Vaccine Clinical Trials During Pandemic

January 22, 2021

Information

Inci Yildirim, MD, PhD, MSc, associate professor of pediatrics (infectious diseases) discussed trial phases, covid-19 vaccine trials, and pandemic-related challenges that her team faced.

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00:00Thank you for the opportunity.
00:02I will briefly talk about what we
00:05went through with the clinical
00:07trials during the pandemic.
00:09Um, related to COVID-19 vaccines.
00:12These are my disclosures I have in
00:16an investigator at the vaccine and
00:19Treatment Evaluation Unit founded
00:21by NIH room 2015 to 20 until my
00:26relocation to Yale mid Pandemic in 2020.
00:29I'm a member of M RNA 1270 three study group.
00:35I'm discussing only what we have publicly
00:39available and I have no idea my dear.
00:42If you or approval for
00:44my current presentation,
00:46I had received funding through my
00:48institution to conduct clinical trials
00:51through from different companies
00:52and the bodies as listed here.
00:55I will briefly talk about the
00:58trial phases and then I will.
01:01Discuss what we did differently with
01:03the code 19 vaccine trials and I will
01:07share some pandemic challenges that
01:09we faced during during this time.
01:11So the term vaccinology or vaccination
01:14was first used by Doctor Edward Jenner.
01:19As many of you would know,
01:22Great Britain,
01:23although the idea of protecting
01:26unimpacted using some sort of transferred
01:29immunity from the infected individuals
01:32has been had been around for awhile.
01:36We have documentation from the 10th
01:39century that shows that variolation.
01:42Which is different form of transferring
01:46immunity had been used in China and
01:50then in 16th century in automating
01:53prior but doctor Jenner had no tist
01:56in 18th century was the milkmaids
01:59who are often getting infected
02:01with the car parks were somehow
02:04protected against against smallpox.
02:07They were either not getting
02:09the disease or when they got.
02:13The disease they were,
02:14they were mild cases compared to other
02:17individuals who were dying quickly,
02:20like 30% mortality rate almost and
02:23the huge scars that they would have.
02:26So based on this information or
02:29observation Doctor Jenner collected pass
02:32from illusion of Milk Maid who had cowpox,
02:35then an inoculated that pass
02:38to an 8 year old.
02:40Otherwise healthy young men.
02:42And then after a couple of weeks,
02:45he this time in equated the same
02:48young man named James Phipps
02:50Phipps with the smallpox.
02:52And then Luckily dreams that very
02:55well and seeing how we rank Doctor
02:57General went on other people and
03:00practice this on many other people.
03:02As far as we know,
03:04Doctor Jenner had the permission
03:06from the parents of this young man
03:09who were actually working for him.
03:11So many of the things that was done
03:14for this will not always do fly in our
03:17day because Luckily we have ministrat
03:20regulations to make sure that we're
03:23maximizing the safety of the parts.
03:25Once in our clinical trials,
03:27including vaccine trials,
03:29and we are maximizing our transparency,
03:31this I think the most important part
03:33of this is we are really diligent
03:36about informed consent process so
03:39that we don't repeat the same mistakes
03:41that we have done within the last
03:44century with the clinical trials.
03:46So typical vaccine trial,
03:48clinical trial,
03:49or we see comes after the laboratory on
03:52the anyone studies where we have an antigen.
03:55That would be the candidate vaccine,
03:58and we test the safety and the ability to
04:01provoke an immune response in animal studies.
04:05And then based on the animal challenge
04:08studies, we come up with a suggested
04:10those we apply to FDA under investigation.
04:14Only drag application and then
04:16we can go to humans phase one
04:19which is first in human studies,
04:22are usually less than 100.
04:24Otherwise completely healthy individuals.
04:26It is non blinded operate open
04:29label study design. It can be age,
04:32the escalation or those escalation.
04:34What we did with the model.
04:37NIH moderner trial.
04:38We started with 18 to 55 year old
04:42individuals and we started between 5 UG
04:45and once we have central participant
04:48skipping 25 UG did fine once we saw
04:52that we went 200 UG and then making.
04:56After seeing that those two cohort,
04:58the sentiment cohorts with 25 and
05:01100 that well in terms of safety,
05:04we went to 250 UG with the safety and
05:07extent of the immune response information
05:11that we collected from phase one trial.
05:15Enrolled 120 individuals
05:16we went to phase two trial.
05:18This time 600 individuals and again
05:21we were looking for more data on
05:24safety and we were trying to figure
05:27out the dosing for the phase three
05:30trial and then with the phase
05:33three trial which followed the 600
05:35individuals from phase two trial,
05:37we enrolled more than 30,000 individuals.
