The Phase I Clinical Testing Bottleneck

In an earlier post, I suggested that an important step that could be taken to expedite herpes simplex virus 2 (HSV-2) Vaccine Development would be to “Streamline the Path to Phase I Human Clinical Testing of HSV-2 Vaccines.”

In today’s post, I wish to expand upon this point, and suggest that a “Compassionate Use Trial” of a HSV-2 vaccine might be one means to achieve a better balance between (1) the need to ensure the safety of all HSV-2 vaccine candidates tested in human clinical trials versus (2) the need for TIMELY TESTING of new HSV-2 vaccine candidates.

Over the past 25 years, a single HSV-2 vaccine approach (glycoprotein subunits) has advanced to human clinical testing, and has failed in 6 trials.  Recently, a new and completely different type of HSV-2 vaccine (Sanofi Pasteur’s ACAM-529 vaccine) was approved for Phase I Clinical Tests, which are to begin in late 2013 or early 2014.   At this rate of testing (i.e., 1 new HSV-2 vaccine strategy every 25 years), it could take us another 25 to 75 years to identify an effective HSV-2 vaccine if the ACAM-529 vaccine does not succeed.

In contrast, if we change the rules such that any and all reasonable HSV-2 vaccine approaches may be advanced to Phase I Human Clinical Trials as soon as they become available (i.e., as opposed to languishing on the sidelines for 10 years as ACAM-529 has), then it is likely that we could identify a safe and effective HSV-2 vaccine in a fraction of the time (i.e., 10 years or less).

This ridiculously long lag time between identification of a viable HSV-2 vaccine candidate and its advancement to a Phase I Human Clinical Trial is the key rate-limiting factor that explains why efforts to identify a clinically viable HSV-2 vaccine are proceeding at a snail’s pace.

Below, I offer one suggestion for what we might do differently in the future to streamline the path to Phase I Clinical Testing of all new HSV-2 vaccine candidates for which there is credible evidence that the approach is both safe and effective in animal models.

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CURRENT BOTTLENECK ON HUMAN TESTING OF HSV-2 VACCINES

When it comes to HSV-2 vaccines, I would suggest that the current FDA regulatory system lies somewhere between cumbersome and dysfunctional.  In particular, I refer to the process by which HSV-2 vaccine candidates progress from animal-based studies to human clinical trials in the United States.

At issue is the fact that by the time a scientist has worked out how to elicit robust vaccine-induced protection against HSV-2 in two species such as mice and guinea pigs, scientifically much of the “heavy lifting” is done, and it is simply time to “put up or shut up.”  Sure, some refinements will have to be made in terms of (1) cleaning up the HSV-2 vaccine formulation and removing impurities (i.e., producing a GMP, pharmaceutical-grade product) and (2) optimizing the vaccine dosage and route of delivery for humans.  At the end of the day, however, the primary thing that needs to happen is simply to immunize a small group of human subjects, and determine if a dose of the HSV-2 vaccine candidate in question (1) elicits a respectable immune response and (2) is well tolerated by human subjects.  This is effectively what a “Phase I Human Clinical Trial” of any HSV-2 vaccine would involve.

Such cursory tests do not address how effective a HSV-2 vaccine will be in the long term in a larger population of patients, but proceeding from Phase I Clinical Trials to test these larger questions in Phase 2 and 3 Clinical Trials has been less of a bottleneck in the past.

History informs us that in the United States, a single HSV-2 vaccine approach has made it to such Phase I Clinical Tests in the past 25 years.  Just like its close relative, varicella-zoster virus (VZV; which causes chickenpox and shingles), a live-attenuated HSV-2 vaccine would crush the genital herpes epidemic and bring this chapter of history to a close just as the live-attenuated VZV Oka vaccine has vastly reduced the burden of human disease caused by VZV.

Against this background (i.e., HSV-2 genital herpes should be vaccine-preventable), I find the current rate of HSV-2 vaccine development to be unacceptably slow.  I would vastly prefer the low and manageable risk of a well-designed, live-attenuated HSV-2 vaccine to the certainty that at least another 500 million people will contract new infections with wild-type HSV-2 and/or genital herpes if we continue our current pace of HSV-2 vaccine testing.

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WHAT DOES A PHASE I CLINICAL TRIAL ENTAIL?

There is no mystery, scientifically, regarding how to execute a Phase I Clinical Trial, and in principle such a trial could be planned and executed in less than 6 months, as they typically involve a small number of human subjects (i.e., 10 to 20).  In principle, a Phase I Clinical Trial is the equivalent of putting your toe in the water of a lake to figure out how cold it is before you jump in.  If something is really off with an Investigational New Drug, such as a new HSV-2 vaccine candidate, a Phase I Clinical Trial is your first look and opportunity to figure out if the drug is safe and/or well tolerated.  You may garner a little more information, but safety and tolerability are the primary focus of such trials.

