Lecture 4: Malaria and malaria vaccine development

Question 1

What is the prevalence of malaria?

Answer 1

Malaria causes probably several hundreds of millions of cases per year and almost half a million deaths. The highest prevalence is in the tropics, in particular sub-Saharan Africa. However, there used to be malaria in western Europe too. Malaria was eliminated from the Netherlands in the 1960s by getting rid of the mosquitos.

Question 2

What causes malaria?

Answer 2

Malaria is a parasite, of which there are four that infect humans the most important being Plasmodium falciparum and one that infects monkeys: Plasmodium knowlesi. Plasmodium falciparum is the most widespread.

Question 3

What are the vector, definitive host and intermediate hosts of the malaria parasite?

Answer 3

The malaria vector is anopheles mosquitos. It is also the definitive host, is the sexual stages take place in the mosquito. The human is the intermediate host.

Question 4

What is the lifecycle of malaria?

Answer 4

The lifecycle of malaria is: when an infected malaria mosquito bites a human, there are sporozoites in the mosquito’s salivary glands, which then get injected into the host’s blood. Sporozoites then quickly migrate to the liver, where they invade hepatocytes (liver cells). They develop into schizonts over about six or seven days, multiply and release parasites (now called merozoites) into the blood. This cycle takes between 24-72 hours depending on the species of malaria. It continues as an ongoing multiplication and the parasite load will increase until either the host dies or the host manages to control or treat the disease. Finally as an escape mechanism the parasite can make male and female gametocyte forms which can continue the cycle in a new host if sucked up by a mosquito.

Question 5

Which part of the malaria lifecyle causes symptoms?

Answer 5

It is important to realize that the patient does not feel very sick during the liver stage of the disease. The ongoing multiplication in the blood causes clinical symptoms and eventually death.

Question 6

What is the difference between simple and severe malaria?

Answer 6

Simple malaria has flu-like symptoms: fever, chills, headache. This can go on to become severe malaria, which almost only happens when infected wit Plasmodium falciparum. Symptoms of severe malaria include: cerebral malaria, failure of other organs, anaemia due to ongoing multiplication of parasites.

Question 7

What is the difference between simple and severe malaria?

Answer 7

Simple malaria has flu-like symptoms: fever, chills, headache. This can go on to become severe malaria, which almost only happens when infected wit Plasmodium falciparum. Symptoms of severe malaria include: cerebral malaria, failure of other organs, anaemia due to ongoing multiplication of parasites.

Question 8

At which plasmodium species is most of the vaccine development aimed?

Answer 8

Most of the vaccine development is aimed at Plasmodium falciparum

Question 9

Who is at risk of malaria?

Answer 9

Mainly children in sub-Saharan Africa. Most deaths are in children under 5 in sub-Saharan Africa. The reason for this is that there is a lot of malaria there and people living in a highly malaria endemic area will slowly build up some immunity to malaria (so children under 5 do not have this immunity yet). Pregnant women and people who were born in endemic areas, but have lived in non-endemic areas for many years are also vulnerable. In low-endemic areas and non-endemic areas, everyone is vulnerable.

Question 10

Why has the US military provided a lot of money to malaria research?

Answer 10

Because during the Vietnam war malaria caused more American soldiers to be out of service than bullets did.

Question 11

Who was the first to describe malaria parasites under the microscope?

Answer 11

Charles Laveran (lecture) or Alphonse Laveran (google) was the first to describe malaria parasites under the microscope.

Question 12

Who was the first to describe three different species of Plasmodium and figure out the disease was related to malaria mosquitos?

Answer 12

Giovanni Grassi described three different species of Plasmodium and was the first to figure out the disease was related to malaria mosquitos.

Question 13

Who figured out the Plasmodium lifecycle?

Answer 13

Ronald Ross is often credited with figuring out the Plasmodium lifecycle, but there is evidence that Grassi had figured that out before Ross. Ross however published his work on it and received a Nobel prize for discovering the life cycle of malaria

Question 14

Why is Julius Wagner important in malaria research?

Answer 14

Julius Wagner was the first to use malaria as a treatment. He used the high fever caused by malaria to cure neurosyphilis. They would inject blood from a malaria patient into a neurosyphilis patient. This sometimes worked. About half of people benefitted from this therapy. The benefit was that while a cure for syphilis (antibiotics) was not discovered yet, malaria could be treated with quinine. Wagner received a Nobel prize for this and his discoveries led to the development of controlled human malaria infections.

Question 15

What were big milestones in malaria treatment and prevention?

Answer 15

The discovery of chloroquine was a big milestone, as it could be produced in much larger quantities than quinine. Another big milestone were insecticides like DDT that killed the mosquitos and helped remove a large part of the mosquitos and thus a large part of malaria in many parts of the world.

Question 16

What changes did the 20th century bring to malaria treatment and prevention?

Answer 16

By the mid-20th century, the first parasites resistant to chloroquine emerged. Furthermore, some mosquitos became resistant to DDT. In addition, they realised that spraying DDT across entire ecosystems was killing more than the “bad insects”. Rachel Carson’s book “the silent spring” brought these environmental concerns to public attention, which led to a ban on its use as an environmental insecticide. These setbacks changed the goal of the WHO from eradicating to controlling malaria

Question 17

At the end of the 20th century/the beginning of the 21st century, there was renewed interest in malaria eradication. Why?

