Study Setting and Sample Size
The study was carried for the population of Nigerian children aged < 5 years at risk of having diarrhoea. The population figure was estimated from the 2019 population report [5]. The starting population used was children aged < 1 year, since it is the vaccination age for rotavirus vaccine. Children aged < 1 year were followed for up to 5 years to capture the associated costs and benefits of rotavirus vaccination. Ten consecutive cohorts were used in the analysis from the year 2021 to 2030, which represent periods during and after the transition out of Gavi support.
Study Perspective
The study was carried out from two perspectives: the health sector (payer) and the societal. The payer perspective represents the government perspective, which captures the effect of Gavi support for Nigeria. In this perspective, the costs of the vaccines used were the co-financed costs that will be incurred by the Nigerian government and the associated cost of immunization delivery (cold chain cost, transportation cost, personnel cost, and other logistics-related costs). The societal perspective included the complete cost of the vaccines (assuming no Gavi subsidy).
Interventions
This study compared four scenarios. The first scenario was ‘no vaccination’. The second scenario was vaccination with ROTARIX, a live attenuated monovalent human liquid oral rotavirus vaccine (RV1) manufactured by GlaxoSmithKline Biologicals, Belgium. The third scenario was vaccination with ROTAVAC, a live attenuated monovalent human-bovine liquid frozen oral rotavirus vaccine (RV1), manufactured by Bharat Biotech, India. The fourth scenario was vaccination with ROTASIIL, a live attenuated pentavalent bovine-human reassortant lyophilized oral rotavirus vaccine (RV5), manufactured by the Serum Institute of India. The ‘no vaccination’ scenario was compared with the rotavirus vaccine scenarios. The three rotavirus vaccine scenarios were also compared to determine which scenario would optimize resource utilization.
Model and Assumptions
The study employed a simulation-based Markov model using retrospective data for Nigeria. The states in the model were well, moderate diarrhoea, severe diarrhoea, and death. The starting age in the model was 1 week. The population aged < 1 year was modelled from week 1 to week 260, which implies that the children were followed up for 5 years. The infants were modelled to start from the well state, and they could move to any or remain in a health state or die as a result of diarrhoea or all-cause mortality. The model states and transitions are illustrated in Fig. 1.
The transition probabilities of moving to the different health states (well, moderate, or severe diarrhoea), transition probabilities to diarrhoeal death for < 1 year, 1–4 years, and all-cause mortality, and the disability weights for moderate and severe diarrhoea were obtained from the 2019 IHME report for Nigeria [1]. The probabilities of recurrent moderate and severe diarrhoea were estimated from a systematic review [6], and the life table data were obtained from the World Health Organisation (WHO) report [7]. The yearly probabilities were modelled as weekly probabilities.
For each cycle, the model estimated the number of moderate and severe rotavirus gastroenteritis (RVGE) cases and the number of deaths and accumulated deaths over 5 years for each scenario. Based on the care-seeking characteristics of caregivers for children aged < 5 years in Nigeria [8,9,10], 75% of moderate RVGE and 50% of severe RVGE will be managed at home with oral rehydration salt (ORS) or other fluids purchased at drug stores, traditional approaches, or other means. Only 25% of moderate RVGE cases will seek outpatient healthcare [8,9,10], and 50% of severe RVGE cases will seek care and be managed in hospital [9, 10]. The duration of moderate RVGE was estimated to be 5 days, and severe RVGE was 8 days [6]. Children with moderate RVGE received ORS and zinc for 5 days; children with severe RVGE received ringer’s lactate intravenous fluid (IVF) (for 3 days), ORS (for the following 5 days), and zinc (for 10 days) [11]. From observed practices in Nigeria, for moderate RVGE, it was assumed that patients would visit the clinic once as outpatients except if the case worsened and led to severe diarrhoea, whereas patients with severe RVGE would be hospitalized for 3 days and visit the clinic on the last day (8th day). Details of the input parameters are shown in Table 1 and in the electronic supplementary material (ESM).
