Immunization Against HIV – A Formidable Task

By Adem Lewis / in , , , , , , , , , , , , , , /

you very much, Sean, for that introduction. And thanks to the
Department of Lab Medicine. And thank all of you
for joining us today. So the landscape of HIV
vaccines over the past 35 years has had many ups and downs. And I’ll highlight
some of those, highlight some of the progress
that we’re making today, some of the overall challenges. And most of this is in
the context of my work at the HIV Vaccine
Trials Network, the HVTN. I also, as Sean mentioned,
am the medical director of the Seattle Malaria
Clinical Trials Center where we infect altruistic
Seattleites with malaria to evaluate drugs and
vaccines and also run a lab that investigates the role
of the microbiome in training the immune system and
influencing vaccine responses. So one cannot really talk about
HIV without providing some context and background
to this enormous pandemic that’s occurred and probably
started over a hundred years ago in several trans-species
transmission events from non-human primates to humans
and the subsequent dramatic distribution of what became
human immunodeficiency virus around Central African Republic,
the Democratic Republic of Congo, and via Kinshasa
to the rest of Africa. And from this article,
you do see the two groups, group M and O, of HIV
that spread dramatically within that region. And the article does
highlight as well that iatrogenic or
physician-caused medical interventions
in Kinshasa and its surrounding area
probably contributed to this dramatic
distribution of HIV. And indeed, when I
was living in Malawi with my family
for three years, I was investigating
the interaction between HIV and malaria. And of course, one of
the most dramatic upticks of HIV among children
who had malaria was transfusion-related
HIV acquisition when they were transfused
for severe malaria anemia. But we’ve seen that when HIV
really emerged in the United States, it was indeed isolated
among predominantly gay populations in San
Francisco and in New York in the coastal areas,
a few sporadic cases in the middle of the country. But because of that demographic
and because of the time, there was a tremendous
amount of stigma that was related to HIV and,
in fact, some tragic delays in attending to the urgent
public health crisis that was emerging in the 1980s. And indeed, many
of the characters who were present at that
time are still with us today, such as the former
mayor Rudy Giuliani. And the delayed response
to the HIV epidemic as it was observed at
that time was the result resulting from that was
really a tremendous activism and advocacy effort that
prompted the FDA to take a great deal of action. And I attended this quilt
on the National Mall in Washington, DC, in 1987. It was a very emotional
and heavy event. The quilts covered almost
the entire National Mall. In 1996, it expanded
even further, of course. And subsequent to that,
they could no longer hold this event
in Washington, DC, because there simply were
too many quilts for those– recognizing those who
passed away from HIV. Fortunately, we’ve
come to recognize some of the complexity
of the virus, investigating the virology,
the immunology that surrounds HIV vaccine research. And on the left, you see an
image generated by Bette Korber over 20 years ago
that was highlighting the tremendous diversity of HIV. In the large aquamarine
outlined area, you see the diversity
of HIV as it was represented in the
Congo in a single year, and upper left, the
global influenza diversity in that
same period of time, and a more recent
publication on the right highlighting the tremendous
diversity of glycosylation and of sequence variation that
exists within HIV compared to influenza or RSV
virus, this providing one of the most significant
challenges to developing an HIV vaccine. Now fortunately, we have
seen tremendous progress in HIV therapy. And in contrast to those
years in the late ’80s when I was working in New
York City in which all of the young men who looked
like me were under hospice care, we saw in the ’90s a
tremendous advance with regard to HIV therapy. And I’ve highlighted
in the figure on the left some of
the seminal events that were very significant for
advances in laboratory medicine with regard to HIV diagnosis,
testing for HIV viral loads, and FDA-approved tests to
identify resistant strains and profiles of viruses
to better manage those individuals who
were HIV-infected. And on the right, we see the
HIV medication chart for 2019, this year, and the tremendous
diversity and combination antiretrovirals,
single pills that can be taken by individuals who
are HIV-infected, controlling their HIV virus,
which, of course, when I was in medical
training was just a fantasy. Now throughout
the past 30 years, HIV has provided us a tremendous
opportunity to work globally and to enter into
communities who are heavily affected by HIV. And this exists in practically
every country around the world. And indeed, HIV
and AIDS research has claimed to provide the
foundation for what many of us are now calling global health. But the stigma
and the challenges of working with these
communities has not gone away. This is just from two years
ago, ACT UP protesters in New York demonstrating
against Uganda’s controversial
anti-homosexuality bill. We work in Uganda. We work in sub-Saharan Africa. And the sensitivity
around working especially among men who have sex with
men, transgender populations, and commercial sex workers
makes our work that much more challenging,
especially in engaging with these
communities, obtaining adequate informed
consent, and working on these HIV vaccine efficacy
trials in these communities. So where are we in 2019? Well, on the left, we see
the figures highlighting the 90-90-90, the
