ABSTRACT
Subcutaneous vaccine (SC) administration is an outmoded practice which complicates vaccine administration recommendations. Local adverse events following immunization (AEFIs) are a recognized determinant of vaccine hesitancy/refusal which can lead to an increased prevalence of vaccine-preventable disease.
This extensive narrative review provides high-grade evidence that intramuscular (IM) administration of all vaccine types [adjuvanted, live virus and non-adjuvanted (inactivated whole cell, split cell and subunit)] significantly reduces the likelihood of local adverse events. This, combined with moderate grade evidence that IM injection generates significantly greater immune response compared with SC injection, allows a strong recommendation to be made for the IM injection of all vaccines except BCG and Rotavirus.
This will simplify vaccination practice, minimize the inadvertent misadministration of vaccines and potentially improve public trust in vaccination.
Introduction
Vaccination has made, and will continue to make, a very significant contribution to world health.Citation1 However, adverse events following immunization (AEFTs), including injection site reactions (ISRs), are a significant driverCitation2,Citation3 of vaccine hesitancy and refusal. The latter has resultedCitation4 in significantly increased risks of pertussis, varicella and pneumococcal infections in non-vaccinated children compared with vaccinated children.
Consequently, the definition and implementation of best vaccination practice (site, route and technique of injection) in terms of AEFIs (reactogenicity) and immune response (immunogenicity) are mandatory.
The current mantraCitation5 for vaccination practice has been to administer adjuvanted vaccines by intramuscular injection, live virus vaccines by subcutaneous injection and non-adjuvanted, inactivated whole cell, split and subunit vaccines by either route. This complicated regimen for vaccine administration is due to the unacceptable reactogenicityCitation6 of subcutaneously administered adjuvanted vaccines.
Evidence-based medicine (EBM) has been championedCitation7 as a way of improving the quality of patient care through a stepwise process of formulating the clinical questions to be answered, collating and appraising relevant data and defining the optimal response.
The purpose of this review is to use EBM to seek to rationalize the route of administration of vaccines given by SC, IM or either routes. The PICO elementsCitation8 for this review are P = human vaccine recipients, I = intramuscular route of injection, C = subcutaneous route of injection and O = reactogenicity and immunogenicity of vaccines.
Methods
Searches were made using Pubmed. Google Scholar, Scopus, Embase, Biological Abstracts, Science Citation index, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL) and Databases of Abstracts of Reviews of Effects (DARE) using the following search terms and their word variants; “vaccines,” “administration,” “subcutaneous,” “intramuscular,” “adverse reactions” and “immunogenicity.” Manual searches were made from the following journals for the date in parenthesis to January 2020: Acta Paediatrica (1998), Acta Tropica (1980), American Journal of Medicine (1946), American Journal of Public Health (1971), American Journal of Tropical Medicine and Hygiene (1998), Annals of Internal Medicine (1995), Annals of Tropical Pediatrics (1999), Archives of Diseases of Childhood (1926), Bio Drugs (1998), Biologicals (1990), British Medical Journal (1991), Canadian Medical Association Journal (1911), Clinical Infectious Diseases (1999), Clinical and Vaccine Immunology (2006), European Journal of Pediatrics (1997), Infection and Immunity (1970), Journal of Pediatrics and Childhood (1998), Expert Review of Vaccines (2002), Human Vaccines (2005), Human Vaccines & immunotherapeutics (2012), Journal of Pediatrics (1995), Journal of Travel Medicine (1997), Journal of Tropical Pediatrics (1995), Lancet (1990), Medical Journal of Australia (2004), New England Journal of Medicine (1992), Pediatrics (1960), Pediatric Infectious Disease Journal (1995), Pediatrics International (1999), Public Health (1995), Scandinavian Journal of Infectious Disease (1997), Transactions of the Royal Society of Tropical Medicine and Hygiene (1920), Vaccine (1983) and to find additional studies where these were not abstracted.
Bibliographies of all relevant articles were searched for additional studies. All route comparative studies were included for analysis except those involving patients with chronic cutaneous, subcutaneous and muscular disorders and non-English language studies unless the full article was available for translation.
Results
Fifty-eight studies, which satisfied the inclusion criteria, were retrieved by the searches (51 by literature search, 7 by a manual search of appropriate Journals). They were divided into two study design groups, randomized trials and observational studies, as recommended in the GRADE guidelines.Citation9 The former has the potential to provide moderate to high-grade evidence whilst the latter could only give very low to low-grade evidence.
Local reactogenicity data were recorded as warmth, pain, redness and swelling. These and immunogenicity data were collated into vaccine groups; adjuvanted vaccines, live virus vaccines and non-adjuvanted vaccines (inactivated whole cell, split cell and subunit). These are presented as respectively.