Table 1 Parameters used in the analysis Time Horizon and Discount Rate
The model simulated costs and outcomes within the period of 260 weeks for the population at risk of having diarrhoea for the different scenarios and cohorts (the year 2021–2030). A recommended discount rate of 5% for low- and middle-income countries was used in the costs and outcomes analysis [20].
Vaccine Coverage, Effectiveness, and Wastage
The diphtheria-tetanus-pertussis (DTP3) coverage rate of 57% for Nigeria was used in estimating the costs and outcomes of the analysis [12]. The effectiveness of the first and last doses of ROTARIX was obtained from a systematic review for countries with high diarrhoeal mortality [13]. The effectiveness of the first, second, and last doses of ROTAVAC was estimated from a clinical trial in India [14], and the effectiveness of the first, second, and last doses of ROTASIIL was estimated from two clinical trials in India and Niger [15, 16]. The first dose of ROTARIX, ROTAVAC, and ROTASIIL was administered at week 6 after birth in the model. The second dose of ROTAVAC and ROTASIIL was administered at week 16, whereas the last dose of the three vaccines was administered at week 24 after birth. The effect of herd immunity with rotavirus vaccination was applied in the model by incorporating the post-vaccination effectiveness of the vaccine to the cohort in the model at 2, 4, 8, 12, 24, 36, 48, 72, 96, 144, and 192 weeks after vaccination [17].
Using the WHO vaccine wastage rates calculator, wastage rates were estimated at 4% for ROTARIX from the year 2021 to 2030; 50% for ROTAVAC (five-vial size) from the year 2021 to 2025 and 51% for the same pack size from the year 2026 to 2030; 21% for ROTASIIL (two-vial size) from the year 2021 to 2026 and 22% for the same pack size from the year 2027 to 2030 [18]. Details of the vaccines’ effectiveness and wastage are shown in Table 1.
Calculation of Cost
The WHO guidelines for estimating the costs of introducing new vaccines into the national immunization system were adopted to estimate the resource use and costs associated with the introduction of ROTARIX, ROTAVAC (five-vial size), or ROTASIIL (two-vial size) [25]. A bottom-up costing approach was used in the analysis. Costs were estimated from the payer and societal perspectives, respectively. The costs included vaccine cost (full dose), personnel cost (including salaries to healthcare professionals, health assistants, and administrative staff; advocacy and social mobilization costs; surveillance costs), and logistic costs (costs of vaccine storage in the cold chain, vaccine transportation, vehicles and vehicle maintenance, training/education of immunization staff, and wastage cost). The vaccine price used was the United Nations Children’s Fund (UNICEF) supply price for Gavi-eligible countries [2]. Based on vaccination coverage, population, and gross domestic product per capita (GDP), the immunization delivery costs were estimated from the immunization delivery cost catalogue of the Immunization Costing Action Network, Washington [23]. Costs captured all personnel and logistics costs related to immunization delivery, including buildings and utilities, safety boxes, syringes, and other recurrent costs. The UNICEF international handling cost of 3.5% for new vaccines for non-least developed countries and an international transportation cost of 7.5% of the vaccine price were included in the vaccine cost [22]. The waste-adjusted vaccine cost and the waste-adjusted cold chain volume and cost were factored in the final cost of each vial of vaccine and the immunization delivery cost. In calculating the annual vaccine cost based on the vaccination coverage and the WHO guideline [25], the cost of reserve stock was included in the first year. The reserve stock was estimated as 25% of the vaccine cost in the year 2021. The cost of rotavirus vaccination was calculated for each year from 2021 to 2030 using the formula c = p × n, where p is the price per dose of new vaccine (including wastage cost and international handling and freight) and n is the number of doses.
