Needle size for vaccination procedures in children and adolescents
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of needle size for administering vaccines to children and adolescents on vaccine immunogenicity (the ability of the vaccine to elicit an immune response), procedural pain, and other reactogenicity events (adverse events following vaccine administration).
We will assess the effects of two dimensions of needle size (gauge and length) separately and in combination, i.e. we will assess the effects of:
needle gauge on vaccine immunogenicity, procedural pain and other reactogenicity events
needle length on vaccine immunogenicity, procedural pain and other reactogenicity events
needle gauge and length on vaccine immunogenicity, procedural pain and other reactogenicity events
In the United States (US), the Centers for Disease Control and Prevention (CDC) recommends routine vaccination to prevent 17 vaccine-preventable diseases (CDC 2011). Under the current US immunisation schedule, children may receive up to 24 skin puncturing injections by the age of 2 years and up to 5 injections in a single visit (IOM 2013). In many other developed countries, the average child who adheres to recommended immunisation schedules receives at least 18 injections before the age of 16 years, the majority of which are administered during the first 6 years of life (Curtis 2012). The aim of administering any vaccine should be to ensure the attainment of maximum immunity, with the least possible harm (RCPCH 2002). An important harm is the pain and distress associated with vaccination procedures, which have been described as the most common source of iatrogenic (medically-induced) pain in childhood (Taddio 2009b).
Pain has been defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (IASP 2004). Acute pain during a vaccination procedure results from the stimulation of peripheral nociceptive sensory neurons (pain sensors) during two separate events: 1) needle puncture of the skin and underlying tissues; and 2) injection and deposition of the vaccine constituents into the tissue (Taddio 2009a). Delayed pain following a vaccination procedure may arise due to an inflammatory process in damaged tissue (Gidudu 2012). Pain can be experienced irrespective of the age at which vaccines are administered, as the physiological and biochemical prerequisites for nociception are developed in utero, and neonates and infants are able to demonstrate physiological and behavioural pain responses (RCN 2009).
The vast majority of vaccines are administered during the developmentally-critical first 6 years of life (Curtis 2012) and pain associated with the procedure may have significant physiological, psychological and behavioural sequelae. The immediate physical effects of pain are related to the stress response and can affect cardiopulmonary function, metabolic and inflammatory response and immune competence (Czarnecki 2011). Exposure to painful stimuli in infancy has also been associated with anticipatory fear of future medical procedures, increased sensitivity to pain and heightened responsiveness to painful stimuli, pain avoidance in later life and negative effects on healthcare behaviour and attitudes (Johnston 1996; Taddio 1997; Andrews 1999; Porter 1999; Taddio 2002; Young 2005; Taddio 2009a; Kassab 2011). In addition, negative experiences with needle-related procedures, particularly in childhood, can contribute to the development of needle phobias (Hamilton 1995; Wright 2009) which reduce compliance with future immunisation schedules and other preventive healthcare measures (Hogan 2010; Gidudu 2012). Vaccination-related procedural pain is also a source of anxiety and distress for the parents of children undergoing vaccination and the healthcare workers who administer the injections (Schechter 2007; Taddio 2010; Kassab 2011). Both parents and vaccinators have admitted to non-compliance with childhood immunisation schedules to reduce pain and distress to children (Woodin 1995; Luthy 2009; Taddio 2012).
In light of the potential adverse short-term and long-term consequences of pain related to vaccination procedures, every conceivable effort should be made by healthcare providers to minimise its occurrence. These efforts to reduce pain should not, however, compromise vaccine immunogenicity (the ability of the vaccine to elicit an immune response). One aspect of vaccination procedures that has the potential to influence both the immune response and the pain experienced is the size of the needle used to administer the vaccine.
Description of the intervention
Hypodermic needles are available in a wide range of sizes for delivering drugs, vaccines and other substances into the body or for extracting fluids and tissue samples (Gill 2007). The term 'needle size' is used to refer to two aspects of hypodermic needle geometry, namely gauge (diameter) and length. The gauge refers to the nominal outside diameter of the needle tube and the length refers to the nominal length of the needle tube (ISO 1993). Both dimensions are typically expressed in millimetres (mm), although in some countries (e.g. United States (US), United Kingdom (UK)) needle length is also expressed in inches ("). The most commonly-used system for describing the gauge of needles is the Stubs Iron Wire Gauge system developed in England in the early 19th century (Iserson 1987; Ahn 2002). The gauge of a needle is often abbreviated as 'G' or 'ga', and the larger the needle gauge, the smaller the diameter of the needle lumen (hole) (Pöll 1999). The International Organisation for Standardisation (ISO) has established ISO standards for the inner and outer diameters of hypodermic medical needles of a specified gauge number (ISO 2001). International standards have also been developed for colour coding of needles to enable rapid visual identification of the outside diameter of single-use hypodermic needles (ISO 1992). The standards for the most commonly recommended needle gauges for administering vaccines to children and adolescents are presented below.
| International Standards pertaining to the gauge and colour coding of hypodermic needles that are commonly recommended for administering vaccines to children and adolescents1 |
| Gauge Number|| Nominal outside diameter of needle (mm)|| Colour Coding|| Range of outside diameters (mm)|| Inside diameter of tubing (mm)|
| || || ||Min.||Max.|
|23 G||0.60||Deep blue||0.6||0.673||0.317||0.37||0.46|
|24 G||0.55||Medium purple||0.55||0.58||0.28||0.343||-|
|27 G||0.40||Medium grey||0.4||0.42||0.184||0.241||-|
1.Vaccinations typically require injection of less than one millilitre (1 ml) of fluid (Gill 2007) and the viscosity of most vaccines is such that 22 G to 25 G needles are generally recommended for most vaccines that are administered intramuscularly and subcutaneously to children and adolescents (Atkinson 2008; CDC 2011; DoH UK 2012a) and 25 G to 27 G for vaccines administered intradermally (ATAGI 2009; NIAC 2011).
Table adapted from the following sources: (ISO 1992; ISO 1993; ISO 2001)
Different needle lengths are available for a given gauge number. For example, in many countries 25 G (orange) needles are available in lengths of 16 mm (⅝"), 25 mm (1"), 32 mm (1¼ ") and 38 mm (1½") (Ajana 2008). Various needle gauges are also available for a given needle length. For example, 25 mm (1") needles are available in 22 G (black), 23 G (deep blue), 24 G (medium purple) and 25 G (orange).
Factors influencing needle size selection for vaccination procedures
It is generally recommended that clinical decisions regarding the choice of an appropriate needle size (gauge and length) for a particular vaccination procedure should take into account the age and body mass of the person receiving the vaccine (see Appendix 1). Obesity increases the subcutaneous tissue thickness, and overweight and obese children and adolescents receiving intramuscular injections may require longer needles to ensure that the vaccine is administered into muscle (Koster 2009). Several other factors influencing needle size selection include the prescribed route of vaccine administration (intramuscular (into muscle), subcutaneous (under the skin) or intradermal (into the skin)), the injection site and the injection technique.
Route of administration and injection site
The recommended routes of administration (intramuscular, subcutaneous or intradermal) for injectable vaccines are specified in manufacturers' summaries of product characteristics (SPCs) and in recommendations published by National Immunisation Technical Advisory Groups (NITAGs) in different countries (Atkinson 2008). Injectable vaccines should be administered in sites where local, neural, vascular or tissue injury is unlikely and where they will elicit the desired immune response (Atkinson 2008; CDC 2011).
The intramuscular route is recommended for the vast majority of vaccines administered to children and adolescents (CDC 2011; DoH UK 2012a). The vastus lateralis muscle in the anterolateral thigh (located on the outside of the leg in the mid to upper thigh) is the generally recommended site for infants under 1 year old and the deltoid muscle of the upper arm for older children and adolescents (Diggle 2007). Many NITAGs have issued needle size recommendations for intramuscular vaccinations that take into account the age or size (body mass) of the vaccine recipient and the injection site (see Appendix 1). These recommendations are not, however, consistent between countries. For example, in the UK a needle 25 mm in length with a gauge of 23 G or 25 G is recommended for intramuscular injections in the deltoid of children older than 1 year of age (DoH UK 2012a). By contrast, in New Zealand, 23 G to 25 G 16 mm needles are recommended for deltoid site injections in children aged 15 months to 7 years (MoH NZ 2011). In the US, the recommended needle gauges and lengths for intramuscular deltoid site injections in children and adolescents aged 3 to 18 years range from 22 G to 25 G and from 16 mm to 25 mm, depending on injection technique (CDC 2011).