Table 1. Adjuvanted vaccines and intramuscular compared with subcutaneous administration – reactogenicity and immunogenicity
Table 2. Live virus vaccines and intramuscular compared with subcutaneous administration – reactogenicity and immunogenicity
Table 3. Non-adjuvanted (whole cell, split cell and subunit) vaccines and intramuscular compared with subcutaneous administration – reactogenicity and immunogenicity
Thirty studiesCitation10–39 comparing intramuscular with subcutaneous administration of adjuvanted vaccines are presented in alphabetical order in (6 anthrax10–15, 1 botulinum toxoid,Citation16 9 diphtheria and tetanus toxoid containing vaccines,Citation17–25 4 hepatitis,Citation26–29 7 hepatitis, Citation30–36 1 herpes zoster,Citation37 1 influenzaCitation38 and 1 tick-borne encephalitisCitation39). These studies could be subdivided into two groups; one with 21 randomized trials and the other with 7 observational studies and 2 randomized trials with unacceptable biases.
The 21 randomized trials being; 6 anthrax10−15, 1 botulinum toxoid,Citation16 5 diphtheria toxoid containing vaccines,Citation17,Citation19-22 3 hepatitis, Citation27–29 3 hepatitis, Citation32,Citation34,Citation35 with 1 each of herpes zoster,Citation37 influenzaCitation38 and tick-borne encephalitisCitation39 vaccines. There were 7 observational studies. These were 4 diphtheria/tetanus toxoid containing vaccinesCitation18,Citation23-25 and 3 hepatitis B vaccines.Citation30,Citation33,Citation36
Two studies were excluded from the randomized trial group due to unacceptable biases. In the study, Ragni et al.Citation26 with hepatitis A vaccine, patients with hemophilia were given SC injection and compared with non-hemophilic siblings given IM injection. Whilst in the study by Probst et al.Citation31 with hepatitis B vaccine IM injection was given into the deltoid muscle and SC injection was given into the volar surface of the forearm.
Five studiesCitation20–24 with diphtheria/tetanus toxoid were included where the vaccines were given with a 16 mm compared with 25 mm long needle as the former was considered to give SC injection and the latter to give IM injection.
In the 21 randomized trials, local reactogenicity data were provided in 20 studies. In 18 studies,Citation10–17,Citation19–22,Citation28,Citation29,Citation34,Citation37-39 SC injection gave significantly greater rates of reaction than IM injection. In two other studies,Citation27,Citation35 SC gave greater rates of reaction than IM injection but this did not reach statistical significance. Subcutaneous nodules were significantly more frequent for SC compared with IM injection for anthrax vaccine10−15, botulinum toxoid vaccineCitation16 and a combination diphtheria toxoid vaccine.Citation17 In an observational studyCitation18 with diphtheria toxoid containing vaccines, sterile abscess formation was significantly greater for SC compared with IM injection.
Pain immediately after injection (assessed with a pain analogue scale) was reportedCitation11 to be significantly less for a 4 IM regimen of anthrax vaccine compared with a 4 SC regimen. Mark et al.Citation19 reported a similar trend but this did not reach statistical significance.
Immunogenicity data were recorded in 19 of the randomized trials.Citation10–12,Citation14–17,Citation19,Citation20,Citation22,Citation27-29,Citation32,Citation34,Citation35,Citation37-39 Immunogenicity was greater for IM compared with SC injection in six studiesCitation27,Citation32,Citation34,Citation35,Citation37,Citation38 being significantly greater in the studies by Kishino et al.Citation34 (hepatitis B vaccine) and Ikeno et al.Citation38 (first dose of an influenza vaccine). In the remaining 13 studiesCitation10–12,Citation14–17,Citation19,Citation20,Citation22,Citation28,Citation29,Citation39, the immune response was comparable for IM and SC injection.
Seventeen studies comparing IM with SC administration of live virus vaccines are presented in alphabetical order in (1 cytomegalovirus,Citation40 1 herpes zoster,Citation41 3 human Immunodeficiency virus,Citation42–44 5 measles-mumps-rubella,Citation45–49 1 Rift Valley fever,Citation50 4 vaccinia,Citation51–54 1 varicellaCitation55 and 1 yellow feverCitation56). Fifteen of the 17 studies were randomized trials.Citation40–45,Citation47-55
In 13 studiesCitation40-44,Citation47–53,Citation55 out of the15 studies where reactogenicity data were provided, SC injection gave significantly greater rates of local reaction than IM injection. In the study by Lafeber et al.,Citation45 pain immediately after injection was greater with SC compared with IM injection but this did not reach statistical significance. Two subcutaneous nodules were observed following SC injection of one HIV vaccineCitation44 but not with IM injection.
IM and SC immunogenicity data were comparable in 15 randomized trials.Citation40–45,Citation47-55 Immunogenicity was greater for IM compared with SC injection in one study.Citation54 In this study by Seaman et al.Citation54 immunogenicity was greater for IM compared with SC injection but this did not reach statistical significance.
