Evidence based route of administration of vaccines

Abstract

Vaccination is a proven public health initiative, however it is imperative in the context of increasing concerns about vaccine induced adverse reactions and a decreasing incidence of diseases they prevent that the optimal route for their administration is defined. Traditionally all vaccines were given by subcutaneous injection until it was recognized that adjuvanted vaccines given via this route induced an unacceptable rate of injection site reaction. Evidence-based medicine has been championed as a way of improving the quality of patient care. Application of this methodology to the route of administration of vaccines demonstrates that vaccines should be given by intramuscular injection in preference to subcutaneous injection as the intramuscular route is associated with better immune response and a lower rate of injection site reaction. The basis of this superiority is discussed.

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Vaccination is a proven public health initiative, however it is
imperative in the context of increasing concerns about vaccine
induced adverse reactions and a decreasing incidence of diseases
they prevent that the optimal route for their administration is
defined.
Traditionally all vaccines were given by subcutaneous injection
until it was recognized that adjuvanted vaccines given via this route
induced an unacceptable rate of injection site reaction.
Evidence‑based medicine has been championed as a way of
improving the quality of patient care. Application of this method‑
ology to the route of administration of vaccines demonstrates that
vaccines should be given by intramuscular injection in preference
to subcutaneous injection as the intramuscular route is associated
with better immune response and a lower rate of injection site reac‑
tion. The basis of this superiority is discussed.
Evidence Based Route of Administration of Vaccines
Evidence based medicine has been championed
1
as a way of
improving the quality of patient care through the stepwise process
of formulating the question to be answered, collating and appraising
relevant data and developing the best practice solution to the clinical
question.
Review of the evidence base for route of administration of vaccines
(subcutaneous or intramuscular injection) through the assessment of
published clinical data and manufacturers’ websites reveals practice
based on tradition rather than clinical data.
Strengthening the evidence base for route of administration of
vaccines has the potential to simplify vaccination practice, whilst
maximizing the immunogenicity and minimizing the reactogenicity
of vaccines.
In this commentary, clinical trial data on the reactogenicity
and immunogenicity of vaccines administered by subcutaneous
or intramuscular injection are presented. The methodology of
these studies is variable in terms of site of injection, needle param‑
eters (needle length and gauge) and technique of vaccine injection.
These data, where available, are presented in the tabulated
summaries.
Traditional vaccination practice has been to give all vaccines,
excluding BCG, by the subcutaneous route, with the study by
Semple
2
in 1910 with typhoid vaccine seeming to support this posi‑
tion.
However, with the observation of increased immunogenicity
of aluminum salt adsorbed vaccines by Glenny,
3
it soon became
apparent
4
that administration of this type of vaccine by the subcuta‑
neous route gave an unacceptable rate of injection site reaction.
Aluminum‑Adjuvanted Vaccines
It is currently recommended that all aluminum‑adjuvanted
vaccines be given by intramuscular injection except anthrax
vaccine.
5
The twelve studies comparing subcutaneous with intramuscular
administration of aluminum‑adjuvanted vaccines, presented in
Table 1, support this recommendation.
Injection site reaction was greater with subcutaneous compared
with intramuscular injection in the two studies in which needle
parameters and injection technique were specified.
6,7
It was also
greater in four
9,10,12,17
of the other five studies in which adverse reac‑
tion data were presented including the study with anthrax vaccine.
17
Immunogenicity was also greater with intramuscular compared with
subcutaneous injection in six of the studies.
8,11‑13,15,16
Live Attenuated Virus Vaccines
Live virus vaccines have traditionally been given by subcutaneous
injection as it is asserted
18
that it may be less painful and associated
with a lower risk of bleeding. It had also been maintained
19
that
“any vaccination using less than the standard dose or a non‑standard
route or site of administration should not be counted, and the person
should be revaccinated according to age.” Although this recommen‑
dation has been rescinded,
20
it is demonstrably invalid for live virus
vaccines (Table 2).
