Malaria Vaccine Pipeline Development Challenges • Historically, work on malaria vaccines has been...
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Malaria Vaccine Pipeline Perspectives and Challenges Carla Botting World Vaccine Congress Asia 2008 3 June 2008
Malaria Vaccine Pipeline Development Challenges • Historically, work on malaria vaccines has been conducted by the military, government and academia, due to – Limited financial
Malaria Vaccine PipelinePerspectives and Challenges
Carla BottingWorld Vaccine Congress Asia 20083 June 2008
Discussion PointsScope of the problem: the burden and challenge of malaria
Malaria vaccine goals
State of malaria vaccine development
Vaccine challenges
MVI focus and perspective
Malaria’s Reach and Retreat
Presenter
Presentation Notes
Malaria is one of the oldest diseases known to humans. The World Health Organization (WHO) estimates that 350 million to 500 million people suffer malaria episodes every year. Mortality estimates start one million (WHO) and some put the number closer to three million. About 80% of those are children. Map shows how far malaria extended in 1900 and how it retreated over time…was in parts of Europe up until the late 1940s. Today, the world is once again making important progress toward controlling malaria. To win the war against malaria, we will need to both extend existing strategies and develop new tools.
Ultimate Goal (again): Malaria Eradication
Presenter
Presentation Notes
Eradicating malaria is our long term goal. The graphic here commemorates the “first day of issue” malaria eradication US postage stamp from 1962. It refers to the last major attempt to eradicate malaria: the WHO campaign from 1955 to 1969. That attempt relied mainly on spraying insecticides in designated “malarious areas.” Malaria has been eradicated from large swathes of East Asia, North America, and Eastern and Mediterranean Europe Worldwide eradication efforts have failed because: Complex and highly adaptive plasmodium parasite Limited access within malaria-endemic countries to effective prevention and control tools (drugs, insecticides, bed nets) No disease has been eradicated without a vaccine!
What is the Goal of the Malaria Vaccine Community?
• To develop an 80% efficacious malaria vaccine by 2025 that would provide protection for longer than four years.
Presenter
Presentation Notes
By 2015 we hope to have a malaria vaccine that is at least 30% effective and lasts longer than 1 year. Even this partially effective vaccine has the potential to save hundreds of thousands of lives and would be welcomed by many malaria-endemic countries until we develop a more efficacious vaccine.
The Deadliest Parasite: Plasmodium Falciparum
• > 90% of disease burden in sub-Saharan Africa
• Africa's leading cause of mortality (20%) in children age 0 to 5 years
• Main cause of clinical and severe malaria and death Image: Plasmodium falciparum
from Medical Structural Genomics of Pathogenic Protozoa
Presenter
Presentation Notes
Current malaria vaccine R&D targets two species p. vivax p. falciparum P. vivax is the most common source of malaria infection in the world. It is especially prevalent in Southeast Asia, India, and South America. While not associated with a high death rate, it recurs frequently in people once they are infected. P.falciparum is the deadliest of the malaria parasites Most of the malaria vaccine development focus is on P. falciparum for children: every 30 seconds a child dies of infection from a p. falciparum parasite.
State of Malaria Vaccine Development
*Source: The Malaria Product Pipeline, The George Institute for International Health, September 2007, modified to reflect recent changes in MVI’s portfolio
0
5
10
15
20
25
30
Preclinical Safety trials-non-endemic
Safety trials -endemic
Efficacy trials-endemic
MVI sponsored Others
Num
ber o
f vac
cine
can
dida
tes
Presenter
Presentation Notes
More than 40 malaria vaccine candidates are in development 16 are in clinical trials GlaxoSmithKline Biologicals’ RTS,S, is the vaccine candidate closest to licensure; it is targeted for submission to regulatory authorities by 2015. Second-generation vaccine candidates are unlikely to be available until after 2015. RTS,S only demonstrates partial efficacy—a reflection of the scientific challenges of developing vaccines against the parasitic disease. However, studies show that even a partially efficacious malaria vaccine could be a valuable public health tool.