Eleven studies comparing IM with SC administration of non-adjuvanted, inactivated (whole cell, split cell and subunit) vaccines are presented in alphabetical order in (1 Hemophilus influenzae type b,Citation57 6 influenza,Citation58–63 1 leptospirosis,Citation64 2 meningococcal,Citation65,Citation66 1 pneumococcalCitation67).
Nine of the 11 studies were randomized trials.Citation58–65,Citation67 In 8Citation58–60,Citation62-65,Citation67 of the 9 studies where reactogenicity data were provided, SC injection was associated with significantly greater rates of reaction than IM injection. In seven of the nine randomized trials where immunogenicity data were provided,Citation58–61,Citation64,Citation65,Citation67 IM gave comparable results with SC injection in four studies.Citation61,Citation64,Citation65,Citation67 In three studies,Citation58–60 antibody response was significantly greater for IM compared with SC injection for influenza A.
Discussion
This extensive narrative review provided high-grade evidenceCitation9 that intramuscular (IM) injection significantly reduced the likelihood of local reactogenicity compared with subcutaneous (SC) injection. High-grade evidence was drawn from studies with all vaccine types (adjuvanted n = 18, live virus n = 13, non-adjuvanted inactivated (whole cell, split and subunit) n = 8).
The greater rates of reactogenicity were also seen for vaccines recommendedCitation5 to be given by SC injection (quadrivalent meningococcal polysaccharide (4vMenPV), varicella (VV), measles-mumps-rubella/varicella (MMR/V), herpes zoster vaccine) and vaccines recommended to be given by either IM or SC route (influenza and 23-valent pneumococcal (23vPPV)).
Direct route comparative studies have not been reported for inactivated polio (IPV), Japanese encephalitis (Imojev®), Q fever and rabies vaccine. Studies with IPVCitation17,Citation68 given IM or SC with other antigens have shown comparable immunogenicity for IPV. Consequently, the recommendation for IPV alone to be given by SC injection is inconsistent with these data.
Older rabies vaccines were derived from animal neural tissue and given by subcutaneous injection.Citation69 Currently recommendedCitation70 rabies vaccines are derived from cell cultures and are given by IM injection. The latter are more immunogenic and associated with less severe adverse reactions than the older rabies vaccines.
Subcutaneous nodules are uncommonly reported in this review and almost entirely with adjuvanted vaccines (anthrax10−15, botulinum toxoidCitation16 and diphtheria combination vaccineCitation17). A single reportCitation44 of the transient formation of two nodules was made with an HIV vaccine. Subcutaneous nodules have been consideredCitation71 to be benign, self-limiting AEFIs but this is clearly not the case as demonstrated by Bernstein et al.Citation72 who reported 11.4% of nodules persisting at 180 d post anthrax vaccination. These nodules may persistCitation73 for years and are often associated with pruritis and superficial dermatological features such as eczema, lichenification and hyperpigmentation.
Route of administration and use of aluminum salt adjuvants are recognizedCitation71 determinants of their formation. However, the role of aluminum hydroxide sensitivity in the pathogenesis of these nodules is controversial with some authors demonstrating this phenomenonCitation74 whilst othersCitation75 claiming that nodule formation reflects SC rather than IM injection of aluminum adjuvanted vaccines. Sterile abscess formation was also significantly greater with SC than IM injection for an adjuvanted diphtheria toxoid vaccine in an observational study.Citation18
Pain immediately after injection might be expectedCitation76 to be greater with IM compared with SC injection as the former has a dense supply of nociceptive nerve endings with the subcutaneous space being relatively devoid of pain receptors. Pain assessed (using standardized pain assessment scales) was significantly greater with SC than IM with anthrax vaccineCitation11 in this review. The same trend was seen with MMRCitation45 and DT toxoid vaccinesCitation19 using the same methodology but did not reach statistical significance.
This review provided moderate grade evidence that IM injection significantly improved the immunogenicity of vaccines compared with SC injection. This grade of evidence was drawn from better antibody response/seroconversion data with adjuvanted vaccines n = 6, live virus vaccines n = 1 and non-adjuvanted, inactivated (whole cell, split and subunit) vaccines n = 3 for IM compared with SC injection. In this review, no study with SC injection was observed to be more immunogenic than IM injection. The extent and availability of the immunogenicity data were influenced by trial design factors (e.g. set to demonstrate non-inferiority between routes of administration and Phase I studies)
Phase I studiesCitation77 are safety and tolerance studies with one of their objectives to identify preferred routes of administration. In the randomized trials of this review, 33% had less than 100 patients (3/21 adjuvanted vaccines,Citation14,Citation20,Citation37 9/15 live virus vaccinesCitation40,Citation42,Citation44,Citation45,Citation50-54 and 3/9 non-adjuvanted, inactivated (whole cell, split cell and subunit vaccines)).Citation61,Citation62,Citation64
The combination of high-grade reactogenicity evidence with the moderate grade immunogenicity evidence allows a strong recommendationCitation78 that all vaccines, except BCG (intradermal) and rotavirus (oral), should be given by IM injection. This will simplify vaccination practice and prevent the inadvertent misadministration of vaccines (meningococcal conjugate vaccineCitation79 and recombinant zoster vaccineCitation80). It may potentially reduce vaccine hesitancy/refusalCitation2,Citation3 due to a lower rate of ISRs with IM compared with SC injection.