Vaccines recommended for subcutaneous delivery include some formulations of Japanese encephalitis vaccine (e.g. 'Green Cross' vaccine, Imojev®) and varicella vaccines (DoH UK 2012a; ATAGI 2013). Subcutaneous vaccine injections are usually administered into the anterolateral thigh area of infants aged less than 12 months, and the upper, outer triceps area of persons aged 12 months or older (Atkinson 2008; CDC 2011). Needles 16 mm in length with gauges ranging from 23 G to 26 G have been recommended by several NITAGs for administering vaccines subcutaneously (CDC 2011; NIAC 2011; ATAGI 2013). By contrast, the World Health Organisation has suggested that 23 G, 25 mm needles can be used for subcutaneous administration of measles and yellow fever vaccines (WHO 2004).
Only a small number of vaccines are administered intradermally using hypodermic needles. Bacille Calmette-Guérin (BCG) vaccine against tuberculosis is administered using the Mantoux method, and concentrated and purified cell-culture (CCV) rabies vaccines can also be delivered intradermally using the same technique (WHO 2010; Kim 2012). The preferred site for intradermal injection of the BCG vaccine is over the insertion of the left deltoid muscle, avoiding the tip of the shoulder due to an increased risk of keloid scar formation at this site (DoH UK 2012a). Needles of between 10 mm and 16 mm in length with gauges ranging from 25 G to 27 G have been advocated for administering intradermal injections (Atkinson 2008; NIAC 2011).
Injection technique for intramuscular vaccinations
For an intramuscular vaccination procedure, two aspects of injection technique may influence the length of needle chosen: i) the angle of needle insertion and ii) whether the skin is ‘bunched’ or ‘stretched’ before needle insertion.
Angle of insertion
NITAGs in several countries including Australia, New Zealand, the US, Ireland and the UK currently recommend that intramuscular injections should be administered at a 90° angle to the skin (CDC 2011; MoH NZ 2011; NIAC 2011; DoH UK 2012a; ATAGI 2013). However, recommendations on injection angle have varied over time. For example, before 2005 New Zealand endorsed a 45° angle and Australia a 45° to 60° angle (NHMRC 2000; NHMRC 2003; Petousis-Harris 2008). The angle of insertion will impact on the depth of needle penetration and an insertion angle that deviates from the perpendicular may require the use of a longer needle to ensure that the vaccine is administered into muscle (Petousis-Harris 2008).
Bunching or stretching
One technique for intramuscular injections entails gently 'bunching' the muscle using the free hand whilst inserting the needle perpendicular to the skin. A second technique involves 'stretching' the skin flat over the injection site and then inserting the needle perpendicular to the skin. A longer needle may be required to reach the muscle with the former rather than the latter technique.
Injection technique for subcutaneous vaccinations
For subcutaneous injections, it is generally recommended that the needle is inserted into the subcutaneous tissues below the dermal layer at a 45° angle to the skin (CDC 2011; DoH UK 2012a). To avoid administering the vaccine into muscle, some NITAGs recommend that the skin and subcutaneous tissue should be 'bunched' (DoH UK 2012a) or 'pinched-up' to raise these tissues from the muscle layer before inserting the needle into the resulting skinfold (NIAC 2011). Other NITAGs make no specific recommendation in this regard (MoH NZ 2011).
Injection technique for intradermal vaccinations
Intradermal injection technique requires special training and should only be administered by a trained provider (ATAGI 2009; DoH UK 2012a). It is generally recommended that the skin should be stretched between the thumb and forefinger on one hand and the needle inserted almost parallel to the skin surface with the bevel facing upwards into the superficial layers of the dermis. The recommended insertion depth varies from approximately 2mm (DoH UK 2012a) to 5mm (NIAC 2011).
How the intervention might work
Unintentional deviation from the prescribed route of administration (intramuscular, subcutaneous, intradermal) for an injectable vaccine can occur if a needle of an inappropriate length is used. This can affect both vaccine immunogenicity (the ability of the vaccine to elicit an immune response) and reactogenicity (adverse events following vaccine administration). The majority of vaccines administered to children and adolescents are given via the intramuscular route and the needle used must be sufficiently long to reach the muscle mass, but not excessively long as to involve underlying nerves, blood vessels, or bone (Zimmerman 2006; CDC 2011). If the needle used is too short, the vaccine may be inadvertently administered into the layer of subcutaneous or deep fatty tissue rather than muscle and this may compromise immune response and vaccine efficacy (Zuckerman 2000). Inadvertent subcutaneous or intradermal administration, particularly of adjuvant containing vaccines, can also increase the risk of reactogenicity events including pain, local irritation, induration (hardening of the tissue at or near the injection site), skin discolouration, inflammation and abscess formation (Atkinson 2008; CDC 2011). If the needle used is too long, there is a risk of over-penetration of the muscle which can result in pain and damage to the underlying bone or periosteum (a fibrous membrane covering the surface of bones) (Lippert 2008).
Needle gauge may also influence the pain experienced during a vaccination procedure. Progressive decreases in the frequency of pain and bleeding on needle insertion into the skin of human subjects were recorded when needles of successively smaller outer diameters (23 G, 27 G, 30 G, 32 G) were used in an automated needle injection system where velocity, angle of insertion and depth of injection were controlled (Arendt-Nielsen 2006). However, any reduction in insertion pain associated with using a higher gauge (narrow/thin) needle may potentially be offset during the subsequent injection procedure. It has been hypothesised that the passage of the vaccine through a narrow bore needle may produce an ‘injection jet’ under high pressure, thereby inducing more severe local reactions at the injection site (Watson 2001). By contrast, although a wider bore needle may be associated with greater pain on needle insertion, the vaccine may be dissipated over a wider area, potentially resulting in less severe local reactions (Zuckerman 2000; RCN 2001). Needle size (gauge and length) may therefore influence both vaccine immunogenicity and reactogenicity, and clinicians should endeavour to select a needle for performing a specific vaccination procedure that will ensure the attainment of maximum immunity with the least possible harm.
Further indirect evidence to support the hypothesis that needle size may have an impact on vaccination-related procedural pain and the incidence of other reactogenicity events is provided by trials that have reported differences in patient preference, injection-related pain scores and injection-related side-effects (including bleeding and bruising) when using needles of different sizes to perform Mantoux skin testing for tuberculosis (Flynn 1994), breast fine-needle aspiration cytology (Daltrey 2000) and when administering insulin subcutaneously (Schwartz 2004; Kreugel 2007; Hirsch 2010), Botox intradermally into the axilla (Skiveren 2010) and lidocaine intradermally into the volar surface of the forearm (Palmon 1998). Although the gauges and lengths of the needles used for many of the aforementioned procedures are different to those typically recommended for vaccinations, it is reasonable to postulate that similar effects may be observed when needles of different sizes are used to administer vaccines via intramuscular, subcutaneous and intradermal routes.
Why it is important to do this review
There are inconsistencies in the recommendations made by NITAGs in different countries regarding the sizes of needles that should be used when administering vaccines to children and adolescents of specific ages or body masses at preferred injection sites via intramuscular, subcutaneous and intradermal routes (see Appendix 1). There is also some evidence of variation in clinician adherence to these recommendations. For example, surveys conducted in Australia (Cook 2001), Scotland (McKinstry 2004) and the US (Schechter 2010) have documented that, contrary to guideline recommendations, clinicians prefer to use a shorter (16 mm) rather than a longer (25 mm) needle when administering paediatric intramuscular vaccinations. Clinicians' reluctance to use longer needles may be due to concerns about the possibility of damaging deep tissue and bone and causing more discomfort to patients (Zuckerman 2000; McKinstry 2004).
The inconsistencies in NITAG recommendations coupled with the evidence of poor clinician compliance with these recommendations suggest medical uncertainty in this area. This review may help to reduce uncertainty by providing a critical summary and synthesis of the evidence from randomised controlled trials on the beneficial and adverse effects of using needles of different sizes to administer vaccines to children and adolescents. The review may also help to improve outcomes for people undergoing vaccination, by assisting clinicians to make well-informed decisions regarding the choice of needle size (gauge and length) for specific vaccination procedures that will minimise pain and discomfort whilst ensuring that an optimum immune response is attained. Reducing the pain associated with vaccine injections has the potential to improve parental, child and adolescent satisfaction with the vaccination experience, thereby enhancing vaccine uptake and compliance with recommended immunisation schedules. This is critically important in light of recent global concerns regarding sub-optimal vaccine uptake and outbreaks of vaccine-preventable diseases in many countries (WHO 2009; Barret 2010; Roehr 2010; WHO 2011; Diekema 2012; HPSC 2012; Kmietowicz 2012; Wise 2013).
