Hepatitis B Vaccination in Infants
Condition: Meningococcal Disease; Pneumococcal Disease; Haemophilus Influenzae Serotype b Disease; Diphtheria, Tetanus and Pertussis; Hepatitis b
MeSH terms: Hepatitis B; Diphtheria; Meningococcal Infections; Pneumococcal Infections; Hepatitis
Study type: Interventional
Phase: Phase 4

Summary: 
      In the UK, infants currently receive a 5-in-1 vaccine (Pediacel) at 2, 3 and 4 months of age,
      which protects against diphtheria, tetanus, pertussis (whooping cough), polio and Haemophilus
      influenzae type b (Hib). Infants also routinely receive a meningococcal group C vaccine
      (MenC) at 3 and 4 months and a 13-valent pneumococcal vaccine (Prevenar13) at 2 and 4 months
      of age. This study aims to offer infants a 6-in-1 vaccine (Infanrix-Hexa)that also helps
      protect against hepatitis B alongside the other routine vaccinations in the UK infant
      immunisation schedule and assess their immune responses to the different vaccines. Hepatitis
      B virus infects the liver and usually affects adults, but children can be infected through
      close contact with carriers of the virus. Children with hepatitis B infection may not have
      symptoms for many years but may go on to develop liver failure, cirrhosis and cancer. Many
      other countries already use Infanrix-Hexa and this study is being undertaken to help decide
      whether the UK can do the same. Babies taking part in this study will receive Infanrix-Hexa
      instead of Pediacel. All other vaccines given will be the same as in the routine schedule but
      will include one MenC vaccine instead of 2 doses because the UK infant immunisation schedule
      is soon going to change so that all babies will receive only one MenC vaccine at 3 months of
      age.

      There are currently several licensed MenC vaccines that can be given to babies. In order to
      check whether there are differences in protection, babies taking part will randomly receive
      one of 3 MenC-containing vaccines: NeisVacC, Menjugate or Menitorix. Studies have already
      shown that one dose of Neis-Vac or Menjugate given to babies at 3 months provides similar
      protection against MenC infection as two doses given at 3 and 4 months. Menitorix protects
      against both Hib and MenC, so babies in the group receiving MenitorixTM will have an extra
      dose of Hib which is also included in Infanrix-Hexa but might have a lower antibody response
      to MenC compared to the other two MenC vaccines, although all infants should be
      well-protected after their 12-month booster vaccinations, which also contain Menitorix.
    

Detailed description: 
      Infants in the United Kingdom are routinely immunised against diphtheria, tetanus, pertussis
      (whooping cough), polio and Haemophilus influenzae type b (Hib) as a single 5-in-1
      (DTaP5-IPV-Hib) combination vaccine given as a 2-3-4 month schedule. They also receive
      vaccines against Neisseria meningitidis serogroup C (MenC) at 3 months and against 13
      pneumococcal serotypes (PCV13) at 2-4 months. From 01 July 2013, infants will also receive an
      oral rotavirus vaccine at 2 and 3 months of age. Combination vaccines reduce the number of
      injections administered to infants and, therefore, minimise the number of visits to general
      practitioners while, at the same time, improving compliance, parental satisfaction and the
      cost-effectiveness of vaccination programmes.

      The development and manufacture of combination vaccines, however, is complex because of
      possible interactions between different antigens, carrier proteins and adjuvants used in such
      vaccines. Administration of Hib conjugate vaccine as part of a diphtheria-tetanus-pertussis
      (DTP-Hib) combination results in much lower Hib antibody concentrations compared to the Hib
      conjugate vaccine administered separately (Eskola et al., 1996; Schmitt et al., 1998; Schmitt
      et al., 2000). Similarly, the immunogenicity of the Hib component of combination vaccines
      containing acellular pertussis (DTaP-Hib) is significantly lower when compared to those
      containing whole cell pertussis (DTwP-Hib) (Bar-On et al., 2009).