UNAIDS target for 2020– that’s just next year– identifying those
who are HIV-infected, 90% of those, putting those
90% on adequate antiretroviral therapy, and hopefully
suppressing 90% of those such that their viral loads
are below detectable. But still, there are globally
over a million new infections annually. That’s 5,000 acquisitions a day,
over 180,000 newborns infected, 37 million people
living with HIV. And that number just
continues to grow as we’ve made tremendous
advances with therapeutics. And now, only 770
million deaths in 2018, which is down now
below the millions that it was every year for the
past 30 years and surpassed, as you may know, recently by
TB being the most significant infectious– single infectious
agent causing mortality worldwide. So why an HIV vaccine? Why is an HIV vaccine
necessary in the context of such successes with therapy? As Tony Fauci and
Hilary Marston stated, ultimately, we believe
the only guarantee of a sustained end
of the AIDS pandemic lies in a combination of
non-vaccine prevention methods and the development of a safe
and effective HIV vaccine. And the need for an HIV
vaccine persists even with the very recent data
that’s come out this summer on treatment as prevention. There were three publications
in The New England Journal on July 18 highlighting both
the progress and the limitations of our expectations and making
progress against the pandemic with treatment as prevention. Now U equals U is
a correct equation. That’s undetectable
equals uninfected– uninfectable. And that is those
individuals who do have adequate treatment
who are suppressing their viral loads are
not transmitting HIV to their partners, which
is a tremendous advance. PrEP, pre-exposure prophylaxis,
has worked very effectively, especially among MSM populations
in pockets in the United States and in Europe, in some
areas in South America, and in southern Africa. But significant challenges
remain with regard to the further deployment
of PrEP worldwide. And just today, the
Office of AIDS Research released a report stating,
to bring about a lasting end to the global pandemic, we
must continue research efforts to find a safe and
effective vaccine, echoing what Tony Fauci
said five years ago. So the impact of an HIV
vaccine is very significant, even if partially effective. And we’ve seen recent advances
with a partially effective malaria vaccine. However, malaria is curable. HIV, with the exception
of the balloon patient, has not been cured. And so when we look at the
projections and the models of using a partially effective
vaccine in combination with these prevention
modalities that already exist, we see a dramatic reduction in
the number of new infections that occurred worldwide, the
number of deaths that occur, of course, the incidence
dropping precipitously with and effectively-deployed
vaccine. And we’ve also
recently published on how cost-effective
an HIV vaccine is compared to other
standards of care, PrEP, or PrEP combinations. And the cost of HIV therapy
and the different prevention interventions that are used
around the world is in the tens if not hundreds of millions
of dollars annually, very significant,
significant dollars. So how do we go about
developing a vaccine? On the left is it a
cartoon illustrating the many different
strategies that one can use to develop a vaccine. We’re not pursuing whole
inactivated HIV virus vaccines. There have been some efforts
directed toward that. But fundamentally,
the community feels that is simply too risky for the
virus and the sequelae of HIV infection. And there are several different
endpoints or potential outcomes of an HIV vaccine. Of course, we can
prevent HIV acquisition. This is a cartoon about
potential endpoints for an HIV vaccine efficacy trial. If there is prevention
of acquisition, quote, “sterilizing immunity
induced,” then you would see no infections
in the vaccine arm. If the vaccine arm can
prevent systemic infection or potentially abort
that infection, we would see a transient
infection, but eventually elimination of that
virus from the body, or preventing HIV disease. And that is as some of the elite
controllers have demonstrated, the immune system can
suppress HIV if sufficiently directed against critical
epitopes in the virus. So to provide the context
of where we are today, I think it’s very important to
describe a couple events that have led us at
this point in time, especially these two tectonic
events that have occurred in the past decade. The Step and Phambili
trials, which I’ll describe to you briefly,
demonstrated no efficacy. And then there was
an actual increase in acquisition in the
active arm versus placebo. And fortunately, the RV144
Thai trial, as it’s called, demonstrating 31% efficacy
in reducing acquisition in the vaccine arm. And we at the HVTN have
been involved in both of these vaccine trials. The first one was
run by the HVTN and sponsored initially by
Merck and transferred to Dates at NIH, the second one by the
military HIV research program. And we have worked
very closely with them in much of this follow-up work. So on the left is a
table that highlights the risk of HIV
acquisition over time by Ad5 and circumcision status
in the Step clinical trial. Now this clinical trial used
the adenovirus type 5 vector that had gag, pol, and nef
genes stitched into that vector. There were no envelope proteins
or genes in the vector. And you see that
the hazard ratio is increased in this
subpopulation who were uncircumcised
and Ad5 0 positive. That means they had pre-existing
immunity to the Ad5 vector. That immunity, especially
in mucosal surfaces such as the foreskin,
likely provided an increased acquisition of
HIV into those CD4 T cells. And we see on the right the
