Only adding stationary storage to vaccine supply chains may create and worsen transport bottlenecks.

Although vaccine supply chains in many countries require additional stationary storage and transport capacity to meet current and future needs, international donors tend to donate stationary storage devices far more often than transport equipment. To investigate the impact of only adding stationary storage equipment on the capacity requirements of transport devices and vehicles, we used HERMES (Highly Extensible Resource for Modeling Supply Chains) to construct a discrete event simulation model of the Niger vaccine supply chain. We measured the transport capacity requirement for each mode of transport used in the Niger vaccine cold chain, both before and after adding cold rooms and refrigerators to relieve all stationary storage constraints in the system. With the addition of necessary stationary storage, the average transport capacity requirement increased from 88% to 144% for cold trucks, from 101% to 197% for pickup trucks, and from 366% to 420% for vaccine carriers. Therefore, adding stationary storage alone may worsen or create new transport bottlenecks as more vaccines flow through the system, preventing many vaccines from reaching their target populations. Dynamic modeling can reveal such relationships between stationary storage capacity and transport constraints.

Impact of introducing the pneumococcal and rotavirus vaccines into the routine immunization program in Niger.

OBJECTIVES: We investigated whether introducing the rotavirus and pneumococcal vaccines, which are greatly needed in West Africa, would overwhelm existing supply chains (i.e., the series of steps required to get a vaccine from the manufacturers to the target population) in Niger. METHODS: As part of the Bill and Melinda Gates Foundation-funded Vaccine Modeling Initiative, we developed a computational model to determine the impact of introducing these new vaccines to Niger's Expanded Program on Immunization vaccine supply chain. RESULTS: Introducing either the rotavirus vaccine or the 7-valent pneumococcal conjugate vaccine could overwhelm available storage and transport refrigerator space, creating bottlenecks that would prevent the flow of vaccines down to the clinics. As a result, the availability of all World Health Organization Expanded Program on Immunization vaccines to patients might decrease from an average of 69% to 28.2% (range = 10%-51%). Addition of refrigerator and transport capacity could alleviate this bottleneck. CONCLUSIONS: Our results suggest that the effects on the vaccine supply chain should be considered when introducing a new vaccine and that computational models can help assess evolving needs and prevent problems with vaccine delivery.

Impact of changing the measles vaccine vial size on Niger's vaccine supply chain: a computational model.

BACKGROUND: Many countries, such as Niger, are considering changing their vaccine vial size presentation and may want to evaluate the subsequent impact on their supply chains, the series of steps required to get vaccines from their manufacturers to patients. The measles vaccine is particularly important in Niger, a country prone to measles outbreaks. METHODS: We developed a detailed discrete event simulation model of the vaccine supply chain representing every vaccine, storage location, refrigerator, freezer, and transport device (e.g., cold trucks, 4 × 4 trucks, and vaccine carriers) in the Niger Expanded Programme on Immunization (EPI). Experiments simulated the impact of replacing the 10-dose measles vial size with 5-dose, 2-dose and 1-dose vial sizes. RESULTS: Switching from the 10-dose to the 5-dose, 2-dose and 1-dose vial sizes decreased the average availability of EPI vaccines for arriving patients from 83% to 82%, 81% and 78%, respectively for a 100% target population size. The switches also changed transport vehicle's utilization from a mean of 58% (range: 4-164%) to means of 59% (range: 4-164%), 62% (range: 4-175%), and 67% (range: 5-192%), respectively, between the regional and district stores, and from a mean of 160% (range: 83-300%) to means of 161% (range: 82-322%), 175% (range: 78-344%), and 198% (range: 88-402%), respectively, between the district to integrated health centres (IHC). The switch also changed district level storage utilization from a mean of 65% to means of 64%, 66% and 68% (range for all scenarios: 3-100%). Finally, accounting for vaccine administration, wastage, and disposal, replacing the 10-dose vial with the 5 or 1-dose vials would increase the cost per immunized patient from $0.47US to $0.71US and $1.26US, respectively. CONCLUSIONS: The switch from the 10-dose measles vaccines to smaller vial sizes could overwhelm the capacities of many storage facilities and transport vehicles as well as increase the cost per vaccinated child.

A stochastic programming model of vaccine preparation and administration for seasonal influenza interventions.

This study considers the integration of vaccine preparation and administration decisions for seasonal influenza interventions. We examine actual vaccination activities of sharing multiple vaccine products and supplementary vaccinations. A two-stage stochastic program is formulated to determine the optimal ordering and allocation of vaccines under uncertain attack rates, vaccine efficacies, and demands. We present an algorithm based on the sample average approximation and warm-start solution to solve the stochastic integer program with continuous random variables. Furthermore, the optimal solution for the deterministic model using the expected value is analyzed and obtained directly. Our analysis compares the deterministic and stochastic solutions to assess the impact of uncertainties on the immunization outcomes and costs. The result shows that the stochastic programming model provides a more robust solution than the deterministic model, and uncertain characteristics should consider when making public health decisions.

