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AS malaria candidate vaccine
Vaccine 27S (2009) G67–G71
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Development of the RTS,S/AS malaria candidate vaccine Johan Vekemans ∗ , Amanda Leach, Joe Cohen GlaxoSmithKline Biologicals, 89 rue de l’Institut, 1330 Rixensart, Belgium
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Article history: Received 15 June 2009 Received in revised form 25 September 2009 Accepted 2 October 2009
Keywords: Malaria vaccine RTS,S/AS Development
a b s t r a c t A vaccine against malaria which complements existing control tools is an urgent medical need. RTS,S/AS, a pre-erythrocytic candidate vaccine, which targets the circumsporozoite protein, is the most advanced in clinical development. The safety, immunogenicity and efficacy of this candidate vaccine have been investigated in a series of trials in children and infants in endemic African countries. The vaccine shows promise for providing important public health benefits and a multicenter Phase III trial has started in Africa, aiming to further characterize the efficacy of the candidate vaccine and generate the regulatory data required for the licensing approval of the vaccine. © 2009 Published by Elsevier Ltd.
1. Malaria vaccine: an unmet medical need The availability of a malaria vaccine would contribute greatly to the efforts aimed at controlling this major threat to global health. It is estimated that in 2007, more than 2.37 billion people were living in areas where Plasmodium falciparum malaria transmission occurs [1]. Sub-Saharan Africa carries the highest burden of the disease, with an estimated 250 million cases and nearly 1 million deaths each year [2,3]. Malaria represents a huge burden on health care systems and economical losses [4]. Over 80% of fatalities occur in African children under the age of 5 [4] justifying the development of a vaccine targeting primarily this vulnerable population. Recently, hopes for the possibility of long term control, elimination and even eradication of the disease have re-emerged, encouraged by important reductions in malaria burden in countries, such as Rwanda, Zambia, Madagascar, Zanzibar and The Gambia where large scale malaria control programs have been implemented [3]. These recent successes are great news, but no reason for complacency. Currently implemented malaria control strategies include interventions such as insecticide-treated net, insecticide residual spraying, intermittent preventive treatment to pregnant women, and Artemisin based combination treatment. Unfortunately, both the malaria parasite and the transmitting mosquitoes have shown a very high capacity to develop pharmaceutical escape mechanisms and drug resistance, as demonstrated by the previously failed World Health Organisation (WHO) malaria eradication program, also based on malaria drugs and mosquito control. The addition of a vaccine to the anti-malaria arsenal is an
∗ Corresponding author. Tel.: +32 2 656 5659. E-mail address: [email protected] (J. Vekemans). 0264-410X/$ – see front matter © 2009 Published by Elsevier Ltd. doi:10.1016/j.vaccine.2009.10.013
urgent medical need, and may possibly contribute to reduce the risk of emergence of parasite drug resistance, thereby increasing the sustainability of existing malaria control strategies. 2. The RTS,S/AS malaria candidate vaccine construct The most advanced malaria vaccine candidate is RTS,S formulated with GSK proprietary Adjuvants Systems (AS) AS01 or AS02. This candidate vaccine has been in development for over 20 years, and since 2001 under the leadership of a public-private product development partnership between GSK Biologicals and the PATH Malaria Vaccine Initiative (MVI), with support from the Bill and Melinda Gates Foundation. The overall objective of the RTS,S/AS program is to reduce the burden of disease related to P. falciparum malaria in infants and children residing in sub-Saharan African malaria-endemic countries. The vaccine would ideally be implemented through the existing infant vaccine delivery program, the Expanded Program on Immunization, in conjunction with other malaria control interventions. The vaccine candidate targets the pre-erythrocytic phase of the parasite life cycle, comprising the sporozoite and liver stages. Sporozoites, which are injected in the circulation following a bite from an infected mosquito, rapidly target the liver, and invade hepatocytes. The parasite then develops into a schizont containing 10,000–30,000 merozoites, which are later released from the liver into the blood, whereby the disease-associated erythrocytic phase of the infection is initiated. The target antigen is the circumsporozoite protein (CS), a 412 amino acids protein abundantly associated with the sporozoite surface, also expressed by liver forms and exported in the cytoplasm of hepatocytes. It has a characteristic central conserved NANP repeat region and non-repeat flanking regions with both conserved and
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variable segments. This protein is thought to play a role in the entry of the parasite in the liver through an interaction with liver sinusoidal heparan sulphate proteoglycans, and interference with the hepatocyte cellular processes, down regulating NF-KB mediated inflammation, thereby creating a favourable niche for the parasite and allowing the development of the liver stage [5]. The feasibility of developing a pre-erythrocytic vaccine was demonstrated in the late 1960s, when it was shown first in rodents then in humans that immunization with irradiated sporozoites can induce complete protection against experimental sporozoite challenge [6,7]. In this immunization model, the CS has been shown to be a major target of protective immunological effectors [8]. Both CS-specific antibodies and T cells have been shown to be implicated in protection [9]. Anti-CS antibodies can block sporozoite liver cell invasion in vitro [10] and prevent experimental infection in animals [11]. Passive transfer of both CS-specific CD4 and CD8 T cells can protect animals from experimental infection [11,12]. In humans the activation of CD4+ T cells and cytotoxic CD8 T cells has been reported [13–15]. Initial candidate vaccine constructs targeting only the central repeat region of the CS protein failed to provide substantial protection [16,17]. The recruitment and activation of T cells through the development of innovative technologies became a key objective of the team working collaboratively at the Walter Reed Army Institute of Research and GSK Biologicals in the 1980s. A new vaccine construct was generated [18] based on a large segment of CS (Amino Acids 207–395 of the CS from the NF54 P. falciparum strain) that included 19 NANP conserved repeats and the C-terminal part of the non-repeat region (excluding the hydrophobic membrane anchor) known to contain T cell epitopes, and covalently bounded to the HBs antigen (adw serotype), the hepatitis B vaccine antigen. When recombinantly expressed in Saccharomyces cerevisiae the fusion protein (RTS), together with a free transcript of the hepatitis B antigen (S), spontaneously assemble to form virus-like particles, known to favour antigen presentation to the T cell compartment [19,20]. The vaccine construct was formulated with two Adjuvant Systems, AS01 and AS02, shown to induce both strong humoral and cellular immune responses. Both include the immunostimulants MPL and QS21. The monophosphoryl lipid A molecule MPL consists of a chemically detoxified form of the parent lipopolysaccharide (LPS) from the Gram negative bacterium Salmonella minnesota. QS21 is a natural saponin molecule purified from the bark of the South American tree, Quillaja saponaria. AS02 contains in addition an oil in water emulsion while AS01 contains a liposomal suspension [21]. 3. Early RTS,S/AS02 evaluation in adults Early clinical development of the RTS,S malaria candidate vaccine was initiated in studies in malaria-naïve adults in collaboration with the Walter Reed Army Institute of Research (WRAIR). The first challenge study demonstrated the importance of the adjuvant in the generation of protective immunity. Volunteers vaccinated with three different adjuvant formulations of RTS,S and controls were subjected to experimental sporozoite challenge. Out of seven volunteers vaccinated with the RTS,S/AS02 formulation, six were protected against challenge, while the two other formulations protected one of eight and two of seven participants. Immunological analysis showed that as compared to the other formulations the RTS,S/AS02 induced a high level of anti-CS and anti-HBs antibodies as well as IFN-␥ producing T cells. When re-challenged 6 months later, out of seven protected volunteers in the initial challenge experiment (across the three vaccine formulations tested) who accepted to participate to a second challenge, two were protected again [22–24]. Across several challenge studies conducted over the years, it was consistently shown that RTS,S/AS02A vaccination
provides protection against sporozoite challenge of a magnitude of 40%. It was observed that in addition to providing full protection (sterile protection, characterised by the absence of parasitemia after challenge) in some of the vaccinated individuals, the development of parasitemia in the breakthrough cases was delayed for 48 h or longer compared to non-vaccinated controls. It is hypothesized that this delay reflects a diminished merozoite release from the liver. Such a decrease in the parasite load initiating the blood stage may allow the immune system to better cope with the growing parasitemia, with a possible impact on the development of associated symptoms, and decrease the risk of progression towards the more severe forms of the disease [25]. The results of the challenge studies led to evaluation of RTS,S/AS02 in malaria-endemic regions.
