Emerging Infections of International Public Health Importance
Malaria and Vaccine Development
Gina Rabinovich, MD
Dr. Gina Rabinovich is the director of the infectious diseases program for the Bill & Melinda Gates Foundation. She is also the director of the Gates Foundation's Malaria Vaccine Initiative (MVI), run by Seattle-based PATH, the Program for Appropriate Technology in Health. MVI's mission is to accelerate the development of promising malaria vaccines and ensure their availability and accessibility in the developing world.
Global epidemiology of Malaria
This map shows where the majority of child deaths occur around the world.
This map includes children of all ages. As you can see, the deaths are concentrated primarily in Sub-Saharan Africa and in Asia. If we look at the map based on disease profiles and its relation to childhood deaths we can see that malaria is also concentrated in sub-Saharan Africa and certain areas of Asia.
This pie-chart shows the breakdown and burden of infectious diseases on the global population based on Disability Adjusted Life Years (DALYs).
DALYs measure the impact of a particular disease on a population. This chart excludes TB, HIV and other STDs, but you can see that Malaria is the third largest infectious disease burden in the world, after respiratory and diarrheal illnesses.
Malaria indeed has a great burden globally. 2.4 billion people around the world are threatened by the disease, and there are 300-500 million cases of malaria each year. The illness kills 2.7 million people annually, mostly children in Africa. It accounts for 42 million DALY’s annually.
Why talk about malaria as an emerging disease when it has been around for so long? There has been a change in the public health risk of malaria in recent years. This is primarily due to the increase of drug resistance to the existing anti-malaria medication. Less talked about is also the resistance that can occur to the anti-mosquito sprays as well.
Several studies have shown evidence of this recent emergence of malaria. This graph shows the seasonal malaria epidemics in Kericho, Western Kenya from 1965 until 1999.
The data comes from a paper by Dennis Shanks et al (2000). As you can see the number of persons requiring hospitalization has risen dramatically since around 1994. This translates into a 300-350 fold increase of malaria in this region.
This slide shows a study by Marlies Craig et al (in press) who looked at reported malaria cases in KwaZulu Natal from 1980 to 2000.
We see that not only are cases of malaria increasing but there is a rapid rise in drug resistant malaria starting around 1990.
This is a map of Sub-Saharan Africa showing the endemic regions of P. falciparum--the most lethal and drug resistant form of the malaria parasite.
There are several reasons why we have seen these rapid increases in the number of malaria cases:
Biology and natural history of malaria
Malaria is a type of large parasite called Plasmodium. It has the ability to acquire resistance similar to viruses and bacteria. Malaria is transmitted primarily through the vector mosquito, Anopheles. Here is a picture of the Anopheles mosquito.
The life cycle of the malaria parasite is quite complex. Within the vector mosquito there is a sexual stage of the parasite. This is the stage when the parasite enters the human through a mosquito bite. The sporozoite then enters the liver (intra hepatic stage) for one to two weeks and then is released into the bloodstream as a merozoite. This is usually the stage when symptoms are common, including fever, anemia, and cerebral malaria. A non-infected mosquito could take a blood meal during this stage and become infected--then the cycle begins again when this mosquito infects another person.
There are four primary species of malaria that affect humans:
Plasmodium falciparum is the most lethal species. P. vivax and P. ovale also have a hypnozoite stage which can remain dormant for months or years.
The severity of the disease is related to what the parasite does, such as hemolysis of red blood cells, which can contribute to anemia and enlarged spleens. The parasitized red blood cells can also cause tissue ischemia and anoxia which can lead to multiple problems including cerebral capillary occlusion, liver necrosis, renal failure, miscarriage, and diarrhea.
Malaria drugs and drug resistance
The primary drug for treatment was sulfadoxine-pyrimethamine (Fansidar) which was cheap and readily available. However, genes which confer antifolate resistance are already prevalent. Clinical resistance to this medication is already greater than 50% in some African countries (e.g. Tanzania). Other drugs used to treat malaria are 10 times more expensive. Combination drugs are the recommended solution; those such as Fansidar and Atovaquone have been suggested but there has been resistance emerging with these as well.
Newer drugs such as Artemisinin look promising and so far no resistance has been observed. Artemisinins are potent and rapidly acting drugs. They are well tolerated. Combinations of this medication with mefloquine have been proven effective against multi-drug resistant malaria. The combinations of these drugs, however, are twice as expensive. Still, the combination approach may prolong their utility due to reduced risk of rapid resistance. Resistance to this new class of drug would be a disaster for Sub-Saharan Africa.
Prevention strategies for malaria
Since treatment options for malaria are limited, prevention strategies are also important and are utilized widely. This is an envelope and stamp from 1962 commemorating malaria eradication in the United States.