The immunogenicity of yellow fever
21
and varicella
18
vaccines was
greater with intramuscular compared with subcutaneous injection.
Whilst measles,
22
measles/mumps/rubella
23,24
and varicella
25
vaccines gave good immune responses when administered by intra‑
muscular injection.
Injection site reaction was greater with subcutaneous compared
with intramuscular injection with varicella
18
and measles/mumps/
rubella
23
vaccines.
Correspondence to: I.F. Cook; University of Newcastle; Health Faculty;
School of Medical Practice and Population Health; Callaghan, New South Wales
2308 Australia; Tel.: +04.07.525844; Email: drifcook@bigpond.com
Submitted: 05/02/07; Accepted: 07/15/07
Previously published online as a Human Vaccines E-publication:
www.landesbioscience.com/journals/vaccines/article/4747
Commentary
Evidence based route of administration of vaccines
I.F. Cook
University of Newcastle; School of Medical Practice and Population Health; Callaghan, New South Wales, Australia
Key words: vaccine administration, subcutaneous, intramuscular, injection site reaction, immunogenicity
[Human Vaccines 4:1, 67‑73; January/February 2008]; ©2008 Landes Bioscience
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Evidence based route of administration of vaccines
Table 1 Aluminum‑adjuvanted vaccines—Intramuscular/subcutaneous administration
Study Method Patients Intervention Outcome
Carlsson et al.
6
Open, randomized, Swedish infants Diphtheria toxoid; Diphtheria/ SC injection caused more
prospective study. n = 287 Tetanus toxoid; Diphtheria/Tetanus injection site reaction than IM
toxoid/inactivated Polio (IPV/DT) injection, but did not affect
reconstituted with Hib-T(Act-Hib) given immune response to any
at 3, 5, 12 months with defined antigen.
injection technique. SC - 30-45˚ angle,
25 mm long needle, thigh IM - 90˚ angle,
25 mm long needle, thigh
Mark et al.
7
Open, randomized Swedish school students, DT Vaccine (SBL Vaccin AB) SC n = 127, SC injection caused more
prospective study. 10 years of age. n = 252 IM n = 125. SC - 30˚ angle, IM - 90˚ angle, injection site reaction than IM
deltoid 25 mm long needle, deltoid. injection, but did not affect
immune response to any
antigen.
Holt & Bousfield.
8
Prospective study English children, age not PTAP with varying amounts of magnesium, IM gave significantly greater
clearly defined. n = 895 aluminum, phosphate. SC n = 339, Schick conversion rate than SC
IM n = 556 injection. Difference thought to
be due to “fibrous encapsulation
of much of the material injected”
Rothstein et al.
9
Double blind, American infants aged DTaP-US (Connaught), No difference in immune
comparative study 2,4,6 months n = 80 formaldehyde-inactivated PT and FHA with response between SC and IM
their currently licensed diphtheria and injections. SC > IM for: -Erythema
tetanus toxoids. SC n = 40, IM n = 40 <2.5 cm at 4,6 months. -Induration
Subcutaneous injections given with 25 at 6 months -any local reaction
gauge 16 mm needle. Intramuscular at 4 and 6 months.
injections with 25 gauge 16 mm needle
at 2 months of age and 25 gauge 25 mm
needle at 4 and 6 months of age,
injections into the anterolateral thigh.
CERTIVA
®
(DTaP) (a)Data Trollfors et al (a)Swedish infants (a)DTaP n =1724 DT n =1726 Vaccine DTaP Any redness dose 1 22.2%
product N Eng J Med 1995; Aged 3 to 12 months, given by SC injection anterolateral dose 2 50.9% dose 3 57.6% any
information
10
333: 1045-50. n = 3450 (b) American thigh at 3, 5 and 12 months (b)DTaP swelling dose1 10.8% dose
Randomized double infants, aged 2 to 15 n=2480. Vaccine given by IM injection 2 34.7% dose 3 45.9%
blind placebo controlled months n = 2480 anterolateral thigh at 2, 4, 6 and (b) DTaP Any redness dose
study. (b) Data on file 15 months 1 4.4% dose 2 7.7% dose
Certivam at North 3 10.9% dose 4 21.0% Any
American Vaccines Inc. swelling dose 1 3.6% dose
2 5.4% dose 3 7.9% dose
4 12.7%
Ragni et al.