Everyone can agree that it is imperative that a treating physician should disclose any and all potential risks of administering an investigational new drug to a human subject in a Phase I Clinical Trial.  Typically, this is done both verbally and via a 20- to 40-page disclosure form that (1) each patient signs to acknowledge the risks of being enrolled in a human clinical trial of an investigational new drug whose potential risks and complications are not fully vetted, and (2) this document spells out in no uncertain terms ALL of the potential adverse consequences that a patient might conceivably suffer as a result of being treated with an investigational new drug.  Moreover, each and every patient must be monitored closely after treatment to assure that adverse events do not occur, are recorded and documented if they do occur, and all of the resulting data is reported to a Data Safety Monitoring Board that oversees the Clinical Trial, and ensures that the trial is proceeding in a manner that is both safe and fully transparent.

I don’t think anyone questions the wisdom of all of these important safeguards in the structure of a Phase I Human Clinical Trial of a new drug or vaccine.

The problem lies in the many layers of bureaucracy that separate (1) a research team asking the FDA for permission to initiate a Phase I Human Clinical Trial and (2) the actual execution of the Phase I Clinical Trial.

I have spoken about this process with representatives of three major pharmaceutical companies (Merck, Sanofi Pasteur, and Crucell).  Each of them has offered a ballpark figure of 5 years and $20 million to satisfy the FDA evaluation requirements for a new HSV-2 vaccine, and each has questioned whether or not the FDA would ultimately be willing to allow a live-attenuated HSV-2 vaccine to advance to Phase I Human Clinical Trials.  Given these lingering doubts (“What if the FDA says no?”), none of these 3 companies expressed eagerness to shell out $20 million or walk uphill into machine gun fire as they sought to buck the prevailing wisdom that a live-attenuated HSV-2 vaccine would be “too dangerous,” and seek FDA approval for a Phase I Clinical Trial of this new vaccine approach.  Intriguingly, this reticence to pursue a live-attenuated HSV-2 vaccine as a pharmaceutical product is in spite of overwhelming scientific evidence that the approach I am proposing is (1) very safe in animal models, and is (2) 100 times more protective than the FDA-sanctioned HSV-2 subunit vaccines of the past 20 years.

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THE CURRENT CONUNDRUM

I don’t pretend to understand which specific facets of FDA rules, regulations, and procedures have every company with whom I have spoken unwilling to “go to bat” for a live-attenuated HSV-2 vaccine regardless of the proof that this HSV-2 vaccine would work 100 times better than what we have been doing.   However, common sense tells me that something is wrong when the prevailing belief system of FDA regulators trumps scientific observations and facts, to the point that 99% of scientists and companies are unwilling to act upon experimental evidence that, in no uncertain terms, indicates that a live-attenuated HSV-2 vaccine would serve as an effective genital herpes vaccine.

Regardless of the whys and wherefores, what is apparent is that the FDA has fostered a culture in which the pharmaceutical industry and business-minded scientists only consider “FDA friendly” HSV-2 vaccines that will get the green light to proceed to Phase I Human Clinical Trials.  This is why HSV-2 subunit vaccines are so prevalent today…..not because they work well, but because the FDA will approve their advancement to Phase I Human Clinical Trials.

The downside of allowing the FDA to effectively dictate HSV-2 vaccine development policy in the United States is simple; the FDA is not well versed in the rules of herpes immunology (which I have been studying for 20 years), which suggest that a live-attenuated HSV-2 vaccine may be the only approach that can yield a sustainable victory over HSV-2 genital herpes.  If this interpretation of the available evidence is correct (which I believe to be the case), then current FDA policies and procedures are effectively blocking human testing of the one class of HSV-2 vaccine that is actually capable of stopping the spread of HSV-2 genital herpes.

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THE NEED TO TEST ALL HSV-2 VACCINE OPTIONS IN PARALLEL

I expect and respect the fact that other scientists and regulators will not necessarily agree with the premise I propose above, that a live-attenuated HSV-2 vaccine is the only feasible approach to devise a clinically viable genital herpes vaccine.  Such discourse, disagreements, and debates are as fundamentally important to the advancement of science as good experiments.

Likewise, I would suggest that other scientists and regulators should respect the reciprocal possibility that a live-attenuated HSV-2 vaccine may indeed, as I propose, be the only approach that will work.

