The importance of vaccine stockpiling to respond to epidemics and remediate global supply shortages affecting immunization: strategic challenges and risks identified by manufacturers

Abstract

While stockpiling vaccines adds another layer of complexity to vaccine manufacturing, it constitutes a crucial component of comprehensive disease preparedness and control strategies in public health management. Stockpiling provides the ability to immediately respond to epidemics, disease outbreaks, vaccine shortages or stock-outs at local, regional or global levels. Some stockpiles are static, not shipped until an emergency occurs; other stockpiles are rotating with vaccines used in on-going routine immunization programmes. Programmatic use indicates which vaccines to stockpile, the nature of the stockpile and the amount of vaccine to be held at any time. For immediate shipment, fully released product must be stockpiled with the challenge of monitoring remaining shelf-life requirements and the potential risk of expiry. Existing stockpiles are managed and financed globally under the purview of international organizations in the global immunization community, except for buffer stocks held by manufacturers for short periods. The added challenges to manufacturers of stockpiling vaccines, including storage, human resources and other related costs including vaccine destruction when no longer useable, needs to be recognized. This is all the more so with the likelihood of vaccine stockpiling becoming more prominent with changing disease patterns due to climate change and population movements, as well as the significant investment in the research and development of new epidemic prevention vaccines. While vaccine stockpiles managed and financed globally provide rapid response to country requests, more attention is needed in the future to ways that vaccine stockpiling can be brought under the direct purview of individual countries or regional groupings.

1. Introduction

Sustainable and uninterrupted vaccine supply is crucial to achieve global immunizations goals [1]. Stockpiles are an essential part of disease control strategies to address vaccine shortages in various scenarios to satisfy unmet demand, including unpredictable outbreaks. The Developing Countries Vaccine Manufacturers’ Network (DCVMN) has identified vaccine stockpiling as a priority issue in its considerations for strengthening the vaccine supply chain due to the potential risks manufacturers may have in holding vaccines stocks with the uncertainty of their being used [2].

Stockpiles address situations where the very fast deployment of vaccines is needed without advance planning given that fully released vaccines that have already passed regulatory requirements are not normally available for immediate purchase.

Emergency vaccine stockpiles may be considered in two simple classes: static, i.e. waiting for disease outbreaks to occur, such as the case of the Ebola vaccine; or rotating, where vaccines are used in on-going immunization programmes and emergencies, such as the case of the yellow fever (YF) vaccine. Further, if the stockpile is for epidemic response, a static stockpile of a set quantity of doses is required, and the characteristics and size of stockpile will depend on the nature of the disease, e.g. transmission dynamics, Ro (reproduction rate of the specific infectious agent), case fatality rate, etc., as well as the characteristics of the vaccine, e.g. shelf life, formulation, presentation, stability, production cycle, cold chain requirements. With the increasing likelihood of epidemics, these types of static stockpiles are likely to increase in number and size. Globally-funded and managed vaccine stockpiles have provided countries with the capacity for rapid response to emergency situations, such as outbreaks of yellow fever and meningococcal meningitis [3]. Stockpiles can remediate the critical issues of poor forecasting, both in volume and timing, often resulting in the need for unplanned vaccination campaigns. WHO has opined that the setting up of a vaccine stockpile has transformed a vicious cycle of low demand, low production, high price and inequitable distribution to a virtuous cycle of increased demand, increased production, reduced price and greater equity of access [4].

The shift in the global health landscape, with increased pressure from climate change, population increases and mass urbanization, heightens the risk of occurrence of large-scale outbreaks and urban epidemics which would overstretch vaccine supplies and continuously re-define the role and size of vaccine stockpiles [5]. The Coalition for Epidemic Prevention Innovations (CEPI), a global partnership launched in 2017 to develop vaccines to stop future epidemics, focuses on developing phases I/II clinical data for proof of concept to then enable phase 2b-3 clinical trials to take place, eventually leading to vaccine licensure [6].

