Conjugate vaccines for preventing Haemophilus influenzae type b infections in children under 5 years of age

  • Protocol
  • Intervention

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

  1. To determine the effects of conjugate Hib vaccine in preventing Hib disease or death in children under five years of age.

  2. To determine any variation in vaccine effectiveness with type of vaccine; number of doses; age at first dose; known HIV infection; or in high-income and low-income countries.

  3. To determine any clinically relevant mild, moderate or serious adverse outcomes.

  4. To identify costs associated with the vaccination, adverse events and illnesses in vaccinated and unvaccinated children.

Background

Description of the condition

Haemophilus influenzae (H. influenzae) type b, or Hib, is a bacterial pathogen that is commonly found in the oro-pharynx of healthy unimmunised individuals (Watt 2009). It is transmitted by droplets and after inhalation can enter the bloodstream and cause infections such as meningitis, pneumonia, epiglottitis, septicaemia, cellulitis, arthritis, osteomyelitis and pericarditis (Asensi 1995; Watt 2009).

The true burden of Hib disease is not quantifiable as laboratory diagnosis is challenging (Watt 2009). It is estimated to be responsible for some three million serious illnesses and an estimated 386,000 deaths per year (WHO 2006). The majority of these deaths are in low-income countries, largely due to Hib pneumonia (WHO 2005). In both low-income and high-income countries, Hib causes more than 80% of bacterial meningitis cases, especially in children aged between two to five years. A review of 127 studies with information on case fatality rates found that the mean case fatality rate for children with Hib meningitis was 13.8% with a range of 0% to 65% (WHO 2002).

The epidemiology of Hib disease is thought to be changing (Peltola 1992; Peltola 2000). Large population studies have shown a dramatic decline in the incidence of Hib disease in children under five years of age, along with a reduction in the prevalence of oro-pharyngeal Hib colonisation among both vaccinated children and unvaccinated children and adults (Adderson 2001; McConnell 2007; Peltola 2000). However, following an initial decline there has been an increase in both Hib and non type b H. influenzae disease (Ladhani 2011; von Gottberg 2012).

Description of the intervention

Several Hib conjugate vaccines have been developed. Initial vaccines developed in the early 1970s, consisting of type b capsular polysaccharide, polyribosylribitol phosphate (PRP), were found to be ineffective in infants due to poor generation of immune memory. Immunogenicity was improved by conjugating the capsular polysaccharides with protein carriers (Morris 2008). Four such vaccines, conjugated with different carrier proteins, were initially licensed for use in infants (PRP-T, Hb-OC, PRP-OMP and PRP-D: see Table 1) (Heath 1998; Morris 2008).

Table 1. Haemophilus influenzae type b conjugate vaccines
AbbreviationCarrier proteinTrade name
PRP-TTetanus toxoidActHIB
Hb-OCCRM197 (non-toxic mutant diphtheria toxin)HIBTITER
PRP-OMPOuter membrane protein of N. meningitidisPedvax
PRP-DDiphtheria toxoidProhibit
  1. Hb-OC or H. influenzae type b conjugated to oligosaccharide-mutant diphtheria toxin is currently not available.

  2. PRP-T or polyribosylribitol phosphate-tetanus vaccine conjugates PRP to tetanus toxoid. There are several brands of PRP-T conjugate vaccines in use either alone or in varying combinations with diphtheria, tetanus, pertussis, hepatitis B, the inactivated poliovirus (IPV) vaccine or whole-cell pertussis vaccine (DTP).

  3. PRP-OMP - polyribosylribitol phosphate-outer membrane protein conjugate vaccine conjugates PRP to protein components of outer membrane vesicles of a strain of serogroup B Neisseria meningitidis (N. meningitidis) to improve immunogenicity. It has a higher immunogenicity compared with PRP-T and is used mostly in high-risk children.

  4. PRP-D is no longer used in young infants because of its poor immunogenicity.

Each dose of Hib conjugate vaccine consists of 0.5 mL administered intramuscularly and can be given as two to three injections in varying schedules with or without a booster dose.

