Sanofi Pasteur HSV529 Vaccine - subunit?

[Unrequited]

http://www.sanofipasteur.com/en/articles/sanofi-pasteur-and-immune-design-collaborate-on-a-vaccine-to-treat-herpes-simplex-virus.aspx

https://clinicaltrials.gov/ct2/show/NCT01915212?term=hsv-529&rank=2

This study is ongoing, but not recruiting participants.  - Last updated: December 2, 2016

Sanofi Pasteur and Immune Design Collaborate on a Vaccine  to Treat Herpes Simplex Virus

- The two companies will develop a product jointly through phase II -

 

Lyon, France - October 16, 2014 - Sanofi Pasteur, the vaccines division of Sanofi and Immune Design Corp., a clinical-stage immunotherapy company, today announced that they have entered into a broad collaboration for the development of a herpes simplex virus (HSV) immune therapy.

Sanofi Pasteur and Immune Design will each contribute product candidates to the collaboration: Sanofi Pasteur will contribute HSV-529, a clinical-stage replication-defective HSV vaccine product candidate, and Immune Design will contribute G103, its preclinical trivalent vaccine product candidate. The collaboration will explore the potential of various combinations of agents, including Immune Design’s GLAASTM platform, with the goal to select the best potential immune therapy for patients.

“We intend to develop the best in class HSV therapeutic vaccine by pooling assets of Sanofi Pasteur and of Immune Design,” explained John Shiver, PhD, Senior VP for R&D, Sanofi Pasteur. “Given the challenges of vaccine development,” Shiver continued, “collaborations are important to help ensure that the medical need will eventually be met.”

The two companies will develop the products jointly through Phase II clinical trials, at which point Sanofi Pasteur intends to continue development of the most promising candidate and be responsible for commercialization. Sanofi Pasteur will bear the costs of all preclinical and clinical development, with Immune Design providing a specific formulation of GLA from the GLAAS platform at its cost through Phase II studies. Immune Design will be eligible to receive future milestone and royalty payments on any product developed from the collaboration; other financial terms of the agreement have not been disclosed.


About GLAAS
Immune Design’s GLAAS platform works in vivo and is based on a small synthetic molecule called GLA, which stands for glucopyranosyl lipid adjuvant. GLA selectively binds to the TLR4 receptor and causes potent activation of dendritic cells (DCs) leading to the production of cytokines and chemokines that drive a Th1-type immune response. When GLA is accompanied by an antigen and injected into a patient, the combination is taken up by DCs and leads to the production and expansion of immune cells called CD4 T helper lymphocytes with a Th1 phenotype. These CD4 T cells play a key role in boosting pre-existing cytotoxic T cells that are specific to the same antigen and providing help to other immune cells, including B lymphocytes that are the precursor to antibodies, and natural killer cells that are also important in the overall immune response.


About Sanofi Pasteur’s HSV Vaccine Program
Sanofi Pasteur’s HSV vaccine candidate is classified as a replication-defective virus, where the virus possesses all the components of wild-type virus with the exception of two proteins that are involved in viral DNA replication. The vaccine candidate is still capable of infecting cells but does not have the necessary machinery to undergo replication and establish latent or long-term infection.  Because of these attributes, the candidate is capable of eliciting a broad immune response, both a B-cell and T-cell response that is directed against the majority of the antigenic components of the virus. The investigative vaccine is currently being studied in a phase I trial sponsored by the U.S. National Institutes of Health (NIH) in people with the infection as well as those without in the United States. Due to the lengthy follow-up of volunteers in the trial, results are expected in 2016. Encouraging preclinical results have been generated by the vaccine candidate where protection against infection has been demonstrated in the guinea pig genital herpes challenge model.


