PCV10 Immunogenicity Study Nepal 2015
Condition: Streptococcus Pneumoniae
MeSH terms: Pneumonia, Pneumococcal
Study type: Interventional
Phase: Phase 4

Summary: 
      A single centre open-label, parallel group, randomised controlled trial, recruiting healthy
      Nepalese infants aged 40-60 days, who present to the immunisation clinic at Patan Hospital,
      Kathmandu, Nepal, randomised to receive a 10-valent pneumococcal conjugate vaccine (PCV10) at
      either;

        1. 6+10 weeks and 9 months OR

        2. 6+14 weeks and 9 months The study will enroll 152 healthy Nepalese infants in each
           treatment arm (304 in total). Demographic and clinical data will be collected on an
           electronic case report form to allow monitoring remotely. Participants will receive the
           study vaccine according to their allocated treatment arm in addition to their other
           routine vaccines. The investigators will collect 3 blood samples for analysis of serum
           antibody responses to the PCV10 vaccine serotypes throughout infancy (see Table 1). The
           data collected will be analysed in order to determine whether the 6+10 schedule is
           non-inferior to the 6+14 schedule in generating immune responses against the vaccine
           serotypes above the ≥0•35μg/mL threshold. These data will then be used to inform
           decision-making around augmenting the currently recommended 6+14 schedule to a 6+10
           schedule in Nepal. The investigators will collect a nasopharyngeal swab at 2 time points
           to look at carriage of pneumococcus over time and to assess differences between the 2
           groups. This is of critical importance because much of the programmatic impact of PCV is
           ultimately conferred by reductions in carriage at the community level and indirect
           effects resulting from that nasopharyngeal (NP) protection.
    

Detailed description: 
      BACKGROUND AND RATIONALE Streptococcus pneumoniae is the predominant cause of bacterial
      pneumonia, meningitis and septicaemia in children worldwide, and disproportionately affects
      children from developing countries. Pneumococcal conjugate vaccines (PCVs) reduce
      pneumococcal disease burden by direct protection and by reducing nasopharyngeal carriage,
      thereby preventing transmission and inducing herd protection.

      In Nepal, invasive pneumococcal disease (IPD) is responsible for a substantial disease burden
      in children. Surveillance conducted since 2005 at Patan Hospital, Kathmandu indicates the
      majority of IPD is due to serotypes 1, 5 and 14, and that the greater proportion occurs in
      late infancy and toddlerhood.7 Vaccine introduction began in January 2015 with PCV10. GAVI
      (Gavi, The Vaccine Alliance) has funded an impact assessment programme (including IPD,
      pneumonia, nasopharyngeal (NP) colonization and health economics), which is underway.

      A randomised controlled trial conducted by investigators at Patan Hospital in collaboration
      with the Oxford Vaccine Group, using a 10-valent PCV, demonstrated a two-dose prime (at 6 and
      14 weeks) and 9-month booster to have non-inferior immunogenicity at 18 weeks and 10 months
      and superior immunogenicity in early childhood (2-4 years of age) compared to a conventional
      three-dose priming only schedule (6, 10, and 14 weeks). This two-dose prime and boost
      schedule, with an 8 week interval between the priming doses, has been adopted as an
      acceptable schedule by the World Health Organization (WHO) and recommended in late 2014 by
      the Nepal Ministry of Health as a result of the study. However the WHO have also recommended
      the introduction of a single inactivated poliomyelitis virus vaccine at 14-weeks of age in
      order to mitigate the risk of outbreaks from vaccine derived serotype 2 poliomyelitis virus,
      to protect against serotype 2 poliomyelitis virus once countries switch to bivalent OPV (oral
      polio vaccine) from trivalent OPV, and to enhance immunogenicity to poliomyelitis vaccine
      serotypes 1 and 3. This has created a programmatic dilemma and concerns around vaccine
      coverage as a result of requiring three injections at the 14-week visit. Thus the Nepalese
      Ministry of Health, based on these concerns around public acceptance and feasibility have
      decided to move the second PCV10 priming dose from 14 weeks to 10 weeks of age. Given this
      decision it is essential to evaluate the immunogenicity of the intended schedule, comparing
      it to the schedule that has been shown to provide a level of immunogenicity that would
      predict substantial program impact on disease and colonisation. This importance is further
      increased given that the Nepal PCV10 impact study is currently underway and the limited data
      on two-dose priming schedules with a one-month interval between priming doses in other
      settings shows a reduction in immunogenicity.

