Table 3 Main findings for each cost...

Table 3

Main findings for each cost category

R&D, preclinical, early clinical and registration costs	With regards to R&D costs (8 out of 39 contributions selected contained details on costs related to vaccine R&D), most of the studies just report total costs, which range from US $100 million estimated for Ebola vaccines (Phelps et al., 2017) to 2 billion (Oyston and Robinson, 2012) that refer to some common estimates for a single vaccine, based on development costs for new drugs previously elaborated (Light et al., 2009)
	However, only little R&D costs estimation is present in the literature (Waye et al., 2013). Furthermore, no clear detail is provided about the methodology used to come up with the total figure, pointing out the need to improve the R&D costs data. The only exception among the selected articles is represented by the study from Light et al. (2009) that, comparing two different rotavirus vaccines, provides information on estimated trial and development costs, finely distinguishing also among Phase I, II and III and considering both a low and a high estimate scenario. For both vaccines, in the low scenario, Phase III accounted for more than 98% of total costs (99.3 and 98.6%). Still, in the high estimation, which included US $200 million for possibly setting up new manufacturing capacity, Phase III covered around 50% of costs (50.3 and 48.4%)
Investments in production plant and Cost of goods sold	The next two categories are usually overlooked when estimating cost of vaccine introduction (respectively, 3 and 1 out of the 39 contributions contain related information). As for production plant, there are two main scenarios to be considered: one in which the vaccine requires the construction of a new production plant and the other in which only an incremental cost for an already existing plant is required. A range between US $50 to 700 million is reported (Plotkin et al., 2017) and includes facilities and equipment capitalized costs that depreciate over time, considering a period of 10 (Aguado et al., 2015) and 15 years (Light et al., 2009). According to Light et al. (2009), in the first scenario, the cost is about US $200 million. Examined studies do not provide cost estimations for the second scenario
Investments in production plant and Cost of goods sold	As for the cost of goods sold, precise estimations are lacking. The per-dose cost of goods sold to develop a meningococcal group A vaccine for a US manufacturer is estimated between US $0.35–1.35, considering volumes of 25–50 million doses annually and depending on composition, doses/vials number and formulation type (Aguado et al., 2015)
Vaccine delivery costs	Among the 39 analyzed studies, 14 contain quantitative information on delivery costs. Most of them provide overall costs, without distinguishing between service and vaccine delivery costs, but dividing them according to the following variables: vaccine type, doses, immunization campaigns, country and immunization site (facilities, urban and rural settings)
	As reported in Table 4, when estimated as a unique figure, mass vaccination campaigns costs range from US $0.30 to 2.09 (Cravioto et al., 2012). Range estimation is much wider for routine immunization: US $0.50 is the lowest bound (Diop et al., 2015), while US $8.07 is the highest (Schütte et al., 2015)
	Unit delivery cost per fully immunized individual with mass vaccination campaign against cholera ranges from US $0.53 to 2.09 (Cravioto et al., 2012). Unit delivery cost per fully immunized child of new and underutilized vaccines is significantly higher and it is also affected by the hospital where immunization takes place. Estimations for Ghana range from US $23.64 for urban reproductive and child health facilities to US $80.94 for rural community health-based planning and services facilities (Le Gargasson et al., 2015). Some articles, focusing on vaccine supply chain per dose costs, report a range between US $0.43 and 1.21 (Mvundura et al., 2015). Others provide specific components estimations, such as cold chain (Constenla, 2015; Vaughan et al., 2020; Memirie et al., 2020), transportation (Cravioto et al., 2012), vehicles, gas price per liter and personnel costs (Vaughan et al., 2020; Portnoy et al., 2015). Some contributions interestingly distinguish between urban and rural facilities (Schütte et al., 2015): delivery costs to rural centers, on average, are almost three times the costs of urban centers. Only one study explicitly provides delivery costs as an estimated incremental cost per dose (US $0.50), assuming that existing immunization program staff are involved (Diop et al., 2015)
