- Good afternoon, welcome back to UCSF Medicine Grand Rounds. I'm Bob Wachter chair of the
UCSF Department of Medicine. Welcome to our live
audience from our department who are colleagues from around USCSF and throughout our health network. And as usual, we'll post this video at about 7:30 tonight on YouTube. I'll tweet out a notice of
that and the web address and our previous Grand Rounds are now I think over 1.5 million views. A few quick ground rules for
the audience are shown here, you'll be on mute. If you have a question, please type it in the Q and A box, we'll monitor them and try
to ask as many as we can and we've added a closed captioning option by popular demand and so to do that, there's a closed caption
button at the bottom and if you click on that, and go to show subtitles,
that should do it. So we've entered what feels like a new phase of the pandemic we are in the middle
of a very large surge, although there are some
mild signs of improvement particularly in here in
California, not enough though, and still many, many people
are dying nationally. We're still having about a
9/11 worth of deaths every day. Vaccines are here but the distribution has been rocky at best with complaints about the speed and fairness. UCSF has done overall quite well in its vaccination program and you'll hear more about
that in a few minutes but it is a real challenge to get it right in every dimension,
operationally and ethically. And the vaccine issue is
really one of the more interesting issues in that for
now we have massive demand, not enough supply, and at some point in
the next several months, that will toggle to a
different kind of problem where we need to make sure
people take their vaccines and we'll have the issue of
vaccine hesitancy to deal with, so it has many different dimensions to it and finally now hanging over all of this is a change in the threat. We thought we were running
a race against a virus that we didn't know a year ago but we'd come to understand and mostly hate over the past year and it now seems to have morphed into a few different versions of itself, some of which are better at
some of the things that it does, including infectivity and
maybe even evading the vaccine to some extent. So the stakes have been raised and the need for speed has grown even more in the last couple of months. And of course all of this we won't talk about it today comes against the backdrop of
the horrifying events we saw in Washington last
week and are still seeing and a new administration
that will take over in 140 hours and 57 minutes, not that I'm counting. So today with all of that as background, I'll focus on vaccines
and variants for vaccines, we'll do two parts, one is an update on how
we're doing here at UCSF, from the leaders of our
vaccine team, Desi Kotis, who is UCSF's chief pharmacy executive and Susan Smith, who is our
chief faculty practice officer. Susan and Desi and Gina Intinarelli and several other
colleagues have been leading our vaccine response and I have to say, even before we start, doing
a magnificent job of it. I'm sure they feel like they're
the complaint department but I think we've mostly gotten it right and we'll talk about that. We'll then broaden the
vaccine conversation and I'm thrilled that we have Paul Offit making
a return appearance with us. I won't go into his bio in great detail, but Paul was one of the foremost experts on vaccines in the world. He's the professor of Vaccinology at Children's Hospital Philadelphia, a professor at Penn where he
runs Vaccine Education Center and Paul's been a member of
every key advisory committee on vaccines in the universe, including the one that advised the FDA on what to do about the
Pfizer and Moderna vaccines and he's gonna talk us through where we are in the world of vaccines, so Paul welcome back, thank you for being here and so that part of the discussion where we're talking about
vaccines will take us to about 12:50 and then we'll switch gears to spend the last 20, 25 minutes talking about the new variants,
what they are, what they do, and whether they're a distant threat that's over the horizon or something that represents a clear and present danger to us. And I'm pleased that we have
one of the world's experts on viral diagnostics to help us with that, that's Charles Chiu who's a professor here in our Department of Laboratory Medicine and our own Department Of
Medicine in our ID division. Charles is also director
of the UCSF-Abbott Viral Diagnostics and Discovery Center and associate director of our Clinical Microbiology Laboratory and so he will educate us
on what these variants mean and we should think about this and what kind of threat it represents so and that will go till about 1:15 So that's the intro, let's go ahead and get started, beginning with a review of where we are on the vaccines situation here at UCSF and so let me bring on Susan and Desi. - So thanks very much,
Bob, for the introduction and inviting us back
to give you an update. Let's go to the (indistinct), so first I just I'm gonna show you how many vaccines we have delivered, so we've delivered just
over 20,000 vaccines as of early this morning. A reminder that we began
vaccinating about four hours after our vaccine
arrived on December 16th. Went through the holidays, dose two began on the
6th of January for us and you can see the distribution we're still mostly on first doses, but starting to pick
up on the second doses. Next slide. Drilling down a little bit more, this is our phase one A, it's part of our dashboard, it's a little bit more
complicated dashboard but just thought I'd call out where we are in total for phase one A, so our population of phase
one A is just over 23,000. As you can see of those about 91% or 21,000 are active on MyChart and of those we've offered
the vaccine to about 99%, we're pretty close. This represents both our
West and East Bay operations and of those 82% have consented and said, "Yep, I want the vaccine." 79% have scheduled and 77% of the total of phase one A has actually
received the first dose, you can see the second dose numbers there. And the two circles there
are to point out our gaps that we're working actively to resolve, so there are a couple thousand people who have not actually activated MyChart and of those there's, sorry, can you hear me okay still? I'm sorry, there's a buzzing noise. - [Bob] Yeah, just keep talking. I think people are used
to Zoom kinds of things, so it's fine. - I actually went up and told
them not to buzz during this, but that's okay. Okay, so they have not activated MyChart, so there may be technical
problems, language problems, or other reasons why
people have not activated and then of the people who have activated, there are still people
who have not consented and again, not sure whether
those are technical problems or language barriers
or a vaccine hesitancy. So we have teams working on
mitigation strategies for those, we have held some special
sessions to help get those people in who don't live on the web, don't necessarily have
active email addresses, have language issues, and
we're beginning to work on what are the root causes
for the vaccine hesitancy to the extent that they exist. Next slide is for Desi. - Thanks, Susan. So good afternoon, everybody. Here's another way to look at our vaccine and again, this was from a
little earlier in the week when we had just over
18,000 people vaccinated and this is really to look at
our just-in-time inventory, Bob talked about this as well. The vaccine is not coming
by any way shape or form through traditional
supply chain for drugs, so wanted to show you, and you could see various
points where we're at, but the bottom line is that
all of our first doses, almost 85% of them, have been administered or are reserved for appointments next day. 100% of our second doses
have either been administered or are reserved for appointments, so that's really the gist of all of this. Also gives us our run rate to let us know, and this was before we had
a delivery in this week, that we would be at our
run rates out of vaccine within a couple of days, so that's on the 18th or Monday. Susan, next slide, please.
