FormalPara Key Points for Decision Makers

Expanding flexible vaccine manufacturing capacity (FVMC) for routine vaccines could facilitate more timely access to novel vaccines during future pandemics.

Stated and revealed preference studies, macroeconomic modelling, and benefit–cost analysis are three promising methods to estimate the societal value created by additional FVMC.

Considering this value within health technology assessment provides a potential long-term approach to help incentivise FVMC and increase pandemic preparedness.

1 Introduction

The COVID-19 pandemic has highlighted the importance of rapid vaccine development and manufacturing in a pandemic scenario. In the case of COVID-19 there were critical delays between the development of effective vaccines and the ability to provide these vaccines to the population. Expanding flexible vaccine manufacturing capacity (FVMC) for routine vaccines could facilitate more timely access to novel vaccines during future pandemics [1]. Vaccine manufacturing capacity is ‘flexible’ in this context if it is built on a technology platform that allows rapid adaption to new infectious agents, such as the mRNA technology used for some COVID-19 vaccines. As we recently outlined [2], the added value of routine vaccines produced using a flexible platform for pandemic preparedness is not currently recognised through conventional health technology assessment (HTA) methods. This paper aims to highlight the role of additional FVMC as a proactive measure to help mitigate the devastating impact of future pandemics and to explore the value drivers of FVMC, potential approaches and methods for estimating this value and ways in which this value could be rewarded, including through the HTA process.

In the context of pandemic preparedness, the extent to which manufacturing capacity is flexible depends on the speed with which production can be shifted from routine vaccines to pandemic vaccines and/or can be updated to reflect new strains or variants at short notice [3]. It is important to recognise that there are several manufacturing technologies which are “situated on a spectrum” in terms of the degree to which they are flexible and platform-based [1, 4, 5]. These technologies represent a departure from the traditional model of developing specific vaccines for individual pathogens, instead embracing a pathogen-agnostic ‘plug-and-play’ approach [4,5,6]. Prominent examples of emerging vaccine platform technologies include mRNA-based, DNA-based, and vector-based vaccines [4]. The successful use of mRNA COVID-19 vaccines has demonstrated the promise of flexible technologies and highlighted the importance of ensuring continued development and proliferation of these technologies to help combat future pandemics [2].

1.1 Economic Theory of (Product-Agnostic) Flexible Manufacturing

Economists have long recognised that there is economic value in the ability of producers to have a flexible output mix when the demand for each product varies unpredictably over time, regardless of the product being produced. If a firm invests in flexible production technologies, it can then adjust its output mix in response to changes in both output and input prices. Several research efforts have described the optimisation problem faced by a firm with a choice of whether to install and utilise product-specific manufacturing capacity or ‘flexible’ capacity which can be more easily adjusted to switch between outputs [7,8,9]. When prices are efficient, the incentives are in place for firms to make efficient decisions about which manufacturing technologies to utilise, considering the two advantages of installing production with a flexible output mix: the ability of the firm to optimise production when faced with uncertain future demand, and the firm’s ability to rapidly adapt production to new product models [7, 8].

This general concept of the ‘value of flexibility’ maps neatly onto two relative advantages of flexible vaccine manufacturing platforms: firstly, enabling a shift to production of pandemic vaccines when appropriate; and, secondly, the ability to adapt production to new pathogen strains or variants [10]. This suggests an inherent value of FVMC in making the manufacture of pandemic vaccines more responsive to changes in demand through the price mechanism—in economic terms, more ‘elastic’ [11]. However, market prices for pandemic vaccines are likely to be inefficient insofar as they are significantly lower than their societal value due to budgetary, political, and ethical issues [11,12,13,14]. As a result, economic models which suggest that firms will choose the socially optimal choice of flexible manufacturing technologies have limited applicability in the case of production of pandemic vaccines. Accordingly, firms will underinvest in FVMC unless additional support is established to reward this value.