This review may also help to reduce international variations in manufacturers’ packaging and presentation of vaccines which may influence clinicians’ decisions regarding the size of needle to use for specific vaccination procedures. For example, packages of the Human Papilloma Virus vaccine GARDASIL® currently supplied to the market in Ireland include two needles: a 23 G, 25 mm needle and a 25 G, 16 mm needle (HSE 2010; NIO HPSC 2010). However, some presentations of GARDASIL® available in other countries offer clinicians no choice when selecting a needle as only one 25 G, 25 mm needle is included in the packaging (MERCK 2007). Our review may help to inform manufacturers’ decisions regarding the gauges and lengths of hypodermic needles that are supplied with specific vaccines.
Finally, this review will complement existing reviews published in The Cochrane Library that have evaluated the effects of other interventions for needle-related procedural pain in children and adolescents, including sweet tasting solutions (Harrison 2011; Kassab 2012) and psychological interventions (Uman 2006).
To assess the effects of needle size for administering vaccines to children and adolescents on vaccine immunogenicity (the ability of the vaccine to elicit an immune response), procedural pain, and other reactogenicity events (adverse events following vaccine administration).
We will assess the effects of two dimensions of needle size (gauge and length) separately and in combination, i.e. we will assess the effects of:
needle gauge on vaccine immunogenicity, procedural pain and other reactogenicity events
needle length on vaccine immunogenicity, procedural pain and other reactogenicity events
needle gauge and length on vaccine immunogenicity, procedural pain and other reactogenicity events
Criteria for considering studies for this review
Types of studies
We will only include randomised controlled trials (RCTs) in this review. We will exclude quasi-randomised trials due to the increased risk of systematic differences between comparison groups (i.e. selection bias) if allocation is performed on the basis of a pseudo-random sequence (e.g. odd/even hospital number or date of birth, alternation).
The nature of the intervention under consideration in this review may preclude blinding of study participants and some trial personnel. Blinding will not therefore be a prerequisite for trial inclusion in this review. We will assess the 'Risk of bias' in relation to blinding procedures (or lack thereof) in included trials using the Cochrane Collaboration’s ‘Risk of bias’ tool (see Assessment of risk of bias in included studies)
Types of participants
We will include trials involving children and adolescents, from birth to age 24 years, undergoing vaccination with any type of vaccine injected using hypodermic needles in any setting (hospital or community). Participants may be undergoing vaccination with any type or formulation of vaccine administered via intramuscular, subcutaneous or intradermal routes. For the purposes of this review, a child will be defined as a person aged less than 10 years and an adolescent will be defined as a person aged 10 to 24 years. The upper limit of 24 years has been chosen because "many researchers and developmental specialists in the U.S. use the age span 10 - 24 years as a working definition of adolescence" (DHHS 2013).
Types of interventions
We will include trials evaluating the effects of hypodermic needles of any size (i.e. any gauge or length) used to administer any type of injectable vaccine to children and adolescents.
We will not include microneedle devices using solid or hollow, dissolvable or non-dissolvable microneedles for intradermal vaccine delivery. In addition, we will exclude jet injectors, devices for administering vaccines via intranasal injection and bifurcated needles used to administer smallpox vaccine.
We will include trials making any of the following comparisons:
1. Comparisons of the effects of using needles with the same gauge but different lengths to administer the same volume of the same vaccine via the same prescribed route at the same site using the same injection technique. For example:
25 G, 25 mm needle versus 25 G, 16 mm needle used to administer 0.5 ml of the 'six-in-one vaccine' intramuscularly in the anterolateral thigh with the skin stretched flat and the needle inserted at a 90° angle to the surface of the skin.
2. Comparisons of the effects of using needles with different gauges but the same length to administer the same volume of the same vaccine via the same prescribed route at the same site using the same injection technique. For example:
25 G, 25 mm needle versus 23 G, 25 mm needle used to administer 0.5 ml of the Human Papillomavirus (HPV) vaccine intramuscularly into the deltoid muscle with the skin stretched flat and the needle inserted at a 90° angle to the surface of the skin.
3. Comparisons of the effects of using needles with different gauges and lengths to administer the same volume of the same vaccine via the same prescribed route at the same site using the same injection technique. For example:
25 G, 16 mm needle versus 26 G, 10 mm needle used to administer 0.1 ml of the Bacillus Calmette-Guérin (BCG) vaccine intradermally over the insertion of the left deltoid muscle with the skin stretched and the needle inserted almost parallel to the skin surface with the bevel facing upwards to a depth of 2mm.
Types of outcome measures
We will include all outcomes reported by trial authors that are likely to meaningful to clinicians, patients (consumers), parents and policy makers. These will include the following primary and secondary outcomes:
Post-vaccination incidence of vaccine-preventable diseases: The diagnosis of these diseases should be made using standard clinical and/or bacteriological and/or serological criteria (e.g. a diagnosis of pertussis (whooping cough) should be based on a characteristic clinical history as well as isolation of B. pertussis from a clinical specimen or positive PCR assay for B. pertussis. A diagnosis of Hepatitis B infection should be based on detection of HBsAg, HBe antigen (HBeAg), HBV DNA, or antibody to HBc antigen in serum (anti-HBc) with or without clinical or laboratory features of hepatitis or its complications).
Pain, experienced during the vaccination procedure or at any time point post-vaccination measured via self-report, observer global reports or behavioural measures using any age-appropriate pain assessment tool with established validity and reliability (see Appendix 3).
Self report measures of pain may include:
Visual Analogue Scales (VAS)
Numerical Rating Scales (NRS)
Verbal Rating Scales (VRS)
Other scales with established validity and reliability (see Appendix 3).
Observer global reports: Observer versions of the self-report measures listed above (completed by parents, researchers, healthcare professionals or other observers) will also be included (see Appendix 3).
Crying incidence following vaccination
Persistent crying incidence following vaccination (defined as the presence of crying which is continuous (not episodic) and unaltered for ≥ 3 hours) (Bonhoeffer 2004)
Total cry duration (onset of first cry to cessation of all crying (seconds))
Duration of crying (in seconds) during a specified time period (e.g. three minutes) following vaccination
Percentage of time spent crying during a specified time period (e.g. three minutes) following vaccination
Surrogate measures of vaccine efficacy or correlates of vaccine-induced immunity: These may include, but will not be limited to, measures of serum antibody responses to the administered vaccine including Geometric Mean Concentration (GMC), Geometric Mean Titre (GMT), Geometric Mean Fold Increase (GMFI) or percentage of people with a predefined antibody level (e.g. for Yellow Fever vaccine, the proportion of individuals with a log neutralisation index (LNI) of 0.7 or higher). Antibody responses to core vaccine antigens must be assessed using standard tests, as described in Plotkin 2013. Thresholds of vaccine-induced correlates and surrogates of protection for selected vaccines are provided in Appendix 4.
Physiological measures: These may include, but will not be limited to, the following adverse cardio-respiratory events measured by standard cardio-respiratory monitors (e.g. monitors that detect central apnoea using thoracic impedance and bradycardia using electrocardiography and beat-to-beat heart rate recording) and/or observation by trained healthcare professionals or researchers or other personnel:
Episodes of oxygen desaturation – defined as a spontaneous fall in SpO2 of 85% for 10 seconds or longer in duration as measured with pulse oximetry
Episodes of bradycardia – defined as a fall in heart rate of more than 30% below the baseline
Episodes of apnoea – defined as a cessation of breathing for more than 20 seconds or a shorter pause associated with bradycardia or cyanosis.
Incidence of common adverse events following vaccine administration: fever, erythema (redness), swelling, induration, tenderness at the site of injection, local ‘hypersensitivity reactions’, malaise, irritability, headache and loss of appetite. It is widely acknowledged that some of the aforementioned terms have different meanings to different healthcare providers or reporters of adverse events following immunisation (Beigel 2007). Furthermore, until recently there have been no standardised guidelines for recording many of these events in vaccine clinical trials (Kohl 2005). We will therefore include trials reporting any of these adverse events, irrespective of how the events have been defined and measured or recorded by trial authors. We will clearly report the 'case definitions' of any adverse events used by trial authors and how these events were measured by trial researchers. Data relating to many of these common adverse events are often combined in analyses of vaccine trials. For example, data on induration, swelling and erythema (redness) are frequently combined and collectively referred to as 'local reactions' (Gidudu 2008). We will include trials where data on common adverse events are reported separately or combined. Where trial authors have combined data on various adverse events we will report precisely what events (e.g. redness, swelling, induration etc) have been included in the aggregated data.