fact that fortunately, the HIV acquisition decreased over time. The vaccine regimen was
completed at six months. It decreased over time
by 12 to 18 months. And those individuals were
no longer at persistent risk. Now we do obviously have to
take this very seriously. And engaging the community
and communicating with the community and
the study participants forced us into this
remarkable equipoise in which we had to
explain we did not know that this was going to
be an outcome of this vaccine clinical trial. And the experience
really forced us into a much more
community-engaged exercise than we would have anticipated. Now that said, it also
generated an enormous amount of basic science biological
research trying to understand why such an event could occur. In large part, there
were vaccine studies that were stopped. There was no progress
moving forward into any further
vaccine efficacy trials. And we really had to
reevaluate the strategies that we were undertaking to
induce immune responses that we thought would be
protective against HIV. And indeed, this impacted the
fields much beyond HIV research and even impacted the Ebola
vaccine development plan. And that was highlighted in
this article in Forbes magazine because there was a
tremendous momentum to try to deploy Ebola vaccines
during the epidemic of 2014 and ’15. And indeed, Tony Fauci
highlighted the Step study as an example as to why a
placebo-controlled randomized clinical trial is so important. Fortunately, about
a year afterwards, the Thai trial results were
published in The New England Journal. And we see here a
significant difference between vaccine and placebo
with the probability of HIV infection being
lower in the vaccine. And this estimated
vaccine efficacy over time is illustrated in the
figure on the right. And you see that
vaccine efficacy appearing to peak over
50%, potentially 60%, and also waning over the
course of 12 to 18 months. The overall vaccine
efficacy is reported as 31%. But again, it’s during this
critical period in the first 12 months that we saw a
relatively high vaccine efficacy of upwards of 60%. And this vaccine was
a unique combination of a pox, ALVAC canarypox
vector with a protein boost, the AIDSVAX
gp120 protein boost. So there was a tremendous
effort in trying to interrogate what may be
the correlates of protection for this vaccine. And when we talk about
an immune correlate, this is a central goal
of vaccine research. It’s one of the major
grand challenges that the Gates Foundation
and the NIH have identified. And it’s something
that is incredibly useful for shortening trials,
reducing costs, guiding the entire development
of vaccines. When you have that
biomarker that’s a correlative protection,
you can take it from 60% and iteratively
investigate early phase clinical trials
in just a handful of people to optimize that
correlative protection such that you can project a
vaccine efficacy beyond 90%. Now we don’t have that
confirmed for an HIV vaccine. But there are many
examples of vaccines that have identified a
mechanistic correlative protection, or a non-mechanistic
correlative protection but still is reliable for
these types of correlations. And I illustrate some
of these examples here just to make it
clear that sometimes, both mechanistic and
non-mechanistic correlates of protection are known. And sometimes, neither are
known, or only one of them is known. Yet nonetheless,
these are incredibly useful to further the
vaccine development of this particular candidate. So for the RV144 trial,
an intensive investigation of these correlates of
protection were undertaken. It took over two years
and tremendous effort of about 30 labs around
the world validating these endpoints reproducible,
if not validated, then qualified assays. And one of the
significant correlates that fell out of that is
the V1V2 gp70 scaffold. And this is a part
of the gp120, part of the trimer that
is the envelope protein on the surface of HIV. And indeed, those individuals
with a high V1V2-binding antibody assay demonstrated
vaccine efficacy of over 70%. So when we look at how
then to carry this further, we also looked at subsequent
samples from that study. And that initial New England
Journal article publication on the correlative
protection was followed up by about 30 additional
publications investigating this V1V2 correlate. And much of that work was
done by sieve analysis. And that is illustrated in this
cartoon that highlights that simply with a natural
barrier that each of us have for preventing HIV acquisition–
and it may be only one in a hundred exposures
that truly results in HIV-established infection– we have these natural mucosal
barriers and immune barriers. And we see a
certain distribution of infecting strains
among the population in these natural cohorts. Ideally, when we see a
vaccine-inducing effect, we see pressure against the
virus and only a limited number of strains then infecting
those individuals who do become infected who
have received the vaccine. And it’s in those
individuals who have received the vaccine,
yet who have acquired HIV, that we’re looking for
critical comparisons to those individuals
who receive the vaccine and did not acquire HIV. So a central question
post-RV144, the Thai trial, is can we extend these findings? Can we increase the
vaccine efficacy and increase the durability
of that efficacy? Can we extend these findings
to other populations? The Thai trial was conducted
as a community-based clinical trial among 16,000 Thais
at primary care clinics who had all sorts of different
risk for HIV, most of them not at significant risk
for HIV acquisition. So when we think about
transferring this to a high risk population
such as in South Africa, who generally have a
higher viral load, a higher viral load within individuals,