- Next slide. Okay, so you can see we're sort of running just-in-time on vaccine, and we're trying to make
sure as much as we can, that those from phase
one A have been offered a real opportunity to schedule while we're still in phase one A but we are quickly moving
towards a phase one B. We're carefully following
the CDPH guidelines that are aligned with the CDC guidelines and they a week or so ago, broke phase one B and
tier one and tier two, it's changed again
since this was published and their website isn't yet updated, but last week they were starting with individuals 75 and older and then they've broken essential workers into various groups. The second tier of one B
is individuals 65 to 74, we probably will start with 75 year olds just to get our feet wet with making sure we can
get elderly patients through our vaccine
process without problems and then we'll be opening it more broadly to the 65 and older. It's not until phase one C, that underlying health conditions weigh in on the priority for vaccination,
at least at this point. With that I think we're, that's all we were gonna
cover on slides, Bob so back to you. - That is perfect. Thank you, thank you both so much. So there are a lot of
questions that have come in, I'd say that a lot of them are on the, would go into the category of how exactly is this going to work as we begin rolling it
out to these other groups? Been challenging enough to
do kind of our own people and they're in our HR system but now we're rolling it out to patients, so if I am a UCSF patient, how am I gonna find out that it's my turn and how are you deciding
on the allocation order among patients and between
patients and other folks that we're also offering a vaccine to? - Yeah, great question and honestly, we're learning and adjusting things
pretty much on a daily sometimes hourly basis to make
sure that we can manage this. So there's sort of two
interesting things to think about, we've also been asked by
the City of San Francisco to help vaccinate healthcare
workers in San Francisco who are not working for UCSF-Kaiser, one of the big organizations. So those people if and when we
can get that figured out will not be patients or employees, so they represent yet another challenge. What we're gonna try to
move towards is an ability to do scheduling from the web. We've been very much relying on MyChart and MyChart has some limitations, the first set of invitations that we send to our patients will
probably still be on MyChart but we're working on a more
open access to the appointments. It will be based on our
staff and our patients and any healthcare workers attesting that they in fact belong in the group that we are then vaccinating and then being allowed to schedule. So we're gonna rely on the honor system and hope that people
will really respect that and not take advantage of it. - And so if I'm a 76 year old person who's been seen in the
neurology clinic at UCSF, do I just go to my, can I expect that I'm
gonna get an email sometime in the next number of days or weeks? Is that how it's going to work? - Yeah, we will notify. We've sent out one blast
patient message telling them that we're about to start this process and when we get the details of how to have people
schedule on their own and sort themselves into
the appropriate group, we will send out emails to let people know exactly how to do that. We still, again, don't have the details of that exactly ironed out, so I can't show you a
screenshot on how that happens but we will be able to do that shortly. - Okay. Desi you talked about the
predictability of supply and this comes unlike anything else that's ever come to us. So as you're doing your planning, I'm mean, you have this now, all right, all clinicians
and people in their offices in San Francisco are
part of the eligible pool and maybe 75 year olds
and up but maybe 65 years, in doing that, there's this other factor of we're gonna have 5,000
doses or 12,000 doses. When do you find that out? Is it when the truck pulls
up to the loading dock or you have a day or two notice? - So we usually get a notice
almost a week in advance that there's going to be a shipment. So actually just before this call, I found out that we'll be
getting a shipment on Tuesday, so again, it's what is said
that we're going to receive from either San Francisco
Department of Public Health or through our multi-county entity and University of California in total and usually, we've been doing
this a little over a month, I think it's five going on six weeks, we do get what we are
told we're gonna get, but there are times where we have not received what we're told. So, again, this is a just in
time, day-to-day sort of piece that Susan, Gina and I
have been working through, so I'm in contact on a daily basis with the Department of Public Health and those that are allocating inventory and also letting them know that supply is not sitting in a freezer somewhere. It is almost just in time
when you have less than 15% of your supply for a 48
hour appointments from now. - So, we're gonna need
to move on in a second. I have a couple of quick
final questions for you but just to highlight a number
that may have sort of flown by people that we have given out and injected 84% of our supply. The national average is 30, California's average is 25, so we're doing amazingly well in terms of sort of getting it from the freezer to people's arms really, really quickly. Vaccine hesitancy, I
think, Susan, you mentioned that we're not sure
why that 20-ish percent of people are not signing up, do you have a sense of, are there people who just do
not want to get vaccinated and what are the things
you're hearing about that? - I'd say we haven't heard a large number of people saying, "I don't
wanna get vaccinated." So we've started the focus
on the technical problems and those have been significant, just getting people
over the digital barrier can be a big problem, but we also know that there
are some differences in signups between in the race and ethnicity data and so we're gonna take a
deeper dive in conjunction with some of our diversity
equity inclusion people at GCSF to understand that better and see if there's mitigations
that we can help with. - Great, maybe last one. Desi, there are a ton of
questions in the Q and A, we're just not gonna get to them. You guys keep doing
town halls all the time and we'll get you the questions as well in case there are some that
you wanna answer offline. Desi, everybody was worried
about side effects and all that, so now we've even out 20,000 vaccines. I had my first shot and my arm ached a tiny bit the next day, but it was a big nothing
burger, I thought, but that's because I'm too old
to have an immune response. Can you tell us what the
experience has been so far in terms of what people's
side effects have been? And have we see any of
these allergic reactions we've heard about? - We've been tracking and
actually Susan did present that data that we've seen from UCSF and we've not had to
administer an epinephrin shot, we have given diphenhydramine
or Benadryl a couple of times, we've seen some dizziness, there are people that are very emotional about receiving the vaccine, there's this sigh of relief. I mean, walking through the clinics and seeing people's reactions,
people are so grateful and so thankful, and the hope is there. So we have basically
observed people for longer than the recommended amount of time but seen some reactions,
nothing really intense thus far. - Great, Susan anything to add? - I would say that the second dose people I've heard anecdotally are
having a lot more myalgias, fever kinds of things that are expected from the vaccine as well,
but maybe not so comfortable. - Great. Well, we'd go on forever, but I really appreciate the update and again, I think I
speak for everybody here, we are grateful to you and
your teams for doing this work. It is really hard. It's a lot of emotion associated with it but really important that we got it right and I think the evidence
is very clear that we have, so thank you, I'm sure we'll
have you back on in a few weeks just to see where we are then but really appreciate it. Let's bring on Paul. There he is. So Paul, before you start, I'd just love for you to
react to what you heard, I'm sure you're seeing
an experience in Penn about how it's rolling out. What are your thoughts
from what you've heard about what's happening here? - Yeah, at Children's
hospital Philadelphia we're pretty good about vaccinating, we have several sites, you sign up, they vaccinate about 12
people every 30 minutes, it's very well organized, you're not waiting more than a few minutes and you'll have a place to
wait for 15 or 30 minutes, depending on your previous
history with anaphylaxis and we do about 2,500
people a week, roughly. So we're getting there and we
have about 15,000 employees at our hospital, but it's
a little easier for us. I mean, we're a children's hospital, so although we certainly
see cases of COVID, we're not overwhelmed by it by any means. We're a hospital so we're
used to giving vaccines, the nurses are used to giving vaccines, so if it doesn't work well in a place like Children's
Hospital Philadelphia, it's never gonna work well. - Well, I have to say that
part of my sort of engagement on this issue was seeing the challenges that many of our other academic state, certainly Stanford had problems, MGH had problems. There was a big report in New
York Times about challenges and it was sort of like if
big academic health systems that have HR systems, computer systems, and mostly clinicians, if
they can't get it right, how is this going to work when we go to 300 million other people? So it was almost an early warning signal that this is harder than it looks. So let's let you, I think you're gonna make some
sort of introductory comments on kind of what you've been seeing over the last couple of weeks. Why don't you go ahead and do that and then we'll go and do
a discussion after that. All right?
