Framework for Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases: Application to Measles and Cholera Vaccines as Contrasting Examples.

Risk Analysis

DOI: 10.1111/risa.12265

Framework for Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases: Application to Measles and Cholera Vaccines as Contrasting Examples Kimberly M. Thompson1,2,∗ and Radboud J. Duintjer Tebbens1

Managing the dynamics of vaccine supply and demand represents a significant challenge with very high stakes. Insufficient vaccine supplies can necessitate rationing, lead to preventable adverse health outcomes, delay the achievements of elimination or eradication goals, and/or pose reputation risks for public health authorities and/or manufacturers. This article explores the dynamics of global vaccine supply and demand to consider the opportunities to develop and maintain optimal global vaccine stockpiles for universal vaccines, characterized by large global demand (for which we use measles vaccines as an example), and nonuniversal (including new and niche) vaccines (for which we use oral cholera vaccine as an example). We contrast our approach with other vaccine stockpile optimization frameworks previously developed for the United States pediatric vaccine stockpile to address disruptions in supply and global emergency response vaccine stockpiles to provide on-demand vaccines for use in outbreaks. For measles vaccine, we explore the complexity that arises due to different formulations and presentations of vaccines, consideration of rubella, and the context of regional elimination goals. We conclude that global health policy leaders and stakeholders should procure and maintain appropriate global vaccine rotating stocks for measles and rubella vaccine now to support current regional elimination goals, and should probably also do so for other vaccines to help prevent and control endemic or epidemic diseases. This work suggests the need to better model global vaccine supplies to improve efficiency in the vaccine supply chain, ensure adequate supplies to support elimination and eradication initiatives, and support progress toward the goals of the Global Vaccine Action Plan. KEY WORDS: Dynamic modeling; measles; stockpile; vaccine; vaccine-preventable disease

1. INTRODUCTION

ufacturers arises from the dominance of a few large purchasers (e.g., UNICEF, Pan American Health Organization Revolving Fund, U.S. Centers for Disease Control and Prevention) with the power to significantly impact demand, prices, and profits.(8–11) Most vaccines perish (i.e., they require use prior to their expiration dates), which implies large risks for manufacturers if they produce vaccine with uncertain demand. Risk also arises from uncertainty about the long-term commitment of funds to pay for vaccines, particularly for relatively lower income countries, and the relative lack of coordination at the regional and global level with respect to many disease

Despite the enormous public health benefits of immunization,(1–7) vaccine production remains a risky business, with relatively few manufacturers participating in the market.(8–10) Part of the risk for man1 Kid

Risk, Inc., 10524 Moss Park Rd., Ste. 204-364, Orlando, FL, USA. 2 University of Central Florida, College of Medicine, Orlando, FL, USA. ∗ Address correspondence to Kimberly M. Thompson, Kid Risk, Inc., 10524 Moss Park Rd., Ste. 204-364, Orlando, FL 32832, USA; tel: 617-680-2836; [email protected].

1

C 2014 Society for Risk Analysis 0272-4332/14/0100-0001$22.00/1

2 management activities. Most vaccines require a relatively long time to produce, which implies time delays between the order date and delivery date. These delays necessitate forecasting and advance orders to ensure steady supplies. The GAVI Alliance seeks to increase financial support for and national commitments to vaccination, particularly in lower income countries,(12) and its remarkable success continues to significantly improve global health.(13) In 2005, the Global Immunization Vision and Strategy (GIVS), 2006–2015, offered the first 10-year plan to globally expand the sustained use of vaccines to prevent disease,(14) which included encouraging countries to develop comprehensive multiyear plans for financing immunization.(15) The 2012 Global Vaccine Action Plan (GVAP)(16) further expanded on the expensive and not-yet fully funded GIVS(17) with a vision to create a world by 2020 “in which all individuals and communities enjoy lives free from vaccine-preventable diseases.”(16) Realizing the vision of the GVAP will require additional funds and access to sufficient vaccine supplies. Currently, purchasers order vaccines with annual and/or multiyear contracts based on forecasts to meet their expected needs in the context of budgeted resources. When managing an endemic vaccine-preventable disease (i.e., one that continues to circulate within a population due to sufficient numbers of infectible individuals), ongoing vaccination represents a major component of control, and annual quantities of vaccine ordered should at a minimum depend on the expected size of the birth cohort and the pediatric routine immunization schedule.(9,18) However, many factors, including wastage, outbreaks, special initiatives or campaigns, and/or changes in vaccine formulation (multivalent or combination vaccines), presentation (e.g., vial size), schedule, and/or inventory capacity may also influence national vaccine demand and lead to special orders (i.e., unexpected or pulse demands).(9) In addition, marginalized or migrant populations often remain unrecognized and un(der)counted until outbreaks occur, and populations get displaced due to conflicts or natural disasters, which can also lead to unexpected demand. Mobilizing vaccine supplies to respond to an outbreak (i.e., an epidemic that affects many people during a short period of time and may spread throughout one or several communities) can lead to competition between preventive and reactive efforts, as occurred with polio vaccine shortages.(19) On the supply side, production problems and unforeseen events can result in real vaccine short-

Thompson and Tebbens age risks,(8,9,20–27) which can lead public health authorities to temporarily modify routine immunization recommendations(28,29) (see current U.S. modifications(30) ). For example, shortages of Haemophilus influenza type b (Hib) and DTaP vaccine led to persistent reduced coverage for affected cohorts.(25–27) The risk of shortages compounds when a single manufacturer holds a large market share and insufficient independent capacity exists to compensate for a supply disruption. Shortages in vaccine supply may lead to ethical issues related to rationing(31) and may also lead to competition between preventive and reactive efforts. Table I summarizes our assessment of some of the characteristics of current vaccine-preventable diseases and the associated vaccines. Table I includes the type of disease (e.g., bacterial, viral), any known nonhuman hosts or reservoirs (which may complicate transmission modeling), the nature of any available treatment, whether the disease is primarily only prevented by vaccine, and the year of first license of a vaccine for the disease in the United States.(32–35) With the evolution of immunization, many vaccines come in combined (i.e., combination or multivalent) formulations that contain more than one antigen (e.g., diphtheria, tetanus, and pertussis or DPT vaccine) and/or more than one valence or serotype (e.g., inactivated polio vaccine (IPV) includes components for all three poliovirus serotypes). We refer to these as combined vaccines because they require multiple production lines, and we note that some combined formulations may include both multiple antigens and multiple serotypes (e.g., DPTIPV). Table I indicates the potential availability of a vaccine for the disease in a combined vaccine formulation, the total number of countries reporting use of vaccine for each disease in their routine immunization schedule for the 194 World Health Organization (WHO) member states (with values in parentheses showing the number of countries that include the vaccine only for specific risk groups) as reported to WHO as of October 2013,(33) and the number of WHO prequalified manufacturers of a vaccine for the disease.(34) Table I shows large variations, with some vaccines used by all countries (i.e., universal vaccines) and others used by only some countries or only in some cases (i.e., nonuniversal vaccines). We show the diseases in Table I according to their decreasing use by countries, starting with universal vaccines used by all 194 WHO member states at the top (i.e., diphtheria, measles, polio, pertussis, and tetanus), and nonuniversal vaccines at the bottom. Table II shows the number of

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases

3

Table I. Characteristics of Vaccine-Preventable Diseases and Available Vaccines as of May 2014(32–35) VaccinePreventable Disease Pertussis Diphtheria Tetanus Polio Measles Hepatitis B Haemophilus influenza type b Tuberculosis (BCG) Rubella Mumps Pneumococcal infections Influenza Yellow fever Rotavirus Human Papillomavirus relatedc Meningococcal disease C A W Y B Varicella and Herpes Zoster Hepatitis A Typhoid Japanese encephalitis Cholera Rabies Hantavirus (hemorrhagic fever with renal syndrome, HFRS) Influenza A (H1N1) Adenovirus

Type

Host or Reservoir

Treatment

VaccinePreventable Onlya

Year U.S. Vaccine Licensed

Combined Vaccine Available

Member States with Vaccine in Schedule (Risk Groups Only)b

WHO 2014 Prequalified Manufacturers

1915 1923 1937 1955 1963 1981 1985

Yes Yes Yes Yes Yes Yes Yes

194 194 194 194 194 183 (9) 183 (5)

8 9 10 4 (IPV), 6 (OPV) 6 10 10

Bacterial Bacterial Bacterial Viral Viral Viral Bacterial

No No Environ No No No No

AB AB, AT AB

AB

Yes Yes Yes Yes Yes Yes Yes

Bacterial

Animals

AB

No

1927

No

157 (16)

4

Viral Viral Bacterial

No No No

AB

Yes Yes Yes

1969 1967 1977

Yes Yes Yes

130 (4) 117 (3) 106 (9)

4 4 2

1942 1935 1998 2006

No No No No

36 (38) 30 (36) 64 (2) 41 (17)

5 4 2 2

Yes Yes Yes Yes Nod Yes

31 (20) 10 (20) 7 (18) 7 (16) 1(2) 20 (13)

3 3 1 1 0d 0

Viral Viral Viral Viral

Bacterial

No Insects F/W No

AV

Yes No Yes Yes

No

AB, AV

Yes

No

AV

Yes

1974 1981 1981 1981 n/ad 1995

Viral Bacterial Viral

F/W F/W Animals

ORS, AB

Yes No Yes

1995 1914 1992

Yes Yes No

13 (14) 2 (21) 5 (7)

1 1 1

Bacterial Viral Viral

Water Animals Rodents

ORS, AB

No No No

1896e 1914 1990f

Yese No No

1 (3) 0 (6) 0 (1)

2 4 0

Viral

No

AV

Yes

2009

No

0

6

Viral

No

AV

Yes

1956

Yes

0

0

Viral

(Continued)

WHO prequalified manufacturers offering different vaccine formulations and presentations as of May 2014.(34) The global adoption of vaccines takes time and depends on national conditions, any regionally or globally coordinated disease control efforts, and the risks, costs, and benefits of the vaccine relative to any

nonvaccine disease control interventions. For example, all countries currently vaccinate against many diseases only preventable by vaccination in their routine immunization programs, largely through their expanded program on immunization (EPI). Countries continue to increasingly adopt the relatively newer vaccines, including hepatitis B,

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Thompson and Tebbens Table I. (Continued)

VaccinePreventable Disease Anthrax Plague Q fever Tick borne encephalitis (TBE) Typhus (exanthematicus)

