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).
|Abbreviation||Carrier protein||Trade name|
|Hb-OC||CRM197 (non-toxic mutant diphtheria toxin)||HIBTITER|
|PRP-OMP||Outer membrane protein of N. meningitidis||Pedvax|
Hb-OC or H. influenzae type b conjugated to oligosaccharide-mutant diphtheria toxin is currently not available.
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).
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.
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).