Vaccination program preparation costs	Seven out of the 39 contributions analyzed contain information on program preparation costs. As shown in Table 4, estimation for overall program preparation costs range between US $0.42 and 1.22 (Mogasale et al., 2016). Some articles provide specific information on the subcategories described in Table 2. In particular, costs for microplanning ranges from US $0.040 per dose in supplementary activities for measles (Cravioto et al., 2012) to $0.53 per fully immunized child in South Sudan with oral cholera, expressed in 2014 dollars (Mogasale et al., 2016) The lower bound for training preparation costs is US $0.040 per dose, estimated for measles (Cravioto et al., 2012), while the upper bound is US $0.53 for a child fully immunized against cholera in Tanzania (Mogasale et al., 2016). Sensitization and social mobilization are often estimated together and range from US $0.05 for a child fully immunized against cholera to US $0.069 (Mogasale et al., 2016). Program preparation costs include training as well: sometimes the cost of training is computed as a separate element (Memirie et al., 2020), while in other papers it is computed with other components, Gosset et al. (2021) estimate the cost of planning, budgeting, training, for the introduction of the Hepatitis B birth dose, in Senegal as equal to US $0.00535
Vaccination program preparation costs	Preparation costs are sometimes included in operating costs and considered as direct costs together with cold chain maintenance and vaccine administration costs (Carias et al., 2015) or they are not distinguished from service delivery and monitoring and surveillance costs (Colombini et al., 2015)
Vaccine administration costs	Nineteen studies out of those selected contain information on materials and supplies costs, either in percentage or in monetary terms. As reported in Table 4, costs per dose of vaccine supplies range from US $0.06 (Schütte et al., 2015) to US $0.19 (Antillón et al., 2017). Here vaccine injection and other supplies costs are also distinguished between urban and rural facilities (Antillón et al., 2017). Some studies estimate vaccine and injection material costs together with others: mean costs per dose of meningococcal routine vaccination equal to US $0.90 and 0.73 when computed on the projection period 2015–2035 are reported (Colombini et al., 2015)
	No specific information can be retrieved on site preparation costs, while detailed costs are provided for personnel's costs. Some contributions contain useful data on hourly wage in specific African countries (Portnoy et al., 2015). The personnel's cost per dose ranges from US $0.05, which is the minimum immunization-specific, routine recurrent personnel cost per dose, estimated for 94 countries by Portnoy et al. (2015) to US$ 4.44 for routine immunization in rural health centers in Zambia (Schütte et al., 2015). Salaried labor routine immunization costs per dose differentiate according to facility type and location (Schütte et al., 2015): in urban health center cost per dose is US $1.00, while in rural health center the same cost rises up to US $4.44. Interestingly, the opportunity cost of volunteers' time is equal to US $0.80 per dose. Some estimates include not only the time cost per dose of health workers, but also transport costs: using this classification, costs of US $0.99 (0.82) and US $2.15 ($1.64) are reported in Kenya and in Tanzania, respectively (Mvundura et al., 2015)
	Supervision and monitoring costs range from US $0.006 for Hepatitis B birth dose (Gosset et al., 2021) to 0.12 (Irurzun-Lopez et al., 2016) including personnel, transportation, laboratory, office and recurrent and capital costs. Erondu et al. (2019) focus their systematic review on vaccine preventable disease surveillance, which includes the on-going collection, analysis and dissemination of health data and report per-capita costs ranging from US $0.02 to 0.16
	Specific estimations on waste management are lacking, as they are often included in overall vaccine administration costs. The evaluation of the resources needed for effective waste management, including both capital costs (i.e. incinerators and any buildings required) and recurrent costs (i.e. incinerator fuel and maintenance, training and salaries) is actually difficult (WHO, 2002)
	In some studies, vaccine administration costs are included into operational costs (Carias et al., 2015). Values range from US $0.30 for operational cost per dose of cholera vaccines in Bangladesh, including logistics, social mobilization, training, monitoring and surveillance, and personnel costs, to US $3.61 for typhoid conjugate vaccines in Kenya, both for routine and catch-up vaccination (Cravioto et al., 2012) when transportation costs and injection materials are included as well (Antillón et al., 2017)
