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Immunity Project – HIV Vaccine Development Program [pdf]

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

#31

Post by j2d3 »

1457389 wrote: post #29
j2d3 wrote: post #25

Earlier quoted context omitted.

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 instrumenta…

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?

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

#32

Post by 1457389 »

j2d3 wrote: post #31
1457389 wrote: post #29

Earlier quoted context omitted.

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 instrumenta…

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…

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.

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

#33

Post by sjg007 »

rgejman wrote: post #24
icinnamon wrote: post #21

Earlier quoted context omitted.

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 T…

Thanks for this thread. I really enjoyed seeing the science discussed. I've been interested in computational vaccine design and HIV evolutionary dynamics for a long time. I kind of see the whole thing as a dynamical system and a hidden Markov model. Essentially since the copy mechanism is leaky and produces multiple variants, and the immune system produces a selective response, how do you know that the single epitope you vaccinate against will be sufficient? I would expect their to be multiple stable populations and hence a need multiple vaccine epitopes (including populations that are stable under specific drug regimes).

This is what makes rgejman's phage display comments so interesting. We already know two major populations (Hiv-1 and Hiv-2 exist).

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

#34

Post by reidrubsamen »

rgejman wrote: post #24
icinnamon wrote: post #21

Earlier quoted context omitted.

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 T…

This sounds really interesting! Let me talk to my team. I would love to discuss this with you further. Please email me at team@immunityproject.org

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

#35

Post by reidrubsamen »

1457389 wrote: post #30
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…

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…

Thanks for the question! PLGA is the one of the most commonly implanted biodegradable materials in the world - primarily because it is used is used in dissolving suture (check out this link to very popular PLGA based suture material).

Aston S, Rees T. Vicryl Sutures. Aesthetic Plastic Surgery 1977;1:5.

The "threatening point" is just a way of describing what TLR-4 (MPLA) and TLR-9 (CpG) do. In particular, MPLA "looks like" bacterial cell wall and CpG "looks like" bacterial DNA to the immune system.

Steinhagen F. TLR-based immune adjuvants. Vaccine, 2011: 12.

We did not consider using nano spheres because we wanted to get as much payload as possible into the antigen presenting cells without requiring multiple phagocytosis events per cell.

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

#36

Post by reidrubsamen »

shiven wrote: post #27
icinnamon wrote: post #20

Earlier quoted context omitted.

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, finge…

Thanks very much for the kind note! I would be happy to send you a link to the paper the guys working on the statistical analysis of beneficial HIV target regions when it is published.

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

#37

Post by reidrubsamen »

sjg007 wrote: post #33
rgejman wrote: post #24

Earlier quoted context omitted.

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 T…

Thanks for this thread. I really enjoyed seeing the science discussed. I've been interested in computational vaccine design and HIV evolutionary dynamics for a long time. I kind of see the whole thing as a dynamical system and a hidden Markov model. Essentially since the copy mechanism is leaky and produces multiple variants, and the immune system produces a selective response, how do you know that the single epitope…

Great comments! We expect the beneficial targets to be HLA restricted. We need to do more work to understand if any one individual needs to hit two targets - we think right now that a "master vaccine" would need to contain multiple peptides to cover multiple HLA type individuals yielding at least one "valid" target per individual.

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

#38

Post by rposborne »

icinnamon wrote: post #13
midas007 wrote: post #4

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.

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

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

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

#39

Post by reidrubsamen »

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…

Sorry for the delay! It is certainly an interesting application and one that I am personally very interested in pursuing at some point. For now we are focusing on the preventative potential of this new vaccine concept.

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

#40

Post by 1457389 »

reidrubsamen wrote: post #35
1457389 wrote: post #30

Earlier quoted context omitted.

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…

Thanks for the question! PLGA is the one of the most commonly implanted biodegradable materials in the world - primarily because it is used is used in dissolving suture (check out this link to very popular PLGA based suture material). Aston S, Rees T. Vicryl Sutures. Aesthetic Plastic Surgery 1977;1:5. The "threatening point" is just a way of describing what TLR-4 (MPLA) and TLR-9 (CpG) do. In particular, MPLA "looks…

Got it, thanks and all the best! I for one will be watching closely so keep the updates coming.
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