Incidence of other local, systemic or allergic adverse events following vaccine administration reported by trial authors, irrespective of how these events have been defined and measured or recorded. These adverse events may include, but will not be limited to, the following:
local reactions: injection site nodule, granuloma, cyst, hematoma, rash, abscess, cellulitis, ulceration (necrosis), warmth or any other reported morphological or physiological change at or near the injection site.
other adverse events: disturbed sleeping, drowsiness/tiredness, nausea, vomiting, diarrhoea, syncope (vasovagal or vasodepressor reaction), anaphylaxis, febrile convulsions, hypotonic-hyporesponsive episode (HHE), generalised rash, paraesthesia, brachial neuritis (see Appendix 5 for explanations of selected terms).
We will report in our review any adverse events related to the equipment used to deliver vaccines including, but not limited to, needle bending, needle breakage or detachment of the needle from the syringe.
We will also report in our review any other outcomes recorded by trial authors that we may have omitted to mention in this protocol but that are judged likely to be meaningful to clinicians, patients (consumers), parents and policy makers. If any outcomes are reported in our final review that were not mentioned in our protocol, we will clearly explain our reasons for reporting these outcomes in the section of the review entitled 'Differences between protocol and review'. These outcomes will also be clearly labelled as 'non-prespecified outcomes' in the Results section of our review.
Time points for outcome measurement
We have not specified time points for measurement of all primary and secondary outcomes that will be considered in this review, as the timing of outcome measurement will vary from trial to trial depending on the vaccine administered and the nature of any adverse events recorded in the trial. For example, the timing of obtaining venous blood samples for the purposes of measuring immunogenicity outcomes will vary depending on the timing of the 'plateau antibody phase' following administration of different vaccines. In addition, some adverse events may occur within a wide range of time points following vaccine administration. For example, following administration of varicella vaccine, a pustular rash may appear at the injection site or occasionally other parts of the body between five days and a month after vaccination (ATAGI 2009). We will therefore report all outcomes irrespective of time points, as adverse events may be missed if a specific time point is selected. We will clearly report and comment on the timing of all outcome measurements in trials included in our review. Meta-analyses will only be conducted for outcomes measured at time points deemed to be sufficiently similar to render statistical synthesis appropriate and meaningful.
Search methods for identification of studies
To identify trials for inclusion in this review, detailed search strategies will be developed for each electronic database searched. These will be based on the search strategy developed for MEDLINE and revised appropriately for each database. The search strategy will combine the subject search with the appropriate study design filter as described in section 6.4.11 of theCochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011). The subject search will use a combination of controlled vocabulary and free text terms based on the strategy for searching MEDLINE which can be seen in Appendix 6.
Databases to be searched
We will search the following databases, with no language restrictions, from the date of inception of the database to the present day:
The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library) (current issue)
MEDLINE via OVID (1966 to present)
EMBASE via OVID (1980 to present)
CINAHL via EBSCOhost (1982 to present)
Searching other resources
We will search the bibliographies (reference lists) of all included trials, key textbooks and previously conducted narrative reviews, systematic reviews and evidence-based clinical practice guidelines of pain-reduction/pain management strategies for vaccination procedures.
We will contact the authors of all included trials and will enquire if they are aware of any unpublished or ongoing trials that meet the selection criteria for our review. We will also search the US National Institutes of Health clinical trials database (available at: www.clinicaltrials.gov) and the meta-register of controlled trials (available at: www.controlled-trials.com/mrct/searchform) to identify a) any trials that may have been registered, but not published and b) any ongoing trials meeting the selection criteria for our review. Details of any ongoing trials will be recorded in the review for inclusion in future review updates.
The search will attempt to identify all relevant trials irrespective of language. Non-English language papers will be assessed and, if necessary, translated, with the assistance of a native speaker.
Data collection and analysis
Selection of studies
Three review authors (PB, FS, SH) will independently screen the titles and abstracts of search results for eligibility for inclusion in our review in accordance with our prespecified selection criteria. We will retrieve the full texts of any potentially relevant papers. We will correspond with trial authors where necessary to clarify study eligibility. Any disagreements regarding study inclusion will be resolved by discussion and consensus. If consensus cannot be reached, then we will involve a fourth review author (FML) as an arbiter. At all stages of the screening and selection process, we will record the reasons for including and excluding studies.
For any potentially relevant non-English language papers, we will contact the editorial team of the Cochrane Pain, Palliative and Supportive Care (PaPaS) Group for assistance in locating a suitable translator. We will use the two-stage approach for translation of clinical trial reports recommended by the PaPaS group (PaPaS 2009a). Stage one involves an assessment of the 'Methods' section of trial reports by the translator to help review authors to decide if a trial is likely to be included or excluded. If a trial meets the inclusion criteria we will then proceed to stage two which involves the translator reading the full report and completing a data extraction form. Additional details regarding the data extraction form are provided in the Data extraction and management section below.
We plan to include a PRISMA study flow diagram in the full review (Liberati 2009) to document the screening process, as recommended in Part 2, Section 11.2.1 of the Cochrane Handbook (Higgins 2011a).
Data extraction and management
Three review authors (PB, FS, SH) will extract data independently from the included trials using a pre-designed data collection form. This form will be a modified version of the Cochrane PaPaS Group's data extraction form (PaPaS 2009b) that will be adapted specifically for the purposes of this review. The design of the form will take into account the recommendations contained in Chapter 7 of the Cochrane Handbook for Systematic Reviews of Interventions, specifically, the checklist of items included in Table 7.3a (Higgins 2011c). The contents of the form will also take into account the Brighton Collaboration's guidelines for the collection, analysis and presentation of vaccine safety data in pre-licensure and post-licensure clinical studies (Bonhoeffer 2009).
The data extraction form will be piloted independently by three review authors (PB, FS, SH) on one of the included trials selected at random. The three review authors will then meet to discuss the outcome of the piloting process and any necessary modifications to the data collection form will be made before proceeding with data extraction for the remaining included trials. Following completion of the data extraction process, the three review authors (PB, FS, SH) will meet to formally compare the details recorded in the three completed data collection forms for each trial. In instances where data are missing from included trials, we will contact the trial authors to obtained the required information. Any disagreements regarding the details recorded on the data extraction forms will be resolved by discussion and consensus. A fourth review author (FML) will be involved as an arbiter if necessary. All decisions taken will be formally recorded. For non-English language papers, a translator will be asked to complete a data extraction form in consultation with one review author (PB).
The information recorded on the data extraction form will include, but may not be limited to:
General trial information: Trial ID, title of publication, source of publication, year of publication, country where the trial was conducted, details of trial authors, contact addresses or other contact details (e.g. email addresses) for trial authors.
Characteristics of the study: Trial design (e.g. parallel group), trial setting (e.g. general practice), details necessary for assessing the risk of bias as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) including:
Details of methods used to generate a random allocation sequence
Details of methods used to conceal the allocation sequence
Details of all measures used, if any, used to blind trial participants and trial personnel
Details of all measures used, if any, to blind outcome assessors
Details of the completeness of data for each outcome, including attrition and exclusions from the analysis.
Details of any other concerns about bias
Characteristics of the trial participants: Details of the inclusion and exclusion criteria for the trial, baseline characteristics of trial participants in the study groups including the age, gender and weight of trial participants and the numbers randomised to each group
Characteristics of the interventions: Needle size (length and gauge) used to administer the vaccine to different study groups, details of any colour coding on the needle hubs, details of the needle composition (e.g. surgical grade stainless steel, chrome nickel steel), any coating on the needle (e.g. silicone), the needle bevel (e.g. 3-bevel needle, 5-bevel needle) and the needle hub (e.g. luer lock plastic hub, luer lock aluminium hub). Type and formulation of vaccine administered, including details of the 'biological' characteristics of the vaccine (e.g. live attenuated or inactivated component vaccine, pH and osmolality of the vaccine) and the composition of the vaccine (e.g. presence or absence of adjuvant). The volume of vaccine administered and details of the vaccine manufacturer. Details of the personnel who administered the vaccination. Details of the injection technique used including, but not limited to: ;'bunching' or 'stretching' of skin and underlying tissues before needle insertion, the angle of needle insertion, the depth of needle insertion (e.g. needle inserted to full depth (i.e. to the needle hub), 2 mm of needle exposed between the skin and needle hub).
Characteristics of the outcome measures: Details of all outcomes measured, definitions of outcomes and the time points of measurements. Details of the outcome assessors and methods/instruments used to measure outcomes. Units of measurement (where relevant), upper and lower limits for any scales used.
Trial results: For each outcome we will record details of the numbers in each study group for whom outcome data were available at each time point and details of, and reasons for, any attrition or exclusions and any re-inclusions in analyses performed by the trial authors. For dichotomous outcomes we will record the numbers of participants experiencing the outcome of interest in each study group at each time point. For continuous outcomes we will record the mean value and standard deviation of the outcome measurements in each study group at each time point.