Study designs in malaria efficacy trials, in conditions of natural malaria exposure Several study designs can be used to assess efficacy of a malaria candidate vaccine in conditions of natural malaria exposure. Evaluation of efficacy against rare endpoints such as severe malaria is relevant to public health but requires large sample size and is reserved for late vaccine evaluation. Early in vaccine development programs, studies focus on more frequent events like occurrence of P. falciparum infection, defined as the presence of P. falciparum parasites in the blood, or uncomplicated malaria disease, defined as P. falciparum parasitemia above a specific threshold in a participant that is unwell with fever. This inclusion of a parasitemia threshold increases the specificity of the case definition [26]. In the following sections, Active Detection of Infection (ADI) will be referred to when investigators screen study participants on a regular basis, looking for parasitemia on a blood slide. Passive Case Detection (PCD) is referred to when cases are captured when a child who is unwell is brought for treatment in a health facility. Active Case Detection (ACD) is when investigators visit study participants on a regular basis, measure temperature and do a blood slide if fever is present.
The first efficacy study under conditions of natural exposure started in 1998 in The Gambia, a region of seasonal malaria transmission. The vaccine prevented 34% (95% CI: 8–53; p = 0.014) of infections over a surveillance period of 15 weeks during the malaria season [27]. Protection was shown not to be strain-specific [28]. When a booster dose of the vaccine was given before the subsequent malaria transmission season a year later, there was a 47% protection against infection over 9 weeks [27]. The follow-up safety evaluation, over a 5-year period, was favourable [29]. 4. RTS,S/AS02 evaluation in children and infants, in malaria-endemic countries The evaluation of RTS,S/AS02 progressed to the paediatric population initially with age de-escalation and dose optimization studies [30,31]. A large trial in Mozambican children aged 1–4 years was then started, enrolling a total of 2022 subjects. The study included two cohorts. In the first, largest cohort, efficacy against clinical malaria was assessed by PCD. Over the first 18 months of follow up the efficacy against clinical malaria was 35.3% (95% CI: 21,6, 46.6; p < 0.0001). The study also showed a 48.6% (95% CI: 12.3, 71.0; p = 0.02) reduction in the number of RTS,S/AS02 vaccinated participants having developed severe malaria, as compared to controls [32]. The follow up of study participants continued, and showed over 43 months an efficacy of 25.6% (95% CI: 11.9–37.1; p < 0.001) in prevention of clinical malaria episodes, and the absence of rebound in malaria or severe malaria occurrence in the vaccinated group. At the end of the 43 months post vaccination follow up, the prevalence
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of P. falciparum parasitemia was 34% lower in the RTS,S/AS02A group as compared to the control group. 12 deaths, had occurred in the RTS,S/AS02 group, as compared to 22 in the control group, of which and 5 and 1, respectively, were attributed to malaria [33]. In the second cohort, a 45% (95% CI 31.4–55.9; p < 0.0001) vaccine efficacy against infection was demonstrated, through ADI for 6 months [34]. Although not initially foreseen, an exploratory analysis showed 35.4% (95% CI 4.5–56.3; p = 0.029) vaccine efficacy against clinical malaria over the initial 6 months, based on data reported through PCD for safety. Measured efficacy in cohort 2 thereafter waned, suggesting that the intensive surveillance in the context of an ADI study with early treatment of infections or differences in the intensity of exposure to malaria may affect the long term protection mechanisms induced by the vaccine [35]. An alternative explanation would be that other unknown factors, such as heterogeneity in exposure, affect our ability to characterise duration of protection using standard statistical models. RTS,S/AS02 vaccination was then investigated in infants of the EPI age group (infants aged 6–12 weeks at first vaccination). A two-step approach was taken, with assessment of safety, immunogenicity and efficacy initially when given 2 weeks apart from EPI vaccines, then in co-administration. When given apart, in a study in Mozambique, it was demonstrated that the reactogenicity of RTS,S/AS02 was similar to that of hepatitis B and diphtheriatetanus whole cell pertussis-Haemophilus influenzae (DTPw-Hib) tetravalent vaccines. Anti-CS antibody GMTs induced by the vaccine were similar to those observed in older children. The study also demonstrated a 65.9% (95% CI: 42.6–79.8; p < 0.001) vaccine efficacy against infection through ADI over a 12-week surveillance period [36]. When given in co-administration with DTPw-Hib in infants in a study in Tanzania, RTS,S/AS02 was shown to induce more low grade fever (<39 ◦ C) than Hepatitis B vaccine (29.6% and 13.6%, respectively). Pre-defined non-inferiority of EPI immune responses was demonstrated, and seroprotection rates to EPI antigens were high, despite a trend towards lower GMT’s to EPI antigens upon RTS,S/AS02 co-administration. Although 98.6% infants vaccinated with RTS,S/AS02 had seropositive titres for anti-CS antibodies, the anti-CS immune response was lower than that seen in previous trials. Despite this, efficacy against infection assessed by ADI was 65.2% (95% CI: 20.7–84.7; p = 0.012) over a 6 months follow up period. The study also showed a lower occurrence of serious adverse events in RTS,S/AS02 vaccine recipients as compared to controls. This was true also when non-malaria-related events were analyzed, notably pneumonia. This finding suggests that RTS,S/AS vaccination may have indirect health benefits, possibly reducing the increased susceptibility to other diseases resulting from malaria exposure [37]. 5. RTS,S/AS01: a superior formulation In parallel to the evaluation of RTS,S/AS02 in children in SubSaharan African endemic countries, new data from preclinical studies established the potential to improve the vaccine’s immunogenicity by combining the RTS,S antigen with the Adjuvant System AS01 [38,39]. A challenge study conducted at WRAIR in adults non-immune volunteers showed that, as compared to RTS,S/AS02, RTS,S/AS01 had a similar reactogenicity profile, a higher humoral immunogenicity, a favourable Th1 cell mediated immune profile and a trend towards higher vaccine efficacy [40]. RTS,S/AS01 was then tested in Kenyan adults in conditions of natural malaria exposure. The study confirmed the higher immunogenicity as compared to RTS,S/AS02. The study was underpowered to detect differences in efficacy between the two vaccine formulations [41]. Age deescalation safety and immunogenicity studies were conducted in Gabon and Ghana and confirmed the favourable safety and immunogenicity profile seen in adults [42,43].