CEPI has followed the WHO Blueprint of prioritizing diseases for research and development in emergency contexts, including 8 categories of priority diseases, which would lead to multiple stockpiles once safe, effective vaccines are licensed [7]:

• •Crimean-Congo haemorrhagic fever
• •Ebola virus disease and Marburg virus disease
• •Lassa fever
• •Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS)
• •Nipah and henipaviral diseases
• •Rift Valley fever
• •Zika
• •“Diease X” (unknown pathogen causing a serious international epidemic)

Of these priority diseases, 6 were in the midst of outbreaks at the same time in 2018 [8]. COVID-19 was added to the list highlighting that the significant risk of future epidemics is already evident with the current SARS-CoV-2 pandemic.

While there is considerable focus and investment on vaccines stockpiles tied to disease elimination strategies and to epidemic and outbreak response, short-term shortages and stock-outs are widespread and disrupting routine and supplementary immunization activities, such as vaccination campaigns. Between 2010 and 2015, 30% of countries across all income groupings (low, lower-middle, upper-middle and high) reported vaccine stock-outs for an average of 37 days, most commonly for DTP-containing and BCG vaccines, due to poor forecasting, deficient stock management, delayed funding and procurement [9]. No stockpiles of these vaccines have been established to date, with the stock-outs delaying the immunization of vulnerable populations. These data also imply that many countries do not hold sufficient stock in the event of shortages or sudden increased demand. Effective stock management is one of the criteria for an effective vaccine supply chain [10].

The DCVMN Secretariat supported manufacturers from emerging economies in 2019 in creating a working group focused on the vaccine supply chain, which as one of its priorities articulated the need to share experiences in effectively managing vaccine stockpiles and identifying common challenges and successes towards establishing a set of best practices. The DCVMN vaccine supply chain working group1 agreed that stockpiling management is one of the priorities for manufacturers to improve supply efficiency [1] and the stockpile topic was specifically discussed in a working group meeting, organized by DCVMN Secretariat, where information was shared by independent subject matter experts and manufacturer members of DCVMN.

2. Methodology

Relevant manufacturers with global stockpile experience voluntarily outlined their practices and challenges to a group of 52 participants from DCVMN members, facilitators from the Secretariat and an observer from UNICEF, in an informal open-discussion workshop held virtually on 30 and 31 March 2021. Guidance was provided to manufacturers for their presentations relating to the stockpiling of specific vaccines, covering the following points:

• •Data on the throughput of vaccines from the stockpile (last 5 years);
• •Clarifying the contractual arrangements for keeping the stockpile;
• •The lead time required for shipping the vaccine from order receipt;
• •Details on the storage requirements of the stockpile and whether for bulk and/or finished product;
• •The challenges faced in managing the stockpile;
• •Suggested ways stockpile management could be made more efficient.

Discussions were led by four expert manufacturers on the cholera, meningitis, polio and yellow fever vaccine stockpiles, with an additional discussion led by one manufacturer on the holding of buffer stocks. The measles-containing vaccine stockpiles were not included in the discussions given time limitations. Summaries of the discussions are included as case studies exhibits in this paper. The discussion outcome was an agreement on the main challenges facing the management of vaccine stockpiles.

3. Results

3.1. Main challenges of stockpiles identified by manufacturers

The stockpiling of vaccines needs to be seen in the context of the challenges facing the production of vaccines, the vaccine supply chain and the financing requirements. Vaccine manufacture is considered one of the most challenging industries as it is committed to producing vaccines in a manner that is safe, effective and consistent over the vaccine life cycle with product development, facilities and equipment, direct labour, overhead, licensing, registration and commercialization as the principal cost drivers [11]. The increasing demand for complex vaccines, such as combination formulae, has led to constraints in supply due to intrinsically intricate manufacturing and regulatory procedures [12]. An additional concern is the widespread pressure on vaccine affordability, given there is a probable association between price pressure and shortages as manufacturers exit from low-profit products [13]. The challenge around pricing is to set a level that both rewards innovation while making affordable products accessible for cash-strapped health systems [14].

