Prevention of invasive pneumococcal disease (IPD) is the primary goal of pneumococcal conjugate vaccination in infants. Effectiveness against overall IPD has generally remained high although IPD caused by non-PCV7 types has increased in some high risk groups and regions, particularly associated with serotypes 19A, 6A, and 33F. These increases have been described as a 'replacement phenomenon'. In addition there are ongoing outbreaks of IPD due to non-PCV7 types; in the NT and WA serotypes 1 and 12F account for resurgence in IPD cases in otherwise low risk groups. Effectiveness of PCVs for all-cause pneumonia and otitis media has been greatly compromised by replacement serotypes and the broad diversity of non-pneumococcal respiratory bacterial pathogens which continue to cause high rates of disease, such as non-typeable H. influenzae (NTHi). Replacement serotypes, particularly 19A(2,3) and NTHi, are the targets of new generation vaccines. In Australia two new PCVs are licensed: 10-valent pneumococcal-Haemophilus influenzae protein-D conjugate vaccine, PHiD-CV10 (Synflorix, GSK) and 13-valent PCV, PCV13 (Prevenar13, Pfizer). The two vaccines have 10 pneumococcal serotypes in common (1,4,5,6B,7F,9V,14,18C,19F,23F), however these are conjugated to different carrier proteins and immune correlates indicate potential vaccine differences in efficacy for individual serotypes. PHiD-CV10 has protein D of NTHi as the carrier for some serotypes and PCV13 is non-toxic diphtheria protein (CRM197)-conjugated, as was its precursor PCV7, and has three additional serotypes (3, 6A and 19A) but not HiD. There have been no efficacy trials that directly compare these vaccines; licensure has been based on immune correlates of protection in comparison with PCV7. Evidence of HiD efficacy has come from a single RCT in which otitis media was a primary outcome. In that trial of the original formulation (PHiD-CV11) there was ~55% efficacy for vaccine type AOM, and 35% efficacy for NTHi AOM following a 3+1 schedule.(3) This trial also demonstrated a 43% (95% Confidence Interval (CI): -17 to 72, ns) reduction in the carriage of vaccine serotypes and a 43% (95% CI: 1-67) reduction in the carriage of H. influenzae. This finding has not been replicated in later trials, partially due to very low baseline rates of NTHi carriage (<10%) and thus low power to achieve statistical significance. The PREV-IX_COMBO trial will therefore be very important in providing data on immunological correlates and carriage for different PHiD-CV10 schedules. However, an extended follow-up and comparison of booster dose (this PREV-IX_BOOST proposal) will provide further evidence for or against inclusion of PHiD-CV10 as a booster (compared to the NT standard PCV13 at 18 months).