Where to vaccinate: arm or the bum?

QUESTION:

Dear Dr. Bill,

Let’s discuss the therapeutic effect of a future vaccine. So basically the patient gets a vaccine shot in his arm, just like all other vaccines are given. How does the human immune system respond next in the case of Acam-529 as an example?  Antibodies and T-Cells get generated. Would an arm shot be enough or yet better a shot in the behind area / under the belt? How would an arm shot benefit the genital area for protective or therapeutic purpose?

– Curing

————————————

Dear Curing,

I responded to your first question last week, which was “1) How does the human immune system respond to a HSV-2 vaccine?”

I now respond to the 2nd question, 2) “Would a shot of HSV-2 vaccine in the arm be enough or would a shot in the behind provide better protection against genital herpes? How would an arm shot benefit the genital area for protective or therapeutic purpose?”

—————————

In my previous post addressing this question, I reviewed and highlighted why all vaccine-induced protection against infectious disease effectively reduces to vaccine-induced (1) activation and (2) clonal expansion of microbe-specific B-cells and T-cells.

In the case of B-cells, the effector mechanisms by which vaccine-induced B-cells would contribute to host control of HSV-2 infection would be exclusively mediated by the antibodies that some of their progeny cells (plasma cells) secrete.  Because of their antibody-mediated mechanism of contributing to a host immune response, an effector B-cell may contribute to the host response of HSV-2 infection without being even remotely close to the site of HSV-2 replication / infection.

In the case of CD4+ T-cells and CD8+ T-cells, the effector mechanisms by which vaccine-induced T-cells would contribute to host control of HSV-2 infection would be exclusively mediated by the T-cells themselves either through serving as (1) cytokine-secreting cells or by serving as (2) cytolytic killers of virus-infected cells.  Importantly, cytokines (unlike antibodies) cannot act at a distance, and thus T-cells can only influence events in their local environment (e.g., a draining lymph node or a virus-infected tissue.

The primary point of this background is to reiterate there is a very good reason that we refer to lymphocytes, neutrophils, macrophage, and dendritic cells as white blood cells (as opposed to red blood cells).   White blood cells primarily inhabit our bone marrow, bloodstream circulation, lymphatic circulation, and the lymphoid organs that filter the bloodstream (e.g., the spleen) and the lymphatics (i.e., lymph nodes).  Against this background, it is obvious that our immune systems are a system, or network, of cells that is spread throughout all the blood and lymph that carries oxygen and nutrients to (and CO2 and waste away from) all the cells in our body.  Thus, the immune system courses throughout your entire body, and in general effective immune responses tend to be systemic in nature.

bum-arm-3Given the systemic nature of the host immune response, I would suggest than an effective HSV-2 vaccine should be able to provide robust protection against HSV-2 genital herpes regardless of whether the shot is administered in the arm, the leg, the buttocks, the back, or the stomach.  A HSV-2 genital herpes vaccine might be slightly more effective if delivered in the buttocks simply because the draining lymph nodes (where much of the immune response to the vaccine occurs) for this anatomic region are largely overlapping with the lymphatics that drain the genital region with several major lymph nodes occurring in the groin (which explains why some people with severe genital infections could potentially feel a generalized ache in their groin as the local lymph nodes swell in size, as the lymphocytes inhabiting those nodes respond to a microbe’s antigens).

In my own studies in mice, I find that an effective live HSV-2 vaccine fully protects mice against HSV-2 genital herpes regardless of the anatomic location of where the vaccine is administered to mice (i.e., nostrils, eyes, vagina, or rear footpads; http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0017748#pone-0017748-g002).  However, as I indicate above, a more careful analysis does support the interpretation that vaginal immunization with the live HSV-2 vaccine offers slightly (subtly) better protection against HSV-2 vaginal challenge relative to, say, mice that receive a nasal immunization with the live HSV-2 vaccine.  If this seems counterintuitive, just remember that no matter where a mouse is immunized, the predominant route by which HSV-2-specific antibodies and HSV-2-specific T-cells arrive at the scene of the crime (site of HSV-2 invading the vaginal mucosa) is via the bloodstream, and movement / leakage through the blood vessel walls at the site of infection (i.e., site of inflammation).  It is important to remember that inflammation is not an accident, but is a feat of nature / highly orchestrated process by which our bodies get immune components (including antibodies and T-cells) out of our bloodstreams and to locations where a potential infection is in progress.