Miscellaneous information: Source of funding for the trial, key conclusions of the trial authors, miscellaneous comments made by the trial authors, references to other relevant studies, miscellaneous comments by the review authors completing the data extraction form.
All relevant data will be entered into Review Manager 5.2 (RevMan 2012) by one review author (PB) and will be re-checked by two review authors (FS, SH). Contextual factors recorded in the data extraction form for each trial (i.e. conditions and circumstances relevant to the application of the intervention such as the country (e.g. developing, developed) where the trial was conducted and the trial setting (e.g. general practice, other setting)) will be taken into consideration when interpreting the overall results of the final review. We will also consider the applicability, transferability and external validity of findings for disadvantaged groups, as recommended in the 'Equity checklist for systematic review authors' (Ueffing 2012). For example, the results of trials involving well-nourished children in developed countries may not be applicable in resource poor countries with less well-nourished children.
Assessment of risk of bias in included studies
The risk of bias in trials meeting the selection criteria for this review will be assessed independently by three review authors (PB, FS, SH) using the approach recommended in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). Any disagreements in the independent assessments will be resolved by discussion and by involvement of a fourth member of the review team (FML) as an arbiter if necessary. Review authors will not be blinded to the authors of each trial, the trial location/setting, sources of funding for the trial or trial acknowledgements.
The following domains will be assessed for each included trial:
Random sequence generation [selection bias]
Allocation concealment [selection bias]
Blinding of participants and personnel [performance bias]
Blinding of outcome assessment [detection bias]
Incomplete outcome data [attrition bias]
Selective reporting [reporting bias]
Other sources of bias [other bias]
For each domain we will reach a judgement of either 'Low risk' of bias, 'High risk' of bias or 'Unclear risk' of bias and we will provide support for all judgements. In reaching our judgements we will consider the risk of material bias, defined as 'bias of sufficient magnitude to have a notable impact on the results or conclusions of the trial' (Higgins 2011b). We will produce a separate 'Risk of bias' table for each trial included in our review. In addition we will also produce a 'Risk of bias graph' figure and a 'Risk of bias summary' figure for inclusion in our review, as described in section 8.6 of the Cochrane Handbook (Higgins 2011b).
Sensitivity analyses according to selected aspects of trial quality will be undertaken as described in the Sensitivity analysis section of this protocol.
Measures of treatment effect
All statistical analyses in our review will be overseen by the review team statistician (TF).
We will calculate relative risks (risk ratios) (RR), risk differences (RD) and numbers needed to treat (NNT) as effect measures for dichotomous outcomes. Any meta-analyses of dichotomous data will be performed using relative risks (risk ratios) (RR) (see the Data synthesis section).
We will calculate mean differences or standardised mean differences (SMD) with 95% confidence intervals (CIs) as effect measures for continuous outcomes. We will use the mean difference if the included trials have used the same scale to measure the same outcome. We will use the SMD If the included trials have used different scales to measure the same outcome.
Unit of analysis issues
Due to the nature of the intervention under consideration in this review, it is anticipated that only parallel group randomised controlled trials will have been conducted with randomisation on the basis of individual patient only.
If trial results are presented at more than one time point (e.g. local reactions at 24, 48, 72 hours following a vaccination procedure), then we will analyse data separately for each time point for studies in which this information is presented.
Dealing with missing data
Every effort will be made to contact the authors of included trials to obtain missing data or for data clarification. If some (or all) of the trial results are presented graphically and if it is not possible to contact trial authors, then the values will be estimated from the graphs independently by three review authors (PB, FS, SH) and disagreements resolved by discussion. We will involve a fourth member of the review team (FML) as an arbiter if necessary.
We will record details of any discrepancies between the numbers of participants randomised and the numbers analysed in each treatment group for each outcome and will report this information in the 'Risk of bias' tables for each trial. If more than 20% of the data for a particular outcome are missing from a trial, then we will exclude the trial from any meta-analysis relating to that outcome.
If missing outcome data can reasonably be assumed to be 'missing at random', then we will analyse only the available data (i.e. an 'available case analysis' will be conducted). Where the latter analysis strategy is adopted in our review we will clearly explain the reasons why we deemed it reasonable to assume that the data were 'missing at random'. In instances where data cannot be realistically assumed to be 'missing at random' and where the nature of the outcome renders it reasonable to do so, we will impute the missing data with replacement values and conduct sensitivity analyses to investigate how sensitive results are to changes in assumptions that are made regarding the replacement values. We will use both 'best case' and 'worst case' imputation scenarios for dichotomous outcome data. For continuous outcome data, we will consider the use of the last observation carried forward (LOCF) approach where the nature of the outcome renders it reasonable to do so and where individual participant data are available from trial authors.
In the Discussion section of our review we will discuss the potential impact on the findings of the review of missing data and our analysis strategies for dealing with missing data.
Assessment of heterogeneity
Inconsistency between the results of individual studies included in the review will be quantified using the I2 statistic (Deeks 2011) which describes the percentage of variability in effect estimates that is due to heterogeneity rather than to chance. The values of I2 will be interpreted in accordance with the following 'rough guide' as specified in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a):
0% to 40%: might not be important
30% to 60%: may represent moderate heterogeneity
50% to 90%: may represent substantial heterogeneity
75% to 100%: considerable heterogeneity
If present, heterogeneity will be investigated by a) performing further quality control checks of data extraction from included studies and data entry into RevMan and b) by conducting the a priori subgroup analyses as described below at Subgroup analysis and investigation of heterogeneity.
Assessment of reporting biases
The likelihood of publication bias will be investigated by producing a funnel plot using data from included trials. Tests for funnel plot asymmetry will only be conducted if at least 10 studies are included in the meta-analysis (Sterne 2011). We will also explore different reasons for funnel plot asymmetry such as differences in the methodological quality of trials or true heterogeneity in intervention effects.
Outcome reporting bias
Three review authors (PB, FS, SH) will examine the reports of all included trials for evidence of selective outcome reporting. We will contact trial authors to obtain missing outcome data. Trials will be judged as having a 'low risk of bias' due to selective outcome reporting if they fulfil the following criteria specified in the Cochrane 'Risk of bias' assessment tool (Higgins 2011a):
The study protocol is available and all of the pre-specified outcomes that are of interest to our review have been reported in published trials.
The study protocol is not available, but it is clear that the published reports included all expected outcomes.
All statistical analyses and data syntheses will be conducted using Review Manager software (RevMan 2012) in consultation with the statistician (TF).
Statistical synthesis of the results from individual trials included in this review will only be conducted if the trials are deemed to be sufficiently similar in terms of the populations, interventions, comparisons and outcomes to render calculation of a pooled estimate meaningful. If meta-analysis is deemed inappropriate or is not feasible (e.g. due to the heterogeneity of included trials), then we will present a comprehensive narrative summary of the results of individual trials.
We will use the relative risk (risk ratio) as the summary statistic in meta-analyses of dichotomous outcomes. Relative risks will be pooled using the random-effects Mantel-Haenszel method (Higgins 2011a).
The mean difference will be used as the summary statistic in meta-analyses of continuous data when outcome measurements in included trials are all made on the same scale. Mean differences will be pooled using the random-effects inverse variance method. In instances where the included trials assess the same continuous outcome (e.g. pain) but do so in a variety of ways (e.g. using different pain scales), the SMD will be used as the summary statistic in meta-analyses. SMD will be pooled using the random-effects inverse variance method.
Subgroup analysis and investigation of heterogeneity
If sufficient trials are available and if there is evidence of statistical heterogeneity, we will investigate the following characteristics of trials for their possible influence on the magnitude of the intervention effect:
Participant characteristics: age, weight (kilograms) or body mass index (BMI), gender
Vaccine characteristics: type of vaccine, formulation of vaccine (including vaccine viscosity)
Site of vaccine administration: deltoid, antero-lateral thigh, other
Co-interventions administered during trial: e.g. multiple vaccines administered to trial participants
Technique of vaccine administration: 'bunching' or 'stretching' of skin before needle insertion, angle of needle insertion
Person administering the vaccine: doctor, nurse, other healthcare professional.
If sufficient trials are available, we will conduct the following analyses to determine if the conclusions of our review are robust to decisions made during the review process:
In instances where missing outcome data have been imputed with replacement values and included in a meta-analysis, we will repeat our analyses using different assumptions about the replacement values (see section of this protocol entitled: Dealing with missing data)
We will repeat meta-analyses including and excluding trials that are judged to have unclear or inadequate allocation concealment
We will repeat meta-analyses including and excluding trials that are judged to have unclear or inadequate blinding of outcome assessors
We will repeat meta-analyses using both fixed-effect and random-effects models.
