RTS,S Malaria Vaccine Clinical Trials The RTS,S Malaria kills close to one million people a year worldwide and sickens millions more, Malaria Vaccine most of them children living in sub-Saharan Africa. The international community Candidate urgently needs a safe and effective vaccine to control the disease. A vaccine, even a partially effective one, is a necessary component of a comprehensive malaria program and could potentially save hundreds of thousands of lives a year. RTS,S is the world’s most advanced malaria vaccine candidate and the first to demonstrate in clinical trials that it can protect young children living in malaria-endemic areas against infection and clinical disease caused by Plasmodium (P.) falciparum, the most deadly form of the malaria parasite. The RTS,S malaria vaccine candidate was created in 1987. Its early development was undertaken by GlaxoSmithKline (GSK) Biologicals, the vaccine division of GSK, in close collaboration with the Walter Reed Army Institute of Research (WRAIR). In January 2001, GSK and the PATH Malaria Vaccine Initiative (MVI)—with support from the Bill & Melinda Gates Foundation—entered into an agreement to develop the vaccine for infants and young children, with a geographic focus on sub-Saharan Africa. The RTS,S vaccine candidate is a recombinant protein that fuses a part of the P. falciparum circumsporozoite (CS) protein with the hepatitis B surface antigen. Com- bined with a proprietary GSK adjuvant system, RTS,S induces the production of antibodies and T cells that are believed to diminish the capacity of the malaria parasite to infect, survive, and develop in the human liver. In addition to inducing partial protec- tion against malaria, the RTS,S vaccine candidate is also designed to protect against hepatitis B, a severe form of hepatitis and an important etiological factor in end-stage liver disease and liver cancer. RTS,S Results Clinical evaluation of RTS,S began in adults in the United States and Belgium in 1992. To Date Results of a trial of more than 2,000 children, started in 2003 in southern Mozambique, demonstrated the feasibility of administering a malaria vaccine in children. Findings from this trial, published in 2004 and 2005 in the medical journal The Lancet, showed that RTS,S was effective for at least 18 months in reducing clinical malaria by 35 percent and severe malaria by 49 percent, thus establishing RTS,S as the most advanced malaria vaccine candidate. Recent data, published on October 17, 2007, showed that RTS,S reduced infection by 65 percent over three months of follow-up, after a full vaccination course in infants—the group most vulnerable to malaria. The RTS,S KEY 1984 1992 1997 2001 2007 GSK/WRAIR First clinicaltests Key Proof-of-Concept GSK/PATH-MVI Key PoC study MILESTONES begin pre-clinical begin in adults in (PoC) study shows 6 of 7 pertnership in infants in studies US and belgium volunteers in challenge begins Moambique trial is 100% protected. 1987 1995 2001 2004-2005 RTS,S is first created First trials in Key PoC study Key PoC in Mozambique by combining the Africa begin in adults in shows 49% efficacy against malariaCS protein and in The Gambia The Gambia severe malaria for 18 mo. in Hepatitis B antigen. and Kenia children (1-4yrs old) vaccine also reduced the risk of clinical malaria by 35.5 percent over a six-month period following the first dose. Importantly, it also displayed a promising safety and tolerability profile, similar to standard Expanded Program of Immunization vaccines commonly given to infants, including comparable pain and swelling. The trial is the first proof-of- concept in infants of any malaria vaccine candidate, and substantially advances the vision that a vaccine could contribute to reducing the intolerable burden of disease and death caused by malaria. Next steps Based on the successful 2004 Mozambique STEPS IN MALARIA VACCINE CANDIDATE DEVELOPMENT in advancing trial, GSK, MVI and leading local research Research and Pre-clinical Development: RTS,S institutions are conducting additional clinical Identify relevant antigens and create trials in infants and young children. Research- vaccine concept; pre-clinical evaluation; ers are exploring ways to maximize the develop vaccine manufacturing process. vaccine candidate’s potential by testing Phase 1 Clinical Trials: Establish the different formulations, dosing, and schedules. safety and measure immune response in malaria-naïve and malaria-exposed In collaboration with Africa-based research populations. institutions, a series of clinical trials are Phase 2 Clinical Trials: Monitor safety and ongoing in Mozambique, Tanzania, Gabon, potential side effects; measure immune Ghana, and Kenya, with other sites under response; measure preliminary efficacy against infection and clinical disease; and consideration. determine optimum dosage and schedule. If the Phase 2 trials are successful, a large- Phase 3 Clinical Trials: Continue to monitor safety, potential side effects, and scale Phase 3 trial—the last stage of develop- evaluate efficacy on a large scale. ment before licensure—will be launched in the Submission to Regulatory Authorities: second half of 2008. The Phase 3 studies are Submit vaccine application to regulatory designed to fully determine the efficacy of the authorities for approval to market vaccine and could become the largest clinical Introduction: Make vaccine available trial ever conducted for a vaccine in Africa. for use. Phase 4 Clinical Trials: Post-marketing If all goes well, the RTS,S vaccine could be safety monitoring; measure duration of submitted to regulatory authorities in 2011. protection and assess vaccine compliance. The partners are committed to working with governments and supranational organiza- tions to determine demand and to develop policies and systems for financing the procurement of a prospective malaria vaccine and the implementation of vaccination programs. Once RTS,S is licensed, GSK and MVI will work to ensure this revolutionary vaccine candidate reaches the children who most need it. THE PATH MALARIA VACCINE INITIATIVE (PATH/MVI) is a global program established at PATH through an initial grant of $50 million from the Bill & Melinda Gates Foundation. MVI’s mission is to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world. MVI’s vision is a world free from malaria. For more information, please visit www.malariavaccine.org. PATH is an international, nonprofit organization that creates sustainable, culturally relevant solutions that enable communities worldwide to break longstanding cycles of poor health. By collaborating with diverse public- and private-sector partners, PATH helps provide appropriate health technologies and vital strategies that change the way people think and act. PATH’s work improves global health and well-being. For more information, please visit www.path.org. GLAXOSMITHKLINE BIOLOGICALS (GSK BIO), one of the world’s leading vaccine manufacturers, is headquartered in Rixensaart, Belgium, where the majority of GlaxoSmithKline’s activities in the field of vaccine research, development and production are conducted. GSK Bio employs more than 1,500 scientists, who are devoted to discovering new vaccines and developing more cost-effective and convenient combination products to prevent infections that cause serious medical problems worldwide. In 2006, GSK Bio distributed more than 1.1 billion doses of vaccines to 169 countries in both the developed and the developing world, an average of more than 3 million doses per day. GlaxoSmithKline–one of the world’s leading research-based pharmaceutical and healthcare companies–is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information please visit www.gsk.com.