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The proof-of-concept, double-blind, randomized controlled trial of RTS,S/AS01E was conducted recently in 5–17 months old children in Kilifi, Kenya, and Korogwe, Tanzania. 894 children were enrolled. This was an ACD trial and the control vaccine was rabies. The point estimate of vaccine efficacy against clinical malaria disease was 53% (95% CI 28–69, p < 0.001), over an average follow up period of 8 months, which was higher than what had previously been seen with RTS,S/AS02. As had been seen in the study of RTS,S/AS02 in infants [37], there were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only attributable to a reduction of malaria-related events [44]. The evaluation of RTS,S/AS01 progressed to infants, in co-administration with EPI vaccines in a multicenter ongoing study in Gabon, Tanzania and Ghana.
The immunological evaluation of the RTS,S malaria candidate vaccine The immune response induced by the vaccine was investigated at depth in several of the RTS,S trials. While natural exposure generates minimal anti-CS antibodies [45], vaccination induces high levels of antibodies targeting the repeat region of the CS protein, mostly of IgG1 and IgG2 isotypes [22], with opsonising capacity [46]. High levels of antibodies against HBs are also induced, making RTS,S/AS a potential anti-hepatitis B vaccine. The activation of T cells, especially Th1 type CD4+ T cells secreting IFN-␥ and other cytokines have also been demonstrated [23–25,47–49]. The activation of CD8 cells, although reported [24,50], remain to be demonstrated conclusively as this observation has not been confirmed in subsequent studies. The immunological techniques that have been used to assess the RTS,S induced cellular immune response include cell proliferation, cytotoxicity assays, cytokine secretion in supernatant, IFN-␥ short term and long term ELISPOT, IL2 ELISPOT, ex-vivo intra-cellular cytokine staining, memory B cell ELISPOT, system biology microarrays. Pre-erythrocytic immunity, blood stage immunity, regulatory T cell responses, NK cell activation have been studied. Some of these results have been reported and others will be reported in the future. As of now, these assays have not allowed the identification of antibody or T cell protective thresholds. An association between anti-CS antibody levels and protection against infection have been found in the challenge model and ADI trials [23,25,27,34,36,37,51,52], but not in ACD or PCD trials [34,44]. A statistically significant association between the magnitude of the CD4 T cell response and protection has also been found in the challenge model [25]. In contrast to the challenge model, field conditions are not ideal for the definition of a correlate of protection, as exposure is not controlled. Indeed a “protected” individual, defined as not having had an episode of P. falciparum infection or malaria may not have been bitten by an infectious mosquito during the observation period; he may also have had infection or malaria if the follow up period had been longer; a child that has developed malaria may have been bitten several times by an infectious mosquito prior to eventually developed patent infection or disease. Another consideration to take into account is the difference in endpoint definition: in the challenge model or in ADI studies the endpoint is highly specific (P. falciparum parasitemia demonstrated on a blood slide). The characterization of a correlate of protection using a case definition including a parasitemia threshold as in case detection studies is more complex.
6. RTS,S/AS safety evaluation Up to early May 2009, in phase II clinical studies, over 1800 children under 6 years of age have received over 5000 doses of RTS,S/AS02. Over 1100 children have received over 3000 doses of RTS,S/AS01E. The safety evaluation in these trials assessed the
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occurrence of previously defined adverse events (AEs) that were actively monitored (solicited symptoms, all together defining the reactogenicity of the vaccine) for a period of six subsequent days after each vaccine dose. Non-solicited AEs were recorded for 30 days after each vaccine dose and Serious Adverse Events (SAEs) were recorded up to study end. The only SAE condition that occurred in the program and was estimated to be related to vaccination was simple febrile seizure, with a favourable clinical evolution [44]. Monitoring of haematology, renal and hepatic function were included in key studies and generated no concern. The monitoring of safety data in the program is under close scrutiny of an Independent Data Monitoring Board with paediatric, malariology, statistics, epidemiology and safety expertise.