11
Open, non randomized, American children aged Hepatitis A vaccine (Havrix 720) IM injection gave greater GMT’s
prospective study 2–8 yrs; 45 with administered at 0 and 6 months by than SC at 1 and 8 months.
haemophilia, 41 SC injection to haemophiliacs and No difference in injection site
siblings IM to siblings reaction between routes of
administration.
Fisch et al.
12
Open, randomized, French adults aged Inactivated HAV absorbed onto Injection site reaction greater
prospective study 19.2 to 46.8 years. aluminum hydroxide. Injections given with both primary and booster
n = 147 with injector device or SC or IM with dose for SC compared with IM
needle. IM n = 50, SC n = 49, injection. Seroconversion IM > SC
injector device n = 48 Deltoid. at week 4, GMT IM > SC
at 4 & 28 weeks.
Parent du Open, randomized, French adults 18 years - Hepatitis A Vaccine (AVAXIM) GMT at 4 weeks, 1mule
Chatelet et al.
13
prospective study 60 years n = 147 n = 48 1 mule n = 50 IM 305 mIU/ml IM 211 mIU/ml SC
n = 49 SC 116 mIU/ml Seroconversion
at 4 weeks 1 mule 100% IM
100% SC 97.5%
Fessard et al.
14
Prospective study French adults, no age Hepatitis B vaccine (HEVAC) SC & IM equal rates of
given, who failed to SC n = 43, IM n = 42 seroconversion.
seroconvert (>10 IU/l) SC given into suprascapular area,
after primary course of IM given into deltoid area
subcutaneous injections
of HEVAC n = 85
Continued
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Evidence based route of administration of vaccines
Non‑adjuvanted Subunit / Whole cell vaccines
Indecision about the optimal route of administration of these
vaccines is clear:
1. ActHib
®
(Hib‑TT) is recommended by its manufacturer
26
to be given by intramuscular injection but it has been
given by subcutaneous injection in studies in Chile,
27
France,
28
Niger
29
and Sweden.
30
2. Subunit, non‑conjugated polysaccharide vaccines for
Salmonella typhi,
31‑33
Neisseria meningitidis
34
and
Streptococcus pneumoniae
35
have been given by
intramuscular and subcutaneous injection.
3. Whole cell inactivated plague,
36
influenza
37
and polio
38
have also been administered by both intramuscular and
subcutaneous injection.
However, route comparative studies favor intramuscular over
subcutaneous injection in terms of injection site reaction and
immune response (Table 3).
Injection site reaction was greater with subcutaneous compared
with intramuscular injection in the two studies in which needle
parameters and injection technique were specified.
39,40
In another seven studies
41‑44,47‑49
injection site reaction data were
presented;
 • Subcutaneous injection was associated with a greater rate
of local adverse reaction than intramuscular injection in five
studies
41‑43,48,49
and
 • Pain at time of injection was greater with intramuscular
compared with subcutaneous injection in one study.
44
 • No difference in rates of injection site reaction was seen in
a small study with influenza vaccine.
47
Intramuscular injection gave a better immune response than
subcutaneous injection in three studies
39,43,46
where these data were
presented. In a study with an inactivated whole cell leptospirosis
vaccine
49
and an influenza vaccine,
48
no difference in immune
response was noted between the two routes of administration. Frayha
et al.
45
observed reduced anti PRP antibody levels when PRP‑D was
administered subcutaneously compared with other studies where this
vaccine was given by intramuscular injection.