The use of evidence-based medicine in vaccinology should replace highly idiosyncratic and divergent practices that are outmoded by promoting accountability based on best scientific principles.
References
- Greenwood B. The contribution of vaccination to global health: past, present and future. Phil Trans R Soc Lond Biol Sci. 2014;369(1645):20130433. doi:10.1098/rstb.2013.0433.
- Gowda C, Dempsey AF. The rise (and fall?) of parental vaccine hesitancy. Hum Vaccin Immunther. 2013;9(8):1755–62. doi:10.4161/hv.25085.
- Salmon DA, Moulton H, Omer SB, DeHart MP, Stokley S, Hansey NA. Factors associated with refusal of childhood vaccines among parents of school-aged children: A case-control study. Arch Pediatr Adolesc Med. 2005;159(5):470–76. doi:10.1001/archpedi.159.5.470.
- Siddiqui M, Salmon D, Omer SB. Epidemiology of vaccine hesitancy in the United States. Hum Vaccin Immunother. 2013;9(12):2643–48. doi:10.4161/hv.27243.
- Australian Immunisation Handbook. Canberra. Australia. 10th ed. Australian Government Department of Health. Vaccination procedures, Administration of vaccines, Route of administration; 2016 update. immunisationhandbook.health.gov.au/vaccination-procedures/administration-of-vaccines.
- Volk VK. Safety and effectiveness of multiple antigenic preparations in a group of free-living children. Am J Pub Health. 1949;39:1299–313. doi:10.2105/AJPH.39.10.1299.
- Bauchner H. Evidence-based medicine: A new science or an epidemiologic fad. Pediatrics. 1999;103(5):1029–31. doi:10.1542/peds.103.5.1029.
- Brockmeier AJ, Meizhi J, Przybyla P, Ananiadou S. Improving reference prioritization with PICO recognition. BMC Med Inform Decis Mak. 2019;19(1):256. doi:10.1186/s12911-019-0992-8.
- Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64(4):401–06. doi:10.1016/jclinepi.2010.07.015.
- Wright JG, Plikaytis BD, Rose CE, Parker SD, Babcock J, Keitel W, El Sahly H, Poland GA, Jacobson RM, Keyserling HL. Effect of reduced dose schedules and intramuscular injection of anthrax vaccine adsorbed on immunological response and safety profile: A randomized trial. Vaccine. 2014;32(8):1019–28. doi:10.1016/j.vaccine.2013.10.039.
- Marano N, Plikaytis BD, Martin SW, Rose C, Semenova VA. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months. JAMA. 2008;300(13):1532–43. doi:10.1001/jama.300.13.1532.
- Pittman PR, Kim-Ahn G, Pifat DY, Coonan K, Gibbs P, Little S, Pace-Templeton JG, Myers R, Parker GW, Friedlander AM. Anthrax vaccine: immunogenicity and safety of a dose-reduction, route-change comparison study in humans. Vaccine. 2002;20(9–10):1412–20. doi:10.1016/s0264-410x(01)00462-5.
- Pittman PR. Aluminum-containing vaccines associated adverse events: role of administration and gender. Vaccine. 2002;20(Suppl 3):S48–50. doi:10.1016/s0264-410x(02)00172-x.
- Campbell JD, Clement KH, Wasserman SA, Donegan S, Chrisley L, Kotloff KL. Safety, reactogenicity and immunogenicity of a recombinant protective antigen anthrax vaccine given to healthy adults. Hum Vaccin. 2007;3(5):205–11. doi:10.4161/hv.3.5.4459.
- Pondo T, Rose CE, Martin SW, Kietel WA, Keyserling HC, Babcock J, Parker S, Jacobson RM, Poland GA, McNeil MM. Evaluation of sex, race, body mass index and pre-vaccination serum progesterone levels and post-vaccination serum anti-anthrax protective immunoglobulin G on injection site adverse events following anthrax vaccine adsorbed (AVA) in the CDC-AVA human clinical trial. Vaccine. 2014;32(28):3548–54. doi:10.1016/j.vaccine.2014.04.025.
- Edelman R, Wasserman SA, Bodison SA, Perry JG, O’Donnoghue M, De Tolla LJ. Phase II safety and immunogenicity study of type F botulinum toxoid in adult volunteers. Vaccine. 2003;21(27–30):4335–47. doi:10.1016/s0264-410x(03)00460-2.
- Carlsson R-M, Claesson BA, Kayhty H, Selstam U, Iwarson S. Studies on a Hib-tetanus toxoid conjugate vaccine: effects of co-administered tetanus toxoid vaccine, of administration route and of combined administration with an inactivated polio vaccine. Vaccine. 2000;18(5–6):468–78. doi:10.1016/x0264-410x(99)00238-8.
