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Immunity Project – HIV Vaccine Development Program [pdf]

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Re: Immunity Project – HIV Vaccine Development Program [pdf]

#21

Post by icinnamon »

rgejman wrote: post #18
reidrubsamen wrote: post #11

Earlier quoted context omitted.

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 s…

#1 suffers from the critique I mentioned above. The peptide(s) you are using are designed for H2d. Do you have evidence that their human analogs* are immunogenic? #2 I assume now you are using the human version of the peptide? I'm not sure why you're doing this in vitro when you can now do it in vivo. Why not (a) infect the mouse with HIV, (b) look at viral titers w/ and w/o pre-vaccination, (c) look for specific CD8…

Ian from the Immunity Project team here.

Thanks for the follow up!

No evidence yet that human analogs are immunogenic. Doing new experiment to find out.

Yes! Using human version of the peptide for the new experiment. The NOG mouse model we are using will not infect with HIV - hence the in-vitro arm - I realize that humanized mice do exist that we could infect - we may try that later. Looking to take CD8/CD4 cells from vaccinated mice. Infect the (isolated) CD4 cells, combine and follow p24.

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#22

Post by 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.

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#23

Post by naveenspark »

kayhi wrote: post #16

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 helpin…

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!

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#24

Post by rgejman »

icinnamon wrote: post #21
rgejman wrote: post #18

Earlier quoted context omitted.

#1 suffers from the critique I mentioned above. The peptide(s) you are using are designed for H2d. Do you have evidence that their human analogs* are immunogenic? #2 I assume now you are using the human version of the peptide? I'm not sure why you're doing this in vitro when you can now do it in vivo. Why not (a) infect the mouse with HIV, (b) look at viral titers w/ and w/o pre-vaccination, (c) look for specific CD8…

Ian from the Immunity Project team here. Thanks for the follow up! No evidence yet that human analogs are immunogenic. Doing new experiment to find out. Yes! Using human version of the peptide for the new experiment. The NOG mouse model we are using will not infect with HIV - hence the in-vitro arm - I realize that humanized mice do exist that we could infect - we may try that later. Looking to take CD8/CD4 cells fro…

That's an interesting approach.

Re not knowing if the human analogs are immunogenic yet: An alternative way to to answer your question would be to identify a T cell receptor (TCR) clone that recognizes your peptides of interest. There are several ways of identifying TCR clones that match your peptide of interest. Probably the best way is via phage display. The advantages here are manifold:

1. By identifying a human TCR you immediately prove that your peptide is recognized by the human immune system (immunogenic)--you still need to do a bit more work to show that the immune system will produce this antibody in response to your peptide--but that's a pretty good start.

2. You could perform phage display separately on TCRs from elite controllers and more susceptible patients. The differences in these TCRs would likely make for a very interesting academic publication.

3. You could make a TCR-like antibody based on this TCR. If your vaccination strategy failed, hey at least now you have an antibody you can take into trials!

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#25

Post by j2d3 »

howiediamond wrote: post #19
vertis wrote: post #6

Earlier quoted context omitted.

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?

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.

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.

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#26

Post by naveenspark »

ciokan wrote: post #22

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…

Thank you for the kind words and support! We are very focused on our stated goal which is ending HIV/AIDS with a free vaccine. We haven't received any pressure to stop our work yet. If we do we will definitely let you know so we can get your help in fighting back!

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#27

Post by shiven »

icinnamon wrote: post #20
shiven wrote: post #15

Earlier quoted context omitted.

Wait! But what HIV protein(s) is the peptide(s) derived from? Let's not overlook the decades of prior data! The field is littered with names like VRC01, Camelid and so many other players. I know, I know, antibodies all versus antigen in this case. But keep reading ... HIV is a master at developing resistant forms of itself. What if it changes the epitope and evades the vaccine induced antibody(ies), again!?! (Edit: D…

Hey shiven! Thanks for your question. This is Ian Cinnamon from the Immunity Project team. The targets we are trying to immunize with are believed to be beneficial by a statistical analysis similar to what is described here: 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(2…

Thanks for answering with a reference!

I am not asking about the peptide sequence, just the protein it is derived from. But, if you cannot share that right now, that's OK too. I'll look out for the publication.

However, assuming I am making an educated guess about the parent protein, I'd go with gp120/gp41 envelope (env). I may be totally wrong there and you guys may have another ace up your sleeve (do hope so, fingers crossed!). Good luck!

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#28

Post by j2d3 »

vertis wrote: post #17
rposborne wrote: post #9

Earlier quoted context omitted.

The definition of a vaccine is that it is preventative vs. a cure which is removing a disease from a previously infected patient. "A vaccine is a biological preparation that improves immunity to a particular disease."

Yes, but immunity has many definitions, including 'to fight off'. Since it's essentially teaching the immune system, why does this not work when the patient is already infected. I thought there may be some difference between this and traditional vaccines as well.

This story discusses other HIV vaccine efforts that are targeted at already infected and stop the dependence on the HIV meds:

http://www.livescience.com/18107-hiv-therapeutic-vaccines-pr...

according to that article there are 34 million people already infected worldwide.

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#29

Post by 1457389 »

j2d3 wrote: post #25
howiediamond wrote: post #19

Earlier quoted context omitted.

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.

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 worldw…

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.

Re: Immunity Project – HIV Vaccine Development Program [pdf]

#30

Post by 1457389 »

reidrubsamen wrote: post #11
rgejman wrote: post #3

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…

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 s…

The role of the TLR-4 and TLR-9 agonists; Are they essentially acting as adjuvants for your vaccine when delivered in conjunction with the peptide on the surface of the same microsphere?

Also, did you consider using nanospheres? Why PLGA?

EDIT: This is the bit I want some clarification on, from your white paper:

>These microspheres make the very small targets look large and threatening to the immune system, provoking an immune response after a single dose

EDIT2: Got my answer in the white paper, yes they are adjuvants. Still would like to know why PLGA and what the mechanism of how they appear more "threatening" is.

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