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Evidence based route of administration of vaccines



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.
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
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
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
Review of the evidence base for route of administration of vaccines
(subcutaneous or intramuscular injection) through the assessment of
published clinical data and manufacturerswebsites 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
Traditional vaccination practice has been to give all vaccines,
excluding BCG, by the subcutaneous route, with the study by
in 1910 with typhoid vaccine seeming to support this posi‑
However, with the observation of increased immunogenicity
of aluminum salt adsorbed vaccines by Glenny,
it soon became
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
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.
It was also
greater in four
of the other five studies in which adverse reac‑
tion data were presented including the study with anthrax vaccine.
Immunogenicity was also greater with intramuscular compared with
subcutaneous injection in six of the studies.
Live Attenuated Virus Vaccines
Live virus vaccines have traditionally been given by subcutaneous
injection as it is asserted
that it may be less painful and associated
with a lower risk of bleeding. It had also been maintained
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,
it is demonstrably invalid for live virus
vaccines (Table 2).
The immunogenicity of yellow fever
and varicella
vaccines was
greater with intramuscular compared with subcutaneous injection.
Whilst measles,
and varicella
vaccines gave good immune responses when administered by intra‑
muscular injection.
Injection site reaction was greater with subcutaneous compared
with intramuscular injection with varicella
and measles/mumps/
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:
Submitted: 05/02/07; Accepted: 07/15/07
Previously published online as a Human Vaccines E-publication:
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 Human Vaccines 67
Evidence based route of administration of vaccines
Table 1 Aluminum‑adjuvanted vaccines—Intramuscular/subcutaneous administration
Study Method Patients Intervention Outcome
Carlsson et al.
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.
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
Holt & Bousfield.
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.
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.
(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
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.
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
Fisch et al.
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.
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.
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
68 Human Vaccines 2008; Vol. 4 Issue 1
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
to be given by intramuscular injection but it has been
given by subcutaneous injection in studies in Chile,
and Sweden.
2. Subunit, non‑conjugated polysaccharide vaccines for
Salmonella typhi,
Neisseria meningitidis
Streptococcus pneumoniae
have been given by
intramuscular and subcutaneous injection.
3. Whole cell inactivated plague,
and polio
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.
In another seven studies
injection site reaction data were
• Subcutaneous injection was associated with a greater rate
of local adverse reaction than intramuscular injection in five
• Pain at time of injection was greater with intramuscular
compared with subcutaneous injection in one study.
• No difference in rates of injection site reaction was seen in
a small study with influenza vaccine.
Intramuscular injection gave a better immune response than
subcutaneous injection in three studies
where these data were
presented. In a study with an inactivated whole cell leptospirosis
and an influenza vaccine,
no difference in immune
response was noted between the two routes of administration. Frayha
et al.
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,
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
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.
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
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.
• 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.
Laurichesse et al.
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.
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.
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.
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 Human Vaccines 69
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
compared with muscle
can be attributed to delayed absorption of
substances from the subcutaneous injection site.
In humans, immunoglobulin is more rapidly absorbed after
intramuscular compared with subcutaneous injection.
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
) 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
(Table 1) and Fox et
(Table 2).
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.
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
Dennehy et al.
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.
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.
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.
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.
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%
70 Human Vaccines 2008; Vol. 4 Issue 1
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.
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
IM - 23 gauge 25mm needle,
technique - needle introduced
at 90˚ to skin’s surface,
Cook et al.
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
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
Scheifele et al.
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.
Open, randomized, American adults Meningococcal polysaccharide Immunogenicity:
prospective study IM = 21.9 years vaccine, A,C,Y and W
. 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.
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 Human Vaccines 71
Evidence based route of administration of vaccines
Route of administration is a poorly developed area of vaccinology
with Poirier et al.
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
This standardization will allow better inter‑trial comparison
of vaccines, maximize their immunogenicity and minimize their
injection site reaction rates.
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Table 3 Non‑adjuvanted subunit and whole cell vaccines—Intramuscular/subcutaneous administration (Continued)
Study Method Patients Intervention Outcome
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No difference in immune
et al.