How the intervention might work

Humans are the only known reservoir of Hib. Vaccines prevent H. influenzae type b (Hib) infection in children by inducing B-cell humoral immunity, through which the body produces antibodies against the disease. Vaccinating children with Hib conjugate vaccine confers immunity to these children by directly decreasing nasopharyngeal carriage. This direct effect results in a reduction in the number of nasopharyngeal carriers in the population, thereby reducing the pool of infectious children in the community. Thus unvaccinated children are less likely to be exposed to the organism in highly vaccinated communities. This low burden of carriage in highly vaccinated communities protects not only the children being immunised but also the unvaccinated, a mechanism referred to as indirect or herd protection (Blanchard-Rohner 2008).

Why it is important to do this review

Since the introduction of conjugate Hib vaccines into routine immunisation schedules in high-income countries, there has been a rapid decline in disease occurrence. However, many low-income countries have not introduced Hib vaccine into their routine immunisation programmes due to cost constraints, lack of information on burden of disease and how best to provide the vaccine cost-effectively (Mahoney 1999). The size of the effect of Hib vaccine is important in determining its cost-effectiveness in low-income countries, particularly in competition with other priorities. A previous Cochrane Review, last updated in February 2007, suggested an 80% reduction in invasive Hib disease as a result of vaccination (Swingler 2007). The relative risk for invasive Hib disease was 0.20 (95% confidence interval (CI) 0.07 to 0.54). No significant differences were seen in terms of the number of doses, type of vaccines, age at first vaccination or use in high-income versus low-income countries. No statistically significant effect was found on Hib-related mortality. Insufficient evidence of an effect on all-cause mortality was found. Since then, further randomised controlled trials (RCTs) have been conducted that will contribute additional data to the current review. Also there have been certain changes in the methodology for assessment of risk of bias and inclusion of quasi-randomised trials in the pooled analysis (Higgins 2011b). The previous review included a quasi-randomised trial in their pooled analysis. We will include quasi-randomised trials in this review but their results will be reported separately from randomised trials. We intend to conduct this review to incorporate all previous and new evidence available to determine the size of effect of the vaccine.

One of the secondary objectives of the previous review was to look at the variation in vaccine effectiveness with known HIV infection. However the authors were unable to retrieve any data regarding this. There are an estimated 3.3 million HIV-infected children under 15 years of age and an additional 300,000 children newly infected with HIV each year, mostly in low-income countries (UNAIDS 2012). HIV-infected children are also at a significantly higher risk for invasive Hib disease than uninfected children. Immunisation is an important approach to reducing the risk of infections (including Hib) in HIV-infected children (Mangtani 2010).

Objectives

  1. To determine the effects of conjugate Hib vaccine in preventing Hib disease or death in children under five years of age.

  2. To determine any variation in vaccine effectiveness with type of vaccine; number of doses; age at first dose; known HIV infection; or in high-income and low-income countries.

  3. To determine any clinically relevant mild, moderate or serious adverse outcomes.

  4. To identify costs associated with the vaccination, adverse events and illnesses in vaccinated and unvaccinated children.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs or quasi-RCTs in which children were followed up until at least two years of age.

Types of participants

Children younger than five years old, irrespective of HIV status.

Types of interventions

Conjugate H. influenzae type b vaccines, compared with placebo or no treatment.

Types of outcome measures

Primary outcomes
  1. All definitive Hib disease (clinical and bacteriological or serological confirmation).

  2. Hib-specific mortality.

Secondary outcomes
  1. All invasive H. influenzae diseases, for example, meningitis, pneumonia, bacteraemia, cellulitis, epiglottitis and arthritis.

  2. Overall mortality as well as cause-specific mortality from meningitis and pneumonia.

  3. All reported adverse events resulting from Hib vaccination, including but not limited to common but mild adverse events like fever, injection site swelling etc. as well as moderate to severe adverse events.

  4. Costs associated with vaccination, with the incidence of disease among vaccinated/unvaccinated and harms resulting from the vaccine

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL, latest issue) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (January 1966 to present date), EMBASE (1990 to present date), CINAHL (1981 to present date), Current Contents (1998 to present date), Science Citation Index (1985 to present date), IMSEAR (to present date) and LILACS (1982 to present date).