but also as estimated in the community, these
are significant challenges. So these were some
of the questions that we were posing
after these– after the initial RV144 results. And what I’m going to
do now is walk through a number of the novel
efficacy strategies that we currently have
underway within the HVTN, first highlighting
HVTN 702, which is the follow-on
study to the RV144. And this study could
not have happened without a very large
collection of partners, the P5 partnerships, pox-protein
public-private partnership. We’ve said that a
few times quickly. And this is
dedicated to building on the Thai trial results. Having such a large collection
of partners can be good. But it also can be quite
challenging in herding these fairly large
behemoth partners into the direction of an
efficient clinical development plan for an HIV vaccine. But the real strategy was
foundational to building on these RV144 results. We had a new construct
of ALVAC made that was focused on
the clade C virus, a new construct of
bivalent proteins manufactured that
were also subtype C. These were gp120 proteins. And then added a
booster at 12 months to hopefully improve
the durability of these immune responses. And these are some of the
clinical trials 097, 100, and ultimately, 702 that we’ve
progressed through to evaluate the potential efficacy of
the pox-protein combination. We did establish very firm
go/no-go criteria to move into the large clinical trial
called HVTN 702 or uhambo. And that clinical
trial has enrolled– it completed enrollment
in June of this year– 5,400 men and women
in South Africa with a one-to-one randomization
of vaccine to placebo. Initially, the vaccine regimen
included the prime of ALVAC at months 0 and 1 and a booster
of ALVAC plus protein at months 3, 6, and 12. And this is a cartoon that
illustrates what we’re really trying to target, the area
under the curve, of what we’re expecting to be the protective
efficacy of this vaccine. And now, as you see
here in the top, we have a vaccine efficacy
at six to 12 months in RV144 estimated
to be about 60%. The observed V1V2
correlative protection was 64% at six and a half
months from that clinical trial. We observed 63% at six and
a half months in HVTN 702. That increased to 72%
at 12 and a half months. And we needed to
achieve an observed– observe a vaccine
efficacy greater than 50%, needed V1V2 responders
of 69% at 24 months. Unfortunately, we saw the
vaccine correlate protection, putative correlative protection,
these V1V2 markers, decrease considerably and precipitously. Many of the binding
antibodies persist for months, if not years. But some of them
decreased very rapidly. And that included
the V1V2 responses. So we looked at how best to
optimize this and improve to ensure that we
had an opportunity to do the correlative
protection analysis from this clinical trial and
added the booster at month 18 to provide that
additional vaccine boost to the V1V2 biomarker,
which will hopefully provide sufficient data for
the correlates analysis that we’re anticipating. As I mentioned, we
completed enrollment in June of this year. On the right is our
number of visits per day by month at the
average number of visits a day that some of these
sites have taken on. Some of these
clinical trial sites have enrolled hundreds of
individuals within the studies and, as you can see there, each
day may see up to 200 people. We’re now, of course,
past this hump and are looking forward to the
upcoming interim analyses, some of which are based on futility. We’ve made it through those
interim analyses that would have detected potential harm. So we know the vaccine is
not increasing acquisition. And hopefully then, we’ll
see some vaccine efficacy that we can interrogate
further for confirmation of a correlated protection. The second strategy
that we have underway is a neutralizing
antibody approach. And this is based on a passive
immunoprophylaxis strategy. It’s why the title of my talk
was focused on immunization against HIV, not
simply vaccination, because passive
immunoprophylaxis has been used for many years. There’s a long history
of using antibodies to prevent infection,
or disease. And many of these
interventions have been developed into
products for a number of different indications. And most effective
vaccines induced antibodies that neutralize the pathogen. Now fortunately,
over the past decade, we’ve seen a
tremendous explosion in the isolation of broadly
neutralizing antibodies against HIV. Despite the work that was
done in the ’80s and ’90s, there were tremendous
recognition of swarms of antibodies
that were binding to HIV. But very few of them, if
any, were neutralizing. But now, we have many of
these neutralizing antibodies. They’re broadly neutralizing. And they have been developed
into monoclonal products. So antibodies can teach
us an enormous amount about vaccine development. And we’re focused on these
passive immunoprophylaxis strategies to not
only potentially use these monoclonal
antibodies as a product to prevent HIV acquisition
if we can improve the half-life of
these antibodies, if we could include them
in some kind of depot that goes into the arm and
extends the distribution of those antibodies over the
course of months, if not years, but we’re also very interested
in how then we can apply the knowledge gained from
passive immunoprophylaxis to active vaccination
strategies. What levels of these
antibodies would be required to protect HIV acquisition? And is it possible to
actively induce these broadly neutralizing antibodies? So the first monoclonal
antibody broadly neutralizing that went into humans
was called VRC01. This is a CD4 binding
site antibody. It was developed by the
Vaccine Research Center. It demonstrated very effective
prevention of acquisition in the non-human primate model