Type

Host or Reservoir

Treatment

VaccinePreventable Onlya

Year U.S. Vaccine Licensed

Combined Vaccine Available

Member States with Vaccine in Schedule (Risk Groups Only)b

WHO 2014 Prequalified Manufacturers

Bacterial Bacterial Bacterial Viral

Animals Animals Animals Insects

AB AB AB

No No No No

1970 1897f 1989f n/af

No No No No

0 0 0 0

0 0 0 0

Bacterial

Insects

AB

No

n/af

No

0

0

Acronyms: AB = antibiotics; AV = antiviral drugs; AT = antitoxins; BCG = Bacille Calmette-Guerin vaccine; Environ = environmental reservoir; F/W = food/water reservoir; IPV = inactivated poliovirus vaccine; n/a = no licensed formulation available currently in the United States; OPV = oral poliovirus vaccine; ORS = oral rehydration salts; VPD = vaccine-preventable disease; WHO = World Health Organization a Indicates our subjective assessment that vaccines represent essentially the only intervention to prevent widespread transmission (i.e., no in this column indicates the existence of viable nonvaccine interventions that by themselves can significantly reduce disease burden and prevent transmission, as demonstrated by the abilities of some countries to eliminate the circulation of the disease prior to the development of the vaccine). Nonvaccine interventions may include treatment and isolation of infected individuals, vector control, personal hygiene, sanitation and water treatment, quarantine, and some of these (e.g., isolation) might help in control for some diseases that we characterized here as vaccine-preventable only. b Numbers in parentheses show the number of countries that only recommend the vaccine in their schedule to specific risk groups, including travelers, exposed individuals, or women only for HPV and rubella. c HPV-related diseases include: cancers of the cervix, anus, vagina, and vulva and genital warts. d No vaccine containing Meningococcal disease B licensed in the United States, but the United States used some vaccine for recent outbreaks,(102) and no current WHO prequalified vaccines containing Meningococcal disease B, but Cuba lists vaccine with Meningococcal diseases B and C in its schedule and this vaccine was previously a WHO prequalified vaccine. e Date of vaccine invention, no cholera vaccine currently licensed in the United States, but two WHO prequalified vaccines available and a combined cholera-enterotoxigenic Escherichia coli (ETEC) vaccine exists. f No currently licensed vaccine in the United States. g Licensed TBE vaccine (including a combination vaccine) available in some countries outside the United States.

Haemophilus influenza type b (Hib), rubella, mumps, human papillomavirus (HPV), and rotavirus into their routine immunization programs, in large part with support from organizations like the GAVI Alliance and other external funders. In contrast, some vaccines only make sense in countries with endemic disease, and these represent nonuniversal niche vaccines (e.g., cholera, yellow fever). Several of the details in Table I affect decisions related to creating and maintaining vaccine stockpiles, including the current level of adoption of the vaccine, the availability and market share of combination vaccines, the availability of nonvaccine disease control interventions and treatment options, and the number of manufacturers in the market, which affects capacity and vaccine prices. This article presents a conceptual framework for optimization of stockpile management for endemic or epidemic vaccine-preventable diseases, which differs from a framework for optimizing stockpile management for an eradicated disease in the absence

of ongoing vaccine production and demand.(36) We provide a brief overview of experience with vaccine stockpiles, different potential stockpile objectives and scopes, and a conceptual framework that explicitly considers the key factors that influence stockpile management for currently available vaccines. We then consider the framework in the context of a universal vaccine with large global demand, for which we consider measles vaccine as an example, and in the context of a nonuniversal vaccine used only by some countries or for specific individuals, for which we use oral cholera vaccine as an example.

2. EXPERIENCE WITH VACCINE STOCKPILES Vaccine manufacturers manage their inventories to optimize production based on their costs and incentives (e.g., maximize profits and minimize loss


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Table II. Available Formulations and Presentations of WHO Prequalified Vaccines(34) Presentation (Doses per Unit) Vaccine Bacille-Calmette-Guerin (BCG) Cholera Diphtheria–Tetanus Diphtheria–Tetanus-Pertussis (acellular) Diphtheria–Tetanus–Pertussis (whole cell) Diphtheria–Tetanus–Pertussis (whole cell)-Haemophilus influenzae type b Diphtheria–Tetanus–Pertussis (whole cell)–Hepatitis B Diphtheria–Tetanus–Pertussis (whole cell)–Hepatitis B–Hemophilus influenzae type b Haemophilus influenzae type b Hepatitis A Hepatitis B Human Papilloma Virus Influenza (Seasonal) Influenza A (H1N1)—Pandemic Japanese Encephalitis Measles Measles and Rubella Measles, Mumps, and Rubella Meningococcal A Conjugate Meningococcal A+C Meningococcal ACYW-135 (polysaccharide) Meningococcal ACYW-135 (conjugate vaccine) Pneumococcal (conjugate) Polio Vaccine—Inactivated (IPV) Polio Vaccine—Oral (OPV) Bivalent Types 1 and 3 Polio Vaccine—Oral (OPV) Monovalent Type 1 Polio Vaccine—Oral (OPV) Monovalent Type 2 Polio Vaccine—Oral (OPV) Monovalent Type 3 Polio Vaccine—Oral (OPV) Trivalent Rabies Rotavirus Rubella Tetanus Toxoid Typhoid Yellow Fever

1

2

5

6

10

3

4

3

3

2

3

2

2

1

7

4

4

6 1 9 2 3 3 1 1 1 4

1

3

3 1 1

1 1 2

3

3

1 1 1 1

20

2 2 1 1 2

1

17

1

8 5 6 4 1 2 1 2

50

3

1 1

1 1

1

2 3

1 1

5 4 1 3

1

1

due to expiry and missed opportunities from unmet vaccine demand). As part of this process, they may maintain a small safety stock of vaccine that they can use to manage small disruptions, but these safety stocks will generally not suffice if a large disruption

1

3

1 1

6

1

5

1

1

1

2

4

6

1 5 4

6 1 1

1

occurs.(8,9,20–27) Public health authorities with sufficient resources may commission vaccine stockpiles to ensure rapid access to a vaccine supply due to large disruptions and/or unexpected demand. As appropriate, these stockpiles should include syringes, diluents,

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Thompson and Tebbens Table III. Characteristics of Current Global Vaccine Stockpiles(43,45–47)

safety boxes, and other bundled products required to effectively use the vaccine. 2.1. U.S. Vaccine Stockpiles

Vaccine

Using its universal immunization approach, the United States rapidly controlled or eliminated indigenous transmission of vaccine-preventable respiratory and enteric diseases (e.g., polio, measles, rubella, pertussis, Hib, etc.) and cases of disease associated with environmental exposure (e.g., tetanus) following the introduction of each new vaccine into the pediatric routine immunization schedule.(37) The United States maintains relatively constant annual vaccine demand, and after experiencing numerous vaccine shortages, the United States created a pediatric vaccine stockpile in 1983, which the 1993 Omnibus Reconciliation Act funded through the Vaccines for Children Program to ensure access to a six-month supply of all vaccines in the recommended routine immunization pediatric schedule.(18) Prior studies related to optimizing the U.S. pediatric vaccine stockpile used (1) a stochastic inventory model to explore the adequacy of a six-month supply, with the length of a production downtime considered as the primary uncertainty;(38,39) (2) a static model to estimate the potential health and financial costs associated with vaccine shortages for different stockpile sizes assuming that missed children do not get caught up;(18) and (3) a multiattribute approach to optimizing the opportunities to use vaccine supplies to increase immunization coverage.(40) The last of these(40) assumed that the U.S. public health authorities wish to increase coverage up to the point that the population benefits from herd immunity and no further. However, in the United States, public health authorities aim to vaccinate all children with all appropriate vaccines to ensure individual protection and to maintain coverage levels that prevent transmission, which means achieving and maintaining coverage levels always above the seasonally varying herd immunity threshold accounting for waning immunity.(41) The U.S. pediatric vaccine stockpile relies on some supply of filled (i.e., finished, quality tested, labeled, etc.) vaccines held at government-contracted national distribution centers, and some contracts with manufacturers to hold some vaccine in inventory as a rotating stock. The United States also maintains a strategic national stockpile that includes vaccines to respond to unexpected events like an influenza pandemic.(42)

Meningitis Yellow fever Oral cholera vaccine

Year Stockpile Created

Doses in 2014

1997 2002 2013

12.4 million 6 million 2 million

2.2. Global Vaccine Stockpiles Currently, no global stockpile exists for universal vaccines. The WHO and partners currently maintain stockpiles for nonuniversal vaccines to support emergency response activities for meningitis, yellow fever, and cholera outbreaks under the management of an International Coordinating Group (ICG).(43–47) Table III provides some characteristics of these nonuniversal vaccine stockpiles, which do not rely on rotating stocks given the lack of routine demand for these vaccines, although the ICG seeks to use any vaccine in these stockpiles prior to their expiration. When an outbreak occurs, a country must complete a standard application form to request access to vaccine from one of these stockpiles.(43) The ICG rapidly evaluates the request and decides about distribution of the vaccine to the country based on the epidemiological situation, current vaccine supplies in the country, the planned intervention, and coordination and operational aspects.(43) The ICG expects the country receiving the vaccine from the stockpile to replenish the stockpile such that the mechanism should largely function as a resource that allows immediate purchase and acquisition of a vaccine for an emergency. Market forces alone did not support the development of a market for these vaccines or the creation of these stockpiles (i.e., the lack of a guaranteed purchase agreement created insecurity for manufacturers, which led them not to maintain supplies of these vaccines for potential use if needed to respond to an outbreak). However, use and experience with the vaccines from these stockpiles for reactive efforts can lead to regular demand of the vaccine for prevention, as appears to be occurring for the meningitis vaccine. The WHO plans to create an emergency stockpile for each of the monovalent oral poliovirus vaccines as part of the endgame,(36,48) although the details remain a topic of discussion. Recognizing the important role that vaccine stockpiles can play in disease management efforts and the increasing demand to create them, we

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases consider the currently available vaccines for managing endemic and epidemic diseases and provide a framework that we hope will provide useful context to support discussions and analyses related to the process of designing and maintaining appropriate vaccine stockpiles. We build on the framework that we previously developed for the planned global stockpile for oral polio vaccines (OPVs),(36) which will exist for a short time to facilitate rapid response to any potential poliovirus outbreaks that might occur soon after coordinated cessation of OPV use following the eradication of wild polioviruses.(49,50) In contrast to existing U.S. stockpile models,(18,38–40) we focus our conceptual framework on fully dynamic vaccine stockpiles that consider the changing levels of population immunity using transmission models that track infections, and we explore what it would mean to maximize the expected utility of vaccine stockpiles for different potential objectives considering both health and financial costs. Analysts must use dynamic models of transmission to appropriately capture the economic benefits of many vaccines.(51–53) We focus on managing population immunity as the cumulative level or “stock” that determines the potential for transmission relative to the variable and dynamic herd immunity threshold.(41,50) Consistent with the GVAP,(16) we assume that obtaining the full benefit of vaccines requires achieving and maintaining levels of population immunity above the threshold required to stop and prevent disease transmission and appreciating that all successfully vaccinated individuals benefit from individual protection in case of exposure to an infectious individual (e.g., importations, individual travel to endemic areas). The next section discusses potential objectives and assumptions related to the scope of public health vaccine stockpiles, which we distinguish from the small safety stocks that manufacturers may hold as noted above. Following discussion of potential objectives, we develop a conceptual framework for endemic and epidemic vaccine stockpile design and management using stock-and-flow diagrams, which help make assumptions and tradeoffs more transparent, facilitate visualization of the supply chain, and improve understanding of the impact of key time delays. We then discuss the concepts of the framework to measles and cholera vaccines as contrasting examples.

