Pneumococcal conjugate vaccines, including PHiD-CV, are being introduced in African countries under the Advance Market Commitments for pneumococcal disease piloted by GAVI [2
]. In our study, PHiD-CV was immunogenic for all vaccine pneumococcal serotypes and NTHi protein D when given as a 3-dose primary vaccination course at 6, 10 and 14 weeks of age and co-administered with DTPw-HBV/Hib and OPV to Malian and Nigerian infants. Vaccine tolerability was comparable between the group administered PHiD-CV and the control group administered DTPw-HBV/Hib and OPV only.
One month after PHiD-CV primary vaccination at 6, 10 and 14 weeks of age, for each of the 10 vaccine serotypes high percentages of infants had an antibody concentration ≥ 0.2 μg/mL and an OPA titre ≥ 8. For several serotypes, this was despite high percentages of infants with pre-vaccination antibody concentration ≥ 0.2 μg/mL. These immune responses are consistent with previous primary vaccination studies in which PHiD-CV was administered using the same schedule [15
] or at 2, 4 and 6 months of age [15
]. As in other pneumococcal conjugate vaccine studies [8
], serotype 6B was one of the low immunogenic serotypes. However, pneumococcal conjugate vaccine trials have reported high efficacy against IPD or acute otitis media even for serotypes with lower antibody responses [8
]. The high proportions of infants with a pre-vaccination antibody concentration ≥ 0.2 μg/mL we observed in this study for several vaccine serotypes can probably be explained by maternal antibodies transferred during the last months of pregnancy rather than early exposure to S. pneumoniae
, given that antibody concentrations and percentages of infants with antibody concentration ≥ 0.2 μg/mL significantly declined in the control group by the time of post-vaccination blood draw at approximately 5 months of age. Our data however indicate that the presence of these high levels of maternal antibodies did not hamper immune responses to early infant PHiD-CV primary vaccination. It is well known that pneumococcal exposure and acquisition of pneumococcal nasopharyngeal carriage may start very early in sub-Saharan infant populations [35
] and recent publications have indicated that pneumococcal colonization at the time of primary vaccination could possibly have a negative impact on infant pneumococcal conjugate vaccine responses [37
]. Our results therefore seem to support the need to maintain early vaccination with pneumococcal conjugate vaccines in this population.
Anti-pneumococcal immune responses in this population of infants tended to be higher than those observed in European PHiD-CV primary vaccination studies [15
]. A PHiD-CV study conducted in Chile also reported stronger immune responses for all serotypes compared to European data [21
] and a study of PHiD-CV conducted in the Philippines and Poland found greater immunogenicity in Filipino infants [15
] despite the use of an accelerated schedule compared to the more immunogenic 2, 4 and 6 months schedule in Poland. Genetic factors, early exposure to pneumococcal serotypes or nasopharyngeal carriage of pneumococcal serotypes might have contributed to this effect [40
Good immune responses were also observed against DTPw-HBV/Hib, which was consistent with another study of PHiD-CV co-administered with DTPw-HBV/Hib [15
], and proportions of infants who were seroprotected or seropositive for antibodies against the DTPw-HBV/Hib antigens were high (≥ 97.8%). Antibody concentrations against the PRP, tetanus and diphtheria antigens were higher when PHiD-CV was co-administered, presumably due to enhancement of these immune responses by the tetanus toxoid and diphtheria toxoid carrier proteins used for serotypes 18C and 19F, respectively, in PHiD-CV [28
]. High antibody GMCs and seroprotection rates were however observed for these antigens in both groups, including the PRP antigen, confirming the good immunogenicity of a reduced PRP content Hib vaccine (2.5 μg of PRP) compared to the more usual 10 μg PRP vaccines [41
Addition of PHiD-CV to the routine EPI vaccination schedule at 6, 10 and 14 weeks of age did not result in increased incidences of AEs (solicited or unsolicited) relative to DTPw-HBV/Hib and OPV administered alone in the control group. There were no SAEs considered causally related to the vaccines. The overall incidences of solicited symptoms were similar between the 2 groups, with pain and fever being the most frequently reported local and general symptoms. The incidences of pain and swelling were higher at the DTPw-HBV/Hib injection site than at the PHiD-CV injection site, which was in line with another study of PHiD-CV or 7vCRM co-administered with a DTPw-based vaccine [15
]. Prophylactic use of antipyretics is recommended when PHiD-CV is co-administered with whole-cell pertussis containing vaccines [46
]. In our study, antipyretic medication use at the time of vaccination was common in both groups (for 87-89% of the doses) and antipyretic prophylaxis was used in 8-10% of vaccine doses, with similar prophylactic antipyretic use after each dose (data not shown). The incidences of grade 3 solicited symptoms were low, apart from the incidence of grade 3 swelling at the DTPw-HBV/Hib injection site after the first vaccine dose. The overall incidence of unsolicited AEs was also comparable between groups and the most frequent unsolicited AEs reported were in line with events expected in the paediatric age group studied.