for both rectal and vaginal challenge. And we now have a
tremendous opportunity to learn more from a proof
of concept in humans. And as I’ve mentioned,
what level of antibody, what level of
neutralizing antibody is needed to prevent infection? Could we potentially convert
that monoclonal antibody level to serum levels of
neutralization that are needed to protect
that we could measure from active vaccination? Just a couple of
the potential tools that we could use
from these antibody mediated prevention
studies or AMPs. These are the first trials to
assess if antibodies can be used to prevent HIV infection. The two AMP trials that are
currently underway essentially are using the same
product VRC01. They’re given every two
months through an IV infusion at two different
doses, again, to try to focus in on what is the titer
of antibody that is required to prevent HIV acquisition. As you can see,
we’ve enrolled now it’s over 4,600 individuals
around the world. This effort has required an
enormous troupe of individuals around the world. We’ve given over 40,000
infusions of VRC01. There were kilograms
of monoclonal antibody manufactured by the
VRC that were required for these clinical trials. And we’re still underway. I mean, we’re very intent
on trying to, of course, address the primary objectives,
the safety and tolerability of VRC01, given the tremendous
growth in monoclonal antibodies as products over the
past two decades. There’s a tremendous
amount of data on how tolerated these products are. Some of them are not
tolerated very well. We’ve seen in these 40– over 40,000 infusions very
few infusion reactions. And so the monoclonal antibody
appears to be very safe. And ultimately, we hope to
determine the concentration of the antibody that may
prevent acquisition and provide some insights into
the mechanism, the mechanistic
correlates of protection. Is it dependent on Fc
binding to the antibody by other immune cells? So this study was
fully enrolled. We announced that
almost a year ago. And as you can see on
the right, the number of visits at each of– at all
of our sites is decreasing. It’s almost completed in the US. And we have no follow-up
visits in South America and South Africa. Lastly, I’d like to
highlight some of the work that we’re doing in
partnership with Janssen. And they are a
recent participant in HIV vaccine development. And we’re very thankful
for that because they have focused on a new
platform and technology. It isn’t directed at
inducing broadly neutralizing antibodies. So it is similar in that respect
to the P5 program in that it is focused on the induction
of non-neutralizing antibodies that yet may prevent
HIV acquisition. And we, similarly
to the P5 program, identified go/no-go
criteria in moving forward. These criteria
were– have recently been published and are based on
the non-human primate challenge studies that demonstrated
significant protection when administered this Ad26 vectored
vaccine in combination with HIV envelope proteins. And so the first study, we
started Imbokodo, again, in southern Africa,
entirely in women, 2,600 women randomized
one-to-one and followed– will be followed for
at least two years up to three or more years if a
significant vaccine efficacy is found so that we can
be sure to assess the durability of
the vaccine effect. This strategy is
an interesting one. I mentioned the Ad26 factors it
includes gag and pol, the two non-envelope genes of HIV,
but also HIV envelope, not only that which is
a clade B-like envelope, but a mosaic antigen. And
then the boost of the vaccine regimen is the
Ad26 in combination with the gp140 clade
C trimer protein. And this is the first time
that a trimer envelope protein has gone into an
HIV vaccine efficacy trial. So we’re very
excited about that. And then we have an
upcoming clinical trial that I’ll also
describe for you that has added on this additional
mosaic envelope protein. And these mosaic
constructs are, again, back to Bette Korber,
who provided us tremendous insights into
the diversity of HIV 20, 30 years ago. She’s been
influential in helping us design vaccine inserts
and envelope proteins that reflect the tremendous diversity
of HIV around the world. And that diversity
is, of course, illustrated here
in South Africa, where HIV incidence and
prevalence is highest anywhere in the world is
predominantly clade C. And the Ad26 vector has
these mosaic gene inserts. And then the trivalent gp140
protein and the mosaic protein are all reflective
of this diversity. So we have now HVTN 706,
which is the MOSAICO study, starting in the Americas
and Europe next month. Or rather, this month now. We’re in October. We’re slated to start by
the end of this month. And this will target 3,800
participants, predominantly men who have sex with men and
some transgendered populations randomized one-to-one,
1900 in each arm. So conducting these
clinical trials, especially in the age of PrEP
and this HIV prevention tool box, is not an easy endeavor. And so we anticipated in HVTN
706, which we’re just starting, some significant
challenges in trying to find individuals who were
at risk for HIV acquisition. And in the Americas and
in many parts of the world and in Europe where PrEP
uptake is very high, we know that it
works effectively. If you’re adherent to PrEP,
if you’re taking daily PrEP, you’re not at increased
risk for HIV acquisition. The effectiveness of PrEP is
incredible if you’re adherent. So we convened
this meeting a year ago to try to get community
input on how do we move forward identifying trial design and
different approaches that can provide us direction? And there was a tremendous
discussion with community, with advocates, with the
scientists, with the funders about how best to move forward. And fundamentally,