Acknowledgements
7. The RTS,S/AS01 multicenter Phase III pivotal trial
[1] Hay SI, Guerra CA, Gething PW, Patil AP, Tatem AJ, Noor AM, et al. A world malaria map: Plasmodium falciparum endemicity in 2007. PLoS Med 2009;6(3):e1000048. [2] Greenwood BM, Fidock DA, Kyle DE, Kappe SH, Alonso PL, Collins FH, et al. Malaria: progress, perils, and prospects for eradication. J Clin Invest 2008;118:1266–76. [3] WHO publication. World Malaria report 2008, “WHO/HTM/GMP/2008.1”. [4] Organization UatWH. Immunization Summary: The 2007 Edition. In: UNICEF and the World Health Organization; 2007. [5] Singh AP, Buscaglia CA, Wang Q, Levay A, Nussenzweig DR, Walker JR, et al. Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite. Cell 2007;131(3):492–504 [Erratum in: Cell 2008;133(2):375]. [6] Nussenzweig RS, Vanderberg J, Most H, Orton C. Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei. Nature 1967;216:160–2. [7] Clyde DF, Most H, McCarthy V, Vanderberg JP. Immunization of man against sporozoite-induced falciparum malaria. Am J Med Sci 1973;266(3):169–77. [8] Kumar KA, Sano G, Boscardin S, Nussenzweig RS, Nussenzweig MC, Zavala F, et al. The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites. Nature 2006;444(7121):937–40. [9] Herrington D, Davis J, Nardin E, Beier M, Cortese J, Eddy H, et al. Successful immunization of humans with irradiated sporozoites: humoral and cellular responses of the protected individuals. Am J Trop Med Hyg 1991;45:539– 47. [10] Egan JE, Hoffman SL, Haynes JD, Sadoff JC, Schneider I, Grau GE, et al. Humoral immune responses in volunteers immunized with irradiated Plasmodium falciparum sporozoites. Am J Trop Med Hyg 1993;49:166–73. [11] Schofield L, Ferreira A, Altszuler R, Nussenzweig V, Nussenzweig RS. Interferongamma inhibits the intrahepatocytic development of malaria parasites in vitro. J Immunol 1987;139(6):2020–5. [12] Good MF, Currier J. The importance of T cell homing and the spleen in reaching a balance between malaria immunity and immunopathology: the moulding of immunity by early exposure to cross-reactive organisms. Immunol Cell Biol 1992;70(Pt 6):405–10. [13] Doolan DL, Southwood S, Chesnut R, Appella E, Gomez E, Richards A, et al. HLA-DR–promiscuous T cell epitopes from Plasmodium falciparum preerythrocytic-stage antigens restricted bymultiple HLAclass II alleles. J Immunol 2000;165:1123–37. [14] Moreno A, Clavijo P, Edelman R, Davis J, Sztein M, Herrington D, et al. Cytotoxic CD4+ T cells from a sporozoite-immunized volunteer recognize the Plasmodium falciparum CS protein. Int Immunol 1991;3:997–1003. [15] Malik A, Egan JE, Houghten RA, Sadoff C, Hoffman SL. Human cytotoxic T lymphocytes against the Plasmodium falciparum circumsporozoite protein. Proc Natl Acad Sci USA 1991;88:3300–4. [16] Ballou WR, Hoffman SL, Sherwood JA, Hollingdale MR, Neva FA, Hockmeyer WT, et al. Safety and efficacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet 1987;1(8545):1277–81. [17] Herrington DA, Clyde DF, Losonsky G, Cortesia M, Murphy JR, Davis J, et al. Safety and immunogenicity in man of a synthetic peptide malaria vaccine against Plasmodium falciparum sporozoites. Nature 1987;328(6127):257–9. [18] Gordon DM, McGovern TW, Krzych U, Cohen JC, Schneider I, LaChance R, et al. Safety, immunogenicity and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein/HBsAg subunit vaccine. J Inf Dis 1995;171:1576–85. [19] Chackerian B. Virus-like particles: flexible platforms for vaccine development. Exp Rev Vaccines 2007;6(3):381–90. [20] Grgacic EV, Anderson DA. Virus-like particles: passport to immune recognition. Methods 2006;40(1):0–5. [21] Garc¸on N, Chomez P, Van Mechelen M. GlaxoSmithKline Adjuvant Systems in vaccines: concepts, achievements and perspectives. Expt Rev Vaccines 2007;6(5):723–39. [22] Stoute JA, Slaoui M, Heppner DG, Garc¸on N, Kester KE, Desmons P, et al. A preliminary evaluation of a recombinant circumsporozoite protein malaria vaccine against Plasmodium falciparum. N Engl J Med 1997;36:86–91. [23] Stoute JA, Kester KE, Krzych U, Wellde BT, Hall T, White K, et al. Long term efficacy and immune responses following immunization with the RTS,S malaria vaccine. J Infect Dis 1998;178:1139–44.
The potential for AS01 Adjuvant System to improve vaccine efficacy conferred by AS02 and favourable safety data led to the selection of the RTS,S/AS01 formulation for further evaluation in a Phase III pre-licensure pivotal efficacy trial. The study will be conducted at 11 research centres in seven African countries (Gabon, Mozambique, Tanzania, Ghana, Kenya, Malawi, and Burkina Faso), reflecting a wide range of epidemiological settings. This will be a first-ever malaria Phase III vaccine trial with up to 16,000 participants of two age groups—6–12 weeks and 5–17 months at first vaccination. The trial cohort will be as representative as possible of children usually attending EPI visits. Low birth weight infants, moderately malnourished children and HIV infected children will be eligible. The study will assess efficacy against clinical malaria as the primary endpoint, and a range other endpoints relevant to public health will be evaluated (severe malaria, fatal malaria, anaemia, all cause hospital admission and mortality, non-malaria-related morbidity). The collection of non-malaria-related morbidity will allow the further investigation of possible indirect benefits of vaccination that were seen in previous Phase II RTS,S trials [37,44]. 8. RTS,S/AS clinical development: a collaborative endeavour The preparation of this multicentre trial has required the collaboration of multiple partners. The study, as the rest of the pediatric clinical development plan of the malaria candidate vaccine, is being implemented by the Clinical Trial Partnership Committee (CTPC), a collaboration of leading African research institutes, Northern academic partners, PATH-MVI and GSK, with support from the Malaria Clinical Trials Alliance (MCTA), coordinating the capacity building efforts supporting the African malaria research centre network. The research centres were selected for their experience in the conduct of clinical research to high standards, their strong community relations and commitment towards highest international ethical and regulatory standards. The trial has been reviewed by appropriate regulatory authorities and designed in consultation with the World Health Organization (WHO). WHO and PATH-MVI have led the development of a Malaria Vaccine Decision-Making Framework, with the aim of preparing for rapid implementation, once licensed, of a future malaria vaccine, avoiding unnecessary delay between regulatory approval and availability to those who need it. If the Phase III program progresses as expected, RTS,S could be submitted for regulatory review as early as 2011, paving the way to strengthened, sustainable malaria control strategies. Conflict of interest statement JV, AL and JC are GlaxoSmithKline Biologicals employees and own GSK shares. JC is an inventor on patented malaria vaccine candidates.