1.2 Existing Government Initiatives

There are notable examples of prior government support for additional FVMC. For example, the U.S. Department of Health and Human Services has funded measures to maintain FVMC to improve the country’s capability to respond to emergent pandemic pathogens [15, 16]. Furthermore, in light of the COVID-19 pandemic, the European Commission (EC) has established the ‘EU FAB’ network with a budget of €160 million/year [17, 18]. This programme funds a network of ‘ever-warm’ flexible production capacity in Europe for mRNA-based, vector-based, and protein-based manufacturing capacities. The EC is granted a ‘priority manufacturing right’ in ‘crisis’ pandemic situations [19]. The aim of this initiative is to “ensure heightened supply in case of a surge in demand due to public health emergencies, by reducing the time needed between development and industrial scale-up... If needed, access and use can be activated and made available. During ‘non-crisis’ times, these facilities are used for their regular activities” [20]. The programme follows a points-based system to evaluate tenders based on price and quality criteria [19,20,21]. While these efforts demonstrate progress, it remains unclear whether current funding amounts are sufficient at both national and global levels. Further investigation into the value of FVMC is required to provide a more comprehensive understanding of its role in global pandemic preparedness.

2 What Are the Value Drivers of Flexible Vaccine Manufacturing Capacity (FVMC)?

Flexible platform technologies have distinct advantages over conventional vaccine manufacturing methods. For example, they can be more rapidly adapted to manufacture vaccines for a wider variety of potential pandemic pathogens compared with conventional technologies [4, 22]. These relative advantages are particularly pronounced when an emerging infectious disease is sufficiently serious so as to cause significant health, social, and economic disruption, such as during a future pandemic. As such, we mainly focus on the value of FVMC as a countermeasure against potential emerging pandemic scenarios.

We start by characterising how additional FVMC compares as a countermeasure to additional capacity of conventional vaccine manufacturing, considering that in both cases this capacity can either be ‘warm’ (in-use during non-pandemic times for production of routine vaccines, and repurposed for pandemic vaccine production) or ‘spare’ (sitting idle unless it is brought online for pandemic vaccine production). Table 1 shows the theoretical value of each combination in terms of four key dimensions.

Table 1 Theoretical use of flexible platforms and conventional vaccine manufacturing technologies during a future pandemic scenario
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Within the framework of ‘warm’ and ‘spare’ capacity, there are two approaches to increasing FVMC that could be potentially helpful in a future pandemic: firstly, warm production of non-pandemic routine vaccines currently produced using conventional technologies can be shifted over time to warm production on flexible platforms, meaning that this manufacturing capacity could then be converted to produce a more high-demand vaccine during a pandemic. The manufacture of any non-pandemic vaccines on ‘warm’ capacity will ensure that personnel and expertise are already in place to enable more rapid scale-up of a new vaccine using that platform. However, repurposing this capacity would come at the cost of displacing routine vaccine production during a pandemic scenario. The extent to which this is costly depends on the routine vaccine being produced and the extent of displacement, however, advanced planning could help limit this shortfall by using stockpiles or slack capacity of conventionally produced vaccines targeting the same disease [2].

Secondly, additional FVMC can be created by maintaining spare capacity or implementing ‘ever-warm’ (under-utilised) production which operates below peak capacity, lying between ‘warm’ and ‘spare’ utilisation. ‘Ever-warm’ production retains some of the benefits of ‘warm’ capacity by keeping supply chains and technical staff in place and ready to rapidly expand production to a vaccine targeting an emerging pandemic [23], with less displacement of routine vaccine production [19].

Regardless of the approach used, there are two expected advantages of increasing the levels of FVMC: first, that the production of new vaccines targeting novel emergent infectious diseases can be scaled up more quickly, facilitating faster initial vaccine access; and second, that a higher share of manufacturing capacity would be used to produce vaccines which can be more rapidly modified to target emerging variants, potentially leading to higher vaccine efficacies.

2.1 Key Factors for Estimating the Value of Additional FVMC

FVMC will exist on some scale regardless of whether or not policymakers create incentives for additional capacity. Having previously argued that additional capacity is likely warranted as a pandemic countermeasure, the focus of this section is to consider how researchers could assess the incremental value of additional manufacturing capacity in a future pandemic to inform the degree to which additional capacity should be targeted through further incentives. We have identified three key factors that are important to consider:

  1. 1.