Vaccines failures,
50,51
associated with death, have been observed
with rabies vaccine given by injection into the subcutaneous fat
of the gluteal area rather than by intramuscular injection into the
deltoid area.
Clearly, for all vaccine groups which induce active immunity
(subunit, toxoid, live attenuated and inactivated whole cell), intra‑
muscular injection was associated with better immune response and
a reduced rate of injection site reaction compared with subcutaneous
injection.
Pathogenesis of the increased injection site reaction and
impaired immune response with subcutaneous compared with
intramuscular vaccinations
Two theories have been advanced for the pathogenesis of the
observed increased rate of injection site reaction with subcutaneous
compared with intramuscular injection of vaccines.
Lindblad
52
has suggested that, “immunizing by the subcutaneous
route (sc) the vaccine inoculin is introduced into a compartment
with numerous sensory neurons (in contrast to the intramuscular
compartment)."
This is an unlikely explanation of the observed difference as:
 • Although it is generally assumed that innervation
density decreases in the order skin, muscle and viscera, this
is unproven.
53
 • It can not be assumed, even if this gradient exists, that
subcutaneous tissue as compared with skin, has greater
innervation density than muscle.
 • Information from muscle and cutaneous nociceptors is
processed differently in the spinal cord with the former
subject to stronger descending inhibition than the latter.
54
Laurichesse et al.
49
has suggested that injection site reaction,
“could be explained by participation of the immune system and the
inflammatory cells located in the skin and deep dermis.”
Table 1 Aluminum‑adjuvanted vaccines—Intramuscular/subcutaneous administration (Continued)
Study Method Patients Intervention Outcome
de Lalla et al.
15
Open, randomized, Italian adults, 299 aged MSD Hepatitis B vaccine Seroconversion with MSD vaccine
mean 26.3 to 28 years. IM buttock n = 71; IM arm > SC arm.
n = 299 SC arm n = 76, IM arm n = 75; SC arm > IM buttock
Pasteur Hepatitis B Vaccine SC arm n = 77. MSD vaccine, SC and IM
arm better than Pasteur vaccine
SC arm but Pasteur vaccine
SC arm > MSD IM buttock.
Yamamoto et al.
16
Open, randomized, Japanese adults n = 124 Recombinant Hepatitis B Seroconversion at 7 months
prospective study Vaccine (HBX-R) SC and IM n = 62. IM 98%, SC 97%
10 mg given as 3 dose regimen GMT
0,1,6 months, IM 791 IU/L
25 gauge, 25mm needle. SC 168 IU/L
Pittman et al.
17
Open, randomized, American adults aged 18 Anthrax vaccine (AVA) was administered SC more injection site reaction
prospective study to 64 years. n = 173 via seven different protocols than IM injection. No difference
0-2-4 SC, n = 28 in immune response between
0 SC, n = 25 routes of administration.
0 IM, n = 25
0-2 SC, n = 25
0 - 2 IM, n = 25
0 - 4SC, n = 23; 0 -4 IM, n = 22
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Evidence based route of administration of vaccines
This thesis is supported by animal and human data. In the cat
model, the observed greater tissue reaction in subcutaneous tissue
55
compared with muscle
56
can be attributed to delayed absorption of
substances from the subcutaneous injection site.
57
In humans, immunoglobulin is more rapidly absorbed after
intramuscular compared with subcutaneous injection.
58
The relative
retention of injected antigens in the subcutaneous tissue compared
with muscle results in a greater degree of processing by antigen
presenting cells (e.g. dendritic cells
59
) in the subcutaneous tissue with
consequent greater inflammatory reaction in this tissue. Trapping of
antigens in the subcutaneous tissue has been suggested as the basis
of the poorer immune response with subcutaneous compared with
intramuscular injection; Holt and Bousfield
8
(Table 1) and Fox et
al.
21
(Table 2).
Conclusion
Although the data presented came from studies with varying
methodological standard, route of administration (subcutaneous or
intramuscular) does affect the immune response and injection site
reaction rate of vaccines.