A good scientist knows that going into a problem from the front end, it is not possible to know what will happen.  Thus, good science boils down to (1) defining / considering all of the possibilities and then (2) figuring out which possibility is actually correct.

This has, and always will be, the landscape on which science is conducted.  We can pretend that HSV-2 vaccine research is different and that we “know” the next HSV-2 vaccine candidate will work.  However, I note that such claims date back to the 1980s, and yet we still lack an effective HSV-2 vaccine.

The simple reality is that, as in all other areas of scientific inquiry, we cannot know which HSV-2 vaccines will achieve a desirable balance between safety and effectiveness in preventing HSV-2 genital herpes in a clinical setting until we positively identify such an entity in a Human Clinical Trial…..period…..end of sentence.

For this reason, I would suggest that it is imperative that we devise a new paradigm that allows any and all HSV-2 vaccines that have proven, beyond a reasonable doubt, to be safe and effective in animal-based studies to advance in A TIMELY MANNER to Phase I Human Clinical Testing (i.e., in 10 – 20 human subjects).  There is no legitimate reason that the process of asking for permission to run such a small scale, Phase I Clinical Trial should require millions of dollars and 5 years of paperwork filings with the FDA.  Again, each year that we tarry and fill out FDA paperwork ensures that ANOTHER 20 MILLION PEOPLE WILL BE NEWLY INFECTED WITH HSV-2.   This is bad policy, plain and simple.  Stated another way, this is the scientific equivalent of sticking our heads in the sand and ignoring the available mountain of evidence that we are in the middle of a HSV-2 genital herpes epidemic.  The danger is not the HSV-2 vaccine candidates that have been proposed; the danger is our ongoing failure to develop a meaningful countermeasure to slow the spread of the HSV-2 epidemic.

It is time to change the system by which HSV-2 vaccines are allowed to advance to Phase I Clinical Trials so that we may, for the first time, honestly assess our available options for identifying a clinically viable HSV-2 vaccine today (i.e., not 50 years from today).

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COMPASSIONATE USE TRIALS OF NEW HSV-2 VACCINES?

I would suggest that people who live with frequent recurrences of HSV-2 genital herpes represent a group of patients who have not been adequately considered as a target population for Phase I Human Clinical Testing of new HSV-2 vaccine candidates.  First, I describe this patient population, and second I consider why this patient population should be granted immediate access to any HSV-2 vaccine that offers the hope of improving their condition.

Regarding the patient population in question, a significant fraction of patients infected with HSV-2 suffer from recurrent HSV-2 genital herpes disease that recurs so often that these patients essentially live with a CHRONIC VIRAL DISEASE.  Nearly all such patients are aware of the available antiviral drugs (e.g., acyclovir, famvir, valtrex), but these drugs are insufficient to control their chronic HSV-2 genital herpes symptoms.  Such patients may experience HSV-2 outbreaks that recur 10 to 20 times per year, and each outbreak may last for 7 – 14 days in duration.  Such patients describe only brief respites from active disease, and thus are best described as living with a chronic viral disease.  Aside from the visible symptoms of HSV-2 genital herpes, many of these patients also describe an episodic neuralgia (nerve pain) in the tailbone area, which is where HSV-2 permanently resides in the sensory ganglia that innervate the genital area.

One can imagine that such a chronic viral disease might take a tremendous toll on a patient’s psyche over a single year.  However, in some patients, this unaddressed condition of chronic HSV-2 genital herpes outbreaks lasts for periods of 5 years or more.

Some women report the onset of such symptoms associated with and on the heels of menopause.  For other patients, medical management of organ transplants or autoimmune diseases may require that a patient chronically take immunosuppressive drugs.  Chronic immunosuppression can compromise the body’s ability to keep the HSV-2 virus in check, and thus chronic outbreaks may become the norm.  In short, for a variety of reasons, some patients live with chronic HSV-2 genital herpes outbreaks.

For such patients, I would suggest that the FDA’s guidelines for a “Compassionate Use Trial” exemption could be modified to include tests of new HSV-2 vaccine candidates that have the potential to serve as “a therapeutic HSV-2 vaccine,” and reduce the symptoms of HSV-2 genital herpes in patients who live with a chronic disease.  The following is one website that discusses the FDA’s Compassionate Use Trial guidelines:  http://www.raps.org/focus-online/news/news-article-view/article/3418/new-fda-draft-guidance-aims-to-clarify-compassionate-use-process.aspx.