	When costs are distinguished among different facility types (Le Gargasson et al., 2015), costs per routine dose administered appear to be higher in rural community health-based planning and services facilities (US $8), and lower in urban clinics (US $2.16), emphasizing the additional costs associated with reaching children in various settings. When vaccine administration costs are computed as a unique figure, costs per dose range from US $0.41, in the case of pre-emptive vaccination in a refugee rural camp in Uganda, to US $5.10 when referring to pre-emptive vaccination, taken in a rural and urban setting in Tanzania (Mogasale et al., 2016)
Vaccine procurement costs	Fifteen studies report information on vaccine FOB price (Freight on Board, i.e. the vaccine price before shipping, insurance and customs costs are added). In the initial phases of production, when there is often only one producer, the public sector has limited information and the initial price tends to be high. Then, price declines overtime due to improvements in production capacity, economies of scale and potential competition (Kulkarni et al., 2015). In developing countries, vaccine price strategy differs from the one usually applied in developed countries, where the price derives from the amount the market will bear rather than from the cost (Diop et al., 2015)
	As Table 4 shows, the literature provides a wide range of estimations on vaccine prices per dose, from US $0.09 for tuberculosis computed as an average price for 73 GAVI eligible countries between 2011 and 2020 (Portnoy et al., 2015), to US $7.00 for rotavirus and pneumococcal vaccine in Ghana (Le Gargasson et al., 2015; Atherly et al., 2009). Estimations for oral cholera range from US $1.00 to US $6.70 (Mogasale et al., 2016). For pneumococcal, the low estimate of the vaccine price is US $2.60 and the high one 7.00 (Le Gargasson et al., 2015), while the estimates for the initial price for rotavirus vaccine are around US $2.50 in Kenya, Uganda and Ghana (Sigei et al., 2015).Estimates below or around US $0.50 can be found for measles (Le Gargasson et al., 2015; Portnoy et al., 2015) and meningitis A (Le Berlier et al., 2015; Portnoy et al., 2015)
	Specific information on customs, insurance and freight can be found in IVI (International Vaccine Institute) Report (Cravioto et al., 2012). IVI includes infectious disease experts, health professionals and humanitarian leaders and its mission reads: “Discover, develop and deliver safe, effective and affordable vaccines for global public health” (https://www.ivi.int/). Hence, there is a clear lack of information in the literature concerning additional costs to be applied to vaccine price in order to be able to compute full procurement costs, the so-called CIF (Cost, Insurance and Freight). These additional costs per dose of oral cholera are estimated as being equal to $0.22 for shipping and handling, corresponding to 15% of the vaccine price
	Mogasale et al. (2016) report estimations on total procurement costs for fully immunized individual against oral cholera in Guinea, South Sudan and Uganda, pointing out that this category accounts for the highest proportion of total vaccination program costs. Results range from $0.29 for Dukoral oral cholera vaccination, in rural Uganda, in a refugee camp and in a pre-emptive vaccination setting, to $7.96 for Shancol oral cholera vaccination, in South Sudan, in the case of a pre-emptive vaccination setting
Costs borne by households	This review includes also the costs borne by households to obtain the vaccination that, although being a minor cost category, should be considered in order to provide a more cost accountability (Cravioto et al., 2012). This cost category, mainly referring to time and transportation needed to reach the vaccination point and get the vaccination, tends to be overlooked because of poor data and information availability. Among the analyzed contributions, the 2012 IVI Report (Cravioto et al., 2012) estimates such cost as being equal to US $0.11. Other studies attempt at analyzing the travel time for households to the nearest public hospital, which is a useful piece of information to assess the costs borne by households (Marsh and Rouhani, 2018)
Costs associated with AEFI	In the contributions analyzed, Adverse Events Following Immunization are widely described and their occurrence explained (Enwere et al., 2015; Gessner and Halsey, 2017) but a quantitative evaluation of the costs associated with their management is lacking. The latter should include salary of trained staff engaged in monitoring, food and transportation costs, medical and advisory service provision and laboratory investigation (Mogasale et al., 2016). The only estimation found is computed for India (Mogasale et al., 2016) as reported in Table 4