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study haemorrhagiae serogroup, vaccination site.
inactivated with formaldehyde. Injection site reaction significantly
SC vaccine n = 30, more frequent after SC compared
IM vaccine n = 30 with IM route.
SC placebo n =12 Suggested this difference due
IM placebo n =12 to “local inflammation could be
Given by deltoid injection. explained by participation of the
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.”
72 Human Vaccines 2008; Vol. 4 Issue 1
Evidence based route of administration of vaccines
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... Most vaccines are given to young infants and children intramuscularly because of their simplicity, and there is no significant difference in immunogenicity. It was reported that, depending on several kinds of vaccines given intramuscularly and subcutaneously, fewer episodes of severe local reactions were experienced in infants administered vaccines using a longer needle [18][19][20]. A stronger immune response and lower incidence of adverse events were reported in female elderly immunized with influenza and 23-valent pneumococcal vaccines intramuscularly, compared with immunized subcutaneously [21,22]. ...
... Recently, a significant immune response was reported among the Japanese elderly immunized with the subunit herpes zoster vaccine, and a lower incidence of adverse events was noted [23,24]. Lower incidences of local reactions, redness, swelling, induration, and pain were reported in infants and the elderly through IM administration of vaccines [17][18][19][20][21][22][23][24]. ...
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Adjuvanted vaccines are administered through intramuscular injection. To perform appropriate injection using an appropriate needle in different age groups or different daily living activities, we investigated the depth from the skin surface to muscle fascia and bone in the deltoid muscle area in 156 elderly aged ≥ 50 years by ultrasonic echography. Subjects consisted of 50 healthy elderly aged 50–64 years, 50 subjects aged 65–74 years, and 56 subjects aged ≥ 75 years (20 outpatients, 18 who needed nursing care, and 18 bedridden in a nursing home). The mean depth ± 1.0 SD from the skin surface to muscle fascia was 7.52 ± 2.13 mm for subjects aged ≥ 75 years, being shorter than 9.16 ± 3.02 mm in those aged 50–64years (p < 0.01). The depth from the skin surface to bone was 22.54 ± 3.85 mm for subjects aged ≥ 75 years and 25.41 ± 4.24 mm for those aged 65–74 years, significantly shorter than those aged 50–64 years (p < 0.01), depending on the reduced muscle volume. The subcutaneous volume length was greater in females (8.29 ± 2.63 mm) than in males (5.62 ± 2.80 mm) aged 50–64 years (p < 0.01). A similar result was obtained in those aged 65–74 years, but there was no difference in the muscle volume length. Our study found that a five-eighths of an inch (16 mm) needle was an appropriate length for average-sized elderly aged ≥ 50 years, but it should be longer for those with large body sizes.
... The basis of evidence-based routes for vaccine administration is discussed elsewhere. 77 Nasal administration of peptide vaccines is often recommended over the oral route because nasal mucosa contain fewer proteolytic enzymes and are rich in immune cells. 8 Also, SC administration of influenza or yellow fever virus vaccines enhanced immune responses compared with IM injections. ...
The tremendous advances in genomics, recombinant DNA technology, bioengineering and nanotechnology, in conjunction with the development of high-end computations, have been instrumental in the process of rational design of peptide-based vaccines. The use of peptide vaccines was limited owing to their inherent instability when systemically administered; however, advanced formulation techniques have been developed for their systemic delivery, thereby overcoming their degradation, clearance, cellular uptake and off-target effects. With the rise of sophisticated immunological predictors and experimental techniques, several methodological advances have occurred in this field. This review examines contemporary methods to identify and optimize epitopes, engineer their immunogenic properties and develop their safe and efficient delivery into the host.
... Dose and route of vaccination also influence the induction of protective immunity. Intramuscular administration is recommended for adjuvant-containing vaccines to minimize the reactogenicity associated with subcutaneous administration [11] . Vaccines against HBV include T cell vaccine, DNA vaccines, viral vector HBV protein vaccine and recombinant HBsAg vaccine [12] . ...