As noted in Section 9.7 of the Cochrane Handbook, "many issues suitable for sensitivity analysis are only identified during the review process where the individual peculiarities of the studies under investigation are identified" (Higgins 2011a). For example, we have specified in this protocol (see Dealing with missing data) that if more than 20% of the data for a particular outcome are missing from a trial, then we will exclude the trial from any meta-analysis relating to that outcome. However, in some circumstances it may be deemed acceptable to include trials in meta-analyses with more than 20% missing data. For example, trials involving disadvantaged populations may frequently experience losses of greater than 20%, and it may be preferable to allow a greater bias risk in these analyses rather than exclude a large proportion of the existing data. Thus it might be considered appropriate to repeat meta-analyses including and excluding trials where more than 20% of the data for a particular outcome are missing. If it is deemed appropriate during the review process to conduct further sensitivity analyses (in addition to the pre-specified analyses outlined above), then we will clearly explain the reasons for conducting these additional analyses in our review and these analyses will be clearly labelled as 'non-prespecified analyses'. We will report any sensitivity analyses in a summary table.
'Summary of findings' tables
We will summarise the results for the main comparisons specified in the Types of interventions section of this protocol in 'Summary of findings' tables. The quality of evidence in relation to each outcome included in these tables will be assessed using the evidence grading system developed by the GRADE collaboration as described in Section 12.2 of the Cochrane Handbook (Schünemann 2011b).
In the Types of outcome measures section of this protocol we have listed the outcomes (primary and secondary) in terms of perceived order of importance for decision-making and we will include in the 'Summary of findings' tables the first seven outcomes listed. However, as noted in section 18.104.22.168 of the Cochrane Handbook, the importance of an outcome "may only become known after the protocol was written or the analysis was carried out and [review authors] should take appropriate action to include these in the 'Summary of findings' table" (Schünemann 2011a). In the event that during the review process: a) we become aware of an important outcome that we have omitted to include in our protocol or b) we become aware that we have failed to accord sufficient priority to a specific outcome(s) listed in our protocol, then we will include the relevant outcome(s) in the 'Summary of findings' tables. If it is necessary to include outcomes in the 'Summary of findings' tables that were not pre-specified in our protocol, then we will clearly explain the reasons for this in our review, as recommended by Kirkham 2010.
We offer our sincere thanks to Jane Hayes, former Trials Search Co-ordinator with the Pain, Palliative Care and Supportive Care (PaPaS) Group, for her invaluable assistance in devising the search strategy. We would also like to thank Jessica Thomas, former Managing Editor of the PaPaS group, for her advice, support and encouragement during the title registration process. We are extremely grateful to Mairead McIntyre, Elizabeth Royle and Manal Kassab for their insightful comments on the draft protocol.
Appendix 1. Needle size recommendations for administering vaccines via intramuscular, subcutaneous and intradermal routes made by National Immunisation Technical Advisory Groups (NITAGs) in four countries
| Table A. Needle size recommendations made by National Immunisation Technical Advisory Groups (NITAGs) in four countries regarding intramuscular vaccine injections at ‘preferred injection sites’ in children and adolescents|
| Country|| Age or size of vaccine recipient|
| Needle Size|
| Gauge|| Length|
|UK (DoH UK 2012a)||Preterm or very small infants||A-L thigh||NS||16mm (⅝")|
|Infants under 1 year||A-L thigh||23G or 25G||25mm (1")|
|Older children and adults||Deltoid|
|Ireland (NIAC 2011)||Infants under 2.5 to 3kgs||A-L thigh||NS||16mm (⅝")|
|Birth to 12 months||A-L thigh||23G to 25G||25mm (1")|
|12 to 36 months||A-L thigh or deltoid|
| From 3 years upwards1||Deltoid|
|United States2 (CDC 2011)||Neonates (first 28 days) and preterm infants||A-L thigh||NS||16mm (⅝")3|
| Infants < 12 months||A-L thigh||22G to 25G||25mm|
|Toddlers 12 months to 2 years||A-L thigh||NS||25mm to 32mm (1-1¼")|
|Children aged 3 to 18 years||Deltoid||22G to 25G||16mm4 to 25mm (⅝" - 1")|
|Australia (ATAGI 2013)||Preterm babies(< 37 weeks gestation) up to age 2 months; and/or very small infants||A-L thigh||23G or 25G5||16mm (⅝")|
|Infants < 12 months||A-L thigh||23G or 25G5||25mm (1")|
|Children ≥ 12 months, adolescents, and adults6||Deltoid|
NS = gauge not explicitly specified. A-L = anterolateral
A 38 mm needle is recommended in women > 90 kg and men > 118 kg (gauge not specified)
The guidance states that “a decision on needle size and site of injection must be made for each person on the basis of the size of the muscle, the thickness of adipose tissue at the injection site, the volume of the material to be administered, injection technique, and the depth below the muscle into which the material is to be injected” (CDC 2011: 15).
16mm is deemed adequate if the skin is stretched flat between the thumb and forefinger and the needle is inserted at a 90-degree angle to the skin
If the skin is stretched tightly and subcutaneous tissues are not bunched
If using a narrow 25 G needle for an intramuscular vaccination, it is recommended that the vaccine is injected slowly over a count of 5 seconds to avoid injection pain and muscle trauma
A 23 G or 25 G, 38 mm needle is recommended for a very large or obese patient.
The precise reasons for some of the disparities in needle size recommendations between different countries are unclear, but one contributory factor may be the use of different research evidence to inform the recommendations (see Appendix 2).
|Table B Needle size recommendations made by National Immunisation Technical Advisory Groups (NITAGs) in four countries regarding subcutaneous vaccine injections at ‘preferred injection sites’ in children and adults|
| Country|| Age |
| Needle Size|
| Gauge|| Length|
|UK (DoH UK 2012a)|
Infants < 1 year
Older children and adults
A-L thigh area
| a|| a|
|Ireland (NIAC 2011)|
Birth to 12 months
Toddlers 12 to 36 months
Children and adults
A-L thigh area
A-L thigh or triceps area
|23G to 25G||16mm (⅝")|
|United States (CDC 2011)|
Infants < 12 months
Age ≥ 12 months
A-L thigh area
|23G to 25G||16mm (⅝")|
|Australia (ATAGI 2013)||All persons||A-L thigh area or deltoid areab||25G or 26G||16mm (⅝")|
a. The needle gauge and length are not explicitly stated but the guidance appears to imply that a 23 G or 25 G, 25 mm needle should be used for subcutaneous (SC) injections. The relevant extract from the guideline is as follows : “For IM and SC injections, the needle needs to be sufficiently long to ensure that the vaccine is injected into the muscle or deep into subcutaneous tissue. Studies have shown that the use of 25mm needles can reduce local vaccine reactogenicity (Diggle et al., 2000, Diggle et al., 2006). The width of the needle (gauge) may also need to be considered. A 23-gauge or 25-gauge needle is recommended for intramuscular administration of most vaccines (Plotkin and Orenstein 2008)” (DoH UK 2012a p 29).
b. The guidance states that "Subcutaneous injections should be administered either over the deltoid muscle or over the anterolateral thigh" (ATAGI 2013 p 82).
| Table C. Needle size recommendations made by National Immunisation Technical Advisory Groups in four countries regarding intradermal injection of BCG vaccine at ‘preferred injection site’ in children and adults|
| Country|| Age|| Preferred injection site|| Needle Size|
| Gauge|| Length|
|UK (DoH UK 2012a)||All ages||Over region of insertion of left deltoid muscle||26G||10mm (⅜")|
|Ireland (NIAC 2011)|
|Over the distal insertion of the deltoid muscle||25G or 26G||10mm (⅜") to 16mm (⅝")|
|United States (CDC 2011)||Not specified||Not specified||Not specified|
|Australia (ATAGI 2013)||All ages||Over region of insertion of left deltoid muscle into the humerus||26G or 27G||10mm|
Appendix 2. Evidence used to support needle size recommendations for administering vaccines intramuscularly made by National Immunisation Technical Advisory Groups (NITAGs) in four countries
| Table A: Evidence used to inform needle size recommendations for intramuscular injections made by National Immunisation Technical Advisory Groups in four countries|
| Evidence/Publications cited to support needle size recommendations|
| Systematic Reviews|| RCTs or CCTs|| Ultrasound studies of muscle and subcutaneous fat thickness|| Other: e.g. guidelines, textbooks, editorials, opinion piece [OP] etc.|
|UK/JCVI (DoH UK 2012a)a ||0|
1 textbook (Plotkin 2008a)
1 guideline (VATF 2001)
1 editorial/OP (Zuckerman 2000)
|Ireland/NIACb (NIAC 2011)||0||-||-|
(AAP 2006; DoH UK 2006)
|United States/ACIPc (CDC 2011)||0|
(Zuckerman 2000; Bergeson 1982)
|Australia/ATAGId (ATAGI 2013)||0|
|1 guideline (CDC 2011)|
JCVI = Joint Committee on Vaccines and Immunisation; NIAC = National Immunisation Advisory Committee; ACIP = Advisory Committee on Immunization Practices; ATAGI = Australian Technical Advisory Group on Immunisations
a. The publications recorded in the Table are those cited in the section of the guidance entitled “Choice of needle size” (pp 29 - 30)
b. The publications recorded in the Table are those cited in the Bibliography of Chapter 2 (General Immunisation Procedures) - no references are cited in the main text of Chapter 2.
c. The publications recorded in the Table are those cited in the section of the guidance entitled “Intramuscular Injections” (pp 15 - 16) which explicitly relate to needle size for administering intramuscular injections
d. The publications recorded in the Table are those cited in Section 2.2.5 entitled “vaccine injection techniques” (pp71 - 74) which explicitly relate to needle size for administering intramuscular injections.