Bottom line:  I don’t think the anatomic location of a HSV-2 vaccine relative to which limb is injected is super-critical.  In contrast, I believe that the precise collection of antigens / formulation of a HSV-2 vaccine will be critically important in differentiating effective versus ineffectual vaccines.  Likewise, for whole HSV-2 viral vaccines such as ACAM-529, it may be very relevant to inject the vaccine into the skin where HSV-2-susceptible cells clearly reside.  While an intramuscular injection of ACAM-529 may be equally effective, it would be relevant to explicitly test this in people immunized with ACAM-529 by the intramuscular route versus the more certain intradermal route (where HSV-2-susceptible cells clearly reside).

– Bill H.

 

49 COMMENTS

  1. Hi Dr H,
    I hope you don’t think I was rude or disrespectful to Dr Corey or the NIH as I wasn’t. I did express my frustration
    However and pointed out that there has been virtually no progress made in 30 years from at least my perspective and a few million other folks. It’s just frustrating that cures for Hep C and Ebola and things like that are being brought to market and this plague continues to fly under the radar as always and is the butt of jokes which are especially painful coming from Dr Corey. I guarantee if him or one of his associates had the incredible misfortune of being infected with this garbage there would be a little more sense of urgency. Anyways I’m just howling at the moon at this point. I only have one question, how much cash do you need to move your research forward – can I get a number?

    • Hi Keep The Faith,

      Any amount of money will help move the research forward. If you wish to donate to the Halford Vaccine Fund, please follow the directions below. I will talk to the necessary officials in my university, and set up a dedicated weblink for donating to the Halford Vaccine Fund later this year. The reason I do not wish to provide a number is that let’s say that it will require $100 million to bring a HSV-2 vaccine to market over the next 20 years, would that encourage anyone to donate? However, I have people working in my lab, and at this point all my lab is working on is the advancement of the HSV-2 vaccine and a better herpes serology test for diagnostic purposes. Therefore, 100% of the donated money goes to the cause. $10, $20, $100, etc………..it all helps, and donations to the lab over the past 4 years have been a very real help to my ability to move the science forward.

      – Bill H.

      Write a check payable to “SIU Foundation” and either in a letter or on the Memo line of the check write “Halford Vaccine Fund,” and mail the check to the following address:
      Mrs. Risa Kirkpatrick, Business Administrator
      Dept of Microbiology and Immunology
      Southern Illinois University School of Medicine
      P.O. Box 19626
      Springfield, IL 62794-9626

      These funds will be used solely for the purposes of HSV-2 vaccine research.

      • Will do sending a check today. All readers of this blog & post send something, any amount helps!!!!

  2. Dr. Halford,
    It seems like, from what I can tell, the bigger problem than the NIH is industry perception. Would we need a grass-roots campaign if the drug industry believed the FDA would approve a replication competent HSV vaccine? I’m a layman by all rights when it comes to biotech and desperate for something better than what we have but I frequently work on in getting concepts through regulatory bodies and I can’t imagine what the unknown unknowns factor of a novel vaccine one gene from wild type must look like to corporate entities considering licensing. Especially in today’s litigious biotech climate.
    An ICP0- mutant is obviously both immunogenic and protective. Would an ICP0- and 10- mutant still work well enough and possibly have a chance at getting licensed/approved? Would an ICP0- with the temperature mutation of the Oka vaccine? All three? Have biotechs (or people familiar with the FDA) ever mentioned modifications they believe would make it attractive in this sense? I mean, a vaccine that is 70% effective with a shot at FDA approval seems 1 billion dollars more useful than a 100% effective one that never leaves the lab.
    I hope this doesn’t come off as ingratitude for your tireless effort or willingness to entertain the musings of we terribly unhelpful sufferers. I’m simply curious if you’ve ever considered a more regulation attractive variation of your vaccine? Maybe such a creature doesn’t exist but I thought it might be interesting to ask.

    -StayingUpbeat

  3. hi Keep the faith/Dr H,

    Thanks for all the efforts, I think if all the person here start donating directly to the research funds this will help in giving a starting kick to the trials. Bill has already the cure. Also we can ask for the donations over the internet, I desperately need the cure.