    The likelihood and severity of potential future pandemic scenarios.

  2. 2.

    The extent to which additional FVMC would expedite the rollout of vaccines during each scenario.

  3. 3.

    The societal value associated with accelerating vaccine rollout in each scenario.

To inform the first factor, historical data can be used to estimate the joint likelihood of pandemic occurrence and severity [24, 25]. Addressing the second factor requires an understanding that the primary advantage of flexible over conventional manufacturing capacity lies in its potential ability to accelerate access to vaccines targeting emerging infectious diseases. The speed advantage of flexible over conventional manufacturing techniques is well established [1,2,3], but the extent to which roll-out is accelerated would need to be estimated, for example, by soliciting expert input and by examining experiences with vaccine production using different flexible platform technologies. A critical part of this estimation process will involve understanding the extent to which additional FVMC will speed up the roll-out of a novel vaccine for an emergent threat, given that some level of FVMC will exist even without additional incentives. This is important because the value of a pandemic vaccine depends on the timing of its rollout relative to the timing of the risk from the emergent disease threat. A vaccine which comes into mass production a year after the emergence of a novel, highly contagious disease may be significantly less valuable if a majority of the population has already been infected [26]. Any speed advantage of additional FVMC during the initial phases of a future pandemic may also depend on whether capacity was warm or idle.

The third question forms the crux of the estimation exercise. The value of additional FVMC is closely intertwined with the value of pandemic vaccines themselves. Several efforts—spurred further by the COVID-19 pandemic—have sought to more comprehensively understand and measure the value of both routine and pandemic vaccines in terms of individual health benefits as well as broader societal and economic value [27,28,29,30,31]. The broader value elements go beyond the ‘core’ costs and benefits included in most conventional cost-effectiveness estimates (i.e., the net effects on aggregate healthcare costs and quality of life, potentially including those from herd protection) to consider other factors such as macroeconomic effects and productivity gains to patients and carers [32,33,34]. Incorporating these broader value elements can significantly impact the cost effectiveness of health technologies like vaccines [35]. In addition to estimating the value of more rapid access to a pandemic vaccine from additional FVMC, attempts could also be made to incorporate the potential efficacy advantage associated with being able to more rapidly modify the vaccine to target emerging variants.

Although not an exhaustive list, we discuss several salient conceptual value factors relevant to FVMC and pandemic vaccines below.

2.2 Examples of Broader Value Drivers That Are Relevant to FVMC

The availability of additional FVMC in the event of a pandemic provides reassurance during non-pandemic times that a vaccine will be available more rapidly when it is needed. The peace of mind that healthcare will be available when needed, which in turn reduces physical and financial risks, is generally referred to in the existing literature as ‘insurance value’ [28, 33, 34]. The two components—physical risk protection and financial risk protection—refer to the aversion of individuals to health risks and the ability of individuals to insure against them [34]. In the context of FVMC, insurance value is generated even during non-pandemic times [26]. The significance of insurance value becomes even more apparent when the health and/or financial risks at play are large, as would be the case in a catastrophic pandemic.

Closely related to the idea of ‘insurance value’ is the concept of ‘fear of contagion’ associated with emerging infectious diseases. This factor is a form of psychological distress, and there is a corresponding value in reducing this fear [33, 34]. A stronger capability to combat a pandemic, should one arise, is expected to help to reduce this fear. This value element is conceptually similar to insurance value but is primarily focused on the period after the emergence of a new infectious disease, such as after an initial outbreak before vaccination is available to provide protection against the contagion. By accelerating access to vaccines, FVMC could shorten the window during which this fear affects the at-risk population.

