

Immunity Project – HIV Vaccine Development Program [pdf] - humanfromearth
https://dl.dropboxusercontent.com/u/702869/Immunity%20Project%20White%20Paper.pdf

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rgejman
Some thoughts on this white paper, with the caveat that I'm not sure how much
of what is discussed they have done and how much of it is what they are
planning to do. The white paper is light on details and I re-iterate my appeal
for them to release their data (at least in summary form). My apologies for
some of the technical language--I want to write this first and then I can
clarify the hard stuff (or you can google it)

This vaccine relies on inducing immunity to an HIV peptide* (i.e. a ~9 amino
acid cleavage product of an HIV protein) that is predicted to bind to HLA
molecules. At first blush, this sounds like a great idea--let's immunize
people to the very thing that the immune system is supposed to recognize as
bad! Unfortunately, this has been tried lots of times and usually doesn't work
very well, if at all. It's been tried in cancer, it's been tried in HIV, it's
been tried in practically any system you can imagine. I'm not saying that
peptide vaccines don't ever work (hell, my lab has worked on one)--I'm just
saying that they have had lots of promise and limited successes. In fact,
animals and patients have been immunized to many cleavage products of many
cancer associated antigens to little, if any, effect—or effects in animals but
not in humans. We can hem and haw all day about what the specific studies
show, but suffice it to say that peptide vaccines are an old idea. Perhaps
Immunity will get lucky here, but I'd be surprised if there isn't a lab
somewhere that has tried immunizing animals to every single breakdown product
of HIV proteins already.

Immunity's white paper says that their putatively immunogenic human peptide
cannot be tested in animal models because it will only bind to human HLA. So
they are planning to use a mouse-analog of the human peptide to do their
animal testing (or have already done this?). That is, they are planning to use
(or maybe have already used?) a completely different peptide (probably 1-3
amino acids different from the human version) in animal studies than what they
would use in patients. This may be a significant difference... or it might not
be. There's no way to tell a priori. A more classical and IMO better approach
would be to identify T cell receptor clones from patients with HIV (or without
HIV) that bind to these peptides (using tetramer staining, phage display or
some other high-throughput technology), demonstrate that humans are capable of
creating T cells that recognize their putatively immunogenic peptide followed
by T cell killing assays on cells presenting their peptide of interest. There
are other approaches, but that is a commonly used one in the field.

* in some places the white paper says "peptides" and in other it says "peptide" so it's not clear if we are talking about 1 peptide or multiple. I think they are mostly talking about multiple peptides, because they want to immunize people no matter their HLA type. Different HLA types bind to different peptides. So if you have HLA A02 you will bind different peptides than if you have HLA A24... and so on for all the different HLA types.

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reidrubsamen
Hi there, Reid from Immunity Project. Thanks for the great question! Would
love to talk with you off line about your research, by the way.

1\. We have successfully gotten an immune response with memory (by elispot)
after a single dose of the PLGA microspheres containing one or two peptides
when combined with TLR-4 (MPLA) and TLR-9 (CpG) agonists. We used H2d
restricted epitopes to do the study in C57BL/6 mice – this study is done and
in the PRJ review process. We are being careful about posting the results in
the event we need to re-submit to a journal who would get heartburn if they
saw the data posted.

2\. We are raising money now to essentially repeat the experiment (on a
smaller scale because we think we understand the optimal formulation
configuration now) in C57BL/6 NOG mice (with human PBMCs grafted in from a
donor with known HLA type). The new experiment starts off looking like the
experiment in (1) above: intradermal tail injection, wait 14 days, sacrifice,
get the spleen, confirm immune response to peptide target by flurospot. The
next part is new: separate CD8 from CD4 cells (from the mouse spleen), infect
the CD4 cells with HIV, see if the vaccination attempt was good enough to see
p24 antigen suppression and/or a change in the CD4 counts (all in-vitro). We
can finish this study in a couple months, assuming the crowd funding keeps
going well and we start in a couple weeks. We will use a different mechanism
to publish our paper around this experiment so that we can get it out right
away in a fashion that will lead to peer review and open access (We just
learned about peerj.com – thoughts on that?).

Looking forward to hearing your thoughts on our approach.

