Randomized, open-label study of the impact of age on booster responses to the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine in children in India.

Randomized, Open-Label Study of the Impact of Age on Booster Responses to the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine in Children in India Sanjay Lalwani,a Sukanta Chatterjee,b Jugesh Chhatwal,c Anna Simon,d Sudheer Ravula,e Nancy Francois,f Shailesh Mehta,g Ana Strezova,h Dorota Borysf Department of Pediatrics, Bharati Vidyapeeth Deemed University Medical College, Pune, Indiaa; KPC Medical College, Kolkata, Indiab; Department of Pediatrics, Christian Medical College and Hospital, Punjab, Indiac; Department of Child Health, Christian Medical College, Vellore, Indiad; GlaxoSmithKline Pharmaceuticals Ltd., Bangalore, Indiae; GlaxoSmithKline Vaccines, Wavre, Belgiumf; GlaxoSmithKline Pharmaceuticals, Mumbai, Indiag; XPE Pharma Science, Wavre, Belgiumh In this phase III, open-label, multicenter, and descriptive study in India, children primed with 3 doses (at ages 6, 10, and 14 weeks) of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were randomized (1:1) to receive a booster dose at 9 to 12 (early booster) or 15 to 18 months old (late booster) in order to evaluate impact of age at booster. We also evaluated a 2-dose catch-up vaccination plus an experimental booster dose in unprimed children age 12 to 18 months. The early booster, late booster, and catch-up vaccinations were administered to 74, 95, and 87 children, respectively; 66, 71, and 81 children, respectively, were included in the immunogenicity according-to-protocol cohort. One month postbooster, for each PHiD-CV serotype, >95.2% (early booster) and >93.8% (late booster) of the children had antibody concentrations of >0.2 ␮g/ml; >96.7% and >93.0%, respectively, had opsonophagocytic activity (OPA) titers of >8. The postbooster antibody geometric mean concentrations (GMCs) were in similar ranges for early and late boosters; the OPA titers appeared to be lower for most PHiD-CV serotypes (except 6B and 19F) after the early booster. After dose 2 and postbooster, for each PHiD-CV serotype, >88.6% and >96.3%, respectively, of the catch-up immunogenicity according-to-protocol cohort had antibody concentrations of >0.2 ␮g/ml; >71.4% and >90.6%, respectively, had OPA titers of >8. At least 1 serious adverse event was reported by 2 children in the early booster (skin infection and gastroenteritis) and 1 child in the catch-up group (febrile convulsion and urinary tract infection); all were resolved, and none were considered by the investigators to be vaccine related. PHiD-CV induced robust immune responses regardless of age at booster. Booster vaccination following 2 catch-up doses induced robust immune responses indicative of effective priming and immunological memory. (These studies have been registered at www.clinicaltrials.gov under registration no. NCT01030822 and NCT00814710; a protocol summary is available at www .gsk-clinicalstudyregister.com [study ID 112909]). S treptococcus pneumoniae is the leading cause of pneumonia, meningitis, and septicemia. Worldwide, pneumococcal infections are estimated to have been responsible for 541,000 deaths in 2008 in children ⬍5 years of age, with a high burden in Southeast Asia (108,000 deaths in 2008 in children ⬍5 years) (http://www.who.int/ immunization/monitoring_surveillance/burden/estimates/Pneumo _hib/en/). The 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) has been shown to be immunogenic and well tolerated in infants in India (1). Moreover, recent double-blind randomized controlled trials demonstrated that infant vaccination with PHiD-CV was effective in preventing vaccine-type invasive pneumococcal disease (2, 3), communityacquired pneumonia (4, 5), and acute otitis media (6). PHiD-CV is typically given as a 2- or 3-dose primary series in infants, with a booster dose administered in their second year of life. However, in some countries, vaccination visits beyond the first year are not routine; thus, vaccination ends at the age of ⱕ6 months, without a booster dose being administered. Developing countries generally opt for a 3-dose primary schedule for PHiDCV, without a booster dose. Moreover, compliance with vaccination decreases as children get older (7). Nevertheless, epidemiological and clinical evidence with other pneumococcal conjugate vaccine (PCV) formulations suggest that booster vaccination may be of high value (8). Recently, the World Health Organization 1292 cvi.asm.org Clinical and Vaccine Immunology (WHO) has also endorsed a 2-dose schedule starting at 6 weeks of age, followed by a third dose at 9 to 15 months of age (9). The current study compared the immunogenicity and safety of PHiD-CV booster doses given at 9 to 12 months and at 15 to 18 months old. Antibody persistence in both groups was assessed up to the age of 24 months (9 to 15 months after booster vaccination). In addition, this study assessed the immunogenicity and safety of PHiD-CV administered as a 2-dose catch-up schedule in unprimed children in their second year of life, followed by an experimental booster dose. Received 13 February 2014 Returned for modification 13 March 2014 Accepted 13 June 2014 Published ahead of print 9 July 2014 Editor: D. L. Burns Address correspondence to Sanjay Lalwani, . Supplemental material for this article may be found at http://dx.doi.org/10.1128 /CVI.00068-14. Copyright © 2014, American Society for Microbiology. All Rights Reserved. doi:10.1128/CVI.00068-14 The authors have paid a fee to allow immediate free access to this article. p. 1292–1300 September 2014 Volume 21 Number 9 PHiD-CV Booster and Catch-Up Vaccination FIG 1 Study design for the early and late booster vaccination (A) and catch-up vaccination (B). W, weeks; M, months; syringe, vaccination; BS, blood sampling. Due to a delay in the study start, the age range for receiving the booster dose in the 9- to 12-month group was extended to 9 to 18 months of age, but only the results for the 9- to 12-month subgroup were used for the assessment of the early booster. MATERIALS AND METHODS Study objectives. The primary objective was to assess the immune responses following vaccination with a PHiD-CV booster dose in children age 9 to 12 months (early booster group) or 15 to 18 months (late booster group) who were previously vaccinated with 3 PHiD-CV doses at 6, 10, and 14 weeks of age (1). The secondary objectives comprised an assessment of antibody persistence following primary vaccination and booster vaccination up to approximately 24 months of age, as well as an assessment of the safety and reactogenicity of the booster dose. Additionally, we assessed the immunogenicity and safety of PHiD-CV when administered as a 2-dose catch-up immunization during the second year of life (12 to 18 months of age at the time of first vaccination), followed by an experimental booster dose at 18 to 24 months of age. Study design. This was a phase III randomized study (Cl (...truncated)