What are the Challenges?
• R&D Challenges• Business Development
Challenges• Financing Challenges
R&D Challenges• No vaccine has ever been developed for
human use against parasites
• There are no known correlates of immunity for malaria vaccines to establish proof of concept
Presenter
Presentation Notes
Malaria pathogens are much more complex than viruses and bacteria. We have not been able to identify the immune response that correlates with protection. So malaria vaccine candidates can only be shown to work (or not work) by going through clinical trials. This need for an empirical process greatly adds to the cost and to the amount of time it takes to develop a vaccine.
Business Development Challenges
• Historically, work on malaria vaccines has been conducted by the military, government and academia, due to– Limited financial return anticipated– Major technical and scientific hurdles– Complicated regulatory pathways
Presenter
Presentation Notes
Partnerships are key in the development of a malaria vaccine. Partners play a critical role in moving vaccine candidates from the research stage into clinical trial and development pathways. It has been difficult to attract partners with expertise in product development.
Financing Challenges
• Current funding for malaria research is starkly inadequate– Vaccine costs at least $500 million from “lab to jab”
• Government and NGO “push” funding is essential (i.e. MVI with Gates Foundation support)
• “Pull” mechanisms also needed– Advance market commitments from governments and
promises of future purchases by the public sector
Presenter
Presentation Notes
Push mechanisms are financial incentives to drive research in areas where the market is not as robust as others. A government will choose among various options and gives its favorites---universities, pharmas, the military---a push to conduct R&D with grants or subsidies. (In fact, that’s what the United States did at the beginning of the nineteen-eighties, when it funded a number of malaria-vaccine projects—none of which panned out.) MVI funding typically functions as a push mechanism. We provide financing for organizations to develop technologies. Pull mechanisms are pre-commitments by donors to buy a vaccine when an effective one is actually developed, which guarantees a market for it. Drug companies would thus have an incentive to invest in promising candidates. Rather than pushing vaccines into existence, this approach pulls them. Anticipation of future purchasing from the GAVI Alliance, the Global Fund to Fight AIDS, Tuberculosis and Malaria and from similar major financing initiatives increase the credibility of a future market for malaria vaccines. Malaria vaccines are under consideration for an Advance Market Commitment (AMC), a binding contract, typically offered by a government or other financial entity, used to guarantee a viable market if a vaccine is successfully developed. With an AMC, the market for that vaccine would be comparable in size and certainty to the market for vaccines in wealthier countries.
PATH Malaria Vaccine Initiative
• Created in 1999 with a grant from the Bill & Melinda Gates Foundation• A program of PATH• Mission: To accelerate the development of malaria vaccines and ensure
their availability and accessibility in the developing world• Vision: A world free from malaria
Presenter
Presentation Notes
Why was MVI established? Because many people believe that the world urgently needs a safe and effective vaccine to reduce the suffering malaria causes. Because good ideas were languishing in the lab, largely because of a lack of market incentives: young children in poor countries are the primary market. MVI is a program of PATH (Don’t forget to mention this!) MVI is a malaria investor, not an inventor We organize our R&D strategy around the concept of a global malaria vaccine portfolio. This means that we invest in a diversity of vaccine candidates and we refine our R&D strategy through active engagement with the malaria community and reliance on the best available data. We are also organized around partnerships. Partnerships are key at every step of the way along the development process Our partners in the development process include for-profit pharmaceutical and biotech companies, non-profit academic institutions, US government agencies, and other vaccine development programs, such as those run by the European Malaria Vaccine Initiative, EMVI. We also partner with malaria-endemic countries as they decide what their vaccine needs are. Most importantly we partner with the scientists, many of them Africans, who work in clinical trial sites in Africa. Today, thanks to the support of the Gates Foundation and other donors like the ExxonMobil Foundation– we are closer than ever to having a first-generation vaccine.
Malaria Vaccine Targets and the Plasmodium Lifecycle
If the vaccine targets….
Its goal is to….