The idea of a “Compassionate Use Trial” is that it provides a formal mechanism to request an exemption from the normal FDA policies and procedures to streamline delivery of an Investigational New Drug (IND) to a patient population who (1) could immediately benefit from the new treatment; (2) lack an available medical option to alleviate their symptoms;  and who (3) suffer from a chronic and/or progressive medical condition that is so miserable that they have nothing to lose (and a lot to gain) by enrolling in a clinical trial of a new treatment that may offer some relief.

As I read the current FDA rules and regulations, it appears that “Compassionate Use Trials” only appear to apply to medical conditions that are life-threatening.  I would suggest that the law could (and should) be changed to include any disease that is “chronically and physically debilitating” and for which patients lack any satisfactory treatment options.

I would suggest that many of the HSV-2 vaccines that have been proposed have the potential to serve as “therapeutic vaccines,” which have the potential to re-educate the host immune response to HSV-2 such that it becomes more efficient in its recognition of sites of HSV-2 infection.   In particular, it is well known that the human immune system may, through a variety of mechanisms, become tolerant of foreign antigens.  Thus, it is conceivable that the immune systems of individuals who live with chronic HSV-2 outbreaks may have become “tolerant” of HSV-2’s foreign proteins, and thus it is a selective (HSV-2-specific) defect in their immune response to HSV-2 that explains why they live with chronic herpetic disease.

I cannot offer any proof in support of this hypothesis, but I note that it is an obvious potential explanation for the pattern of infection in people who live with chronic HSV-2 herpes outbreaks, and this possibility could be very simply tested in a “Compassionate Use Trial” in a patient population who have nothing to lose, and a great deal to gain if this hypothesis is correct.

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This post has grown far too long, and so I will stop and leave it here.  The topic of “Compassionate Use Trials” and streamlined delivery of HSV-2 vaccines into Phase I Human Clinical Trials will be a topic that I re-visit in the future.  The bottom line is that I don’t know where the answer lies, but I believe that scientists, regulators, and members of the U.S. Congress need to come together on this issue and figure out a more efficient system for bringing the power of an effective HSV-2 vaccine to bear in a timely manner, so that we may end the HSV-2 genital herpes epidemic sooner rather than later.

– Bill Halford

27 COMMENTS

  1. Hi this is truly a very notorious virus Bill how r u and how’s urs work going on is there a hope for us we will get rid of this virus in 2-3 years we can’t marry we cant have healthy babies

  2. Bill,
    I have ready many posts in which you explain in great detail, your knowledge of HSV and your personal opinions on the FDA and vaccine potential in the future. I want to thank you for being so human and empathetic. When I first read one of your threads, I cried because many people suffer like me and there are scientists who care and are actively trying to fight this disease, but encounter huge setbacks do to government red tape.

    I am HSV 2 positive genitally and HSV 1 orally. All it takes is one relationship. I am proof of that. For 5 years..I would only get one or two outbreaks a year. Fast forward to 2012, out of nowhere, I started having genital and oral outbreaks simultaneously every month. Sometimes twice a month lasting 10 days! I don’t understand why my body would change so rapidly. Also I would only get cold sores on my lips previously…Now I never have a cold sore, but rather swollen painul gums and roof of my mouth. I get flu like symptoms with every outbreak. Not just the initial. My lymph nodes in my neck hurt, I have headache, malaise, and its like nerve pain down my neck. This radication prompted me to start reading up on this virus. What I have read scares me so bad. I’m wondering if this disease could one day end my life.

    I’ve read people who lack a certain protein can be susceptible to constant outbreaks (inferon lambda??) I’ve read about immunocomprimised individuals having risk of mortality with this virus if hepres encephilitis develops. Or if you have cancer, than its extremely difficult to control this virus since cancer patients take immunosuppressive drugs. I’ve read of this virus spreading to organs!

    Since I have seemingly constant outbreaks, am I more likely to develop herpes encephalitis? Is my immune system currently comprised since suddenly I have been having nearly chronic outbreaks orally and vaginally?

    I have asked my primary and obgyn..and neither seem to know enough about this virus to help me understand. My obgyn said it sounded obsurd that I would have nearly constant outbreaks. Well here you go, I’m right here telling you that it’s happening.

    I’m now on valcyclovir and that has helped substantially. I nearly quit having outbreaks and then out of nowhere…BAM! Massive attack and it lasted 8 days. Now I fear that maybe I have built a resistance to the medication or it is now demanding a higher dose, to which I don’t want to do. I’m scared. I’m depressed. I’m lonely.

    I was kind of hoping…praying really, that you could shed some light on my situation. Help me understand why all of a sudden my body has changed it tune agsinst this virus.

    I read about all of the current vaccines under way in clinical trials. It sounds like acam529 is the best thing so far. But will it give a theraputic cure for me?