We will use the following search strategy to search CENTRAL and MEDLINE. We will combine the MEDLINE search with the Cochrane highly sensitive search strategy for RCTs (Lefebvre 2011). We will adapt this search strategy to search the other databases.

MEDLINE (Ovid)

1 Haemophilus influenzae type b/
2 Haemophilus influenzae/
3 (haemophilus influenzae or hemophilus influenzae).tw.
4 "h. influenzae".tw.
5 Hib.tw.
6 or/1-5
7 Vaccines, Conjugate/
8 conjugat*.tw.
9 (immuni* or vaccin* or inoculat*).tw.
10 or/7-9
11 6 and 10
12 Haemophilus Vaccines/
13 ((haemophilus or hemophilus or hib) adj5 (vaccin* or conjugat*)).tw.
14 (prp-t or hb-oc or prp-omp or acthib or hibtiter or pedvax).tw,nm.
15 or/11-14

Searching other resources

We will search the WHO ICTRP and clinicaltrials.gov trials registers.

We will also scan reference lists of identified articles and contact trial authors in an attempt to locate additional published and unpublished trials. We will not impose any language or publication restrictions.

Data collection and analysis

Selection of studies

Three review authors (MN, FJ, YS) will independently screen each reference identified by the searches to decide if they meet the inclusion criteria. We will resolve disagreements through discussion.

Data extraction and management

Two review authors (MN, FJ) will independently extract data by using a standardised data extraction form which will be piloted prior to data extraction. We will resolve all disagreements by discussion. We will extract the following data from each study: type of conjugate vaccine (PRP-D, HbOC, PRP-OMP, PRP-T), the nature of the control, number of vaccine doses, target age at first vaccination, HIV status, country in which the trial was conducted, data on pre-specified outcomes listed above and serious adverse effects. We will attempt to contact the trial authors if required information is missing.

Assessment of risk of bias in included studies

Two review authors (MN, FJ) will independently assess the quality of each trial. We will use the domain-based evaluation approach as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will compare the assessments and any discrepancies between the two review authors. We will assess the following domains as low risk of bias, unclear risk of bias or high risk of bias. We will use the following definitions to assess trial quality.

Randomisation/generation of the allocation sequence
  1. Low risk of bias: if the allocation sequence was generated by a computer or random number table. Drawing of lots, tossing of a coin, shuffling of cards or throwing dice will be considered as adequate if a person who was not otherwise involved in the recruitment of participants performed the procedure.

  2. Unclear risk of bias: if the trial was described as randomised, but the method used for the allocation sequence generation was not described.

  3. High risk of bias: if a system involving dates, names or admittance numbers was used for the allocation of patients. These studies are known as quasi-randomised and their results will be reported separately from randomised trials.

Allocation concealment
  1. Low risk of bias: if the allocation of patients involved a central independent unit, on-site locked computer, identically numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed envelopes.

  2. Unclear risk of bias: if the trial was described as randomised, but the method used to conceal the allocation was not described.

  3. High risk of bias: if the allocation sequence was known to the investigators who assigned participants.

Blinding of participants and personnel

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess the methods as:

  1. low, high or unclear risk of bias for participants;

  2. low, high or unclear risk of bias for personnel.

Blinding of outcome assessment

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes. We will assess methods used to blind outcome assessment as low, high or unclear risk of bias.

Incomplete outcome data
  1. Low risk of bias: the numbers and reasons for dropouts and withdrawals in all intervention groups were described or if it was specified that there were no dropouts or withdrawals.

  2. Unclear risk of bias: the report gave the impression that there had been no dropouts or withdrawals, but this was not specifically stated.

  3. High risk of bias: the number or reasons for dropouts and withdrawals were not described.

We will further examine the percentages of dropouts overall in each trial and per randomisation arm and we will evaluate whether intention-to-treat (ITT) analysis has been performed or could be performed from the published information.

Selective outcome reporting
  1. Low risk of bias: pre-defined or clinically relevant and reasonably expected outcomes are reported on.

