Combined DTP‐HBV‐HIB vaccine versus separately administered DTP‐HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB)
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The purpose of the review is to assess the effectiveness of a combined DTP, HBV and conjugate HIB vaccine, in comparison with separate vaccinations of DTP, HBV and conjugate HIB, in infants aged up to two years.
Background
Description of the intervention
Childhood vaccinations provide a clinically effective and cost‐effective method of protecting against many diseases. Combination vaccines have been in widespread use since the 1940s. Diphtheria, tetanus and pertussis (DTP) is one such vaccine and it is estimated that the DTP infant vaccine coverage exceeds 80% worldwide (Faingezicht 2002).
There are many advantages to combining vaccines: reduced patient discomfort by sparing them from multiple injections, reduced costs, increased compliance and hence overall effectiveness of vaccination programs. The World Health Organization (WHO) recommends that routine infant immunization programs include a vaccination against Haemophilus influenzae (H. influenzae) type B (HIB), in the combined DTP‐HBV vaccination (WHO 1998).
Why it is important to do this review
The strategy of combining hepatitis B vaccination (HBV) with DTP vaccine has already been adopted into immunization programs (Riedemann 2002). The effectiveness of adding a conjugate HIB vaccination to the DTP‐HBV vaccine, compared with separate administration, for preventing these diseases has yet to be assessed. Despite its use in accordance with the WHO recommendation in several countries, no systematic reviews of the effectiveness and safety of the combined vaccine are available.
Objectives
The purpose of the review is to assess the effectiveness of a combined DTP, HBV and conjugate HIB vaccine, in comparison with separate vaccinations of DTP, HBV and conjugate HIB, in infants aged up to two years.
Methods
Criteria for considering studies for this review
Types of studies
Randomized or quasi‐randomized clinical trials addressing the effectiveness of combined DTP‐HBV‐HIB vaccine administered as a single injection versus separate administration of DTP‐HBV and HIB vaccines administered to infants up to two years of age.
Types of participants
Healthy male and female infants aged up to two years at the time the intervention was administered.
Types of interventions
Vaccination with any combined DTP‐HBV‐conjugate HIB vaccine given independently in any dose, preparation or time schedule, compared with separate vaccines or placebo, administered to infants aged up to two years. All studies identified testing the effectiveness of combined DTP‐HBV‐conjugate HIB vaccine.
Types of outcome measures
Primary outcomes
Incidence of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae type B.
Secondary outcomes
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Immunogenicity defined as antibody responses to tetanus, diphtheria, pertussis, hepatitis B and Haemophilus influenzae type B.
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Systemic and local adverse events: including fever, pain, redness, swelling, irritability, drowsiness, loss of appetite, vomiting and more generalized and severe signs (including potential adverse events which have been hypothesized).
Search methods for identification of studies
Electronic searches
We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library latest issue) which contains the Cochrane Acute Respiratory Infections (ARI) Group Specialized Register; MEDLINE (1966 to present); and EMBASE (1990 to present) using the Cochrane highly sensitive search strategy, parts one and two (Clarke 2003).
We will conduct a comprehensive search in an attempt to identify all relevant studies, regardless of language or publication status, using the following search terms.
1. ((diphtheria and tetanus and pertussis) OR (diphtheria tetanus pertussis or DTP) OR ((diphtheria toxoid and tetanus toxoid and whole cell pertussis) OR DTPw OR (diphtheria tetanus acellular pertussis) OR (DTPa adj10 vaccin$)))
2. exp Haemophilus influenzae type b/ OR exp Haemophilus/ OR exp Hemophilus/ OR (haemophilus or hemophilus) OR Hib
3. exp Hepatitis B/ OR (hepatitis b or HBV)
4. 1 AND 2 AND 3
5. exp Diphtheria‐Tetanus‐Pertussis Vaccine/ And exp Haemophilus Vaccines/ AND exp Hepatitis B Vaccines/
6. 4 OR 5
We will limit the search strategy to randomized controlled trials in all databases except CENTRAL by using the search strategy suggested in the Cochrane Reviewers' Handbook (Alderson 2003): (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double‐blind method [mh] OR single‐blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp]) NOT (animals [mh] NOT human [mh]).
Searching other resources
The bibliographies of all included studies and pertinent reviews will be scanned for additional references. In cases of missing data or need for clarification, trial authors will be contacted. We will contact vaccine manufacturers for unpublished data. We will search the following conference proceedings for unpublished trials: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) 1995 to 2004; European Congress of Clinical Microbiology and Infectious Diseases 2001 to 2004 (available at http://www.akm.ch/eccmid2001‐2004/); Annual Meeting of the Infectious Diseases Society of America (IDSA) 2001 to 2004 (available at http://www.idsociety.org/).
Data collection and analysis
Selection of studies
Two review authors will independently inspect each reference identified by the search and apply the inclusion criteria. The reasons for excluding studies will be clearly reported. For possible relevant articles, or in cases of disagreement between the two review authors, the full article will be obtained and inspected independently by the two review authors. A third independent review author will be consulted in cases of continued disagreement. Two independent review authors will extract data. In cases of disagreement a third review author will be consulted.
Assessment of risk of bias in included studies
Two review authors will independently perform the quality assessment of each study. We will use an individual component approach to quality assessment (Chalmers 1990) with the following variables: generation of the allocation sequence, allocation concealment, blinding and intention‐to‐treat analysis. Allocation, concealment and generation will be graded as adequate (A), unclear (B), inadequate (C), or not used (D), using the criteria suggested in the Cochrane Reviewers' Handbook. Assessment of bias will be performed through sensitivity analyses for allocation concealment, based on previous evidence showing over‐estimation of effects with inadequate allocation concealment (Schulz 1955). Studies with a dropout rate above 30% will be excluded unless an intention‐to‐treat analysis is possible for any outcome.
Unit of analysis issues
Dichotomous data will be analyzed by calculating the relative risk (RR) for each trial with the uncertainty in each result expressed using 95% confidence intervals (CI). Heterogeneity in the results of the trials will be initially assessed by inspection of graphical presentations and by calculating an estimate of heterogeneity (chi square, I2 statistic). A random‐effects model will be used throughout the review. Data will be pooled stratifying for number of doses received. Sensitivity analysis will be performed in order to assess the impact of possible sources of heterogeneity on the main results. A funnel plot estimating the precision of trials (the inverse of the standard error plotted against relative risk) will be examined in order to estimate potential selection bias (publication or other). Asymmetry of the funnel plot will be formally expressed using the method described by Egger (Egger 1997).