      Therefore this study will be undertaken in order to evaluate the immunogenicity of the
      10-valent PCV priming at 6 and 10 weeks being implemented by the Nepal Ministry of Health,
      compared to priming at 6 and 14 weeks of age in healthy Nepali infants. In both groups a
      PCV10 booster will be given at 9 months of age.

      Nepal Nepal is a low-income country in South Asia with a population of 25.8 million people
      and an estimated under 5 year mortality of 54/1000 live births. Access to health care varies
      considerably within the country, but as few as 18% of children under 5 years with pneumonia
      are taken to health care facilities. The capital city, Kathmandu, resides in a large valley,
      which in 2011 had a total population of about 1,744,240 people, with approximately 10% of
      these being children under 5 years of age.

      The majority of children in Nepal receive immunisation through local government outpatient
      clinics. The national Expanded Programme of Immunisation (EPI )schedule being followed in
      Nepal currently includes Bacillus Calmette-Guérin (BCG) at birth, diphtheria-tetanus-whole
      cell pertussis-hepatitis B-Haemophilus influenzae type b (DTwP-HBV-Hib) and oral Polio (OPV)
      vaccines at 6, 10 and 14 weeks of age, IPV at 14 weeks of age, measles and rubella vaccine at
      9 months of age, Japanese Encephalitis (JE) vaccine at 12-23 months of age (in endemic
      regions only; Kathmandu is one of these regions) and tetanus toxoid during pregnancy. Vaccine
      coverage is high in Nepal with over 90% of infants receiving DTP, by 14 weeks of age in the
      past 3 years. PCV10 vaccine at 6 and 10 weeks and a booster at 9 months of age was initiated
      in the new birth cohort only (i.e. no catch up program is being instituted ) as of January
      2015 with roll-out beginning in the west of the country and expected to reach the whole of
      the country by late 2015.

      The Patan Academy of Health Sciences and Patan Hospital will lead this study in Nepal. Patan
      Hospital is one of only two hospitals in Kathmandu with paediatric referral and inpatient
      services and is based in Lalitpur, in the south of the City. Over 300 children commence
      immunisation at the 'Under 14 clinic' in the Patan Hospital paediatric outpatient department
      each month.

      Pneumococcal Disease in Kathmandu On-going surveillance of IPD serotypes has been occurring
      at Patan Hospital in Kathmandu since 2005, identifying all paediatric admission from whom
      pneumococcus is isolated from normally sterile body fluids. This programme was initially
      funded through PneumoADIP as part of the South Asia Pneumococcal Alliance (SAPNA) with
      extensive collection of clinical, radiological and laboratory data, demonstrating
      pneumococcus to be a significant cause of disease in children in Kathmandu, and is currently
      funded by the World Health Organisation.

      Analysis of these data up until late 2012, show a predominance of non-vaccine serotypes in
      early infancy, followed by a shift towards vaccine serotypes, particularly serotype 1, in
      late infancy and into childhood. The finding of serotypes 1, 5 and, 14 to be the most
      frequent disease causing isolates is in keeping with data summarized in the Global Serotype
      Project which demonstrated serotype disease order of frequency in low-income countries was
      14, 5, 1, 6B, 19F, 23F and 6A. The age distribution of vaccine type disease reinforces the
      importance of initiating vaccine coverage early in infancy such that early boosting at 9
      months may be performed to maintain coverage into early childhood.