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3. VACCINE STOCKPILE OBJECTIVES AND SCOPE The optimal public health vaccine stockpile design will depend on the objective, which we assume would extend beyond a focus on potential supply disruptions to also include unexpected demand. We assume that the stockpile may include both bulk and filled vaccine components. For universal vaccines, public health authorities could potentially better anticipate nonregular vaccine demand using models to characterize population immunity, which might improve efficiencies in planning and forecasting vaccine needs. For nonuniversal vaccines, models might also help with planning for vaccine introductions, expanded utilization, preventive vaccination campaigns, and/or outbreak response immunization. While the expected demand for any one country may be too small or periodic to lead to orders for production, looking over multiple countries could potentially support the expectation of some annual demand, and this represents an important benefit of coordination. In the absence of better planning, inefficiencies in the ordering, distribution, and utilization of vaccines occur, and these inefficiencies lead to spot shortages despite what should be an adequate overall supply. Vaccine stockpiles require a financial investment and, consequently, their creation and maintenance depends on some valuation of the potential health benefits and tradeoffs between financial and health costs. Potential objectives of a public health vaccine stockpile include the following:

r Minimize total social costs, which would create r

an objective function to optimize the combined health and financial outcomes. Minimize expected cases within some “acceptable” level, which would establish a level of cases tolerated and lead to estimation of the cost of the stockpile required to meet this level. Establishing a very low level of “acceptable cases” could imply a very large and costly stockpile, although for vaccines that require a single dose to provide life-long protection, the stockpile may only need to contain enough doses to potentially vaccinate all susceptible individuals once, with some excess to allow for loss or wastage.

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Thompson and Tebbens

r Maximize

r Regular

r

r

the expected health benefits within some “acceptable” financial cost of the stockpile. Maximize the available inventory given current production capacity, which would create a stockpile limited by existing demand and production to add surge capacity to the system.

Competing objectives can lead to tough choices and real health and financial tradeoffs, and different stakeholders will prefer different objectives, in part due to their values, access to resources, and the conditions that exist in their country or region related to the disease or global goals. Real constraints may also apply (e.g., limited resources, restrictions on use for outbreak response only, existing vaccine production facilities, and/or time delays associated with expanding production capacity, etc.). Although stockpiles could exist on multiple levels (i.e., global, regional, national, state, city, health-care facility, and physician office), we assume that maintaining the high-level, global stockpile at the manufacturer(s) will represent an optimal choice since a rotating stock minimizes costs and wastage of vaccine due to expiry.(8) This approach also offers benefits associated with quality assurance, safety, and mobilization, without imposing significant transportation or distribution delays (assuming that mechanisms exist to support decisions about requests and distribution of vaccine). However, leaving the vaccine stockpile with the manufacture(s) can lead to some delays (e.g., if the manufacturer does not actually maintain the filled inventory as expected), and it requires paying for storage and maintenance costs (which the manufacturers could build into the vaccine price, but we keep separate) as well as an added level of monitoring by stockpile managers.

4. FRAMEWORK 4.1. Overall Decision Problem For each vaccine-preventable disease, countries decide on their preferred national immunization strategy, which may include one or more of the following:

r Regular

(i.e., planned) vaccination in an age-dependent routine immunization schedule and/or for high-risk individuals (e.g., travelers)

r r

national preventive supplemental immunization activities (pSIAs) of a targeted population Event-triggered pSIAs of a targeted population in areas at risk of outbreaks (e.g., triggered by outbreak in neighboring country, or new data showing population immunity gaps) or based on a specific risk criterion (e.g., missed children, migrants, and displaced populations) Reactive or outbreak response SIAs (oSIAs) of a targeted population No vaccination (i.e., reliance on nonvaccine interventions).

The first and second bullets represent regular (planned and expected) vaccine use and the third and fourth bullets represent nonregular (unplanned or unexpected) vaccine use. National strategy and vaccine formulation and presentation choices translate to national vaccine demand, and these aggregate to global demand. Those countries that produce their own vaccines will most likely consider the option of creating a national stockpile, although theoretically they may also participate in the global market and/or a global stockpile (for supply and/or demand). However, in practice, vaccine licensing and regulatory requirements may restrict participation of countries and vaccine suppliers in some exchanges, particularly if the vaccine is not prequalified by WHO. Ultimately, the global vaccine supply will need to consider the expected number of doses of each of the available vaccines over time by formulation and presentation. Thus, a vaccine stockpile may include different forms (e.g., bulk vs. filled),(36) formulations (e.g., stand-alone or combination, single- or multivalent), and presentations (e.g., different vial sizes) constrained by any regulatory and licensing requirements. In addition, supply chain and stockpile management involves other choices, such as the number and location of physical facilities producing and storing vaccine, number of manufacturers, financing mechanisms, and governance.(36) Fig. 1 shows the potential role of a global vaccine stockpile in the context of the overall global management strategy. The overall disease control strategy represents the aggregation of all national strategies, and thus determines the regular global vaccine demand. We assume that a global disease control strategy exists either explicitly or implicitly (i.e., we recognize that even the choice to do nothing or not to coordinate represents a strategy,(50,54–56) albeit not a good strategy for supporting ambitious


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Global disease management strategy Regular vaccine use Surveillance Nonvaccine interventions Treatment Other programmatic activities

Potential stockpile demand (nonregular vaccine use) Outbreak response Event-triggered (population displacement, disasters) Supply disruptions Others

Vaccine supply optimization Number of doses by formulation, form (bulk, filled), and presentation (e.g., vial size)

Costs Stockpile vaccine production and filling Storage costs Monitoring/supervision costs

Benefits Cases prevented Treatment and response cost savings Macroeconomic impacts

Fig. 1. Main components related to vaccine supply management for a global stockpile for an endemic or epidemic vaccine-preventable disease.

global initiatives like the GVAP). Different stakeholders interact and face different incentives, but for purposes of a global stockpile, we assume a societal perspective and we seek to minimize total social costs (i.e., inclusion of all health and financial costs and benefits) within the context of any constraints. The GVAP motivates the consideration of global strategies to maximize the benefits of vaccines(16) and several strategies already exist (e.g., for polio,(48) measles and rubella,(57) and neonatal tetanus(58) ), although managing vaccine supply to achieve the objectives remains an underappreciated aspect of planning. Besides decisions about vaccine use, the disease control strategy also includes policies related to surveillance, any nonvaccine interventions to prevent or control the disease, and treatment. For all diseases, surveillance represents a critical component of management because decisionmakers need good information about the presence and burden of disease and the impact of interventions. Even for vaccine-preventable diseases, nonvaccine interventions that reduce transmission typically exist, and in some cases, they may represent a significant component of the overall disease control strategy that can affect the prevalence of the disease and there-

fore vaccine demand. Finally, investing resources in treatment can mitigate the health outcomes associated with cases of disease and generate direct health benefits. The effect of treatment on health outcomes varies by disease from merely relieving symptoms without affecting the disease progression to allowing full recovery and preventing long-term morbidity, mortality, and/or costs. Unlike nonvaccine interventions, we assume that treatment generally does not affect participation in transmission. The vaccine supply and stockpile optimization process determines the expected amount of vaccine available to meet demand as a function of time, which implicitly influences demand by constraining it. This represents an issue particularly for nonuniversal vaccines for which some or all countries operate fully or partially under a more reactive strategy, resulting in nonregular vaccine demand (e.g., demand after an outbreak occurs). Countries relying on nonregular demand strategies will either need to: (1) hope that their demand can get covered by the existing supply held by manufactures, (2) wait until manufacturers can produce the vaccine to fill their order, (3) cause a disruption or delay in some other country’s supply, or (4) obtain vaccine from a stockpile, if one exists.

10 Ultimately, the process of creating a global vaccine stockpile involves making tradeoffs between costs and benefits and requires raising the funds to finance it based on the economics (i.e., the investment case). Costs arise from the use of real physical resources to create and maintain the stockpile (including vaccine production and filling costs for the doses actually in the stockpile, storage, rotation, and monitoring/supervision costs). Benefits derive from the prevention of cases and deaths attributable to the vaccine used from the stockpile, and include the intrinsic value of avoided adverse health outcomes (including those difficult to quantify), real cost savings from treatments avoided, and savings of the macroeconomic costs lost when an outbreak decreases trade and/or tourism. Poor vaccine supply and stockpile management may translate into greater financial costs (e.g., vaccine doses that expire) or foregone health benefits (e.g., cases or death not prevented due to insufficient availability of vaccine). At the global level, we assume that creating a stockpile would include the creation of a management structure (e.g., the ICG) and a decision process for distribution, which would evaluate the expected benefits and costs of using vaccine from the stockpile and consider any ethical issues that arise in the event that demand for vaccine from the stockpile exceeds supply. Since a limited set of manufacturers produce vaccines, supply management must consider overall capacity. Expanding actual capacity involves capital investments (e.g., building new facilities), which typically implies multiyear time delays prior to increasing overall supply of annual quantities of licensed vaccines.

4.2. Supply Chain, Vaccine Demand, and Time Delays Building on our prior approach, we use simplified stock-and-flow diagrams to further identify key stocks (i.e., current amounts or levels of vaccine in the supply chain depicted) using boxes, and incoming and outgoing flows using arrows with valves that move vaccine through the stocks as a function of time.(36) Fig. 2 shows the seven stocks we use to provide a simplified conceptual model of a vaccine supply chain with a stockpile: vaccine in production, bulk vaccine, bulk stockpile, other vaccine bulk (for combined vaccines), vaccine in filling, filled vaccine, and a filled stockpile. We simplify the diagram by omitting

Thompson and Tebbens the arrows showing the dependencies of the flows on the stocks on which they depend (we consider these arrows as implied). In reality, vaccine in production goes through multiple stages to become bulk vaccine (e.g., cell culture, fermentation, purification, inactivation, testing, adjuvant formulation, testing, or others) and we use a bold outline to convey the aggregation of multiple stages into a single stock.(36) Manufacturers can store bulk vaccine in a bulk stockpile, and rotate these stocks (if sufficient demand exists), or send all of the bulk vaccine on for filling. Any vaccine in a bulk stockpile can go back to the bulk vaccine to go into filling as needed, albeit perhaps with some delay due to testing or other processing (i.e., we assume no distribution of bulk vaccine except to filling in the overall supply chain, with the possibility of different or multiple companies involved in the supply chain). Given the batch production of vaccines, the storage of some bulk occurs inherently in most vaccine supply chains, but in Fig. 2, we intend the bulk stockpile to represent an extra supply that the manufacturer stores due to contractual arrangements with one or more purchasers. The production starts depend on regular orders and special orders, with some loss adjustments that account for expected loss in the supply chain and any corrections needed due to prior supply disruptions or nonregular demand previously met. The production constraints lead to a delay between the initiation of vaccine in production from production starts and the availability of bulk vaccine. The delay occurs both as a result of capacity constraints, which limit the number of doses that can go through the production process per unit of time, and the duration of the various processes in the production supply chain.(36) As indicated, a large supply disruption can lead to delays in production starts (e.g., due to missing raw materials or issues at the production facility) or loss anywhere in the supply chain. Fig. 2 does not show the potential for loss downstream of distribution because this occurs outside of the supply chain. In addition, vaccine bulk may expire as a function of the storage life. Fig. 2 depicts the process for one antigen (or valence for multivalent vaccines for which manufacturers produce each single-valence component separately), but some vaccines come in combined (i.e., combination or multivalent) formulations, for which the filling process leads to the final combined vaccine product. Consequently, Fig. 2 includes a stock for other vaccine bulk for use in filling to produce a combined vaccine formulation. Fig. 2 shows that


