e n i n C o h o r t 2 .
- f i r s t o r o n l y c l i n i c a l m a l a r i a e p i s o d e ( A x i l l a r y t e m p e r a t u r e e" 3 7 . 5 C + P . f a l c i p a r u m a s e x u a l p a r a s i t a e m i a > 1 5 0 0 0 p a r a s i t e s / l ) d e t e c t e d b y p a s s i v e c a s e d e t e c t i o n o r a c t i v e d e t e c t i o n o f i n f e c t i o n o v e r a 6 m o n t h o b s e r v a t i o n p e r i o d s t a r t i n g 1 4 d a y s a f t e r d o s e 3 ( s t u d y m o n t h s 2 . 5 t o 8 . 5 ) i n c h i l d r e n i n C o h o r t 2 .
- f i r s t o r o n l y c l i n i c a l m a l a r i a e p i s o d e ( A x i l l a r y t e m p e r a t u r e e" 3 7 . 5 C + P . f a l c i p a r u m a s e x u a l p a r a s i t a e m i a > 5 0 0 0 0 p a r a s i t e s / l ) d e t e c t e d b y p a s s i v e c a s e d e t e c t i o n o r a c t i v e d e t e c t i o n o f i n f e c t i o n o v e r a 6 m o n t h o b s e r v a t i o n p e r i o d s t a r t i n g 1 4 d a y s a f t e r d o s e 3 ( s t u d y m o n t h s 2 . 5 t o 8 . 5 ) i n c h i l d r e n i n C o h o r t 2 .
- t o t a l n u m b e r o f c l i n i c a l m a l a r i a e p i s o d e s ( A x i l l a r y t e m p e r a t u r e e" 3 7 . 5 C + P . f a l c i p a r u m a s e x u a l p a r a s i t a e m i a > 2 5 0 0 p a r a s i t e s / l ) d e t e c t e d b y p a s s i v e c a s e d e t e c t i o n o r a c t i v e d e t e c t i o n o f i n f e c t i o n o v e r a 6 m o n t h o b s e r v a t i o n p e r i o d s t a r t i n g 1 4 d a y s a f t e r d o s e 3 ( s t u d y m o n t h s 2 . 5 t o 8 . 5 ) i n c h i l d r e n i n C o h o r t 2 .
- f i r s t o r o n l y c l i n i c a l m a l a r i a e p i s o d e ( A x i l l a r y t e m p e r a t u r e e" 3 7 . 5 C + P . f a l ciparum asexual parasitaemia >2500 parasites/l) detected by passive case detection or active detection of infection over a 3.5 month observation period starting 14 days after dose 3 (study months 2.5 to 6) in children in Cohort 2.
- The number of asexual stage falciparum parasites per l of blood for each subject at first or only infection.
- Titres of anti-CS antibodies 30 days post-dose 3.
Materials and methods (Statistical methods and case definitions)Sample size7The sample size of cohort 2 was calculated at the beginning of the study to estimate vaccine efficacy against first or only infection in cohort 2, which was reported in the primary analysis article: 116 assessable children per group were needed to provide 86% power to detect a vaccine efficacy of 50% in the prevention of new infections with a coger confidence limit of 20%, assuming a rate of new infections of 50% over the surveillance period ADDIN EN.CITE Alonso PL2004760Alonso PL,Sacarlal J.,Aponte J. J.,Leach A.,Macete E.,Milman J.,Mandomando I.,Spiessens B.,Guinovart C.,Espasa M.,Bassat Q.,Aide P.,Ofori-Anyinam O.,Navia M. M.,Corachan S.,Ceuppens M.,Dubois M. C.,Demoitie M. A.,Dubovsky F.,Menendez C.,Tornieporth N.,Ballou W. R.,Thompson R.,Cohen J.,2004Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trialLancet36494431411-20.(Alonso PL 2004).
In this exploratory analyses, based on the incidence of clinical malaria in the control group of cohort 2 (0.944 episodes per person years at risk during the first six months of follow-up and 0.511 during the following 12 months), the power to detect a vaccine efficacy against clinical malaria of 40% or higher at a 5% significance level during the first six months of follow-up is of 65.8% and during the following 12 months is of 68.0%.
Materials and methods (Statistical methods and case definitions)Randomization --Sequence generation8Randomization methods are not specified in the current manuscript. They were described in the article reporting the primary analysis:
Block randomisation was done at GSK Biologicals with SAS software version 8 (1/1 ratio, block size six) ADDIN EN.CITE Alonso PL2004760Alonso PL,Sacarlal J.,Aponte J. J.,Leach A.,Macete E.,Milman J.,Mandomando I.,Spiessens B.,Guinovart C.,Espasa M.,Bassat Q.,Aide P.,Ofori-Anyinam O.,Navia M. M.,Corachan S.,Ceuppens M.,Dubois M. C.,Demoitie M. A.,Dubovsky F.,Menendez C.,Tornieporth N.,Ballou W. R.,Thompson R.,Cohen J.,2004Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trialLancet