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Background Vaccines against hepatitis B virus (HBV) infection became available from 1982, however, the HBV infection remains as a public health issue due to infection among susceptible individuals. Many HBV vaccines are available and until 2012, Sri Lanka has been using vaccines produced by different Pharmaceutical companies. Since 2012, Sri Lanka imported HBV vaccine from Serum Institute of India as the product was more cost effective. However, the immune response to this vaccine has never been studied in the country. Objective The current study was carried out to assess the immune response (anti-HBs) to the recombinant HBV surface antigen (HBsAg) vaccine (Serum Institute, India), which is currently used in the state healthcare sector of Sri Lanka. Study design A sample of vaccinated healthy adults (n=529), age ranged between 20-29 years were enrolled in this study after completing the standard 3-dose regimen of HBV vaccination from early 2015 to 2016. Sociodemographic data were collected using a self-administrated questionnaire. Serum samples were tested to detect the presence of anti-HBs using an enzyme linked immunosorbent assay (ELISA) and the results were analyzed using MS-Excel 2010. Results Based on the results, 96.8% of the healthy adults had protective immune response with anti-HBs levels > 10 mIU/mL. Gender did not show an association with levels of anti-HBs. All the ethnic groups in the study sample exhibited >90% of protective immune response. Conclusion The more cost effective recombinant HBsAg vaccine taken by the healthy adults in the present study was effective in inducing the protective immunity.
... [4][5][6] Aluminum-adsorbed vaccines within the vaccination schedule in Ireland include diphtheria, tetanus, hemophilus, hepatitis B, and Pneumococcus. The ideal route of administration of aluminium-adjuvanted vaccines is intramuscular, [7] however, subcutaneous administration may occur. [8] All abnormalities in the current case series were located in the subcutaneous tissues, between the dermis and the muscle fascia. ...
Palpable thigh nodularity is a relatively frequent indication for imaging of vaccination-age children, with patients often referred by their community physician or general practitioner. Ultrasound (US) is the imaging modality of choice to delineate the abnormality, and we present a number of characteristic findings that permit the radiologist and pediatrician to accurately identify the cause. A retrospective review was performed at the largest children's hospital in a European country between 2015 and 2017 over a 30-month period. A search was performed of the hospital's Picture Archiving and Communication System (PACS) for all children referred for a soft-tissue, upper limb, or lower limb US between January 2015 and July 2017. The findings were collated and stored in a spreadsheet. Nine patients were identified who developed subcutaneous nodules in the thigh at some point during their childhood vaccination schedule. Three of these patients had clinical histories strongly suggestive of a diagnosis of abscess or foreign body. The remaining six patients were selected for more in-depth analysis. Four of these patients had US features consistent with vaccination granuloma. Two patients were ultimately diagnosed with venolymphatic malformations. Palpable thigh nodularity in a child of vaccination age is encountered with a reasonable frequency. When encountered, granulomas tend to be located within the subcutaneous tissues, and we postulate that this is due to erroneous administration of a vaccine into the subcutis rather than into the muscle.
... However, little is known regarding the tra cking of cells within the lymphatic vessels that connect the muscle injection site with the local lymph node and whether this may contribute to altered immune responses observed between the routes of administration. Although previous works have shown that subcutaneous injections of adjuvanted inactivated vaccines are associated with increased rates of site reactions compared to the intramuscular vaccinations (Cook, 2008;Diez-Domingo et al., 2015), the present study detected very minimal reaction at the site of subcutaneous injection of the antigen (nape of the neck). ...
Background: We hypothesized that intramuscular administration of autologous total immunoglobulin G (IgG) could induce an immunomodulatory effect in human subjects. In our previous studies, we showed that intramuscular administration of autologous total IgG could induce significant clinical improvements and increases of the serum levels of interleukin-10 (IL-10) and interferon-gamma (IFN-γ) in patients with atopic dermatitis. Objective: To investigate the mechanism of immunomodulation induced by intramuscular administration of autologous total IgG, we evaluated changes in T cells before and after intramuscular administrations of autologous total IgG in this study. Methods: Thirteen healthy adults received 8 intramuscular injections of 50 mg autologous total IgG for 4 weeks (from week 0 to week 4). The percentages of IL-10- or IFN-γ-producing peripheral blood T cells, as well as serum levels of IL-10, IFN-γ, and immunoglobulins, were measured at baseline (week 0) and at weeks 4, 8, and 12. Results: The percentage of IL-10-producing CD4+ T cells was significantly increased at weeks 8 and 12 compared to baseline (P < .05), while the percentage of IFN-γ-producing CD3+ T cells was significantly increased at week 12 compared to baseline (P < .05). There were no significant differences in the serum levels of IL-10, IFN-γ, and immunoglobulins before and after intramuscular administration of autologous total IgG (P > .05). No serious adverse events were observed. Conclusion: Intramuscular administration of autologous total IgG induced immunomodulatory effects on T cells in healthy human subjects. This simple intervention could be a safe, effective, and economical T cell immunomodulation method for human subjects (NCT03695757).