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Fig. 2. Stocks and flows for vaccine production, filling, and storage relevant to a public health stockpile and the distribution decision process.

the combined starts depend on the formulation constraints such that inadequate supplies of the other vaccine bulk required for the formulation would delay filling of the combined vaccine (similar to a supply disruption of the primary antigen). Like vaccine in production, vaccine in filling involves numerous steps (e.g., finishing, testing, labeling, etc.), and consequently we depict this stock using a bold outline. The filling constraints lead to a delay between vaccine in filling and filled vaccine and they depend on the presentation (i.e., vial size), which impacts the utilization of filling capacity. The filled vaccine generally represents the regular amount of vaccine that manufacturers produce to manage and meet their regular demand plus any additional vaccine produced due to loss adjustments that remains in the stock. Some loss may occur for various reasons as mentioned previously, and expiry may occur due to the limited shelf life of finished vaccine, which is generally shorter than the storage life of bulk vaccine. Manufacturers lack incentives to keep excess inventory in a bulk stockpile or filled stockpile without a contract that guarantees purchase of the vaccine and compensation for storage, rotation (if possible), and management costs. Keeping vaccine in a bulk stockpile typically implies less expiry than vaccine in a filled stockpile, but it also implies longer lead times until use. The choice to keep the stock-

pile in bulk or filled form will depend on the relative importance of rapid deployment in the context of health costs, the time required to fill vaccine, and the financial costs of expiry and stockpile maintenance. Maintaining excess inventory serves to accommodate spikes in demand given the long lead times that exist for vaccine supply replenishment, but the amount of excess inventory that manufacturers can hold with minimal cost (i.e., without expecting to waste doses) remains constrained by the amount of demand for regular use for available formulations (i.e., rotating stock levels depend on regular demand and the storage life for bulk vaccine and shelf life for filled vaccine(59) ). Consequently, we distinguish between universal and nonuniversal vaccines, which for our purposes reflect the scale of overall demand and the potential for stock rotation. Regular demand and nonregular demand represent key inputs to stockpile design because demand triggers the distribution of vaccine, which triggers orders and production. However, we assume purchasers forecast regular demand such that manufacturers deliver ordered supplies when needed, whereas nonregular demand leads to special orders. We allow for the possibility that both types of demand may lead to distribution of some available filled vaccine because manufacturers may potentially accommodate relatively small nonregular demand requests with filled vaccine on hand.

12 However, in general, nonregular demand and supply disruptions will lead to requests for release of vaccine through the stockpile distribution decision process (if one exists) for rapid filling from the bulk stockpile and/or release of vaccine from the filled stockpile through stockpile deployment. 4.3. Characterizing the Benefits and Costs of a Public Health Vaccine Stockpile Characterization of the benefits and costs of a stockpile requires consideration of the supply chain in Fig. 2 within the broader context of Fig. 1. Fig. 3 shows the stocks in Fig. 2 along with surveillance, nonvaccine interventions other programmatic activities, and treatment shown on the right. Surveillance plays a key role in determining the target population for vaccination and the effectiveness of vaccination or other measures, and it provides critical information for modeling disease incidence and characterizing the benefits of interventions that may impact disease incidence. Other programmatic activities, including research, training, and coordination efforts, may also impact disease incidence. While disease management programs may consider outbreak response and vaccine stockpiles as part of their overall programmatic activities, for purposes of this article, we keep them as a separate focus. Nonvaccine interventions may affect both regular demand and nonregular demand by leading to reductions in the total population at risk (e.g., good hygiene and sanitation may eliminate the need for some vaccines in some areas, and isolation or quarantine measures may prevent the spread of an ongoing outbreak to other areas). For all of the interventions and investments that impact the disease incidence, we assume that they represent inputs to the dynamic transmission model used to characterize incidence. The number of cases prevented by vaccine equals the difference in incidence with vaccination, which depends on the vaccination rate and incidence without vaccination. Vaccine distribution and stockpile deployment of filled vaccine determine the vaccination rate. Due to logistical constraints, a significant delay may exist between delivery of vaccines to purchasers and their actual use in the field for previously unanticipated activities. For regular demand, the relatively long planning horizon and existing health systems should reduce or eliminate these delays. In addition to depicting the various components of the system, Fig. 3 shows how they lead to the main

Thompson and Tebbens components of total social costs (i.e., public health benefits and total financial costs). The framework shows the explicit translation of cases prevented into economic values.(4) In the absence of good data on valuation of morbidity and mortality, the annual per-capita gross national income provides a possible means to estimate the monetary value of an averted disability-adjusted life year (DALY),(60,61) and thus the average economic value per prevented case. Finally, we anticipate that the reduction in disease incidence due to vaccine use may save significant treatment costs, which we include as part of the monetized public health benefits of the stockpile. The treatment costs saved depend on the fraction of the cases that receive treatment and treatment cost per case (i.e., the unit cost per treatment). To simplify Fig. 3, we did not show the unit costs for: (1) treatment costs saved, (2) regular demand for the nonvaccine costs associated with operating the national immunization program, (3) nonvaccine interventions, (4) other programmatic costs, (5) surveillance, (6) vaccination costs for vaccine purchase and for administration (which we note will differ by country, regular vs. nonregular use, and planned vs. unplanned use), or (7) stockpile costs for the contracts for the bulk stockpile and filled stockpile and support of the stockpile distribution decision process. Thus, we assume that these unit costs are implied. 4.4. Optimization We assume that dynamic optimization of a stockpile would maximize the difference between public health benefits and total financial costs. In the absence of financial constraints, the optimization problem depends on determining the highest possible difference between public health benefits and total financial costs in terms of net present values, which discount cumulative benefits and costs over some time horizon. In the limiting case in which the costs of vaccination always outweigh the expected benefits, the optimal solution involves no vaccination and thus no stockpile at all. For example, the withdrawal of LYMErixTM vaccine for lyme disease prevention followed perceptions that its costs exceeded the benefits,(62) which stopped all use of the vaccine without creation of a stockpile. The stockpile for a monovalent OPV following coordinated global cessation of that OPV serotype should also exist only until the point at which the potential benefits of its use for outbreak response(63) exceed the potential risks. Otherwise, the optimal solution will involve

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases total costs of global investments

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Fig. 3. Framework for the development of a vaccine stockpile for an endemic or epidemic vaccine-preventable disease represented as a stock-and-flow diagram to support optimization of total social costs. Legend: Rectangular boxes show stocks representing quantities of vaccine; diamond indicates the dynamic transmission model used to estimate disease incidence as a function of all of the factors that influence incidence; bold blue (color visible in online version) inputs (i.e., public health benefits and total financial costs) represent the two components of total social costs; red italic inputs indicate a decision process or model results; black inputs represent other factors; hexagon indicates the process for stockpile distribution; double arrows with valves show flows of vaccine to, from, or between stocks; blue arrows depict influences between inputs.

some vaccination, although the role of vaccination in the context of the overall disease control strategy could vary by country. For example, people living in developed countries would not expect to benefit from cholera vaccination given the high effectiveness of nonvaccine interventions. In contrast, in developing countries with endemic cholera, the vaccine may represent a good option to complement nonvaccine measures. For universal vaccines, the ideal solution without any financial constraints would represent a strategy to vaccinate all individuals at sufficiently high risk if the vaccine proves highly effective and cost effective. However, even without financial constraints, the capacity constraints in the supply chain may imply that the system cannot meet the desired level of vaccination of the optimal policy (even with a stockpile). In that case, international efforts would logically turn toward creating incentives to appropriately increase capacity. In the context of the more realistic world with financial constraints, public health authorities would maximize the net present value of the public health benefits while satisfying a constraint on the total financial costs. The financial constraint implies that decisionmakers must adjust their regular orders depending on the total financial costs already incurred in other parts of the system. Importantly, in the con-

text of the overall global strategy, the overall level of national and international investment represents the financial constraint that affects the stockpile and vaccination decisions, and investments in nonvaccine interventions and the treatment fraction. The reality of financial constraints highlights the existence of tradeoffs between different uses of these resources, and underscores the need for an integrated approach involving all elements of disease control to determine the best use of scarce resources, for which countries must first recognize the need for active management and coordination.(64) 5. EXTENSION TO CURRENT VACCINES Vaccine stockpiles can quickly become complicated by the increasing availability of different vaccine formulations and presentations (Table II). In the context of this complexity, vaccine manufacturers may not maintain sufficient capacity for some formulations, including stand-alone formulations of vaccines that countries may need for supplemental campaigns and/or outbreak response.(59) For example, some components of the combined vaccines may make them not appropriate for older children and adults. In those cases, stockpile designs may need to consider the appropriateness of the available

14 formulations for all potentially susceptible individuals who may need vaccine as a function of age and the impact of time delays associated with manufacturers needing to produce (extra) stand-alone doses in the context of an emergency, which may lead to the creation of a bulk stockpile and/or filled stockpile.(59) Shared vaccine stockpile resources can also run into challenges related to licensing and regulatory issues, which motivates WHO prequalification,(34) although prequalification will not necessarily help in all cases. The left column in Table IV highlights some of the ideal attributes of a vaccine with respect to creating and maintaining a stockpile. The ideal vaccine is highly stable, produced and delivered cost effectively, does not cause any serious adverse events no matter when or how many times it is given, and provides life-long full protection from infection and disease rapidly after a single dose. These characteristics imply significant benefits associated with population immunity. Thus, stockpile designers need to consider whether protection of the vaccine wanes, which may necessitate a requirement for booster doses and thus larger quantities of vaccine. The ideal vaccine to stockpile also possesses a long shelf life and requires very low packaged volume, which implies easy storage for as long as necessary. Downstream capacity constraints (e.g., cold chain limitations) influence choices related to vaccine volumes and may lead to a preference for multidose vials for some vaccines that can maintain their quality and integrity in a multidose presentation. However, policies about open vials that ensure safety will also lead to some of the doses in many multidose vials being discarded. The wastage that occurs in practice (for single-dose and multidose vials) represents a factor that vaccine purchasers must consider when ordering and account for this correction in their regular demand. A vaccine stockpile may help support efforts to manage population immunity, which represents a dynamic stock influenced by the inflow of susceptible individuals born each year and the outflow of immune individuals who die or whose immunity wanes.(41,65,66) As a starting point, the vaccine demand should also account for the quantities required to catch up susceptible people of older ages accumulating in the population. Providing all of the required vaccine doses for regular demand using routine immunization represents the ideal, but given the reality of poor health systems, many countries will need to conduct SIAs to boost population immunity, and pSIAs also factor into regular demand.