Evaluating the impact of soy compounds on breast cancer using the data mining approach.

Accumulating evidence has shown that soy intake is associated with the promotion of health and prevention of cancers. However, the relationship between the intake of soy compounds and the risk of breast cancer is still debatable. In this study, we use mathematical models for assessing the impact of soy phytoestrogens and protein/peptide intervention on breast cancer development using the datasets acquired from a large number of published studies. We used data mining models, including the decision tree classification and association rule methods, to analyze 478 data collected from 201 research papers. The results indicated that the intervention of soy proteins and peptides, especially lunasin (LUN) and bowman-birk protease inhibitor (BBI), has a positive impact on different types of breast cancer, while the effects of soy phytoestrogens are inconsistent in breast cancer development. Among soy phytoestrogens, daidzein (DAI) exhibited the highest negative impact on breast cancer, followed by coumestrol (COU), soysapogenol (SAP), genistein (GEN), and equol (EQ). With regard to the type of cancer, phytoestrogens should be carefully considered in estrogen receptor (ER)+ or progesterone receptor (PR)+ breast cancer. In the case of ER-, PR- or triple negative type, both soy categories can be used as auxiliary interventions. In summary, this is the first study to use data mining to explore the relationship between the intake of soy phytoestrogens or proteins/peptides and breast cancer development. Our findings indicate that soy intervention might reduce breast cancer development. However, the specific soy compound and cancer type should be considered before allocating a precise nutrient intervention.

Optimizing influenza vaccine policies for controlling 2009-like pandemics and regular outbreaks.

BACKGROUND: This study examined the effectiveness of various vaccine policies against influenza. The transmission rate was calculated by use of the time-series influenza-like illness case during the year of 2009 and recent epidemics in Taiwan. METHODS: We developed a stochastic compartmental model to analyze the transmission of influenza, where the population was stratified by location and age group, and the vaccine distribution was considered using the current policy. The simulation study compared the previous vaccine policy and a new policy with expanded coverage and various lengths of the vaccination campaign. The sensitivity analysis investigated different levels of vaccine efficacy to confirm the robustness of the recommended policies. RESULTS: Doubling vaccine coverage can decrease the number of infections effectively in the regular epidemic scenario. However, a peak of infections occurs if the duration of implementing vaccination is too long. In the 2009-like pandemic scenario, both increasing vaccine doses and reducing the program's duration can mitigate infections, although the early outbreak restricts the effectiveness of vaccination programs. CONCLUSIONS: The finding indicates that only increasing vaccine coverage can reduce influenza infections. To avoid the peak of infections, it is also necessary to execute the vaccination activity immediately. Vaccine efficacy significantly impacts the vaccination policy's performance. When vaccine efficacy is low, neither increasing vaccination doses nor reducing vaccination timeframe prevents infections. Therefore, the variation in vaccine efficacy should be taken into account when making immunization policies against influenza.

Economic benefits of sharing and redistributing influenza vaccines when shortages occurred.

BACKGROUND: Recurrent influenza outbreak has been a concern for government health institutions in Taiwan. Over 10% of the population is infected by influenza viruses every year, and the infection has caused losses to both health and the economy. Approximately three million free vaccine doses are ordered and administered to high-risk populations at the beginning of flu season to control the disease. The government recommends sharing and redistributing vaccine inventories when shortages occur. While this policy intends to increase inventory flexibility, and has been proven as widely valuable, its impact on vaccine availability has not been previously reported. MATERIAL AND METHODS: This study developed an inventory model adapted to vaccination protocols to evaluate government recommended polices under different levels of vaccine production. Demands were uncertain and stratified by ages and locations according to the demographic data in Taiwan. RESULTS: When vaccine supply is sufficient, sharing pediatric vaccine reduced vaccine unavailability by 43% and overstock by 54%, and sharing adult vaccine reduced vaccine unavailability by 9% and overstock by 15%. Redistributing vaccines obtained greater gains for both pediatrics and adults (by 75%). When the vaccine supply is in short, only sharing pediatric vaccine yielded a 48% reduction of unused inventory, while other polices do not improve performances. CONCLUSIONS: When implementing vaccination activities for seasonal influenza intervention, it is important to consider mismatches of demand and vaccine inventory. Our model confirmed that sharing and redistributing vaccines can substantially increase availability and reduce unused vaccines.

Landscaping the structures of GAVI country vaccine supply chains and testing the effects of radical redesign.