- Volk VK, Top FH, Bunney WE. Significance of “cysts” following injections of antigens. Am J Public Health. 1954;44:1314–25. doi:10.2105/AJPH.44.10.1314.
- Mark A, Carlsson R-M, Granstrom M. Subcutaneous versus intramuscular injection for booster DT vaccination of adolescents. Vaccine. 1999;17(15–16):2067–72. doi:10.1016/s0264-410x(98)00410-1.
- Rothstein EP, Kamiya H, Nii R, Matsuda T, Bernstein HH, Long SS, Hosbach PH, Meschievitz CK. Comparison of diphtheria-tetanus-two component acellular pertussis vaccines in United States and Japanese infants at 2, 4 and 6 months of age. Pediatrics. 1996;97:236–42.
- Diggle L, Deeks JJ. Effect of needle length on incidence of local reactions to routine immunization in infants aged 4 months: randomized, controlled trial. BMJ. 2000;321:931–33. doi:10.1136/bmj.321.7266.931.
- Diggle L, Deeks JJ, Pollard AJ. Effect of needle size on immunogenicity and reactogenicity of vaccines in infants: randomized, controlled trial. BMJ. 2006;333:571–74. doi:10.1136/bmj.38906.704549.7C.
- Jackson LA, Starkovich P, Dunstan M, Yu O, Nelson J, Dunn J, Rees T, Zavitkovsky A, Maus D, Froeschle JE. Prospective assessment of the effect of needle length and injection site on the risk of local reaction to the fifth diphtheria-tetanus-acellular pertussis vaccination. Pediatrics. 2008;121(3):e646–52. doi:10.1542/peds.2007-1653.
- Ipp MM, Gold R, Goldbach M, Maresky DC, Saunders N, Greenberg S, Davy T. Adverse reactions to diphtheria, tetanus, pertussis-polio vaccination at 18 months of age: effect of injection site and needle length. Pediatrics. 1989;83:679–82.
- Holt LB. Bousfield G. P.T.A.P.: the present position. BMJ. 1949;1(4607):695–99. doi:10.1136/bmj.1.4607.695.
- Ragni MV, Lusher JM, Koerper MA, Manco-Johnson M, Krause DS. Safety and immunogenicity of subcutaneous hepatitis A vaccine in children with haemophilia. Haemophilia. 2000;6:98–103. doi:10.1046/j.1365-2516,2000.00386x.
- Frosner G, Steffen R, Herzog C. Virosomal hepatitis A vaccine: comparing intradermal and subcutaneous with intramuscular administration. J Travel Med. 2009;16(6):413–19. doi:10.1111/j.1708-8305.2009.00351.x.
- Fisch A, Cadilhac P, Vidor E, Prazuck T, Dublanchet A, Lafaix C. Immunogenicity and safety of new inactivated hepatitis A vaccine: a clinical trial with comparison of administration route. Vaccine. 1996;14(12):1132–36. doi:10.1016/0264-410x(96)00044-8.
- Parent Du Chatelet I, Lang J, Schlumberger M, Vidor E, Soula G, Genet A, Standaert SM, Saliou P. Clinical immunogenicity and tolerance studies of liquid vaccines delivered by jet-injection and a new single-use cartridge (Imule®): comparison with standard syringe injection, Imule Investigators Group. Vaccine. 1997;15(4):449–58. doi:10.1016/s0264-410x(96)00173-9.
- Ogawa M, Akine D, Sasahara T. Comparison of hepatitis B vaccine efficacy in Japanese students: a retrospective study. Environ Health Prev Med. 2019;24:80. doi:10.1186/s12199-019-0837-1.
- Propst T, Propst A, Lhotta K, Vogel W, Konig P. Reinformed intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination. Am J Kidney Dis. 1998;32(6):1041–45. doi:10.1016/s0272-6386(98)70081-2.
- Yamamoto S, Kuroki T, Kurai K, Iino S. Comparison of results of phase I studies with recombinant and plasma-derived hepatitis B vaccines and controlled study comparing intramuscular and subcutaneous injection of recombinant hepatitis B vaccine. J Infect. 1986;13(SupplA):53–60. doi:10.1016/s0163-4453(86)92698-8.
- Suzuki H, Iino S, Shiraki K, Akahane Y, Okamoto H, Domoto K, Mishiro S. Safety and efficacy of a recombinant yeast-derived pre-S2 + S containing hepatitis B vaccine (TGP-943): phase 1, 2 and 3 clinical testing. Vaccine. 1994;12(12):1090–96. doi:10.1016/0264-410X(94)90178-3.
- Kishino H, Takahashi K, Sawata M, Tanaka Y. Immunogenicity, safety and tolerability of a recombinant hepatitis B vaccine manufactured by a modified process in healthy young Japanese adults. Hum Vaccin Immunother. 2018;14(7):1773–78. doi:10.1080/21645515.2018.1452578.