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Ensuring high vaccination and even booster vaccination coverage is critical in preventing severe Coronavirus Disease 2019 (COVID-19). Among the various COVID-19 vaccines currently in use, the mRNA vaccines have shown remarkable effectiveness. However, systemic adverse events (AEs), such as postvaccination fatigue, are prevalent following mRNA vaccination, and the underpinnings of which are not understood. Herein, we found that higher baseline expression of genes related to T and NK cell exhaustion and suppression were positively correlated with the development of moderately severe fatigue after Pfizer-BioNTech BNT162b2 vaccination; increased expression of genes associated with T and NK cell exhaustion and suppression reacted to vaccination were associated with greater levels of innate immune activation at 1 day postvaccination. We further found, in a mouse model, that altering the route of vaccination from intramuscular (i.m.) to subcutaneous (s.c.) could lessen the pro-inflammatory response and correspondingly the extent of systemic AEs; the humoral immune response to BNT162b2 vaccination was not compromised. Instead, it is possible that the s.c. route could improve cytotoxic CD8 T-cell responses to BNT162b2 vaccination. Our findings thus provide a glimpse of the molecular basis of postvaccination fatigue from mRNA vaccination and suggest a readily translatable solution to minimize systemic AEs.
The development and widespread use of vaccination over the past centuries has been the single most impactful intervention in public health, by effectively preventing morbidity and mortality from infectious diseases. Vaccination is generally well tolerated in the vast majority of the population, and the benefits of vaccination largely outweigh the risk of severe adverse events in the majority of patients. Vaccine hesitancy can be a significant concern and lead to infectious disease outbreaks. All health care providers play an important role in maintaining public confidence in vaccines because their attitude and knowledge is often critical in facilitating acceptance of a vaccine. The purpose of this review is to first, provide an understanding of the basic concepts that are relevant to vaccine pharmacovigilance, and secondly, to provide an overview and discuss management of both immune and nonimmune adverse events after vaccination.
Preventive vaccination has played a crucial role in protecting the host from infectious diseases. However, the antigens currently developed as vaccines require a delivery vehicle in order to evoke the desired immune activation. Bioinspired materials (both natural or synthetic) are the materials whose structure or functionality is designed to mimic biological systems. They have currently gained significance in order to improve the antigen stability and immunogenicity of the vaccines. With their ability to load both hydrophilic and hydrophobic payload and the propensity to induce significant immune response with minimized systemic toxicity, bioinspired materials can substitute the conventional viral vector- based vaccine technology in the future. This chapter details the recent advancements in the applications of different bioinspired materials as efficient carriers for the delivery of vaccines.
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To date, multifunctional nanohybrids have been proposed for catalysis, sensing, energy storage, imaging, and stimuli active therapies. Further, nanosized smart materials exhibit significant impact in targeted drug delivery applications. So far, various nanohybrids like porous silica, porous carbon, polymeric nanohybrids, liposomal particles, carbon nanotubes, iron nanoparticles, gold nanostructures have been considered as bioinspired smart nanohybrids for drug delivery applications due to high surface area, good biocompatibility, high cargo-loading capacity, long circulation time, specific biodistribution, easy surface modifications, etc. However, complicated synthesis process, poor control on premature cargo release, low product yield, poor stability, uncontrolled growth, and particle size are remaining challenges so far. Here in this chapter, a detailed review on the evolution of bioinspired nanohybrids for drug delivery applications has been discussed. Particularly, basic requirements of bioinspired nanohybrids for stimuli responsive drug delivery are highlighted here. In addition, various types of functional nanomaterials and their synthesis routes with their limitations have been discussed in detail. Overall, this chapter explains the current scenario of engineering stimuli responsive drug delivery system and application of bioinspired systems with their significant impact in nanomedicine.
