Research and Development

Drugs
As long as malaria persists as a global health problem, new drugs will be needed to replace old ones as they lose effectiveness. Just a few years ago, there were few new drugs in the pipeline and antimalarial resistance was rising. The situation was desperate. Until the end of the 1990ies research activities for malaria were minimal: Between 1975 and 2004, only eight of the almost 1.556 new drugs developed worldwide were antimalarials.(2) The reasons for this were quite straightforward. A comprehensive engagement in any area of modern drug discovery and development requires a huge investment of manpower and resources that needs to be matched by an adequate commercial return. For diseases such as malaria this return was not available, hence malaria is a rarity in high-income countries and the only real commercial market is travellers, which totals only U$ 200-300 million per year. The market for innovative new drugs for neglected diseases is further depressed by poor regulatory infrastructure in many countries, and by competing counterfeit drugs. The net effect is that about 10 percent of global drug R&D resources are directed at diseases accounting for 90 percent of the global disease burden. Malaria is among the most poorly resourced diseases and a classic example for a neglected disease, characterized by a high disease burden in the developing world, a low disease burden (3) in high-income nations, and a low level of funding in relation to the disease burden. The size of the costs of R&D varies from indication to indication and also from country to country, but they are large and require a high level of funds and long-term commitment. A single project, supported from discovery through to development and registration will probably require 10s of millions of dollars. Given that most projects fail over the 15 year period it takes to produce a drug, the total research costs for a portfolio of projects to produce drugs usually amount to 100s of millions of dollars per drug.
Recently, however, the situation has improved noticeably with several new combinations and entirely new classes of drugs under development. Besides increased funding for antimalarial R&D, genuine progress has resulted from the creation of public private partnerships (PPPs) such as Medicines for Malaria Venture (MMV), which started in 1999. The goal of MMV is to develop a portfolio of drug discovery and development projects that will enable the registration and commercialization of one new antimalarial drug every five years. MMV, WHO´s special Programme for Research and Training in Tropical Diseases and Walter Reed Army Institute for Research (WRAIR) are the main innovators in antimalarials. Despite the emergence of PPPs in drug development, which account for around 70 percent of drug R&D for neglected diseases (nearly half of these PPP projects are for malaria), current funding is still modest and inadequate to complete development as products move downstream. Direct expenditure for malaria drug R&D totalled less than US$ 50 million in 2004, even including a large proportion of in-kind expenditures. MMV has estimated its needs at US$ 30 million per year for development and early clinical studies. As compounds progress through advanced clinical and field trials, at least an additional US$ 10 million per year will be needed. Equal amounts totalling US$ 30 million per year plus extra funding for clinical trials and industry investments will be needed for the WRAIR program to remain productive. The European and Developing Countries Clinical Trials Partnership (EDCTP) established in 2003 targeted to spend 600 million Euros for R&D for the three main poverty-related diseases until 2008, including 200 million provided by the European Commission.(4) But till to date (September 2008) only 63 million Euros have been granted. (5)

Insecticides  
For over 20 years, there have been no new classes of insecticides introduced for mosquito control, mainly due to the missing return on investment for private companies when researching solely for poverty related diseases.  Currently, the WHO recommends 12 insecticides for indoor residual spraying and treatment of bed nets. But insecticide resistance is widespread to every chemical class of insecticides in major insect vectors from every genus. Despite the ongoing research, it will take some time until new chemicals will be on the market and of course, it will only be a matter of time until the parasite has developed new resistances. Consequently research and development have to be a continuous task for the decades to come.

Vaccines
Despite of many decades of research, scientists have so far been unable to develop an effective malaria vaccine. Reasons for this are the size and genetic complexity of the parasite when thousands of antigens enter the human body after the bite of an infected mosquito. The problem scientist are confronted with is to find out which of these antigens can be a useful target for the development of a vaccine. Until today at least 40 promising antigens could be identified. Another difficulty is the fact that the parasite changes its form in the human body through several life stages presenting the immune system with various subsets of molecules at each stage. Additionally, the parasite has developed methods to hide and misdirect the human immune system.
There are three scientific approaches for malaria vaccines:

Pre-erythrocytic vaccines
This type of vaccine aims at combating the parasite in its first stage of its lifecycle, namely when the sporozoite enters the blood stream and heads rapidly for the liver. So far, the Pre-erythrocytic vaccine candidates have proven to be most successful.

Blood-stage vaccines
This type of vaccine targets the parasite in its merozoite stage, after it has emerged from the liver into the bloodstream. The challenge here is that the number of parasites is now much larger than in the previous stage.

Transmission-blocking vaccines
Transmission-blocking vaccines target gametocytes that enter the mosquito as it feeds on an infected human. Such vaccines would try to cut the transmission cycle or use the human immune system’s machinery to act on the parasite’s lifecycle in the mosquito itself.

Figure 3: Breaking the Cycle with Vaccines