Concerns around the increasing burden of national-level registration strongly suggests moving towards greater standardization of procedures and documentation, ensuring fast-track approvals in the case of emergencies. Half of the countries receiving the highest numbers of vaccines for humanitarian emergencies require full national licensure. Different regulatory considerations can make it difficult for manufacturers to rapidly respond to changing vaccine needs around the world [15].

The batch failure of any specific vaccine under manufacture can lead to time delays as well as increased costs. Added to these challenges are externalities such as greater demand for data, environmental factors, tender procurement methods, transport disruptions, macroeconomic issues and natural disasters. Such uncertainty and externalities are confounded by preparedness rarely ranking high on the list of country priorities, with weak domestic resources leading to under-investment in preparedness [16].

There are appeals to consider stockpiles for all vaccines given inefficiencies in vaccine supply chains. Rabies vaccine is one that has been reviewed for consideration of a global stockpile due to many countries' difficulty in procuring the vaccine [17]. For COVID-19 vaccines, the COVAX facility under its Access and Allocation rubric does indicate the provision for an emergency buffer [18]. COVID-19 vaccines have, however, already benefitted from multiple advance purchase commitments from countries and international organizations, which can reduce the financial risk to manufacturers by lessening the uncertainty around demand. [19]

3.2. Vaccine emergency stockpiling approaches

The stockpiling of vaccines that have already passed regulatory requirements enables manufacturers to ship vaccines immediately to countries experiencing epidemics or disease outbreaks2, as well as to locations where shortages or stock-outs3 have occurred halting immunization programmes and increasing disease risk to vulnerable populations.

UNICEF, which is the main contractor of vaccine stockpiles, distinguishes stockpiles in 5 types, recognizing that any individual stockpile may be based on more than one type:

• Buffer stock: Quantity produced and kept ready on top of vaccines for other markets or programme activities, with volumes determined by manufacturers based on sales experience;

• Rotating stock: Quantity produced, kept ready and rotated with vaccines for other markets or programme activities, with volumes determined by global programmes;

• Revolving stock: Static stockpile is replenished after being deployed to outbreaks to ensure the volume available remains constant;

• Set quantity of stock: Static stockpile kept with the manufacturer until deployed to outbreaks or until vaccine expiry;

• Surge stock capacity: Static volumes of bulk or unlabelled vials for replenishing the stockpile when depleted.

A rotating stockpile is continuously replenished as the vaccine is used for both emergency (outbreak) and non-emergency immunization programmes, always keeping the agreed stockpile number of doses in storage (e.g. YF). A revolving stockpile is replenished after an emergency order is shipped to an outbreak - i.e. the replenishment is periodic, not continuous, and fills back to the agreed stockpile volume (e.g. Ebola). In general, types 1 and 2 are rotating stockpiles that continuously replenish their volumes as both non-emergency and emergency orders are filled for customers, while types 3, 4 and 5 are static stockpiles that only replenish their volumes upon the shipment of emergency orders. Still, they are all different and with different levels of complexity and the vaccine must be ready for immediate shipment. Table 1 summarizes the main types and characteristics of emergency stockpiles defined by UNICEF, including their purposes, number of suppliers reflecting risks, number of doses and time to shipping.

Table 1.

Emergency stockpiles contracted by UNICEF.

