SARS CoV-2 Vaccines ... Hot Updates on Cold Vaccines
January 22, 2021Information
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.