Thompson and Tebbens 5.1. Extension of Stockpile Framework to Universal Vaccines with Measles as an Example We consider all of the vaccines used in national immunization schedules by more than 100 countries as universal such that their current utilization should support some stock rotation with existing supplies, albeit noting that different formulations of the vaccine may not exist in sufficient quantities for rotation of all formulations. We discuss measles vaccine stockpile development as an example. Measles vaccines include many of the attributes identified in Table IV as favorable for a stockpile.(32,67) With respect to the considerations in Fig. 1, measles control efforts benefit from a strong global surveillance system(68) and the support of the Measles and Rubella Initiative,(57,69) which provides a forum for the development and coordination of some global activities. Measles represents a relatively inexpensive and highly effective and cost-effective vaccine,(70) and vaccination represents the primary tool for measles prevention and outbreak control. Currently, all six WHO regions remain committed to eliminating measles transmission by various dates following the success of global measles mortality reduction commitments(71) and commitments to the GVAP.(16) The existing regional measles elimination goals create significant regular demand for measles vaccine, with estimates suggesting that global demand in 2010 exceeded approximately 375 million measles-containing vaccine (MCV) doses.(72) The substantial regular demand for measles vaccine implies that manufacturers could rotate relatively large amounts of stock to create a stockpile (including a bulk stockpile and/or filled stockpile). With the global number of infants surviving to age 1 estimated at approximately 135 million for 2014(73) and WHO indicating that “reaching all children with 2 doses of measles(-containing) vaccine should be the standard for all national immunization programs,”(74) the estimated global demand of 375 million doses appears low relative to the WHO objective once we consider wastage(75,76) and the need to conduct SIAs that give some children more than two doses as part of regular efforts to reach missed children. For example, assuming 30–35% wastage overall (i.e., given the reliance on multidose vial presentations that vaccinators must use within four hours or the end of the immunization session [whichever comes first] or discard due to potential contamination and loss of efficacy(77) ) implies 386–415 million doses of demand to cover the birth cohort with exactly two doses.


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Table IV. Ideal Attributes for Stockpiling and Use of Current Vaccines and Current Assessment of the Options Related to Measles-Containing and Oral Cholera Vaccines(32,67) Ideal Vaccine Attributes for a Stockpile High existing filled vaccine amounts Cheap to produce Cheap and easy to deliver Long shelf life Low volume, easy to store Highly effective Single dose Rapid protection Flexibility in dosing interval Long-lasting immunological protection Highly stable (i.e., resilient in actual field conditions) No serious adverse events Effectively reduces transmission (herd immunity)

Measles-Containing Vaccines

Oral Cholera Vaccine

Yes Yes Somewhat No Somewhat Yes Yes Yes Yesa Yes Yes Rareb Yes

No Somewhat Somewhat No No Somewhat No Somewhat No No Yesc Limited data Limited data

a Vaccine

effectiveness reduced in children less than nine months of age due to interference with maternal antibodies. and possible risk for death resulting from anaphylaxis or disseminated disease in immunocompromised individuals.(67) c Only licensed for use through cold chain, although actual stability in outside temperature may be adequate. b Thrombocytopenia

Ideally, every country should annually procure enough vaccine to provide two doses of MCV to theoretically reach 100% of the children in the target age group living within its borders, with upward adjustment to account for wastage and additional doses for SIAs or other efforts to immunize missed children. Thus, although current demand and supply may appear reasonably well matched assuming relatively constant demand for measles vaccines overall, the system does not appear to contain sufficient capacity to support all regular demand if we include SIAs and the likelihood that they lead to the receipt of more than two doses for some children, or for nonregular demand surges or supply disruption. Thus, the measles vaccine supply chain may not support existing national commitments to regional measles elimination goals, although it appears to balance current regular demand and supply.(72) Adding complexity to the current system, countries currently use several different formulations of MCVs in their schedules, including measles (M), measles and rubella (MR), measles, mumps, and rubella (MMR), and measles, mumps, rubella, and varicella (MMRV) formulations.(54) Most countries use a single MCV formulation for all doses given within their borders, but as of 2013 a few countries used different formulations.(54) Recently, the WHO recommended that countries “using different MCVs (i.e., measles (M), MR or MMR) for the 1st and 2nd doses should use the same vaccine (either MR or MMR) for both routine doses to simplify vaccine

procurement, logistics, recording, reporting, and to increase coverage and decrease vaccine wastage.”(78) As countries increasingly adopt rubella-containing vaccines, the use of M will stop, such that global supply will primarily split into MR and MMR vaccines. Supply management could become easier with a global policy to phase out all M vaccine and switch all countries to MR or MMR by a specific date, which would encourage planning for the transition and forecasting of increased demand for rubellacontaining formulations both for routine immunization and pSIAs. In the absence of coordinated planning, shortages of specific formulations may occur, and this may impact the phase-in of rubella vaccine introduction. We expect that during the phasein of increased adoption of MR, creating a stockpile and rotating stock of MR would significantly help to facilitate the transition because as countries adopt MR, they will want to conduct catch up campaigns (pSIAs) to increase population immunity for rubella and we should anticipate these increases in demand and order increased supply of MR vaccine. Outbreak response efforts, which represent inherently unplanned events, address failures of the combined routine immunization and SIA activities as needed and when possible. Due to the explosive nature of measles outbreaks, early detection and rapid delivery of vaccine represent key determinants of the success of a reactive outbreak response campaign (i.e., faster is better).(79–82) Efforts to reduce measles mortality during the past decade developed

16 the strategies and infrastructure required to respond cost effectively to measles outbreaks,(79,83–85) and experience with preventive versus reactive campaigns for measles suggests higher costs associated with conducting emergency response activities compared to planned routine activities.(86–88) Although some logistical challenges exist, including gaining access to outbreak areas in some countries and issues with vaccine acceptance,(86,89) in 2012, the GAVI Alliance allocated $162 million to support measles outbreak response efforts.(90) With funding available to support outbreak response activities, ensuring sufficient supplies of vaccine to support these efforts should also represent a priority. With respect to determining the likely size of nonregular demand for vaccine from a stockpile, planning efforts must consider the dynamic nature of outbreak risks.(66,80) As demonstrated by the rapid spread, resurgence, and outbreaks in Africa in 2009– 2010,(89) measles does not respect borders. The stockpile needs for response will depend on population immunity management by all of the countries covered by the stockpile, which depends on the quality and amount of prevention activities (i.e., routine immunization and SIAs). Overall, the amount of measles vaccine needed to meet nonregular demand should represent a much smaller quantity than the existing global supply, and this suggests that public health authorities could contract with manufacturers to maintain and rotate sufficient quantities of inventory to create a stockpile. In addition, the risk of supply disruptions creating shortages and delaying the achievement of regional elimination goals should motivate discussions with manufacturers to at a minimum create a filled stockpile of the size supported by rotation of stocks that support existing regular demands and most likely also a bulk stockpile. As mentioned above, the United States already implements this strategy as part of its annual order of approximately 11 million doses of MCVs, with approximately 4 million doses maintained as a filled stockpile under contract with manufacturers (CDC, unpublished data, 2011). Although measles eradication probably will occur at some point given regional elimination goals, manufacturers can reasonably anticipate continued high demand for measles vaccines for the foreseeable future and even after eradication.(54,66) We emphasize that the development of a stockpile for universal vaccines should include creating a mechanism to distribute vaccines and maintain appropriate national incentives. Specifically, any coun-

Thompson and Tebbens try needing to use vaccine from the stockpile should pay to replenish the stockpile immediately (i.e., countries need to purchase vaccine from the stockpile at a price at least as high as the price that they pay for regular demand) so that creating the global stockpile does not distort national incentives or discourage investments in prevention. We caution that the practice of bailing out countries that fail to invest in prevention may create bad incentives that favor reactive efforts, which increase nonregular demand. Thus, while access to a stockpile may offer significant benefits by facilitating vaccine use when needed and lead to increases in regular demand as countries gain experience with the vaccine, reliance on the stockpile may undermine the ultimate implied GVAP goal of country ownership of the sustained responsibility for maintaining national population immunity with regular demand. Recognizing the value of prevention and not rewarding failures to prevent outbreaks represent critical attributes of systems that create proper incentives.(91–93) The recent shortfall of funding for measles pSIAs leading to demands of vaccine for outbreak response campaigns provides an important indication that stability in funding will represent a prerequisite to effective planning and management. 5.2. Extension to Nonuniversal Vaccines with Oral Cholera Vaccine as an Example Nonuniversal vaccines include both new vaccines that will become universal and niche vaccines. These vaccines present a different and much greater challenge with respect to developing a stockpile due to the lack of large-scale (e.g., global) strategic planning, potential underutilization, and/or inadequate disease surveillance. With respect to surveillance, some likely-endemic countries may not report cases of some diseases because they do not adequately monitor disease and/or because they fear the potential stigma and economic consequences associated with reporting known cases. For fully utilized niche vaccines (i.e., those vaccines with regular demand for all of the affected areas that always ensures sufficient vaccine supply to meet demand in the absence of supply disruptions), the creation of a vaccine stockpile could potentially rely on rotation of stocks. This would effectively represent a global stockpile by including all of the affected countries even though not all countries are affected. We did not identify any of the nonuniversal vaccines associated with the diseases in Table I as fully utilized, so we keep all of them in this section.