      Immunogenicity of PCV10 in Kathmandu We previously conducted an open-label, parallel group,
      randomised controlled trial at Patan Hospital, Kathmandu, Nepal from June 2010 to November
      2011 with follow-on between February and October 2013. In this study we compared the then WHO
      recommended PCV schedule of three priming doses in early infancy (6, 10, and 14 weeks) to a
      two-dose prime (6 and 14 weeks) and boost at 9 months of age. We demonstrated using the
      ten-valent PCV (PCV10) that the two-dose prime with booster at 9 months provided analogous
      immunogenicity to the three-dose prime schedule during early infancy, with improved
      protection through early childhood.

      Global Polio Eradication Initiative Over the last decade the oral poliomyelitis vaccine (OPV)
      has been extremely efficacious in preventing wild-type polio disease across the world,
      including Nepal. The OPV used in the routine vaccine schedule contains three serotypes of
      weakened poliomyelitis virus (types 1, 2 and 3), and has facilitated the eradication of
      wild-type poliomyelitis in Nepal. On very rare occasions disease may occur as a result of
      circulating vaccine derived polio viruses (cVDPV), particularly of serotype 2. Thus, in
      countries such as Nepal, there is the situation where wild-type disease has been eradicated
      yet there remains a rare risk of vaccine derived disease outbreaks. This had led to the
      proposal to switch to a bivalent OPV (types 1 and 3), globally. This cannot happen however,
      unless populations are protected from type 2 disease through some other means. Furthermore
      the inactivated poliomyelitis vaccine (IPV), which is administered as an intramuscular
      injection, generates immunity using killed strains of the three poliomyelitis serotypes, and
      thus does not produce vaccine type disease or result in the emergence of cVDPV outbreaks.
      This has led the WHO to recommend the introduction of IPV in order to interrupt and mitigate
      the risk of cVDPV type 2 disease, prior to the phasing in of the bivalent OPV and cessation
      of OPV-type 2 use. In Nepal a single dose of the IPV at 14 weeks of age in addition to the
      routine schedule of trivalent OPV, has now been implemented (September 2014). Nepal was the
      first GAVI (Gavi The Vaccine Alliance) country to introduce IPV, and is ready to participate
      in the globally synchronized switch to bivalent OPV that will be coordinated by WHO in 2016 .
      IPV is given at 14 weeks of age; the proposed PCV10 schedule of 6 weeks, 14 weeks, and 9
      months of age meant that children would receive three injections at 14 weeks of age (IPV,
      PCV10 and dose 3 of DTwP-HBV-Hib vaccine). The perception by the health care providers and
      the Ministry of Health is that this will not be acceptable and will lead to reduced vaccine
      coverage. Therefore the Nepal Ministry of Health has introduced in January 2015 PCV10 on a
      schedule of 6 weeks, 10 weeks, and 9 months of age.

      Based on locally available IPD data and a prior immunogenicity study in Kathmandu,
      pneumococcal conjugate vaccination utilising PCV10 with two priming doses at 6 and 14 weeks
      followed by a 9-month booster has been demonstrated to be the WHO preferred schedule in
      comparison to a three-dose prime only schedule. However the WHO have also recommended the
      introduction of a single dose of IPV at 14 weeks of age in order to eradicate poliomyelitis
      serotype 2 vaccine strain disease. Local experts anticipate a poor uptake of vaccine at 14
      weeks of age due to the increase in number of injections from one to three at this
      time-point. The Nepali government has thus suggested moving the 14 weeks PCV10 priming dose
      to the earlier 10 week time-point, however there are no immunogenicity data to support this
      decision. Therefore this study will aim to compare the immunogenicity of giving the two PCV10
      priming doses at 6 and 10 weeks to that of 6 and 14 weeks. In addition this study will also
      evaluate the adverse event profile following the 14 weeks of age visit in the two treatment
      arms.
    

Intervention name(s): 10-valent pneumococcal conjugate vaccine
Intervention type(s): Biological
Other intervention name(s): Synflorix
Intervention MeSH terms: Heptavalent Pneumococcal Conjugate Vaccine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Immunogenicity