In a placebo-controlled trial, the GEN-003 vaccine “achieved a 40% reduction” in viral shedding when administered to persons already infected with HSV-2 and living with recurrent genital herpes.
Most lay people don’t get scientific phrase-ology and what it means, so I paraphrase the results for everyone below. As a way of introduction to this concept, my older brother Keith sent me a 1-page document entitled “UNDERSTANDING AND WRITING SCIENTIFIC RESEARCH PAPERS,” when I was a graduate student in the mid-1990s. This simple document was pretty eye-opening to a naive 27-year-old graduate student because it reflected a simple truth that I had yet to experience.
There is a language that scientists have evolved to deal with the reality (1) that more than one-half of avenues of research are dead-ends (the real number is >90%), but (2) because of our funding systems, it is scientific suicide to report, “Well those 4 years and $2 million dollars you gave me…….yeah, that didn’t work out. I mean, dude, it was just a total waste of time and money. So, Mr Gates, I have this new idea and I was wondering if I you could spare another $2 million?”
Rather, scientists have evolved a language for reporting research that allows them to (1) turn the equivalent of a big, fat stinking turd into very positive language about what they learned over the past 2- to 4-years at a cost of $0.5 – 2 million and (2) on the heels of doing so, ask, without so much as flinching or twitching, for a similar or greater amount of money to turn the crank again and “further advance this promising avenue of scientific inquiry.”
As a scientist who is now 21 years older and a bit more jaded by the realities of scientific funding, I can tell you that one of the buzz phrases that gets any real scientists’ ears to perk up and smell blood in the water is the phrase, “Our findings were statistically significant.”
Don’t get me wrong; statistics are very important to provide an unfamiliar audience with a mathematical calculation of the probability of randomly observing a difference this large. The threshold for “statistical significance” is 5%. That is, if I ran this experiment 20 times, then 1 out of 20 times, the random noise of the measurements would give me the minute difference (e.g., 40%) that I am reporting.
That said, it is common knowledge amongst scientists that if you have to lead with statistics as your front story, what this effectively means is…..”While our actual results and treatment under study may convey the impression that NOTHING HAPPENED (because that is what happened), we ran enough replicate tests over and over again that we can proudly confirm that the needle did in fact move above 0%, and that movement was “statistically significant.” Real scientifically-measured differences that are worth discussing typically have statistical significance at the level of 0.01% or less (i.e., not the minimum 5% required to claim “statistical significance”). In other words, I would have to run this experiment 10,000 or more times to randomly observe this large of a difference. In terms of HSV-2 virus shedding, a study would have to show a 5,000 to 10,000% reduction in HSV-2 shedding (50- to 100-fold) to achieve statistical significance at the p< 0.0001 level, and if GEN-003 vaccination elicited a 50- to 100-fold reduction in HSV-2 shedding, then they would not be leading with the “consolation prize argument” of achieving statistical significance at the p<0.05-level.
In practical terms, less than a 2.0-fold effect in science is generally a losing proposition, and a 1.0-fold effect is, by definition, “NO EFFECT” at all. Real scientific discoveries that are worth talking about are generally based upon 5- to 500-fold effects. The latest GEN-003 vaccine press-release reports that their therapeutic HSV-2 vaccine achieves a 1.7-fold reduction in HSV-2 shedding that is simply not worth discussing.
Getting the needle of “HSV-2 shedding” to move is fine, but the relevant questions are:
(1) How far do you need the needle to move to merit discussion? (i.e., what is your medically relevant endpoint?) and
(2) How close did you come to reaching this endpoint? I would suggest that the reported GEN-003 vaccine-induced reductions in HSV-2 shedding in genital herpes sufferers are about 2% of the medically relevant endpoint. So, the results may be “statistically significantly greater than 0%,” but they are nowhere remotely close to the 50- to 100-fold reduction in HSV-2 shedding that is likely possible with a live-attenuated HSV-2 vaccine (read more here), and that is what would be required to meaningfully reduce the chronic symptoms of recurrent herpetic disease.
I copy-and-paste the relevant “blood in the water” excerpt from the latest GEN-003 vaccine press release below, and then I put these results into context of what it means in practical terms.
Genocea Touts Early Look at Placebo-Controlled Herpes Vaccine Study
“One of two tested doses of the vaccine led to a statistically significant reduction of what’s known as “viral shedding”—when the patient is releasing the virus and is contagious—compared to a placebo. Patients got three injections of GEN-003 or a sham—one every 21 days—and were then observed 28 days later.
The dose that succeeded….led to a 40 percent reduction in viral shedding, compared to a 6 percent increase for placebo patients. The dose that failed led to a 27 percent reduction, and didn’t hit statistical significance.”
