Two readers recently asked me about the Agenus HerpV trials.  Given that this is a topic of broad concern to genital herpes sufferers, I have converted the original query and my response to a blog post as follows.

– Bill H.


November 8, 2013

Dr. Halford,
Agenus released their initial phase 2 results: . I’m trying to appreciate why a 15% reduction in viral shedding would be clinically significant since, if I understand the explanation of the Genocea results, it is barely statistically Significant. Am I misunderstanding the significance of the results? It seems like this trial was a flop.

Also, assuming they weren’t grinding the participants up and measuring viral protein, is the viral load reduction estimate simply a measure of how much virus was being picked up by the culture swabs?

– Staying Upbeat


November 12, 2013

Hi Staying Upbeat,

I have read the link to the press release you cite and I am deeply troubled. I am not sure who I am more upset with…..the scientists who are willing to distort the truth and say that these results are “exciting,” or the biomedical investors and NIH reviewers who will likely continue to support this folly. The “statistically significant” 15% reduction in HSV-2 shedding they report is a non-event. What is the cutoff for a non-result here? What % reduction in HSV-2 shedding does valtrex achieve? Probably well above a 200% reduction if I had to guess. The goal of a therapeutic HSV-2 vaccine should be to do better than valtrex……not worse.

If I had 6 genital herpes outbreaks in 2012 that lasted for an average of 10 days, and then I enrolled in the Agenus trial in 2013 and experienced 6 genital herpes outbreaks that “only lasted” for 8 days, that would be a 20% reduction in genital herpes symptoms and this might be accompanied by a 40 – 60% reduction in HSV-2 shedding. This type of response for a herpes therapeutic would seem pretty weak to me, but in the bizarro world that “herpes vaccinologists” have entered, apparently as long as you can clear the bar of p < 0.05, then apparently your herpes vaccine is a home run and the results should be trumpeted from the highest tower.

I suspect that there is a single motivation for this press release………the only logical reason for putting lipstick on this pig is if Agenus hopes to ask (1) NIH reviewers and/or (2) biomedical investors to support the continued folly of testing the HerpV vaccine in human clinical trials.

I would hope that any science-minded person would recognize that a “15% reduction” is an average across a group, and that in the real world a 15% reduction in HSV-2 shedding would have a standard error on the order of +/- 50%.

In the world of science, the way we formally state such a result is…….”This HSV-2 vaccine produces a 15 +/- 50% reduction in HSV-2 shedding from the genital tract.” What most scientists would conclude from this result is……”This HSV-2 vaccine is a waste of time, since what I was looking for was a vaccine that elicited at 1000 +/- 300% reduction in HSV-2 shedding (i.e., a 10-fold reduction in HSV-2 shedding).”

For me, the take-home message is simple from the Herpevac trial, the Genocea (GEN-003) trial, and now the Agenus HerpV Trial……..It is time for scientists to put on their big boy pants, and admit that the molecular reductionist approach to HSV-2 vaccines has simply not panned out. It is time to move on and test some fundamentally new ideas like a live-attenuated HSV-2 vaccine that elicits 100 times greater protection in animal models.

Millions of lives continue to be destroyed each year by the vaccine-preventable disease that is HSV-2 genital herpes. People deserve better than the continued folly of HerpV and all of the other HSV-2 vaccine approaches that continue to ignore the obvious………..when you immunize people with 0.2% of HSV-2’s antigens, you tend to harvest only 0.2% of the protection against HSV-2 that is possible.

Dear Staying Upbeat, thank you for your query. I am, of course, not in the least upset with you. Rather, I am upset with people who continue to occupy “leadership positions” in the HSV-2 vaccine world despite their chronic inability to differentiate promising HSV-2 vaccines from hollow promises like HerpV.

The reason I find the claims that “the HerpV 15% reduction is exciting” so troubling is that a scientist either has to be (1) ignorant of what a real HSV-2 vaccine-induced change would look like or (2) willing to distort the truth and pretend like a vaccine that induces a 15% reduction in HSV-2 shedding is anything other than an abject failure. I note that all of my colleagues who study herpesviruses or herpes vaccines tend to be exceedingly smart people, and thus I don’t really question their intelligence; by-and-large, these are people who I consider much smarter than myself and certainly better able to navigate the NIH funding system. However, intelligent or not, I fear that these individuals may be selling out their integrity to support a flavor-of-the-day herpes vaccine (i.e., the HerpV vaccine) that the objective measurements indicate is in the process of sinking, much like the Titanic after it hit that iceberg in the North Atlantic. The only question left in my mind is how much more time and money are we going to waste on the HerpV vaccine before a critical mass of scientists agree that this is not a viable herpes vaccine candidate.

One of the quotes I learned as a junior scientist that deeply resonated with me was that of Charles Sanders Pierce (, and the quote is as follows: “There is one thing even more vital to science than intelligent methods; and that is, the sincere desire to find out the truth, whatever it may be.”

The truth is that the concept of “antigenic breadth” explains both why HSV-2 subunit vaccines like HerpV keep failing (i.e., because 0.2% of HSV-2’s foreign peptides is too little to make for a good HSV-2 vaccine), and the concept of “antigenic breadth” explains why whole HSV-2 viral vaccines are far superior…..because they present 50 to 99% of HSV-2’s peptides to the vertebrate immune system in the proper context of virus-infected cells.

Perhaps it is time to consider some new ideas that might actually lead us to the important goal of making a HSV-2 genital herpes a vaccine-preventable disease of the past, and sparing tens of millions of our children from the needless suffering caused by this disease. For this reason, I look forward to the results of the HSV-2 ACAM-529 whole virus vaccine trial (, as this is the only new HSV-2 vaccine idea of any scientific substance that has advanced to human clinical trials in the past 10 years. ACAM-529 truly offers a new and real hope of eliciting some type of real protection against HSV-2 genital herpes, and I hope that my colleagues in the vaccine industry and the NIH will support its rapid advancement through human clinical trials. ACAM-529 may not be the final solution to our HSV-2 vaccine needs, but at least it is the first concrete step that we have made in the right direction in the 21st century.

– Bill H.

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