R&D, preclinical, early clinical and registration costs	With regards to R&D costs (8 out of 39 contributions selected contained details on costs related to vaccine R&D), most of the studies just report total costs, which range from US $100 million estimated for Ebola vaccines (Phelps et al., 2017) to 2 billion (Oyston and Robinson, 2012) that refer to some common estimates for a single vaccine, based on development costs for new drugs previously elaborated (Light et al., 2009)
	However, only little R&D costs estimation is present in the literature (Waye et al., 2013). Furthermore, no clear detail is provided about the methodology used to come up with the total figure, pointing out the need to improve the R&D costs data. The only exception among the selected articles is represented by the study from Light et al. (2009) that, comparing two different rotavirus vaccines, provides information on estimated trial and development costs, finely distinguishing also among Phase I, II and III and considering both a low and a high estimate scenario. For both vaccines, in the low scenario, Phase III accounted for more than 98% of total costs (99.3 and 98.6%). Still, in the high estimation, which included US $200 million for possibly setting up new manufacturing capacity, Phase III covered around 50% of costs (50.3 and 48.4%)
Investments in production plant and Cost of goods sold	The next two categories are usually overlooked when estimating cost of vaccine introduction (respectively, 3 and 1 out of the 39 contributions contain related information). As for production plant, there are two main scenarios to be considered: one in which the vaccine requires the construction of a new production plant and the other in which only an incremental cost for an already existing plant is required. A range between US $50 to 700 million is reported (Plotkin et al., 2017) and includes facilities and equipment capitalized costs that depreciate over time, considering a period of 10 (Aguado et al., 2015) and 15 years (Light et al., 2009). According to Light et al. (2009), in the first scenario, the cost is about US $200 million. Examined studies do not provide cost estimations for the second scenario
Investments in production plant and Cost of goods sold	As for the cost of goods sold, precise estimations are lacking. The per-dose cost of goods sold to develop a meningococcal group A vaccine for a US manufacturer is estimated between US $0.35–1.35, considering volumes of 25–50 million doses annually and depending on composition, doses/vials number and formulation type (Aguado et al., 2015)
Vaccine delivery costs	Among the 39 analyzed studies, 14 contain quantitative information on delivery costs. Most of them provide overall costs, without distinguishing between service and vaccine delivery costs, but dividing them according to the following variables: vaccine type, doses, immunization campaigns, country and immunization site (facilities, urban and rural settings)
	As reported in Table 4, when estimated as a unique figure, mass vaccination campaigns costs range from US $0.30 to 2.09 (Cravioto et al., 2012). Range estimation is much wider for routine immunization: US $0.50 is the lowest bound (Diop et al., 2015), while US $8.07 is the highest (Schütte et al., 2015)
	Unit delivery cost per fully immunized individual with mass vaccination campaign against cholera ranges from US $0.53 to 2.09 (Cravioto et al., 2012). Unit delivery cost per fully immunized child of new and underutilized vaccines is significantly higher and it is also affected by the hospital where immunization takes place. Estimations for Ghana range from US $23.64 for urban reproductive and child health facilities to US $80.94 for rural community health-based planning and services facilities (Le Gargasson et al., 2015). Some articles, focusing on vaccine supply chain per dose costs, report a range between US $0.43 and 1.21 (Mvundura et al., 2015). Others provide specific components estimations, such as cold chain (Constenla, 2015; Vaughan et al., 2020; Memirie et al., 2020), transportation (Cravioto et al., 2012), vehicles, gas price per liter and personnel costs (Vaughan et al., 2020; Portnoy et al., 2015). Some contributions interestingly distinguish between urban and rural facilities (Schütte et al., 2015): delivery costs to rural centers, on average, are almost three times the costs of urban centers. Only one study explicitly provides delivery costs as an estimated incremental cost per dose (US $0.50), assuming that existing immunization program staff are involved (Diop et al., 2015)