- All right, so certainly things right
now are pretty grim. I mean, we're over 4,000 deaths a day, I think we have more deaths yesterday than South Korea has had
during this entire pandemic and I think also more than Japan has had in this entire pandemic which shows you how bad we are at this. And I think it's gonna continue to be grim as long as the weather's cool, as long as people still aren't very good about masking and social distancing and but the vaccine is just rolling out. But I'm gonna make the
following optimistic statements, remembering that I'm a Philadelphia Eagles season ticket holder, so my optimism should be graded on that, but you have two vaccines
that are now getting out there that are 95% effective against disease, that's remarkable and we're at least 95%
against severe disease and in people over 65 and in people with a variety of comorbidities. I think a year ago when we
first isolated this virus and sequenced it in January of 2020, I don't think there was a scientist on the face of this planet
who would have thought that these two mRNA vaccines
would have been subjected to large phase three trials
found to be this effective in getting out there, so that's good. I think the other two vaccines
that are around the corner, AstraZeneca's vaccine and
Johnson and Johnson's vaccine, I'm on the FDA's vaccine
advisory committee, so I think we're not going to be hearing about them in the month of January. I'm pretty sure likely would be hearing about at least one of them
in the month of February with a goal hopefully to getting those vaccines out in March, you
have two other vaccines, the Novartis vaccine and
the Sanofi-GSK vaccines which are purified protein vaccines that hopefully will be
coming online by April as those trials finish out. So more help is on the way that's good. Then we'll get warmer and
this is an envelope virus that's spread by small droplets, usually when the weather gets more humid, those small droplets will acquire water and tend to drop more quickly, so usually these kinds of
viruses are less transmissible in the summer months when
it gets hot and humid, so that's good. You have an administration
that has a clue, that's actually interested in
trying to stop this pandemic instead of asking you to engage
in some cult of denialism, so that's good and I think that the other thing is that we don't talk about this
much because it's so horrible, the price that was paid
for this was so horrible, but in terms of deaths and
suffering and hospitalizations. But the report is at about 23 million people have been infected in the United States. Well that's people who've been tested and found to be infected, I mean there are a lot of
people who had mild disease or asymptomatic disease
who just never got tested. So it's only with
antibody surveillance data that you can really get a sense of how many people have been infected and there were studies in November and then more recent studies showing that that number is probably off by a factor of three to four. So assume three, three times 23 million, now you're in the sort of
65 to 70 million people who have already been
infected in this country, who when they were exposed to
this virus are very unlikely, I think, to get certainly sick or certainly significantly sick. So that's a base of about
20% of the US population that's already at some level vaccinated, I mean for all practical purposes and you have if you use the, there's a book called
"Plotkin's Vaccines". There's a chapter in it
called Community Immunity by Paul Fine. There was actually a formula
to answer the question what percentage of the
population needs to be vaccinated in order to stop spread, in order to get the R0 to less than one and that formula is RO minus one over R0 divided by the vaccine efficacy, so let's assume just for the
purpose of this discussion that the R0, the
contagiousness index is two. Two minus one over two is .5, divided by an efficacy of .95, 95%, then that gets you 2.55
or said another way, that you need to have 55%
of the population immunized in order to stop spread, knowing that you've already
gotten a certain percentage of people who are already protected. So with all that, I think
that if we can vaccinate one to one and a half million people a day and certainly that's the Biden goal, we're already vaccinating
about 500,000 a day, so I don't think it's a leap
to believe we can get there. What we're trying to do that's so hard is we're trying to create a
public health infrastructure that doesn't currently exist, which is the same infrastructure
for mass vaccination but you're starting to see it. I mean, Pennsylvania Convention
Center now is a site, Dodger Stadium, I think is a site, and that's what you wanna
see, mass vaccination. And I think we will get there and so I'm going to predict that as sort of February turns to March, we're gonna start to see things improve and I think that if we can continue at a high immunization rate in this sort of one to
one and a half million, we could start to see, we will start to see, I
think, a gradual diminution with I think us being in
pretty good shape by June. So that is my prediction, but then again, I think the Eagles, we're gonna win the Super Bowl every year, so you need to know that. - Big, big grain of salt
when listening to you. Well, first of all, I rarely criticize you but I will that I think
before you give people that much math there needs
to be a trigger warning, so you just launched right in to formula. Let's spend a minute on the formula. Are you saying that we reach
herd immunity at a lower number or are you saying the curve starts bending in a meaningful way when we get to half the people
being immune, let's say? - I think we reach herd
immunity at around 60%. I'm going to predict that
we will reach herd immunity. See the one thing it's not, that I didn't explain was
when you say 95% efficacy, what I'm talking about, published efficacy is
efficacy against disease. What you really care about is efficacy against contagiousness, I mean, efficacy against transmission, that's what you care about. We don't know to what extent
these vaccines are protective against asymptomatic infection, where you can have significant shedding, but I really do believe
when we do those studies, we're gonna find although you may be asymptomatically infected
that you will shed less virus, if you're immune, if you've been vaccinated
than if you haven't. I was fortunate to be part of a team at Children's Hospital
that created the strains, became with the rotavirus
vaccine, RotaTeq, and that vaccine doesn't protect against asymptomatic infection. Nonetheless, we have virtually eliminated that virus in the United States, so I think that although
we make a big deal about this asymptomatic shedding, I predict that we will shed less virus which is really the critical issue. - And people talk about the Moderna study where they actually did
some testing of that and it was sort of hopeful in terms of answering that question. Do you feel like we sort
of partly know the answer but we're being reluctant
to sort of say it out loud? - I think you can't look at shedding because usually we look at genome. We don't usually look at infectious virus and the real right way to answer that question is through contact tracing. That's the way to answer the
question about contagiousness, and then you can go back and look to see what
extent shredding of genome at what cycle time you can then say, "Okay, here's the correlate," but you really have to do contact tracing to answer the real question about shredding and that hasn't been done. - Okay, we'll stick with
the math for a second 'cause I guess you got my head there and we'll get out of it soon. If we only need to get to 60%, I guess you're implying
that that number is not just the number of people vaccinated, it's number of people
vaccinated plus other people who had prior infection, assuming that infection yields an immunity that is still good enough. - And remember we are vaccinating people who've been infected. - Exactly, you just can't
add those pools together 'cause we're starting on
vaccinations with at least it's, some of the people already were infected, so you sort of have to subtract them out a little bit track that. - Completely 20% of the people you're gonna vaccinate
have already been infected. Probably.
