Answer by Tirumalai Kamala:

What constitutes the best immune response? I’m not sure there is such a thing as a best immune response per se. It might be more fruitful to ask instead if a given immune response could be the most appropriate. As an example, let’s consider an IgA response to given antigen (same dose). An IgA response could indeed be quite effective in the mucosa but probably not effective in the skin. On the other hand, a delayed type hypersensitivity (DTH) response of particular strength might well be tolerated at a particular skin site but a DTH of the same strength in the eye might well destroy it. In my view, what constitutes an appropriate immune response varies according to the site of the response. This would make sense if we agree with the assumption that tissues can actively control and modulate the immune responses that occur within them. As a place to start considering this assumption and its implications in greater detail, I suggest this review (Page on Nature) where we explore this issue at length.

However, a consideration of the tissue site alone does not completely address this question. Immune responses are triggered in response to “something”. We now understand that a given “something” has a typical portal of entry and an associated natural sequence of events preceding the immune response, both of which appear to influence the nature and strength of the immune response. It therefore appears reasonable to me to assume that an injection mimicking the natural portal of entry would be likely to also mimic the associated sequence of events that should immediately follow. It is not clear to me that most of the currently used modes of injection, developed during the course of the past century, entailed the consideration of matching the injection site to the natural portal of entry. Rather, commonly used injections appear to be rooted more in tradition rather than on solid evidence-based rationale (Intramuscular injections: a review of best practice for mental health nurses). In that light, it is in itself interesting to consider the history of a commonly used injection route such as the intramuscular injection.

Why do we so frequently use intramuscular injection for inducing immunity? If we think about it, most extraneous agents that induce immune responses enter via skin, mucosae or blood (vector-borne). I know of none that directly enter the muscle. Is it not then reasonable to ask if there is indeed a strong scientific rationale as to why intramuscular injection has become such a common route of administration for inducing immunity? While there is not an abundant literature on this topic, what there is, such as these reviews (Intramuscular injections: a review of best practice for mental health nurses) (The importance of injecting vaccines into muscle | BMJ) raise yet more questions. For instance, as the authors of one of the reviews themselves allude, did it have more to do with cosmetic considerations becoming increasingly important from the 1960s? There are some obvious questions such as these but I’m not sure that the answers are that easy to find.

Another avenue to explore for this question would be to examine the rather more abundant literature suggesting that different routes of administration induce different kinds of immune responses. I link to one such recent article here (A cross-sectional evaluation of particulate antigen-delivery systems).

Another consideration to keep in mind is that different types of injections have different degrees of technical difficulty. Even the intramuscular injection has different degrees of difficulty depending on different muscle sites. For example, among other considerations, evidence with regard to uptake and adverse events suggests that intramuscular injection into the ventrogluteal might be more optimal compared to the dorsogluteal (Intramuscular injections: a review of best practice for mental health nurses) that was  more frequently used historically. Documented anatomic differences between male and female could also influence the ensuing immune response. For example, it has been reported that “ultrasound studies in adults (references 117, 118 in linked article) have shown that females have a thicker subcutaneous layer than males of comparable weight and body mass index (BMI). Consequently, injection with the same length needle is more likely to give subcutaneous injection rather than intramuscular injection in females compared with males” (Sex differences in injection site reactions with human vaccines). Yet another consideration is that intradermal injection is technically more difficult compared to subcutaneous (I assume this is what you mean by hypodermal), and I can attest to this from personal experience of having performed both these types of injections many times over the years. Such considerations suggest that technical variables between the different injection types themselves could also potentially greatly influence the ensuing immune response.

Which could induce the best immune response? Same antigen, same dose: Injected intradermally; hypodermally; intramuscularly; IV; and why?