    I want to believe that ian frazier has found a cure, but like you, I agree that he has not published any significant data proving so.

    I am devastated and want so badly to be rid of this virus. Honestly I can handle the social and mental stigmatism. Its the fear of not knowing what this virus can truly do to me and the fear of dying from it that tortures me.

    Also if you have a vaccine in your possession, that would fundamentally cure me of this debilitating disease, I will give you my current life savings of $300,000 right now if you will inject me with it. Oh yes I would pay $300,000 for it. I’d pay a million. No joke.

  3. Dr. Halford, I would really appreciate if you could give me your thoughts about this Supposed therapeutic vaccines I found in Herpes blogs…two of them are used in Russia and one of them is European,….1) Vitaherpavac 2) Panavir 3) Lupidon …
    Have you heard of them? are they usefull or is a lie?
    Thanks a lot for the blog and all the support !

    • Vitaherpevac is an approved vaccine in Russia. It is said to have an effectiveness ofaround 60% in therapy of reccurent lesions. Could be in fact very less effective, who knows.

      Panavir is some russian drug, containing mostly different forms of sugar.. i think it’s more of a homeopathy or placebo.

      Lupidon, do not know what this is.. could be some sort of dead virus vaccine, if it worked people would hear about it but it supposedly does not.

  4. Bill,

    It seems that Ian Frazer and your lab would make a natural partnership. They have the influence to be able to raise funds, you have the vaccine with the efficacy they may or may not have. Have you thought about joining forces, and using their hype machine to make progress getting your vaccine to the next stage?

    • April 12, 2014
      Dear JD,

      I am happy to partner with anyone who can help me move the live HSV-2 vaccine concept forward. However, if Ian Frazer’s group is involved in a company that is developing a totally different HSV-2 vaccine concept, my experience suggests to me that his company (Coridon) is unlikely to be interested in dropping their current concept (i.e., the foundation of the company) in favor of an alternative approach (i.e., my lab’s live HSV-2 vaccine). This is not generally how biotech companies operate.

      I will certainly maintain my primary focus, which is doing herpes simplex virus basic science research that helps inform scientists of the profound difference between highly effective HSV-2 vaccines (my lab’s live HSV-2 vaccine being one example) versus ineffective HSV-2 vaccines like Herpevac and many other molecular reductionist approaches. How the scientific community chooses to use (or not use) this information is really a much more complex and multifactorial question than my shooting an e-mail or a letter to Coridon or other companies who have an established interest in HSV-2 vaccines.

      Again, happy to partner with a company on my lab’s live HSV-2 vaccine, but at the end of the day if that comes to pass, it will most likely happen because a company approaches me (not vice-versa).

      – Bill H.

  5. Wow Bill H, as someone who has spent 15 years trawling the internet about Herpes and hoping for positive news, this is the best read I’ve had yet. Thank you, good luck, and I look forward to more news.

  6. what can a multitude of sufferers and health gurus do to help you solve this? Do you need human volunteers, here I am.

  7. i just cannot believe that such a traumatizing, dangerous and nasty epidemic is running wild and rampant.

    i just recently got infected not even through sexual contact but through casual contact and i never thought that i was getting a dead check, this virus open the system completely to what ever deadly infection wish to come in.

    i am frighten to touch my kid, i am frighten to do the most mundane things my whole body is changing i am in a permanent state of depression, anger and anxiety.

    i am willing to put my life at stake on vaccine trails, just to be part of something that will stop this hideous and what i have deem the 21st century pandemic.

    is so horrible to think that the FDA and CDC will allow this to rise to the point of pandemonioum, before the choose to take action.

    dr.bill with my humble regards i hope that if you don’t find a cure to at least bring enough attention to what is happening.

    i live in one of the states that recently pass legalization of marijuana, people are sharing pipes freely all over the place and this disease amongst others are changing the landscape.

    i hope that you can make a report about this and warn the general public about it.

    i have taken this personal and i am warning people how i got infected with what i believe is the worst thing that has ever happen to me.

    • Dear Joshy,

      I have heard people who are newly infected express this sentiment many times……and still, just like the first time I heard this, all I feel is a feeling of frustration and helplessness that I cannot say or offer something meaningful to help you out. As far as a vaccine and a cure, I would suggest that such options are too far off on the horizon to be useful to you today and so I don’t think this is where you want to focus your energy.