- de Lalla F, Rinaldi K, Santoro D, Pravettoni G. Immune response to hepatitis B vaccine given at different injection sites and by different routes: a controlled randomized study. Eur J Epidemiol. 1988;4(2):256–58. doi:10.1007/bf00144763.
- Carpenter SL, Soucie JM, Presley RJ, Ragni MV, Wicklund BM, Silvey M, Davidson H. The hemophilia treatment center network investigators. Hepatitis B vaccination is effective by subcutaneous route in children with bleeding disorders: a universal data collection database analysis. Haemophilia. 2015;21(1):e30–43. doi:10.1111/hae.12569.
- Vink P, Shiramoto M, Ogawa M, Eda M, Douha M, Heineman T, Lal H. Safety and immunogenicity of a Herpes Zoster subunit vaccine in Japanese population aged ≥ 50 years when administered subcutaneously vs intramuscularly. Hum Vaccin Immunother. 2017;13(3):574–78. doi:10.1080/21645515.2016.1232787.
- Ikeno D, Kimachi K, Kino Y, Harada S, Yoshida K, Tochihara S, Itamura S, Odagiri T, Tashiro M, Okada K. Immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1, NIBRG-14) vaccine administered by intramuscular or subcutaneous injection. Microbiol Immunol. 2010;54:81–88. doi:10.1111/j.1348-0421.2009.0091.x.
- Hopf S, Garner-Spitzer E, Hofer M, Kundi M, Wiedermann U. Comparable immune responsiveness but increased reactogenicity after subcutaneous versus intramuscular administration of tick-borne encephalitis (TBE) vaccine. Vaccine. 2016;34(17):2027–34. doi:10.1016/j.vaccine.2015.12.057.
- Bernstein DJ, Reap EA, Katen K, Watson A, Smith K, Norberg P, Olmsted RA, Hoeper A, Morris J, Negri S. Randomized, double-blind, phase I trial of an alphavirus replicon vaccine for cytomegalovirus in CMV seronegative adult volunteers. Vaccine. 2010;28(2):484–92. doi:10.1016/j.vaccine.2009.09.135.
- Diez-Domingo J, Weinke T, Garcia de Lomas J, Meyer CU, Bertrand I, Eymin C, Thomas S, Sadorge C. Comparison of intramuscular and subcutaneous administration of a herpes zoster live-attenuated vaccine in adults aged ≥ 50 years: A randomized non-inferiority clinical trial. Vaccine. 2015;33(6):789–95. doi:10.1016/j.vaccine.2014.12.024.
- Koblin BA, Casapia M, Morgan C, Qin L, Wang ZM, Defawe OD, Baden L, Goepfert P, Tomaras GD, Montefiori DC. Safety and immunogenicity of an HIV adenoviral vector boost after DNA plasmid vaccine prime by route of administration: a randomized clinical trial. PloS ONE. 2011;6(9):e24517. doi:1371/journal.pone.0024517.
- Peters BS, Jaoko W, Vardas E, Panayotakopoulos G, Fast P, Schmidt C, Gilmour J, Bogoshi M, Omosa-Manyonyi G, Dally L. Studies of a prophylactic HIV-I vaccine candidate based on modified vaccinia virus Ankara (MVA) with and without DNA priming: effects of dosage and route on safety and immunogenicity. Vaccine. 2007;25(11):2120–27. doi:10.1016/j.vaccine.2006.11.016.
- Enama ME, Ledgerwood JE, Novik L, Nason MC, Gordon IJ, Holman L, Bailer RT, Roederer M, Koup RA, Mascola JR. Phase I randomized clinical trial of VRC DNA and rAd5 HIV-I Vaccine delivery by intramuscular (IM), subcutaneous (SC) and intradermal (ID)administration (VRCOII). PloS ONE. 2014;9(3):e91366. doi:10.1371/journal.pone.0091366.
- Lafeber AF, van der Klis FRM, Marzec AHJO, Labadie J, van Ommen R, Strieder TG, Berbers GAM MMR vaccine in 14 months old children, intramuscular versus subcutaneous administration RIVM Report 00002 001.
- Kuter BJ, Brown M, Wiedmann RT, Harzel J, Musey L. Safety and immunogenicity of M-M-RII (combination measles-mumps-rubella vaccine) in clinical trials of healthy children conducted between 1988 and 2009. Pediatr Infect Dis J. 2016;35(9):1011–20. doi:10.1097/INF,000000000001241.
- Knuf M, Zepp F, Meyer CU, Habermehl P, Maurer L, Burow H-M, Behre U, Janssens M, Willems P, Bisanz H. Safety, immunogenicity and immediate pain of intramuscular versus subcutaneous administration of a measles-mumps-rubella -varicella vaccine to children aged 11-21 months. Eur J Pediatr. 2010;169:925–33. doi:10.1007/s00431-010-1142-6.