About HSV
Herpes is a common sexually transmitted disease (STD) that any sexually active person can acquire. Most people with the virus don’t have symptoms. It is important to know that even without signs of disease, it can still spread to sexual partners. You can get herpes by having vaginal, anal, or oral sex with someone who has the disease. Fluids found in a herpes sore carry the virus, and contact with those fluids can cause infection. You can also get herpes from an infected sex partner who does not have a visible sore or who may not know that he or she is infected, because the virus can be released through your skin and spread the infection to your sex partner(s). Genital herpes is common in the United States, as about one out of every six people aged 14 to 49 years have genital herpes.¹


About Sanofi
Sanofi, an integrated global healthcare leader, discovers, develops and distributes therapeutic solutions focused on patients’ needs. Sanofi has core strengths in the field of healthcare with seven growth platforms: diabetes solutions, human vaccines, innovative drugs, consumer healthcare, emerging markets, animal health and the new Genzyme. Sanofi is listed in Paris (EURONEXT: SAN) and in New York (NYSE: SNY).
Sanofi Pasteur, the vaccines division of Sanofi, provides more than 1 billion doses of vaccine each year, making it possible to immunize more than 500 million people across the globe. A world leader in the vaccine industry, Sanofi Pasteur offers a broad range of vaccines protecting against 20 infectious diseases. The company's heritage, to create vaccines that protect life, dates back more than a century. Sanofi Pasteur is the largest company entirely dedicated to vaccines. Every day, the company invests more than EUR 1 million in research and development. For more information, please visit: www.sanofipasteur.com or www.sanofipasteur.us

[honey_6974]

I'm not sure why “subunit?” appears in the title. Knipe's HSV-529 is a “Live, Attenuated Replication-Defective HSV” vaccine.

This is made clear in this handy table: https://en.wikipedia.org/wiki/Herpes_simplex_research#Vaccine_candidate

In any case, the fact that an alternative to Halford's vaccine — that isn't a subunit — is in development is Good News™.

[Unrequited]

I put subunit in as a question

[LillianPanos]

Thanks for this!

[Unrequited]

http://knipelab.med.harvard.edu/vaccine.html

More information

[Unrequited]

Youtube interview with Knipe -

 

[Joseph_Esp]

Shit, this looks promising right???

[Unrequited]

Especially seeing as it is in Phase 2 trials by Sanofi Pasteur who are global players in vaccine production

[OFMDH]

On 12/30/2016 at 1:48 PM, Joseph_Esp said:

Shit, this looks promising right???

Nope. This is a dead end as there is nothing to cause a durable immune response with the virus.

Also Knipe actually didn't create the vaccine, rather it was his student Lynda Morrison Phd decades ago. She has since moved on and is now researching chemotherapy drugs against HSV. 

There is a reason some people are asymptomatic and never have outbreaks while others have it all the time. As Knipe says in the YouTube clip T-cell responses are notoriously hard to get for therapeutic use. You have them already but they're ignoring half the antigens an asymptomatic person's immune system recognizes . Well it has nothing to do with antigenic breadth per se, but as Halford mentions on his blog T-cell exhaustion (and deactivated dendtritic cells) from constant antigen stimulation that they are ignoring the other antigens.  

When you give a live vaccine or subunit vaccine for therapeutic use you may stimulate mono or polyfunctional T-cells to more antigens to try and improve the breadth but they compete with pre-existing anergic T-cells and as I posted in a gallery on this website you get a really small bump in new T-cells; even with a live vaccine modified to stimulate CD8 cells and very poor restimulation from future antigen presentation.

Experiments with with other chronic virus infections (including HSV-1) to convert those cells into memory cells you need to interrupt the exhaustion pathway (t-cells being signaled to die off without creating a memory pool), otherwise all you've done is stimulated cells which give a majority of people a temporary effect. A prime example is all these therapeutic vaccinations wearing off - Chiron? gB2+gD2 vaccine only diminished 1 OB;The HSV2-gH mutant (aka disabled infectious single cycle (DISC) mutant) showed 0% reduction in OBs and shedding in people. Deactivated virus? Vitaherpavac, Lupidron G, etc. all required constant injections. Basically all these vaccines can elicit a response but the cells die off without leaving much of a pool of T-memory cells to keep clearing the virus.

The assumption symptomatic people are missing antigens is a half truth in my opinion. HSV deactivates immature dendtritic cells and LAT proteins cause T-cell exhaustion the B/T-cells aren't recognizing them because they probably actually instead started to ignore them. Thus while your missing antigenic breadth its because your immune system is ignoring it on purpose. Thus the person is stuck in this loop where the body has to relearn it each OB and after every OB the body downregulates and kills their CD8+ T-cells without leaving much of a memory pool. The only way to break free from that loop is to take a PD-L inhibition drug when T-effector cells are accumulating PD-IL. This isn't new, it was figured out 10 years ago and is now on the market.... for skin cancer.