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Dendritic cells (DCs) are antigen-presenting cells with a unique ability to induce primary immune responses. DCs capture and transfer information from the outside world to the cells of the adaptive immune system. DCs are not only critical for the induction of primary immune responses, but may also be important for the induction of immunological tolerance, as well as for the regulation of the type of T cell–mediated immune response. Although our understanding of DC biology is still in its infancy, we are now beginning to use DC-based immunotherapy protocols to elicit immunity against cancer and infectious diseases.
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In this study we compared the recommended subcutaneous administration of the RIVM MMR vaccine with the intramuscular administration for both safety and immunogenicity. Study subjects were 14 months old children, living in Amersfoort or Utrecht, who were eligible for their first MMR vaccination. The participants (N=67) were 'at random' assigned to one of the study groups based on route of administration of the vaccine (intramuscular or subcutaneous). Pain immediately after vaccination was the most reported adverse reaction. Serious pain was more often reported after subcutaneous vaccination. But because of the low number of participants in this study it is only an indication without an exact statistical foundation. It is known that adverse reactions due to infection by the vaccine virus are often seen in the second week after the MMR vaccination. In this study we also found a peak in the general health complaints in the second week after vaccination. The route of administration of the vaccine did not influence these complaints. It is difficult to assess which complaints are directly related to the MMR vaccine, because they often can not be distinguished from symptoms of common diseases in 14 months old children. Both subcutaneous and intramuscular administered MMR vaccine induced a good immune response. The levels of the ELISA antibodies against mumps and rubella after subcutaneous vaccination are the same as those after intramuscular vaccination. The titres against measles were somewhat higher after subcutaneous vaccination as compared to those after intramuscular injection, both for ELISA antibodies as well as antibodies measured with the virus neutralisation assay. However, this difference was not statistically significant. Besides, the injection route had no effect on the percentages of children with antibodies above the protective level against mumps (92%), measles (100%) and rubella (100%). This study shows that inadvertent intramuscular administration of MMR vaccine is no reason for revaccination. In the future it can be considered to adjust the instructions for use of the RIVM MMR vaccine so that both subcutaneous and intramuscular vaccination are allowed. In deze studie is de gebruikelijke en in de bijsluiter geadviseerde subcutane toedieningsroute van het BMR vaccin vergeleken met intramusculaire toediening, zowel wat betreft veiligheid als immunogeniciteit. De studie populatie bestond uit 14 maanden oude kinderen uit Amersfoort of Utrecht die in aanmerking kwamen voor hun eerste BMR vaccinatie. De deelnemers (N=67) werden 'at random' verdeeld over twee onderzoeksgroepen gebaseerd op de toedieningswijze van het vaccin (intramusculair of subcutaan). Pijn direct na vaccinatie was de meest gemelde lokale reactie. Heftige pijn kwam wat vaker voor na subcutane injectie. Het aantal deelnemers is echter te klein om dit statistisch te onderbouwen. Bijwerkingen door de infectieverschijnselen, die door het vaccinvirus veroorzaakt kunnen worden, treden met name op in de tweede week na de BMR vaccinatie. Ook in dit onderzoek was een piek in de algemene gezondheidsklachten te zien in de tweede week na vaccinatie. Deze klachten waren onafhankelijk van de toedieningsroute van het vaccin. Het is echter moeilijk te bepalen welke klachten een direct gevolg van de BMR vaccinatie zijn, omdat deze vaak niet te onderscheiden zijn van symptomen van ziektes die bij 14 maanden oude kinderen veel voorkomen. te een goede immuunrespons op. De hoogte van ELISA titers tegen bof en rubella lijkt onafhankelijk van de toedieningsroute van het vaccin. De antistoffen tegen mazelen lagen na subcutane vaccinatie op een iets hoger niveau dan na intramusculaire vaccinatie, zowel voor antistoffen gemeten met ELISA als met de virusneutralisatie assay. Dit verschil was echter niet statistisch significant. De toedieningsroute was niet van invloed op de percentages kinderen met antistoffen boven het als beschermend beschouwde niveau tegen zowel bof (92%), mazelen (100%) als rubella (100%). Dit onderzoek toont aan dat er geen reden voor revaccinatie is, wanneer het BMR vaccin per ongeluk intramusculair toegediend is. In de toekomst kan mogelijkerwijs in de bijsluiter van het RIVM BMR vaccin opgenomen worden dat het vaccin zowel subcutaan als intramusculair toegediend mag worden.