      The best advice I can offer is to remind you that I am only a researcher. Yes, I can help point everyone in the right direction of how we beat genital herpes in the long term. But that is not so helpful to you today. In my experience, doctors are as a rule not very well educated about genital herpes and all the ways the infection can play out. I don’t mean this statement as an insult to doctors, but rather what I am saying is that scientists and clinicians in my field of study have done a poor job of offering up a simple (short and sweet) explanation of how HSV-2 genital herpes can play out for doctors in training (i.e., medical students). As a result, medical students are offered a very poor snapshot / explanation of how HSV-2 genital herpes can present in patients and affect patients. Thus, it takes a very motivated doctor (typically an infectious disease specialist) to take the time to learn more on their own then what is presented to them during their medical training.

      So, I arrive at my take-home message: if you want the best advice on how to deal with a new case of herpes, I would suggest talking to some of the people in support groups who have genital herpes. By-and-large, such groups tend to have the benefit of some of the most motivated, helpful, and best informed people around who can help you weigh your options for how to deal with a new infection. Two such herpes support sites are here:

      http://www.herpes-coldsores.com/
      and
      http://www.racoon.com/herpes/

      If you join these groups, I think you will find the people there are far better equipped to address the many questions you may have. Also, if you have not looked into acyclovir or valtrex, these are two antiviral drugs that many people can use to help manage / reduce their symptoms.

      Sorry to hear of your troubles. I think becoming well informed and talking to other people who share your experience is your best defense against runaway fear and depression. In the meantime, I will keep chipping away at the HSV-2 vaccine effort, and will keep trying to correct the myriad of little errors in logic/thinking that explain why our “leaders” think it is important to deliberately avoid human testing of a live-attenuated HSV-2 vaccine that is (1) very safe and (2) works 100 times better than the class of HSV-2 vaccines they keep advocating.

      – Bill H.

      • doctor, i have already lost hope of any governmental entity bringing any type of solution that is not more than a patch, like this retro viral pills.

        what i am trying to do is warn you about the way hsv2 took over my mouth and i think there is going to be a future problem with this virus jumping on to people this way.

        iwas using my neighbors pipe just to wake up a week later with this nightmare, i think this virus is adapting better to pass on like this and if i am right more people should be aware of this.

        i am just doing what i can to fight back not to mention that i quit smoking.

        the cdc doesn’t mention this type of contagion that’s why i am frustrated, as a matter of fact it said this is not the way this thing pass.

  8. Doctor
    You in essence have the vaccine now. Bypass the bureaucracy and start your own treatment clinic. Such an idea could be “sold” to a small independent nation such as Nauru in the Pacific or Malta or a couple in the Caribbean. For permission to operate you bring medical tourism. You could charge what you wanted and bring a million people to you willing to pay. You get extremely wealthy, the small nation prospers and the people begin to get what they need. Such on operation could be started relatively small and be ramped up as revenue came in…you might even be able to get the host nation to underwrite a start up….hell…the people following your blog could probably raise enough to get started. The impact you could begin to have in just a year from now could be phenominal. Think big….start small and NOW. Thanks

    • Dear OTB,

      I am completely in harmony with what you suggest with some minor caveats.

      First and foremost, I will go out on a limb and say that I am quite a competent scientist and know how to (1) figure out how things work and (2) devise solid experiments to test my ideas and figure out what is true, and what is not. This phase of the live HSV-2 vaccine development project is done. However, as comfortable as I am with science, I am simply not a businessman. I have a full time gig teaching and doing research, and would absolutely be open to partnering with someone who hoped to develop a business such as you suggest above……and I agree that the time to start is now, not later. However, there are just not enough hours in the day, and thus I need a viable commercial partner. If anyone wishes to step forward, I am ready to talk.

      Second, the reality is that we don’t know how a live HSV-2 vaccine would perform in people. Thus, I would suggest that between (1) where we are now and (2) the vision you offer of a clinic that is offering a new HSV-2 vaccine in a country that supports the enterprise, there needs to be an intermediate step where we do run an honest-to-God clinical trial. I don’t think that such a clinical trial would need to be dragged out for 5 years. However, on the other hand, I don’t think it would be ethical to simply start charging people today $250 per shot for a HSV-2 vaccine candidate where none of the safety and efficacy parameters have been worked out in humans. Thus, any such business venture would have to be willing to absorb the cost of vaccinating at least 100 or 200 people / patients for free to work out some of the critical issues of (1) proving a live HSV-2 vaccine is well tolerated by humans and (2) finding an appropriate dose of a live HSV-2 vaccine that elicits a potent and durable immune response to HSV-2.