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases Not surprisingly, developed countries remain unlikely to consider creating and maintaining stockpiles for vaccines they do not routinely use. Thus, when national disease management strategies do not include a vaccine given successful elimination of the disease with maintenance of disease-free conditions using only nonvaccine strategies, countries will mainly consider the use of these vaccines for small, specific populations (e.g., citizens traveling to endemic areas). This occurs particularly if the vaccines offer a relatively small benefits compared to their risks and/or costs for the national population (e.g., cholera, yellow fever, and tuberculosis). We discuss the development of a cholera vaccine stockpile as an example for a nonuniversal vaccine. Cholera vaccines exhibit fewer of the ideal characteristics of a vaccine for a stockpile than measles vaccine (Table IV). For cholera, vaccines represent only one of the options for control, and the vaccine prevents only some of the disease burden that nonvaccine interventions can prevent (i.e., cholera vaccine targets only those cases of diarrheal disease caused by cholera, but water, hygiene, and sanitation interventions reduce all diarrheal disease). In addition, cholera control and elimination occurs in most of the world without vaccination, and treatment with oral rehydration solutions significantly reduces the burden of disease. Due to the current limited regular demand and the absence of coordination, the filled vaccine for nonuniversal vaccines, like oral cholera vaccine, remains virtually nonexistent. For example, prior to creation of the stockpiles for the meningitis and yellow fever vaccines, manufacturers produced very limited amounts of these vaccines due to insecurity about demand. However, use and experience with meningitis vaccine from the stockpile over the last decade led to increases in regular demand, which led to sequential increases in the size of the stockpile. For nonuniversal vaccines, the nonregular demand from a stockpile can far exceed the global capacity in the event of a large outbreak, which would mean that even purchasing all of the existing capacity from a dedicated stockpile may prove insufficient. For example, despite the potential availability of small quantities of oral cholera vaccine to respond to the devastating 2010–2011 cholera outbreak in Haiti, public health authorities did not use any vaccine, at least in part due to insufficient amounts of vaccine,(94) and this event motivated creation of the current emergency stockpile.(64) Vaccine production and stockpiling for a potential

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pandemic and/or bioterrorism event represent the extreme case, since essentially no market exists for these vaccines prior to a triggering event. Due to the current lack of substantial regular demand for some nonuniversal vaccines, manufacturers would most likely put vaccine produced into the bulk stockpile and/or filled stockpile, which could expire (i.e., assuming finite storage life or shelf life) if no nonregular demand leads to stockpile deployment prior to expiry. Thus, any increase in regular demand may facilitate better vaccine supply chain and stockpile management by potentially allowing prioritization of vaccine that approaches expiry for distribution. Recommendations for greater use of the vaccine in endemic areas may help to increase demand, but only if vaccines show superiority compared to nonvaccine interventions. Evidence related to the cost effectiveness of nonuniversal vaccines typically remains limited, and this suggests the need for early investments in studies that will help countries determine the potential benefits, risks, and costs of using the vaccine. In contrast to immunization programs like measles that can focus on relatively young children, because most older children and adults benefit from life-long historical protection (i.e., either from prior vaccination as children or exposure to the pathogen), vaccines for which protection wanes like oral cholera vaccine will probably require relatively much larger stockpiles. For example, with well over a billion people living in countries or areas with endemic cholera,(64) a stockpile that equally protects everyone in endemic countries from cholera greatly exceeds the current or anticipated global supply, and creating such a large supply and massive vaccination strategy would require a huge investment. The recently created emergency stockpile of oral cholera vaccine(46) should provide some opportunities to collect and synthesize information that will help countries make informed decisions about the potential role of cholera vaccines in their national cholera disease control efforts going forward. Using nonuniversal vaccines from stockpiles for outbreak response to deal with epidemics requires managing complex logistics and politics. Public health authorities may find it difficult to gain public acceptance of a vaccine not currently used by the population, and delays are likely in the context of distributing vaccine in emergency situations.(95) Vaccines like oral cholera vaccine may lead to some impact through immediate protection of individuals as well as reduction of transmission at the population

18 level,(96–99) and this necessitates adequately characterizing the effect of herd protection to estimate the incidence with vaccination and incidence without vaccination, which will most likely require the use of a dynamic transmission model. Further, the ability to treat cases of disease will also factor into the relative value of using vaccine in the context of outbreak response. Similar to the situation for universal vaccines, in the event of an outbreak, resources for preventive measures (nonvaccine interventions or vaccination) may compete with those for treatment, and carefully balancing these remains an important consideration in the context of establishing and managing a vaccine stockpile. One of the most significant issues to resolve prior to designing a stockpile for a nonuniversal vaccine clearly relates to understanding whether the current lack of demand for the vaccine represents a lack of need for ongoing disease control interventions altogether (e.g., a niche vaccine for a small disease burden with sufficient vaccine supplies available), appropriate national preferences for nonvaccine management strategies, or a true market failure. Market failures occur when countries for which the benefits of vaccines exceed their costs fail to invest, which may result from information asymmetries (e.g., uncertainty about the vaccine) and/or lack of resources to pay the high initial costs associated with adopting the vaccine. The costs of delivering vaccines begin with the initiation of use of the vaccine and this may include the need for catchup campaigns to support vaccine introduction. Catchup campaigns will come with additional costs and imply additional benefits, and countries will need to weigh the long-term benefits against the long-term costs. For countries with limited resources, large short-term costs that exceed short-term benefits may represent a significant barrier for which support from external funders may represent an important incentive. Innovative financing methods may help to address short-term market failures.(91,100) National perceptions about vaccination will need to focus on cases prevented instead of looking myopically at the current burden of disease. The benefits of prevention, which we cannot see or count, will not be as obvious as vaccine costs.(3,4) Although real limitations may exist with respect to vaccine production capacity, we suggest that efforts to invest in adoption of vaccine might consider development of a stockpile as an incentive to increase production capacity. However, such efforts will need to ensure that they do not

Thompson and Tebbens inappropriately distort development of the market for the vaccine or encourage countries to rely on reactive vaccination when better alternatives exist. 6. DISCUSSION This stockpile framework for endemic and epidemic diseases highlights important considerations related to stockpile establishment decisions and management. One of the most significant issues discussed relates to the challenges of managing incentives. Although all countries should theoretically order the amount of each vaccine that they need to achieve the mission of the GVAP,(16) the revealed preferences of countries demonstrate a tendency to underinvest in prevention. Countries order vaccine consistent with the current coverage levels instead of the entire target population and/or without sufficient consideration of wastage, and accept cases of preventable endemic and epidemic disease due to insufficient resources. Successful control of vaccine-preventable diseases can change perceptions about the relative risks and benefits of vaccines compared to the disease itself.(3,101) Ideally, once a stockpile exists, the funds required for its continuation at the current size could essentially revolve such that donors only need to support the upfront establishment costs, any ongoing maintenance cost (e.g., storage, rotation, and management), and/or expansion costs of the stockpile countries should pay to buy the vaccine they use from the stockpile and this should cover the cost of stockpile replenishment. However, in the absence of specific disease management strategies, the potential and appropriate role of a vaccine stockpile remains unclear. The current lack of demand for nonuniversal vaccines for some diseases may appropriately reflect the preferences of countries to use their limited resources for other investments that they perceive as more cost effective or net beneficial. For example, water, sanitation, and hygiene interventions may provide benefits beyond cholera control, making these preferable overall in comparison to cholera vaccination. In such cases, the lack of demand does not represent a market failure, so long as countries make well-informed choices. In this context, the creation of a vaccine stockpile for which no demand exists could potentially impact nonvaccine interventions, and public health authorities and donors should exercise caution with respect to any incentives they create. Specifically, creating an artificial market could distort

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases overall disease control efforts if countries perceive that the existence of a global stockpile means that they can invest less nationally in their disease control activities due to the availability of a global good. However, the impact of creating a market for a vaccine by commissioning a stockpile could prove highly beneficial, particularly if creation of the market facilitates use and increases experience with a relatively new vaccine and if it stimulates innovations that significantly improve the vaccines and make them more cost effective. Given the relative newness of stockpiles for nonuniversal vaccines, future studies should carefully examine the incentives created by donor efforts and ensure that the net effect is not one that rewards failures by bailing out countries for mismanagement instead of rewarding countries that perform well. Planning for a vaccine stockpile must occur with complete understanding of the real time delays in the supply chain and recognition of the challenges associated with managing a complex dynamic system in the face of (sometimes highly) uncertain demand. For universal vaccines, we can easily anticipate the routine global demand simply based on population estimates, planned routine immunization and pSIAs, and current and historical vaccine use. The creation of a stockpile would help to manage surges in demand and reduce the impacts of any supply disruptions that occur. We suggest that sufficient capacity most likely exists to easily create a stockpile for MCVs and for many other universal vaccines, and that global health authorities would find value in creating such stockpiles using the U.S. pediatric stockpile as a proof of concept. Based on recent experience with measles outbreaks and potential support for outbreak response from the GAVI Alliance, the Measles and Rubella Initiative should develop the economic case for donors to invest in creating an emergency stockpile with a mechanism for a revolving fund for replenishment. These efforts should focus on supporting appropriately increased regular demand to support the achievement of regional elimination goals, which will ultimately require managing population immunity to prevent all transmission. In contrast, for nonuniversal vaccines, the current lack of demand and uncertainty about the potential role of the vaccines and national acceptability make demand forecasts difficult, and therefore the lack of a current market significantly constrains the ability of the system to manage surges. However, for some new vaccines, particularly those for

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which GAVI supports introduction, we suggest that GAVI and UNICEF should develop aggressive, multiyear forecasts of demand that will help manufacturers manage current capacity and expand as appropriate, and they should also create vaccine stockpiles that will mitigate the risks of any supply disruptions to ensure steady access to supplies. For nonuniversal vaccines and nonregular use, it may prove useful to frame the question for countries as one of exploring the best use of incremental resources available for managing each specific disease and type of disease (e.g., diarrheal control). If international donors are willing to invest an additional $10 million or $1 billion or any other amount to help endemic countries fight a specific disease or type of disease (e.g., diarrheal disease more broadly), then we should ask: What interventions will provide the most cost effective use of these resources over a reasonable time horizon and promote sustainable efforts for disease control? We suggest that asking this question may help to further develop appropriate markets for vaccine and nonvaccine interventions that will reduce the burden of vaccine-preventable diseases, and that vaccine stockpiles may represent a small, but very important, part of the solution to the problems of dynamic complexity and poor management. The opportunity to create vaccine stockpiles exists at multiple levels, and the existence of regional or national stockpiles may influence global stockpile decisions, and vice versa. In the context of determining the need for a national stockpile, countries will most likely consider the extent to which they believe that they can access any existing regional or global stockpile and/or mobilize effective nonvaccine measures to deal with outbreaks. In the context of cooperation and coordination, regional and global stockpile managers will need to develop a mechanism for distributing vaccine that ensures that the process occurs rapidly and fairly, particularly if the amount of vaccine available requires prioritization due to insufficient supply to cover all requests. Finally, vaccine stockpiles require ongoing management as vaccine products and experiences with diseases change. For example, as new vaccines become available, these may need to replace or supplement existing stockpiled vaccines. Stockpile managers will also need to deal with the complexities that arise from responses to resistance, antigenic drift, and changing formulations, including large shifts toward combination vaccines. Future studies may need to develop specific investment cases and management plans for vaccine stockpiles for endemic and