- Yeah. Got it. But when you say herd immunity 60% that's like the most hopeful number I've heard for a whole long time and Fauci was saying 70% of that and then said actually
it's really more 80 or 85. So where is the difference? It would seem to me this
is a knowable number so why is there, I mean, we're talking about tens of millions of people different in terms and months different
when we will reach that, the right place. Why is there sort of
dispute on that number? - I'm going to say it was,
I'm taking that 95% number literally as protecting
against not only disease but contagiousness and I'm also saying that
I think that the 20% of people who are essentially
(indistinct) or immune, so and understanding that we're going to, that if you take the 55%
number, remember so, you know whatever 20% of 55% is one 10%, so that's where it gets knocked down, so then now put it up to maybe 60, 65%. That's what gets me to that number, but I will say, we'll
see how this plays out but I choose to be optimistic on this, I really do think we can get there. - Love to choose to be optimistic. So let's talk about, I mean you were sort of remarkably
un-grumpy about the rollout, it sounds like you feel
like it was predictable, this is hard, we don't have the
public health infrastructure we'll figure it out learning curve. Is that right? When you heard in November that we had two vaccines that
were 95% effective and safe did you think that, and it felt like the bottleneck might just be supply, we're just not going to have
enough doses rolling out. Did you imagine that we might
be in a situation where, we thought we'd have injected
25 million people by now and we've done 10 or 12 million
or was that predictable? - Well, I mean it was
certainly predictable in the sense that we don't
have a mass immunization public health system,
so that was predictable. I think that in retrospect I maybe I should have sounded grumpier, but I think that, that when we were essentially
mass producing this vaccine at risk, the government
was willing to basically put $24 billion into this effort according to the Foundation
for Vaccine Research that's an amazing amount of money and they got their money's worth, we paid, the government
paid for phase three trials and with the exception of Pfizer's trial, the government paid to mass
produce these vaccines at risk, not knowing whether it was safe, not knowing whether it was effective, obviously companies
aren't going to do that, they're going to wait until
they do the phase three trials and show that something works
before they mass produce so we did that at risk. At the same time we were doing that we should have also put an
infrastructure in at risk not knowing whether these
vaccines were going to work and we didn't do that. I think we just thought great. and I think at some level
it's a little bit of a clash of cultures between the
Department of Defense and the CDC. You hear a lot from general Perna, who's the Department of Defense guy and their culture is a lot different, I mean, he talks a lot
about making sure that these supplies aren't attacked, from some of nefarious foreign agent I would much rather have Anne Shuk talk talk to me every day about how they're going to be distributing and administering I think we can mass produce this, that doesn't worry me so much, what worries me is the
distribution administration that you distributed in the
right place in the right way and that we administer
it in the right place the right way, I'm on this, Rachel Deans our secretary of health, I'm on the this committee
that helps advise her, but she wants to set
up immunization clinics in the central part of
the state where we have, kind of retail pharmacy free zones that she feels should exist she needs personnel, she needs money, and she's trying to talk
to the federal government about what she needs, how she needs it and that's been very frustrating for her so that's at least part of the problem. - They really didn't
appreciate the complexity of the last mile problem here and they thought if they could get it to a freezer in your state they were good and they didn't understand
that until it's injected it's not good. - Right we're Philly in the east stop, Pittsburgh in the west and Alabama in the
middle for the most part but it's the Philly
and Pittsburgh are easy it's gonna be the center part
of the states that are harder. - So tell us, when we
began learning about these obviously you've understood this and been in the middle of
it for much longer than that but most of the rest of us
lay people kind of first heard about these vaccines two months ago and we heard about 95% effective and we heard about safety profiles and freezers and all that kinda stuff. What have you learned
in the last two months and maybe in the last month about these vaccines that has changed your thinking about them? Have we learned anything more about safety the short term safety,
the long-term safety? - Well, so anaphylaxis is an issue roughly 11 cases per
million doses distributed, which is frightening to watch but on the bright side,
it is immediately evident, there is a treatment for it,
and we know to watch for it so that's good. In the trials, there were seven cases of Bell's palsy among the 37,000
people that were vaccinated with Pfizer, Moderna's vaccine. There was one case in the placebo group among the 37,000 people, that one case in the
placebo group was roughly the background rate of
what you would expect, so the seven cases was higher, so I've been really
curious to see what happens as this rolls out, we're approaching about
10 million doses now and I haven't heard that
story, the Bells palsy story, I think you need to give it
a couple of months to see, but I feel encouraged
that that may have been, a coincidental and not causal association, so was the tyranny of small numbers generated from large databases. I mean, we've seen this all the time, like the hepasil B vaccine, for example, the third of the hepatitis B vaccines. I mean, there were a
statistically all based on small numbers, a statistically
significant increase in myocardial infarction
in the vaccine group, but there was also a
statistically significant decrease in prostate cancer. So, both of those things
I think were wrong and you sort of see this,
although our vaccine the rotavirus vaccine, 70,000 person trial there were five cases
of arm and leg fractures in the placebo group and
none in the vaccine group, therefore we made a vaccine that prevented arm and leg fractures, the FDA didn't give us
an indication for that, but you know, that, that's what we found. - Yeah, so and you mentioned when we spoke to you maybe a month and a half ago that when people worried about the safety and how fast these trials were, and okay, maybe we didn't see anything
nasty after two months but what about six months? And I'm going to wait, you made the point that in the history of
vaccines that you knew of that was essentially
nothing that emerged later after two months, you still feel that way, that if something has
not shown itself by now, if you say I want to wait six months to be sure of this vaccine's okay, that's not an evidence based thing to do? - Yes, that's the way they use
polio from the polio vaccine visceral trophic disease from
the yellow fever vaccine, the (indistinct) from
the influenza vaccine, narcolepsy from (indistinct) and national flu vaccine used in Europe. I mean, those can cause long-term problems but they do occur within
six weeks of a dose. I actually had a conversation with someone at the CDC where we sat down and tried to think of a side
effect that wasn't detected in that first six weeks
and couldn't find it. So when people are
worried, the safety issues, we look two months after this last dose for those two big trials,
those trials were the size of any pediatric vaccine trial. The HPV vaccine was a 30,000 person trial, meningococcal pneumococcal vaccine 35,000. So this was the same size, I mean, the only difference
really was efficacy, you only knew that this was effective for, three or four months. That's all you knew, but you know when you have such a
high level of efficacy and you can see evidence
for T-cell immunity suggesting it's going to
be longer lived immunity I think you can feel pretty comfortable, that you're not taking an unnecessary leap and you're not going to do it two or three or four year trial to see
how long it's effective when you know almost 400,000
people have died this year. - Yeah, so let's talk about
some of the strategies that people have proposed,
I've been one of those people for kind of moving things along and whether you think
these are worth considering or silly ideas, one is
delaying the second dose and that has kind of two flavors. One is sort of to strategically
delay the second dose and the other is what, at least both this and the next administration
have said they're gonna do which is no longer
reserve the second dose to kind of free it up and sort of taking the
risk that some people might be a little bit late in getting it. So what do you think about that when you think about the risk of delay? Go for it. - I have weighed in on this on the PBS News Hour on Friday, I went with you and Dr. Gile Rone in the Washington Post and have a problem with it,
so here's my problem with it. We know that as two
doses, that this vaccine is highly effective at preventing disease. We do have some data between dose one and two for the Pfizer vaccine,
some data between dose one and two for the Moderna vaccine, where the Pfizer was about 52% and Moderna depending on
how you slice it, 80, 90%. But we only know that for a few weeks we also know that you have
a lesser immune response after dose one to dose two, we clearly know you get a booster response with dose two, we also know that you get a more
detectable T-cell response after dose two, as compared to dose one, suggesting longer lived immunity. I don't have a problem with getting all the vaccine out there. I think vaccinate as
many people as you can but you have to get that second dose in and I think what worried me in this not so much that instead of
getting it three weeks later you get it four weeks
later or five weeks later, that doesn't bother me so much. I don't think that vaccines were based on like the lunar month. I don't think a week or
two makes a difference, but I do think that if you
send a message out there that people, because
people have told me this "look, I read that it's 80 or
