Immunogenicity of 3+1 Versus 2+1 Schedule for PCV7

Study Overview
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Brief Summary
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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
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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.

Official Title
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Comparison of the Immunogenicity of the 3+1 Schedule and the 2+1 Schedule of 7-valent Pneumococcal Conjugated Vaccine in Young Chinese Infants

Conditions
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Infectious Disease

Intervention / Treatment
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* Biological: 7-valent pneumococcal conjugated vaccine
* Biological: 7-valent pneumococcal conjugated vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chinese infants born in Hong Kong Exclusion Criteria: (i)Previous administration of PCV7 or other pneumococcal vaccines (ii)History of immunodeficiency (iii)Known or suspected impairment of immunologic function including, but not limited to, clinically significant liver disease; diabetes mellitus; moderate to severe kidney impairment (iv)Malignancy, other than squamous cell or basal cell skin cancer (v)Autoimmune disease (vi)History of asthma or reactive airways disease (vii)Cardiovascular and pulmonary disorder, chronic metabolic disease (including diabetes), renal dysfunction or hemoglobinopathies requiring regular medical follow-up or hospitalization during the preceding year (viii)Use of immunosuppressive medication (ix)Receipt of blood products or immunoglobulin in the past 6 month

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 9 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 4-Dose Regimen<br>3+1 schedule of 7-valent pneumococcal conjugated vaccine: Infants who are randomized for 3+1 schedule will be administrated one dose of PCV7 at the age of 2 months old, 4months old and 6 months old. A booster dose will be administrated at the age of 12 months old. Infants will be followed up for 12-16 months starting from vaccination of first dose. There is no restriction on the use of other medications before or during the follow-up period. | Biological: 7-valent pneumococcal conjugated vaccine<br>* 3+1 doses vs 2+1 doses<br>|
| Active Comparator: 3-Dose Regimen<br>2+1 schedule of 7-valent pneumococcal conjugated vaccine: Infants who are randomized for 2+1 schedule will be administrated with one dose of PCV7 at the age of 2 months old and 4months old. A booster dose will be administrated at the age of 12 months old. Infants will be followed up for 12-16 months starting from vaccination of first dose. There is no restriction on the use of other medications before or during the follow-up period. | Biological: 7-valent pneumococcal conjugated vaccine<br>* Pneumococcal vaccine 3+1 and 2+1 schedule comparison<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serological response in terms of geometric mean titres after the primary dose series and booster for the 2+1 and 3+1 schedules. |  | An average of one month post vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of infants with Immunoglobulin G concentrations above 0.35ug/ml to the 7 serotypes |  | An average of one month post vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Comparison of pneumococcal conjugated vaccine regimes