This vaccine development program is dependent on a large number of committed individuals and organizations including GSK Biologicals, PATH-MVI, MCTA, The Bill and Melinda Gates Foundation. The Clinical Trial Partnership Committee is a network of African based research centres and Northern partners, MVI and GSK Biologicals that oversees the clinical development plan implementation. Our deepest appreciation goes to the study participants, their families and communities.
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[39] Mettens P, Dubois PM, Demoitié MA, Bayat B, Donner MN, Bourguignon P, et al. Improved T cell responses to Plasmodium falciparum circumsporozoite protein in mice and monkeys induced by a novel formulation of RTS, S vaccine antigen. Vaccine 2008;26(8):1072–82. [40] Kester K, Cummings JF, Ofori-Anyinam O, Ockenhouse CF, Krzych U, Moris P, et al. Randomized, double-blind, phase 2 trial of Falciparum malaria vaccines RTS,S/AS01 and RTS,S/AS02 in malaria-naïve adults; Safety, Efficacy and Immunologic Associates of Protection. J Infect Dis; in press. [41] Polhemus M, Remich SA, Ogutu BR, Waitumbi JN, Otieno L, Apollo S, et al. Evaluation of RTS,S/AS02A and RTS,S/AS01B in adults in a high malaria transmission area. PLOS One, in press. [42] Lell B, Agnandji S, von Glasenapp I, Haertle S, Oyakhiromen S, Issifou S, et al. Safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in children in Gabon. Personal communication (submitted for publication). [43] Owusu-Agyei S, Ansong D, Asante KP, Owusu-Kwarteng S, Owusu R, Wireko Brobby O, et al. Evaluation of RTS,S/AS02D and RTS,S/AS01E Malaria Candidate Vaccines when given according to different Vaccination Schedules in Ghanaian Children. Personal communication (submitted for publication). [44] Bejon P, Lusingu J, Olotu A, Leach A, Lievens M, Vekemans J, et al. Efficacy of RTS, S/AS01E vaccine against malaria in children 5 to 17 months of age. New Engl JMed 2008;359:2521–32. [45] Hoffman SL, Wistar Jr R, Ballou WR, Hollingdale MR, Wirtz RA, Schneider I, et al. Immunity to malaria and naturally acquired antibodies to the circumsporozoite protein of Plasmodium falciparum. N Engl J Med 1986;315(10):601–6. [46] Schwenk R, Asher LV, Chalom I, Lanar D, Sun P, White K, et al. Opsonization by antigen-specific antibodies as a mechanism of protective immunity induced by Plasmodium falciparum circumsporozoite protein-based vaccine. Parasite Immunol 2003;25:7–25. [47] Lalvani A, Moris P, Voss G, Pathan AA, Kester KE, Brookes R, et al. Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine. J Infect Dis 1999;180(5):1656–64. [48] Reece WH, Pinder M, Gothard PK, Milligan P, Bojang K, Doherty T, et al. A CD4(+) T-cell immune response to a conserved epitope in the circumsporozoite protein correlates with protection from natural Plasmodium falciparum infection and disease. Nat Med 2004;10(4):406–10. [49] Pinder M, Reece WH, Plebanski M, Akinwunmi P, Flanagan KL, Lee EA, et al. Cellular immunity induced by the recombinant Plasmodium falciparum malaria vaccine, RTS,S/AS02, in semi-immune adults in The Gambia. Clin Exp Immunol 2004;135(2):286–93. [50] Hoffman SL, Weiss W, Mellouk S, Sedegah M. Irradiated sporozoite vaccine induces cytotoxic T lymphocytes that recognize malaria antigens on the surface of infected hepatocytes. Immunol Lett 1990;25(1-3):33–8. [51] Kester KE, McKinney DA, Tornieporth N, Ockenhouse CF, Heppner DG, Hall T, et al. A Phase IIa safety, immunogenicity, and efficacy bridging randomized study of a two-dose regimen of liquid and lyophilized formulations of the candidate malaria vaccine RTS, S/AS02A in malaria-naïve adults. Vaccine 2007;25:3559–66. [52] Kester KE, Cummings JF, Ockenhouse CF, Nielsen R, Hall BT, Gordon DM, et al. Phase 2a trial of 0, 1 and 3 month and 0, 7, and 28 day immunization schedules of malaria vaccine RTS, S/AS02 in malaria-naïve adults at the Walter Reed Army Institute of Research. Vaccine 2008;26(18):2191–202.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Development of the RTS,S/AS malaria candidate vaccine Johan Vekemans ∗ , Amanda Leach, Joe Cohen GlaxoSmithKline Biologicals, 89 rue de l’Institut, 1330 Rixensart, Belgium
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Article history: Received 15 June 2009 Received in revised form 25 September 2009 Accepted 2 October 2009
Keywords: Malaria vaccine RTS,S/AS Development
a b s t r a c t A vaccine against malaria which complements existing control tools is an urgent medical need. RTS,S/AS, a pre-erythrocytic candidate vaccine, which targets the circumsporozoite protein, is the most advanced in clinical development. The safety, immunogenicity and efficacy of this candidate vaccine have been investigated in a series of trials in children and infants in endemic African countries. The vaccine shows promise for providing important public health benefits and a multicenter Phase III trial has started in Africa, aiming to further characterize the efficacy of the candidate vaccine and generate the regulatory data required for the licensing approval of the vaccine. © 2009 Published by Elsevier Ltd.