05:40We similar to other studies.
05:42It was randomized.
05:43We had a civil.
05:45We were still looking for the safety because
05:48our phase one and phase two trials were
05:51not powered to catch rare side effects,
05:54but this was the first time officially,
05:57the outcome was the efficacy of the vaccine
06:00as defined for the modern NIH Moderna trial.
06:03It was defined as this symptomatic COVID-19
06:06infection 14 days after those two,
06:08and then with that information,
06:10or we should be at the
06:12company went to FDA got April.
06:15What can follow up there?
06:17This is phase four trials which is not.
06:20Industry if the manufacturer wants in,
06:23you know as if they have the funding.
06:27They can continue to test the
06:30vaccine for safety, effectiveness,
06:32and other potential users.
06:34This process from identification are
06:36the valid validation of the antigen
06:40in animal models to completion
06:42of the regulatory process usually
06:45takes almost two decades.
06:47We just heard from Doctor Grace
06:50about the about the Ebola vaccine,
06:52but I think many of us can remember
06:55the rotavirus which was implemented
06:58to try with immunization in 2006.
07:01It took more than three decades
07:03for the hepatitis B.
07:05This was about two decades
07:07and again for Zika.
07:09It is still an ongoing process with HIV.
07:12It is still an ongoing process
07:15and with murr's the same way.
07:17Have the vaccine up there couple
07:20years and even longer with Zika.
07:23We did better with the most
07:25recent influenza pandemic,
07:26which was item and identified in
07:292009 and by October in the United
07:32States we got the vaccines but
07:34with the influenza pandemic H1N1
07:36it was using the same platform.
07:39It was almost like a
07:41proving for any big litters.
07:44Have review process was similar
07:46to seasonal influenza vaccine.
07:48What happened with COVID-19
07:50was quite impressive.
07:51They the after the identification
07:54and reporting of the first unusual
07:57pneumonia cases late December 2019.
07:59It took less than two weeks for the China
08:04CDC to share the genome of the Navy,
08:08identified coronavirus and impressively
08:10it took almost two months from having
08:14this information to having our first
08:17participant get getting the vaccine.
08:19And for for Phase one trial,
08:22this is 5 days after the
08:26Bleacher calling in pandemic.
08:28And then I guess even more
08:30impressive is after consenting,
08:32this young man for Phase one I got my
08:35first dose of inage modern vaccine here
08:38at yeah less than nine months after it.
08:42Um?
08:43And the whole process from
08:45identification of the SARS,
08:47Co E22 vaccine rollout,
08:49at least in the United States,
08:51was a year or even less.
08:54So there are a couple of things
08:56that were unique to quit 19 and how
08:59we ran clinical trials and how we
09:02identified our vaccine candidate.
09:04First of all, we had tryouts.
09:06We had SARS, we had the first one.
09:09We had Merce,
09:11so we were very familiar with
09:13the corner viruses.
09:15And we were lucky to have Doctor
09:18Korba and Doctor Graham who
09:20had been working on Murs Spike
09:23protein and they had item fight
09:26that died in animal studies.
09:29The antibodies against spike
09:31protein were protective and they
09:33were inducing niessing response.
09:36So this part was fast.
09:38We already had the antigen to
09:41be included in the vaccine.
09:44The second unique feature of
09:46this pandemic is we had a huge
09:49federal initiative that is called
09:52Operation Warp Speed that targeted
09:54914 months for the whole process.
09:57This initiativ came with a large.
10:00Large funding,
10:01but I guess the most important
10:03thing that they were able to do was
10:06bringing many people who are on the
10:09networks together to work on COVID-19 Maxine.
10:12These individuals who had been
10:14doing vaccine trials for decades
10:16they had the reach.
10:18They did not have to run clinical trials.
10:21They were very familiar with
10:23the regulatory process,
10:24so they came under the umbrella
10:26of COVID-19 Prevention Network Co.
10:28BPN, and it was not.
10:30Only in Indiana State,
10:32but it was a global global effort.
10:38And then we all watched.
10:40I guess online or once on news
10:45outlets that within 10 to 1213 months.
10:49All of this was completed.
10:51What was different in addition to the
10:55preclinical phrases and the network
10:58creation about code 19 vaccine trials,
11:02was this unique approach in a
11:05regular traditional vaccine trial.
11:08Usually phrase one completes its enrollment,
11:11then the data is under review for
11:14awhile and then once it is locked
11:17and the analysis are completed,
11:19we start phase two.
11:21So it is 123 in a stepwise.
11:24But with the COVID-19 trials what
11:27we did it was overlapping faces,
11:30not skipping faces by overlapping
11:32them telescope fashion.