* In this protocol, these references are "Classification pending references" and hence have not been 'linked' in the text
Appendix 3. Pain assessment tools with established validity and reliability
For the purposes of this review we will use the same definition of "established validity and reliability" specified in the protocol for a Cochrane review of psychological interventions for needle-related procedural pain (Uman 2005), namely "prior publication in at least one scientific paper from a peer-reviewed journal." These validated and reliable pain assessment tools will include, but may not be limited to, the tools recommended by the Brighton Collaboration for assessing immunisation site pain (Gidudu 2012), the tools listed in the Royal College of Nursing's clinical practice guideline on the recognition and assessment of pain in children (RCN 2009) and the tools specified in the protocols for Cochrane reviews that have evaluated the effects of interventions for needle-related procedural pain or procedural pain (Pillai Riddell 2006; Lander 2002; Uman 2005; Harrison 2010; Kassab 2010; Hogan 2012). The names of these tools are provided in the tables below.
|Table A: Pain assessment tools recommended by the Brighton Collaboration for assessment of acute and delayed pain following immunisation (Gidudu 2012)|
| Age|| Assessment methods for acute pain following immunisation: Assessor and tool|| Assessment methods for delayed pain following immunisation: Assessor and Tool|
| Pre-verbal child|
|≤ 18 months|
|Parent: NRS (for pre-verbal children ≤ 3 years)|
|> 18 months|
| Verbal child|
|≥ 3 to 6 years||Child: Poker Chip||Child: Poker Chip|
|≥ 4 years||Child: FPS-R||Child: FPS-R|
|≥ 9 years||Child: NRS||Child: NRS|
MBPS = Modified Behavioural Pain Scale (Taddio 1995)
NRS = Numerical Rating Scale (Miró 2009; von Baeyer 2009; Bailey 2010)
FLACC = Face Legs Activity Crying Consolability scale (Merkel 1997)
FPS-R = Faces Pain Scale Revised (Hicks 2001)
Poker Chip = Poker Chip tool (Hester 1979)
NOTE: the references cited above are those specified by the Brighton Collaboration (Gidudu 2012)
The following tables summarise pain scales described by the Royal College of Nursing (RCN 2009) as valid and reliable tools for assessing pain intensity in a) neonates (Table B) b) non-verbal children with cognitive impairment (Table B) and c) infants and verbal children without cognitive impairments (Table C). References for all scales mentioned in the tables are provided in RCN 2009.
| Table B: Pain scales for assessing pain intensity in A) neonates and B) non-verbal children with cognitive impairment|
| A) Pain Scales for neonates|| B) Pain Scales for non-verbal children with cognitive impairment|
| Tool Name|| Features|| Tool Name|| Features|
|COMFORT||OR; T; PM||Face, Legs, Activity, Cry, Consolability(FLACC)||OR|
|CRIES||OR; T; PM||Paediatric Pain Profile (PPP)||OR|
|Neonatal Facial Coding System (NFCS)||OR; T||Non-communicating Children’s Pain Checklist – Revised (NCCPC-R)||OR|
|Nepean NICU Pain Assessment Tool (NNICUPAT)||OR; T||NCCPC-PV (Non-communicating children’s Pain Checklist – Post-operative Version)||OR|
|Neonatal Infant Pain Scale (NIPS)||OR; T|| |
|Objective Pain Scale (OPS)||OR; T; PM|
|Pain Assessment Tool (PAT)||OR; T; PM|
|Premature Infant Pain Profile (PIPP)||OR; T; PM|
| OR = Observer Rated; T = requires training; PM = Tool includes physiological measures|
| Table C: Pain Scales for Infants and verbal children|
| Tool Name|| Features|
|Alder Hey Triage Pain Scale (AHTPS)||OR; T|
|Cardiac Analgesic Assessment Tool (CAAT)||OR; T|
|Chedoke-McMaster Paediatric Pain Management Sheet||OR; T; SR|
|Colour Analogue Scale|| T; SR|
|Children’s Hospital of Eastern Ontario Pain Scale (CHEOPS)||OR|
|COMFORT||OR; T; PM|
|Derbyshire Children’s Hospital Pain Tool (DCHPT)||OR; T|
|FACES scale (Wong-Baker)||OR; T|
|FACES scale (a six-graded faces scale by Tree Takarn)||SR; T|
|Faces Pain Scale (FPS; by Bieri)||SR; T|
|Face, Legs, Arms, Cry, Consolability (FLACC)||OR; T|
|Nursing Assessment of Pain Intensity (NAPI; a modification of CHEOPS)||OR; T|
|Poker chip tool||SR; T|
|Post-operative Pain Score (POPS)||OR; T|
|Pain Rating Scale||OR; T|
|Sheffield Children’s Hospital Facial Expression Scale||SR; T|
|Toddler Preschool Post-operative Pain Scale (TPPPS)||OR; T|
|University of Wisconsin Pain Scale||OR; T|
|Visual Analogue Scale (self rated)||SR; T|
|Visual Analogue Scale (observer rated)||OR; T|
|Verbal Rating Scale||SR; T|
|Word Descriptor Scale||SR; T|
|Word Graphic Rating Scale||SR; T|
OR = Observer Rated; T = requires training;
PM = Tool includes physiological measures
SR = Self-report tool
Tools not mentioned in Tables A to C (above) but that are cited in protocols for Cochrane reviews that have evaluated the effects of interventions for needle-related procedural pain or procedural pain include the following:
Baby Facial Action Coding System; Maximally Discriminative Facial Movement Coding System; Children's and Infants postoperative Pain Scale; Clinical Scoring System; Modified Postoperative Comfort Score; Liverpool Infant Distress Scale; Neonatal Pain, Agitation and Sedation Scale (N-PASS); Scale for Use in Newborns (SUN); Pain Assessment in Neonates Scale (PAIN); Bernese Pain Scale (cited in protocol by Pillai Riddell 2006)
References for all of these tools are provided in the protocols by Pillai Riddell 2006; Kassab 2010; and Hogan 2012.
Appendix 4. Quantitative correlates and surrogates of protection after vaccination
|Table A: Thresholds of vaccine induced correlates and surrogates of protection for selected vaccines (adapted from Plotkin 2010; Thakur 2012)|
| Vaccine|| Test|| Threshold of Protection|| Serum IgG|| Mucosal IgG|| Mucosal IgA|| T cells|
|Diptheria||Toxin neutralisation||0.01 to 0.1 IU/ml||++|| || || |
|Hepatitis A||ELISA||10 mIU/ml||++|| || || |
|Hepatitis B||ELISA||10 mIU/ml||++|| || || |
|Hib polysaccharides||ELISA||1μg/ml||++||+|| || |
|Hib conjugate||ELISA||0.15 μg/ml||++||++|| || |
|Japanese encephalitis||Neutralisation||1:10 titer||++|| || || |
|Measles||Microneutralisation||120 to 200 mIU/ml||++|| || ||+(CD8+)|
|Meningococcal||Bactericidal|| 1/4 (human complement)||++||+|| || |
|Pertussis||ELISA (toxin)||5 units|| || || || |
|Pneumococcus||ELISA; opsonophagocytosis||0.20 to 0.35 μg/ml (for children); 1/8dilution|| || || || |
|Rubella||Immunoprecipitation||10 to 15 IU/ml||++|| || || |
|Tetanus||Toxin neutralisation||0.01 IU/ml|| || || || |
|Varicella||FAMA gp ELISA||≥ 1:64 titer; ≥ 5 IU/ml||++|| || ||+(CD4+)|
|Yellow Fever||Neutralisation||0.7 LNI||++|| || || |
LNI = log neutralisation index; IU/ml = international units per millilitre; mIU/ml = milli-international units per millilitre
ELISA = enzyme-linked immunosorbent assay; FAMA =fluorescent antibody-to-membrane-antibody
Appendix 5. Glossary of selected terms used within the review
The Brighton Collaboration: An international voluntary collaboration that facilitates the development, evaluation and dissemination of high-quality information about the safety of human vaccines (Bonhoeffer 2002). The Brighton Collaboration "develops standardized case definitions [for adverse events following immunisation] and guidelines for data collection, analysis and presentation via participation of more than 500 experts from 57 countries from public health, clinical care, academic, regulatory organizations and industry" (Kohl 2005).
