Controlled Human Infections to accelerate vaccine development Flashcards
Most important water associated parasites?
200 million ppl infected: Schisto, found in shallow water
500 million ppl infected: Hookworm helminth
200 million ppl infected: Malaria, mosquito mate in water, lay its eggs
Why no vaccines for these parasites? /recent developments
For covid: 100 studied, 8 approved
Malaria: 10 studied, Hookworm: 2, Schisto:4 = no vaccine yet
Reason:
-Poverty related disease
Recently: they try to lower the costs of vaccines, also in high-income countries, good for poor countries, but the downside: manufacturers don’t get a profit much, so they won’t invest in something that they think there’s no market = Leading to neglected diseases!
-Dual market required
examples: Although it’s really hard to develop something for HIV (only 4/100 research is useful) market still invests in it: because there’s a market in both rich and poor countries/dual market
Malaria: no investment at all, although the whole world is infected = if in high-income countries only travelers and military needs it, it results in a tiny market that no one wants to invest
Influenza: both dual market/high entry probability (10/100 research makes it) = most investment
-Also parasite vaccines are harder to develop/there’s antigenic variation, but it’s way worse in COVID
Who needs vaccines more :high or low income?
Low income needs millions of more, even increasing much faster
How can you solve the problems of vaccine development? /hows the current status
Normal process: You discover something, academia, industry, biotech companies, foundations of specific diseases = all fund that lab stage, phase I-II
Late development: Clinical trials, human studies = no one invests in those except industry, its also very expensive involving all patients, huge investment = huge risk
Also afterward in mass production, everyone supports. So there’s this huge gap in funding in late development = so vaccines cannot be developed unless there’s a great market/compensation at the end
How to solve this:
1) Derisk research and development:
You can: select the candidates for Phase I trial, Run Phase I-II fast: then infect humans
-you know whether it’s safe/or which dose you need anyway (immunogenicity) from phase I-II, so it’s doable.
If it doesn’t work at all= FAIL FAST. stop the trials, reformulate without going further, you initially invest a bit more, but its better than doing a whole phase III and evaluating everything
2.) Advanced market commitments:
countries can promise to buy your vaccine if you develop it, eg. they did it for COVID, so market was already ready
3) Product development partnerships:
A company collaborates with public institutions to bring it to market = so they put the money together, very important for poverty related diseases to help the industry
Controlled human infection models - how to do
1) Vaccinate 1 group, don’t vaccinate the other, randomize/double-blind, no one knows who got what
2) Infect everyone: ppl who got the vaccine might be protected, might not be either = decide whether the vaccine is useful or not
3) Treat everyone
Everyone started to use this recently, for companies its much better
Controlled human infection model examples
Girl drinking typhoid in UK, they check fever/bacteremia, and treatment is very simple with antibiotics. This vaccine is very important for very poor countries/poor hygiene, especially 4 kids: India, Bangladesh Pneumonia trials (important vaccine for elderly): if no colonization in respiratory tract, probably vaccine works Schistosoma mansoni Eg. the Jansen vaccine, they decided on 1 dose, then realized it was kind of too few, 2 doses would be better = so an error in Phase II, but this kind of errors in fast development does not mean that vaccine is not safe, phase I is always done elaborately
What should be considered while doing these trials?
- you need good treatment to do this, years ago most diseases did not have good treatment, so it could not be done - you cannot still do it on diseases like HIV, everyone has to leave the trial healthy.
- need to be careful that it doesn’t lead to any persistent infections, eg. pneumococcus in the elderly, so the elderly is not included in studies
- ethical considerations: injecting people with so many not working vaccines? but still, they are safe, and you cannot get this information elsewhere without spending millions of dollars.