Pre-
erythrocytic Stage
Prevent infection
Blood-stage Reduce clinical disease
Sexual transmission blocking
Prevent the spread of parasites by mosquitoes
Presenter
Presentation Notes
This is the focus of our scientific work at MVI: the life cycle of the parasite. We pursue different vaccine development approaches. We invest in candidates that target the parasite at different stages of its development. We target different parts of the parasite. We have one candidate that is using a whole-parasite approach. Many scientists believe that a malaria vaccine will need to encompass more than one approach to reach a high degree of efficacy. First, we have the stage between when the mosquito bites and the parasite reaches the liver. On the basis of the positive data we have today from RTS,S, we think a first vaccine should focus on the stage before the liver. To develop a vaccine with a higher level of efficacy, however, we will have combine vaccine components and strategies that focus on different stages of the parasite (before the liver, after the liver). And, following the call for eradication by Bill and Melinda Gates last October, we are expanding our scope of collaboration to support vaccines that would actually block the transmission of the parasite: this would mean that even as the mosquito bites, antibodies are transferred to the mosquito.
Antigens
Platforms(& Delivery)
Evaluation Technologies
Adjuvants /Formulations
≥80%efficacious
vaccine
SBRI WEHI
Viral andbacterialvectorsetc.
IDRIIntercelletc.
ELISA, GIA, T Cell, ADCI
Human Challenge
MVI R&D Strategy
Presenter
Presentation Notes
This slide shows the priority issues we are addressing in order to have a comprehensive R&D strategy. Identifying and selecting antigens: we have identified new initiatives and partners that can provide or identify new antigens that have the potential to enter our portfolio. Gaining access to adjuvants to boost immune responses (as malaria antigens are weakly immunogenic as recombinant proteins in vaccine formulations). At this time, known adjuvants are few and most are proprietary and highly restricted. MVI has joined with a partner who will assist in the identification of new adjuvants. Diversification of vaccine delivery platforms: we need to diversify platform approaches. We plan to diversify into other vector systems (such as Listeria Monocytogenes) as well as other platform systems (such as the virosome technology). We do plan to continue working with adenoviruses since they offer many clear advantages such as overall safety, their ability to produce powerful immunological responses, and their relative ease of scale-up and manufacture. [This need was reinforced by the recent disappointing results of the HIV adenovirus trials. What happened with the HIV adenovirus vaccine trial is not necessarily applicable to malaria vaccines; it is extremely unlikely that anyone will die from clinical trial-induced malaria; it is a normal part of the scientific process for clinical trials to determine that some vaccine candidates are not successful. ] Evaluation Technologies: MVI engages partners to drive the development and qualification of tools for assessing vaccine candidates, including a human challenge model, functional bioassays, and novel biomarker and genomics assays.
GenVecAd5/CSP-
LSA1-Ag2 +Ad5/MSP1-
AMA1
MonashMSP4
ICGEB/BBIPvRII
WRAIR/GSKAMA1
AS01/AS02
GSKRTS,S
AS01/AS02
ConstructSelection
ProcessDev
Final FormulationToxicology
Phase 1aPhase 1/2a Phase 1b Phase 2b Phase 3
SanariaPfSPZ
MVDBAMA1-C1ISA 720
LaTrobeMSP2
ISA 720
MVI’s Portfolio, June 2008
Adjuvanted Recombinant Proteins
Viral Vectored
Live Attenuated
Future Portfolio Goals:• 8 Preclinical Candidates (4)• 4 Early Clinical Programs (3)• 1 Late Clinical Program (1)
Presenter
Presentation Notes
Here is our portfolio today … The MVI portfolio is a collection of promising and diverse vaccine candidates. MVI has 8 vaccine projects in various stages of development. Some are in the preclinical stage, others are in later stages of development. Our portfolio includes RTS,S, the most advanced vaccine candidate in the world pipeline. These vaccines focus on prompting an immune response at one of two stages: during the pre-erythrocytic stage or before the parasites enter the red blood cells; and during the blood stage, a point where the parasites have invaded the red blood cells. One vaccine candidate (GenVec) targets both stages. Most candidates work with one or more components of the parasite while one candidate (Sanaria) is focusing on the entire parasite. Most of our candidates focus on p. falciparum; one focuses on p.vivax Let me share some information about two of our candidates…RTS,S and Sanaria