  2. Unclear risk of bias: not all pre-defined or clinically relevant and reasonably expected outcomes are reported on or are not reported fully, or it is unclear whether data on these outcomes were recorded or not.

  3. High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; although data on these outcomes were likely to have been measured.

Free of other bias
  1. Low risk of bias: the trial appears to be free of other components that could put it at risk of bias.

  2. Unclear risk of bias: the trial may or may not be free of other components that could put it at risk of bias

  3. High risk of bias: there are other factors in the trial that could put it at risk of bias, for example, no sample size calculation made, early stopping, industry involvement, research funded by vaccine manufacturers or an extreme baseline imbalance.

We will consider trials that achieve a 'yes' for generation of allocation sequence, adequate allocation concealment, adequate blinding, adequate handling of incomplete outcome data, no selective outcome reporting, and that are without other bias risks, as low risk of bias. Trials assessed as moderate risk of bias will be between the low risk and high risk trials. Trials at high risk of bias are either 'No' or 'Unclear' in the majority of domains.

Measures of treatment effect

We will use risk ratio (RR) to measure treatment effect. To aid interpretation, we will also compute absolute risk reduction (ARR) and the number needed to treat for an additional beneficial outcome (NNTB) from the results of the meta-analysis of RRs.

Unit of analysis issues

We will use the individual participants as the unit of analysis. For cluster-RCTs, the number of clusters will be the unit of analysis.

Dealing with missing data

We will attempt to contact the trial authors for missing information.

Assessment of heterogeneity

We will perform a quantitative analysis using the intention-to-treat (ITT) principle. We will use the Chi2 test to assess the likelihood of heterogeneity (significance set at P < 0.10). We will perform a meta-analysis using a random-effects model, with a sensitivity analysis using the fixed-effect model. We will calculate risk ratio (RR) with 95% confidence intervals (CIs).

Assessment of reporting biases

We will quantify statistical heterogeneity using the I2 statistic, which describes the percentage of total variation across trials that is due to heterogeneity rather than sampling error. We will consider there to be significant statistical heterogeneity if the I2 statistic is greater than 50% (Deeks 2011).

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2011). We will use fixed-effect inverse variance meta-analysis for combining data where trials are examining the same intervention and the trials’ populations and methods are judged sufficiently similar. Where we suspect clinical or methodological heterogeneity between studies sufficient to suggest that treatment effects may differ between trials, we will use random-effects meta-analysis. If substantial heterogeneity is identified in a fixed-effect meta-analysis we will note this and repeat the analysis using a random-effects model.

Subgroup analysis and investigation of heterogeneity

We will conduct subgroup analyses to compare the effectiveness according to the type of vaccine used, the number of doses given, age at first vaccination, children with known HIV infection status and high-income versus low-income countries. In an attempt to assess the impact of herd immunity, we will conduct a further subgroup analysis comparing vaccine effectiveness in trials of individually randomised children with that in cluster-randomised trials.

Sensitivity analysis

If sufficient trials are identified, we plan to conduct a sensitivity analysis comparing the results of all trials. We will classify studies as having a 'low risk of bias' versus those identified as having a 'high risk of bias' (Deeks 2011). We will also evaluate the risk of attrition bias, as estimated by the percentage of participants lost. We will exclude from the meta-analysis, but include in the review, trials with a total attrition of more than 20% or where differences between the groups exceed 10%, or both.

Acknowledgements

We would like to acknowledge George H Swingler, Desiree Michaels and Gregory GD Hussey who authored a previous version of the review. We also thank the following people for commenting on this draft protocol: Theresa Wrangham, Sallie Bernard, Mahomed Patel, Ray Borrow, Sree Nair and Michelle Guppy.

Contributions of authors

Zohra S Lassi (ZL) and Anita KM Zaidi (AZ) provided methodological support.
Muhammad I Nisar (MN), Fyezah Jehan (FJ) and Yasir Shafiq (YS) wrote the final protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • Aga Khan University, Karachi, Pakistan.

External sources

  • No sources of support supplied

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