20 epidemic vaccine-preventable diseases, and we hope that this framework highlights both opportunities and challenges. ACKNOWLEDGMENTS We thank Drs. Kamran Badizadegan, Lisa Cairns, Claire Lise Chaignat, Stephen Cochi, Alejandro Costa, Alya Dabbagh, Jim Goodson, Raymond Hutubessy, Peter Strebel, Greg Wallace, and Parida Wubulihasimu for helpful information and comments that improved this article. We acknowledge support for background work on measles and oral cholera vaccines from the World Health Organization under Contracts APW200470477 and APW201056718, respectively. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions, policy, or views of the World Health Organization. REFERENCES 1. Ehreth J. The global value of vaccination. Vaccine, 2003; 21(7–8):596–600. 2. Bloom DE. The value of vaccination. Advances in Experimental Medicine and Biology, 2011; 697:1–8. 3. Thompson KM, Tebbens RJD. Eradication versus control for poliomyelitis: An economic analysis. Lancet, 2007; 369(9570):1363–1371. 4. Tebbens RJD, Pallansch MA, Cochi SL, Wassilak SGF, Linkins J, Sutter RW, Aylward RB, Thompson KM. Economic analysis of the global polio eradication initiative. Vaccine, 2011; 29(2):334–343. 5. Nelson EA, Sack D, Wolfson L, Walker DG, Seng LF, Steele D. Financing children’s vaccines. Vaccine, 2009; 27(Suppl 5):F12–F17. 6. Ozawa S, Stack ML, Bishai DM, Mirelman A, Friberg IK, Niessen L, Walker DG, Levine OS. During the “decade of vaccines,” the lives of 6.4 million children valued at $231 billion could be saved. Health Affairs, 2011; 30(6):1010–1020. 7. Stack ML, Ozawa S, Bishai DM, Mirelman A, Tam Y, Niessen L, Walker DG, Levine OS. Estimated economic benefits during the “decade of vaccines” include treatment savings, gains in labor productivity. Health Affairs, 2011; 30(6):1021–1028. 8. Klein JO, Myers MG. Strengthening the supply of routinely administered vaccines in the United States: Problems and proposed solutions. Clinical Infectious Diseases, 2006; 42(Suppl 3):S97–103. 9. Rodewald LE, Orenstein WA, Mason DD, Cochi SL. Vaccine supply problems: A perspective of the Centers for Disease Control and Prevention. Clinical Infectious Diseases, 2006; 42(Suppl 3):S104–110. 10. Robbins MJ, Jacobson SH. The altruistic monopsonist vaccine formulary pricing and purchasing problem: Informing public health policy. Omega, 2011; 39(6):589–597. 11. Jacobson SH, Sewell EC, Jokela JA. Survey of vaccine distribution and delivery issues in the USA: From pediatrics to pandemics. Expert Review of Vaccines, 2007; 6(6):981–990. 12. Wittet S. Introducing GAVI and the global fund for children’s vaccines. Vaccine, 2000; 19(4–5):385–386.

Thompson and Tebbens 13. GAVI Alliance. GAVI progress report 2011. Available at: http://gaviprogressreport.org/2011/, Accessed July 24, 2012. 14. WHO-UNICEF. Global Immunization Vision and Strategy 2006–2015. Geneva: World Health Organization, 2005. Available at: http://www.who.int/immunization/givs/en/, Accessed July 24, 2012. 15. WHO-UNICEF. WHO-UNICEF Guidelines for Developing a Comprehensive Multi-Year Plan. Report WHO/IVB/05.20. Geneva: World Health Organization, 2005. Available at: http://www.who.int/immunization/documents/WHO IVB 05.20/en/, Accessed July 24, 2012. 16. Decade of Vaccines. Global Vaccines Action Plan. Available at: http://www.dovcollaboration.org/action-plan/, Accessed July 24, 2012. 17. Wolfson LJ, Gasse F, Lee-Martin SP, Lydon P, Magan A, Tibouti A, Johns B, Hutubessy R, Salama P, Okwo-Bele JM. Estimating the costs of achieving the WHO-UNICEF Global Immunization Vision and Strategy, 2006–2015. Bulletin of the World Health Organization, 2008; 86(1):27–39. 18. Shrestha SS, Wallace GS, Meltzer MI. Modeling the national pediatric vaccine stockpile: Supply shortages, health impacts and cost consequences. Vaccine, 2010; 28(38):6318–6332. 19. Jarrett S. Vaccine shortages: Stephen Jarrett, Deputy Director, UNICEF Supply Division, 2012. Available at: http://www.unicef.org/immunization/23244 shortage.html, Accessed January 6, 2014. 20. Stokley S, Santoli JM, Willis B, Kelley V, Vargas-Rosales A, Rodewald LE. Impact of vaccine shortages on immunization programs and providers. American Journal of Preventive Medicine, 2004; 26(1):15–21. 21. Hinman AR, Orenstein WA, Santoli JM, Rodewald LE, Cochi SL. Vaccine shortages: History, impact, and prospects for the future. Annual Review of Public Health, 2006; 27:235– 259. 22. Lane KS, Chu SY, Santoli JM. The United States pediatric vaccine stockpile program. Clinical Infectious Diseases, 2006; 42(Suppl 3):S125–129. 23. Traynor K. Vaccine shortages persist despite lessons from past. American Journal of Health-System Pharmacy, 2004; 61(23):2458, 2460, 2462. 24. Rivera A, Orengo JC, Rivera AL, Rodriguez C, Calderon E, Rullan J, Yusuf H, Rodewald L. Impact of vaccine shortage on diphtheria and tetanus toxoids and acellular pertussis vaccine coverage rates among children aged 24 months– Puerto Rico, 2002. Morbidity and Mortality Weekly Report 2002; 51(30):667–668. 25. Santibanez TA, Santoli JM, Barker LE. Differential effects of the DTaP and MMR vaccine shortages on timeliness of childhood vaccination coverage. American Journal of Public Health, 2006; 96(4):691–696. 26. Santibanez TA, Shefer A, Briere EC, Cohn AC, Groom AV. Effects of a nationwide Hib vaccine shortage on vaccination coverage in the United States. Vaccine, 2012; 30(5): 941–947. 27. Groom AV, Cheek JE, Bryan RT. Effect of a national vaccine shortage on vaccine coverage for American Indian/Alaska native children. American Journal of Public Health, 2006; 96(4):697–701. 28. Centers for Disease Control and Prevention. Interim recommendations for the use of Haemophilus influenzae type b (Hib) conjugate vaccines related to the recall of certain lots of Hib-containing vaccines (PedvaxHIB and Comvax). Morbidity and Mortality Weekly Report, 2007; 56:1318– 1320. 29. Centers for Disease Control and Prevention. Updated recommendations for use of Haemophilus influenzae type b (Hib) vaccine: Reinstatement of the booster dose at ages 12– 15 months. Morbidity and Mortality Weekly Report, 2009; 58:673–674.

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases 30. Centers for Disease Control and Prevention. Current vaccine shortages & delays, 2014. Available at: http://www.cdc. gov/vaccines/vac-gen/shortages/, Accessed May 10, 2014. 31. Wynia MK. Ethics and public health emergencies: Rationing vaccines. American Journal of Bioethics, 2006; 6(6):4–7. 32. Plotkin SA, Orenstein WA, Offit PA. Vaccines, 6th ed. Philadelphia, PA: Saunders Elsevier, 2013. 33. World Health Organization. Vaccine preventable diseases monitoring system – 2013 global summary. Available at: http://apps.who.int/immunization monitoring/globalsummary/ schedules, Accessed May 16, 2014. 34. World Health Organization. WHO prequalified vaccines, 2014. Available at: http://www.who.int/immunization standards/vaccine quality/PQ vaccine list en/en/, Accessed May 16, 2014. 35. Immunization Action Coalition. Vaccine timeline: Historic dates and events related to vaccines and immunization. Available at: http://www.immunize.org/timeline/, Accessed May 17, 2014. 36. Duintjer Tebbens RJ, Pallansch MA, Alexander JP, Jr., Thompson KM. Optimal vaccine stockpile design for an eradicated disease: Application to polio. Vaccine, 2010; 28(26):4312–4327. 37. Roush SW, Murphy TV, Vaccine Preventable Disease Table Working Group. Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. Journal of the American Medical Association, 2007; 298(18):2155–2163. 38. Jacobson SH, Sewell EC, Proano RA. An analysis of the pediatric vaccine supply shortage problem. Health Care Management Science, 2006; 9(4):371–389. 39. Jacobson SH, Sewell EC, Proano RA, Jokela JA. Stockpile levels for pediatric vaccines: How much is enough? Vaccine, 2006; 24(17):3530–3537. 40. Proano RA, Jacobson SH, Jokela JA. A multi-attribute approach for setting pediatric vaccine stockpile levels. Journal of Industrial and Management Optimization, 2010; 6(4):709– 722. 41. Thompson KM, Pallansch MA, Tebbens RJD, Wassilak SGF, Cochi SL. Modeling population immunity to support efforts to end the transmission of live polioviruses. Risk Analysis, 2013; 33(4):647–663. 42. Esbitt D. The strategic national stockpile: Roles and responsibilities of health care professionals for receiving the stockpile assets. Disaster Management and Response, 2003; 1(3):68–70. 43. World Health Organization. International Coordinating Group (ICG) on Vaccine Provision for Epidemic Meningitis control. Available at: http://www.who. int/csr/disease/meningococcal/icg/en/, Accessed May 11, 2014. 44. World Health Organization. International Coordinating Group (ICG) on Vaccine Provision for Epidemic Meningitis Control. Report of the Seventh Meeting. Geneva: World Health Organization, Report No.: WHO/CDS/CSR/GAR/2002.2, 2001. 45. World Health Organization. Yellow fever vaccine: A global partnership, 2011. Available from: http://www.who.int/csr/disease/yellowfev/global partnership/en/, Accessed May 11, 2014. 46. World Health Organization. Technical Working Group on Creation of an Oral Cholera Vaccine Stockpile, 2012. Report No.: WHO/HSE/PED/2012.2. Available at: http://www.who.int/cholera/publications/oral cholera vaccine/ en/index.html, Accessed January 6, 2014. 47. World Health Organization. Oral cholera vaccine stockpile, 2013. Available at: http://www.who.int/ cholera/vaccines/ocv stockpile 2013/en/, Accessed January 6, 2014.

