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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: Background:Children 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. Methods:This 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. Results:This 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. Conclusion:Laboratory 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 registration:ClinicalTrials.gov CTN NCT01619462, retrospectively registered on May 28, 2012.

SUBMITTER: Lehmann D

PROVIDER: S-EPMC5742486 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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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.

Lehmann Deborah D Kirarock Wendy W van den Biggelaar Anita H J AHJ Passey Megan M Jacoby Peter P Saleu Gerard G Masiria Geraldine G Nivio Birunu B Greenhill Andrew A Orami Tilda T Francis Jacinta J Ford Rebecca R Kirkham Lea-Ann LA Solomon Vela V Richmond Peter C PC Pomat William S WS

Pneumonia (Nathan Qld.) 20171225

<h4>Background</h4>Children 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.<h4>Methods</h4>This report describes the rationa ...[more]

PMID: 29299402

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Project description:BackgroundPneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial.MethodsPVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative '1+1' schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard '3+0' schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements.DiscussionAnalysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules.Trial registrationInternational Standard Randomised Controlled Trial Number 72821613 .

Project description:Previously, the Fiji Pneumococcal Project (FiPP) evaluated reduced dose immunization schedules that incorporated pneumococcal protein conjugate and/or polysaccharide vaccine (PCV7 and 23vPPV, respectively). Immune hyporesponsiveness was observed in children vaccinated with 23vPPV at 12 months of age compared with children who did not receive 23vPPV. Here we assess the long-term impact of 23vPPV vaccination on nasopharyngeal carriage rates and densities of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Nasopharyngeal swabs (n=194) were obtained from healthy children who participated in FiPP (now aged 5-7 years). S. pneumoniae were isolated and identified by standard culture-based methods, and serotyped using latex agglutination and the Quellung reaction. Carriage rates and densities of S. pneumoniae, H. influenzae, S. aureus and M. catarrhalis were determined using real-time quantitative PCR. There were no differences in the rate or density of S. pneumoniae, H. influenzae or M. catarrhalis carriage by PCV7 dose or 23vPPV vaccination in the vaccinated participants overall. However, differences were observed between the two main ethnic groups: Fijian children of Indian descent (Indo-Fijian) were less likely to carry S. pneumoniae, H. influenzae and M. catarrhalis, and there was evidence of a higher carriage rate of S. aureus compared with indigenous Fijian (iTaukei) children. Polysaccharide vaccination appeared to have effects that varied between ethnic groups, with 23vPPV vaccination associated with a higher carriage rate of S. aureus in iTaukei children, while there was a lower carriage rate of S. pneumoniae associated with 23vPPV vaccination in Indo-Fijian children. Overall, polysaccharide vaccination had no long-term impact on pneumococcal carriage, but may have impacted on S. aureus carriage and have varying effects in ethnic groups, suggesting current WHO vaccine schedule recommendations against the use of 23vPPV in children under two years of age are appropriate.

Dataset Information

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.

Publications

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.

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