Before offering a scientific explanation of what the above means, let me reiterate that what I am saying in this post is common knowledge amongst those who live in the science world. That is, there can be a profound difference between (1) how scientific results are spun to keep the funding coming and (2) the scientific reality that the results being reported equal nothing short of direct proof that the scientific proposal that the authors are advocating is simply not supported by the data they are presenting.
I think this is eloquently summarized in an email that a very talented professional science editor passed along to me as a junior faculty member pointing out the frequent disconnect between (1) the overly elaborate language authors often use to delude themselves into believing that a failing line of scientific inquiry warrants publication and (2) the simple reality of what any observer with common sense will conclude upon reading such a manuscript:
“This sort of reminds me of some papers I have recently edited….
Sherlock Holmes and Dr Watson went on a camping trip. After a good meal and a bottle of wine they lay down for the night, and went to sleep. Some hours later, Holmes awoke and nudged his faithful friend awake “Watson, look up at the sky and tell me what you see.”
Watson replied, “I see millions and millions of stars.” “What does that tell you?” Holmes questioned.
Watson pondered for a minute. “Astronomically, it tells me that there are millions of galaxies and potentially billions of planets. Astrologically, I observe that Saturn is in Leo. Horologically, I deduce that the time is approximately a quarter past three. Theologically, I can see that God is all powerful and that we are small and insignificant. Meteorologically, I suspect that we will have a beautiful day tomorrow. What does it tell you?”
Holmes was silent for a minute, then spoke. “Watson, you idiot. Someone has stolen our tent.”
So, in similar terms, let me paraphrase what the GEN-003 results mean.
- The GEN-003 vaccine achieves a 1.7-fold (40%) reduction in HSV-2 shedding in individuals suffering with recurrent genital herpes. A 1.0-fold reduction is “NO EFFECT,” and in practical terms, anything less than a 2.0-fold (50%) reduction does not merit discussion.
- Valacyclovir is known to reduce HSV-2 shedding by 50%; hence, the GEN-003 vaccine does not offer a significant improvement relative to the current standard of medical care.
- Valacyclovir has not slowed the epidemic spread of genital herpes because a 2-fold reduction is not biologically / medically relevant.
- HIV antiviral drugs, by comparison, actually work unlike the garbage that herpes patients have been provided for the past 20 years. HAART (anti-HIV treatment regimens) reduce HIV RNA loads in the bloodstream by 100,000 – 1,000,000-fold (i.e., about 100,000,000%; not 40%). For each 10-fold drop in infectious HIV in the bloodstream, there is a 2.4-fold reduction in HIV transmission risk. Hence, when HAART is effective in patients, these individuals have a 100-fold lower risk of transmitting HIV to another person…..and that is based on a 100,000-fold drop in infectious HIV in the bloodstream.
- So, against that background, everyone can do the math. What does a 1.7-fold drop in HSV-2 shedding mean in recipients of the GEN-003 vaccine? It means that the NIH has been duped, again, into throwing an inordinate amount of time and money at a vaccine that is effectively an ever-so-slight tweak of the same glycoprotein D-2 subunit vaccine (plus a dash of ICP4) that has been failing in human clinical trials for the past 30 years.
I close by noting that the antigenic breadth of the GEN-003 vaccine is about 2% of the entire HSV-2 virus. Guys, has it ever occurred to you that the 98% of HSV-2’s potential antigens missing from gD-2 subunit vaccines could, perhaps, limit their efficacy? Six years of papers from the Halford Lab and now the Carr Lab (Royer, et al, 2016) say that this is more than just a nice idea, but is in fact the simple truth……live HSV vaccines work about 50- to 100-times better than gD-2 subunit vaccines. For non-scientists, this is like comparing a Ferrari to a covered wagon…..they both have 4 wheels and they both move at speeds that are statistically significantly greater than 0 miles per hour. However, if you have to travel from New York City to Los Angeles on surface roads, which one would you choose? Personally, I will take a 21st-century car capable of moving at 200 mph over the outdated technology of a covered wagon that moves at 2 to 4 mph.
If you want a therapeutic or preventative HSV-2 vaccine that work, then there is only one viable solution…….a live-and-appropriately attenuated HSV-2 viral vaccine. I feel like Bernie Sanders and his average donation……yeah, $27, we know, you said it a thousand times. Quit repeating yourself old man.
And so it is for Bill Halford and his repetitive message. If you want a HSV-2 vaccine that works, then you will need a live-and-appropriately attenuated HSV-2 virus that retains the potential to present 99% of HSV-2’s antigens to the immune system in the correct 3-dimensional context of (1) HSV-2 infected cells that are actively producing (2) intact HSV-2 virions that spread from the initial site of immunization, but which do not cause overt disease because their spread is self-limited (by the host interferon response).
– Bill H.