On the Einstein Vaccine

Einstein photo

Enough blog readers have badgered me about this question for a long time, and I have held my tongue for long enough.  My honest and unfiltered thoughts on the “Einstein Vaccine” follow.  I begin with the query (straw) that broke the camel’s back.

– Bill H.

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Hi Bill

I find your work inspiring and amazing. It does give hope to many. I have two questions.
1. Is there a crowd funding site established to foster a non us trial of your vaccine, so people like me can donate?

2.. And aren’t you being perhaps a bit dismissive of the Einstein vaccine? The examples you cited did not show adoptive transfer. They elicited neutralizing antibodies, while the Einsten vaccine elicited non neutralizing ADCC antibodies. They got some latency, The Einstein vaccine got absolutely none.

That last one alone seems to be a very different animal. I am with you a thousand percent that no approach like this has ever worked in the past. But I think they do have something slightly novel. Maybe not worth years of exceptional money and time when you seem so close, but still worth discussion.

Mark Twain

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April 10, 2016

Hi Mark Twain,

I wanted to clarify one point in your comment. You wrote, “And aren’t you being perhaps a bit dismissive of the Einstein vaccine?” Therefore, please allow me to clarify that I am being completely dismissive of the “Einstein Vaccine”….I think it is another iteration of a 20-year old concept called a replication-defective HSV-2 vaccine which I believe is (1) grossly overattenuated and therefore (2) is vanishingly unlikely to elicit a DURABLE immune response to HSV-2 that will endure over a human lifetime.

I have no doubt someone will say, but Betsy Herold is in a pre-eminent institution on the East Coast. Without a doubt her academic CV is much, much bigger than mine, but I have never been a fan of using the size a person’s CV or the name of their academic institution to evaluate an investigator’s potential to solve a particular scientific problem.

So, let’s compare the investigator under question, Betsy Herold, and her qualifications to solve the HSV-2 vaccine problem versus my qualifications to do the same. The problem in question, developing a vaccine capable of eradicating all forms of herpetic disease, lies squarely at the interface of herpes simplex virus virology and immunology which I have been studying in earnest since 1992. As evidence of this claim, here is a list of my publications:

http://www.ncbi.nlm.nih.gov/myncbi/browse/collection/40425465/?sort=date&direction=ascending

Now, how many publications establish Betsy Herold as a bona fide herpes immunologist? I am right now going to PubMed to exhume this exhaustive list. I hope that it does not take up too much space on my blog. Let’s see…..

1. First off, here are a complete list of the investigator’s 144 publications…..
http://www.ncbi.nlm.nih.gov/pubmed/?term=herold+BC
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2. Second, let’s see how many touch upon the investigation of herpes immunology? Being generous, here is what I can find:

1: Boukhvalova M, McKay J, Mbaye A, Sanford-Crane H, Blanco JC, Huber A, Herold
BC. Efficacy of the Herpes Simplex Virus 2 (HSV-2) Glycoprotein D/AS04 Vaccine
against Genital HSV-2 and HSV-1 Infection and Disease in the Cotton Rat Sigmodon
hispidus Model. J Virol. 2015 Oct;89(19):9825-40.

2: Petro C, González PA, Cheshenko N, Jandl T, Khajoueinejad N, Bénard A,
Sengupta M, Herold BC, Jacobs WR. Herpes simplex type 2 virus deleted in
glycoprotein D protects against vaginal, skin and neural disease. Elife. 2015 Mar
10;4. doi: 10.7554/eLife.06054.

3: Keller MJ, Madan RP, Shust G, Carpenter CA, Torres NM, Cho S, Khine H, Huang
ML, Corey L, Kim M, Herold BC. Changes in the soluble mucosal immune environment
during genital herpes outbreaks. J Acquir Immune Defic Syndr. 2012 Oct
1;61(2):194-202. PubMed PMID: 22820806; PubMed Central PMCID: PMC3685489.

4: Cheshenko N, Trepanier JB, Segarra TJ, Fuller AO, Herold BC. HSV usurps
eukaryotic initiation factor 3 subunit M for viral protein translation: novel
prevention target. PLoS One. 2010 Jul 27;5(7):e11829.

5: Fakioglu E, Wilson SS, Mesquita PM, Hazrati E, Cheshenko N, Blaho JA, Herold
BC. Herpes simplex virus downregulates secretory leukocyte protease inhibitor: a
novel immune evasion mechanism. J Virol. 2008 Oct;82(19):9337-44.

6: Hendrickson BA, Guo J, Brown I, Dennis K, Marcellino D, Hetzel J, Herold BC.
Decreased vaginal disease in J-chain-deficient mice following herpes simplex type
2 genital infection. Virology. 2000 May 25;271(1):155-62.

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So, I arrive at my conclusion, from an investigator whose career is a basically a shotgun blast of publications that focus on all things that touch upon “genital infections” (HIV, gonorrhea, HSV, chlamydia, microbicidal gels, seaweed treatments for herpes [i.e., griffithsin)), I must confess that within the scatter of that shotgun blast, I do see a handful of publications that intersect with my core area of expertise……….herpes immunology. But, as someone who has been a dinky-dye herpes immunologist for 20+ years, I find this person’s understanding of the complex and intricate interface of molecular virology and host defense to be lacking. So, to answer your question, I long ago dismissed the Einstein vaccine….completely, not partially. Mr, Twain, if you think I am simply denigrating a competitor, that is your perogative. If you would like to think of me as a mean-spirited and horrible person, please feel free to do so.

For those of you die-hard enough to be curious what I think is the real biology of HSV-2 that must be factored in if one wishes to obtain an effective HSV-2 vaccine, I attach links to two of my publications below.

The first publication is a very short editorial that marks the beginning of my transition from a HSV latency-reactivation guy to the inventor of a live HSV-2 ICP0- mutant vaccine capable of eradicating all forms of HSV-2 induced herpetic disease.  Importantly, the same technology can be easily adapted to HSV-1 to eradicate HSV-1 induced herpetic disease.  A link to this short editorial is here:

Halford, 2007 (Future Virology Editorial)

The second publication is a rather long, but complete description of what I believe is the essence of how HSV-1 and HSV-2 regulate their transitions from active replication to latent infection and back again to active replication (reactivation).  Oddly  enough, I think HSV’s latency-replication balance hinges on a delicate dance between the LAT-ICP0 (RL) region of the HSV genome and the host immune response to HSV……two inseparable partners that a control a single biological process.  I find this delicate dance between these two partners to be nothing short of a stunning example of the simple, elegant beauty of biological systems once you drill down to how they really work.  Including myself, I am not sure if there are even 20 scientists in the world who understand this biological system in the way I lay out (with my former mentor, Bryan Gebhardt) in this book chapter.  This has been my passion since 1992, and the advancement of an effective HSV-2 vaccine is simply a by-product of investing 15 years beforehand (1992 – 2007) to take the time to properly understand the biological system in question.  The molecular intricacies of this system remain a complete riddle, but I believe the book chapter offers a realistic and empirically justifiable model / framework to at least enable a coherent discussion between scientists of the major variables that impinge upon, and regulate, HSV’s alternations between latency (periods of dormancy) and reactivation (periods of activity that may cause recurrent disease).  The book chapter may be found here:

Halford & Gebhardt, 2010 (Viruses and Interferon Ch5)…..please note that the color Figures at the end of the document are far cooler and easier to interpret than the B & W Figures that were put into this landmark book that I doubt anyone even knows exists.

–  Bill H.