Antigen Vaccine	Stockpile Types as to UNICEF	Purpose	Number of suppliers	Total Size of Stockpile (in million doses)	Agreed delivery time from manufacturer to shipping (in hours)
Oral polio vaccine (OPV)	Rotating	Buffer for surge needs	5	100	72
Novel OPV/ monovalent OPV type 2/ trivalent OPV	Static	Set quantity for outbreaks	3	100	72
Oral cholera vaccine (OCV)	Rotating	Revolving for outbreaks	2	3	48
Yellow Fever (YF) vaccine	Rotating	For outbreaks	2	6	48
Measles	Rotating	For outbreaks	1	2	72
Measles-Rubella	Rotating	For outbreaks	1	1	72
Meningococcal A conjugated	Revolving	For outbreaks	1	1.5	48
Meningococcal C/W polysaccharide	Static	Set quantity for outbreaks	3	4	48
Ebola vaccine	Static	Set quantity for outbreaks	1	0.5	48

Existing specific vaccine stockpiles for global supply managed by UNICEF. The main vaccine emergency stockpiles per antigen antigen are listed in the first column, and characteristics of each stockpile are listed in columns 2 to 6, including types of stockpile, their purposes, number of suppliers reflecting risks, total number of doses kept available annually, and time from manufacturers to shipping, as referred in this report.

Manufacturers commonly hold stockpiles of bulk vaccine, also called drug substance, but the turnaround time from bulk to released final product after filling, finishing and regulatory release can take up to three months, so bulk stockpiles do not meet the needs of immediate supply, e.g. for emergency situations. Stockpiles of released final product can be shipped immediately but may have shorter shelf lives than often requested by countries directly or through international organizations. This issue of shelf life is particularly critical to vaccines with a 24-month shelf life, even if the vaccine is continuously being provided to immunization programmes, as the stockpile hold-time may need to be as short as four months to comply with remaining shelf-life requirements of dispatch from manufacturers’ premises [20]. In determining stockpile size and type, supply criteria such as production capacity and speed, on-going production volume, replenishment time and the projected demand from markets have to be taken into account. A potential solution is if countries reduce their shelf-life requirements, given stockpiles would be accessed for emergency use and therefore quickly used. As an alternative, new stability data and shelf-life extension have regulatory implications, with costs both in time and resources. Reducing the remaining shelf-life requirement is precisely one policy that should be established.

3.3. Existing vaccine stockpiles for global supply

UNICEF is the principal actor managing nine distinct vaccine stockpiles for access by emerging economies (Table 1): Gavi finances the cholera (Exhibit 1), yellow fever (Exhibit 2) and meningococcal (Exhibit 3) vaccine stockpiles, and is working to mitigate the risk of outbreaks including creating the right market conditions to bolster vaccine stockpiles [21].

Exhibt 1.

The Cholera vaccines' Emergency Stockpile - example of a rotating stockpile [23]. Courtesy of EuBiologics Co. Ltd. Republic of Korea.

Exhibt 2.

The Yellow Fever Emergency Stockpile – example of a rotating stockpile [24]. Courtesy of Bio-Manguinhos/Fiocruz, Brazil.

Exhibt 3.

The Meningococcal “A” conjugate vaccines’ Emergency Stockpile – example of a rotating stockpile [25], [26]. Courtesy of Serum Institute of India.

A global stockpile of Ebola vaccine has recently been set up by Gavi/UNICEF, aimed at reaching 500,000 doses [22] to tackle any potential new outbreak. For Ebola vaccines there is no preventive recommendation from SAGE, but if there were the vaccine going to expire in the stockpile could be used to vaccinate populations at risk in endemic areas and HCWs/FLWs. These stockpiles come under the governance of the International Coordinating Group (ICG) on vaccine provision4. Poliovirus vaccines (Exhibit 4) and measles-containing vaccine stockpiles come under the purview of the Global Polio Eradication Initiative (GPEI) 5and the Measles and Rubella Initiative6 respectively.

Exhibt 4.

The Oral poliovirus vaccine Emergency Stockpiles - example of a static stockpile for outbreak response [27], [28]. Courtesy of PT Bio Farma (Persero) Indonesia.