      Interactions can also occur between vaccines that are given during the same visit (Dagan et
      al., 2008, Borrow et al, 2011). Vaccines that use a diphtheria mutant toxin (CRM197) as their
      primary carrier protein, for example, have been shown to interfere with the immune response
      to the Hib component of combination vaccines in a dose-dependent manner, even when the
      vaccines are administered on different limbs.

      On the other hand, MenC vaccines that use tetanus as their carrier protein (e.g. NeisVac-C™)
      may enhance immune responses to the Hib component of combination vaccines. In the UK, the
      current acellular-pertussis-containing 5-in-1 combination vaccine (DTaP5/Hib/IPV; Pediacel™)
      has been extremely effective at maintaining control of the diseases it is aiming to prevent.
      In particular, control of invasive Hib disease is now the best that has been achieved since
      the introduction of routine Hib vaccination almost 20 years ago (HPR, 2011).

      IMMUNISATION AGAINST HEPATITIS B Hepatitis B virus (HBV) infection is a major global problem.
      HBV is highly infectious and is transmitted mainly through sexual intercourse, perinatal
      transmission during childbirth, injecting drug use and blood-to-blood contact (National
      disease surveillance centre, 1988). HBV can cause acute or chronic infection. Most of the
      burden of HBV infection is due to chronic infection, which may be asymptomatic for many years
      but is associated with an increased long-term risk of cirrhosis and hepatocellular carcinoma
      (Beasley, 1988).

      The risk of chronic HBV infection is inversely related to age, with up to 90% of those
      infected in childhood developing chronic infection compared with <10% among those infected as
      adults (Edmunds et al., 1993; Kane, 1995; McMahon et al., 1985; Medley et al., 2001). Because
      of the high global burden and chronic nature of the disease, the WHO has recommended that all
      countries should include hepatitis B vaccine in national immunisation programmes (World
      Health Organization, 1992). By 2008, 177 countries had introduced routine neonatal, infant
      and/or adolescent vaccination into their national immunisation programme (World Health
      Organization, 2009).

      The UK, however, adopted a selective HBV immunisation strategy targeting infants born to
      carrier mothers & close family members, individuals who change sexual partners frequently,
      injecting drug users, prisoners, individuals with frequent exposure to blood (including
      healthcare workers) and certain high-risk patient groups (Department of Health, 2006). The
      most recent data based national epidemiology and laboratory surveillance of acute HBV
      infections suggest that the risk of acquiring the infection within the UK is low, with only
      512 acute or probable acute cases reported in 2010 in England (rate 0.99 per 100,000
      population), mainly in adults (Health Protection Agency, 2011).

      A recent cost-effectiveness analysis estimated that the introduction of a HBV vaccine into
      the UK infant immunisation programme could prevent 81% of HBV-associated morbidity and
      mortality but at a cost of £260,000 per QALY gained (Siddiqui et al., 2010). An adolescent
      vaccination programme was less effective, with only 45% morbidity prevented at a cost of
      £493,000 per QALY gained (Siddiqui et al., 2010). For the UK, the threshold cost per
      vaccinated child at which a universal infant vaccination programme would be considered
      cost-effective was less than £4.09, indicating clearly that a HBV vaccine could only
      realistically be considered cost-effective in the UK immunisation programme as part of a
      combination vaccine (Siddiqui et al., 2010).

      There are concerns, however, that the only two Hepatitis B-containing combination vaccines -
      DTaP/Hib/IPV/HepB (Infanrix- Hexa™, GSK Biologicals, Rixensart, Belgium) and DTa3P-HBV-IPV
      (Infanrix-Penta, GSK Biologicals, Rixensart, Belgium) - currently licensed in the UK produce
      lower Hib antibody levels compared to Pediacel™ which could result in another Hib resurgence
      as observed in the UK a decade ago (see below).