Answer 17

At the end of the 20th century/the beginning of the 21st century, there was renewed interest in malaria eradication. Melinda Gates, who donates a lot of money to infectious disease research through the Gates foundation, said “Why are we focussing on controlling malaria? The world has the right to be malaria-free. We shouldn’t give up until we’ve eliminated it.” This renewed research into ways to eliminate malaria.

Question 17

At the end of the 20th century/the beginning of the 21st century, there was renewed interest in malaria eradication. Why?

Answer 17

At the end of the 20th century/the beginning of the 21st century, there was renewed interest in malaria eradication. Melinda Gates, who donates a lot of money to infectious disease research through the Gates foundation, said “Why are we focussing on controlling malaria? The world has the right to be malaria-free. We shouldn’t give up until we’ve eliminated it.” This renewed research into ways to eliminate malaria, like a malaria vaccine.

Question 18

What tools exist to control malaria?

Answer 18

What tools exist to control malaria?
•Insecticide-treated bed nets
o Kills the mosquitos and repel them. Even if the bed net has some small holes in it, the person using the bed net is safe
o There is strong evidence that this particularly helps young children.
o One of the most important and cost-effective interventions
•Design houses in a way that keeps mosquitos in the house, so they can’t leave to infect more people.
o Very cost-effective
•Indoor residual spray. The insecticide is only in the house, so it is better for the environment. Mosquitos die when they touch the walls of the house.
o Insecticide needs to be applied every six months-year
•Environmental control. Still some work done.
o Draining of swamps
o Putting fish that eat anopheles mosquito larvae into the environment
o New: releasing mosquitos that are either sterile or genetically modified mosquitos that are either sterile or can’t transmit malaria that then can spread this gene in the population
 Long-term concerns
 Ethical concerns
•Give monthly malaria drugs to e.g. children and pregnant women (you don’t have to check is they have malaria as the drug is very safe). This will reduce the amount of malaria on a population level
•Access to quick and efficient testing and treatment
o Rapid diagnostic tests –> no need for fancy microscopes and electricity.
o Drugs based on artemisinin
 Plant grows almost anywhere. Discovered in China based on writing from 2000-3000 years ago where doctors advised drinking tea from this plant when the patients experienced fevers.
 Works better and faster than quinine
 There is already some resistance developing ☹
•When treating patients for malaria, use a drug in combination that kills the mosquitos that bite them (like Ivermectin) thus preventing spread.

Question 19

What is an underestimated contribution to malaria spread?

Answer 19

Asymptomatic hosts. Interventions on asymptomatic patients (often school-aged children) would decrease

Question 20

What is the recent change in malaria incidence?

Answer 20

In 2010 the amount of malaria cases and deaths from malaria dropped significantly, but has stalled since then.

Question 21

What is the advantage of a malaria vaccine?

Answer 21

A big advantage of a malaria vaccine is that it would be long-lasting (lifelong) and thus cost-effective.

Question 22

What is the main target group of a malaria vaccine?

Answer 22

The main target group of a malaria vaccine is children, as adults already have some resistance to malaria

Question 23

In which three groups can malaria vaccines be split?

Answer 23

Malaria vaccines can be split into three groups:
•Vaccines that act on the sporozoites or the liver stage of malaria. These vaccines will prevent infection
•Vaccines that act against the blood stages. These vaccine helps the body fight the cycle that causes symptoms.
•Transmission blocker vaccines that try to prevent the onward spread of malaria to the mosquito.

Question 24

Can people who have previously have had malaria still get infected?

Answer 24

Natural immunity caused by malaria exposure is not sterilizing immunity. People with natural malaria immunity can still get infected with malaria, but they don’t get sick. This is because malaria parasites are much more complicated in their life cycle than bacteria or viruses.

Question 25

What are the different vaccines that have been worked on and their problems

Answer 25

Different vaccines that have been worked on and their problems:
•RTSS: Vaccine containing a protein on the sporozoite stuck to a protein of Hepatitis B to increase the immune response. Developed in the late 1990s. Went through all different stages of testing until tested in large scale on African children in the early 2010s. It protects children better than young infants, who are the main target. It works, but protects only 30%. The protection also disappears quickly. It received a positive recommendation from EMA. The WHO was unsure and requested further trials, which started a couple of years ago.
RTSS combined with seasonal malaria chemoprevention was found to work significantly better than either of them on its own.
oProblems:
 Low effectivity
 Protection disappears quickly
 Boys have slightly better protection than girls
 Safety issues
•Vaccine like RTSS, but without the Hepatitis B protein. The idea is that this will give stronger immune responses against the malaria. Showed good efficacy in children in Africa.
•Attenuated whole parasite. This year, a publication found that this doesn’t work well in adults in Africa and does not work AT ALL in children and infants in Africa. It did work well in adults in Europe and the US. This possibly caused by the age of the volunteers (adult vs child difference) or previous exposure to malaria (EU/US vs. Africa difference) or variation in parasite population or other environmental factors. The research in a new vaccine of this type continues.
• Genetically attenuated malaria parasites. First generation did not work very well, but the research continues.