SARS CoV-2 Vaccines ... Hot Updates on Cold Vaccines

January 22, 2021

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Onyema Ogbuagu, MBBCh, associate professor of medicine (AIDS); director, HIV Clinical Trials, Yale AIDS Program, discussed his personal experiences as principal investigator of Yale’s COVID-19 vaccine trials.

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00:00So thanks for having me.
00:02I want to spend my time really just
00:05showing my personal experience
00:07with the COVID-19 vaccine trial,
00:10and I think it's just a great segue
00:13from my doctor NGS presentation
00:15and I really I, I, you know,
00:18I definitely understand the constraints
00:20and challenges that she faced.
00:22I also give a global view and tell
00:24you what are some answered questions,
00:27unanswered questions that
00:29we proceeded with files.
00:32So I'm bound by multiple
00:33confidentiality agreement.
00:34I must say with at least three
00:36of the vaccine manufacturers,
00:38but then of course having been does the
00:40PIL for the Pfizer vaccine trial and
00:43selected four through the code VPN,
00:45NIH network,
00:45or the upcoming summer free trial
00:47and also work studies through
00:49our relationships with them,
00:51I will include some data from press
00:53releases and preprint servers,
00:54unfortunately.
00:55But if you know that that's the best
00:57way to be able to give this audience
01:00the latest information around the vaccine.
01:02So this is a busy slide,
01:04but I just want to make a few points.
01:07I think that we all appreciate the fact that
01:09the phase three trials have really been.
01:11You know,
01:12that last leg of the relay race
01:13that really allow us to know,
01:15you know we had safety data
01:17from early phase trials.
01:18But when you do phase three trials you
01:20doing in 10s of thousands of participants.
01:22So you start to detect things
01:24that are probably less common
01:25in smaller free studies and also
01:27allows you to assess you know,
01:28some of the great immunogenicity
01:30results which really look great
01:31for many of these candidates.
01:32How well they would actually do.
01:34With preventing covid disease
01:36and for most people,
01:37the primary endpoint was
01:38was symptomatic disease,
01:39so you know you know you know being
01:42appearing in the trial it was.
01:44You know you had no idea what
01:46the efficacy would be,
01:47so it's kind of really heartwarming
01:49that both eyes and would turn on
01:52both M RNA platforms have reported
01:54very robust efficacy and I like
01:56to say that each study validates
01:57the other because they use the
01:59same platform and you really have
02:01almost superimposable results,
02:02which which is great and you know,
02:05based on this data.
02:06You know we all celebrated the emergency
02:08authorization that was for these studies.
02:11Again,
02:11a lot of our participants in
02:13trials interpret the emergencies
02:15authorization as full approval,
02:17and that's kind of impacted.
02:18You know,
02:19God created some difficulties around
02:22transitioning placebo patients to
02:24do to real vaccine and just really
02:26letting people know that they have
02:28to remain on study and that we're
02:30still collecting very critical
02:32information around much more longer
02:34term safety data and also long term.
02:36Have to see for the Pfizer study.
02:38We've since expanded it both age wise,
02:41down to we initially had done age 18 that 16.
02:44We just concluded last week and
02:46rolling even younger individuals aged
02:4812 to 15 and we had also included
02:50patients with well controlled HIV
02:51who wants to buy interval therapy
02:53and people who had other viral hepatitis.
02:56I will say that there are upcoming
02:58studies looking at pregnant
02:59women and even younger children,
03:01and I know I will be you in Group will be
03:04selected to or has been selected to work.
03:07With the Pfizer study on pregnant women
03:09that we are going to be generating
03:11data on some populations that were
03:13left out of initial phase studies,
03:15I also know modernize also going
03:16to go down to 12 with their study.
03:19Now we know that the Johnson and Johnson
03:21Vaccine is a single dose vaccine,
03:23and given that the other candidates
03:25are to those vaccines and we're still,
03:27you know, they released Phase
03:291 two immunogenicity data,
03:30which I think many of us have seen.
03:32But I have heard that they are
03:34planning a two dose phase three trial,
03:36so that makes me.
03:38Wonder if there's any preliminary data on
03:40you know how well the single dose vaccine is.
03:43Again, you know the bar has been set
03:46really high with the M RNA vaccines,
03:48and so it will be interesting to see you
03:51know how much lower the efficacy would be.
