New ideas in vaccine design: HSV-2

Lets say Im holding in my hand, a syringe.

In this syringe is an experimental vaccine for HSV-2. The dreaded genital herpes.

The vaccine is a live HSV virus with one gene deleted, ICP0 (free paper about this virus). When ICP0 is gone, the virus can still establish life long infection (if you get this vaccine, you will be infected with HSV), but the viruses produced from this infection will be extraordinarily susceptible to interferon. This means that rather than getting a freak-out-inflammatory response where your immune system goes nuts when the vaccine virus reactivates (causing painful sores), your innate immune system can easily clean up most of it (thanks to the interferon), and your adaptive immune system cleans up the little bit of virus that gets away.

Because the crippled herpes virus is almost identical to regular HSV-2, this 'little' adaptive immune response creates cytotoxic T-cells that are specific for the vaccine strain... and HSV-2. You get antibodies that are specific for the vaccine strain... and HSV-2. And because the crippled herpes virus causes a real herpes infection that randomly reactivates, every viral reactivation acts like a tiny booster shot, creating more/better CTLs and antibodies.

This means if you were ever exposed to real herpes, herpes specific CTLs and antibodies would already be there, primed and ready to go, able to prevent the 'bad' herpes from establishing infection. So while you would be infected with the crippled herpes for life, you would never get infected with the 'bad' ones.

Do you want this vaccine?

I sure as hell do, but Im a vaccine junkie (every vaccine I get increases my superpowers), and I really, really dont want HSV-2 (though for all I know, I already have it-- 75% of people infected with HSV-2 never know it because they never get outbreaks).

Well, herpes vaccine design is running into the same walls as HIV-1 vaccine design. Theyve tried everything, and everything has failed. The 'old school' ways of making vaccines just dont work for HSV or HIV-1. So herpes researcher William Halford is like, 'Old school isnt working. Lets try something radically different. Maybe a life-long infection with a vaccine HSV-2 virus can be a safe, effective way to prevent disease." But right now this new HSV-2 'vaccine' is just an idea in the head of Halford and the other herpes researchers who 'believe' him.

Halford isnt a nut suggesting we go straight to clinical trials in people, but he is having difficulty getting The Man to even consider his idea. People are obviously cautious about Halfords approach. You would be infecting people with a real, life-long virus. Jesus just think of the PR "Hi! Im Dr. Brown! Im going to infect your baby with herpes. Genital herpes. BRB!!!" *rolleyes* And the old ways should work. Its just a matter of figuring out the right recipe-- maybe a live vaccine wouldnt be necessary if one of the nice, safe, subunit vaccines worked out. Its hard to win people over to a 'scary' way of vaccinating when the 'safe' way still might be possible.

Halford pleaded his case in an editorial in Future Virology last year (its available online for free, and I recommend it). Subunit vaccines are limited. Dead viruses dont get us the immune response we need. Previous 'live' HSV vaccines are eventually cleared, robbing us of the 'baby boosters' that a real, infectious virus would provide. They are the same damn problems we have with HIV-1 vaccines-- the old ways of doing things dont friggen work!! Halfords idea might not be perfect, but it might just be as perfect as we can get with todays technology.

But rather than screaming 'EXPELLED!! EXPELLED!!' and taking his ideas straight to high schools, Halford is plugging away in the lab. Supporting (or crushing) his own ideas with evidence.

*pokes Halford* Hurry up!

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Thanks for a nice summary about an interesting approach.

I'll have to look at the editorial. What about using DNA vaccines? Or engineering a different virus, with a better reputation, like Vaccinia, say, to produce Herpes 2 antigens? That might be more sellable.

Pardon my ignorance on the subject, but if you can prepare a live HSV with one gene deleted, can't you prepare a live HSV with two or three genes deleted to make a pushover virus for your immune system to practice against? Or maybe one that you wouldn't need ongoing treatments with interferon for?

By Moderately Unb… (not verified) on 03 Dec 2008 #permalink

non-biiologist question...
so would this have a similar effect if you were 'infected' by the vaccine even after infection from the original disease? given that you are introducing a disease to induce a given reaction, I'm not sure I understand why it wouldn't work if done in the 'wrong' order...

btw, interesting point by george... the idea of a contagious vaccine sounds wonderfully ironic. (though the potential lack of profitability would probably worry some...)

the idea of a contagious vaccine sounds wonderfully ironic. (though the potential lack of profitability would probably worry some...)

Not exactly new. The Oral Polio Vaccine is exactly that: the live virus reproduces in the gut and is shed with the feces. In areas where fecal/oral transmission is relatively common (i.e. places subject to polio transmission) others can become immune thanks to the original vaccinee.

Live measles virus also has some transmissibility, although IIRC not as much as the OPV.

By D. C. Sessions (not verified) on 03 Dec 2008 #permalink

Presumably if this was globally abopted after a few generations HSV-2 would be extinct?

Willy-wally, do you spend all day trolling scienceblogs looking to be 'persecuted'?

Hmmm, I don't know. Do I have any resident beneficial or even neutral viruses in my system? Will introducing this new virus to that community create a slum area or will it improve the economy?

Would it be necessary to increase the infrastructure capacity or is the existing system sufficient?

By Gary Bohn (not verified) on 03 Dec 2008 #permalink

Wallace;

Hell no. I'm sure that many children who get diseases they were not vaccinated against, assuming they survive to adulthood, would be happy to sue their parents. Perhaps that would convince stupid parents to decide, all on their own, to take precautions with their kids.

By Gary Bohn (not verified) on 03 Dec 2008 #permalink

Hmm ... would also like to make this bivalent for HSV-1 as well. Do not want cold sores. Also do not want crotch sores.