90% effective after dose one. "Why get the second dose?" And see that would be bad and when I said that on the PBS News Hour, I got a call the next day from someone in the Biden transition team saying, "This is not our plan,
this is a two dose vaccine, "we are not trying to
delay the second dose, "you're going to get that second dose "in three or four weeks. "We just think we can
get the vaccine out there "to give that second dose". And then two people from
the Biden transition team, Mike Osterholm and Celine Gander once CNN that next day saying "That's not our plan,
it's a two dose vaccine". So I think they had a
messaging problem when they were saying, "We're getting
all this vaccine out there "get the second dose when you can, "cause the first dose still works". And that's not it, not just me the FDA made a statement, Dr. Fauci made a statement, so I don't think when you
and Dr. Gile wrote that, that's what you were saying. I don't think you were saying. - We were trying to generate
this discussion and actually trying to move things along in some way and I kind of felt that
the idea of no longer being so prescriptive about we're
just holding half of the doses in a freezer somewhere
and not even releasing it, just felt like it was
more harmful than helpful. You have to get more people
to get their first dose fast but it sounds like you
think that a strategy of delaying the second dose is a bad idea. (indistinct) Yeah, that makes sense. - According to at least I
talked to David Kessler, but who's great and I'm
so glad that he's involved with the Biden team, they believe that by getting
this vaccine out there that they can mass
produce what they need to and get out that second dose, they don't think they needed
to hold the second dose because they believe
they can meet that need. Great, I'm all for it. - Okay, other things that have
been proposed sort of mixing and matching the second
dose, being a different dose than the first dose, in terms of bad idea. - Yeah, don't make this stuff up. I mean, this is why you
do phase one trials. You do phase one trials to
figure out the right dose, to figure out the right dosing interval and then you move forward to
phase two and phase three, you don't sort of tinker
around at phase three to see what looks good. Very unnerving I think
the UK people did that with half those full dose
one month, three months and that's just not the way to do this and so do the phase three trials the way they're supposed to be done, generate the data that's solid
and then follow the signs. - What do you, in terms of
the prioritization scheme? So we had lots of plans and group one A and one A sub whatever, and all that and there's many States are now opening up to new groups and the CDC
is opened up to new groups. So did we get that wrong, were we trying to be a
little bit too precise? What's your sense of
who goes first question and how we're done and what
you think it should be today? - Yeah, I think this is hard, I mean, this is like the
Sophie's choice, right? You want to vaccinate people
who are at highest risk, you want to vaccinate people who help the society move along, it's like the Titanic analogy where you have made a Sophie's choice and a Titanic analogy,
but the Titanic analogy, you only have so many lifeboats, of the a hundred or 150,000 or 200,000 people that are going to die over the next couple of months, would their lives have
been saved by a vaccine? Likely, very likely yet they didn't get it and it's really hard, you only have so many
lifeboats there that enable you to save people and it
just breaks your heart. So get it out there, get
the vaccine out there as much as you can, realize
that you're going to be really upsetting one group or another. I got a call from a governor saying, "look here's my prioritization scheme. "What do you think of that?" And my thinking is like, you're gonna anger people anyway so just do what you think works best. - And what we've seen now is
essentially, maybe in part because of the lack of
national leadership, 50 different experiments, every state doing it their own way. Are there any lessons to be learned from what you've seen so far? Are any states doing this great or any states doing particularly poorly that they need to get better fast? - Yeah, certainly. we don't have the infrastructure
to give mass vaccinations, so states will learn at different levels, states are all different and so they will learn differently, they'll administer it differently and I think two or three years
from when I look back on this and figure out what we
should have done differently and hopefully we'll have things in place so the next time there's a pandemic knowing there's been three
in the last 20 years, that we'll be much better prepared. - Now I know you're gonna have to go in a little bit before Charles speaks but let's talk about the
variants for a second. - Yeah I was hoping to
hear him speak actually but what I want to hear maybe can I ask him a
question before, is he there? - Charles, are you on if
you're causing us to do improv which we do very badly,
but let's see if, Charles? - Can I ask Charles one question? - Of course, there you go. - Okay here's the Golden Gate Bridge. - We are so nimble here, look
at that, welcome Charles. - Here's my question. So I saw it with the UK
variant, the B 117 variant there are pollical, antisera
generated by natural infection as well as polyclonal anesthesia
generated by a vaccination specifically, Phil Dormature's
was making a comment about the vaccination with with Pfizer's vaccine,
that neutralize that virus. Good, okay. Do we have the same kind of data for either the South African strain
or the Brazilian variant? - So the answer is that I don't believe, I haven't seen data yet about the efficacy of a polyclonal sera against
the South African variant and in fact, I was planning
to focus on that shortly but I think the worry is
that the South African variant is, is clearly
of more concern than the UK variant with respect
to potential vaccine evasion, because of the, they have there some
additional spike mutations, most notably the E384K mutation, which may which has been linked
to at least two evasion of neutralizing antibodies
to the spike proteins. - Monoclonal or polyclonal? - Monoclonal, but it
also has been reported that convalescent plasma has less activity which presumably contains
polyclonal antibodies, has less activity specifically
against the variants which include this E484K mutation which is found in the
South African variant. But so far, all of the
data so far supports the idea that the vaccine
should be effective against the UK variant. - Yeah, that I saw and you
wanna make a prediction? Because I guess with
regard to the SA variant, or the South African variant that you it's really how many
epitopes you start to affect before you get a critical decrease, before you cross that line where polycologne lana sera
is no longer effective. And I don't know the
answer to that question, I know this virus
generally mutates slowly, which is to some extent
reassuring, but what do you think? - Yeah, so what I believe is that we've already seen that
there's a tremendous amount of individual variability. If I had to make a
prediction, I would predict that the infection with
the South African variant, probably that the vax,
it does have perhaps a slight or at most,
maybe a moderate impact but it's going to vary from
individual to individuals. So for instance, some
individuals who are vaccinated and maybe if they're infected, if they happen to be infected
with South African vaccine they may generate antibodies
that are effective against the South African
variant, whereas others for some reason, with
different polyclonal sera, would be have less activity
or slightly less activity. It's my hope though that the effect is going to
be minimal or split, but we still have to see. - And just or those of us who
are not a super specialist in the area, Paul the kind of questions you're asking about is it the monoclonal antibody,
the polyclonal antibody? Why is that an important
thing to know in terms of predicting whether the
vaccine still going to work? - The polyclonal sera is really
the more important question. You wanna make sure
that people who've been naturally affected or immunized
are going to be protected against this variant strain. And the only way to know that is to look to see whether their
polyclonal sera do that. I mean, the monoclonal antibodies help us dissect what specific
epitopes are involved, but the important question
is hazard escape recognition by a polyclonal immune response which is the immune response we make. And it bugs me a little bit Charles that we certainly in the United States, we can certainly build up our sequencing much better than we have. And when we identify these variants we should be able to
identify really within a week whether or not they've escaped recognition by polyclonal sera and it seems it's been a little slow and frustrating. - Yeah, that's a great point you make, I really think that part
of the reason is that we do not have, unlike the UK we do not have a nationwide
coordinated network that actually do this type
of genomic surveillance what we call sequencing
to be able to rapidly identify these variants. And I view it as simply
flying with a blindfold on, that we simply, if you don't
know about the existence of the variants, you don't
know what is circulating, what is predominant in your community. There is no way to develop countermeasures or to understand exactly
what impact it will have on both our vaccines and the drugs that we're
using to treat the infection. - I'm sorry, go ahead Paul. - That was completely selfish on my part. I saw the Charles there, I
knew he was going to be talking about this and I knew I was
going to have to miss it. - So Charles let's have
you go away for sec and I'll just finish up with Paul and we'll come back to you and
probably five, six minutes. So let's maybe one more
question to you, Paul on the variants, now that
we know they're out there and we'll hear from
Charles in a second about, more specifics about them but we know that at least for one it's more infectious
and we know for a second that it might be at least
partly resistant to vaccine. How does that change your thinking about the vaccine rollout? The importance of speed? Are we gonna have to retool the vaccines over time as the bug gets smarter? So, or how are you
thinking about now that we about these variants that
actually have changed behavior, how does that change the
whole world of vaccines? - Right, so these are