Pandemic vaccines also produce important economic benefits. One approach to measure this benefit is to apply standard methods of incorporating microeconomic effects into health economic evaluations, such as direct productivity gains of an intervention owing to reduced illness and workplace absenteeism [34]. In this approach, the economy-wide impact is estimated by aggregating these individual-level effects across the affected population. However, pandemics also have significant macroeconomic effects which can be conceptualised at the population level from the outset [36]. For example, timely access to pandemic vaccines can reduce the risk and intensity of pandemic-induced recessions by permitting the earlier relaxation of economically disruptive mitigation measures such as lockdowns or restrictions on trade and travel.

The potentially catastrophic nature of future pandemics also highlights elements of value relevant to FVMC that have received less attention in existing frameworks developed for all medical technologies [34]. A catastrophic pandemic refers to a global outbreak of infectious disease that incapacitates or causes death in a significant portion of the global population [29]. Such an event can result from either naturally emerging pathogens or those released accidentally or intentionally, such as through bioterrorism or biowarfare. Catastrophic scenarios would engender “profound social disruption” and potential long-term alterations to society, “in the extreme [causing] civilisational collapse [and/or] human extinction” [29, p. 2]. Conventional methods of valuing disease risk, and medical interventions to mitigate them, may be insufficient for estimating the value of additional FVMC in catastrophic pandemic scenarios.

To illustrate this, consider whether society should place greater priority on preventing a disease which kills 10% of the population once every hundred years or a disease which causes one in a thousand people to die every year [37]. An individual’s annual mortality risk is one in a thousand in both cases, meaning that conventional economic evaluation methods assign the same burden to each disease. However, large, highly correlated disease risk can lead to catastrophic health, economic, and social outcomes, such as disruptions to essential worker functions, macroeconomic instability, and overwhelming strain on health care systems due to capacity limitations. We argue (as others have) that such highly correlated risks across the population deserves more attention and resources [38].

This would suggest that technologies which mitigate severe highly correlated disease risks have a higher societal value compared with those that address idiosyncratic risks to individuals, all else being equal. This can be conceptualised as either (a) societal risk aversion, indicating a societal preference for lower variance in potential population-level health outcomes, that can be incorporated in a model’s social welfare function; or (b) a broader value element that augments the overall value of FVMC in a similar manner to insurance value. In either case, insofar as FVMC helps to mitigate large, highly correlated disease risk, it has ‘catastrophic risk avoidance value’.

3 Methods for Estimation

There exists a significant gap between the conceptual understanding of the value drivers relevant to FVMC and the availability of accurate and reliable tools for their estimation which can be integrated into the HTA decision-making process [22]. We have identified three specific tools which would be useful and feasible first steps to estimate one or more of the valuable attributes of FVMC: stated and revealed preference studies, benefit–cost analysis (BCA), and macroeconomic modelling. It is unlikely that any single method can comprehensively capture the entire societal value of additional FVMC (key factor #3), including both the ‘core’ value drivers of FVMC as well as broader value considerations. Instead, these methods can be used in two ways; firstly, individual methods could provide an ‘order-of-magnitude’ estimate by capturing specific aspects of the value of FVMC; and, secondly, a more eclectic approach could link together different types of evidence from various methods to estimate a more comprehensive measure of value, taking care to avoid double counting.

3.1 Stated Preference and Revealed Preference Studies

Stated preference (SP) and revealed preference (RP) studies are potential methods for estimating the value which society places on pandemic preparedness measures. For example, through a survey administered to a representative sample, one form of SP study named contingent valuation (CV) elicits individuals’ willingness to pay for specific goods or outcomes [39]. In the context of pandemic preparedness, CV studies have been conducted to estimate the willingness to pay of individuals or society for access (or faster access) to vaccines during a pandemic [40,41,42]. A study of seven European countries found that most respondents were willing to pay for faster access, and would have on average paid €54.36 for immediate access to a 100% effective COVID-19 vaccine, and €43.83 for a 60% effective vaccine in January/February 2021 [43]. RP, on the other hand, uses observations of real-world behaviour to estimate the value people place on accessing a service or avoiding a risk; in the vaccine context, these observations may be market data on how much consumers or governments actually paid to access vaccines (or access vaccines more rapidly) during previous pandemics.