-safety considerations (from being infected, not the vaccines themselves): These trials are done for hundreds of thousands of people and no one got sick so far: only diseases w/ very good drugs are used, in every stage, patients are followed strictly, also the infections are done with susceptible strains
Also, the infections like Malaria cannot spread in a setting like NL bcs (a) not much anopheles, (b) also even if they bite you, the temperature is wrong (c) also you need to catch the sexual stages of parasite so you need to carry the parasite for some time = transmission cannot happen unless you literally don’t inject your blood to someone else
Following the patients are really important because they just travel sometimes xd
- these trials do not really show efficiency or how much protection is provided/or dose efficiency, you still need to follow the trial for that
- if you fail, you can also reformulate your vaccine immediately and try again
Controlled human infection models - Malaria/disease progression and first trial
1) healthy volunteers got infected with lab-made mosquitos/infected w susceptible strain / also you can directly inject Malaria antigen, no need for mosquitos, even better no replication
2) plasmodium goes liver, for first 7 days, it’s asymptomatic, then it goes to blood and starts replicating every 48 hours if its Falciparum
Then you can detect it with PCR
1st trial failed, it just delayed the replication a little bit, especially useless in Africa = FAIL FAST no phase II/III
Controlled human infection models - GA1/GA2 vaccine trial
GA1: They knocked out two genes: that impairs growth, eg. in liver = decided to try this plasmodium as a vaccine
FAIL it just deleted it a bit, only 3 people protected out of 28 = go back lab, reformulate
GA2: CKO another gene needed for replication: another controlled human trial
Hookworm background:
It’s very resistant, on soil, it lives on high temperature, around water
Comes closer to the skin, takes its protective sheet out (useful in soil)
It infects you through skin penetration (stepping on it barefoot), it goes intestine, then goes back to lung, coughed, swallowed then goes back to the intestine to mature
also has a very resistant larvae stage.
Hookworm controlled human study problems:/coupled w trials
-Egg secretion is low and very variable, secretion in trials are even lower than field = hard to know whether people are protected or infected looking at the feces, hard to use it for vaccine development
Maybe increasing the dose could solve the problem
-Some people get random diarrhea/bloating as a side effect or skin rash tho (if its due to dose, then you cant increase it more)
=Skin problem is immediately solved, they spread larvae in eggs, arms, other places etc. and it worked
=They did a trial to check GI effects: no anemia was observed at all in trial patients, normally observed in Africa,
eosinophils increased but not in a dose-dependent way, same with abdominal pain etc. some are just more susceptible than others
-variability decreases the power of the model
Solution: Once they verified side effects have no relation w dose: they increased the dose and it solved their egg problem, because now more eggs are produced, much better for the research
Also taking more samples every day instead of a week shows a better estimate (also would be better to apply on field trials!)
Also, new trials showed that PCR is much better than microscopy
How they do the infection: they just put the worm on ur arm and cover it with film
Schisto background:
Infection from feet, goes urinary tract or intestine, they cuddle together and release eggs: eggs get stuck in tissues and cause inflammation
Schisto controlled human trials
First controlled schistosome infection
They inject the worm directly with a pipette on ur arm, and they saw that the cercariae head enters, tail falls off (?)
Since schisto eggs go every tissue: cant give male and female together, they give male cercariae only, male one matures goes intestine and sits there, no eggs = later treat it with praziquantel
Side effects: mild itching, some dots, not only where they enter, around it.
BUT side effects depend on dose here: but there should not be any pathology technically - there are no eggs???
=It is Acute Schistomoiasis Syndrome/Katayama fever, reported in travellers (people w no prior exposure, same in trials) but they said it’s from eggs. = so it must be also from larvae
Worm also produces Circulating Anodic Antigen (CAA) and they can detect it very specifically. They checked the CAA of volunteers: millions of times less than kids in Uganda, even the highest dose is not comparable. = So its the limitation of model
Also CAA levels showed %100 cure after praziquantel at max 2 doses, they can monitor it really well checking Ag levels now. (if someone was not cured properly)
You can also check worm specific Ab, maybe Ab response is important in protection= can check in future.
Serum CAA / seroconversion: detectable %80 in 4-6 weeks