single-stranded RNA viruses and so they will mutate and
they will create variants. So the question is, if
there's going to be like flu which mutates so much from one year to the next that you have
to get a yearly vaccine, or is it going to be like measles which is also a single-stranded
RNA virus, it also mutates, it also creates variants, but
we've had a vaccine since 1963 and the virus hasn't escaped it which of the two is this going to be like and they'd probably be
somewhere in between, but I think that would be terrible news. I mean, if we really generated
variants in this world that escaped recognition
by the polyclonal sera here that we generated for
natural infection immunization, that's a problem. And then we have to imagine how hard it is just getting this vaccine out there? And we would have to
presumably, there would be a multi-variate vaccine, if you will. I mean, that you have not just the RNA tne codes for the spike
protein, this non variant strain but the RNA also the
code over these others. I think it would be a kind of a multi valent vaccine if you will, but it's hard, you have to
get that out there again that would really be a problem, that would make them much less optimistic about how quickly- - I mean, does that create even
greater incentives to speed? If we get to herd immunity
before that moment are we protected or is
there now a possibility that this new variant sort
of enters our universe and creates 2020 all over again? - Well, again it's an
international community so whatever goes on in
the rest of the world also that's another argument for arguing for giving that second dose earlier. I mean, there's paper that just came out in Science yesterday, that
we saw that the laying that second dose has caused
some urologists to worry or likely to create these escape mutants than if you try and kill
dead, as quickly as possible, so we'll see. - A couple of quick, last questions up, anything, do we know any
more about pregnancy? - Yeah, no I'm negative,
no I'm just kidding. No, you had 23 cases in the Pfizer trial, of people that were pregnant you had 13 cases of the Moderna trial, the be safe system at the CDC is going to be following these people who get vaccines when they're pregnant. It's odd, typically when the
CDC makes the recommendation about pregnancy absent
data, they'll always say it's contra-indicated now because you know that a woman who's pregnant,
who's infected with SARS Covid-2 is a greater risk of a more severe disease in a
woman who is of similar age, that's not pregnant, you know that, there's no good reason to believe, there were certainly a preclinical study in experimental animal showing that there was no effect on
either of the pregnant animal or the unborn little
animal, so that's good. And so they said that a woman essentially may reasonably choose to get this vaccine. Interestingly, there were two
cases of spontaneous abortion, one in the Pfizer trial, the
other in the Moderna trial both in women who were pregnant, both had been in the placebo group. Interesting. - Interesting. Okay, I think I'm having
trouble with my connection but we will try to go on, maybe last question for you, we're starting to hear
about cases of people who got vaccinated and got infected any of them worrisome yet or it's just all the statistics that have, it's 95% effective, somebody will actually get an infection after even
being fully vaccinated? - One in 20 people. So it's not surprising, I
guess, that you hear it. We'll see how this plays out, but so far, it looks like natural infection protects against diseases associated
with re-exposure, that's good, that means
you can make a vaccine, you just have to mimic the immune response from natural infection. I think we've done that
with these MRN vaccines. I'm optimistic that
we'll get on top of this as long as variant stone is
a recognition by the vaccine, that would be a problem. - Yeah all right great and just for us to calibrate, you mentioned the egos, but are you an optimistic kind of guy or is that your nature? - I think any scientist is optimistic. I really think that, I think as scientists we generally go from one failed experiment to the next, with unabashed enthusiasm. - Well, I hope you're right. And thank you for helping us understand this all a lot better. It's really complicated and I think, the point you make is really important. It's easy to sort of look at the short-term speed
bumps that we're seeing and forget that it's a
miracle that we find ourselves in January with two
extraordinarily effective safe vaccines to give out. So we should make sure we
keep our eye on that ball. - Okay.
- All right thanks so much. - Take care my pleasure. - We'll be talking again a couple days, so a another forum but appreciate it. Good talking to you. All right, let's bring on Charles. So Charles, let's bring you out and I'm gonna I'm
actually gonna try to move and see if I can prove my connection but why don't you go ahead
and get started with that. - Absolutely, so I'd
just like to start off by thanking Dr. Wachter and UCSFs for inviting me to speak
with all of you today. I'm going to talk today
about the implications of some of the new variants
that have been circulating around the world and perhaps
even the United States. I think with the first slide, so next slide please, yeah, so with the first slide,
I just want to simply point out in this very simple graph the concept of viral evolutionary rates. So COVID-19 SARS coronavirus
two is an RNA virus and so like all RNA viruses,
it will mutate over time. One thing though that is perhaps specific to coronavirus is that corona viruses they actually encode for a
protein that actually corrects it's called an error correcting protein that actually corrects for the sequence the viral sequence, it corrects
for mutations that occur in the viral genome errors
that occur in the viral genome. And as a result, it tends
to mutate much more slowly than other RNA viruses. For instance, it's about two to six times more slowly in terms of
mutation the influenza, that being said we do
know that it will mutate next slide please. And indeed, one of the
significant mutations that arose and this began in perhaps a
very early stage of the pandemic in March was the emergence of a variant that we call the D614G
spike protein variant. This is a specific mutation at position 614 in the spike protein and you can see here that this is, this variant has rapidly emerged over time and now it's roughly
thought to be about more than 99% of all circulating
viruses currently, next slide. And indeed of the reasons
why it's been postulated to a spread so quickly is that it has been shown
to increase infectivity in cell culture in animal models. So this is how we typically
investigate as virologists how we typically investigate how, the infectivity or how rapidly transmitted these variants could be. These are studies and I just put down they're actually have
been several studies. I just give you reference to two of them below here in this slide where you can see that this
variant, which is shown in red which is the G614, it's a D
to DDG a amino acid change. You can see that this particular
variant does grow better in cell culture as you
can see on the left. In addition to that, it
also replicates better in a mouse model of COVID-19, next slide. But in the meantime, this
virus is continuing to mutate and as you can see here, what
we're worried about now is that we are now there have
been reported variants which have additional
spike protein mutations. So what I show you here this is a met archive
pre-print which shows you the crystal structure of
the virus spike protein or it actually, in this case it might be the cryo electronic cross a microscopy structure of the
complex of the spike protein with its receptor, which
is human ACE, two receptor. And I want to point out the existence of several additions
mutations that have been found circulating in various viruses, currently in both in the US and globally. So there is a mutation
called the N5O1Y mutation, and this mutation is
particularly concerning because it's a mutation directly within the receptor binding sites. It's the part of the spike
protein that directly binds the binding site to the
human ACE two receptor. So you might expect and understandably when
one thing that can occur with mutations in the
receptor binding site is that these mutations
will enable the virus to enter cells more readily, and in fact, essentially make
the virus more infectious, resulting in perhaps a
greater transmissibility or greater infectiousness. Similarly there have been
other types of mutations and the I'll point out
really highlight two of them. One is what we call a
69 70 deletion mutation, so this is a different
type of mutation where it's not a change in the nucleotide or the amino acid that
makes up the protein. It's rather, it's a deletion
it's where you actually lose a nucleotide or a number of series of nucleotides or
amino acids within the sequence. So, and the reason I'm pointing out the 69 70 deletion
mutation is not because it has a functional
impact, even though it may it may potentially have
a functional impact, but it has been useful
for us with respect to, being able to identify these mutations, because what happens is, this particular mutation makes the tests, the tests that we use for
diagnosing coronavirus negative, at least for tests that
target this particular gene the spike protein, or the
spike gene of the coronavirus. And then the last mutation
I'll be talking about, is the E484K mutation. This is another mutation, which can occur in the spike protein And it's of great interest because this mutation has been shown
to be, to have some relevance to the ability of antibodies,
to neutralize the virus. And so the worrisome
nature about mutations at this particular site
484, is that these mutations which may potentially enable the virus to evade vaccines or
monoclonal antibody therapies. So a mutation that potentially may make the vaccine less effective. And I'll be talking today
about two specific variants, one is the UK variant which is otherwise known as B117, this variant contains the N501Y mutation and the 69 70 deletion mutation. In addition to the D614G
that we just went over, notably both of these variants they still have the D614G backbone as part of the backbone in that, more than 99% of all
circling viruses have D614G. The South African variant
has an additional mutations in the spike protein and the one I'm going to
