A brief history of vaccine routes.

This answer covers:

‘Depot‘ effect: How this immunological dogma got started and a brief assessment of its impact.

Role practical field conditions play in choice of vaccination routes.

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A Brief History of Vaccine Routes

Historically, the oldest vaccines, such as for smallpox, were given by scarification of the skin. When a more systematic approach to vaccines took off in the late 19th century, developers simply stuck to the road already traveled by trying to deposit vaccines in the skin, only needles had arrived on the scene by then which made SC injections possible, the only exception being BCG, the tuberculosis vaccine, which empirically seemed to work better as an ID injection.

The switch away from SC started with research by Alexander Glenny who discovered purified toxins such as from diphtheria and tetanus were more immunogenic when adsorbed on aluminum salts, inducing stronger immune responses (1). This discovery became the basis for routinely adding aluminum salts to sub-unit vaccines as an Immunologic adjuvant.

However, giving such adjuvanted vaccines, SC tended to give strong injection site reactions, which predictably led to complaints and drop-offs in vaccination rates. This in turn spurred the search for an alternative route that would be as easy as SC but without its drawback. Empirically, IM jabs of the same vaccine formulations seemed to induce just as strong of an immune response without the inconvenient injection site reaction. This gave the impetus for newer sub-unit vaccines to be formulated and tested typically for IM delivery. Thus, starting in Glenny’s time in the 1920s, IM injections began to supplant SC and dominate vaccinology, helped along by empiricism and cosmetic considerations (2, see below from 3).

‘Deep intramuscular injection generally is recommended for adjuvant-containing vaccines because subcutaneous or intradermal administration can cause marked local irritation, induration, skin discoloration, inflammation, and granuloma formation.[2,][5] However, subcutaneous injection can lessen the risk of local neurovascular injury and is recommended for vaccines that are less reactogenic but immunogenic when administered by this route, such as live virus vaccines. Intradermal administration is preferred for live bacille Calmette-Guérin (BCG) vaccine.[10]‘

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Local responses to IM injections of vaccines aren’t readily visible and haven’t been systematically studied. Few animal model studies bothered to examine muscle tissue after an IM vaccine jab and the few that did found signs of intense, even long-term inflammation (4, 5, 6). However, this issue remained both under-researched and unaddressed for decades, in hindsight seeming to await the revitalization of research into the Innate immune system, something that only got galvanized in the late 1990s. In the meantime, IM injections took firm root in vaccinology while modern medicine also took shape over the same time period and again, from convenience, IM became established as a predominant injection route (7) and thus we reach present-day when most vaccines are IM jabs (see below from 8).

‘Depot’ effect: How this immunological dogma got started and brief assessment of its impact

Though practical and cosmetic considerations helped IM injections dominate vaccinology, another element absolutely crucial in doing so was a dogma that also explains why the IV route became a non-starter for vaccines.

Apart from discovering the adjuvant effects of aluminum salts, currently the most widely used adjuvant in human vaccines, Glenny’s legacy looms over vaccinology and even immunology itself in the form of the dogma called the ‘depot‘ effect.

No question, immunology was in its infancy in Glenny’s time. Key players such as T and B cells were still decades away from being discovered. The question still had to be answered though. How to explain why adding aluminum salts to purified toxins such as diphtheria and tetanus vastly increased the immune responses (measured as antisera) they elicited?

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