      Again, in principle, I absolutely agree with what you are saying…..now is the time to start. But, to clarify, I think now is the time to start a human clinical trial for the purpose of objectively asking the questions, (1) Is this live-attenuated HSV-2 vaccine as safe and well tolerated in people as it appears to be in experimental animals? and (2) Is there any evidence that this HSV-2 vaccine is effective in eliciting an immune response against HSV-2 and/or a tangible clinical benefit?

      Until we answer those two questions in a scientifically sound manner, I don’t think that it is reasonable to ask individuals to pay for an experimental vaccine. Perhaps I am overlooking something here, but I have never heard of a “clinical trial” where patients pay to participate. Rather, patients who volunteer to participate in clinical trials either do so because (1) they want to help science move forward or (2) more often because they receive monetary compensation for their participation from start-to-finish (often over a period of months) in the clinical trial.

      OTB, thanks for your thought-provoking post!

      – Bill H.

      • Thanks….somehow I knew you would offer a comprehensive and sensible reply.
        Agreed….appropriate clinical trial thru the above mechanism.
        $250 for a shot?…who wouldn’t pay a thousand!

        • OTB,

          Again, I am not a businessman. If I had to guesstimate, the actual laboratory cost of producing a shot of a live-attenuated HSV-2 vaccine would be in the range of 25 cents to 1 dollar per dose; so, it seems that $250 per shot would be more than enough to compensate for quality control, salaries, delivery costs, etc.

          However, I will leave such questions to more business-minded people than myself.

          – Bill H.

  9. Hello Dr.Hallford,
    I hope you are doing great. I’m from Puerto Rico. I’m recently was infected with Herpes type 1 (genital) by a person that I really trusted. I was devastated. I’m 26 and have a lot of things to give up. I follow your blog for around a month. I would like to ask you, if you think that Sanofi’s ACAM 529 could work for Herpes type 1 (genital)? When they going to announce the approval of clinical trial phase 1?

    Please, never give up with your research. People like you give us hope for a cure or something? Have a great day. Thanks.

    • Hi Caro,

      I don’t think anyone can be certain that a HSV-2 vaccine like ACAM-529 would cross-protect against HSV-1 genital herpes. My suspicion is that an effective HSV-2 vaccine would elicit enough cross-protection against HSV-1 to reduce the risk of a naive individual contracting HSV-1 genital herpes. However, I have my doubts that even an effective HSV-2 vaccine could work as a therapeutic vaccine against HSV-1 genital herpes. The basic issue is that the bar is going to be much higher for a therapeutic vaccine to be successful.

      All of that said, I don’t think that I can provide a definitive yes/no answer to your question.

      – Bill H.

  10. Since Sanofi Pasteur is a French company is there any plan to test ACAM-529 there? Is it a matter of HSV prevalence in Europe or is the European equivalent of the FDA just as glacial and intransient when it comes to live vaccines as the US.

    With regard to a live attenuated vaccine trial outside the country I seem to recall there being a vaccine trial by AuRx in Mexico of a mutated live virus http://www.aurx.com/main.htm that is ready for phase 3 trial. Was this another protein subunit?

    It is definitely worth writing the contacts you mention at the FDA and I’m going to start doing that as well but with regard to needing a partner to get an international trial started do you think any of international vaccine conferences would be productive to attend? I’m sure we could rally the support to get a trip like that funded if you think it could ultimately end up successful initiating a trial.

    • Hi Upbeat,

      Sanofi is a French company, but the Phase I clinical trial they have pending will be taking place in the Washington DC area to the best of my knowledge.

      Regarding the European equivalent of the FDA…..I am afraid I must plead ignorance. Great question, but I simply lack any firsthand knowledge. My impression is that the United Kingdom is not quite so restrictive as the U.S. when it comes to clinical trials, but I cannot substantiate that statement with facts and figures. Regarding the remainder of Europe, I simply don’t know but my general sense is that most of Europe might even be more restrictive than the U.S. when it comes to live viral vaccines. For example, across Europe, some countries are still reluctant to deploy the chickenpox / shingles vaccines (live-attenuated VZV Oka strain) that have been use in Japan for more than 30 years, and which was first used in children in the U.S. in the mid-1990s. I suspect that the formation of the European Union would make things more difficult, as this would simply add one more layer of bureaucracy / oversight as opposed to letting each European country decide for itself. Again, big picture, I cannot offer any detailed examples, facts, or figures to support these speculations.