Table 2 Live Virus Vaccines—Intramuscular/Subcutaneous Administration
Study Method Patients Intervention Outcome
Fox et al.
21
Quasi randomized, Brazilian adults Yellow fever vaccine - 17D Vaccine more immunogenic
prospective study 15–40 years old. administered: IM > SC
Numbers uncertain IM - 22 gauge, 1.5 inch needle As minimum immunizing dose for mice:
SC - 25 gauge,1/2 inch needle 1.15 - intradermal (ID)
ID 1.60 - IM
Doses given: 2.5 - SC 0.5 ml
ID - 0.1 ml 4.16 - SC 0.1 ml concluded
IM - 0.5 ml “the reduced susceptibility by the
SC - 0.1 ml subcutaneous route may have had a
SC - 0.5 ml more or less mechanical basis.
“Absorption of virus from the
subcutaneous tissue, which is apparently
somewhat more difficult than absorption
of virus placed intramuscularly or
intradermally.”
Dennehy et al.
18
Open, randomized, American children Varicella vaccine(Oka/Merck), Seroconversion greater
prospective study 1–10 years old. n = 166 SC and IM n = 83 each. IM > SC
SC - 26 gauge, 5/8 inch needle 100%/97%
IM - 25 gauge, 1 inch needle Injection site reaction significantly
deltoid injection. greater SC vs IM.
McGraw
22
Open, randomized, American children aged Experimental group, n = 97 Measles seroconversion percentages by
prospective study 7–12months. n = 127 received measles vaccine (MSD) age of initial immunization:
at study entry and MMR at aged 7–8 months 88%
15–18 months. Control group 9–10 months 90%
n = 30 received only MMR(MSD) 11–12 months 88%
at aged 15–18 months
Intramuscular injection
Lafeber et al.
23
Open, randomized, Dutch infants aged MMR vaccine. Pain at time of injection greater with SC
prospective study. 14 months n = 67 Measles (Moraten strain), than IM injection. No difference for other
mumps (Jeryl/Lynn strain), injection site or systemic adverse
rubella (RA27/3 strain) effects. Immune response not significantly
n = 33 IM, n = 34 SC different for measles, mumps, rubella
antigens, but levels somewhat higher
with SC injection than IM injection.
Concluded inadvertent intramuscular
injection of MMR vaccine is no reason
for revaccination.
Dunlop et al.
24
Open, prospective study English infants aged MMR vaccine Seroconversion rates:
15 months. n = 335 measles (Schwartz strain), Measles vaccine- measles
mumps (Urabe strain), 100%.
rubella (RA27/3 strain) MMR vaccine -
n = 319. Measles 95.6%
Measles(Schwartz strain) n =16 Mumps 96.9%
Vaccine given by IM or SC Rubella 100%
injection into gluteal region.
Barzaga et al.
25
Open, prospective study Thai subjects aged Varicella vaccine (Varilrix
®
Seroconversion in seronegative patients:
9 months to 60 years, Oka strain) 0.5 ml intramuscular <7 years 96.6%
n = 246 injection, right deltoid. 7–12 years 100%
≥13 years 86.1%
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Evidence based route of administration of vaccines
Table 3 Non‑adjuvanted subunit and whole cell vaccines—Intramuscular/subcutaneous administration
Study Method Patients Intervention Outcome
Cook et al.
39
Observer blind, Australian adults 65 years Split trivalent influenza Immunogenicity IM > SC,
randomized, and older - well adults, vaccine, 2A strains, 1 B for both A strains but not B strain.
prospective study 55 years and older with strain (Fluvax, CSL). Injection site reaction SC > IM.
chronic disease. IM and SC n = 360 each.
n = 720 Administered:
SC - 23 gauge 25mm needle,
technique - 10-20˚ to skin’s
surface.