Using SP/RP studies to estimate the contribution of additional FVMC to pandemic preparedness presents challenges. The complex link between FVMC and pandemic preparedness may be difficult for individuals without context-specific knowledge to understand [44]. Thus, SP/RP studies should be applied narrowly to estimate the value associated with accelerating vaccine rollout (key factor #3), which could then be combined with the other key factors we outline (key factors #1/2)—which would not be estimated with SP/RP—to estimate the public’s (implied) willingness to pay for additional levels of FVMC. Depending on the research design, SP/RP studies could be used to estimate both ‘core’ and ‘broad’ aspects of value [32, 34].

Another possible use of SP/RP studies in this context is re-estimation of the Value of Statistical Life (VSL) for use in BCA (see Sect. 3.3). Many potential shortcomings of applying established VSL estimates for the pricing of pandemic risks have already been highlighted, including the potential need for adjustments based on the incidence of risk by age or income distribution [45]. Further adjustments may be required as current estimates tend to underestimate the value of avoiding catastrophic risks [46, 47]. SP/RP studies could be conducted to re-estimate VSL in a way that captures the added value of protection against large-scale harm at the population level, such as by incorporating society’s current willingness to pay to avert long-term damage done by catastrophic pandemics to future generations [48, 49].

3.2 Macroeconomic Modelling

Faster access to pandemic vaccines can alleviate the burden on healthcare systems and expedite the return to normal economic activity. Macroeconomic models offer a means to quantify the economic benefits of accelerated vaccine access, for example in terms of the impact on gross domestic product (GDP). Several studies have employed models to estimate the macroeconomic benefits of accelerated COVID-19 vaccine access. Castillo et al. [12] estimated that an extra billion doses per year of capacity brought online in April 2021 (adding to a baseline capacity of 3 billion) would have averted nearly half a trillion dollars in GDP losses alone. Other researchers have employed Computable General Equilibrium models to estimate the macroeconomic effects of pandemics [50, 51], such as COVID-19 [52], and policy interventions to mitigate them, including vaccination programmes [53].

Macroeconomic modelling is well suited to approximate the magnitude of macroeconomic costs associated with delays in vaccine access and to sense check how the cost of an incentive compares to the benefits, as measured by averted macroeconomic losses. However, when the model outcome is economic output (i.e. impact on GDP) rather than the net societal benefit, direct comparison with the cost of the intervention becomes challenging. While some papers estimate pandemic-related economic losses by aggregating foregone GDP with health and mortality losses [54], a more accurate approach is to use ‘equivalent variation’ to convert lost economic output into welfare losses before comparing with costs [52, 55].

3.3 Benefit–Cost Analysis

Benefit–cost analysis (BCA) is a commonly employed tool for evaluating the economic consequences of decisions. The process includes quantifying, monetising, and aggregating various benefits and costs, potentially encompassing both health-related and non-health-related factors depending on the analysis perspective [56]. In the context of FVMC, this method could be used to estimate the (monetised) health and non-health benefits of FVMC for pandemic preparedness, incorporating both the broader value elements (such as those discussed earlier) and ‘core’ value drivers like expected net healthcare costs and health gains [57]. This approach aligns with recommendations to incorporate broader value elements into the economic evaluation of pandemic vaccines within conventional HTA [33].

A 2019 report by the Council of Economic Advisors uses a BCA-style approach to estimate that immediate access to a suitable vaccine could produce US$730 billion in benefit to the US during an ‘average’ influenza pandemic [26]. Taking into account the annual likelihood of an influenza pandemic, this faster access amounts to an estimated annual per capita benefit of US$89.63 assuming that the effectiveness of this (FVMC-produced) pandemic vaccine is the same as one produced using conventional (egg-based) manufacturing. Notably, the study indicated that government payers reimburse FVMC-produced routine vaccines below a value-based price that reflects their contribution to pandemic preparedness, as the annual per capita value of faster pandemic vaccine access likely exceeds the price premium paid to FVMC-produced routine vaccines over those manufactured using conventional techniques [26].