focus on today is the E484K. Next slide. So this the worry about the emergence of this highly transmissible
UK variant B117, it was initially described actually in the United Kingdom in early September, since then has spread
to multiple countries actually more than 31 countries, including the United States and this is data as of yesterday and you can also see that there is, or as of last week, you can also see that the variant has rapidly
increase in its proportion in terms of the number of
cases in the United Kingdom, currently it began in early November it was only five to 10% of cases, where now it's really, as a
majority of cases more than 60% of cases and perhaps even more
are now this B117 variant. And the other point I want to make about this is that this
is a variant that has a rather unusual number of mutations. You know, I did say that this
is corona viruses do mutate including this one and
yet the rate of mutation is typically thought to be
relatively gradual and slow. In general, we see perhaps
one to two mutations a month. You can see, on average
if you look at the current circulating viruses on average
they typically have anywhere from say eight to 11 different mutations, this is a rather unusual variant in that it's suddenly occurred in England, in September and it had 23 mutations. And I'll talk about the significance of that in the next slide. Next slide please. So this is kind of an interesting question is how exactly do this variant come to be? This is basically a kind
of a genetic divergence map and the general idea is what
we want to do is we want to see as mutations begin to accumulate,
we want to track to see how the dates of collection and we want to see how these
mutations are evolving. And you can see in general,
if you look at the line kind of the lower line, this
is a regression line which basically suggests, and this is the case for the vast majority of the strains that have
been circulating is that there's a gradual increase in
the number of mutated viruses or in the rate, evolutionary
rate of mutations. If you look at this
particular lineage though, it appears to be almost like an outlier, it's basically way above there. It's an as if it's suddenly jumped from having say eight to 10 mutations on average to 23 mutations. So how can this actually occur? And how did it occur? There gave been several hypotheses. We don't have the answer yet. One idea is potentially there may have been mutations and evolution of the virus
within a certain individual. This is what we call
quasi species evolution. The idea is that an individual
may be chronically infected with the virus and may be
unable to fully clear the virus, So this may be the case, for instance for immunocompromised individuals patients who have undergone for instance, a bone marrow transplant. Now we don't know yet whether or not this is really the case but we do know that patients
who are chronically infected with SARS coronavirus two,
they can develop many mutations let's say anywhere from five
to 10 additional mutations during the course of their infection, simply because they have
a prolonged infection or prolonged infectious course, another possibility which
has also been hypothesized is that perhaps this lineage arose because there was separate evolution in perhaps an animal reservoir. There have been some instances of, for instance, human to animal and animal to human
transmission of corona viruses and so the idea is
there've been for instance outbreaks of this particular
virus in mink farms in the UK and in other
countries in Europe. And the idea is that
potentially did this strain or variant arise within
evolution, say within a mink and then jump back from
the mink to a human? So we don't know the answer yet but we do know that there
are plausible mechanisms for how these variants
can emerge, next slide. So how do we actually
test for the variants? And as I said before, what
was quite fortunate is that this particular variant, the UK variant it has a 69 70 deletion. And the idea behind it is that when we do testing for the virus we often the common tests
that are being used, they often target more than one gene. So for instance, a very common test will, there may be a test that
tests for the S gene or the spike gene and simultaneously test for the engine or nuclear protein gene. And typically you need to be positive in kind of either one or in some cases both of those genes for you
to call the test positive. Well, what been noted is
that there's this phenomenon called S gene dropout. And what that means is that
you have a test that's positive for one of the genes of the
Corona virus, say the N gene it's not positive for the S gene, and what that indicates is
that you are still infected with the virus, but you were infected with a variant that
causes this S gene dropout and it just happened, fortunately, that this deletion the 69
70 deletion that's found in the UK variant has this phenomenon that it causes an S gene
dropout in our testing. And as you can see here, this gives you a this is basically the
idea, some laboratory data which shows that there's a frequency of S gene dropout viruses
in the tested US population and you can see here that
what's interesting is that we started to see S gene dropouts in November around the time that we saw the emergence of these variants such as the UK variant and now one screening
method that we're using for identifying these variants at least, the UK variant in the US, is by looking at all of the positive COVID cases which have S gene
dropout on their testing. Next slide. So by doing this type of screening you can see that to date that we've identified about as a nation about 76 total cases of the UK variant, understandably many of
them have identified in States that already
have active sequencing centers that are doing kind
of active genomic surveillance and in fact, the state
where the most cases that may identify primarily from San Diego was in California with 32
cases so far, next slide. So this gives you an idea of the spectrum of how we're identifying these variants and what I show you here in red are actually two variants that my laboratory identified from San Bernardino County
cases of these variants so this was the B117 or the UK lineage. What's important to realize
though is just because you have this S gene dropout doesn't mean that you have you're
infected with the UK variant. You may in fact be infected with a different variant that has that also has the same
deletion like B1315, so that was indeed the case. We ended up screening three patients who had all who had S gene dropout and two of them were found to be of the infected with the
UK lineage, next slide. So I wanna talk about the significance, I mean given that the
focus has been on vaccines, well one thing it has been found that, and this is very reassuring data that Sera or polyclonal Sera which a Sera containing
polyclonal antibodies from individuals who have been
vaccinated have been found to neutralize effectively
the B117 UK variant which is really good news
with respect to vaccines. It's likely that vaccines
will be protective against this variant, next slide. I want to move into the
South African variant, but before I'll probably
end by saying that there is additional data
which really suggests that the UK variant although
it may not hopefully impact the efficacy of the vaccine, this is a variant that's similar to D614G has been shown to be more transmissible as you can see from the
experience in the United Kingdom. So our worry is that if the
outbreak is allowed to continue that there may be a
possibility that this variant may eventually expand and grow
to predominate the population and having a more transmissible variant has a lot of implications
because for one idea is that it may overwhelm our healthcare system given that the sheer number of additional cases and
hospitalizations that may result from having a more transmissible
variant in circulation. The second thing is
that it may also hinder our achievement or achieving herd immunity with the use of mass vaccination,
because we will likely with a more transmissible
variant will likely have to vaccinate even more individuals, interview more people for us to be able to successfully achieve herd immunity. I want to end by talking specific about
the South African variant which is yet another variant,
which is quite worrisome. This gives you an example of the sheer number of
cases that have resulted from the South African
variant in South Africa. This is published data. You can see here that the South African variant
is primarily responsible for the second wave of
infections in South Africa and you can see it's really going up like a hockey puck, next slide. So this South African variant, has its own pattern of mutations, I really want you to focus
on these are actually mutations that are just
in the spike protein as you can see here that
there are quite a few, I mean we're talking eight to 10
mutations in the spec protein even more that here are
found in the UK variant, but a particular interest is one mutation, which is a E4K mutation and spike protein. Next slide So these are also reprints, because this data is very recent but there is a lot of worry
about this particular position this E484 mutation, what
you can see on the left these are neutralizing dilutions, so the idea behind this is
that the way the experiment is done that you have basically engineered viruses that have
this particular mutation and then you determine
how well, the question is how infectious is the material after you treat it with
presumably neutralizing serum. So this gives you, and
these are neutralizing sera from convalescent patients. So patients who already
have polyclonal antibodies they're very generated
antibodies they've been infected. So presumably their
antibodies should be able to neutralize the virus. And so what you can see here is that the viruses that contain the mutation they're sort of like the
upper kind of yellow curve, you can see those viruses are
less able to be neutralized, in other words, they remain infectious even though you treat it
with neutralizing antibodies. And what that really suggests
is that there's a potential for neutralizing antibodies, simply not at least the ones that are made in response to natural infection and maybe even those that are induced in response to the vaccine
may not be as effective against viruses that contain
this particular mutation. Another way of looking at
it was a study that was done on the right, where what
these investigators did was they essentially
mutated multiple positions throughout the spike protein. And they found at which
positions the question was at which positions in the spike protein is there a great effect on the ability of
antibodies to bind to it? And if you look here, when
you actually plot that in when you can see there
in the X, Y plot there you can see that 484 is really high, it's almost like it happens to be a very significant position. And what that means is mutations at 484, are likely have the
greatest amount of effect or impact on the ability
of antibodies to neutralize the virus, at least at that position. Next slide Another way to look at
this is actually to see, how does the mutation actually affect antibody neutralization? So this is a really
interesting, these are really interesting studies where
what you see in panel A this is basically
neutralizing activity of, and this is all convalescent
sera from different patients and you can see here that
based on neutralize activity that as you get to, as you
go from wild type virus to a virus that has a D614 gene mutation, the second row, to a virus that
now has this E484K mutation you can see that the neutralizing activity gets weaker and weaker. In other words, sera
is a convalescent sera. that contained polyclonal antibodies are less effective against these viruses as they develop these
significant key mutations. Another way of looking at it is, the bottom panel where
they tested a variety of monoclonal antibodies against various against a spike protein and similarly, you can see here that as you go from a wild type virus
to a virus that has more of the significant
mutations, you can see again that the activity of the
ability of those viruses of antibodies to neutralize,
the viruses decreases. And this is why, and this is data which is in the laboratory. Now, we still haven't directly shown that the South African
variant or infection by the variant or the potential infection of the variant makes
vaccines less effective, or the vaccine is less protective
against these variants. Although this in vitro
data laboratory data is quite worrisome for the possibility. Next slide. So I just want to end with
kind of three key messages and this is really a
tale of three variants. So the first message is that there is a predominant
circulating lineage. It's a D614G spike mutation and in fact, all of the variants
that we're talking about they all have D614G, it's been
more than 99% of the sequence viruses as of January, 2021. There is a circulating
UK variant, which is now in the known to be in the United States. It has 23 mutations. So at lots of mutations it does appear to be more transmissible, both in by epidemiology
and in the community as well as in the laboratory. There's no evidence so far of any impact on vaccine
effectiveness, which is good news. And it may possibly have
originated for chronically infected individual in
animal reservoir, regardless, it did originate and so
what this suggests is that there is a potential of additional variants
that have these types of mutations in the future. And the last point I want to make is that there is also another variant, the South African variant which arose independently
of the UK variant. It has not been found
in the United States yet but now it is in 11 countries
outside of South Africa. It has even more mutations
in the spike protein and as a result, including
the key E484K mutation, these mutations may allow
this particular variant to evade antibody mediated immunity. And so I think the take home
message is that we're really in a race now And really this increases
only increases our urgency to mass vaccinate the population
and protect the population before additional variants
may evolve and emerge. So I'll end there, and I'll be
happy to take any questions. - Great, thank you, Charles, I'm hoping my internet will hold out. Let's take five minutes
for a few questions. What we saw in the UK was that variant quickly
became the dominant strain. Now that we know it's in the US and I assume far more widespread than we know about it,
because we're flying blind. Is there any reason to believe that it won't become our dominant strain? And we know that it's 50% more infectious so is that sort of an
inevitable thing that it will become the dominant strain if it's the it's the faster runner? - We don't know yet and I'd say for a couple of reasons one is that, it does
have the D614G mutation which does make it more
transmissible already at baseline. But in addition to that pretty much every strain
that's circulating has D614G. So the question is how
much more infectious is it than the currently circulating strain? So that's one big question the second reason why I'm not sure, so there may be a very small difference in terms of the absolute
infectivity difference in infectivity between the UK variant and other variants that
are currently circulating. The second reason is that
currently it appears to be at a very low fraction of
the cases that were current that we and others are sequencing
probably less than 0.5%. And the idea is that it may never go beyond a critical threshold
where you start to see exponential growth, especially as we continue to increase
our vaccine efforts. And as we continue to
follow, hopefully follow social distancing and mask wearing and other public health guidelines there is certainly a possibility that we may keep this variant at bay. So it's not inevitable now that
we have kind of a currently at least as of now, appear
to have a low prevalence, it's not inevitable
that we're going to see it become the predominant strain. - I hope you're right in terms of the South African variant, if it does have these
mutations that allow it to partially dodge vaccination, does that imply anything
about infectivity? And if it doesn't and it's as infectious why would it become a dominant strain or would it be inevitably
consigned to become a readily be fairly small part of the
viruses that we're dealing with? - Yeah the evasion of
vaccine immunity, as I said, it's probably the E484K and there may be another mutation
that we didn't talk about in the spike protein that
may reflect it's perhaps the potential to evade immunity, that does appear though to be
different than other mutations in the spike that may affect infectivity. So, one thing of note is that the South African
variant has the same N5O1Y mutation that appears to
be in the UK variant as well. And that may be the the key mutation that affects infectivity. So and based on the
experience of the cases in South Africa and
explosion of cases there, I would suspect that probably
it is also more infectious and more transmissible. I think what the worrisome aspect of it is that has this additional, perhaps these addition mutations
that may confer resistance to or partial resistant of vaccines. I want to make sure though, I
want to make it clear though that we haven't proven,
that's not been proven yet. It's really been laboratory
data that's been suggestive but where it really needs to be done is is direct data that basically
answers the question of, does it really affect
the efficacy of vaccines? As we commented on before
because of the vaccine, the polyclonal antibodies
that are made by individuals in response to vaccination
can vary significantly. I anticipate that if it
does it have an effect it's not going to be a uniform effect. There may be a slight decrease in efficacy for some individuals and not
for others, for instance. And certainly because vaccination induces antibodies pretty much
against the entire genome it gets multiple sites
throughout the genome. It's, more likely that
if we do see an effect, it's hopefully going to be
a very slight difference and not say a significant
difference that may, for instance require a new vaccine, it's my hope that the vaccine will retain to a larger part, quite a bit of efficacy. - Well let's hope so. Well last question is now that you know that these variants have entered our world at least the UK variant and maybe at some point,
the South African variant what's your recommendation to
people about their behavior? Should they still keep doing
what they've been doing? Should they just be sure that
they do it more religiously in terms of masking and distancing or should they even become more rigorous? If you wore one mask, you should wear two. If you were keeping six feet apart you should become nine
and go nine feet apart. How do you think about that? - Yeah, the way I think about it is that although these variants may be considered to be more infectious or may the evidence suggests that, I mean the virus at baseline is
already very infectious, we already know that and I don't think that the existence of these variants would really
change anyone's behavior in the sense that we still
have to adopt the common sense of public health measures guidelines for preventing infection which include mask wearing, social distancing includes
avoiding large gatherings. I mean, the same measures
that we're currently doing to help prevent spread
are going to be effective against these variants. But I do think that what it does from a public health standpoint it really increases the
urgency of really making sure that people get vaccinated
as soon as possible. So the other thing that I
would highly recommend is that if you are eligible
to receive a vaccine that that you should get vaccinated, it's not only good for you yourself in terms of being protective,
but potentially it may it would be good for
public health as a whole. - Great, thank you so much, Charles, Really appreciate it. It's complicated and important, and thank you for a slightly
optimistic spin on it. Obviously there's plenty more to learn, it's not as if all is lost
from what we've heard. So let me close out. First thing to invite
folks to attend the first of a new series that we're starting today in the department from 5:30
to 6:30 on anti-racism. I will send out an email to everybody in the department
in about 10 minutes. Let me thank my great production team. They are listed there, next week we'll go back
to a non COVID topic, and this will be on the use
of social media in medicine, hosted by our chief
resident, Angelina Dakar and Eric Madera and I
will be on as a guest, Kiersten Bins Domingo and Vinnie Aurora from the university of
Chicago will join us. We'll be back for another
COVID grand rounds in about two weeks, actually
in exactly two weeks. And so until then, please stay
safe and we'll see you soon.