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limpon
Hi Reid, as I said before, I wish you all the best but I simply don't
understand how your experiment 2 is going to work. Did I understand correctly
that you will immunize mice and then isolate CD4 T cells from the spleen. Then
infect those cells and see if cells from immunized mice die slower/less/not at
all and don't express p24 in high levels. I'm afraid this experiment will not
work this way. CD4 T cells by itself can not be immunized against HIV. The
immunizing effect comes from memory B cells that produce antibodies. These
antibodies bind to HIV infected CD4 T cells and as such label them as evil to
be killed by other cells. CD4 T cells alone will not show any effect in
regards to susceptibility to HIV no matter how well your immunization works.
As rgejman pointed out, it would be way better to infect the mice with HIV and
do a CD4 T cell count there every week. This would be so much easier and it
might actually show you something relevant.

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rgejman
I think that they will incubate CD8 and CD4 T cells from the same mouse
together. The CD8 (cytotoxic) T cells, if they recognize the antigen, should
kill the infected CD4 cells.

A caveat is activation/co-stimulation. The CD8 T cells _should_ already be
activated due to the vaccination and no longer need co-stimulation from DCs...
but this depends on the vaccine having delivered enough peptide to stimulate a
true immune response in a human/humanized immune system. That's the (first)
big unknown here.

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rgejman
Another thing I want to point out is that your home page touts safety as a
design point. The text under "SAFE" says "Our vaccine does not contain killed
viruses, live viruses, or genetically-modified viruses." I STRONGLY object to
this language as it implies that inactivated (killed) and live* viruses are
unsafe in general. This is simply not true. I believe most clinically used
vaccines are either inactivated or attenuated.

I understand that you're trying to make sure people understand that your
vaccine is safe. However, implying that other vaccines are unsafe because they
are inactivated or attenuated does a disservice to the entire vaccine
industry.

*I think you mean 'attenuated' here, not live

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reidrubsamen
Thanks for the comment! We did not mean to imply that existing vaccines were
dangerous and will modify the language on the site to clarify.

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ciokan
I would be very curious to know if the team received any kind of pressure to
stop what they're doing or if they will communicate if such thing would
happen. Don't want to sound cynical, I just watched a lot on the subject
recently and it seems there's a huge industry behind having a lot more
benefits (material ones) from the actual sick people and their life-long
expensive treatments compared to a vaccine.

Even if it doesn't work God bless to you all for trying this. It's a wonderful
thing to get you up in the morning.

~~~
limpon
I've heard lots of people speculating that the big pharma companies would be
better of if there would always be HIV and they can sell their ART pills for
live. But on the other hand if one of them is the first one to create a HIV
immunization, this alone will make them so extremely rich. An effective HIV
immunization will become standard immunization for all people in the western
world and the WHO and UN will take all in their power to immunize as many
people worldwide as possible. Just imagine the amount of doses that will have
to be produced. And you would be the only one company having this product.
This has way more financial gain that being one of the dozens of companies
that produce ART therapies. On top of that a few people working in high
positions of big pharma companies are still "nice" people who would actually
be proud of curing a disease. Not everyone just counts their dollars every day
and hopes that more people get sick.

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ciokan
yes but op website says they will release it for free, thats why i'm asking in
the first place.

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icinnamon
Ian from the Immunity Project (YC W14) team here! Happy to answer any
questions you may have.

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vertis
Excuse my lack of knowledge in this area, but is this vaccine purely
preventative, or is it possible to administer it to someone already infected.

I know/believe with traditional vaccines that you usually have to do it before
infection. (Though could be wrong in this regard as well)

If not, why not?

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howiediamond
Howie from the Immunity Project here. Thanks for your question! We're really
just focusing on the preventive aspect of this vaccine as we head into our
Phase I human clinical trials.

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j2d3
Hi Howie, can you elaborate? You didn't really address the why / why not
aspect of the question.

Since the Immunity Project concept relies on training the immune system to
mount a successful response against HIV, why would it not present some benefit
to an already-infected person whose infection is otherwise controlled with
drugs?

You may just be focusing on the preventative aspect, but there are many
millions worldwide who are concerned with controlling HIV without depending on
expensive antiviral drugs that in many cases are completely unavailable.

