To understand why vaccines aren’t given intravenously (IV) requires delving into not just science but sociology as well. A combination of convenience, expediency, empirical observations and immunological dogma is why most vaccines are intramuscular (IM) jabs, rest subcutaneous (SC), oral/nasal or intradermal (ID) and why the IV route isn’t used at all.
This answer covers
- A brief history of vaccine routes.
- ‘Depot‘ effect: How this immunological dogma got started and brief assessment of its impact.
- Role practical field conditions play in choice of vaccination routes.
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.
Switch away from SC started with research by Alexander Glenny – Wikipedia 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 – Wikipedia.
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 immune responses 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,] 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.’
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 – Wikipedia, something that only got galvanized in the late 1990s. 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 doubtless 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. 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?
Given the limited understanding of the immune system in the early 20th century, consensus soon coalesced around a physical explanation, namely, that the crystalline aluminum salt and its adsorbed antigen(s) remain at the site of injection as a depot, which would allow the antigen(s) to be released slowly over time to serve as continuing stimulus for sustained antibody production. Clearly, IV injections couldn’t sustain a ‘depot‘ effect so they were never seriously considered for vaccines.
Mechanistic link between antigen-adjuvant ‘depot‘ and robust immunity was challenged almost from the very beginning when animal model studies summarized in a 1950 book (9) showed that strength of the immune response remained unaffected even if the injection site nodules containing antigen-adjuvant were surgically excised a mere 14 days after immunization. However, with no other satisfactory answer forthcoming, the ‘depot‘ effect took root and vaccinology more or less slumbered for decades, at least as far as trying to figure out how aluminum salts and other adjuvants boosted immune responses to the antigens conjugated to them.
The decades-long Rip Van Winkle-like slumber over how adjuvants augment immune responses got jolted in 1989 when Charles Janeway – Wikipedia wrote a hugely influential article (10) about, among other things, the immunologist’s ‘dirty’ little secret, a play of words alluding to the fact that immune responses to purified antigens typically tend to be muted or non-existent unless accompanied by ‘dirt’, by which he meant adjuvants such as CFA (Freund’s adjuvant – Wikipedia) in animal models or aluminum salts in human vaccines.
Janeway’s hypothesis was invigorated and validated by the discovery of the first mammalian Toll-like receptor – Wikipedia (TLR) by his lab in 1997 followed in short order by discoveries of CLRs (C-type lectin – Wikipedia) and NLRs (NOD-like receptor – Wikipedia) and other Pattern recognition receptor – Wikipedia (PRRs), discoveries that offered a biological explanation for the adjuvant effect and opened the door to a molecular basis for understanding how the innate immune system operates and how it co-ordinates with and/or controls the Adaptive immune system – Wikipedia.
Is the ‘depot‘ effect important or even necessary now? Though considerably weakened by the discovery of PRRs, it still retains some of its hold as an immunological dogma to explain the role of even PRRs (11) since we don’t yet fully understand how strong and long-lasting immunological memory forms nor how adjuvants work. However, regardless the need for antigen ‘depot‘, today IM vaccine injections remain a mainstay.
Role practical field conditions play in choice of vaccination routes
Vaccines are typically prophylactic, public health measures given to millions of healthy people. This difference in kind from other medical interventions influences all aspects of vaccines, from how they’re funded to pricing and delivery.
Given their public health nature, meaning intended to be given to as many as individuals as possible, often in field conditions in remote areas, obviously vaccines are designed for ease of administration. Volume, how many can be given vaccine per unit of time, is obviously a function of how easy it is for the person giving the shot. Most often, especially in field conditions, such a person may not even be a doctor or nurse but rather a public health worker. Keeping this frame of reference in mind, IM and SC injections are much easier to give compared to other routes such as ID or IV.
Simplest route would obviously be oral, both from the standpoint of ease of delivery as well as from manufacturing cost since, compared to oral, an injectable is much more expensive, its manufacturing having to pass extremely rigorous quality control measures, making its approval process more cumbersome, lengthy and expensive. Indeed, historically, one of the most used vaccines in the world was oral, the oral polio vaccine, OPV. However, when formulated orally, not all vaccines drive the robust immunity necessary whereas over time, largely empirically, the IM route proved quite effective.
In many parts of the world, birth and infancy still remain the only time period mother and child even come into contact with any type of public health infrastructure, be it a primary health clinic or small local hospital, a logistical reality for why childhood vaccinations are such a crucial fulcrum of public health measures in poorer countries. IV injections are all the more difficult in babies and infants, especially in field conditions, while IM and SC are relatively easy.
1. Tirumalai Kamala’s answer to Why is there aluminum in vaccines?
2. Kroger, A., W. Atkinson, and L. Pickering. “General immunization practices.” Vaccines 6 (2012): 88-111.
3. Kroger, A., Sumaya, C., Pickering, L., Atkinson, W. General Recommendations on Immunization. 2011. https://www.cdc.gov/mmwr/pdf/rr/…
4. RG, WHITE, COONS AH, and CONNOLLY JM. “Studies on antibody production. III. The alum granuloma.” The Journal of experimental medicine 102.1 (1955): 73-82. http://europepmc.org/backend/ptp…
5. Goto, Norihisa, and Kiyoto Akama. “Histopathological Studies of Reactions in Mice Injected with Aluminum‐Adsorbed Tetanus Toxoid.” Microbiology and immunology 26.12 (1982): 1121-1132. Histopathological Studies of Reactions in Mice Injected with Aluminum-Adsorbed Tetanus Toxoid
6. Goto, Norihisa, et al. “Local tissue irritating effects and adjuvant activities of calcium phosphate and aluminium hydroxide with different physical properties.” Vaccine 15.12-13 (1997): 1364-1371.
7. Tirumalai Kamala’s answer to Immunology: Which could induce the best immune response? Same antigen, same dose: Injected intradermally; hypodermally; intramuscularly; IV; and why?
9. Holt, Lewis Burnell. “Developments in diphtheria prophylaxis.” Developments in Diphtheria Prophylaxis. (1950).
10. Janeway, Charles A. “Approaching the asymptote? Evolution and revolution in immunology.” Cold Spring Harbor symposia on quantitative biology. Vol. 54. Cold Spring Harbor Laboratory Press, 1989.
11. Lingnau, Karen, Karin Riedl, and Alexander Von Gabain. “IC31® and IC30, novel types of vaccine adjuvant based on peptide delivery systems.” Expert review of vaccines 6.5 (2007): 741-746. https://www.researchgate.net/pro…