For the payer perspective, a starting fraction of 0.24 was used on the unadjusted vaccine price based on Nigeria’s co-financing contribution for all co-financed vaccines [3, 21]. Based on Gavi’s co-financing guideline for phase 2 transitioning countries, a 1.15 factor of price fraction was applied to the starting fraction in the year 2021 unadjusted vaccine costing [21]. From the year 2022 to 2028, the cost increased linearly to reach 100%. From the year 2029 to 2030, the cost was modelled such that Nigeria will fully self-finance the vaccine cost at the UNICEF’s price. For the societal perspective, Gavi subsidy was not considered. To estimate the cost of RVGE from the health sector or payer perspective, the cost included was the direct medical cost of treatment at the health facilities, whereas the societal perspective costs included direct medical, direct non-medical, and indirect costs of treatment at health facilities plus the costs of self-management at home (for cases that did not visit a health facility). The cost of self-care management at home was assumed to be the cost of ORS since the majority of caregivers use rehydration fluid [8]. An average cost of ORS for 3 days was assumed and used to estimate the costs of self-management at home [8]. The direct non-medical costs included the cost of diapers for 5 days (moderate RVGE) and 8 days (severe RVGE) and transportation costs. Indirect costs were estimated as productivity loss due to work absenteeism of caregiver (half a day for moderate RVGE and 1 day for severe RVGE) based on Nigeria’s 2019 GDP per capita. The direct costs of moderate and severe RVGE, including physician consultancy, nursing service, hospital bed, ORS, IVF, and zinc, were estimated from the Nigerian National Health Insurance Scheme drug price list [26]. The number of moderate and severe RVGE cases averted was multiplied by their respective mean cost of management to obtain the monetary savings. All costs were expressed in $US, year 2019 values. Gamma distribution was used to capture the uncertainty in the cost parameters. Details of the cost components are shown in Table 1 and the ESM.
The budget impact of the programme was also estimated. This was done by calculating the annual cost of RVGE healthcare at health facilities averted from 2021 to 2030. For each year, the net budget impact was estimated as the difference between the vaccination programme cost for that year and the healthcare cost averted for the same year. The total net budget impact was the sum of the net budget impact from 2021 to 2030.
Health Outcomes
The primary outcome was measured as disability-adjusted life-year (DALY) averted. The DALY was calculated as the sum of the years of life lived with disability (YLD) from morbidity and the years of life lost (YLL) from mortality. YLD = number of cases × duration till remission or death × disability weight [27, 28], and YLL = number of deaths due to diarrhoea × life expectancy at the age of death [28]. The DALYs across each cycle were summed and averaged to obtain the standard DALY. The DALY averted was calculated as the difference between the ‘no vaccination’ DALY and the DALY in the rotavirus vaccination scenarios. The primary outcome was used to evaluate the benefit-cost ratio (BCR) and the incremental cost-effectiveness ratio (ICER), which are the two approaches for assessment in this study. In calculating the monetary value of a DALY averted for the BCR evaluation, the Harvard-led guideline for conducting benefit-cost analysis projects was used [29]. The valuation was based on the value of statistical life-year with 1 DALY averted valued at 1.3 times the gross national income (GNI) per capita of a country in sub-Saharan Africa. For the ICER evaluation, a conservative cost-effectiveness threshold of 0.52 times the GDP per capita of Nigeria was used [30].
The secondary outcomes of the study included the total number of RVGE cases averted, the number of moderate RVGE cases averted, the number of severe RVGE hospitalizations averted, and the number of RVGE deaths averted. The averted cases were calculated as the difference between the ‘no vaccination’ scenario and the rotavirus vaccination scenarios.
Data Analyses
The appropriate distribution for each variable was used, as shown in Table 1. Half-cycle correction using the lifetable method was applied in the analysis [31]. Probabilistic sensitivity analysis (PSA) was used to assess simultaneous uncertainty in many variables [32]. To assess how simultaneous change of several variables affected the costs and outcomes, a Monte-Carlo simulation (1000 iterations per vaccine) was performed. This technique runs many simulations by repeatedly drawing samples from probability distributions of input variables. Univariate sensitivity analysis was also performed on the key parameters to observe their effect on the costs and outcomes. A ‘what-if’ scenario if vaccine wastage were reduced by 50% was tested to observe the effect of wastage on the optimal choice between the rotavirus vaccines. All analyses were performed using Microsoft Excel, 365.