4. Discussion and lessons learnt

The working group agreed that there is low risk in stockpiling bulk product, which is a normal practice in vaccine production, enabling orders to be shipped in a relatively short time period, normally between 2-3 months after the fill-finish process and regulatory release procedures are completed. This does not apply, however, for the urgent need of vaccine for disease outbreaks or sudden shortages or stock-outs which can have a disastrous impact on the morbidity and mortality of affected populations in need of immediate vaccination, upon declared outbreaks or disrupted vaccination programmes. Holding fully-released final product brings with it a series of challenges and risks, however, given the uncertainties around the timing of epidemics, outbreaks, shortages or stock-outs.

Holding fully-released product reduces the remaining shelf life and increases the risk of product loss. This can be managed in a rotating stockpile where vaccines are also used for regular immunization programmes, although the logistics has to be carefully monitored in order for vaccines shipped from the stockpile to meet the remaining shelf-life requirements of buyers, whether countries directly or international organizations, such as UNICEF. The OCV shipments have fallen significantly in 2020 to 38%, due to the Covid-19 pandemic, illustrating such risks (see Exhibit 1). Further, some details on the contractual long-term arrangements with UNICEF Supply Division for keeping the Meningitis serotype A vaccine stockpile also illustrates the challenges of holding rotating stockpiles,. (see Exhibit 3) Most of existing stockpiles are either prepaid or have firm commitment contracts in case the vaccine is not used, which lessen the risks to manufacturers. In addition, some manufacturers do voluntarily hold buffer stocks in anticipation of orders, as illustrated by Bharat Biotech (Exhibit 5). Greater flexibility would be secured if buyers were to lower the remaining shelf-life requirements, especially for those vaccines which are rapidly distributed and for immediate use.

Exhibt 5.

Buffer stockpiles – illustrative example of a manufacturer’s voluntary stockpiling to manage short notice increased and/or unplanned orders. Courtesy of Bharat Biotechnology, India.

For static stockpiles used only in the event of epidemics or disease outbreaks (see Table 1), fully-released final product can easily go beyond the remaining shelf-life requirements unless these are waived by the buyer, given the urgency of the demand. Nevertheless, if demand is not forthcoming, vaccines can expire and then need to be destroyed. Meanwhile, static stockpiles need to be continuously replenished in order to hold the agreed-upon quantity with remaining shelf-life requirements intact. This process may increase the volume of finished product being stored at any given time with sufficient vaccines to meet the quantity and shelf-life requirements, in addition to vaccines already beyond the normal remaining shelf-life requirements but not yet destroyed in case of buyer agreement to ship. More static stockpiles for emergency use are likely to be established with new vaccine developments being financed by CEPI, strengthening the need to take a future look at stockpiling. It is unlikely that countries will carry out campaigns just to use up expiring vaccines as they may not have the resources to cover campaign costs.

All held stockpiles have the risk of product expiry which is where manufacturers can be faced with financial losses, unless there are specific contractual agreements mitigating such losses. If the vaccine does not meet countries required remaining shelf-life conditions, the product is subject to loss of income and the additional costs of destruction/disposal.

Recognition of the risks to manufacturers of holding stockpiles is important. These can include additional investments in infrastructure at the manufacturing plant or off-site, typically cold storage, as well as work force requirements to manage and monitor stocks, insurance covering held product, and destruction costs where vaccines have expired or no longer meet remaining shelf-life requirements. Inventory control is a key factor in managing stockpiles and up-to-date digital control systems can facilitate this including the barcoding of products to instantly identify lot numbers and expiry dates, also to aid tracking and tracing the vaccines once shipped and distributed [29]. In addition, as in the case of oral polio vaccine (OPV) stockpiles, recent biosafety and biosecurity measures requiring a dedicated facility significantly increase the cost. Manufacturers need to figure these costs into the offers made to buyers to hold the various vaccine types in stockpiles: novel OPV [28], monovalent OPV type 2 and trivalent OPV. These costs are not fixed, given fluctuating quantities of vaccines held, so long-term fixed pricing is not a favourable option for manufacturers. Losses by EuBiologics in 2016/2017, due to lower than predicted demand, also illustrate the potential financial risks of stockpiling (Exhibit 1). Advance purchase commitments, pricing based on volume delivered or flexible yearly purchasing based on the previous year’s off-take from a stockpile are options to mitigate risks that have been recommended by manufacturers during the working group discussions.

