Where to vaccinate: arm or the bum?

 

arm or bumQUESTION:

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

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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?”

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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.

Given 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.