1. Malaria vaccine: an unmet medical need The availability of a malaria vaccine would contribute greatly to the efforts aimed at controlling this major threat to global health. It is estimated that in 2007, more than 2.37 billion people were living in areas where Plasmodium falciparum malaria transmission occurs [1]. Sub-Saharan Africa carries the highest burden of the disease, with an estimated 250 million cases and nearly 1 million deaths each year [2,3]. Malaria represents a huge burden on health care systems and economical losses [4]. Over 80% of fatalities occur in African children under the age of 5 [4] justifying the development of a vaccine targeting primarily this vulnerable population. Recently, hopes for the possibility of long term control, elimination and even eradication of the disease have re-emerged, encouraged by important reductions in malaria burden in countries, such as Rwanda, Zambia, Madagascar, Zanzibar and The Gambia where large scale malaria control programs have been implemented [3]. These recent successes are great news, but no reason for complacency. Currently implemented malaria control strategies include interventions such as insecticide-treated net, insecticide residual spraying, intermittent preventive treatment to pregnant women, and Artemisin based combination treatment. Unfortunately, both the malaria parasite and the transmitting mosquitoes have shown a very high capacity to develop pharmaceutical escape mechanisms and drug resistance, as demonstrated by the previously failed World Health Organisation (WHO) malaria eradication program, also based on malaria drugs and mosquito control. The addition of a vaccine to the anti-malaria arsenal is an
∗ Corresponding author. Tel.: +32 2 656 5659. E-mail address: [email protected] (J. Vekemans). 0264-410X/$ – see front matter © 2009 Published by Elsevier Ltd. doi:10.1016/j.vaccine.2009.10.013
urgent medical need, and may possibly contribute to reduce the risk of emergence of parasite drug resistance, thereby increasing the sustainability of existing malaria control strategies. 2. The RTS,S/AS malaria candidate vaccine construct The most advanced malaria vaccine candidate is RTS,S formulated with GSK proprietary Adjuvants Systems (AS) AS01 or AS02. This candidate vaccine has been in development for over 20 years, and since 2001 under the leadership of a public-private product development partnership between GSK Biologicals and the PATH Malaria Vaccine Initiative (MVI), with support from the Bill and Melinda Gates Foundation. The overall objective of the RTS,S/AS program is to reduce the burden of disease related to P. falciparum malaria in infants and children residing in sub-Saharan African malaria-endemic countries. The vaccine would ideally be implemented through the existing infant vaccine delivery program, the Expanded Program on Immunization, in conjunction with other malaria control interventions. The vaccine candidate targets the pre-erythrocytic phase of the parasite life cycle, comprising the sporozoite and liver stages. Sporozoites, which are injected in the circulation following a bite from an infected mosquito, rapidly target the liver, and invade hepatocytes. The parasite then develops into a schizont containing 10,000–30,000 merozoites, which are later released from the liver into the blood, whereby the disease-associated erythrocytic phase of the infection is initiated. The target antigen is the circumsporozoite protein (CS), a 412 amino acids protein abundantly associated with the sporozoite surface, also expressed by liver forms and exported in the cytoplasm of hepatocytes. It has a characteristic central conserved NANP repeat region and non-repeat flanking regions with both conserved and
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variable segments. This protein is thought to play a role in the entry of the parasite in the liver through an interaction with liver sinusoidal heparan sulphate proteoglycans, and interference with the hepatocyte cellular processes, down regulating NF-KB mediated inflammation, thereby creating a favourable niche for the parasite and allowing the development of the liver stage [5]. The feasibility of developing a pre-erythrocytic vaccine was demonstrated in the late 1960s, when it was shown first in rodents then in humans that immunization with irradiated sporozoites can induce complete protection against experimental sporozoite challenge [6,7]. In this immunization model, the CS has been shown to be a major target of protective immunological effectors [8]. Both CS-specific antibodies and T cells have been shown to be implicated in protection [9]. Anti-CS antibodies can block sporozoite liver cell invasion in vitro [10] and prevent experimental infection in animals [11]. Passive transfer of both CS-specific CD4 and CD8 T cells can protect animals from experimental infection [11,12]. In humans the activation of CD4+ T cells and cytotoxic CD8 T cells has been reported [13–15]. Initial candidate vaccine constructs targeting only the central repeat region of the CS protein failed to provide substantial protection [16,17]. The recruitment and activation of T cells through the development of innovative technologies became a key objective of the team working collaboratively at the Walter Reed Army Institute of Research and GSK Biologicals in the 1980s. A new vaccine construct was generated [18] based on a large segment of CS (Amino Acids 207–395 of the CS from the NF54 P. falciparum strain) that included 19 NANP conserved repeats and the C-terminal part of the non-repeat region (excluding the hydrophobic membrane anchor) known to contain T cell epitopes, and covalently bounded to the HBs antigen (adw serotype), the hepatitis B vaccine antigen. When recombinantly expressed in Saccharomyces cerevisiae the fusion protein (RTS), together with a free transcript of the hepatitis B antigen (S), spontaneously assemble to form virus-like particles, known to favour antigen presentation to the T cell compartment [19,20]. The vaccine construct was formulated with two Adjuvant Systems, AS01 and AS02, shown to induce both strong humoral and cellular immune responses. Both include the immunostimulants MPL and QS21. The monophosphoryl lipid A molecule MPL consists of a chemically detoxified form of the parent lipopolysaccharide (LPS) from the Gram negative bacterium Salmonella minnesota. QS21 is a natural saponin molecule purified from the bark of the South American tree, Quillaja saponaria. AS02 contains in addition an oil in water emulsion while AS01 contains a liposomal suspension [21]. 3. Early RTS,S/AS02 evaluation in adults Early clinical development of the RTS,S malaria candidate vaccine was initiated in studies in malaria-naïve adults in collaboration with the Walter Reed Army Institute of Research (WRAIR). The first challenge study demonstrated the importance of the adjuvant in the generation of protective immunity. Volunteers vaccinated with three different adjuvant formulations of RTS,S and controls were subjected to experimental sporozoite challenge. Out of seven volunteers vaccinated with the RTS,S/AS02 formulation, six were protected against challenge, while the two other formulations protected one of eight and two of seven participants. Immunological analysis showed that as compared to the other formulations the RTS,S/AS02 induced a high level of anti-CS and anti-HBs antibodies as well as IFN-␥ producing T cells. When re-challenged 6 months later, out of seven protected volunteers in the initial challenge experiment (across the three vaccine formulations tested) who accepted to participate to a second challenge, two were protected again [22–24]. Across several challenge studies conducted over the years, it was consistently shown that RTS,S/AS02A vaccination
provides protection against sporozoite challenge of a magnitude of 40%. It was observed that in addition to providing full protection (sterile protection, characterised by the absence of parasitemia after challenge) in some of the vaccinated individuals, the development of parasitemia in the breakthrough cases was delayed for 48 h or longer compared to non-vaccinated controls. It is hypothesized that this delay reflects a diminished merozoite release from the liver. Such a decrease in the parasite load initiating the blood stage may allow the immune system to better cope with the growing parasitemia, with a possible impact on the development of associated symptoms, and decrease the risk of progression towards the more severe forms of the disease [25]. The results of the challenge studies led to evaluation of RTS,S/AS02 in malaria-endemic regions.