.........the 4 injections cost $120,000. 

One way around the feedback loop is trying to mutate the HSV LAT gene and insert an immunomodulator gene as its the LAT gene in your DRG that is causing T-cell exhaustion and in dendtritic cells its messing them up. Someone has already done this and it was shown to boost the vaccine's efficacy in creating long lasting T memory cells and restoring dendtritic cell function. 

 

Edited January 2, 2017 by OhFuckMyDickHurts

[Peacepleez]

How does this model explain neuropathy without OBs. Different mechanism?

Edited January 2, 2017 by Peacepleez

[OFMDH]

1 hour ago, Peacepleez said:

How does this model explain neuropathy without OBs. Different mechanism?

Where do you think HSV neuropathy fits?

Different? 

1. There's a lot more in your immune cells than just cytotoxic CD8 T-cells and whether HSV specific ones are anergic or not. 

2. CD8 T-cell exhaustion concerns specific antigen presentation, expansion and memory cells dying off.

3. Pain from HSV is a complex situation and most likely a neuro-immune disorder of the DRG and there are some 14 different immune cells found in the DRG, 20 different chemokine receptors, etc. 

 

 

 

Edited January 2, 2017 by OhFuckMyDickHurts

[Peacepleez]

So most definitely different but related?  Do the anecdotal reports of neuralgia relief from Theravax tell us anything as to live attenuated vaccine mechanism?

Edited January 2, 2017 by Peacepleez

[OFMDH]

2 hours ago, Peacepleez said:

So most definitely different but related?

No. T-cell exhaustion of CD8 cells is not directly related to a neuro-immune disorder of the DRG. One is a nonspecific immune response and the other is a specific response to particular antigens.

Quote

 Do the anecdotal reports of neuralgia relief from Theravax tell us anything as to live attenuated vaccine mechanism?

Ask Halford. 

[Joseph_Esp]

50 minutes ago, OhFuckMyDickHurts said:

No. T-cell exhaustion of CD8 cells is not directly related to a neuro-immune disorder of the DRG. One is a nonspecific immune response and the other is a specific response to particular antigens.

Ask Halford. 

Fuck, how discouraging it all sounds. So...we got nothing right? All we talk about on this forum is just random bullshit we say to ourselves to kill some time while nothing is coming on, just like all the "new promising" vaccines coming up in the 70´s, the 80´s, the 90´s,...?

[Brokenforever]

25 minutes ago, Joseph_Esp said:

Fuck, how discouraging it all sounds. So...we got nothing right? All we talk about on this forum is just random bullshit we say to ourselves to kill some time while nothing is coming on, just like all the "new promising" vaccines coming up in the 70´s, the 80´s, the 90´s,...?

Exactly. People waiting for years and nothing came of it . How can this be the epidemic it is with nothing. 

[cantdoit]

3 hours ago, Joseph_Esp said:

Fuck, how discouraging it all sounds. So...we got nothing right? All we talk about on this forum is just random bullshit we say to ourselves to kill some time while nothing is coming on, just like all the "new promising" vaccines coming up in the 70´s, the 80´s, the 90´s,...?

The belief helped by doctors that this is no big deal and harmless has not helped push for a cure. You will even read that crap on here. 

[RVX Patient and Investor]

12 hours ago, OhFuckMyDickHurts said:

but as Halford mentions on his blog T-cell exhaustion (and deactivated dendtritic cells) from constant antigen stimulation that they are ignoring the other antigens.  

When you give a live vaccine or subunit vaccine for therapeutic use you may stimulate mono or polyfunctional T-cells to more antigens to try and improve the breadth but they compete with pre-existing anergic T-cells and as I posted in a gallery on this website you get a really small bump in new T-cells; even with a live vaccine modified to stimulate CD8 cells and very poor restimulation from future antigen presentation.