it came down to this what they described
as a mosaic of options that we needed to provide
people in these communities to determine whether or not
they were truly at risk for HIV. And a fundamental thing there
is the importance of choice– conducting trials of new
products in individuals not successfully
using oral PrEP. But that can be
quite challenging, especially in
resource-constrained areas or in vulnerable
populations, who may not have ready access to PrEP. So you need to provide that PrEP
before they enter the study. And that’s something that
we’ve undertaken intensively over the past year in working
with communities in trying to understand how
best to provide PrEP in these communities so
that individuals can assess whether or not it’s for them. Much of the PrEP
work that’s been done demonstrates that up to 50%
of individuals who go on PrEP are no longer on PrEP
after three months. Now are their sexual
risk behavior indices changing after
those three months? Most times not. They still remain
at risk for HIV. So that’s one
mechanism which we may be able to funnel individuals
into our clinical trials is ensuring that PrEP is
available in the community. If they stay on PrEP, fantastic. They’re not at risk. They cannot be in a
vaccine efficacy trial. If they drop off PrEP
for whatever reason, we would consider them
for the efficacy trial. It raises a tremendous amount
of ethical, moral, educational issues in working in
these communities. And we’ve undertaken
that over the past year. The HVTN Community
Engagement Model relies on foundational community
education and recruitment efforts ensuring that
consent is very clear. We develop videos for these
people, and, of course, reconsenting and ensuring that
we can retain these individuals over time. So with that, I’ve highlighted
these four main strategies that we’re
undertaking right now. This will be a pivotal
event later this month. It will be the fifth consecutive
running vaccine efficacy trial for HIV. In the course of
the pandemic, there have only been five
other efficacy trials. And we now have five of
them running concurrently. The operational logistics
required to conduct this work is highlighted here by the
number of clinical trial sites that we work at in the
Americas and Africa. We’re also going to be working
in 706 in Italy, Spain, and Poland. And the number of enrollees per
year illustrated in the middle highlights the ebb
and flow of how one has to manage these
large clinical trials. This is the site activity
that we projected out over the coming years. It highlights, of
course, the peaks that occurred in 2017 and 2018. But what happens
in the future is largely dependent on what
we observe in these five efficacy trials, some of
which will be providing us results in the next 12 months. And it’s in a landscape of
complex biomedical prevention that includes other modalities,
such as vaginal ring. I mentioned the oral PrEP. Long-acting injectables
will be providing results in January of ’21,
and, of course, the antibodies and
preventive HIV vaccines, which I’ve highlighted. While all of this large
efficacy trial work is ongoing, we have a very robust
broadly neutralizing antibody active vaccination
program very early in phase 1 clinical trials. We have a number of
different approaches to that focused on
stable trimers in vaccine designs, a
lineage-based vaccine, strategies targeting
the germline to induce broadly
neutralizing antibodies, and some of these
epitope vaccine designs using very unique
constructs and scaffold vaccines. We’re looking at experimental
medicine strategies to conduct these clinical trials
as rapidly and iteratively as possible. And this is simply a highlight
of some of these early phase 1 products that we
anticipate to put in the clinic in the
next 12 to 18 months, all of this in the
context of interrogating the immune responses. And this is highlighting– this
figure highlights the HVTN Lab Center’s development of
assays from 2012 to 2019 across these four
broad categories of assays genetic
mucosal, humoral, and cellular responses. And Julie McElrath
and the lab team here have really advanced
the field tremendously as far as how to interrogate
the immune system in both its response to vaccines
but also, of course, in its response to
a natural infection. And for lab medicine, one of the
significant challenges for us happens to be the induction
of these immune responses. And this is an illustration
of the fifth generation of HIV diagnostic assays
that have been developed over the past 30, 35 years. And we’re expecting
and hoping that there will be a significant
sixth or seventh generation in the coming
years in large part because vaccine-induced
seropositivity and reactivity is a very significant ethical
and regulatory consideration that we must take. And this is the induction
of antibodies against HIV that are also reactive in
an HIV diagnostic test. Individuals are not infected,
but they are reacting positive to some of the tests. So that’s what we call VISP. Implications of
VISP test results can range across the
spectrum of potential harm and discrimination to
challenges with pregnancy, being placed on antiretrovirals
when you’re not infected, and even potential for
unblinding unnecessarily or inappropriately in
the conduct of a RCT clinical trial. These tests are very common. They’re not common
with some vaccines. Some may attribute
that to them not being very effective at all. Some of them induce
very high levels of these antibodies that
are durable in years, if not decades. So it’s going to be a
significant challenge for us as the field evolves. And of course, we’ve
developed an enormous amount of resources for participants
and health care providers to ensure that they’re
informed with this. So I go back to the potential
