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.

Global control of pneumococcal disease is hampered by the cost of pneumococcal conjugate vaccine (PCV). GAVI will spend 2.8 billion USD on PCV in the next 5 years and country co-payments to GAVI are substantial. Cost prevents middle-income countries from introducing PCV.

We propose to test a schedule that includes a booster dose at 9 months of age. We hypothesise that the first dose in the new schedule, at age 6 weeks, will provide protection against a low risk of disease from 2-9 months of age in our setting and that the booster dose will provide superior direct and herd protection effects from 1-3 years of age.

The trial will compare two- versus three-dose schedules in a cluster-randomised fashion according to immunisation clinics which serve subpopulations in discrete geographic areas.

We will deliver two-dose ('1+1') or three-dose ('3+0') schedules to infants resident in the trial area over a period of 4 years. The national immunisation programme will administer vaccines at 68 immunisation clinics serving separate catchment populations (clusters). The clusters will be randomised to either group in a 1:1 ratio. Safety monitoring for IPD, radiologic pneumonia and mortality in the 1-59 month age group will be conducted throughout. The trial endpoints will be measured during the 4th year of the trial. The primary endpoint will be the prevalence of nasopharyngeal (NP) vaccine-type (VT) pneumococcal carriage in children aged 1-59 months with clinical pneumonia. The secondary endpoint will be VT pneumococcal carriage in unimmunised infants aged 6-12 weeks. 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. We will conduct a cost-effectiveness analysis comparing 1+1 and 3+0 schedules, and a multi-country investigation of factors influencing the implementation of 1+1 schedules.

The GAVI Alliance will be a major beneficiary of the trial findings. If low-income countries transitioned to two-dose (1+1) schedules for pneumococcal conjugate vaccine (PCV) then GAVI Alliance expenditure could be reduced by up to $330 million USD per year. Donors to the GAVI Alliance may also benefit from reduced requests for finance. The UK for example, has pledged 2.1 billion USD to GAVI in the next 5 years (29% of the total GAVI budget). If Ministries of Health are able to adopt 1+1 schedules, national immunisation programme costs will be reduced by 5%-15% in GAVI eligible countries, 15%-40% in GAVI graduating countries, and upwards of 50% in middle-income countries which must purchase PCV on the open market.

Ministries of Health and immunisation programmes in low-income countries will benefit from our findings as will National Immunisation Technical Advisory Groups. Assuming the 1+1 schedule is non-inferior to the three-dose (3+0) schedule, low-income countries may transition to the new schedule. In doing so they will benefit their whole populations by providing a more flexible, acceptable, and sustainable pneumococcal vaccination programme. The reduction from three to two doses of PCV in the schedule will result in: one less injection to administer, additional 'space' for new vaccines, reduced cold-chain requirements, reduced staff time and reduced injection pain for infants and mothers.

Ministries of Finance may benefit from reduced expenditure on immunisation. Regulatory authorities would use the trial data to evaluate proposals to introduce the 1+1 schedule in their jurisdictions. Other groups with an interest in the trial will be community stakeholders and UNICEF.

Immunisation programmes in middle-income countries may also benefit. The beneficiaries would be children and older individuals gaining access to the benefits of PCV in countries that decide to introduce PCV based on the trial findings and the cost-effectiveness benefits. Even in high-income countries, transition to a 1+1 schedule would result in more sustainable immunisation programmes with greater potential to introduce additional beneficial vaccines.

This trial will complement other studies investigating the role of the 1+1 schedule, providing the only data from a typical African setting. This trial will provide definitive results generalisable to a range of different settings. This is the ideal setting in which a study would detect the inferiority of a PCV schedule that relies on herd protection compared to another because herd protection is most difficult to establish in situations where infection pressure is high. Thus, if this trial demonstrates the non-inferiority of the 1+1 schedule one may infer that it would be non-inferior in a wide range of settings. Importantly, this trial will include disease and mortality measures which will provide confidence in the use of 1+1 schedules in settings with high rates of child morbidity and mortality. Thus, the study will act as a pivotal trial influencing global recommendation for immunisation.

The proposed mathematical modelling will generate further evidence to support the generalisation of the trial findings. The model will illustrate the role of the booster dose, and its coverage, in generating herd protection.

Perhaps the most profound impact of this study is its potential to usher in a new approach to disease control through immunisation. It will demonstrate a fundamentally new approach; an initial schedule introduced to control disease followed by transition to a schedule with fewer doses but able to maintain disease control. If this new approach proves feasible, we may see a new era of more flexible, acceptable, and less costly immunisation programmes worldwide.

The ultimate impact of the trial will be new country introductions of PCV with greater global coverage of PCV and accelerated reductions in child mortality due to pneumococcal disease.