Trial of Pneumococcal Vaccine Schedules in Ho Chi Minh City, Vietnam

Introduction

The overall purpose of this study is to investigate simplified childhood vaccination schedules that are more appropriate for developing country use. This study is specifically designed to address two independent questions within a single study:

• What is the optimal schedule for provision of EPI vaccines with the incorporation of PCV10? Schedules involving a three, two or one dose PCV10 primary series will be evaluated, timed around options for simplification of the Expanded Programme of Immunization (EPI) schedule for developing countries. A simplified schedule with the pneumococcal booster dose brought forward closer to the peak incidence of disease is likely both to increase compliance and vaccine effectiveness. A booster at nine months of age coincides with the usual time for administration of measles vaccine, whereas a booster at six months of age would provide earlier protection and may enable a further abbreviated 1+1 pneumococcal vaccination schedule.
• How do the responses to PCV vaccination with PCV10 or PCV13 compare? PCV10 and PCV13 are the two PCVs available through the Advanced Market Commitment (AMC) mechanism, a mechanism that provides funds for vaccine introduction into developing countries. However, there have been no studies to date directly comparing these two vaccines. Directly comparing these two vaccines will provide useful information to countries considering introduction of PCV. There are important differences between these vaccines. PCV10 includes ten pneumococcal serotypes and PCV13 includes thirteen. PCV10 uses a non-typeable Haemophilus influenzae (NTHi) Protein D carrier, which may confer protection against H. influenzae, and PCV13 uses a CRM197 carrier. It is of interest to know whether these vaccines differ either in their immunogenicity or their impact on nasopharyngeal (NP) carriage.

Design

Infants will be randomized to one of six study arms (A-F). All infant participants receive four doses of Infanrix-hexa (DTaP-Hib-HBV-IPV) and at least two doses of PCV. The PCV schedules to be evaluated are: a 3+1 PCV10 schedule at 2, 3, 4 and 9 months of age (Arm A); a 3+0 PCV10 schedule at 2, 3 and 4 months of age (Arm B); a 2+1 PCV10 schedule at 2, 4 and 9 months of age (Arm C); a 1+1 PCV10 schedule at 2 and 6 months of age (Arm D); a 2+1 PCV13 schedule at 2, 4 and 9 months of age (Arm E). Arm F, the control group, receives two doses of PCV10 at 18 and 24 months of age. An additional control group (Arm G) will be recruited at 18 months of age and will receive Infanrix-hexa at 18 months of age and a single dose of PCV10 at 24 months of age. Reactogenicity will be assessed following all vaccination visits through the use of diary cards.

Participants from arms A-E will provide six NP swabs for analysis of the NP carriage outcomes, at 2, 6, 9, 12, 18 and 24 months of age; and will provide four blood samples over the course of the trial for analysis of vaccine responses. Blood 1 will be taken four weeks post-primary series; Blood 2 will be taken pre-booster (arms A, C, D and E) or at 9 months of age (subset of arm B); and Blood 3 will be taken four weeks post-booster (arms A, C, D and E) or at 10 months of age (arm B). An additional blood sample will be taken at: 18 months of age for a subset of arms A, B, C, D and E; 2 months of age for a subset of arm A; 6 months of age for a subset of arms B and C; 9 months of age for a subset of arm D; or 3 months of age for a subset of arm E. Participants from the control arms will provide NP swabs at 2, 6, 9, 12, 18 and 24 months of age (arm F) or at 18 and 24 months of age (arm G), and will provide blood samples at 18 (Blood 4), 19 (Blood X) and 24 (Blood Y) months of age.