Objective of the RTS,S Program
Successfully test the most advanced malaria vaccine that may protect infants and children,
living in malaria endemic regions, from Plasmodium falciparum malaria disease
Presenter
Presentation Notes
RTS,S, targets the stage between the bite and the liver. RTS,S is the world’s most promising malaria vaccine candidate and the first to show convincingly that it can protect young children living in malaria-endemic areas against infection and clinical disease caused by Plasmodium falciparum. The RTS,S malaria vaccine candidate was created in 1987. GlaxoSmithKline (GSK) Biologicals developed it in close collaboration with the Walter Reed Army Institute of Research. 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. Clinical trials began in adults in 1992. A trial of more than 2,000 children started in 2003 in southern Mozambique demonstrated the feasibility of a malaria vaccine in children. Findings from this trial showed that RTS,S was safe in young children and it was effective for at least 18 months in reducing clinical malaria by 35 percent and severe malaria by 49 percent.
IHDRC, Bagamoyo
CISM, ManhiçaRTS,S -
MVI-GSK Program in Africa
HAS, Lambarene
KHRC, KintampoKCCR, Kumasi
JMP, Korogwe
KEMRI -
Kilifi
KEMRI -
Kisumu
IRSS -
Centre Muraz
UNC, Lilongwe
RTS,S Clinical Research Center Network
Presenter
Presentation Notes
Going into Phase 3, with first trial possibly opening at the end of 2008. Across different transmission areas Approximately 16,000 children Infants EPI co-administration Children 5 to 17 months While assessing efficacy against clinical malaria is our endpoint, safety is a top priority This project is all about partnerships: with GSK Biologicals, with the 10 clinical trial sites in Africa and the scientists who run them, with the communities…. A process that is going to provide a lot of lessons to people working on vaccines and on malaria overall
Sanaria—A Different Approach
• Targets the whole parasite
• Uses a live, attenuated parasite
Presenter
Presentation Notes
Harvests sporozoites from the salivary glands of irradiated mosquitoes Plan is to begin safety and proof of testing trials in the US in 2009 Pictures show the laboratory process, before the material is purified
Going back to our mission, we not only focus on development, but also on delivery. For a vaccine to be successful, its development must be embraced by governments in malaria-endemic countries so assessing the market is an important step in the development of any vaccine. We support efforts within malaria-endemic countries to develop regulatory capacity MVI is ramping up efforts to help generate the data required for malaria-endemic countries to make timely and informed decisions about vaccine use. We are working with WHO and the health ministries of several African countries to develop a tool that will strengthen national decision-making processes and avoid the delays seen in introducing other life-saving interventions in the region. The Malaria Vaccine Decision-Making Framework (DMF) is meant to promote preparation for a new vaccine at the national level.
Final Thoughts…
• Goal is to eradicate malaria: this will not happen without vaccines
• Malaria vaccine R&D needs more funding• Partnerships are the key to success
Presenter
Presentation Notes
Vaccines are going to have a role in controlling malaria and a critical role in eradicating malaria. We are getting closer to have a vaccine approved and available to those who need it. Science and our portfolio indicates that a highly effective, second-generation vaccine is achievable. Partnerships are key to success, whether with other product development partnerships such as MMV, or civil society and non-governmental organizations. Together we are working to help ensure that the political and financial commitment made up until now are sustained and increased. At MVI we are always seeking new partners with new ideas. MVI has coined the term “malaria venture idealists” to describe our approach. Like venture capitalists, we believe in taking calculated risks in our role as investor and catalyst. Unlike venture capitalists, however, the hoped-for return will not be measured in dollars, but in lives saved.