A relevant consideration, particularly salient for the valuation of FVMC, is the adjustment for the value of catastrophic risk avoidance. The prevailing vaccine-valuation literature often assumes a risk-neutral stance, overlooking population-level risks associated with the potential contribution to preparedness against catastrophic and existential risks [29, 38]. Thus, further refinements can be applied to enhance the validity of BCA methods in a pandemic context [58].

4 Methods to Reward Value

As we have argued, additional incentives are needed to achieve the societally optimal level of FVMC [14]. Even once the value of additional FVMC and the appropriate size of incentives are better understood, optimal design of these incentives needs to be comprehensively studied. Government incentives of the sort currently being trialled by EU-FAB are one option (see Sect. 1.2 ‘Existing Government Initiatives’). Another potential strategy involves government guarantees of expected market prices of pandemic vaccines that are more closely aligned with their societal benefits, such as through advanced market commitments (AMCs) [13, 59,60,61]. This mechanism could enable governments to provide financial incentives for firms to expand FVMC during non-pandemic times in anticipation of potential future pandemics; however, in the context of expanding FVMC as a pandemic countermeasure, governments would have to commit to purchasing vaccines when there are still many unknowns.

Another possible approach is to reward the value as part of the routine HTA process for non-pandemic vaccines manufactured using FVMC, for example, based on the expected value of additional FVMC in future pandemics. Building assessment of FVMC into the existing routine HTA process has the potential to ensure that incentives are sustained over the long run, rather than being linked to specific government initiatives. Long-term sustainability is important for pandemic preparedness as the time between future pandemic risks is unknown and can potentially be decades or more.

There are a number of potential approaches used in routine HTA that can be taken to reward value that is not currently captured in conventional cost-effectiveness analyses. One relatively simple approach could be to adjust the cost-effectiveness thresholds applied in specific circumstances to account for the currently unrecognised value of FVMC. For example, HTA could potentially apply a higher cost-effectiveness threshold to routine vaccines manufactured using FVMC. This adjustment would increase reimbursable prices for these vaccines, sending signals (which favour FMVC over conventional manufacturing capacity) to innovators and manufacturers, and potentially allow these vaccines to be funded for populations where they would otherwise not be deemed cost effective. The use of a higher threshold has been put forward for other types of interventions where elements of value or social preferences are not well captured in conventional cost-effectiveness analyses. For example, the National Institute for Clinical Excellence (NICE) has recommended a higher acceptability threshold for its highly specialised technology assessment process which can apply to certain so-called ‘orphan drugs’ [62]. NICE has also recognised that ‘innovation’ could be taken into account when deciding if an intervention should be funded above the standard cost-effectiveness threshold [63]. One limitation of this approach is that the appropriate magnitude of change to the cost-effectiveness threshold is difficult to quantify (e.g. how much higher should a threshold be for a routine vaccine manufactured using FVMC that could be adapted for use in a future pandemic emergency?).

An alternative approach to include unrecognised value is to expand what costs and benefits are considered within (or in addition to) conventional cost-effectiveness analyses for vaccines as part of the HTA process [64]. As previously discussed, in recent years there has been substantial interest in better understanding elements of value that are not currently captured in cost-effectiveness analyses (e.g. the so-called ‘value flower’) [34]. Similar research into the consideration of ‘broader’ value elements has also been explored specifically for vaccines, which, partly due to their population level effects, may have substantial levels of unrecognised value [65, 66]. This research has set the foundations for the potential expansion of the elements of value considered in vaccine HTA decision making. This could theoretically occur in a qualitative way by consideration of these elements separately to cost-effectiveness results in the HTA process, as sometimes occurs for aspects of equity [67], or in a quantitative way through an expansion of the elements of value that can be included within cost-effectiveness analyses. If the former approach is employed, multi-criteria decision analysis (MCDA) may be useful for aggregating different considerations in a deliberative process. If the latter was to be considered, an intermediate step could be to allow inclusion in (supplementary) scenario analysis only, as is sometimes recommended for productivity costs [68].

