Using Pneumococcal Vaccines in Combination for Maximum Protection From Ear and Lung Infections in First 3 Years of Life
Condition: Otitis Media; Febrile Illness; Cough; Lower Respiratory Tract Infection; Upper Respiratory Tract Infection
MeSH terms: Infections; Communicable Diseases; Respiratory Tract Infections; Otitis Media
Study type: Interventional
Phase: Phase 4

Summary: 
      HYPOTHESES:

        1. That infants receiving PHiD-CV10 as a booster at 12 months of age, compared to controls
           having no PHiD-CV10 booster (i.e. standard PCV13), will have higher HiD antibody levels,
           lower carriage of NTHi, and less tympanic membrane perforation at 18 and 36 months of
           age.

        2. That infants receiving PCV13 as a booster at 12 months of age, compared to controls
           having no PCV13 (i.e. PHiD-CV10 booster) will have higher antibody levels to serotypes
           3, 6A and 19A, less carriage of these serotypes, and less tympanic membrane perforation
           at 18 and 36 months of age.
    

Detailed description: 
      BACKGROUND:

      PCV13 is now the recommended PCV in Australia, as 3+0 for non-Indigenous children and as 3+1
      for Indigenous children in Western Australia, Queensland and Northern Territory. The decision
      to recommend PCV13 over PHiD-CV10 has been primarily driven by the increase in cases of
      invasive pneumococcal disease due to serotype 19A(1). However for the NT, in the last 3 years
      there has been one case of serotype 3, 6A or 19A invasive pneumococcal disease (IPD) per year
      in Indigenous children less than 2 years of age. By contrast, almost 20% of young Indigenous
      children have perforated tympanic membranes of which 60% are associated with NTHi, compared
      to 3% having serotypes 3, 6A or 19A.

      The PREV-IX_COMBO trial is a randomised controlled trial (RCT) of these two pneumococcal
      conjugate vaccines currently licensed in Australia. Participating Indigenous infants living
      in remote communities in 4 regions of the NT are randomised between 28 and 38 days of age and
      allocated to one of three groups: PHiD-CV10 at 2, 4, 6 months or PCV13 at 2,4,6 months, or an
      investigational group of a 4-dose combination schedule of PHiD-CV10 at 1,2, and 4 months plus
      PCV13 at 6 months.

      PREV-IX_BOOST builds on PREV-IX_COMBO to address questions not answerable by a booster trial
      in the general population:

      The 7 month visit is the final assessment included in the PREV-IX_COMBO trial. In October
      2011 the standard PCV schedule for all Indigenous babies in the NT switched from PHiD-CV10 to
      PCV13 at 2, 4, 6 and 18 months of age. Thus, all babies in PREV-IX_COMBO will go on to
      receive PCV13 at 18 months of age as a part of standard care. An alternative and innovative
      option is to take this opportunity to answer these questions: should PCV13 or PHiD-CV10
      vaccine be the booster vaccine for infants in the three PREV-IX_COMBO groups, and at what age
      should the booster be given? Secondary questions: By randomising the three different primary
      course groups to booster dose of either PHiD-CV10 or PCV13, a number of secondary questions
      can be proposed. Outputs include the comparative benefit (immune and carriage correlates) of
      schedules such as 3+1 PCV13, 3+1 PHiD-CV10, and mixed vaccine schedules such as single dose
      PCV13 or single dose PHiD-CV10 boosters following alternate vaccines in the primary course,
      and booster options following the early and mixed 4-dose primary course. Furthermore the
      design will allow for an evaluation at 18 months of age, of a 12 month boost versus no boost
      of specific vaccine components unique to each of these vaccines. For example, a comparison of
      the booster effect of HiD (in PHiD-CV10) with no HiD boost (PCV13) on antibody concentration
      and nasopharyngeal carriage at 18 months. By combining some of these groups it will be
      possible to compare more subtle differences such as differences in immunogenicity of
      serotypes shared by the two vaccines (1,4,5,6B,7F,9V,14,18C,19F,23F) but with different
      carrier proteins and thus anticipated differences in immunogenicity.