Malaria was eradicated from the United States using a combination of treatment of active cases with chloroquine and eradicating large numbers of mosquitoes by spraing DDT. DDT was a very effective pesticide used widely around the world at that time. However, due to serious environmental effects, the pesticide is no longer used.
This graph shows the use of bednets in different countries in Africa.
Several studies have been done showing the effectiveness of bednets. Insecticide treated bednets (ITN) are a very effective prevention strategy, but they are under-utilized in Africa. These bednets not only trap the mosquitoes and prevent biting--since Anopheles tend to bite in the evening—but they also kill the mosquitoes because of the insecticide. The netting used is inexpensive and the insecticide (permethrin) can be applied in large groups as a community project. These treated nets are effective for approximately six months and then need to be re-treated.
Another prevention strategy is to treat pregnant women empirically for malaria before illness begins. This graph shows the percentage of women who attend antenatal clinics in Sub-Saharan Africa.
This also varies based on country, but generally there is high use of these clinics by women in most Sub-Saharan countries. Pregnant women are at higher risk of morbidity and mortality from malaria, but treatment can decrease severe malarial illness.
A third preventive strategy is to intermittently treat children with sulfadoxine-pyrimethamine during their first year of life. At the time children come in for their first immunizations with DPT, they could receive the single dose pill as well.
None of these strategies has been completely effective or feasible for prevention and control of malaria. Therefore, the initiative to develop a malaria vaccine is timely and necessary.
Why are there currently no malaria vaccines available? There are perceptions that malaria vaccines are not technically feasible and that the market cannot support their development.
What are the differences between a vaccine and a medication?
This slide shows that vaccines are technically feasible.
If a vaccine can weaken the parasite, this can prevent infection. Studies have shown that irradiated mosquitoes have less effective transmission of the parasite. Long term exposure to the disease has been shown to confer some protection from clinically severe disease. Transfusion of antibody can also impact disease.
This graph shows a model of net cash flow over the product lifetime.
What we can see is that there is a cash flow out in the product development stage (the preclinical and early clinical years). Once a usable vaccine is developed, licensed and ready for the market, there can be a positive cash flow. This phenomenon has been seen with other vaccines such as Hepatitis A and B vaccines.
Malaria Vaccine Initiative
The Bill & Melinda Gates Foundation has undertaken a malaria vaccine initiative (MVI). This is designed to accelerate the development of malaria vaccines and ensure their availability and accessibility for the developing world. This is a serious undertaking. There is a $50 million fund for malaria vaccine development. NIH is giving $400 million per year per vaccine for HIV. Vaccine development for malaria is going to be difficult because of the complex life cycle of the malaria parasite.
This schematic shows the interplay between the life cycle of malaria at the different stages (inner circle), the types of immunity that are generated at each stage of disease (middle circle) and where the prevention strategies fit into this picture (outer circle).
Transmission blocking agents can have a potential for enormous impact (e.g. control of epidemics, malaria control in low endemic areas, and combination vaccine to prevent escape mutants).
There are some antigens in development at this stage.
Disease reduction and antibody dependent protection target children in endemic areas.
Here we see many more vaccines in development for this stage
Disease prevention strategies are also undergoing active development.
Currently there are approximately 81 clinical trials looking at various products at the different stages for vaccine development. This slide shows the number of vaccine candidates in development, how many have gone through some clinical trial and how many have some product.
You can see that a high portion of them are supported by MVI. This world map shows where the MVI-sponsored projects are supported.
The red sites show MVI projects in development and the orange sites where clinical trials have taken place.
This slide points out that the vaccine development is a public-private partnership.
Pharmaceutical and biotech companies partner with the academic and government sectors.
This schematic shows how the vaccine development process works.
First, you start with multiple vaccine candidates which go through Phase 1 trials. Of these, only 20% will succeed past the Phase I trial. These go through a Phase 2 process and then Phase 3 process. Only 20% of those entering phase 3 will succeed this stage. Phase 2 and 3 trials look more closely at safety and efficacy issues. Of those that succeed with Phase 3 they still need to get licensure. You can see that the funnel is very steep. Few candidate vaccines are amenable to being directly turned into a licensed product. Thus, classical and historical antigens are overrepresented. Of these 60% are protein-based vaccines.
This table shows the malaria vaccine research and development expenditures from 1999-2002 from various resources.
Even in 2002, the total expenditure for malaria vaccine development was only $60 million. Historically, we have the example of the polio vaccine: It took 17 years to develop it and cost $25.5 million in the 1940’s and 50’s. It took a major public health and government priority to see this happen.
Our general strategic plan is as follows:
Year 1: institute the policy for the recommendation of vaccine use. Find better ways of procuring malaria commodities. 25% of the Global Fund is designated for malaria.
Over 10 years: New and improved drug treatment development. Offer replacement medications for pregnant women. Continue work on development and testing of vaccines for malaria.
This is our vision. Happy healthy children.