      Regarding the Aurx clinical trials………wow…..had not even seen this website before. The HSV-2 vaccine in question is actually similar to my lab’s live-attenuated HSV-2 vaccine in principle. The lead investigator was Laurent Aurelian, and her lab published several studies in the late 1990s / early 2000s on a live-attenuated HSV-2 vaccine candidate that was attenuated by virtue of a mutation in the ICP10 gene (large subunit of HSV-2’s ribonucleotide reductase). The website link you cite seems to date back to clinical trials they were starting to run in the early 2000s. I personally wish that NIH had gotten behind this approach and supported it, rather than dumping $28 million into yet another glycoprotein D subunit vaccine clinical trial (i.e., the 2003-2009 Herpevac trial). However, I am not aware that Dr. Aurelian and “www.aurx.com” got much support from the NIH, which is presumably why the trial was run in Mexico. The bottom line is that Dr. Aurelian’s HSV-2 ICP10PK-mutant virus is another approach that might yield a viable vaccine, but was (again) not supported adequately by the NIH and so I don’t think that we know how the clinical trial would have gone had it moved forward and actually been supported.

      Great find!! Thanks for bringing up this topic, as it illustrates how a promising HSV-2 vaccine like the one mentioned on “www.aurx.com” can simply peter out without appropriate support. For this reason, I would encourage you to write the FDA.

      – Bill H.

      P.S. I have been to 3 meetings this year, and will be attending a vaccine meeting in Spain in October 2013. If money grew on trees, I would be going to a lot more vaccine meetings, and personally knocking on the doors of anyone I could find in big pharma who is willing to listen. If you identify a connection who may be willing to speak with me, please do not hesitate to let me know.

  11. Dear Dr. Bill H. I admire your courage… may you become succesful and i believed you have the cure and it shows how confident you are… everything you’ve said is true and pure logic… thank you so much…

  12. Dr Halford,

    I spoke with you about two years ago regarding an allergic reaction I developed for valtrex. The suspicion is this was due to recent autoimmune developments. Anyway…….. I would suspect that if you expand your research/development to Central America and developed something there, you will have people flocking from all over world for treatment. We all know how our faulty government operates these days, and my suggestion is, lets just go around them and get this done. I suspect recouping costs for development would not be an issue. We can expedite this process.

    Just a thought……

    • Hi Joe,

      If anyone knows of a lead in Central America or elsewhere where they wish to test a new HSV-2 vaccine, I am always willing to talk by phone or e-mail. Joe, I am absolutely on board with your suggestion…..just need to find the right people with whom I could establish a solid partnership.

      – Bill H.

  13. If you plan on waiting on the FDA to change you may as well wait on the sub-units to work! There’s a reason it works the way it does and this is all rooted in litigation and liability. Find me a politician or gov’t bureaucrat that’s willing to stick their neck out and I’ll show you a soon to be unemployed civil servant. Get this out of the snail mill and on to a country that values ingenuity and courage and it might just happen. I appreciate Dr. Halfords’ openness and hope that an avenue will emerge that is feasible, timely and safe but I have lost all hope in ANY Gov’t run, supervised, or managed program for this or anything else. There are two overriding concerns for them, protect your job and CYA!!!!

    • Hi Dan,

      I can’t dispute your characterization of the current landscape of how the federal regulatory process operates; 99% focused on minimizing liability and 1% focused on addressing the problems of the world.

      That said, all I can do is throw out the suggestion that the FDA approval process could be streamlined, and remain open to the possibility of partnering with an overseas business entity that recognizes that profit is profit, regardless of whether vaccine recipients are paying you in rupees, pesos, or dollars.

      – Bill H.

  14. Dr. Halford,

    A few weeks ago I emailed the FDA/CBER ([email protected]) and expressed disappointment in the fact they have only approved subunit vaccines into clinical trials. I basicly just relayed your message that they need to weigh the RELATIVE RISK of small clinical trials for new HSV-2 vaccine candidates against the RELATIVE RISK of doing nothing or approving the same type of vaccines that continue to fail. Surprisingly I received a reply from Jill Burkoff, a Consumer Safety Officer. She mostly just explained the requirements that need to be compiled into the submission of an IND application. I replied asking her to consider your “Compassionate Use Approach.”

    Thanks for providing the contact information for those that are in position of changing the way HSV-2 vaccine development decisions are made. I plan on writing to each and to my U.S Congress representatives in the hope of getting them to come together.

    • Dear DBD,

      I think that this is the classic case of “the squeaky wheel gets the grease.” If elected officials (e.g., in the U.S. Congress) and public officials (e.g., in the FDA) better understood the frustration of genital herpes sufferers and their doctors (who lack good tools to treat this ailment), then these public officials would better understand why we can and should do better in our efforts to identify a viable HSV-2 vaccine.

      Thank you for your efforts on this front. I hope that more people will join you in raising awareness about this public health issue that has been allowed to fester for too long.

      – Bill H.

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