Rationale and methods of a randomized controlled trial of immunogenicity, safety and impact on carriage of pneumococcal conjugate and polysaccharide vaccines in infants in Papua New Guinea

Abstract

BackgroundChildren in third-world settings including Papua New Guinea (PNG) experience early onset of carriage with a broad range of pneumococcal serotypes, resulting in a high incidence of severe pneumococcal disease and deaths in the first 2 years of life. Vaccination trials in high endemicity settings are needed to provide evidence and guidance on optimal strategies to protect children in these settings against pneumococcal infections.MethodsThis report describes the rationale, objectives, methods, study population, follow-up and specimen collection for a vaccination trial conducted in an endemic and logistically challenging setting in PNG. The trial aimed to determine whether currently available pneumococcal conjugate vaccines (PCV) are suitable for use under PNG’s accelerated immunization schedule, and that a schedule including pneumococcal polysaccharide vaccine (PPV) in later infancy is safe and immunogenic in this high-risk population.ResultsThis open randomized-controlled trial was conducted between November 2011 and March 2016, enrolling 262 children aged 1 month between November 2011 and April 2014. The participants were randomly allocated (1:1) to receive 10-valent PCV (10vPCV) or 13-valent PCV (13vPCV) in a 1-2-3-month schedule, with further randomization to receive PPV or no PPV at age 9 months, followed by a 1/5th PPV challenge at age 23 months. A total of 1229 blood samples were collected to measure humoral and cellular immune responses and 1238 nasopharyngeal swabs to assess upper respiratory tract colonization and carriage load. Serious adverse events were monitored throughout the study. Of the 262 children enrolled, 87% received 3 doses of PCV, 79% were randomized to receive PPV or no PPV at age 9 months, and 67% completed the study at 24 months of age with appropriate immunization and challenge.ConclusionLaboratory testing of the many samples collected during this trial will determine the impact of the different vaccine schedules and formulations on nasopharyngeal carriage, antibody production and function, and immune memory. The final data will inform policy on pneumococcal vaccine schedules in countries with children at high risk of pneumococcal disease by providing direct comparison of an accelerated schedule of 10vPCV and 13vPCV and the potential advantages of PPV following PCV immunization.Trial registrationClinicalTrials.gov CTN NCT01619462, retrospectively registered on May 28, 2012

Immunogenicity and Immune Memory after a Pneumococcal Polysaccharide Vaccine Booster in a High-Risk Population Primed with 10-Valent or 13-Valent Pneumococcal Conjugate Vaccine: A Randomized Controlled Trial in Papua New Guinean Children

“…Antibody responses were assessed one month later for 89 (95%) of the PPV-vaccinated children and 87 (99%) of the PPV-naive children. Reasons for loss to follow-up at different time points were reported previously [13].…”

“…A detailed protocol of this study has been published, describing the trial aims, objectives, design, study population, and methods including consenting procedures, monitoring of adverse events, and sample size calculations [13]. The trial consisted of two parts.…”

“…Between November 2011 and April 2014, 262 infants (28–35 days old) were enrolled in the 10v13vPCV trial and randomized 1:1:1:1 to receive 3 doses of PCV10 or PCV13 at 1, 2 and 3 months of age with or without a booster dose of PPV at 9 months of age [13]. The PPV group allocation was assigned at enrolment, at the same time as PCV randomization, but kept in an unopened envelope until the 9-month visit.…”

“…Prior to any vaccination, the child’s medical history was assessed, and a physical examination was performed to exclude contraindications for vaccination. At age 9 months children received their second dose of measles vaccine and Vitamin A, with or without a dose of PPV [13]. All participants were given 1/5th the normal dose (0.1 mL) of PPV at age 23 months as a pneumococcal challenge.…”

“…Children were observed at the clinic for 1 hour for immediate local and systemic reactions and visited at home 24–48 h postvaccination to assess local or systemic side effects. Children were followed for illness through passive surveillance throughout the study with a pre-specified analysis of the frequency of moderate and severe ALRI as previously defined [13]. A serious adverse event (SAE) was defined as any event requiring hospitalization or resulting in death.…”