~~~
1457389
I'll try and address this since no one has answered yet.

One of the reasons it would be very hard to justify testing this first as a
cure is because AIDS patients are by definition immunodeficient. Their Helper
T cells (the CD4s mentioned) are being rapidly co-opted by the virus and
subject to destruction. In such an environment it is difficult to mount an
immune response because the Helper T cells are so instrumental to enabling the
cytotoxic immune responses instigated by this study (the CD8 cells are your
cytotoxic "killer" T cells).

Any trial run on humans already suffering from AIDS would be muddied by this
effect, where the already compromised immune system cannot mount a robust
response even were it able to develop CD8 killer cells specific to the HIV
epitope they vaccinate with.

Phase I trials are high risk, and especially for a bootstrapped team like
this, have a lot riding on them. An early failure can doom a technology in
this industry, so it is important to focus on testing in an environment where
you have the best shot at success. Downstream studies can focus on other
applications if needed.

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j2d3
There are many millions of people who have HIV but not AIDS. Their immune
systems work well, and their viral levels are controlled by medications. These
people are on US health insurance and are highly monitored already, and easy
to enroll in studies, easily accessed and monitored - as they already conform
to an HIV medication regimen and see their doctors regularly.

Why would a company not test a technology that may well benefit both infected
and uninfected people on both populations? You would only have more data. It
will take much longer to see the results if you are only studying it as a
preventative measure because you have to wait (a really long time, I would
suspect) to see which of your study ends up getting HIV. Additionally, you'd
need to study those that do get HIV (if some do, and some probably would, as
even the best vaccines aren't 100% effective) and try to see if you can tell
if their infection progresses differently or if it is somehow augmented by the
vaccination's boost to the immune system. I mean... your explanation doesn't
actually make that much sense to me.

Why not test both populations?

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1457389
I'd imagine limited funds were the reason. Plus, like I said, your results
from a trial on patients with the virus on heavy courses of anti-retrovirals
would be muddied. You wouldn't know if the antiviral or the vaccine was what
was helping/hurting. Also it's hardly ethical to have a test group stop taking
their proven medications for an experimental drug, which is what you would
have to do to test this properly.

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lvryc
They're also running a kickstarter-style crowdfunding attempt at
[https://pledge.immunityproject.org/the-free-hiv-aids-
vaccine](https://pledge.immunityproject.org/the-free-hiv-aids-vaccine) .

~~~
icinnamon
We are indeed!

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kayhi
Is there more basic research supporting this interaction (crystallographic or
otherwise) between the peptide and T cell? The paper feels like to jumps right
into animal models.

"specific points identified by a data-driven analysis of actual individuals’
immune systems" pg1

What is the data in this case?

What is the sequence of the peptide(s) that are incorporated into the PLGA?

Side note: our start up works on helping biotech companies source reagents,
supplies and equipment, we should be able to save you about ~15% on the ~475k
part of the budget

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naveenspark
Naveen here from Immunity Project. Thanks for the question. We have not done
receptor analysis. We are using animal models as our starting point - we are
looking for an immune response with memory to the administered peptides - if
we get that response in Phase I we should be in good shape!

We received the peptides from researchers who have a manuscript in publication
and would like us to keep the sequences confidential until they publish.
Please see below for similar statistical research looking for targets to
beneficial regions on HIV:

Mothe B, Anuska L, Ibarrondo J, Daniels M, Miranda C, Zamarreno J, et al.
Definition of the viral targets of protective HIV-1-specific T cell responses.
Journal of Translational Medicine 2011;9(208):20.

re: your startup / cost savings on reagents, supplies and equipment, we would
love to talk to you about that. Please email us at team@immunityproject.org.
Thanks!

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midas007
Interesting. Would Gates and a couple others be willing to cut a few large
checks to just make it happen? This is something that should be fast-tracked.
As in right now, please.

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icinnamon
Ian from Immunity Project here. We've actually chatted with a few of these
large foundations and they are very interested. They want to see some Phase I
data first, so that's why we went ahead with the crowdfunding campaign to help
us get to that point! Check it out:
[http://pledge.immunityproject.org](http://pledge.immunityproject.org)

~~~
rposborne
Have any of them giving you all benchmarks to hit to secure funding?

