Description of the condition

Sickle cell disease (SCD) is a group of genetic haemoglobin disorders, caused by the inheritance of a sickle ß globin gene (HbS) from one parent and of another altered ß globin gene (HbS, HbC, ß‐thalassaemia) from the second parent. This includes the homozygous state (SS) as well as compound heterozygous states such as SC, S/ß0thal, S/ß+thal and SD. Sickle cell trait is defined by inheritance of a single sickle ß globin gene and confers some type of protection against falciparum malaria. Therefore, SCD is particularly frequent among people originating from the highly malarious regions, especially Sub‐Saharan Africa (where 85% of all SCD occurs) (Modell 2008), India, the Middle East and the Mediterranean. Due to human migration, the sickle ß globin gene has been spread widely throughout the world (Davies 1997) with over 300,000 homozygous (SS) neonates per year (Piel 2013), making SCD a global public health issue recognised by the United Nations (UN) and the World Health Organization (WHO). Furthermore, SCD is associated with chronic hemolysis, resistance to nitric oxide (NO) bioactivity, small vessel obstruction, ischemia‐reperfusion injury and increased susceptibility to infections (Overturf 1999).

In low‐income countries, SCD is associated with a very high early‐life mortality rate, especially in Africa (Rahimy 2003), where it contributes to 5% of deaths in children under five years of age (WHO 2006a). Invasive bacterial infections are responsible for a substantial percentage of the high mortality rate and it is estimated that half of the patients in Sub‐Saharan Africa die of infection before the age of five years (Fleming 1989). In high‐income countries, such as the USA, before implementation of early screening and prevention programs (prophylactic penicillin, immunization), bacterial infections were also a major cause of mortality and morbidity in SCD, particularly in early childhood (Gill 1995).

Children affected with SCD are at high risk of infection from encapsulated bacteria, especially Streptococcus pneumoniae and Haemophilus influenzae (Powars 1983; Ward 1976). The main reason for this predisposition is that they develop asplenia or hyposplenia as early as three months of age with a loss of splenic function beginning before 12 months of age in more than 80% of patients (Rogers 2011). Thus, by two years of age, half of the children affected with SCD have functional asplenia (Pearson 1985). The other immunopathologic mechanisms contributing to an increased vulnerability to encapsulated bacteria are dysfunctional IgG and IgM antibody responses, defects in alternative pathway fixation of complement and defective opsonisation (Overturf 1999).

A study performed before systematic implementation of conjugate Haemophilus influenzae type b (Hib) vaccination showed that 90% of all hospitalisations for Haemophilus influenzae infections were due to Hib (Asensi 1995). This bacterial infection is an important cause of meningitis, septicaemia, pneumonia, and other invasive diseases, such as epiglottitis, cellulitis, arthritis, osteomyelitis, and pericarditis. It has been estimated to have caused in the pre‐vaccination era two to three millions cases of serious disease and more than half a million deaths annually worldwide (Peltola 2000).

Historically, Hib was responsible for a high mortality rate in children with SCD under five years of age (Zarkowsky 1986) and it has been shown in the early 1980s in the USA that there was a four‐fold increased risk of Haemophilus influenzae septicaemia in children affected with SCD under nine years of age (Powars 1983) with a mortality of two out of eight patients suffering from Hib bacteraemia in a study following 694 children enrolled at less than six months of age over a 10‐year period (Gill 1995). Since the introduction of the conjugate Hib vaccination, a dramatic decrease in the incidence of invasive Hib infections has been observed in the USA with no cases of Haemophilus influenzae bacteraemia in a retrospective study reviewing the medical records of 815 children with SCD followed at the Children's Hospital of Philadelphia from 2000 to 2010 (Ellison 2013). However, this evolution has not been observed on the African continent, where Hib remains one of the most common organisms, accounting for 12% to 19% of bacteraemias in children affected with SCD (Kizito 2007; Williams 2009). This may be due to an extremely low coverage for Hib vaccination, which remains below 10% of the children affected with SCD in many different African countries (Nacoulma 2006).