Aluminium compounds have been used as adjuvants in practical vaccination for more than 60 years to induce an early, an efficient and a long lasting protective immunity and are at present the most widely used adjuvants in both veterinary and human vaccines. Although the last two decades of systematic research into the nature of these adjuvants has contributed significantly to understanding their nature and their limitations as Th2 stimulators the more detailed mode of action of these adjuvants is still not completely understood. We have a comprehensive record of their behaviour and performance in practical vaccination, but an empirical approach to optimising their use in new vaccine formulations is still to some extent a necessity. The aim of the present review is to put the recent findings into a broader perspective to facilitate the application of these adjuvants in general and experimental vaccinology.
The aim of this study was to investigate the subcutaneous tissue response to administration of a single dose of multi-component vaccine in the cat. Three groups of 15 cats were injected with one of three vaccine products with saline as a negative control. Cats in group A received non-adjuvanted vaccine; cats in group B received vaccine with a lipid-based adjuvant; whilst those in group C were vaccinated with a product adjuvanted with an alum-Quil A mixture. The vaccine and saline injection sites were sampled on days 7, 21 and 62 post-vaccination. Biopsies of these vaccine sites were examined qualitatively and scored semi-quantitatively for a series of parameters related to aspects of the inflammatory and tissue repair responses. These data were analysed statistically, including by principal component analysis. At all three time points of the experiment, there was significantly less inflammation associated with administration of non-adjuvanted vaccine (p=0.000). Although there was evidence of tissue repair by day 62 in all groups, those cats receiving adjuvanted vaccines had evidence of residual adjuvant material accumulated within macrophages at this late time point. The severity of tissue reactions may vary significantly in response to vaccines which include adjuvants or are non-adjuvanted.
To assess whether serum antibody responses to diphtheria-tetanus-pertussis (DTP) vaccine were affected by coadministration of Haemophilus influenzae type b capsular polyribosylribitol phosphate polysaccharide-tetanus protein (PRP-T) conjugate vaccine when given to patients at 2, 4, and 6 months of age. Randomized, double-blind clinical trial. Urban Santiago, Chile. Healthy infants assembled from health centers. Two hundred seventy-eight (74%) of 375 eligible infants participated; 222, who complied with the complete protocol, constituted the primary group under analysis. One of three vaccine regimens was given to study participants at 2, 4, and 6 months of age, either DTP mixed in the same syringe as PRP-T (group 1); DTP and PRP-T given at separate injection sites (group 2); or DTP without PRP-T (group 3). Titers of serum antidiphtheria toxoid, antitetanus toxoid, and pertussis agglutinin antibodies were measured in blood samples taken from patients 2 months after each dose. Serum antidiphtheria toxoid and antitetanus toxoid responses showed no important depressions in the patients receiving PRP-T. In contrast, geometric mean titers (GMTs) of pertussis agglutinins, expressed as reciprocal serum dilutions, after both the second and third doses (GMT2, GMT3) were lowest in group 1 (GMT2 = 89; GMT3 = 1230), intermediate in group 2 (GMT2 = 123; GMT3 = 1995), and highest in group 3 (GMT2 = 210; GMT3 = 3090; P less than .05 for trend group 1 less than group 2 less than group 3 after each dose). Antipertussis toxin and antipertussis filamentous hemagglutinin antibody titers also were depressed in patients who received PRP-T. Follow-up of a subset at 18 months revealed an expected decline of pertussis agglutinin titers to near baseline levels in each group. Concurrent administration of PRP-T vaccine with DTP vaccine, either in the same syringe or at different sites, interfered with antipertussis responses to a primary series of immunizations. Although the clinical significance of this antagonism is uncertain, these data underscore the caution required in decisions to add new vaccines to existing immunization regimens.