impact of an HIV vaccine. These are two publications, one
from 2007 on the left and one recently just two years
ago in PNAS highlighting the tremendous impact a
partially effective HIV vaccine will have. And I’d like to close
highlighting much of the HVTN resources that exist
for clinical laboratory by social, ethical
investigations. And we have a treasure
trove of data. All of these different
product types have been tested in over 75
clinical trials in the HVTN. We cannot do this work without
tremendous collaboration with scientists, social
behavioral scientists who– humoral and geneticists
and virologists. And there are unique
opportunities, whether it be within
the local CFAR Center For AIDS Research, some of
the many announcements that come out of NIAID and NIH
and other funders, especially around early stage
investigators. And that is something
that we’re also trying to nurture and
encourage within HVTN. We recently, in the past year,
provided our specimen inventory at and
have over 2 million specimens and, of course, a
tremendous amount of data that exists there. And with that, we’d
like to thank mostly our study participants, the
tremendous teams that we work with around the world,
and thank you very much. [APPLAUSE] Open it up for questions. Yes. AUDIENCE: Thank you for that
very excellent and fascinating talk. Given how much uptake that
there is of the PrEP currently, how would you respond to the
six cases of PrEP failure in people who are known
to be highly adherent? Do you think that are there
concerns that, eventually given the high uptake of PrEP, that
HIV strains may eventually be selected for
resistance in the future? JAMES KUBLIN: Thank
you for the question and repeating it
for those online, the question is,
what are our thoughts about the uptake of PrEP,
particularly those six cases recently reported
that were breakthrough infections among individuals who
were highly adherent to PrEP? And did I reflect your question? AUDIENCE: Yes. JAMES KUBLIN: So there is
a very well-known history of antiretroviral
resistance with HIV. And it’s not that
surprising that it will occur, even among those
who are highly adherent to PrEP. The PrEP landscape is likely to
try to stay ahead of that curve and respond to it by
developing novel drugs. At the International
AIDS meeting this past summer,
there were compounds presented from early
phase studies that have remarkable activity
against the virus with very long half-lives. How they’re applied,
how safe they are, what sort of adverse events
occur in these clinical trials have yet to be determined. But similar to drug
resistance, we’re also concerned about vaccine
resistance, vaccine strain resistance. And that’s been illustrated in
malaria vaccines, of course, which I’m very close to. It’s been illustrated
in dengue vaccines. So it is a natural,
in my opinion, biological conundrum
that we’re going to have to stay ahead of
as we evolve our prevention modalities, whether that be
under antiretroviral-based or immunologic-based. Yes. AUDIENCE: Thank you for
a very exciting talk. The emphasis that
you presented is on antibody-mediated protection. Is there a role,
do you think, still for looking at T cell responses? Or is this all going to be ADCC
and cells helping antibodies? What’s your thought about that? JAMES KUBLIN: That’s
a great question. Well, I love CD4 cells
because you wouldn’t have good antibodies without them. Apologies to those T cell
biologists out there. I didn’t highlight that
sufficiently today. Antibodies are
dependent on T cells. And T cell responses are
going to be critical. Indeed, from RV144, there was a
polyfunctional T cell response. It also was significant
correlative protection. And of course, we’re looking
at that in the P5 program and anticipate that there will
be T cell correlates as well. I think that the hope– the Merck vaccine,
the MRKAd5 vaccine, was directed at
eliciting T cells. And I think it is a very
significant challenge to rely solely on T cells. I do think we need both. AUDIENCE: I have a question. So you mentioned that
in sub-Saharan Africa, viral loads tend to be higher. So that’s one thing. Is that just access
to care question? And then given all the
differences in clades, is it unreasonable to
say that you actually need a geographically-specific
vaccine? Because like in microbiology
we tailor antibiotics. We say microbiology is
local like politics, right? And we would love one vaccine. But is that– JAMES KUBLIN: Is it really
feasible to have one vaccine, or do we more
pragmatically have to rely on strain-specific vaccines? I think that the mosaic
constructs that we’re currently testing will help
us answer that. The P5 program HVTN 702
does not have these mosaic. It is clade-specific. And one can look at in
these sieve analyses the genetic distance between
the strain and the vaccine and the strain that
is circulating, or that is in the
infected individual. So I think we’ll gain a
tremendous amount of knowledge as the results of
these efficacy trials emerge over the next
two to five years, it will help answer
that question. Ideally, no. We can rely on these mosaics. We may have to reconstruct those
mosaics as the pandemic evolves in the coming decades. But that’s the strategy. Noah. AUDIENCE: Sort of a follow-up or
correlate to Sean’s question– what is the regulatory framework
for developing these vaccine products? And is that framework up
to the task of supporting the development of
geographically-targeted vaccines, or vaccines that
have to change over time to accommodate changes
in the population structure of the virus? JAMES KUBLIN: Right, so is
the regulatory framework sufficiently prepared
for the potential of strain-specific HIV vaccines? Well, we see flu vaccines
come out every year. And I don’t think we’ll