Description of the intervention

Since the 1970s, Hib vaccinations have been used to protect children and adults affected with SCD (Pearson 1977); Hib polysaccharide vaccines, consisting of the type b capsular polysaccharide, polyribosylribitol phosphate (PRP), were first available but had a weak immunogenicity when administered under two years of age (Rubin 1989). This was probably because bacterial polysaccharides do not generate memory responses in B cells. Yet, children younger than two years have the highest risk of fulminant infections related to encapsulated bacteria. Since the 1990s, Hib conjugate vaccines have been available; these were created by covalently attaching the PRP to a protein carrier, resulting in a T‐cell‐dependant immune response with the production of high‐affinity antibodies and the formation of memory B cells. Therefore, Hib conjugate vaccines have a much better immunogenicity than Hib polysaccharide vaccines (Frank 1988) and are considered as safe and highly immunogenic in children with SCD (de Montalembert 1993; Goldblatt 1996; Rubin 1992). They are routinely administered to all infants living in high‐income countries with catch–up vaccination until five years of age and the WHO recommends that they should be included in all routine infant immunization programs all over the world. However, immunization against Hib has reached only a fraction of the children living in low‐income countries (WHO 2006b) and therefore the burden of Hib disease is much more significant in those countries, especially in Africa (Watt 2009). Four different Hib conjugate vaccines have been licensed, differing by the type of protein carrier (tetanus toxoid for PRP‐T which is the most widely used, non‐toxic mutant diphtheria toxin for HbOC, outer membrane protein of Neisseria meningitidis for PRP‐OMP and diphtheria toxoid for PRP‐D which is no longer used in young infants because of its poor immunogenicity). They can be administered separately or combined with other vaccines. Different immunization schedules exist depending on the countries. The schedule recommended in all countries by the WHO consists in a three‐dose primary series, including a first dose which may be given to infants as young as six weeks of age, and a second and third doses at four‐ to eight‐week intervals along with diptheria‐tetanus‐pertussis (DTP). If given, the booster dose should be administered between 12 months and 18 months of age (WHO 2006b). In the USA, the schedule recommended by the Advisory Commitee on Immunization Practices (ACIP 2013) includes a primary series at two, four and six months of age (the dose at age six months being not indicated if PRP‐OMP is used at two and four months of age), a booster dose at age 12 months to 15 months and an additional dose for unvaccinated or partially vaccinated persons aged five years or older who have a high‐risk condition, including SCD.

How the intervention might work

A Cochrane Review has shown that Hib conjugate vaccines were safe and effective in preventing Hib diseases in children under five years of age (Swingler 2009). Immunization with Hib conjugate vaccines is considered to have largely controlled infections caused by this pathogen in SCD children living in high‐income countries (Ellison 2013; Overturf 1999).

Why it is important to do this review

The Cochrane Review on conjugate vaccines for preventing Hib infections in children aged less than five years did not undertake a specific analysis of a subgroup of children affected with SCD (Swingler 2009). Considering that the risk of Hib related‐overwhelming infections is extremely high in children affected with SCD, it justifies a specific review of this highly exposed population.

In unvaccinated, or partially vaccinated, paediatric patients aged five years or older who have high risk conditions, including SCD, it is recommended to administer one dose of Hib vaccine (ACIP 2013). However, there is no published systematic review on Hib vaccines in adult patients and therefore, in some clinical guidelines, administration of a single dose of Hib vaccine in unvaccinated adult patients with SCD is recommended (ACIP 2013; Sickle Cell Society 2008), while it is not mentioned in others (NIH 2002).

This review is motivated by the fact that there is no published systematic review on Hib vaccines in paediatric or adult patients with SCD and yet the benefit‐risk ratio could be very different in this population. The availability of such a review could help produce evidence‐based recommendations, especially in African countries, where the introduction of conjugate vaccines against Hib into the childhood immunisation schedules could substantially affect the survival of children with SCD.