Study designs in malaria efficacy trials, in conditions of natural malaria exposure Several study designs can be used to assess efficacy of a malaria candidate vaccine in conditions of natural malaria exposure. Evaluation of efficacy against rare endpoints such as severe malaria is relevant to public health but requires large sample size and is reserved for late vaccine evaluation. Early in vaccine development programs, studies focus on more frequent events like occurrence of P. falciparum infection, defined as the presence of P. falciparum parasites in the blood, or uncomplicated malaria disease, defined as P. falciparum parasitemia above a specific threshold in a participant that is unwell with fever. This inclusion of a parasitemia threshold increases the specificity of the case definition [26]. In the following sections, Active Detection of Infection (ADI) will be referred to when investigators screen study participants on a regular basis, looking for parasitemia on a blood slide. Passive Case Detection (PCD) is referred to when cases are captured when a child who is unwell is brought for treatment in a health facility. Active Case Detection (ACD) is when investigators visit study participants on a regular basis, measure temperature and do a blood slide if fever is present.
The first efficacy study under conditions of natural exposure started in 1998 in The Gambia, a region of seasonal malaria transmission. The vaccine prevented 34% (95% CI: 8–53; p = 0.014) of infections over a surveillance period of 15 weeks during the malaria season [27]. Protection was shown not to be strain-specific [28]. When a booster dose of the vaccine was given before the subsequent malaria transmission season a year later, there was a 47% protection against infection over 9 weeks [27]. The follow-up safety evaluation, over a 5-year period, was favourable [29]. 4. RTS,S/AS02 evaluation in children and infants, in malaria-endemic countries The evaluation of RTS,S/AS02 progressed to the paediatric population initially with age de-escalation and dose optimization studies [30,31]. A large trial in Mozambican children aged 1–4 years was then started, enrolling a total of 2022 subjects. The study included two cohorts. In the first, largest cohort, efficacy against clinical malaria was assessed by PCD. Over the first 18 months of follow up the efficacy against clinical malaria was 35.3% (95% CI: 21,6, 46.6; p < 0.0001). The study also showed a 48.6% (95% CI: 12.3, 71.0; p = 0.02) reduction in the number of RTS,S/AS02 vaccinated participants having developed severe malaria, as compared to controls [32]. The follow up of study participants continued, and showed over 43 months an efficacy of 25.6% (95% CI: 11.9–37.1; p < 0.001) in prevention of clinical malaria episodes, and the absence of rebound in malaria or severe malaria occurrence in the vaccinated group. At the end of the 43 months post vaccination follow up, the prevalence
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of P. falciparum parasitemia was 34% lower in the RTS,S/AS02A group as compared to the control group. 12 deaths, had occurred in the RTS,S/AS02 group, as compared to 22 in the control group, of which and 5 and 1, respectively, were attributed to malaria [33]. In the second cohort, a 45% (95% CI 31.4–55.9; p < 0.0001) vaccine efficacy against infection was demonstrated, through ADI for 6 months [34]. Although not initially foreseen, an exploratory analysis showed 35.4% (95% CI 4.5–56.3; p = 0.029) vaccine efficacy against clinical malaria over the initial 6 months, based on data reported through PCD for safety. Measured efficacy in cohort 2 thereafter waned, suggesting that the intensive surveillance in the context of an ADI study with early treatment of infections or differences in the intensity of exposure to malaria may affect the long term protection mechanisms induced by the vaccine [35]. An alternative explanation would be that other unknown factors, such as heterogeneity in exposure, affect our ability to characterise duration of protection using standard statistical models. RTS,S/AS02 vaccination was then investigated in infants of the EPI age group (infants aged 6–12 weeks at first vaccination). A two-step approach was taken, with assessment of safety, immunogenicity and efficacy initially when given 2 weeks apart from EPI vaccines, then in co-administration. When given apart, in a study in Mozambique, it was demonstrated that the reactogenicity of RTS,S/AS02 was similar to that of hepatitis B and diphtheriatetanus whole cell pertussis-Haemophilus influenzae (DTPw-Hib) tetravalent vaccines. Anti-CS antibody GMTs induced by the vaccine were similar to those observed in older children. The study also demonstrated a 65.9% (95% CI: 42.6–79.8; p < 0.001) vaccine efficacy against infection through ADI over a 12-week surveillance period [36]. When given in co-administration with DTPw-Hib in infants in a study in Tanzania, RTS,S/AS02 was shown to induce more low grade fever (<39 ◦ C) than Hepatitis B vaccine (29.6% and 13.6%, respectively). Pre-defined non-inferiority of EPI immune responses was demonstrated, and seroprotection rates to EPI antigens were high, despite a trend towards lower GMT’s to EPI antigens upon RTS,S/AS02 co-administration. Although 98.6% infants vaccinated with RTS,S/AS02 had seropositive titres for anti-CS antibodies, the anti-CS immune response was lower than that seen in previous trials. Despite this, efficacy against infection assessed by ADI was 65.2% (95% CI: 20.7–84.7; p = 0.012) over a 6 months follow up period. The study also showed a lower occurrence of serious adverse events in RTS,S/AS02 vaccine recipients as compared to controls. This was true also when non-malaria-related events were analyzed, notably pneumonia. This finding suggests that RTS,S/AS vaccination may have indirect health benefits, possibly reducing the increased susceptibility to other diseases resulting from malaria exposure [37]. 5. RTS,S/AS01: a superior formulation In parallel to the evaluation of RTS,S/AS02 in children in SubSaharan African endemic countries, new data from preclinical studies established the potential to improve the vaccine’s immunogenicity by combining the RTS,S antigen with the Adjuvant System AS01 [38,39]. A challenge study conducted at WRAIR in adults non-immune volunteers showed that, as compared to RTS,S/AS02, RTS,S/AS01 had a similar reactogenicity profile, a higher humoral immunogenicity, a favourable Th1 cell mediated immune profile and a trend towards higher vaccine efficacy [40]. RTS,S/AS01 was then tested in Kenyan adults in conditions of natural malaria exposure. The study confirmed the higher immunogenicity as compared to RTS,S/AS02. The study was underpowered to detect differences in efficacy between the two vaccine formulations [41]. Age deescalation safety and immunogenicity studies were conducted in Gabon and Ghana and confirmed the favourable safety and immunogenicity profile seen in adults [42,43].