Objectives

• What is the optimal schedule for provision of EPI vaccines with the incorporation of PCV10? The primary objective is to compare a 2+1 schedule at 2, 4 and 9 months of age with a 3+1 schedule at 2, 3, 4 and 9 months of age, with a primary outcome of the immunogenicity of PCV10, four weeks post-primary series (Arm C vs. Arm A+B). Secondary objectives are to investigate an experimental 1+1 schedule at 2 and 6 months of age (Arm D vs. Arm A+B and Arm D vs. Arm C), and to assess the impact of a booster dose on carriage (Arm A vs. Arm F and Arm A vs. Arm B).
• How do the responses to PCV vaccination with PCV10 or PCV13 compare? The primary objective is to compare a PCV13 schedule at 2, 4 and 9 months of age with a PCV10 schedule at 2, 3, 4 and 9 months of age, with a primary outcome of the immunogenicity of PCV, four weeks post-primary series (Arm E vs. Arm A+B). Secondary objectives are to compare a PCV13 schedule at 2, 4 and 9 months of age with a PCV10 schedule at 2, 4 and 9 months of age (Arm E vs. Arm C), and to compare the responses to a single dose of PCV13 or PCV10 (Arm E vs. Arm D).

Other objectives are: to examine the decline in pneumococcal antibody levels over time (Arm B); to describe the serotype profile of transferred maternal pneumococcal antibodies (Arm A); and to describe the early rates of carriage (Arms A-F); to evaluate a single dose of PCV10 at 18 months of age (Arm F); and to evaluate the immunogenicity of Infanrix-hexa at 18 months of age in children who have received three doses of Infanrix-hexa or three doses of Quinvaxem (DTwP-Hib-HBV) in infancy.

Sample Size

The proposed infant sample size is 1200 with an allocation ratio of 3:3:5:4:5:4, resulting in arm sizes of: A=150, B=150, C=250, D=200, E=250, F=200. Sample size calculations were based on the primary outcomes for each of the two study questions: the post-primary series immunogenicity comparing 1) a two dose (Arm C) and three dose (Arm A+B) PCV10 primary series and 2) a two dose PCV13 (Arm E) and three dose PCV10 (Arm A+B) primary series. A non-inferiority margin of 10% difference in absolute risk (Arm A+B minus Arm C or Arm E), as used by regulatory authorities, is deemed clinically significant. The Farrington-Manning (1990) method was used for the sample size/power estimation, assuming one-sided 5% type I error. If the alternative hypotheses of non-inferiority are accepted for at least 7 out of 10 serotypes, overall non-inferiority will be declared. The power for testing individual serotype hypotheses was calculated using PASS Software 2002. The power for rejecting the overall null hypothesis was estimated by simulation, using a tailor-made simulation program written for implementation in Stata with 10,000 replications. A sample size of 1200 results in >99% power for rejecting the overall null hypothesis for each of the two study questions, allowing for 5% loss to follow-up at four weeks post-primary series. An additional 200 participants aged 18 months (Arm G) will be recruited at the same time as participants from Arms A-F reach 18 months of age, bringing the total sample size of the trial to 1400 participants.

Inclusion criteria

• Aged between 2 months and 2 months plus 2 weeks (Arms A-F) or aged between 18 months and 18 months plus 2 weeks (Arm G)
• No significant maternal or perinatal history
• Born at or after 36 weeks gestation
• Written and signed informed consent from parent/legal guardian
• Lives within approximately 30 minutes of the commune health centre
• Family anticipates living in the study area for the next 22 months (Arms A-F) or 6 months (Arm G)
• Has received three doses of either Infanrix-hexa or Quinvaxem in infancy (Arm G)

Exclusion criteria

• Known allergy to any component of the vaccine
• Allergic reaction or anaphylactic reaction to any previous vaccine
• Known immunodeficiency disorder
• Known HIV-infected mother
• Known thrombocytopenia or coagulation disorder
• On immunosuppressive medication
• Administration or planned administration of any immunoglobulin or blood product since birth
• Severe birth defect requiring ongoing medical care
• Chronic or progressive disease
• Seizure disorder
• History of invasive pneumococcal, meningococcal or Haemophilus influenzae type b diseases, or tetanus, measles, pertussis or diphtheria infections
• Receipt of any 2 month vaccines through the EPI program (Arms A-F) or receipt of PCV (Arm G)
• Family plans on giving the infant Quinvaxem or oral polio vaccine (Arms A-F)