  4. Hi Dr H,
    Thanks for the response, I know how busy you are. I have been emailing the NIH asking them about their reluctance to seriously back your research and they actually responded saying they did give you a grant a few years ago but their response and interest seemed very half ass at best. I also emailed Corey directly asking him why he won’t endorse a live attenuated approach considering he’s been tinkering around in his lab coat for 30 years and hasn’t produced a single viable, tangible contribution to ending this plague but received predictably no response. I know you don’t agree, but the skeptic in me smells a rat with this guy. Why would he want to kill a bug that makes him rich and has given him steady employment for over 30 years. The guy has been in bed with GSK for a long time. GSK makes over $2,000,000,000 annually selling Valtrex and the NIH makes him the point man in finding a cure? Maybe not a conspiracy but a major conflict of interest at the very least no?
    I hope you don’t mind me advocating your research. You have pointed out on numerous occasions that most sufferers sit on their hands and hide in the shadows waiting for someone else to stand up. Well not me I’m going to be a royal pain in the *** for the NIH and Dr Corey until I see some results. All readers of this blog should do the same.

    • Hi Keep the Faith,

      I would just suggest you remember the old adage, “You catch more flies with honey than with vinegar.” When I write a research grant to the NIH, I am making a case for the science and at the same time I am suggesting that good things might come from this avenue of scientific inquiry if I could have a little support ($$$) from the NIH.

      In contrast, I try within my grant applications and papers to suggest a path forward to a better treatment / vaccine for HSV-2 genital herpes, and again all I can ask my colleagues, like Dr. Corey, is whether they would be willing to support my approach. Regardless of how many times they say no, I will continue down this avenue of inquiry because it is the only logical and ethical path left to pursue, and a real permanent solution to HSV-2 genital herpes lies at the end of the road.

      Regardless of what level of frustration I may feel with the NIH or any one person (because they do not share my vision), I try to maintain an even keel as much as possible, and refrain from attacking or demonizing any one person. I would suggest you consider the same approach. Do we need a cure for HSV-2 genital herpes? Absolutely. Is attacking or demonizing Larry Corey the best way to get there? Probably not. While the current solutions we have are imperfect, Dr. Corey and the University of Washington have done a great deal (far more than anyone else) for knowledge of HSV-2 and where the scientific issues lie in the past 20 years. I would suggest that Dr. Corey legitimately deserves the thanks and support of all HSV-2 genital herpes sufferers, as his group has done a lot to advance and improve knowledge in this area.

      The underlying issue lies with the NIH, and the fact that they simply should support other labs…..not just the labs at the University of Washington. The NIH has granted my lab about $350,000 in direct costs to support HSV-2 vaccine research since Spring 2009. In the same period of time, I would not be surprised if Dr. Corey and the other HSV-2 researcher at University of Washington have received $50 – 100 million in NIH grants. So, I will not dispute with the NIH that they have, by accident, funded my research on a live-attenuated HSV-2 vaccine. However, I think any serious scientist knows that $350,000 in support over a 5-year period of time is not really serious support in terms of the NIH. Better than nothing, but not nearly enough to sustain this avenue of research.

      I appreciate your enthusiasm. Just be careful about where you place your effort…you catch more flies with honey than with vinegar.

      – Bill H.

  5. Am I the only one bothered by the fact that Dr Corey is basically the guy who invented acyclovir and is completely in bed with Glaxosmithkline (makers of Valtrex). In over 30 years and over $100,000,000 flushed down the toilet and he still insists a live attenuated virus is not viable. Doesn’t he have a vested interest in the long term viability of Valtrex? Did anyone watch his YouTube video? He was such an insufferable, uppity out of touch academic it was sickening. He referred to hsv2 infection as the Rodney Dangerfield of disease. The guy has no concept of the extent to which this garbage destroys lives. He continues to squander public money and seemingly isn’t one iota closer to developing a therapy. I’m not a big conspiracy theorist but damn I smell a rat no? Anyone else have any thoughts or comments? What does the NIH keep funding this garbage research?

    • Hi Keep the Faith,

      I won’t go so far as to say that the research of Dr. Corey or many of my colleagues at the University of Washington represents a conspiracy. However, what I will say is that I believe that the National Institutes of Health has made a serious tactical miscalculation in effectively deciding that the University of Washington in Seattle is the only place on the planet that merits their financial support to identify a solution to the problems caused by HSV-2 genital herpes.