@Unbalanced Squid
You won't need to take interferon. Your body will rely on the interferon it produces to hold off the HSV.

By Rogue Epidemiologist (not verified) on 03 Dec 2008 #permalink

Yeah, I'm with Cath@VWXYNot? I'm all for any vaccine that can't give me a disease, or even most of the live attenuated vaccines that are just incredibly unlikely to give me a disease, but to vaccinate with a virus that only works if it DOES establish a chronic infection? No thanks! We've already seen mutation of mulitply deleted, live-attenuated SIV in vivo such that weak viruses become stronger over time (or cause AIDS outright in neonates). I spoke to the PI of the paper below a few years ago and she left me with the very strong impression that, especially in the case of SIV/HIV, the virus WILL overcome whatever deletion you give it if given enough time.

http://www.nature.com/nm/journal/v5/n2/abs/nm0299_194.html

Yeah, I'm with these other guys. Even if you could rejigger HSV-1 to not give me cold sores but have it establish a life long infection providing effective resistances for HSV-1, HSV-2, HIV, Ebola, and the Common cold... I wouldn't take it.

Seriously, who would? The thought of a weak virus that can't do much of anything is too freaky.

75% of people infected with HSV-2 never know it because they never get outbreaks.

And those who do may find that the virus incubated for years before an outbreak. I'm not trying to freak anyone, but that can happen, too. I should think that someone would seriously consider taking the vaccination if that person's partner carries HSV-2, and they should have that option.

However, I see absolutely no reason for children to get it unless those fundamentalist parents want to have sex with their kids, Wallace.

Sandra,
From what I've heard at my vaccine conference today (go CAVD!), DNA vaccines are not very immunogenic. That's why vaccines are usually based on some other vector.

On the whole "vaccines causes life long infection" thing; wouldn't that be the way the chickenpox (herpes zoster) vaccine works? I'm not sure, but I was under the impression that it could still cause shingles later in life, which implies that it's a herpes infection.

By JustaTech (not verified) on 03 Dec 2008 #permalink

Willy, did you just volunteer for in vivo trials?

What about people with compromised immune systems? That could be a huge problem for people with HIV or who get an organ transplant.

@Unbalanced Squid
You won't need to take interferon. Your body will rely on the interferon it produces to hold off the HSV.

Thanks. I did not know that the body made its own interferon. :)

By Moderately Unb… (not verified) on 04 Dec 2008 #permalink

It is an interesting idea and I would be willing to participate in a clinical trial of such a vaccine. For what it is worth ($0.00), some years back I was in a phase 3 trial of a HPV2 vaccine and was tested for prior infection with the virus (psst - negative). and had no significant side effects at all. Not that it mattered if I had the test vaccine or placebo since both had the same efficacy - %0.

Agreed that we need new approaches to vaccine design - to add to the list of infections where the standard approach to vaccine design has been useless: Hep C.

Do I want it?

Same as any other vaccine or any other medical treatment for that matter. Evidence of risks vs benefits.

If I was thinking about getting involved in a trial: evidence of risks vs benefits so far, plus potential benefit to mankind (personal altruism). And, where appropriate, remuneration. ($)

To be honest, while HSV2 is a pain in the butt (or wherever else you get it) it's not commonly life threatening, unlike measles or pertussis or tetanus or HPV. Pain-in-the-butt diseases have a higher threshold for judging risk/benefit decisions than potentially lethal ones.

HSV2 isn't "genital" herpes. It's just one of the two HSV viruses that are more likely to cause a recurrent infection below the waist than above it. In fact, these days HSV1 is probably a more common cause of genital herpes, mainly because fewer kids contract it as cold sores before they become sexually active. This also means they miss out on the partial cross immunity to HSV2.

And who said that a disease automatically deserves freak-out status just because it is sexually transmissible? Why are oral cold sores considered a normal part of life while the same disease occurring on your naughty bits is the end of the world?

Dear ERV,

Great synopsis above. I noticed it a few months after it was posted but figured I would wait to comment until the data was written up. You closed your synopsis with the concluding statement......

"Halford is plugging away in the lab. Supporting (or crushing) his own ideas with evidence."

Per the e-mail below, you can see that "supporting" would be my vote for a word choice, and you can arrive at your own decisions after August 17, 2010 when the work is published. Importantly, this is an open-access paper so it will be freely available to anyone in the world immediately upon publication.

Please note that this is only paper #1 which focuses on the remarkable safety of interferon-sensitive HSV-2 viruses (rendered so by mutations in the ICP0 gene). A 2nd paper is being written up on effectiveness, and I believe will lend strong support to what I have been saying for four years.... vaccination with a live-attenuated HSV-2 virus leaves vaccine recipients with meaningful and durable protection against later exposures to wild-type HSV-2. In my hands, the same cannot be said of the most commonly cited of HSV-2 subunit vaccines.

With best regards,
Bill Halford

Date: Fri, 6 Aug 2010 15:06:38 -0700
Subject: PLoS ONE Publication Date

Dear Dr. Halford,

We are pleased to announce that your article entitled "Herpes simplex virus 2 ICP0- mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine" will be published in PLoS ONE on Tuesday, August 17th.

On publication, your paper will be available online at http://dx.plos.org/10.1371/journal.pone.0012251.

... will be published in PLoS ONE on Tuesday, August 17th...

*looks at calendar*

Awwwww... :(

LOL! Cant wait to read it! Sorry in advance if I crush it :P

Crush away! Critical review of one's ideas is a good thing in science, because this is how you (1) figure out the weaknesses in your argument and (2) design the next set of experiments to address those weaknesses. - BH

By Bill Halford (not verified) on 08 Aug 2010 #permalink

hi,

please, i want HSV2 vaccine standard for my research, how i can obtain

Thanks