It is recognized that UNICEF is currently the major stockpile single contractor for global vaccine supply, aiming to provide fair and sustainable prices, which may differ regionally, or from country to country. UNICEF depends on manufacturers documented information on costs of goods and operations to establish price estimates. Some stockpiles, however, are determined by donor agreements, rather than by countries.

The number and production capacity of vaccine manufacturers, and the number of available doses forecast, will determine stockpile size and maintenance, and also affect the capacity for increased dose production, should demand be greater than anticipated [10]. Whether stored as bulk and/or finished product depends on vaccine characteristics, time to fill-finish and the probable urgency of shipment. The United States national influenza pandemic stockpile created in 2005, for example, stores 20 million doses in bulk, which with adjuvants could rise to 125 million doses; it was used during the 2009 H1N1 pandemic when 186 million doses were produced [30].

Global stockpiles held by manufacturers and with international governance, e.g. ICG, do mitigate some of the identified challenges and risks to manufacturers. In 2017, the ICG oversaw and approved the distribution of over 16.5 million doses from the cholera, meningitis and yellow fever stockpiles with all requests circulated for decision-making within one working day and decisions reached within two working days for 95%, 94% of 88% of meningitis, yellow fever, and cholera vaccine allocations [31]. Global stockpiles ensure that countries receive vaccines without adding significant additional financial burdens in emergency response when many lower-income countries are already struggling to prepare for transition from multiple sources of global health financing [32].

UNICEF as major contractor and the ICG mechanism can coordinate and together minimize the financial burden to lower-income countries by globalizing the stockpiling arrangements. Given the inherent complexity and challenges and risks of maintaining stockpiles, manufacturers point to the need for a continuous communication with stakeholders in order for the demand and supply situations to be exchanged on a very regular basis. For the global stockpiles of Ebola, oral cholera, yellow fever and meningococcal vaccines, UNICEF maintains up-to-date availability information [33].

5. Conclusion

Vaccine stockpiling plays an important role in responding to shortages and stock-outs, disease outbreaks, and epidemics, and emergency situations which are unpredictable, and allows the vaccine supply chain to perform satisfactorily for the timely vaccination of targeted populations. There are inherent risks for manufacturers in holding vaccines, given the resources needed and the diminishing shelf life of fully-released products. Three areas are highlighted for mitigating these risks:

• The need for manufacturer investments to be fully computed and recognized, including the costs of additional cold storage, personnel, monitoring systems, insurance and vaccine destruction, when indicated. In cases of disease eradication (e.g. Polio) or elimination efforts (e.g. measles-rubella), dedicated buildings with biosafety and biosecurity measures, including added personnel, may be a significant cost component;

• The establishment of adequate financing measures that not only cover the manufacturer investments but allow for renegotiation in cases where stockpile off-take varies significantly from the agreed-upon projections. Advance purchase commitments, pricing based on volume delivered or flexible yearly purchasing based on the previous year’s off-take from a stockpile are options to be considered depending on the nature and setup of a specific stockpile;

• Agreement on lowering the remaining shelf-life requirements of vaccines held in stockpiles, given the accelerated distribution and use to which these vaccines are, by definition, directed, given they respond to emergency situations whether epidemics or outbreaks, or to the urgent need of shortages or stock-outs.

While global stockpiles managed by international organizations have the capacity to address these mitigating factors, it must also be recognized that manufacturers supply significant volumes of vaccines to countries through direct contracts and more assessment is needed to ensure that vaccine stockpiling can also be addressed under the purview of individual countries or through regional or sub-regional groupings.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.