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The proof-of-concept, double-blind, randomized controlled trial of RTS,S/AS01E was conducted recently in 5–17 months old children in Kilifi, Kenya, and Korogwe, Tanzania. 894 children were enrolled. This was an ACD trial and the control vaccine was rabies. The point estimate of vaccine efficacy against clinical malaria disease was 53% (95% CI 28–69, p < 0.001), over an average follow up period of 8 months, which was higher than what had previously been seen with RTS,S/AS02. As had been seen in the study of RTS,S/AS02 in infants [37], there were fewer serious adverse events among recipients of RTS,S/AS01E, and this reduction was not only attributable to a reduction of malaria-related events [44]. The evaluation of RTS,S/AS01 progressed to infants, in co-administration with EPI vaccines in a multicenter ongoing study in Gabon, Tanzania and Ghana.
The immunological evaluation of the RTS,S malaria candidate vaccine The immune response induced by the vaccine was investigated at depth in several of the RTS,S trials. While natural exposure generates minimal anti-CS antibodies [45], vaccination induces high levels of antibodies targeting the repeat region of the CS protein, mostly of IgG1 and IgG2 isotypes [22], with opsonising capacity [46]. High levels of antibodies against HBs are also induced, making RTS,S/AS a potential anti-hepatitis B vaccine. The activation of T cells, especially Th1 type CD4+ T cells secreting IFN-␥ and other cytokines have also been demonstrated [23–25,47–49]. The activation of CD8 cells, although reported [24,50], remain to be demonstrated conclusively as this observation has not been confirmed in subsequent studies. The immunological techniques that have been used to assess the RTS,S induced cellular immune response include cell proliferation, cytotoxicity assays, cytokine secretion in supernatant, IFN-␥ short term and long term ELISPOT, IL2 ELISPOT, ex-vivo intra-cellular cytokine staining, memory B cell ELISPOT, system biology microarrays. Pre-erythrocytic immunity, blood stage immunity, regulatory T cell responses, NK cell activation have been studied. Some of these results have been reported and others will be reported in the future. As of now, these assays have not allowed the identification of antibody or T cell protective thresholds. An association between anti-CS antibody levels and protection against infection have been found in the challenge model and ADI trials [23,25,27,34,36,37,51,52], but not in ACD or PCD trials [34,44]. A statistically significant association between the magnitude of the CD4 T cell response and protection has also been found in the challenge model [25]. In contrast to the challenge model, field conditions are not ideal for the definition of a correlate of protection, as exposure is not controlled. Indeed a “protected” individual, defined as not having had an episode of P. falciparum infection or malaria may not have been bitten by an infectious mosquito during the observation period; he may also have had infection or malaria if the follow up period had been longer; a child that has developed malaria may have been bitten several times by an infectious mosquito prior to eventually developed patent infection or disease. Another consideration to take into account is the difference in endpoint definition: in the challenge model or in ADI studies the endpoint is highly specific (P. falciparum parasitemia demonstrated on a blood slide). The characterization of a correlate of protection using a case definition including a parasitemia threshold as in case detection studies is more complex.
6. RTS,S/AS safety evaluation Up to early May 2009, in phase II clinical studies, over 1800 children under 6 years of age have received over 5000 doses of RTS,S/AS02. Over 1100 children have received over 3000 doses of RTS,S/AS01E. The safety evaluation in these trials assessed the
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occurrence of previously defined adverse events (AEs) that were actively monitored (solicited symptoms, all together defining the reactogenicity of the vaccine) for a period of six subsequent days after each vaccine dose. Non-solicited AEs were recorded for 30 days after each vaccine dose and Serious Adverse Events (SAEs) were recorded up to study end. The only SAE condition that occurred in the program and was estimated to be related to vaccination was simple febrile seizure, with a favourable clinical evolution [44]. Monitoring of haematology, renal and hepatic function were included in key studies and generated no concern. The monitoring of safety data in the program is under close scrutiny of an Independent Data Monitoring Board with paediatric, malariology, statistics, epidemiology and safety expertise.
Acknowledgements
7. The RTS,S/AS01 multicenter Phase III pivotal trial
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The potential for AS01 Adjuvant System to improve vaccine efficacy conferred by AS02 and favourable safety data led to the selection of the RTS,S/AS01 formulation for further evaluation in a Phase III pre-licensure pivotal efficacy trial. The study will be conducted at 11 research centres in seven African countries (Gabon, Mozambique, Tanzania, Ghana, Kenya, Malawi, and Burkina Faso), reflecting a wide range of epidemiological settings. This will be a first-ever malaria Phase III vaccine trial with up to 16,000 participants of two age groups—6–12 weeks and 5–17 months at first vaccination. The trial cohort will be as representative as possible of children usually attending EPI visits. Low birth weight infants, moderately malnourished children and HIV infected children will be eligible. The study will assess efficacy against clinical malaria as the primary endpoint, and a range other endpoints relevant to public health will be evaluated (severe malaria, fatal malaria, anaemia, all cause hospital admission and mortality, non-malaria-related morbidity). The collection of non-malaria-related morbidity will allow the further investigation of possible indirect benefits of vaccination that were seen in previous Phase II RTS,S trials [37,44]. 8. RTS,S/AS clinical development: a collaborative endeavour The preparation of this multicentre trial has required the collaboration of multiple partners. The study, as the rest of the pediatric clinical development plan of the malaria candidate vaccine, is being implemented by the Clinical Trial Partnership Committee (CTPC), a collaboration of leading African research institutes, Northern academic partners, PATH-MVI and GSK, with support from the Malaria Clinical Trials Alliance (MCTA), coordinating the capacity building efforts supporting the African malaria research centre network. The research centres were selected for their experience in the conduct of clinical research to high standards, their strong community relations and commitment towards highest international ethical and regulatory standards. The trial has been reviewed by appropriate regulatory authorities and designed in consultation with the World Health Organization (WHO). WHO and PATH-MVI have led the development of a Malaria Vaccine Decision-Making Framework, with the aim of preparing for rapid implementation, once licensed, of a future malaria vaccine, avoiding unnecessary delay between regulatory approval and availability to those who need it. If the Phase III program progresses as expected, RTS,S could be submitted for regulatory review as early as 2011, paving the way to strengthened, sustainable malaria control strategies. Conflict of interest statement JV, AL and JC are GlaxoSmithKline Biologicals employees and own GSK shares. JC is an inventor on patented malaria vaccine candidates.
This vaccine development program is dependent on a large number of committed individuals and organizations including GSK Biologicals, PATH-MVI, MCTA, The Bill and Melinda Gates Foundation. The Clinical Trial Partnership Committee is a network of African based research centres and Northern partners, MVI and GSK Biologicals that oversees the clinical development plan implementation. Our deepest appreciation goes to the study participants, their families and communities.
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