IM - 23 gauge 25mm needle,
technique - needle introduced
at 90˚ to skin’s surface,
deltoid.
Cook et al.
40
Observer blind, Australian adults. 65 years Pneumovax 23 (MSD) vaccine No difference in immunogenicity
randomized, and older - well patients. IM and SC n = 127 each for serotypes 3, 4, 6. Injection site
prospective study. 55 years and older with SC - 23 gauge 25mm needle reaction SC > IM
chronic disease. n = 254 inserted at 10-20˚ to skin’s surface.
IM - 23 gauge 25mm needle
inserted at 90˚ to skin’s
surface, deltoid.
Ruben and Open, randomized, American adults aged Influenza vaccines: The three vaccines given SC
Jackson
41
prospective study 18–25 years n = 67. - Subunit vaccine prepared with (Sharples, Zonal and
tri-(n-butyl)phosphate(TNBP) TNBP-subunit) all caused maximal
(Wyeth) A2/Aichi/BMass pain responses graded higher
n = 10, IM, n = 15, SC than 2. The vaccines given IM
Comparison vaccines: (ether-subunit and TNSP-subunit)
- (Sharples - Wyeth had lower maximal pain
conventional) n = 10, SC responses. Erythema and
- (Zonal - ultracentrifuged induration at the local site, which
MSD) n = 10, SC, averaged from 4 to more than
- Subunit ether (Parke-Davis) 5 cm in diameter with vaccines
n = 13, IM given SC was hardly measurable
in the groups vaccinated IM
Systemic adverse reactions were
not different for the two routes of
administration.
Scheifele et al.
42
Non randomized, Canadian children aged Meningococcal quadrivalent Redness and swelling but not
prospective study. 4 to 6 years n = 101 vaccine (Connaught) tenderness were greater with
SC n = 53, SC compared with IM injection.
IM n = 48
Ruben et al.
43
Open, randomized, American adults Meningococcal polysaccharide Immunogenicity:
prospective study IM = 21.9 years vaccine, A,C,Y and W
135
. IM injection gave higher
SC = 20.6 years (Menomune, Aventis Pasteur) GMTs for serogroup A and
n = 141 SC n = 66 IM n = 67 C than SC injection.
completed protocol. Reactogenicity:
SC - administered into patient’s Erythema < 1 inch at injection
arm. site significantly greater for SC
IM - administered into lateral compared with IM injection.
deltoid. Headache at day 1 and 2 also
Both injections with 25 gauge, significantly greater for SC
5/8 inch needle, compared with IM injection.
Leung et al.
44
Quasi-randomized, Canadian children aged Haemophilus influenzae type b Pain manifest as crying, IM more
not blinded study 18 months to 5 years n = 498. - non conjugated (PRP) {Praxis common than SC. Incomplete
Biologics}. data; 194 subjects from each
Equal numbers in each group study groups.
SC 27 gauge 1/2 inch needle
IM 25 gauge 1 inch needle,
upper outer quadrant of buttock.
Continued
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Evidence based route of administration of vaccines
Route of administration is a poorly developed area of vaccinology
with Poirier et al.
60
observing in a review of 83 vaccine trials that
59% described the anatomic injection site, 24% utilizing intramus‑
cularly administered vaccines recorded needle length and only 10%
described the injection technique used.
As intramuscular injection is the preferred route of administra‑
tion compared with subcutaneous injection, for vaccines where
route comparative data exist, it behoves editors of publications
which accept vaccine trials to expect trialists to routinely report
needle length and injection techniques which ensure intramuscular
injection.
This standardization will allow better inter‑trial comparison
of vaccines, maximize their immunogenicity and minimize their
injection site reaction rates.
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immune system and the
inflammatory cells located in the
skin and deep dermis.
Alternatively, local reactions may
also occur in muscle, but are
more frequently clinically silent
because of the depth.”
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©2008 LANDES BIOSCIENCE. DO NOT DISTRIBUTE.
Evidence based route of administration of vaccines
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