      As a whole, I find that the community of scientists who study herpes simplex virus have grown quite disconnected and out of touch with the very problem that they were charged with investigating, and at some point actually solving, starting about 60 years ago. So, conspiracy, no I don’t agree. But, complacency, indifference, and being “out of touch,” well yes, I strongly agree on all counts. But the problem should not be placed at the feet of Dr. Corey, but rather at the feet of the National Institutes of Health (NIH) who have made a series of spectacularly poor strategic decisions about how to tackle the problem of HSV-2 genital herpes.

      Varicella-zoster virus (VZV) is the cause of chickenpox and shingles, and shares about 60 genes (out of ~75) in common with HSV-2. What help and aid did the NIH offer in bringing about the live-attenuated VZV Oka vaccine that has been used to effectively curb the diseases of chickenpox and shingles? The correct answer would be vanishingly close to no support at all. The NIH and the academic elite it supports in the U.S. largely scoffed at the Japanese scientists who developed the VZV Oka vaccine in the 1970s and 1980s without much in the way of public or financial support from the leadership of the NIH. Based on VZV Oka’s overwhelming success in Japan, Merck purchased the rights to the VZV Oka vaccine and it entered the U.S. marketplace in 1995 (or thereabouts) and has been nothing but a positive addition to our current arsenal of preventative childhood vaccines.

      Fast forward 20 years, again a minority of scientists including myself are stating the obvious that a live-attenuated HSV-2 vaccine would be more effective than the NIH and FDA’s pet approach to developing any new viral vaccine…..namely, a subunit vaccine or some iteration of the basic concept that one may prepare the human body to combat a viral infection by showing the immune system a piece of the virus. It was a nice idea when this theory was introduced in the late 70s and early 80s, but the NIH leadership has simply lost touch with the fact that 30 years later, the data is in. Subunit vaccines are great when they work, but most of the time they fail……..as in, >99% of viral subunit vaccines have failed in human clinical trials since the late 1980s.

      So, like the live VZV Oka vaccine, there is every reason to believe that a live-attenuated HSV-2 vaccine is equally feasible, would be as safe or safer than the VZV Oka vaccine, and yet the NIH is repeating the same mistakes it made with the VZV Oka vaccine. As long as they choose to stay on this path, I will continue to berate the NIH leadership and continue to berate my colleagues in the herpes simplex virus field who would prefer to live in their ivory towers rather than explore a simple and easily feasible solution to the world’s ongoing HSV-2 genital herpes epidemic.

      So, in short, conspiracy to keep a solution back from HSV-2 sufferers….probably not. Complacency, arrogance, and ivory towers……probably so. This is what the NIH of 2014 is all about…..funding the most prestigious science, regardless of whether or not that so-called science is anchored in any real understanding of how the cogs and gears of the natural world actually turn.

      – Bill H.

  6. Hi Dr. Halford. I have been doing some research on HSV and found the below article linking it to a host of illnesses, conditions, and cancers:

    http://www.nytimes.com/1982/05/04/science/herpes-now-blamed-for-more-illness-than-any-other-human-viruses.html?pagewanted=all

    However, the article in question is from 1982. Every bit of modern literature I can find makes no mention of any of these other illnesses. In fact many official guidelines for HSV go out of their way to indicate that HSV is relatively harmless and specifically does not cause cancer. My question is this: has the scientific community come to the conclusion 1) that HSV is no longer believed to be linked to these diseases or 2) that HSV is so ubiquitous and as of yet incurable that advising the general public of these completely valid risk factors is counterproductive somehow to prevention/treatment efforts?

  7. Hi Doctor Halford!

    I know you talked about, but there is a possibility of doing this in other countries? I do not understand much of it, but I think there are other countries where it is easier to perform the tests. Or is it more likely await the approval of the United States? Forgiveness for my English, is that I am from Brazil. Thank you for your commitment to the cause!

    Regards
    Bruno

  8. Dear Mr. Halford,

    would your vaccine somehow offer uncovered, revealed or so to speak “uncamouflaged” virus particles for the immune system to see and learn to attack.
    If it is so, would this training of the immune system be enough to keep already infected patients with (usual) wild-type HSV-2 strains outbreakfree ?
    How would your vaccine score (in animals) regarding this scenario ?

    Anyways, in Mexico there is an approved vaccine used for therapeutic HPV purposes, it’s called MEL-1 or MVA-E2. The information on the internet tells that it is administered near infected areas on the skin, so it’s more effective. So it’s not always the best way to vaccinate in the bum or the arm, I suppose.

Comments are closed.