A Herpes Simplex Virus 2 (HSV-2) gD Mutant Impaired for Neural Tropism Is Superior to an HSV-2 gD Subunit Vaccine To Protect Animals from Challenge with HSV-2

[Evaluate]

A paper recently published shows increased support for live, attenuated vaccines vs. subunit.

Would someone be able to send me a copy of the paper via PM?

http://jvi.asm.org/content/90/1/562.abstract

Quote

Abstract

A recent phase 3 trial with soluble herpes simplex virus 2 (HSV-2) glycoprotein D (gD2t) in adjuvant failed to show protection against genital herpes. We postulated that live attenuated HSV-2 would provide more HSV antigens for induction of virus-specific antibodies and cellular immunity than would gD2t. We previously reported an HSV-2 mutant, HSV2-gD27, in which the nectin-1 binding domain of gD2 is altered so that the virus is impaired for infecting neural cells, but not epithelial cells, in vitro and is impaired for infecting dorsal root ganglia in mice (K. Wang, J. D. Kappel, C. Canders, W. F. Davila, D. Sayre, M. Chavez, L. Pesnicak, and J. I. Cohen, J Virol 86:12891–12902, 2012, doi:10.1128/JVI.01055-12). Here we report that the mutations in HSV2-gD27 were stable when the virus was passaged in cell culture and during acute infection of mice. HSV2-gD27 was attenuated in mice when it was inoculated onto the cornea, intramuscularly (i.m.), intravaginally, and intracranially. Vaccination of mice i.m. with HSV2-gD27 provided better inhibition of challenge virus replication in the vagina than when the virus was used to vaccinate mice intranasally or subcutaneously. Comparison of i.m. vaccinations with HSV2-gD27 versus gD2t in adjuvant showed that HSV2-gD27 induced larger reductions of challenge virus replication in the vagina and reduced latent viral loads in dorsal root ganglia but induced lower serum neutralizing antibody titers than those obtained with gD2t in adjuvant. Taken together, our data indicate that a live attenuated HSV-2 vaccine impaired for infection of neurons provides better protection from vaginal challenge with HSV-2 than that obtained with a subunit vaccine, despite inducing lower titers of HSV-2 neutralizing antibodies in the serum.

As a side note, previous research was gone on Guinea Pigs with the same result in 2014. "A Herpes Simplex Virus 2 (HSV-2) Glycoprotein D-expressing Nonreplicating Dominant-Negative HSV-2 Virus Vaccine Is Superior to a gD2 Subunit Vaccine against HSV-2 Genital Infection in Guinea Pigs"

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101373

Is there not enough research out there to stop pharma from being wary of live attenuated vaccines?  Animal trials show them to be both effective and safe.

Edited December 18, 2015 by Evaluate

[lexyz22]

More support for the usage of a Live Attenuated Vaccine  

How many more years of bullshit do we need to go through before the FDA and other regulatory bodies across the world accept the need to at least TRY to pursue a live attenuated HSV-2 vaccine. 

 

[tom343]

Meh the masturbation over live vs subunit vaccines is a joke. If it works who gives a f%ck. 

[Juggalo]

Awesome papers. Some of the live vaccines out there are working awesome.

[Evaluate]

5 hours ago, tom343 said:

Meh the masturbation over live vs subunit vaccines is a joke. If it works who gives a f%ck. 

I'm not sure what that means.  Ultimately the argument is that live attenuated vaccines are at a much higher chance of A) working and B) being more effective.  This paper is further proof that researchers and pharma should stop being fearful of live attenuated vaccines and actually push more research and funding into them.  Instead, as is with the recent case of Sanofi and Immune Design, they have decided to go with with a subunit vaccine.  This, after multiple failures of subunit vaccines and multiple papers supporting live attenuated vaccines.

It's not a case of "whatever works is good," it's that so much effort is going into subunit vaccines which are showing modest results at best.  The quicker more live attenuated vaccines gets into clinical testing the higher the chances of success.

Edited December 19, 2015 by Evaluate

[lexyz22]

13 hours ago, Evaluate said:

I'm not sure what that means.  Ultimately the argument is that live attenuated vaccines are at a much higher chance of A) working and B) being more effective.  This paper is further proof that researchers and pharma should stop being fearful of live attenuated vaccines and actually push more research and funding into them.  Instead, as is with the recent case of Sanofi and Immune Design, they have decided to go with with a subunit vaccine.  This, after multiple failures of subunit vaccines and multiple papers supporting live attenuated vaccines.

It's not a case of "whatever works is good," it's that so much effort is going into subunit vaccines which are showing modest results at best.  The quicker more live attenuated vaccines gets into clinical testing the higher the chances of success.

Hey man, the Immune Design vaccine was a trivalent subunit, but Sanofi's HSV-529 is still in trials due to be reported in October 2016. The one you heard about a few months ago is the one that got a 20% reduction or something. The one in trials due for October is their replication defective vaccine by David Knipe (i think)

[Evaluate]

On 2015-12-19 at 9:31 AM, lexyz22 said:

Hey man, the Immune Design vaccine was a trivalent subunit, but Sanofi's HSV-529 is still in trials due to be reported in October 2016. The one you heard about a few months ago is the one that got a 20% reduction or something. The one in trials due for October is their replication defective vaccine by David Knipe (i think)

Yes, HSV-529 by Sanofi and NIAID is a live attenuated vaccine.  Those results, as you said, are expected in October 2016.  Sanofi also is collaborating with Immune Design but the way they went was with a subunit vaccine.