- Gillet Y, Habermehl P, Thomas S, Eymin C, Fiquet A. Immunogenicity and safety of concomitant administration of a measles, mumps and rubella vaccine (M-M-Rvax Pro®) and varicella vaccine (VARIVAX®) by intramuscular or subcutaneous routes at separate injection sites: a randomized clinical trial. BMC Med. 2009;7(16). doi:10.1186/1741-7015-7-16.
- Haas H, Richard P, Eymin C, Fiquet A, Kuter B, Soubeyrand B. Immunogenicity and safety of intramuscular versus subcutaneous administration of a combined measles, mumps, rubella and varicella vaccine to children 12 to 18 months of age. Hum Vaccin Immunother. 2019;15(4):778–85. doi:10.1080/21645515.2018.1549452.
- Pittman PR, McClain D, Quinn X, Coonan KM, Mangiafico J, Makuch RS, Morrill J, Peters CJ. Safety and immunogenicity of a mutagenized, live attenuated Rift Valley fever vaccine, MP-12, in a Phase I dose escalation and route comparison study in humans. Vaccine. 2016;34(4):424–29. doi:10.1016/j.vaccine.1015.12.030.
- Wilck MB, Seaman MS, Baden LR, Walsh SR, Grandpre LE, Devoy C, Giri A, Kleinjan J, Noble L, Stevenson K. Safety and immunogenicity of modified vaccinia Ankara (ACAM 3000): effect of dose and route of administration. J Infect Dis. 2010;201(9):1361–70. doi:10.1086/651561.
- Vollmar J, Arndtz N, Eckl KM, Thomsen T, Petzold B, Mateo L, Schlereth B, Handley A, King L, Hülsemann V. Safety and immunogenicity of IMVAMUNE, a promising candidate as a third generation smallpox vaccine. Vaccine. 2006;24(12):2065–70. doi:10.1016/j.vaccine.2005.11.022.
- Frey SE, Newman FK, Kennedy JS, Sobek V, Ennis FA, Hill H, Yan LK, Chaplin P, Wollmar J, Chaitman BR, et al. Clinical and immunologic responses to multiple doses of IMVAMUNE (Modified Vaccinia Ankara) followed by Dryvax® challenge. Vaccine. 2007;25(51):8562–73. doi:10.1016/j.vaccine.2007.10.017.
- Seaman MS, Wilck MB, Baden LR, Walsh SR, Grandpre LE, Devoy C, Giri A, Noble L, Kleinjan J, Stevenson K. Effect of vaccination with modified Vaccinia Ankara (ACAM3000) on subsequent challenge with Dryvax. J Infect Dis. 2010;201(9):1353–60. doi:10.1086/651560.
- Dennehy PH, Reisinger KS, Blatter MM, Veloudis PA. Immunogenicity of subcutaneous versus intramuscular Oka/Merck Varicella vaccination in healthy children. Pediatrics. 1991;88:604–07.
- Fox JP, Kossobudzki SL, Fonseca da Cunha J. Field studies on the immune response to 17D yellow fever virus: relation to virus sub-strain, dose and route of inoculation. Am J Epidem. 1943;38:113–38. doi:10.1093/oxfordjournals.aje.a118875.
- Leung AK, Chiu AS, Siu TO. Subcutaneous versus intramuscular administration of haemophilus influenzae type b vaccine. J R Soc Health. 1989;109(2):71–73. doi:10.1177/146642408910900213.
- Cook IF, Barr I, Hartel G, Pond D, Hampson AW. Reactogenicity and immunogenicity of an inactivated influenza vaccine administered by intramuscular or subcutaneous injection in elderly adults. Vaccine. 2006;24(13):2395–402. doi:10.1016/j.vaccine.2005.11.057.
- Ruben FL, Jackson GG. A new subunit influenza vaccine: acceptability compared with standard vaccines and effect of dose on antigenicity. J Infect Dis. 1972;125(6):656–64. doi:10.1093/infdis/125.6.656.
- Sanchez L, Matsuoka O, Inoue S, Inoue T, Meng Y, Nakama T, Kato K, Pandey A, Chang LJ. Immunogenicity and safety of high dose quadrivalent influenza vaccine in Japanese adults ≥ 65 years of age: a randomized controlled clinical trial. Hum Vaccin Immunother. 2020;16(4):858–66. doi:10.1080/21645515.2019.1677437.
- Delafuente JC, Davis JA, Meuleman JR, Jones RA. Influenza vaccination and warfarin anticoagulation: A comparison of subcutaneous and intramuscular routes of administration in elderly men. Pharmacotherapy. 1998;18:631–36.
- Ballester-Torrens MP, Acosta MA, Perez MTM, Perez BI, Brunet CJ, Doval GL, Garre MP. Intramuscular route for the administration of the anti flu vaccine in patients receiving oral anticoagulation therapy. Med Clin (Barc). 2005;124:291–94. doi:10.1157/13072321.
