Assessment of Antibody Responses in UK Infants Given Two Doses of 10 or 13 Valent Pneumococcal Conjugate Vaccine (PCV) in Infancy and PCV13 in the Second Year of Life (Study Code: Pneumococcal in New Combinations (PINC))

The UK Department of Health provides a routine vaccination schedule for children in the UK which is administered by GP surgeries. The schedule is updated by the addition of antigens and amendment of products and schedules over time to improve the protection afforded to the paediatric population and the overall cost-effectiveness of the programme.

It is now well established that the effects of giving different vaccines and antigens together, as well as the order and numbers of doses given for priming and boosting, can affect the immunological responses they elicit. For example co-administration of different polysaccharide conjugate vaccines may enhance responses as shown in a prior study by our group - the National Vaccine Evaluation Consortium (NVEC). This demonstrated that the tetanus-toxoid conjugated MCC vaccine enhanced the response to a co-administered Hib conjugate vaccine if it was also conjugated to tetanus toxoid . In some cases, more than one conjugate vaccine is available for the same disease, as occurred in the early days of the Hib programme when vaccines conjugated to tetanus toxoid or CRM - a natural nontoxigenic diphtheria protein- were both available. NVEC therefore conducted a study to assess the impact of interchanging the two different Hib conjugate vaccines for the three dose primary immunisation course. This showed that interchanging the two different Hib conjugates for primary immunisation did not compromise immune responses and some mixed schedules gave higher antibody responses than those in which all three doses were given with the same conjugate. However, when mixed schedules of MCC-TT and MCC-CRM were subsequently studied by NVEC a MCC-CRM/MCC-TT two dose schedule was shown to be inferior to those in which MCC-TT was given as the first priming dose.

Until now, the UK has used pneumococcal conjugate vaccines from Pfizer in the form of seven or 13 valent PCV, with the current schedule recommending vaccination with PCV13 at 2, 4 and 12 months of age (2+1 schedule). The 13 polysaccharide serotypes in PCV13 are conjugated to CRM. More recently a 10 valent conjugate vaccine manufactured by GSK (PCV10) has been licensed for use in the UK as a 2+1 schedule. The 10 serotypes in PCV10 are also in PCV13 but it lacks serotypes 3, 6A and 19A. No significant protection in vaccinated infants has been shown by PCV13 against serotype 3 [Andrews et al 2014] and for 6A and 19A PCV10 has been shown to provide some cross protection against these serotypes. Like PCV13, PCV10 is safe and efficacious and is in global use. Unlike PCV13, however, the proteins used for conjugation in PCV10 are a mixture of Haemophilus influenzae protein D, tetanus toxoid and diphtheria toxoid. As with Hib and MCC conjugate vaccines, having two PCV products that could be used in the UK schedule would provide reassurance about vaccine supply and could improve cost effectiveness by reducing vaccine cost. However, if PCV10 vaccine is to be considered for use in the UK, particularly if a combination of PCV10 and PCV13 is used in the national schedule, this would require evidence of the adequate immunogenicity of a mixed schedule and this cannot be inferred from the experience with Hib and MCC conjugates.

The results of a clinical trial in which PCV13 was used for the two priming doses at 2 and 4 months followed by a PCV10 booster dose at 12 months has recently been reported. This showed that a protective antibody response post-booster (serotype specific antibody level by ELISA ≥0.35ug/mL) to 9 of the 13 PCV31 serotypes was achieved by at least 97% of infants boosted with PCV10 whereas PCV13 boosted infants achieved at least 97% protective responses to 11 of the 13 serotypes. For 10 of the 13 serotypes the geometric mean concentrations of antibodies were significantly higher in PCV13 boosted infants and for 3 serotypes were higher in PCV10 boosted infants. This study suggests that mixed PCV schedules in which the CRM-based vaccine is given first may not be optimal.

This study will build on this work, and will assess the alternative combination, which will be PCV10 for priming followed by PCV13 for boosting. The comparator arm will be the current standard of care. The study will therefore include two groups: