Will the ongoing use of a two-dose, rather than three-dose schedule of pneumococcal conjugate vaccine, have similar impact in rural Gambia?

Many countries have introduced pneumococcal conjugate vaccines (PCV) using three or four dose schedules with substantial reductions of invasive pneumococcal disease (IPD) and pneumonia. Herd protection effects have prevented more cases than the direct effects in vaccinated children. Many African and Asian countries have now introduced PCV using the standard schedule of three doses in early infancy (3+0 schedule). Data from South Africa and Kenya suggest that direct and herd protection effects of PCV are substantial. In The Gambia, we have observed a 90% reduction in IPD due to vaccine serotypes (VT) following the introduction of PCV. Global control of pneumococcal disease however, is hampered by the cost of PCV. Low-income countries receive subsidised vaccine through the GAVI Alliance. However, when countries' per capita income exceeds the World Bank 'low-income' threshold, they 'graduate' from GAVI support and co-payments increase substantially. GAVI will spend 2.8 billion USD on PCV in the next 5 years, which represents approximately half of its vaccine budget. Cost has prevented most middle-income countries from introducing PCV. To be effective, a two-dose schedule of PCV must provide adequate direct protection in infancy and maintain the low transmission of VT pneumococci in the community that is critical to sustain herd protection. In fact, as immunisation programmes mature the role of herd protection becomes predominant over that of direct protection. Thus, we propose to test a vaccine schedule that includes a booster dose at 9 months of age, which when compared to schedules without a booster dose, has been associated with greater antibody levels at ages 1-4 years and greater protection against pneumococcal carriage at ages 1-2 years. We hypothesise that the first dose in the new schedule (at age 6 weeks) will provide protection against a low risk of VT disease from 2-9 months of age in our setting. We hypothesise that the booster dose at age 9 months will provide superior direct and herd protection effects from 1-3 years of age compared to the 3+0 schedule. This trial will compare two- versus three-dose schedules of PCV delivered according to government immunisation clinics which serve subpopulations in discrete geographic areas. We plan to deliver two-dose (doses at age 6 weeks and 9 months, '1+1') or three-dose (doses at age 6, 10, 14 weeks, '3+0') schedules to infants resident in the trial area over a period of 4 years. The immunisation programme will administer vaccines at 68 immunisation clinics serving separate catchment populations (clusters). The immunisation clinic catchment population will be randomised to either trial group (1+1 or 3+0). Safety monitoring by surveillance for IPD, pneumonia and mortality in the 1-59 month age group will be conducted throughout the trial. After allowing time for the potentially different effects of the two schedules to develop, the study endpoints will be measured during the 4th year of the trial. The primary endpoint will be nasopharyngeal carriage of VT pneumococci in children aged 1-59 months with clinical pneumonia. The secondary endpoint will be VT carriage in infants aged 6-12 weeks presenting for their 1st dose of PCV. The analysis will test whether the difference in VT carriage between the two groups is less than a pre-set threshold. Mathematical modelling will explore the role of the booster dose and the coverage needed to induce herd protection. Modelling inputs will include trial data and data from surveys of pneumococcal carriage and interpersonal contact patterns in the community. We will conduct a cost-effectiveness analysis of the 1+1 versus 3+0 schedule. Finally, working with WHO we will conduct a multi-country investigation of factors that will influence the implementation of 1+1 schedule.