Vaccination program preparation costs	Seven out of the 39 contributions analyzed contain information on program preparation costs. As shown in Table 4, estimation for overall program preparation costs range between US $0.42 and 1.22 (Mogasale et al., 2016). Some articles provide specific information on the subcategories described in Table 2. In particular, costs for microplanning ranges from US $0.040 per dose in supplementary activities for measles (Cravioto et al., 2012) to $0.53 per fully immunized child in South Sudan with oral cholera, expressed in 2014 dollars (Mogasale et al., 2016) The lower bound for training preparation costs is US $0.040 per dose, estimated for measles (Cravioto et al., 2012), while the upper bound is US $0.53 for a child fully immunized against cholera in Tanzania (Mogasale et al., 2016). Sensitization and social mobilization are often estimated together and range from US $0.05 for a child fully immunized against cholera to US $0.069 (Mogasale et al., 2016). Program preparation costs include training as well: sometimes the cost of training is computed as a separate element (Memirie et al., 2020), while in other papers it is computed with other components, Gosset et al. (2021) estimate the cost of planning, budgeting, training, for the introduction of the Hepatitis B birth dose, in Senegal as equal to US $0.00535
Vaccination program preparation costs	Preparation costs are sometimes included in operating costs and considered as direct costs together with cold chain maintenance and vaccine administration costs (Carias et al., 2015) or they are not distinguished from service delivery and monitoring and surveillance costs (Colombini et al., 2015)
Vaccine administration costs	Nineteen studies out of those selected contain information on materials and supplies costs, either in percentage or in monetary terms. As reported in Table 4, costs per dose of vaccine supplies range from US $0.06 (Schütte et al., 2015) to US $0.19 (Antillón et al., 2017). Here vaccine injection and other supplies costs are also distinguished between urban and rural facilities (Antillón et al., 2017). Some studies estimate vaccine and injection material costs together with others: mean costs per dose of meningococcal routine vaccination equal to US $0.90 and 0.73 when computed on the projection period 2015–2035 are reported (Colombini et al., 2015)
	No specific information can be retrieved on site preparation costs, while detailed costs are provided for personnel's costs. Some contributions contain useful data on hourly wage in specific African countries (Portnoy et al., 2015). The personnel's cost per dose ranges from US $0.05, which is the minimum immunization-specific, routine recurrent personnel cost per dose, estimated for 94 countries by Portnoy et al. (2015) to US$ 4.44 for routine immunization in rural health centers in Zambia (Schütte et al., 2015). Salaried labor routine immunization costs per dose differentiate according to facility type and location (Schütte et al., 2015): in urban health center cost per dose is US $1.00, while in rural health center the same cost rises up to US $4.44. Interestingly, the opportunity cost of volunteers' time is equal to US $0.80 per dose. Some estimates include not only the time cost per dose of health workers, but also transport costs: using this classification, costs of US $0.99 (0.82) and US $2.15 ($1.64) are reported in Kenya and in Tanzania, respectively (Mvundura et al., 2015)
	Supervision and monitoring costs range from US $0.006 for Hepatitis B birth dose (Gosset et al., 2021) to 0.12 (Irurzun-Lopez et al., 2016) including personnel, transportation, laboratory, office and recurrent and capital costs. Erondu et al. (2019) focus their systematic review on vaccine preventable disease surveillance, which includes the on-going collection, analysis and dissemination of health data and report per-capita costs ranging from US $0.02 to 0.16
	Specific estimations on waste management are lacking, as they are often included in overall vaccine administration costs. The evaluation of the resources needed for effective waste management, including both capital costs (i.e. incinerators and any buildings required) and recurrent costs (i.e. incinerator fuel and maintenance, training and salaries) is actually difficult (WHO, 2002)
	In some studies, vaccine administration costs are included into operational costs (Carias et al., 2015). Values range from US $0.30 for operational cost per dose of cholera vaccines in Bangladesh, including logistics, social mobilization, training, monitoring and surveillance, and personnel costs, to US $3.61 for typhoid conjugate vaccines in Kenya, both for routine and catch-up vaccination (Cravioto et al., 2012) when transportation costs and injection materials are included as well (Antillón et al., 2017)