      THE INFANRIX-HIB™ VACCINE In the UK, from late 1999 to mid-2002, around 50% of infants
      received a previously licensed DTa3P-Hib (Infanrix-Hib™, GSK Biologicals, Rixensart, Belgium)
      combination vaccine containing a three-component acellular pertussis vaccine (a3P) to
      supplement a shortage of DTwP-Hib supply. This vaccine was known to produce lower Hib
      antibody concentrations in comparison to DTwP-Hib vaccines, although this difference was not
      considered to be clinically significant (Goldblatt et al., 1999; Eskola et al., 1999). In
      2000, however, the number of invasive Hib cases in the UK increased, particularly among
      previously vaccinated toddlers (McVernon et al., 2003). Possible reasons for the resurgence
      include a greater than expected decline in protective Hib antibody concentrations after
      primary infant immunisation without a booster in the second year of life and waning of herd
      protection offered by the initial catch-up campaign (Ladhani et al., 2008). However,
      temporary use of the less immunogenic Infanrix-Hib™ vaccine also contributed to the observed
      increase in cases. A UK case-control study comparing vaccine failure cases from this period
      with healthy children born on the same day found that receipt of each dose of Infanrix-Hib™
      compared to DTwP-Hib in the infant primary schedule resulted in an increasing risk of vaccine
      failure resulting in invasive Hib disease (trend per dose: 1.87; 95% CI, 1.46- 2.40; P<0.001)
      (McVernon et al., 2003). This observation was subsequently confirmed in other studies
      (Johnson et al., 2006; McVernon et al., 2008).

      The response to the increase in Hib cases included suspending the use of Infanrix-Hib™ in
      favour of DTwP-Hib and, in 2003, implementation of a Hib booster campaign for children aged
      >6 months and <4 years, the cohort that would have received Infanrix-Hib™ in infancy (Ladhani
      et al., 2008). In September 2004, the combination vaccine used for routine infant
      immunisation was changed to DT-aP5/Hib/IPV (Pediacel™), which includes five acellular
      pertussis antigens (aP5), after head-to-head comparison with DTwP-Hib administered at the
      2-3-4 month UK schedule showed only marginally lower Hib antibody concentrations with
      Pediacel™ (Kitchin et al., 2007). Moreover, from September 2006, a routine Hib booster dose
      (given as combined Hib-MenC, Menitorix™, GSK Biologicals, Rixensart, Belgium) was added to
      the childhood immunisation programme at 12 months of age. Since 2007, Hib cases started to
      decline again. In 2010, there were only 30 cases of invasive Hib disease, with only 6 cases
      in children aged < 5 years and there have been no Hib-related deaths in this age group since
      2007 (HPR, 2011).

      NEWER INFANRIX™ VACCINES Although Infanrix-Hib™ is no longer available, the currently
      licensed Infanrix-Penta™ and Infanrix-Hexa™ share the same antigens. Therefore, there are
      reasonable concerns that re-introduction of an Infanrix™-based combination vaccine might
      adversely impact on the current excellent control of invasive Hib disease in the UK. There
      are, however, indirect data from some, as yet, unpublished studies conducted in other
      European countries at 3-4-5 and 3-5 month immunisation schedules that suggest that the
      inclusion of IPV into Infanrix-Hib® improves the immunogenicity of the Hib component, while
      the addition of HepB does not appear to have any significant impact on Hib immunogenicity
      (Dagan et al., 2008). On the other hand, immunogenicity data for Infanrix™-based Hib
      combination vaccines have been consistently lower in UK studies compared to those in other
      countries. It is likely that multiple factors, including the accelerated infant schedule (at
      2-3-4 months) and the absence of a booster dose of Hib in the second year of life,
      contributed to the loss of control of Hib disease in the UK. In the Republic of Ireland, the
      use of Infanrix-Hib-IPV™ at a 2-4-6 month schedule without a booster dose may also have
      contributed to an increase in invasive Hib disease (Fitzgerald et al., 2005; Fitzgerald &
      Cotter, 2007).