03:54Well, AstraZeneca we all know the very
03:56confusing data that was released around.
03:58You know people who got two for
04:01those vaccines having 62% protection
04:02against covid as against 90% for
04:04those who got to happen four and at
04:07least one of the missteps there was.
04:10You know later found to be.
04:12You know some dozing errors that were done,
04:14the clinical trial.
04:15And so I hear that Astra Zeneca is going
04:18to be collaborating with the Russian
04:20Group to look for boosting effect of
04:23that vaccine to the Astra Zeneca vaccine.
04:25So to be interesting to see
04:27how that plays out.
04:28And then they're also the protein
04:30based vaccines novaks just started
04:32to enroll in December 31st.
04:34Frankly and Sanofi had some issues
04:36with their early phase results
04:38that were going to lead to a fist.
04:40Those that we're supposed to participate in,
04:43however,
04:43it looks like for individuals
04:45who were each greater than 50,
04:47that there may have been some as suboptimal
04:50immunogenicity results in that setting.
04:51So you know they've been a couple of
04:54missteps with the vaccine clinical
04:55trials they've been manufacturing issues.
04:58They've been dozing issues,
04:59but you know you have emerged,
05:01and in some ways it's kind of set
05:04back timelines for week four vaccine
05:06availability and just the amount of vaccines
05:08available to roll out to the public.
05:11As we get the anticipate,
05:12you know,
05:13no one of the vaccines that have received
05:15FDA emergency use authorization will be
05:17able to meet the US need anytime soon,
05:20and so we're hopeful that some of these
05:22other vaccine candidates will be fine again,
05:25there's lots of data caps,
05:26you know,
05:27and hopefully some of these data
05:29caps will start to be addressed
05:31there in the independent.
05:32In the investigator initiated
05:33studies that are trying to pick
05:35off some of the specialty immuno
05:37compromised groups that people
05:38are discussing and and hopefully
05:40will start to get way more robust.
05:42Data on the vaccines, but again,
05:44it's heartwarming to see that the
05:46FDA in their unit did not did mention
05:49that immune suppressed patients could
05:51have diminished responsiveness,
05:53but there was no specific ideas around,
05:55excluding individuals who are
05:58severely immune compromised.
06:00So again, I think that we still continue
06:02to generate data our six month follow
06:05up visits for our patients in the
06:07study would be about March to April,
06:09and so I think this would be critical
06:11because one of the pieces of information
06:14like gathering from this group is,
06:16you know, just the durability of
06:18antibody responses and I have a
06:20slider to about that afterwards,
06:21and again,
06:22some participants were enrolled
06:23late in the initial data that
06:25we submitted to the FDA.
06:27For example,
06:28HIV infected patients were recruited.
06:29Was the tail end the median duration
06:31of follow up for this subgroup is
06:33really short and did not meet the two
06:36month safety or longer term efficacy
06:37will be interesting as we have longer
06:40data we make will generate some more
06:42data about some groups that were left out.
06:45So we've talked about some of the missteps
06:47with some of the other vaccine trials.
06:50Pay attention to the differences
06:51in endpoints to the Johnson and
06:53Johnson vaccine is not looking at
06:55the symptomatic covid disease,
06:56but the subset of people in
06:58moderate to severe covid disease.
06:59So at some point making comparisons
07:01between endpoints may be challenging,
07:03although you know many of these
07:04also have secondary endpoints
07:06that may allow a good comparison,
07:07but you really want to pay
07:09attention to what's being measured,
07:11and as you're aware of,
07:12is also interested in knowing if
07:14it is vaccine protect against.
07:16Is symptomatic disease and I'll mention
07:18how we're doing it to Pfizer file again.
07:20Like into rightly mentioned,
07:22the window is really closing on placebo
07:24controlled trial as vaccines have
07:26become available and so you know for
07:28some of the those under dating earlier
07:30phase who don't necessarily have a
07:33competitive advantage with the lead
07:35candidates like the M RNA is 95% efficacy.
07:37Great safety profile.
07:38It's going to be stifling upcoming passing
07:40candidates and that's just the reality.
07:42And there's also issues with the vaccine
07:45rollout as informed by the vaccine data.
07:47So when we get more vaccine
07:49candidates available,
07:50let's say you have one at 70%
07:52effective versus 95% effective.