	When costs are distinguished among different facility types (Le Gargasson et al., 2015), costs per routine dose administered appear to be higher in rural community health-based planning and services facilities (US $8), and lower in urban clinics (US $2.16), emphasizing the additional costs associated with reaching children in various settings. When vaccine administration costs are computed as a unique figure, costs per dose range from US $0.41, in the case of pre-emptive vaccination in a refugee rural camp in Uganda, to US $5.10 when referring to pre-emptive vaccination, taken in a rural and urban setting in Tanzania (Mogasale et al., 2016)
Vaccine procurement costs	Fifteen studies report information on vaccine FOB price (Freight on Board, i.e. the vaccine price before shipping, insurance and customs costs are added). In the initial phases of production, when there is often only one producer, the public sector has limited information and the initial price tends to be high. Then, price declines overtime due to improvements in production capacity, economies of scale and potential competition (Kulkarni et al., 2015). In developing countries, vaccine price strategy differs from the one usually applied in developed countries, where the price derives from the amount the market will bear rather than from the cost (Diop et al., 2015)
	As Table 4 shows, the literature provides a wide range of estimations on vaccine prices per dose, from US $0.09 for tuberculosis computed as an average price for 73 GAVI eligible countries between 2011 and 2020 (Portnoy et al., 2015), to US $7.00 for rotavirus and pneumococcal vaccine in Ghana (Le Gargasson et al., 2015; Atherly et al., 2009). Estimations for oral cholera range from US $1.00 to US $6.70 (Mogasale et al., 2016). For pneumococcal, the low estimate of the vaccine price is US $2.60 and the high one 7.00 (Le Gargasson et al., 2015), while the estimates for the initial price for rotavirus vaccine are around US $2.50 in Kenya, Uganda and Ghana (Sigei et al., 2015).Estimates below or around US $0.50 can be found for measles (Le Gargasson et al., 2015; Portnoy et al., 2015) and meningitis A (Le Berlier et al., 2015; Portnoy et al., 2015)
	Specific information on customs, insurance and freight can be found in IVI (International Vaccine Institute) Report (Cravioto et al., 2012). IVI includes infectious disease experts, health professionals and humanitarian leaders and its mission reads: “Discover, develop and deliver safe, effective and affordable vaccines for global public health” (https://www.ivi.int/). Hence, there is a clear lack of information in the literature concerning additional costs to be applied to vaccine price in order to be able to compute full procurement costs, the so-called CIF (Cost, Insurance and Freight). These additional costs per dose of oral cholera are estimated as being equal to $0.22 for shipping and handling, corresponding to 15% of the vaccine price
	Mogasale et al. (2016) report estimations on total procurement costs for fully immunized individual against oral cholera in Guinea, South Sudan and Uganda, pointing out that this category accounts for the highest proportion of total vaccination program costs. Results range from $0.29 for Dukoral oral cholera vaccination, in rural Uganda, in a refugee camp and in a pre-emptive vaccination setting, to $7.96 for Shancol oral cholera vaccination, in South Sudan, in the case of a pre-emptive vaccination setting
Costs borne by households	This review includes also the costs borne by households to obtain the vaccination that, although being a minor cost category, should be considered in order to provide a more cost accountability (Cravioto et al., 2012). This cost category, mainly referring to time and transportation needed to reach the vaccination point and get the vaccination, tends to be overlooked because of poor data and information availability. Among the analyzed contributions, the 2012 IVI Report (Cravioto et al., 2012) estimates such cost as being equal to US $0.11. Other studies attempt at analyzing the travel time for households to the nearest public hospital, which is a useful piece of information to assess the costs borne by households (Marsh and Rouhani, 2018)
Costs associated with AEFI	In the contributions analyzed, Adverse Events Following Immunization are widely described and their occurrence explained (Enwere et al., 2015; Gessner and Halsey, 2017) but a quantitative evaluation of the costs associated with their management is lacking. The latter should include salary of trained staff engaged in monitoring, food and transportation costs, medical and advisory service provision and laboratory investigation (Mogasale et al., 2016). The only estimation found is computed for India (Mogasale et al., 2016) as reported in Table 4

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