need them every year. I mean, that would
be quite a challenge, especially given the biological
complexity of these vaccines. And as you’ve seen, the regimens
are also fairly complex. Now the intent and
why I emphasize so much these correlative
protection is because if we can simplify the regimen, that
makes the implementation of these that much
more feasible. And we’ve seen
significant challenges to the implementation
of HPV vaccine and other highly
effective vaccines that are not deployed sufficiently
in target populations. So I do think the
regulatory framework and the regulatory bodies
will be prepared for it. But it will require a
tremendous amount of work and also sufficient
surveillance of, of course, the circulating
strains that do exist. And there’s a fair amount
of that going on now. But in the broadly
neutralizing antibody arena, whether it be passive
immunoprophylaxis or active vaccination to
induce those being absent, that will also be a
critical component to try to stay ahead
of waning vaccine efficacy as a result of
the evolution of the virus around the vaccine. Yes. AUDIENCE: So I was
wondering about whether you think that the
correlates of protection might actually be different
in different populations so if different risk factors
might cause certain factors to be more or less important. JAMES KUBLIN: No,
that’s a great question. I think it’s very– and that question
is whether or not it’s feasible or
likely that there would be different
correlates of protection among those different
risk populations. So I could envision the
biological protection that occurs in the
rectal mucosa may be somewhat different than
in the cervical mucosa. And the type of effector cells
in those different anatomic compartments may be unique. That is something that we
will also be investigating. We have a tremendous
mucosal immunology program within the network
that is collecting biopsies and biopsies from
just about everywhere. And so I think we’ll be
able to interrogate that. But of course, it
can only be done in the context of these
vaccine efficacy trials, where we have a signal. So stay tuned because these
results will be coming sooner than often, we think. AUDIENCE: Do you see a
therapeutic misconception among some of your
high risk populations where they figure, I’m
in a vaccine trial, and they up their
risky behaviors? And how do you correct for that? How do you deal with that? JAMES KUBLIN: Yeah, so
the question is, do we see therapeutic
misconception that is a risk modification because
people are participating in these clinical trials? And we do have, as I
mentioned, a pretty significant social behavioral
research program. We’re excited to
collaborate with people who have unique ideas and
want to join that effort. We have observed both–
and in large part, this goes back to the
Step study in which we did see increased acquisition
of HIV among the vaccine recipients. And so we did– there was an intensive
interrogation of all of the social
behavioral data that we had and biomarker
data potential exposures in those populations. We saw that when individuals
came into the study, their risk in both vaccine and
placebo came down in both arms. It remained– it came down
in the first six months and then started
to creep up again. And I think that’s a
attribute to the clinic staff and the prevention
counseling that’s provided in the
context of enrolling into the clinical trial itself. And I think we’re
very clear that we don’t know if this is going to
decrease, not work, or increase your risk of HIV acquisition. And of course, we
don’t know if you’re getting vaccine, or placebo. That’s one of the concerns
about the vaccine-induced seroreactive positive issue. If people are
unblinding themselves, and they then know they
received the vaccine, will they disinhibit
their behavior? And we monitor
that very closely. Do one more question. AUDIENCE: Yeah, I was impressed
by the kilogram quantities of monoclonal antibody. Could you tell us a little
bit about that antibody because at first pass
with all the glycosylation variations that you pointed out
at the beginning of your talk, it’s not
straightforward to think about a monoclonal
antibody being efficacious. But it’s an awesome tool
if you have a great one. JAMES KUBLIN: It is an awesome
tool if you have a great one. And the VRC01 monoclonal that
was now identified over a year ago, I have a slide
that illustrates the immense progress
that was made just in this decade
identifying that from an elite
controller from Africa, isolating that monoclonal,
producing it in milligram quantities to evaluate
it in non-human primates, expanding its production into
thousand-liter bioreactors, and cranking that out
over the past four years. And at one point, we had
to slow down enrollment into the clinical trial
because there was not sufficient volume of material. Since that time– and
we could spend an hour talking about bNAbs, broadly
neutralizing antibodies– there are other
antibodies out there that are so much more highly
neutralizing than VRC01, and modifications to
these antibodies to the Fc region in particular that
extends the half-life two, three, four times
more than VRC01. So the technologies that
we have now, or in 18 months, or 12
months from now when we have the results of these
AMP trials and specifically, of course, when you put two or
three of these bNAbs together, you’re really looking at
preventing HIV acquisition. Period. At least that’s what
we’d hypothesize. And that’s what we’ve observed
in vitro and in the non-human primates. So it’ll be a very exciting
time in the next five years as we adjust to the results
and plan for the future. AUDIENCE: Thank you very much. [APPLAUSE] [MUSIC PLAYING]

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