Experiments with with other chronic virus infections (including HSV-1) to convert those cells into memory cells you need to interrupt the exhaustion pathway (t-cells being signaled to die off without creating a memory pool), otherwise all you've done is stimulated cells which give a majority of people a temporary effect. A prime example is all these therapeutic vaccinations wearing off - Chiron? gB2+gD2 vaccine only diminished 1 OB;The HSV2-gH mutant (aka disabled infectious single cycle (DISC) mutant) showed 0% reduction in OBs and shedding in people. Deactivated virus? Vitaherpavac, Lupidron G, etc. all required constant injections. Basically all these vaccines can elicit a response but the cells die off without leaving much of a pool of T-memory cells to keep clearing the virus.

The assumption symptomatic people are missing antigens is a half truth in my opinion. HSV deactivates immature dendtritic cells and LAT proteins cause T-cell exhaustion the B/T-cells aren't recognizing them because they probably actually instead started to ignore them. Thus while your missing antigenic breadth its because your immune system is ignoring it on purpose. Thus the person is stuck in this loop where the body has to relearn it each OB and after every OB the body downregulates and kills their CD8+ T-cells without leaving much of a memory pool. The only way to break free from that loop is to take a PD-L inhibition drug when T-effector cells are accumulating PD-IL. This isn't new, it was figured out 10 years ago and is now on the market.... for skin cancer.

.........the 4 injections cost $120,000. 

One way around the feedback loop is trying to mutate the HSV LAT gene and insert an immunomodulator gene as its the LAT gene in your DRG that is causing T-cell exhaustion and in dendtritic cells its messing them up. Someone has already done this and it was shown to boost the vaccine's efficacy in creating long lasting T memory cells and restoring dendtritic cell function. 

 

correct me if i am wrong, i am trying to read inbetween the lines here:

so you are saying that the current Halford vax will eventually fail or weaken due to the process you state above, that Halford himself is already aware of?  assuming thats correct, thats fair enough, and would seem to be the argument for booster shots.

(having said that, the process above shouldn't negatively impact someone who is uninfected receiving the preventative vax, right?  b/c they won't have pre existing T cells for HSV, right?)

in addition, you say "someone" has already mutated the LAT gene.  who?

and assuming this "fix" could be applied to Halford's vax, it would get his vax past this issue, no?

[OFMDH]

10 hours ago, RVX Patient and Investor said:

you say "someone" has already mutated the LAT gene.  who?

Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses - http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087617 - Homayon Ghiasia

 

Quote

and assuming this "fix" could be applied to Halford's vax, it would get his vax past this issue, no?

In theory yes. 

Quote

"This study lays the framework for a strategy that could be used to prevent and/or significantly reduce T cell exhaustion and thus increase vaccine efficacy..."

 

[Unrequited]

Bump* RVX did you inform Halford of this study? I would've thought he would have found it very interesting.

[RVX Patient and Investor]

i'm pretty sure OFMDH already did.  if not, i will.

[Unrequited]

On 03/01/2017 at 2:50 AM, OhFuckMyDickHurts said:

Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses - http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087617 - Homayon Ghiasia

 

In theory yes. 

 

 

On 03/01/2017 at 2:50 AM, OhFuckMyDickHurts said:

Inclusion of CD80 in HSV Targets the Recombinant Virus to PD-L1 on DCs and Allows Productive Infection and Robust Immune Responses - http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0087617 - Homayon Ghiasia

 

In theory yes. 

 

Please tell me you collaborate with Halford?

[Just want to move on.]

On 1/2/2017 at 4:05 PM, OhFuckMyDickHurts said:

Nope. This is a dead end as there is nothing to cause a durable immune response with the virus.

Also Knipe actually didn't create the vaccine, rather it was his student Lynda Morrison Phd decades ago. She has since moved on and is now researching chemotherapy drugs against HSV. 

There is a reason some people are asymptomatic and never have outbreaks while others have it all the time. As Knipe says in the YouTube clip T-cell responses are notoriously hard to get for therapeutic use. You have them already but they're ignoring half the antigens an asymptomatic person's immune system recognizes . Well it has nothing to do with antigenic breadth per se, but as Halford mentions on his blog T-cell exhaustion (and deactivated dendtritic cells) from constant antigen stimulation that they are ignoring the other antigens.  

When you give a live vaccine or subunit vaccine for therapeutic use you may stimulate mono or polyfunctional T-cells to more antigens to try and improve the breadth but they compete with pre-existing anergic T-cells and as I posted in a gallery on this website you get a really small bump in new T-cells; even with a live vaccine modified to stimulate CD8 cells and very poor restimulation from future antigen presentation.