Correlate of vaccine protection: In this Cochrane review a correlate of protection will be defined in accordance with the definition proposed by (Plotkin 2008b): "A specific immune response to a vaccine that is closely related to protection against infection, disease or other defined end point". Correlates of protective immunity usually entail vaccine-induced immune responses. Historically, these responses have been defined in terms of antibody titres although current technology also allows consideration of cell-mediated, mucosal and memory-based immune responses (Hudgens 2004). Widely accepted immunological correlates of protection exist for certain antigens and consist of "defined humoral antibody responses above which there is a high likelihood of protection in the absence of any host factors that might increase susceptibility to the infectious agent" (EMA 2005).
Geometric Mean: The geometric mean is the average of logarithmic values, converted back to the base. It is less sensitive than the arithmetic mean to one or a few extreme values (CDC 2006). The geometric mean is the measure of choice for variables measured on an exponential or logarithmic scale, such as dilutional titres of assays and it is a standard statistic used to summarise immunogenicity values. If the observations are titres, the Geometric Mean Titre (GMT) is used. If the observations are concentrations, the Geometric Mean Concentration (GMC) is used (Nauta 2011). Both GMC and GMT are commonly used immune response end points in vaccine efficacy trials (Horne 2001).
Hypotonic-hyporesponsive episode (shock, collapse): "the sudden onset of pallor or cyanosis, limpness (muscle hypotonia), and reduced responsiveness or unresponsiveness occurring after vaccination, where no other cause is evident, such as a vasovagal episode or anaphylaxis. The episode usually occurs 1 to 48 hours after vaccination and resolves spontaneously" (ATAGI 2013: 491).
Immunobiologic: "Antigenic substances (e.g., vaccines and toxoids) or antibody-containing preparations (e.g., globulins and antitoxins) from human or animal donors. These products are used for active or passive immunization or therapy. Examples of immunobiologics include antitoxin, immune globulin and hyperimmune globulin, monoclonal antibodies, toxoids, and vaccines" (CDC 2011).
Immunogenicity: The ability of a vaccine to induce a humoral and/or a cell-mediated immune response. The ideal end point for evaluating the immune response to an administered vaccine is the incidence of the disease the vaccine is designed to prevent. However, commonly used end points in vaccine clinical trials include the Geometric Mean Concentration (GMC) or Geometric Mean Titre (GMT) of antibodies elicited by the vaccine.
Jet injectors: These are "needle-free devices that pressurize liquid medication, forcing it through a nozzle orifice into a narrow stream capable of penetrating skin to deliver a drug or vaccine into intradermal, subcutaneous, or intramuscular tissue" (CDC 2011).
National Immunisation Technical Advisory Groups (NITAGs): These groups are "Expert advisory committees that provide recommendations to guide a country's national immunization programs and policies. They consist of independent experts with the technical capacity to evaluate new and existing immunization interventions. The premise of these groups is to facilitate a systematic, transparent process for developing immunization policies by making evidence-based technical recommendations to the national government" (Bryson 2010). A recent global survey of these advisory groups reported the existence of NITAGs in 89 countries (Bryson 2010). Details of the NITAGs in different countries can be obtained from the SIVAC initiative's (Supporting National Independent Immunization and Vaccine Advisory Committees) NITAG Resource Center (AMP 2012a; AMP 2012b).
Paraesthesia: "A sensation of pricking, tingling, or creeping on the skin having no objective cause and usually associated with injury or irritation of a sensory nerve or nerve root" (Merriam-Webster 2013).
Proportion of vaccine recipients with a predefined antibody level: This refers to the proportion of vaccine recipients who respond in a prescribed manner to the vaccine administered.This end point in vaccine clinical trials is particularly meaningful "if there is a particular threshold level of immune response that is believed to be important. For example, for Haemophilus influenzae type b (Hib), proportion of recipients with a postvaccination concentration of anti-polyribosyl ribitol phosphate antibody that is ≥0.15µg/mL and ≥1.00µg/mL have been used to evaluate the immune response to the Hib component" (Horne 2001).
Reactogenicity: In accordance with other Cochrane reviews (Bar-On 2012) the term reactogenicity will be used in this Cochrane review to refer to adverse events following the administration of a vaccine. Common reactogenicity events that occur following vaccination include local events such as pain, redness, swelling, induration and tenderness at the injection site, local 'hypersensitivity reactions' and systemic adverse reactions which include fever, malaise, myalgia, irritability, headache and loss of appetite (DoH UK 2012b).
Vaccination and immunisation: Although the terms 'vaccination' and 'immunisation' are frequently used interchangeably in the international literature, they are not strictly synonymous "because the administration of an immunobiologic cannot be equated automatically with development of adequate immunity" (CDC 2011). In this Cochrane review the term vaccination will be used to refer to the physical act of administering any vaccine or toxoid. The term immunisation will be used to refer to the process of inducing or providing immunity by administering an immunobiologic (CDC 2011). The only exception to this occurs in the context of the phrases "adverse events following immunisation (AEFI)" and "immunisation schedules" which are "established terms" that are consistently used in the international literature. Within the context of these phrases the word immunisation should be understood as referring to vaccine administration rather than the process of inducing immunity.
Six-in-one vaccine: a vaccine that is intended to provide protection against six diseases: diphtheria, tetanus, pertussis, polio, Hib (Haemophilus Influenzae type B) and hepatitis B.
Appendix 6. MEDLINE (Ovid) search strategy
1 exp Immunization/
2 exp Immunization Programs/
3 exp Injections/
4 (immuni* or vaccin* or inject*).mp.
5 1 or 2 or 3 or 4
8 6 or 7
9 randomized controlled trial.pt.
10 controlled clinical trial.pt.
13 clinical trials as topic.sh.
16 9 or 10 or 11 or 12 or 13 or 14 or 15
17 5 and 8 and 16
mp=title, abstract, original title, name of substance word, subject heading word, protocol supplementary concept, rare disease supplementary concept, unique identifier
|4 September 2013||Amended||Slight change to wording in 'Electronic searches' section.|
Contributions of authors
PB drafted the protocol in consultation with the other members of the review team (listed below). For the full review he will co-ordinate the review team and will search for trials, screen titles and abstracts of retrieved records, enter citations into RevMan, select trials for inclusion that meet the prespecified selection criteria, develop and pilot the data extraction form, write to authors of papers for additional information, assess the risk of bias in included trials, extract trial data, enter data into RevMan, decide which analyses to conduct in consultation with the review team statistician (TF) and all other members of the review team, interpret the analysis, draft the final review, and coordinate future review updates.
FS reviewed and approved the final protocol. For the full review she will search for trials, screen titles and abstracts of retrieved records, select trials for inclusion that meet the prespecified selection criteria, assist with the development and piloting of the data extraction form, write to authors of papers for additional information, assess the risk of bias in included trials, extract trial data, decide which analyses to conduct in consultation with the review team statistician (TF) and all other members of the review team, assist with interpreting the analysis, and assist with drafting the final review.
SH reviewed and approved the final protocol. For the full review she will search for trials, screen titles and abstracts of retrieved records, select trials for inclusion that meet the prespecified selection criteria, assist with the development and piloting of the data extraction form, write to authors of papers for additional information, assess the risk of bias in included trials, extract trial data, decide which analyses to conduct in consultation with the review team statistician (TF) and all other members of the review team, assist with interpreting the analysis, and assist with drafting the final review.
TF reviewed and approved the final protocol. For the full review he will provide statistical advice and will oversee all statistical analyses of data. He will also assist with interpreting the analysis and with drafting any aspects of the final review that require statistical input.
FML reviewed and approved the final protocol. For the full review she will act as an arbiter in instances where there are disagreements between PB, FS and SH regarding study selection, data extraction and 'Risk of bias' assessments. She will also decide which analyses to conduct in consultation with the review team statistician (TF) and all other members of the review team. In addition, she will assist with interpreting the analysis by providing a clinical perspective and will assist with drafting the final review.
Declarations of interest
All review authors (PB, FS, SH, TF, FML) report no known conflicts of interest.
Sources of support
University College Cork (UCC), Ireland.
All review authors are employees of UCC and receive support from the University in the form of a salary.