21

48. World Health Organization. Polio eradication and endgame strategic plan 2013–2018. Available at: http://www. polioeradication.org/resourcelibrary/strategyandwork.aspx, Accessed January 6, 2014. 49. Thompson KM, Tebbens RJD. The case for cooperation in managing and maintaining the end of poliomyelitis: Stockpile needs and coordinated OPV cessation. Medscape Journal of Medicine, 2008; 10(8):190. 50. Thompson KM, Tebbens RJD. Current polio global eradication and control policy options: Perspectives from modeling and prerequisites for OPV cessation. Expert Review of Vaccines, 2012; 11(4):449–459. 51. Edmunds WJ, Medley GF, Nokes DJ. Evaluating the costeffectiveness of vaccination programmes: A dynamic perspective. Statistics in Medicine, 1999; 18(23):3263–3282. 52. Thompson KM, Tebbens RJD. Retrospective costeffectiveness analyses for polio vaccination in the United States. Risk Analysis, 2006; 26(6):1423–1440. 53. World Health Organization. WHO Guide for Standardization of Economic Evaluations of Immunization Programmes. Geneva: Initiative for Vaccine Research, Department of Immunization, Vaccine, and Biologicals, Report No.: WHO/IVB/0814, December 2008. 54. Thompson KM, Dabbagh A, Strebel PM, Perry R, GacicDobo M, Cochi SL, Cairns L, Reef S. National and global options for managing the risks of measles and rubella. Journal of Vaccines and Vaccination, 2012; 3:165. doi: 10.4172/21577560.1000165. 55. Thompson KM, Pallansch MA, Tebbens RJD, Wassilak SG, Kim J-H, Cochi SL. Pre-eradication vaccine policy options for poliovirus infection and disease control. Risk Analysis, 2013; 33(4):516–543. 56. Thompson KM, Tebbens RJD. National choices related to inactivated poliovirus vaccine, innovation, and the end game of global polio eradication. Expert Review of Vaccines, 2014; 13(2):221–234. 57. World Health Organization. Global measles and rubella strategic plan, 2012–2020. Available at: http://www.who.int/ immunization/newsroom/Measles Rubella StrategicPlan 2012 2020.pdf, Accessed May 11, 2014. 58. World Health Organization. Maternal and neonatal tetanus elimination by 2005, 2000. Available at: http:// www.who.int/vaccines-documents/DocsPDF02/www692.pdf, Accessed May 11, 2014. 59. Thompson KM, Wallace GS, Tebbens RJ, Smith PJ, Barskey AE, Pallansch MA, Gallagher KM, Alexander JP, Armstrong GL, Cochi SL, Wassilak SG. Trends in the risk of U.S. polio outbreaks and poliovirus vaccine availability for response. Public Health Report, 2012; 127(1): 23–37. 60. Thompson KM, Tebbens RJD. Economic evaluation of the benefits and costs of disease elimination and eradication initiatives. Pp. 115–130 in Cochi SL, Dowdle WR (eds). Disease Eradication in the 21st Century: Implications for Global Health. Cambridge, MA: MIT Press, 2011. 61. World Health Organization Commission on Macroeconomics and Health. Macroeconomics and Health: Investing in Health for Economic Development. Report of the Commission on Macroeconomics and Health. Geneva: World Health Organization, 2001. 62. Nigrovic LE, Thompson KM. The lyme vaccine: A cautionary tale. Epidemiology and Infection, 2007; 135(1):1–8. 63. Thompson KM, Duintjer Tebbens RJ. Modeling the dynamics of oral poliovirus vaccine cessation. Journal of Infectious Diseases, 2014; In press. 64. Thompson KM, Tebbens RJD, Chaignat C-L, Hill A, Badizadegan K, Costa AJ, Namgyal P, Hutubessy RC. Managing cholera as a preventable global threat. Journal of Vaccines and Vaccination, 2013; 4(3):183.

22 65. Fine PEM, Clarkson J A. Measles in England and Wales—II: The impact of the Measles Vaccination Programme on the distribution of immunity in the population. International Journal of Epidemiology, 1982; 11:15–25. 66. Thompson KM, Strebel PM, Dabbagh A, Cherian T, Cochi SL. Enabling implementation of the global vaccine action plan: Developing investment cases to achieve targets for measles and rubella prevention. Vaccine, 2013; 31(Suppl 2):B149–156. 67. Centers for Disease Control and Prevention. Update: Vaccine side effects, adverse reaction, contraindications, and precautions — Recommendation of the Advisory Committee on Immunization Practices (ACIP). Morbidity and Mortality Weekly Report, 1996; 45(RR-12):1–35. 68. Rota PA, Brown KE, Hubschen JM, Muller CP, Icenogle J, Chen MH, Bankamp B, Kessler JR, Brown DW, Bellini WJ, Featherstone D. Improving global virologic surveillance for measles and rubella. Journal of Infectious Diseases, 2011; 204(Suppl 1):S506–513. 69. Christie AS, Gay A. The measles initiative: Moving toward measles eradication. Journal of Infectious Diseases, 2011; 204(Suppl1):S14–S17. 70. Thompson KM, Odahowski CL. Systematic review of health economic analyses of measles and rubella immunization interventions. Risk Analysis, 2014; Submitted. 71. Strebel PM, Cochi SL, Hoekstra E, Rota PA, Featherstone D, Bellini WJ, Katz SL. A world without measles. Journal of Infectious Diseases, 2011; 204(Suppl 1):S1–S3. 72. Smith G, Michelson J, Singh R, Dabbagh A, Hoekstra E, van den Ent M, Mallya A. Is there enough vaccine to eradicate measles? An integrated analysis of measles-containing vaccine supply and demand. Journal of Infectious Diseases, 2011; 204(Suppl 1):S62–70. 73. Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat. World population prospects: The 2012 revision, 2013. Available at: http://esa.un.org/unpd/wpp/index.htm, Accessed September 11, 2013. 74. World Health Organization. Measles vaccine: WHO position paper. Weekly Epidemiological Record, 2009; 84(35):349– 360. 75. Drain PK, Nelson CM, Lloyd JS. Single-dose versus multidose vaccine vials for immunization programmes in developing countries. Bulletin of the World Health Organization, 2003; 81(10):726–731. 76. Lee BY, Norman BA, Assi TM, Chen SI, Bailey RR, Rajgopal J, Brown ST, Wiringa AE, Burke DS. Single versus multi-dose vaccine vials: An economic computational model. Vaccine, 2010; 28(32):5292–5300. 77. World Health Organization. Policy statement. The use of opened multi-dose vials of vaccine in subsequent immunization sessions. Geneva, Switzerland: WHO: WHO/V&B/00.09, 2000. 78. World Health Organization. Meeting of the strategic advisory group of experts on immunization, November 2013 — Conclusions and recommendations. Weekly Epidemiological Record, 2014; 89(1):12. 79. Cairns KL, Perry RT, Ryman TK, Nandy RK, Grais RF. Should outbreak response immunization be recommended for measles outbreaks in middle- and low-income countries? An update. Journal of Infectious Diseases, 2011; 204(Suppl 1):S35–S46. 80. Thompson KM, Tebbens RJD, Pallansch MA. Evaluation of response scenarios to potential polio outbreaks using mathematical models. Risk Analysis, 2006; 26(6):1541– 1556. 81. Grais RFC, Conlan AJ, Ferrari MJ, Djibo A, Le Menach A, Bjornstad ON, Grenfell BT. Time is of the essence: Exploring a measles outbreak response vaccination in Niamey,

Thompson and Tebbens

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94. 95.

96.

97.

Niger. Journal of the Royal Society Interface, 2008; 5(18):67– 74. Goodson JL, Perry RT, Mach O, Manyanga D, Luman ET, Kitambi M, Kibona M, Wiesen E, Cairns KL. Measles outbreak in Tanzania, 2006–2007. Vaccine, 2010; 28(37):5979– 5985. World Health Organization. Response to Measles Outbreaks in Measles Mortality Reduction Settings. Geneva: World Health Organization, Department of Immunization, Vaccines and Biologicals. Report No.: WHO/IVB/09.03, March 2009. Davis RM, Markowitz LE, Preblud SR, Orenstein WA, Hinman AR. A cost-effectiveness analysis of measles outbreak control strategies. American Journal of Epidemiology, 1987; 126(3):450–459. Shiell A, Jorm LR, Carruthers R, Fitzsimmons GJ. Costeffectiveness of measles outbreak intervention strategies. Australian and New Zealand Journal of Public Health, 1998; 22(1):126–132. Parker AA, Staggs W, Dayan GH, Ortega-Sanchez IR, Rota PA, Lowe L, Boardman P, Teclaw R, Graves C, LeBaron CW. Implications of a 2005 measles outbreak in Indiana for sustained elimination of measles in the United States. New England Journal of Medicine, 2006; 355(5):447– 455. Dayan GH, Ortega-Sanchez IR, LeBaron CW, Quinlisk MP. The cost of containing one case of measles: The economic impact on the public health infrastructure—Iowa, 2004. Pediatrics, 2005; 116(1):e1–e4. Chen SY, Anderson S, Kutty PK, Lugo F, McDonald M, Rota PA, Ortega-Sanchez IR, Komatsu K, Armstrong GL, Sunenshine R, Seward JF. Health care-associated measles outbreak in the United States after an importation: Challenges and economic impact. Journal of Infectious Diseases, 2011; 203(11):1517–1525. Centers for Disease Control and Prevention. Measles outbreaks and progress toward measles preelimination— African region, 2009–2010. Morbidity and Mortality Weekly Report, 2011; 60(12):374–378. GAVI Alliance. GAVI boosts global response to measles outbreaks, 2012. Available at:http://www.gavialliance.org/library/news/pressreleases/2012/gavi-boosts-global-response-to-measlesoutbreaks/, Accessed January 6, 2014. Thompson KM, Tebbens RJD. Using system dynamics to develop policies that matter: Global management of poliomyelitis and beyond. System Dynamics Review, 2008; 24(4):433–449. Repenning NP, Sterman JD. Nobody ever gets credit for fixing problems that never happened: Creating and sustaining process improvement. California Management Review, 2001; 43(4):64–88. Repenning NP, Goncalves P, Black L. Past the tipping point: The persistent of fire fighting in product development. California Management Review, 2001; 43(4):44– 63. Clemens JD. Vaccines in the time of cholera. Proceedings of the National Academy of Sciences USA, 2011; 108:8529– 8530. World Health Organization. Use of the Two-Dose Oral Cholera Vaccine in the Context of a Major Natural Disaster. Geneva: World Health Organization. Report No.: WHO/CDS/NTD/IDM/2006.1, 2006. Ali M, Emch M, von Seidlein L, Yunus M, Sack DA, Rao M, Holmgren J, Clemens JD. Herd immunity conferred by killed oral cholera vaccines in Bangladesh: A reanalysis. Lancet, 2005; 366(9479):44–49. Chao DL, Halloran ME, Longini IM, Jr. Vaccination strategies for epidemic cholera in Haiti with implications for the

Optimal Global Vaccine Stockpile Design for Vaccine-Preventable Diseases developing world. Proceedings of the National Academy of Sciences USA, 2011; 108(17):7081–7085. 98. Longini IM, Jr., Nizam A, Ali M, Yunus M, Shenvi N, Clemens JD. Controlling endemic cholera with oral vaccines. PLoS Medicine, 2007; 4(11):e336. 99. Reyburn R, Deen JL, Grais RF, Bhattacharya SK, Sur D, Lopez AL, Jiddawi MS, Clemens JD, von Seidlein L. The case for reactive mass oral cholera vaccinations. PLoS Neglected Tropical Diseases, 2011; 5(1): e952. 100. Thompson KM, Rabinovich R, Conteh L, Emerson CI, Hall BF, Singer PA, Vijayaraghavan M, Walker D. Group report:

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Developing an eradication investment case. Pp. 133–148 in Cochi SL, Dowdle WR (eds). Disease Eradication in the 21st Century: Implications for Global Health. Cambridge, MA: MIT Press, 2011. 101. Thompson KM. Valuing prevention as the new paradigm in global health: Managing population immunity for vaccine-preventable diseases. ICU Management, 2012; 12(4):9–11. 102. Centers for Disease Control and Prevention. Serogroup b meningococcal vaccine and outbreaks. Available at: http://www.cdc.gov/meningococcal/outbreaks/vaccineserogroupB.html, Accessed May 17, 2014

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