[elnino]

So it has been pretty well tested and proven that a live vaccine is superior as a prophylaxis, but what about as a therapeutic?

Genocea and Admedus are in therapeutic trials. I maintain some hope for them only for this reason. 

Halfords recent paper stated that the live vaccine is superior because it creates antibody response in addition to the T-cell response, and the antibodies are what is needed for the first 48 hours after infection. But since those seeking a therapeutic vaccine already have these antibodies, I suppose this deficiency is not significant and the T-cell-only response created by Genocea and Admedus will be effective. 

Any thoughts?

[Zlice]

From what I know is that live vaccine will make our antibodies in always at high alert, so that when the virus come out from its hiding our antibodies could detect it and quickly attack it.

I dunno for the long period effect for these, hopefully the virus will not be so smart to figure out our moves by using live vaccine.

and hopefully they speed up the test so it will be out soon.

I'd rather spend $10k in 1shot than dealing with antivirals everyday.

[dont quit!]

Just now, elnino said:

So it has been pretty well tested and proven that a live vaccine is superior as a prophylaxis, but what about as a therapeutic?

Genocea and Admedus are in therapeutic trials. I maintain some hope for them only for this reason. 

Halfords recent paper stated that the live vaccine is superior because it creates antibody response in addition to the T-cell response, and the antibodies are what is needed for the first 48 hours after infection. But since those seeking a therapeutic vaccine already have these antibodies, I suppose this deficiency is not significant and the T-cell-only response created by Genocea and Admedus will be effective. 

Any thoughts?

The difference with the antibody response is that Halfords vaccine will flood your body with antibodies. It should in theory overwhelm the wild type virus. What tends to happen is that the antibody response weakens while the virus is latent in the DRG. So its like injecting millions of attenuated viruses that produces millions of antibodies to take on thousands of wild type virus. Those millions of antibodies probably wouldn't be  produced any other way.

Edited December 24, 2015 by dont quit!

[elnino]

3 hours ago, elnino said:

So it has been pretty well tested and proven that a live vaccine is superior as a prophylaxis, but what about as a therapeutic?

Genocea and Admedus are in therapeutic trials. I maintain some hope for them only for this reason. 

Halfords recent paper stated that the live vaccine is superior because it creates antibody response in addition to the T-cell response, and the antibodies are what is needed for the first 48 hours after infection. But since those seeking a therapeutic vaccine already have these antibodies, I suppose this deficiency is not significant and the T-cell-only response created by Genocea and Admedus will be effective. 

Any thoughts?

I posted the same question to Halford on his blog today and this is his response:

 

Thanks for your thoughtful comments. Simply put, I wholeheartedly agree with everything you stated. All of my research to date informs us that a live-attenuated HSV-2 vaccine (that is capable of self-limited replication after injection into the body) will most likely be required if the goal is to obtain a PROPHYLACTIC HSV-2 vaccine that works.

For those who are not familiar with the meaning of the term, a PROPHYLACTIC HSV-2 vaccine is something that would most logically be given to children or adolescents before the onset of sexual activity, and the benefit of the vaccine would be very similar to the chickenpox vaccine…..it would vastly reduce the vaccine recipient’s risk of ever contracting HSV-2 genital herpes. It is in this specific setting where my published work is relevant, as it suggests that my lab’s live HSV-2 0deltaNLS virus would serve as a superior PROPHYLACTIC HSV-2 vaccine relative to anything tested in humans to date (e.g., Herpevac).

Chevyboy, you are asking if a subunit vaccine such as is being offered by Genocea or Admedus (or Agenus) would be more appropriate for the very different application of a THERAPEUTIC HSV-2 vaccine for those who are already infected with HSV-2. The simple and honest answer here is, “I have no idea” if the HSV-2 0deltaNLS vaccine would be a good therapeutic HSV-2 vaccine or if it would offer any advantages over the Genocea or Admedus subunit vaccines. Therapeutic HSV-2 vaccines explore a territory in immunological research that is largely uncharted, and thus we are entering the realm of empirical science (i.e., guesswork). Given the landscape where there are so few known principles to draw upon, I am in no position to offer a firm opinion on (1) whether or not GEN-003 should work well as a therapeutic HSV-2 vaccine or (2) whether a live HSV-2 vaccine such as HSV-2 0deltaNLS would work any better at reducing the symptoms of HSV-2 genital herpes in those who are already infected with HSV-2.

I am certainly interested in running clinical trials of the HSV-2 0deltaNLS virus as a therapeutic vaccine, but 20+ years of experience in research informs me that it is always most prudent to tell people when you are standing at the edge of knowledge looking out into the unknown, and thus currently lack sufficient information to predict what you will find as you start the next leg of the journey. I look forward to seeing more data that bears on the questions of (1) What is the viability of a therapeutic HSV-2 vaccination concept?; and (2) If a therapeutic HSV-2 vaccine is possible, then what is the best HSV-2 vaccination regimen (of hundreds of possibilities) to achieve the goal?

Good research is very labor-intensive and takes a lot of thought and planning. I would be happy to see the beginnings of a real answer to these questions by 2019.

– Bill H.