To implement either proposed strategy, we recommend that value assessors follow a two-step process: first, to estimate the potential (incremental) increase in FVMC that would be available during a future pandemic if a vaccine manufactured on FVMC is adopted; and second, to use the valuation methods recommended above to assign an estimated societal value to this additional FVMC. Regardless of whether this value is operationalised in HTA through threshold adjustments or as an expanded value element, companies would incorporate these price signals in internal decision making, for example, by weighing more favourable reimbursement of FVMC-produced vaccines with the financial costs and capital requirements of different vaccine manufacturing processes. See Table 2 for a summary of the available incentive mechanisms discussed herein.

Table 2 Summary of available incentive mechanisms to induce higher levels of FVMC
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The best choice of method to reward the shadow price of FVMC may depend on the particular features of a country’s HTA and reimbursement systems for vaccines. For example, not all settings formally incorporate cost-effectiveness analysis in their decision-making process for vaccines. Whatever the approach used to incentivise/reward FVMC, appropriate contractual arrangements would need to be in place to ensure that additional manufacturing capacity could be effectively used in a future pandemic. Otherwise, decision makers may risk paying more for additional FVMC that is not available when needed. The use of contractual arrangements in a pandemic emergency is a complex and challenging area [11, 14]. It highlights issues around vaccine nationalism, equity and the competition between countries to secure initially limited vaccine supply in the face of a pandemic threat [69]. Finally, it should be recognised that not all FVMC is equal in terms of the degree to which they are flexible and in their likely utility for tackling emergent infectious disease threats [1, 4, 5]. There may also be important benefits in maintaining diversity of vaccine manufacturing capacity and in the consideration of the potential biosecurity risks of different vaccine technologies [2, 70].

4.1 The Role of Uncertainty in the Recognition of the Value of Additional FVMC

One complicating factor in the recognition of the value of additional FVMC is that there is currently a high degree of uncertainty as to the magnitude of the value. Furthermore, parts of this uncertainty are unavoidable as the timing and magnitude of potential future pandemic threats are inherently uncertain. In routine HTA, a high degree of uncertainty in cost-effectiveness estimates is a common reason for funding rejection, particularly where an intervention has a cost-effectiveness estimate that is high compared with standard acceptable thresholds [63]. This reflects the understandable caution that decision makers have around funding interventions where there is high uncertainty. One way to deal with higher levels of uncertainty has been the use of managed entry schemes, such as performance-based agreements [71, 72]. Unfortunately, the funding of non-pandemic vaccines provides little additional information to reduce the uncertainty about the value from additional FVMC. This may leave decision makers in the difficult position of trying to value a potentially very large but highly uncertain unrecognised benefit. Sensitivity analysis can be a useful way to present the uncertain results by making this uncertainty more explicit [73].

Further research may be able to reduce the existing level of uncertainty and provide stronger evidence that the potential value is too large to ignore. Estimating the likelihood of low-probability catastrophic pandemics presents methodological challenges [74], but assuming the value is zero is not an appropriate solution [75]. Future research may be able to draw from methods used in the analysis of environmental goods and climate change, which tackle similar estimation problems ranging from mild to potentially catastrophic scenarios [25, 76].

5 Conclusion

The availability of additional FVMC that shortens lead times between the detection of an emerging infectious disease and the roll out of a vaccine to the population holds significant potential to help mitigate the scale of damage from a future pandemic. Despite a growing awareness of the need to incorporate broader elements of the value of innovations in HTA, the contribution to pandemic preparedness from the manufacturing of routine vaccines using FVMC remains unrecognised. This paper helps to address this gap in the literature by exploring methods for measuring the value of flexible technology platforms and potential strategies to incorporate this value within HTA frameworks. Table 3 provides actionable strategies that key stakeholders can use to address existing gaps in research and practices of HTA related to FVMC. This endeavour is sufficiently complex that it will necessitate multi-stakeholder collaborations and input from researchers, patients, industry, and policy makers. Our research agenda provides direction for future studies and stakeholder collaborations which seek to quantify the value of additional FVMC in ways that can inform the HTA process.

Table 3 Potential actionable next steps for relevant stakeholders
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