Experiments with with other chronic virus infections (including HSV-1) to convert those cells into memory cells you need to interrupt the exhaustion pathway (t-cells being signaled to die off without creating a memory pool), otherwise all you've done is stimulated cells which give a majority of people a temporary effect. A prime example is all these therapeutic vaccinations wearing off - Chiron? gB2+gD2 vaccine only diminished 1 OB;The HSV2-gH mutant (aka disabled infectious single cycle (DISC) mutant) showed 0% reduction in OBs and shedding in people. Deactivated virus? Vitaherpavac, Lupidron G, etc. all required constant injections. Basically all these vaccines can elicit a response but the cells die off without leaving much of a pool of T-memory cells to keep clearing the virus.

The assumption symptomatic people are missing antigens is a half truth in my opinion. HSV deactivates immature dendtritic cells and LAT proteins cause T-cell exhaustion the B/T-cells aren't recognizing them because they probably actually instead started to ignore them. Thus while your missing antigenic breadth its because your immune system is ignoring it on purpose. Thus the person is stuck in this loop where the body has to relearn it each OB and after every OB the body downregulates and kills their CD8+ T-cells without leaving much of a memory pool. The only way to break free from that loop is to take a PD-L inhibition drug when T-effector cells are accumulating PD-IL. This isn't new, it was figured out 10 years ago and is now on the market.... for skin cancer.

.........the 4 injections cost $120,000. 

One way around the feedback loop is trying to mutate the HSV LAT gene and insert an immunomodulator gene as its the LAT gene in your DRG that is causing T-cell exhaustion and in dendtritic cells its messing them up. Someone has already done this and it was shown to boost the vaccine's efficacy in creating long lasting T memory cells and restoring dendtritic cell function. 

 

@OhFuckMyDickHurts in your opinion, in reference to the information you posted above, why would a live vaccine like Theravax be any different to Vitaherpavac in maintaining a T cell response. Thanks

[OFMDH]

13 hours ago, Just want to move on. said:

@OhFuckMyDickHurts in your opinion, in reference to the information you posted above, why would a live vaccine like Theravax be any different to Vitaherpavac in maintaining a T cell response. Thanks

Depends what you're using it for; Theravax seems like a great prophalaxtic for its ability to cause an immune response which can quickly neutralize HSV2 when exposed. Its already shown in lab tests to kick the pants off a dead virus version of itself, I would presume the result would be similar to Vitaherpavac and other past dead vaccines versions of HSV that have failed as a prophalaxtic. 

As for therapeutic.... - sometimes people cross talk to each other without the other understanding what the other is really trying to say. I know Halford dismissed some question from a DrHyder awhile back when Th1 responses were brought up. However Halford is probably just looking at a different variable which measures Th1 activities and simplifying it when thinking about it  - he has written about antibody ratios in the past. Halford I think focuses on the ratio of IgG2a antibodies to IgG1 antibodies which also shows whether the immune response is Th1-polarized or Th2 polarized without talking about Th1/Th2. 
Hyder is right, there is significant data that vaccines that elicit a Th1-polarized immune response lessens the disease symptoms while Th2 increases it. If you get a balanced response it doesn't really do a whole lot of good for you.  What does Halford's NLS (aka Theravax) vaccine cause? I would imagine as its interferon sensitive that its ratio would show Th1 is higher than Th2 but probably not as polarized as one would like for therapeutic use as its only mutated in one spot for one effect.

Maybe if NIH gave Halford some money we could see more experiments with more mutations to try and increase Th1 and IgG2a antibodies as well as mutations to get around HSV deactivating immune cells by adding CD70 protein or removing its ability to enter those immune cells..... If you want to do something, contact NIAID.NIH [email Jeffrey Cohen and ask why live HSV vaccine research has stalled, and why someone like Halford with a live vaccine candidate isn't being explored] 

 

 

 

[Just want to move on.]

Thankyou for the informative response. Very interesting to read. 

[RVX Patient and Investor]

4 minutes ago, jolando123 said:

NIH is allowing one "live" vaccine to be tested. HSV-ACAM529.