Immunogenicity of 3+1 Versus 2+1 Schedule for PCV7
Condition: Infectious Disease
MeSH terms: Communicable Diseases; Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      Pneumonia is one of the most prevalent diseases in infants and children. The incidence of
      pneumonia in children less than 5 years old is about 34-40 cases per 1000 in Europe and
      America and more than 2 million children die of pneumonia annually. It was reported that
      Streptococcus pneumoniae accounted for 13%-53% of lower respiratory tract infections in
      different age group of infants or children. In addition, 7%-9% of bacterial meningitis was
      due to Streptococcus pneumoniae infection. In addition, children infected with Streptococcus
      pneumoniae often transmit the pathogens to adult. As a result, it is evident that
      Streptococcus pneumoniae presents a heavy burden to paediatrics practice.

      Vaccination of 7-valent pneumococcal conjugate vaccines is effective in preventing
      Streptococcus pneumonia .Routine use of PCV7 in the US has rapidly reduced rates of invasive
      pneumococcal disease in children. The impact of the vaccine was noted within 1 year of
      introduction. According to Centre for Disease Control's (CDC) Active Bacterial Core
      Surveillance (ABCs) the incidence of invasive pneumococcal disease among children <5 years
      dropped 75% from 1998/1999 to 2005; disease caused by vaccine-type strains fell 94% from 80
      to 4.6 per 100,000. Currently there are two immunization schedules: manufacturer recommended
      the 3+1 schedule and many countries adopted a 3 dose schedule, either 3+0 or 2+1 schedules.
      In US, it is recommended to give three doses during infancy (scheduled at 2, 4, 6 month) plus
      one dose at 12-15 months (3+1 schedule). Since several studies have demonstrated that two
      doses may provide similar direct protection to three conjugate doses during infancy, it is
      recommended to give two doses during infancy plus a booster dose 12 months in some European
      countries including United Kingdom.

      In this trial, the immunogenicity of the 3+1 schedule and the 2+1 schedule of 7-valent
      pneumococcal conjugated vaccine in young infants will be compared.
    

Detailed description: 
      Streptococcus pneumonia is the most common bacterial pathogen of community-acquired pneumonia
      in children [1]. It may also cause meningitis, bloodstream infections and acute otitis media
      [1]. In 2005, WHO estimated that 1.6 million people a year die from pneumococcal disease,
      including up to 1 million children less than 5 years old worldwide, in particularly for
      infants and children less than 2 years old [1]. Most of the death occur in developing
      countries [2, 3]. Case fatality ratios are highest for invasive infections and range from
      5-20% for bacteremia to 40-50% for meningitis. Among meningitis survivors, long-term
      neurologic sequelae occur in 25-56% of cases [4].

      Most pneumococcal infections can be treated effectively with antibiotics, although meningitis
      still often results in devastating outcomes. Over the last 20 years, the emergence of
      antimicrobial resistance among S. pneumoniae complicates treatment of infections. Penicillin
      and co-trimoxazole resistance are common in many parts of the world, including China [5-9].
      Multidrug resistance has also emerged and is best documented in industrialized countries.
      Treatment failures due to resistance have been documented for acute otitis media, meningitis
      and bloodstream infections [5-6].

      Currently two pneumococcal vaccines are licensed and available. One is the 23-valent
      pneumococcal polysaccharide vaccine (PPV23). However it is not recommended for children less
      than 2 year old. Another one is the 7-valent pneumococcal conjugate vaccine (PCV7) which can
      be used for children 6 weeks to 24 months of age. PCV7 includes the capsular polysaccharide
      of 7 serotypes (4,6B, 9V, 14, 18C, 19F, 23F), each coupled to a nontoxic variant of
      diphtheria toxin, CRM197. The vaccine contains 2 μg each of capsular polysaccharide from
      serotypes 4,9V, 14, 19F and 23F; 2 μg of oligosaccharide from 18C; 4 μg of capsular
      polysaccharide of 6B; 20 μg of CRM197; and 0.125 mg of aluminum/0.5 ml dose as an aluminum
      phosphate adjuvant [10].

      Since the licensure of the PCV7 in 2000, it is being widely used for infants and toddlers in
      most of the developed countries. It has been demonstrated that PCV7 provide great protections
      for pneumococcal invasive disease (meningitis, bloodstream infections), pneumonia and otitis
      media [11, 12]. Routine use of PCV7 in the US has rapidly reduced rates of invasive
      pneumococcal disease in children. The impact of the vaccine was noted within 1 year of
      introduction. According to CDC's Active Bacterial Core Surveillance (ABCs) the incidence of
      invasive pneumococcal disease among children <5 years dropped 75% from 1998/1999 to 2005;
      disease caused by vaccine-type strains fell 94% from 80 to 4.6 per 100,000 [13, 14]. A
      multi-centre study of hospitalized patients found that 77% fewer cases in children <2 years
      were caused by vaccine serotypes in 2002 compared to the average number of cases during
      1994-2000 [15]. Surveillance data on vaccine impact from outside the US are currently
      limited. Data from Calgary, Canada showed a 93% reduction in vaccine-type invasive disease in
      children <2 years of age [16]. In Australia, the rate of vaccine-type invasive pneumococcal
      disease reduced by 78% between 2002 and 2006 in children aged under 2 years [17]. In US, it
      was also found that one or more doses of PCV7 was 96% effective against invasive disease in
      healthy children, 81% effective in children with comorbid medical conditions and 76%
      effective overall against disease caused by strains resistant to penicillin [18]. PCV7 use
      also appears to be reducing non-invasive pneumococcal infections in the US, including otitis
      media and pneumonia [19-22].

      Currently there are two immunization schedules: the 3+1 and the 2+1 schedules. In US, it is
      recommended to give three doses during infancy (scheduled at 2, 4, 6 month) plus one dose at
      12-15 months (3+1 schedule). Since several studies have demonstrated that two doses may
      provide similar direct protection to three conjugate doses during infancy, it is recommended
      to give two doses during infancy plus a booster dose 12 months in some European countries
      including UK [23, 24].

      In China, a recent serogroup distribution study in out-patient department (OPD) patients with
      acute upper respiratory infections showed that coverage with PCV7 was about 55% for
      nasopharyngeal carriage pneumococci isolates, and 75% for the penicillin-nonsusceptible
      pneumococci isolates from 2000 to 2005 [25], suggesting that PCV7 is effective for preventing
      pneumococcal infections. Since PCV7 was only licensed in China by May of 2008, there is no
      data for the effectiveness. For immunization schedule, the manufacturer of PCV7 (Wyeth
      Pharmaceuticals Inc) recommends to use 3+1 schedule in China as that in US. However, China
      may NOT have enough resources for mass vaccination as a developing country because PCV7 is
      very expensive. Therefore, generating our own data in China and developing an alternative
      immunization schedule, such as 2+1, may have great advantage to save more lives by using a
      limited resource.
    

Intervention name(s): 7-valent pneumococcal conjugated vaccine; 7-valent pneumococcal conjugated vaccine
Intervention type(s): Biological; Biological
Intervention description(s): Pneumococcal vaccine 3+1 and 2+1 schedule comparison; 3+1 doses vs 2+1 doses
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Comparison of pneumococcal conjugated vaccine regimes