Lecture 4: Controlled Human Infections to Accelerate Vaccine Development Flashcards
What is the solution to the lack of funding for vaccine research for diseases like malaria?
Advanced market commitment, de-risking research & development, product development partnerships.
Advanced market commitment is promising the company that you will buy their product if they make it. E.g. governments with COVID vaccines.
Product development partnerships are a company pandering with a public institution to bring the product to the market together.
Why are diseases like malaria getting less money to make a vaccine?
Because there is a lack of a dual market: the countries interested are low-middle income countries. This market is too small to get big pharma to invest.
Which step of vaccine development is the most risky?
Late development (phase 3 trials etc)! It is the most expensive and the most likely to fail.
What is a way to reduce the risk of late vaccine development?
The fail fast principle. For fail fast, you invest more early on to find out if the vaccine will be effective. If it is not, research goes back to the drawing board.
What is a condition for performing controlled human infections?
The disease needs to be curable. You purposely infect people, so you have to cure them.
In which phase do controlled human infection trials take place?
After phase 1. There is dose escalation in phase 1 with around 10 people. After it is worked out which dose is safe, the controlled human infection trials can take place.
What do you need to think of before you start a malaria controlled human infection trial?
You need susceptible parasites, Anopheles mosquitos, you need a machine to heat blood to grow the parasites. The strain needs to be very sensitive to different kinds of malarial drugs and this needs to be tested beforehand. When the parasite exits the liver and starts the blood stages, it can be detected by PCR or thick smear. PCR is more sensitive. PCR is done every day, until it is positive after which the volunteer is treated.
What are the advantages and disadvantages of injecting malaria parasites into the blood via syringe versus via parasite?
Advantages: More controlled (you can’t control mosquitos to bite, you keep them hungry and hope they do) Disadvantages: More artificial
Why is the risk of a controlled human infection trial with malaria spreading malaria to the rest of the population small in the Netherlands?
There are very little Anopheles mosquitos, the temperature is too low, for spreading you need the sexual stages of the parasite and these only occur after you have carried the parasites for a long time (waaaaay after the timepoint the volunteers are cured at in these trials).
Which genetic changes were made to Plasmodium to make it into the new GA1 vaccine?
The B9 and SLARP genes were knocked down. B9 is a new member of the Plasmodium 6-Cys family and occasionally involved in blood stage in Pb, Pv formation(?). SLARP is important for the early liver stages and is involved in regulation of transcription. Knockout of these genes causes the parasite stop developing in the liver stage. This is interesting, because this means the parasite can’t induce disease but can induce and immune response!
What was modified on the GA1 vaccine to improve it?
Mei2 was knocked out. Mei2 has a role in nuclear replication. In humanized mice the parasites develop further into the liver, but can’t really come out (a very small very weak population might, but they can possible also be remnants). They don’t replicate in the blood. Phase 1 just ended (6 people were exposed to mosquito bites of mosquitos infected with this modified Plasmodium) and none of the 6 people got malaria, meaning it is safe. In further trials they will be exposed multiple times with this weakened parasite and eventually exposed to malaria parasites.
What is the problem with controlled human infections with hookworm?
Egg secretion is variable and low, so there is a very low egg count (annoying for measuring infection, hard to know if someone is protected by the vaccine or not).
- Egg output is lower than field
- Skin reactions and GI events hamper dose escalation
- Endpoint variability decreases power of the model
What resolved the problem with controlled human infections with hookworm?
The dose of hookworm larvae more spread out in patches over the skin instead of on one patch. Abdominal pain and diarrhoea were reported, but not in a dose-dependent way. Some people were just more likely to develop these reactions, independent of the dose of hookworm larvae. In this way, people tolerated a higher dose of hookworm larvae
What were the conclusions of the controlled human infection trials with hookworm?
• Infection with higher doses of larvae does not result in increased AEs when
doses are spread over multiple sites
• Infection levels more comparable to field situation can be achieved
• Infection levels reach a maximum at ~2000 epg (threshold 100L3)
• PCR is more stable endpoint as compare to Kato-Katz
• Taking multiple samples during plateau phase is the most efficient way of
increasing power of the controlled human hookworm infection model
>this is also true for field trials!
> controlled human infection study informs us on the endpoints of clinical trials
How can you make a controlled human infection model for Schistosomiasis?
The eggs cause the disease and these can’t be removed. A solution is to use single-sex Schistosoma worms for infection, in particular males as they don’t lay eggs. In this way, there won’t be eggs and thus no damage and you can treat with praziquantel.