- Casajuana J, Iglesias B, Fabregas M, Fina F, Valles J-A, Aragones R, Benitez M, Zabaleta E. Safety of intramuscular influenza vaccine in patients receiving anticoagulation therapy: a single-blinded, multi-centre randomized controlled trial. BMC Blood Disord. 2008;8:1. doi:10.1186/1471-2326-8-1.
- Laurichesse H, Gourdon F, Smits HL, Abdoe TH, Estavoyer JM, Rebika H, Pouliquen P, Catalina P, Dubray C, Beytout J. Safety and immunogenicity of subcutaneous or intramuscular administration of a monovalent inactivated vaccine against Leptospira interrogans serogroup Icterohaemorrhagiae in healthy volunteers. Clin Microbiol Infect. 2007;13(4):395–401. doi:10.1111/j.1469-0691.2007.01662.x.
- Ruben FL, Froeschle JE, Meschievitz C, Chen K, George J, Reeves-Hoche MK, Pietrobon P, Bybel M, Livingood WC, Woodhouse L. Choosing a route of administration for quadrivalent meningococcal polysaccharide vaccine: intramuscular versus subcutaneous. Clin Infect Dis. 2001;32:170–72. doi:10.1086/317553.
- Scheifele DW, Bjornson G, Boraston S. Local adverse effects of meningococcal vaccine. Can Med Assoc J. 1994;150:14–15.
- Cook IF, Pond D, Hartel G. Comparative reactogenicity and immunogenicity of 23 valent pneumococcal vaccine administered by intramuscular or subcutaneous injection in elderly adults. Vaccine. 2007;25(25):4767–74. doi:10.1016/j.vaccine.2007.04.017.
- Marshall H, Nolan T, Robertson D, Richmond P, Lambert S, Jacquet M, Schuerman L. A comparison of booster immunization with a combination DTPa-IPV vaccine or DTPa plus IPV separate injections when co-administered with MMR at age 4-6 years. Vaccine. 2006;24(35–36):6120–28. doi:10.1016/j.vaccine.2006.05.017.
- Rupprecht CE, Hanlon CA, Hemachudha T. Rabies re-examined. Lancet Infect Dis. 2002;2(6):327–43. doi:10.1016/s1473-3099(02)00287-6.
- Rabies vaccines: WHO position paper. Weekly epidemiological record No.32, 2010; 85: 309–20. http:/www.who.int/wer
- Silcock R, Crawford NW, Perrett KP. Subcutaneous nodules: an important adverse event following immunization. Expert Rev Vaccines. 2019;18(4):405–10. doi:10.1080/14760584.2019. 1586540.
- Bernstein DI, Jackson L, Patel SM, El Sahly HM, Spearman P, Rouphael N, Rudge TL, Hill H, Goll JB. Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults. Vaccine. 2014;32(47):6284–93. doi:10.1016/j.vaccine.2014.08.076.
- Bergfors E, Bjorkelund C, Trollfors B. Nineteen cases of persistent pruritic nodules and contact allergy to aluminium after injection of commonly used aluminium-adsorbed vaccines. Eur J Pediatr. 2005;164(11):691–97. doi:10.1007/s00431-005-1704-1.
- Bergfors E, Trollfors B, Inerot A. Unexpectedly high incidence of persistent itching nodules and delayed hypersensitivity to aluminium in children after the use of adsorbed vaccines from a single manufacturer. Vaccine. 2003;22(1):64–69. doi:10.1016/S0264-410X(03)00531-0.
- Thierry-Carstensen B. Stellfeld. Itching nodules and hypersensitivity to aluminium after the use of adsorbed vaccines from SSI. Vaccine. 2004;22(15–16):1845. doi:10.1016/j.vaccine.2003.11.048.
- Young B, Heath J. Nervous tissue, wheater’s functional histology. 4th ed. New York (NY): Churchill Livingstone; 2003. p. 140–41.
- Australian Government Department of Health, Therapeutic Goods Administration, Australian Clinical Trials Handbook, Clinical trial phases and stages, 12th October 2018.. www.tga.gov.au/book-page/clinical-trial-phases-and-stages
- Andrews JC, Schunemann HJ, Oxman AD, Pottie D, Meerpohl JJ, Coello PA, Rind D, Montori VM, Brito JP, Norris S. GRADE guidelines: 15. Going from evidence to recommendation – determinants of a recommendation’s direction and strength. J Clin Epidemiol. 2013;66(7):726–35. doi:10.1016/j.jclinepi.2013.02.003.
- Inadvertent misadministration of meningococcal conjugate vaccine – United States. June-August 2005. MMWR Morb Mortal Weekly Report 2006; 55: 1016–17.
- Notes from the Field: Vaccine administration errors involving recombinant zoster vaccine – United States 2017-2018. MMWR. Morb Mortal Weekly Report. 2018;67(20):385–86. doi:10.15585/mmwr.mm6720a4.