      PCVs in the NT: PCV7, PHiD-CV10 (Synflorix) and PCV13 (Prevenar13):

      Prevention of invasive pneumococcal disease (IPD) is the primary goal of pneumococcal
      conjugate vaccination in infants. Effectiveness against overall IPD has generally remained
      high although IPD caused by non-PCV7 types has increased in some high risk groups and
      regions, particularly associated with serotypes 19A, 6A, and 33F. These increases have been
      described as a 'replacement phenomenon'. In addition there are ongoing outbreaks of IPD due
      to non-PCV7 types; in the NT and WA serotypes 1 and 12F account for resurgence in IPD cases
      in otherwise low risk groups. Effectiveness of PCVs for all-cause pneumonia and otitis media
      has been greatly compromised by replacement serotypes and the broad diversity of
      non-pneumococcal respiratory bacterial pathogens which continue to cause high rates of
      disease, such as non-typeable H. influenzae (NTHi). Replacement serotypes, particularly
      19A(2,3) and NTHi, are the targets of new generation vaccines. In Australia two new PCVs are
      licensed: 10-valent pneumococcal-Haemophilus influenzae protein-D conjugate vaccine,
      PHiD-CV10 (Synflorix, GSK) and 13-valent PCV, PCV13 (Prevenar13, Pfizer). The two vaccines
      have 10 pneumococcal serotypes in common (1,4,5,6B,7F,9V,14,18C,19F,23F), however these are
      conjugated to different carrier proteins and immune correlates indicate potential vaccine
      differences in efficacy for individual serotypes. PHiD-CV10 has protein D of NTHi as the
      carrier for some serotypes and PCV13 is non-toxic diphtheria protein (CRM197)-conjugated, as
      was its precursor PCV7, and has three additional serotypes (3, 6A and 19A) but not HiD. There
      have been no efficacy trials that directly compare these vaccines; licensure has been based
      on immune correlates of protection in comparison with PCV7. Evidence of HiD efficacy has come
      from a single RCT in which otitis media was a primary outcome. In that trial of the original
      formulation (PHiD-CV11) there was ~55% efficacy for vaccine type AOM, and 35% efficacy for
      NTHi AOM following a 3+1 schedule.(3) This trial also demonstrated a 43% (95% Confidence
      Interval (CI): -17 to 72, ns) reduction in the carriage of vaccine serotypes and a 43% (95%
      CI: 1-67) reduction in the carriage of H. influenzae. This finding has not been replicated in
      later trials, partially due to very low baseline rates of NTHi carriage (<10%) and thus low
      power to achieve statistical significance. The PREV-IX_COMBO trial will therefore be very
      important in providing data on immunological correlates and carriage for different PHiD-CV10
      schedules. However, an extended follow-up and comparison of booster dose (this PREV-IX_BOOST
      proposal) will provide further evidence for or against inclusion of PHiD-CV10 as a booster
      (compared to the NT standard PCV13 at 18 months).

      In the NT, booster pneumococcal vaccines are recommended at 18 months of age. This is largely
      due to the previous schedule which included 23-valent pneumococcal polysaccharide vaccine
      (23PPV) as a booster dose at 18 months. A 3+1 PHiD-CV10 schedule replaced 3+1 PCV7-23PPV in
      2009, and the booster age remained at 18 months. In Queensland (QLD) and in Western Australia
      (WA) the vaccination schedules allow for PCV13 boost at 12 months of age for high risk and
      Indigenous children.

      At present there are 4 intra-muscular immunizations (IMIs) at 12 months of age for Indigenous
      infants in the Northern Territory childhood vaccination schedule. A combined booster dose
      vaccine (e.g. Menitorix) became available in Australia prior to commencement of first
      enrolment into the BOOST study. This reduces the number of IMIs at 12 months of age and
      provides a 'space' for PCV at 12 months. Administration of PCV booster, originally scheduled
      for 13 months of age, will be at 12 months of age for the trial.

      Surveillance of otitis media in remote communities shows high rates of disease from weeks
      after birth throughout early childhood, particularly tympanic membrane perforations in the
      second year of life, and thus supports the need for a booster dose. Between 2008 and 2010, in
      PCV7-vaccinated children, mean age of tympanic membrane perforation was 18 months; for
      children with AOM with perforation (AOMwiP), the mean age was 13 months and for chronic
      suppurative OM (CSOM) 21 months. IPD cases occurring in Indigenous and non-Indigenous
      children less than 2 years of age for all serotypes; in 2009 there were 7 cases; in 2011 8
      cases. The majority of IPD cases in children under 2 years occurred between 12 and 18 months.

      In summary, the precedent of a 12 month PCV booster for Indigenous children in WA and QLD,
      and the high incidence of IPD and OM in the first half of the second year of life support the
      decision to choose a 12 month booster for this study. The mixed schedules will still allow us
      to compare boost versus no boost for HiD, 3,6A and 19A.