07:53How do we decide what to offer someone?
07:56Or do we take away choice from individuals?
07:58At some point you have
08:00commented single issue,
08:01single dose versus double doors,
08:03and the logistics of those would be critical.
08:05Again, wait against efficacy but
08:07importantly unwanted thought.
08:08I want to leave is we're talking about
08:10herd immunity being the ultimate goal.
08:12If we have a vaccine,
08:14does 50% effective even vaccinating
08:16100% of population may not get us.
08:18To the herd immunity targets.
08:20So I think you know efficacy is
08:22important with also as a key variable
08:24with achieving herd immunity and it'll
08:26be interesting to see how
08:28upcoming vaccine studies form.
08:29And we've talked about less now.
08:33I'm not going to say too much
08:35about this, but you know,
08:36the ad 26 is the platform that Johnson
08:38and Johnson Vaccine uses an amarone,
08:40one of the common questions that we get is,
08:43you know, if I get a vaccine,
08:45should I wear a mask and you know,
08:48you know, why should I continue to wear
08:50a mask and one of the key questions
08:52is that you know we haven't quite
08:54demonstrated robustly in the trials
08:56because I didn't look for them or
08:58haven't really studied it robustly
09:00in the phase three human trials.
09:01But there's, you know.
09:03Robust and elegant animal data from,
09:05you know the the ad 26 vectored vaccine,
09:09as well as the M RNA vaccine.
09:12About, you know when you challenge
09:14nonhuman primates with virus put in,
09:17particularly exposed to lower Airways and
09:19intranasally after vaccinating individuals.
09:21So a post vaccine challenge,
09:23locate the antibody responses.
09:25TC responses have been
09:27characterized in these animals,
09:28but also evaluating if
09:30there's after Mel reputation,
09:32both in upper and lower.
09:34Always in this setting,
09:35and I think the data from both a
09:38viral vector and the M RNA vaccine
09:40suggest that the vaccines definitely
09:42do decrease viral replication,
09:43but in upper and lower Airways,
09:45little bit of a discordance
09:48between these two studies.
09:50At 26 nonhuman primate studies suggested
09:52there may be greater protection of lower
09:55story track and upper estimate tracked,
09:58and Marni study showed little.
10:00Greater protection against virus
10:02replication in the operator truck.
10:03Again,
10:04storage to effect but put together,
10:06these inform that the vaccines should
10:08protect against asymptomatic infection.
10:09The question for me is not if they do but
10:12by but to what degree and for the phase.
10:15Three trials.
10:16For example in the Pfizer trial
10:18we've added on checking antibodies
10:20to non vaccine induced antibodies
10:22and so in follow up and so this
10:24would be one way we can assess for
10:27those who did not have symptoms.
10:29Did they generate antibodies?
10:30The virus is the marker
10:31of asymptomatic infection,
10:32so we're going to learn so
10:34much more about this.
10:35And of course it will have public health.
10:38One of the important thing to mention is
10:41a differential response among the elderly.
10:43This comparison of three different vaccines.
10:46This is the DN.
10:47T162V2 is the Pfizer vaccine.
10:49This is there no vaccine and add 25.
10:52I'm just as an example of a viral
10:54vector vaccine I think across the
10:57board as you move across the spectrum
10:59of age and like has been shown with
11:02almost every other vaccine that
11:04older individuals tend to have at
11:06least numerically lower antibody
11:07titers and neutralization.
11:09Latest,
11:09you know that's pretty clear now
11:11there's differences in the neutralization
11:14assays and not necessarily.
11:18Compare one to another,
11:19but I think the concern still remains
11:22that older individuals may have a little
11:24bit of diminished response. Good enough.
11:27Both modern and Pfizer studies have shown
11:29robust protection independent of age,
11:31which is reassuring.
11:32But then, as you know,
11:34we follow people overtime.
11:36It interesting to see if you
11:38know trajectory's of antibody
11:39levels change overtime.
11:41However, we still know that you know
11:43the quantitative level of antibody
11:45does not always translate to.
11:47They're correlated degree of
11:49immunity against the disease.
11:50So there's interesting data point to
11:52study for the clinical relevance is not
11:55always clear and we can see that forward.
11:57The GSK Sanofi study that
11:59we were to participate in.
12:01The study has been delayed because
12:04of the underperformance of of the
12:06individuals who are older than age 50.