      More recent manufacturer-sponsored studies suggest that Infanrix-Hexa™ may provide an
      adequate Hib response under a 2-3-4 month schedule, although none of the studies took place
      in the UK. In the two reported studies, however, the immunogenicity of the Infanrix™-based
      Hib vaccine was half that of Pediacel. Other EU countries that have used Infanrix™-based
      vaccines have not experienced major increases in Hib incidence. In Germany, where
      Infanrix™-based vaccines have been used at a 2-3-4 month schedule with a booster dose at
      11-14 months for over a decade, control of invasive Hib disease has remained good. Studies of
      vaccine effectiveness for the period August 2000 to December 2004 estimated protection of
      90.4% (95% CI: 70.6-96.8) for the full primary series (Kalies et al., 2008). However, infants
      in Germany rarely receive immunisation on schedule. The median ages at first dose, third dose
      and booster immunisation were 3.3, 6.0 and 14.4 months respectively, in the years when
      Infanrix-Hexa™ was routinely used (Kalies et al., 2006). Such differences in vaccination
      schedules, along with differences in Hib epidemiology and different surveillance methods in
      use mean that the German experience may not be applicable to the UK.

      CHOICE OF MENC VACCINE The UK Joint Committee on Vaccination and Immunisation (JCVI) recently
      recommended reducing the infant MCC schedule to a single dose in infancy and adding an extra
      MCC dose to the adolescent immunisation schedule (JCVI, 2011). There are currently two MCC
      conjugate vaccines used in the UK - NeisVac-C™ (which uses a tetanus toxoid carrier protein)
      and Menjugate™(which uses the CRM carrier protein) that are suitable for use in a single dose
      priming schedule (Findlow et al., 2012). Tetanus-based MCC vaccines (MCC-TT) not only improve
      the immunogenicity of the Hib component of combination vaccines (Tables 2 & 3) , but also
      result in higher MenC primary and booster responses compared with MCC-CRM vaccines under the
      UK accelerated immunisation schedule (Southern et al., 2009; Kitchin et al., 2007). If given
      with a concomitant MCC-TT containing vaccine, therefore, Infanrix-Hexa™ may provide a better
      Hib antibody response under the UK 2-3-4 month schedule. NeisVac-C™ is the only available
      MCC-TT vaccine and has been shown to be adequately immunogenic when given as a single dose at
      3 months of age with Pediacel™ (DTaP5/Hib/IPV) vaccine (Findlow et al., 2009). Use of a
      single dose of the combined MCC-TT/Hib-TT vaccine (Menitorix™) currently used for the routine
      12-month booster in the UK, would be an attractive alternative. Although Menitorix™ contains
      less MenC antigen in the vaccine and, therefore, may not induce as good a post-primary
      antibody response as a single dose of NeisVac-C™ or possibly even Menjugate™, antibody
      response to the routine 12-month booster dose of Menitorix™ is likely to be satisfactory and
      may be better than the booster response in those primed with Menjugate™ (Findlow et al.,
      2012).

      The aim of this study, therefore, is to evaluate the immunogenicity of Infanrix-Hexa™ when
      given at a 2-3-4 month schedule with PCV13 at 2-4 months and incorporating a random study of
      three different MCC vaccines (Menjugate™, NeisVac-C™ and Menitorix™) given at 3 months of
      age.
    

Intervention name(s): Menjugate; Menitorix; NeisVac-C
Intervention type(s): Biological; Biological; Biological
Intervention description(s): Administered with routine vaccinations at 3 months of age; Administered with routine vaccinations at 3 months; Administered with routine vaccinations at 3 months
Other intervention name(s): MenC-CRM; Hib/MenC-TT; MenC-TT
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: vaccines; immunogenicity; adverse reactions