11:34So we had phase two before
11:36we complete started.
11:38Before we had Phase one completed
11:40and the other important feature was
11:43the companies with the guaranteed
11:45funding from Operation Warpspeed.
11:48They did not wait for the results
11:50of Phase three trial to start
11:53manufacturing large amounts of vaccine.
11:56I know we still with the regulatory bodies,
12:00everything was done on fast track.
12:04But we did not see any phrase again,
12:07the information that we were supposed
12:10to collect from each phases were there.
12:13We show with the phase one that the larger,
12:17the higher the dose.
12:18The second dose had been correlated
12:21with the higher reactivation state,
12:23and then we did see that they saw and
12:27after the second dose has a nice human
12:30response and we have it threatening affect.
12:34With 250 UG,
12:35so the decision was made on
12:38the safety and the email.
12:41Jenna City information to go with
12:43hundred UG for the Phase three
12:46trial as it was going to happen.
12:49Work in regular traditional vaccine
12:52trials and we had this nice graph
12:56at the end of at the end of I
13:00think December showing that.
13:02The vaccine was effective more than 90%.
13:06If efficacious, more than more than 99%.
13:09So there are unique challenges
13:11about how things went.
13:13One of them was as a researcher.
13:16We were always late.
13:18There were that lines,
13:20and we were always trying to catch
13:23up something and then everything
13:26outside were changing on daily basis.
13:29The transportation was different.
13:31We had stay at home orders that
13:34prevented our participants to
13:36show up for their visits.
13:39We had cancellation of commercial
13:41flights which caused way to get the
13:44study product from NIH to our site.
13:47And then, you know,
13:49we didn't have enough masks.
13:51You would not have this challenge
13:54with any other study, but remember,
13:57this is March 2020 and.
14:00Masking or masking mandates
14:02are we're not that common.
14:04Then we were staying in the same room
14:07with the participant for two to three hours,
14:10and we have masks,
14:12but we don't know when they're
14:15going to last and how are we going
14:18to have additional masks so we
14:20didn't have any PPE accept.
14:23Accept the gloves and the
14:26homemade masks for awhile an.
14:29The other biggest challenge that
14:31we did not really plan for was two
14:35schools and childcare settings and how.
14:39Lockdown effective.
14:42Functioning society function manual
14:44fire participants didn't have
14:46grandparents who were available to
14:48take care of the younger individuals.
14:51Given the high risk with the code 19.
14:55Many of our staff members
14:58did not have backup plans.
15:01And I guess most right,
15:03most impressively, or Interestingly,
15:05we were online all the time.
15:07There was a huge social media an
15:10interest in what we're doing,
15:13what we're not doing, we.
15:16This was something that we
15:18were not really prepared for.
15:20To be honest,
15:21this young man again here giving his
15:24blood Lisa Ann guitar student nurses
15:27are with the homemade masks and gloves.
15:30Nothing else was available.
15:32And then you know,
15:33after our wizard he is on CNN
15:36with Doctor Sanjay Gupta telling
15:38about how I consented him.
15:40What I told him and what was
15:44in the consent form. Um?
15:46Which is which is in a way a good thing,
15:51because this young man,
15:53as we heard from the CNN,
15:55is an MD PhD student.
15:57He has the you know he can consent
16:01and he can process work or we see
16:04what we are trying to tell him.
16:07But there were many other messages out
16:10there that we had no control and our
16:14participants were on TV or on social media.
16:17We don't talking with us.
16:19We were supposed to have
16:20conversations with them about,
16:22you know, do you have pain?
16:24But we would hear it from news outlet before
16:27we hear it from from our participants.
16:29So there are couple of things I
16:31think remaining as a challenge.
16:33You need to quit 19 first.
16:35One is like what is going to happen
16:38with the placebo recipients for the
16:40phase three trial you I'm sure you
16:43have heard about the unblinding and.
16:45I'm providing vaccines based
16:47on what is recommended.
16:48Recommended with the VA.
16:50We have not included any children,
16:52pregnant women or transplant
16:54recipients to our trials and we
16:57don't know how it is going to work.
16:59And you know with the vaccines
17:02that are shown to be more than 90%
17:05efficacious it is going to be a
17:07different error to test another vaccine
17:10and we will see how it is going to play out.
17:14I want to end by saying none of.
17:17This would happen if we did
17:19not have all into yourself.
17:21I want to thank each of them,
17:24and if you're still interested
17:26in volunteering,
17:26please go to this website.
17:28We have studies with the
17:31vaccines and treatment options
17:33and we still need one tears and
17:36thank you for having me today.