      Antibody decay post-primary PCV7 to pre-booster:

      Furthermore, published data(4) from the PCV7 era which show post-primary antibody levels at
      mean age 15 months (range 0.32 to 0.83 microg/mL for all but serotype 14) have declined
      almost to those detected in cord blood (range 0.3647 to 1.1797 microg/mL). The clinical
      implications of this decay in terms of memory response and duration of protection from
      mucosal infections, pneumonia and otitis media, are not known, however vaccine efficacy is
      lower for mucosal compared to invasive infection(5). Which vaccine for the booster dose?

      Mucosal disease (OM and respiratory illness):

      Culture of ear discharge from these perforations shows 60% of specimens from AOMwiP cultured
      NTHi and 26% cultured pneumococcus. For CSOM, these figures were 47% and 23% respectively.
      Serotyping identified 19A or 6A in 20% of pneumococcal isolates, which translates to 5%
      AOMwip and 4% CSOM specimens. NTHi is also associated with exacerbations of chronic
      suppurative lung disease (CSLD), or bronchiectasis, in young Indigenous children.(6)
      Percentage of ear discharge specimens with OM pathogens pneumococcus (Spn), 19A, NTHi, M.
      catarrhalis or neither Spn nor NTHi.

      Evidence for efficacy of single dose PHiD-CV10 boost & inclusion in Australian PCV13 3+0
      schedule:

      A single dose of PHiD-CV10 might be valuable for many Australian children now receiving the
      3+0 PCV13 schedule, to provide some immune protection from NTHi. Group 2 of the PREV-IX_COMBO
      trial receive either PCV13 at 2,4,6 months and will be randomised in this study to PCV13 (4th
      dose) or PHiD-CV10 (1st dose) at 12 months of age. Vesikari et al.(7) evaluated a single dose
      of PHiD-CV as catch-up (not booster) in 2 to 5 year old children. Following 1 dose in the 2
      to 5 years group ELISA pneumococcal responses were lower than the reference group (reference
      group: 3 primary doses with booster at 12 to 15 months) for several serotypes. Responses
      following 1 dose in children 2 to 5 years of age suggested that 2 doses may be preferable.
      Unfortunately, HiD Geometric Mean Concentrations (GMCs) were not reported. A trial underway
      in Queensland will evaluate a double dose of PHiD-CV10 in preventing exacerbations of CSLD in
      older children. The BOOST trial in non-CSLD children will complement those data.

      Invasive disease due to PCV13 serotypes 3, 6A and 19A:

      In 2009, there were 89 cases of IPD in the NT population, 59 in 2010 and 114 in 2011; 25
      (10%) of these 262 cases were the unique PCV13 serotypes (3, 6A and 19A) and 17(7%) of these
      were Indigenous, four (1.5%) were Aboriginal children < 2 years of age - about one per year
      (unpublished, Centre for Disease Control, NT Health).

      Episodes of AOM and respiratory illness to 3 years of age:

      A very high rate of clinic presentations occurs for babies and young children in remote
      communities. Our antibiotic trial for prevention of OM randomised infants at mean age 5
      months(9,10) and recorded episodes of illness in placebo and active groups during
      approximately 6 months (unpublished). Around 9 episodes of primary respiratory illness or AOM
      (8.2 + 0.8) were recorded in notes per child year in the second 6 months of life. There are
      no published data for illness in the second and third years of life for this population.
      Whilst the BOOST study is unlikely to be sufficiently powered to detect group differences in
      rates of illness, these will be measured and reported.
    

Intervention name(s): Prevenar13; Synflorix
Intervention type(s): Biological; Biological
Intervention description(s): The vaccine is a ready to use homogeneous white suspension for intramuscular injection, supplied as a pre-filled syringe.
Active ingredients
Each 0.5 mL dose contains:
2.2 μg of pneumococcal purified capsular polysaccharides for serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F and 23F 4.4 μg of pneumococcal purified capsular polysaccharides for serotype 6B. Each serotype is individually conjugated to non-toxic diphtheria CRM197 protein and adsorbed on aluminium phosphate (0.565 mg).; The 10-valent vaccine contains 1 µg of purified capsular polysaccharide of pneumococcal serotypes 1, 5, 6B, 7F, 9V, 14, and 23F conjugated to protein D, 3 µg of serotype 4 conjugated to protein D, 3 µg of serotype 18C conjugated to tetanus toxoid and 3 µg of serotype 19F conjugated to diphtheria toxoid.
Other intervention name(s): PCV13; Prevnar13; PHiD-CV; PHiD-CV10
Intervention MeSH terms: Heptavalent Pneumococcal Conjugate Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: randomized controlled trial; pneumococcal conjugate vaccines; booster dose; immunogenicity; nasopharyngeal carriage; Australian Indigenous; pediatric