12:09Above age 60 did not have levels that
12:12approached what everyone is using us to bar,
12:14which is the neutralization antibody.
12:15Titers in convalescent individuals.
12:17I think I have a slider to left and
12:20many of us have heard about the new
12:22strains and concerns about the vaccines,
12:24so we know that the strain that's done
12:26a lot of press is the UK strain because
12:29it does predominated infections in that
12:31part of the world and it's being identified.
12:34But here in the US and other areas,
12:36not surprisingly,
12:37but even the more scary South
12:39African variant which has.
12:40You know single viruses
12:41simulating multiple mutations,
12:43including multiple tations
12:44in the spike protein,
12:45and what that means for for vaccines.
12:48You know,
12:49studies have shown that certain
12:51mutations matter more than others,
12:53especially those that occur in
12:55the receptor binding domain.
12:56And what that does to.
13:00Susceptibility to antibodies.
13:01So for example,
13:02the E484K has been identified as
13:04a mutation that can significantly
13:05have negative impacts.
13:07For example,
13:07looking at the figure at the bottom
13:09on a neutralization for using
13:11convalescent sera from individuals
13:13who have recovered from the vaccine,
13:15the good news for now,
13:17based on Pfizer data,
13:18this is from a preprint server.
13:21It appears that even the mutant seems
13:23to be neutralized equally and then
13:25the non mutant version of the virus,
13:28which is good, so suggesting that.
13:30At least the Pfizer vaccine
13:31should work about them.
13:33There's a flurry of activity
13:34going on trying to identify this.
13:36I do know that discuss South African
13:39group are currently studying
13:40convalescent sera from people
13:41who recovered from Covid as well
13:43as their server from vaccinated
13:45individuals against the new variant
13:47that they have in their study.
13:49And they promised that will have
13:51the some data in the upcoming weeks.
13:53So for now, fine.
13:55But we may have to worry in the future.
13:58The good news though, is that you know.
14:00Yeah,
14:01vaccines can be adapted to new
14:02strains as they occur.
14:04I'm not aware of what regulatory
14:06process will need to be done there,
14:08but I do know following this part
14:09is you know someone else who's
14:11addressing some of the regulatory
14:13processes around
14:14that. Monoclonal antibodies
14:15may be threatened.
14:16Now the next question we get is,
14:19was the durability of vaccine responses.
14:21We don't have our six six
14:23month data from Pfizer yet.
14:25I tried to get that for you,
14:28but I can't disclose
14:29everything but I you know,
14:31one that's published is from
14:33the Moderna study and this shows
14:35that at least at four months you
14:37know the 120 days that both you
14:40know antibody levels as well as
14:42new tab neutralization geometric
14:43mean titers appear to be robust.
14:45Even so far out.
14:47From you know,
14:48from vaccination,
14:49and this was compared to individuals who
14:51had convalesced from you know about a month,
14:54median time from COVID-19 and you
14:56can see the trajectories overtime.
14:57Still seeing results.
14:58In some cases a little bit of a decline,
15:01but they seem robust overtime.
15:03Again, the correlation of protection
15:05are not clearly known,
15:06but these trajectories are really
15:08reassuring and I think you know
15:10conservative estimates are that
15:11immunity may last a couple of years,
15:13probably up to two to three
15:16T three years or so.
15:18So I'm summary is, you know,
15:20again,
15:21the multiple phase three clinical
15:22trials which were very happy
15:24to continue to participate in
15:26battle by early phase data.
15:27But we're still doing a lot
15:29of work to determine what the
15:31durability of me responses are.
15:33The new variants are concerning
15:34and will will continue to follow
15:37to see if you know either this
15:38ones or future emerging variants
15:40would end up being a problem
15:42for our vaccine approaches.
15:44Again,
15:44just certain groups like older
15:46individuals that appear to at
15:47least have numerically lower.
15:48Antibody responses,
15:49but for now it doesn't appear that
15:51they are clinically significant,
15:52at least with the lead candidates
15:54that have reported your data,
15:56and it's reassuring to see that
15:58some of the population that were
16:00left out of the phase three trial.
16:03Hopefully will start to generate
16:04data for some of our patients whom
16:06we wonder how you know how protected
16:08they would be with the vaccines.
16:10So I'll stop here and thanks for having me.