BACKGROUND: Many of the world's vaccine supply chains do not adequately provide vaccines, prompting several questions: how are vaccine supply chains currently structured, are these structures closely tailored to individual countries, and should these supply chains be radically redesigned? METHODS: We segmented the 57 GAVI-eligible countries' vaccine supply chains based on their structure/morphology, analyzed whether these segments correlated with differences in country characteristics, and then utilized HERMES to develop a detailed simulation model of three sample countries' supply chains and explore the cost and impact of various alternative structures. RESULTS: The majority of supply chains (34 of 57) consist of four levels, despite serving a wide diversity of geographical areas and population sizes. These four-level supply chains loosely fall into three clusters [(1) 18 countries relatively more bottom-heavy, i.e., many more storage locations lower in the supply chain, (2) seven with relatively more storage locations in both top and lower levels, and (3) nine comparatively more top-heavy] which do not correlate closely with any of the country characteristics considered. For all three cluster types, our HERMES modeling found that simplified systems (a central location shipping directly to immunization locations with a limited number of Hubs in between) resulted in lower operating costs. CONCLUSION: A standard four-tier design template may have been followed for most countries and raises the possibility that simpler and more tailored designs may be warranted.

A passive cold storage device economic model to evaluate selected immunization location scenarios.

BACKGROUND: The challenge of keeping vaccines cold at health posts given the unreliability of power sources in many low- and middle-income countries and the expense and maintenance requirements of solar refrigerators has motivated the development of passive cold storage devices (PCDs), containers that keep vaccines cold without using an active energy source. With different PCDs under development, manufacturers, policymakers and funders need guidance on how varying different PCD characteristics may affect the devices' cost and utility. METHODS: We developed an economic spreadsheet model representing the lowest two levels of a typical Expanded Program on Immunization (EPI) vaccine supply chain: a district store, the immunization locations that the district store serves, and the transport vehicles that operate between the district store and the immunization locations. The model compares the use of three vaccine storage device options [(1) portable PCDs, (2) stationary PCDs, or (3) solar refrigerators] and allows the user to vary different device (e.g., size and cost) and scenario characteristics (e.g., catchment area population size and vaccine schedule). RESULTS: For a sample set of select scenarios and equipment specification, we found the portable PCD to generally be better suited to populations of 5,000 or less. The stationary PCD replenished once per month can be a robust design especially with a 35L capacity and a cost of $2,500 or less. The solar device was generally a reasonable alternative for most of the scenarios explored if the cost was $2,100 or less (including installation). No one device type dominated over all explored circumstances. Therefore, the best device may vary from country-to-country and location-to-location within a country. CONCLUSIONS: This study introduces a quantitative model to help guide PCD development. Although our selected set of explored scenarios and device designs was not exhaustive, future explorations can further alter model input values to represent additional scenarios and device designs.

Augmenting transport versus increasing cold storage to improve vaccine supply chains.

BACKGROUND: When addressing the urgent task of improving vaccine supply chains, especially to accommodate the introduction of new vaccines, there is often a heavy emphasis on stationary storage. Currently, donations to vaccine supply chains occur largely in the form of storage equipment. METHODS: This study utilized a HERMES-generated detailed, dynamic, discrete event simulation model of the Niger vaccine supply chain to compare the impacts on vaccine availability of adding stationary cold storage versus transport capacity at different levels and to determine whether adding stationary storage capacity alone would be enough to relieve potential bottlenecks when pneumococcal and rotavirus vaccines are introduced by 2015. RESULTS: Relieving regional level storage bottlenecks increased vaccine availability (by 4%) more than relieving storage bottlenecks at the district (1% increase), central (no change), and clinic (no change) levels alone. Increasing transport frequency (or capacity) yielded far greater gains (e.g., 15% increase in vaccine availability when doubling transport frequency to the district level and 18% when tripling). In fact, relieving all stationary storage constraints could only increase vaccine availability by 11%, whereas doubling the transport frequency throughout the system led to a 26% increase and tripling the frequency led to a 30% increase. Increasing transport frequency also reduced the amount of stationary storage space needed in the supply chain. The supply chain required an additional 61,269L of storage to relieve constraints with the current transport frequency, 55,255L with transport frequency doubled, and 51,791L with transport frequency tripled. CONCLUSIONS: When evaluating vaccine supply chains, it is important to understand the interplay between stationary storage and transport. The HERMES-generated dynamic simulation model showed how augmenting transport can result in greater gains than only augmenting stationary storage and can reduce stationary storage needs.

How influenza vaccination policy may affect vaccine logistics.

BACKGROUND: When policymakers make decision about the target populations and timing of influenza vaccination, they may not consider the impact on the vaccine supply chains, which may in turn affect vaccine availability. PURPOSE: Our goal is to explore the effects on the Thailand vaccine supply chain of introducing influenza vaccines and varying the target populations and immunization time-frames. METHODS: We Utilized our custom-designed software HERMES (Highly Extensible Resource for Modeling Supply Chains), we developed a detailed, computational discrete-event simulation model of the Thailand's National Immunization Program (NIP) supply chain in Trang Province, Thailand. A suite of experiments simulated introducing influenza vaccines for different target populations and over different time-frames prior to and during the annual influenza season. RESULTS: Introducing influenza vaccines creates bottlenecks that reduce the availability of both influenza vaccines as well as the other NIP vaccines, with provincial to district transport capacity being the primary constraint. Even covering only 25% of the Advisory Committee on Immunization Practice-recommended population while administering the vaccine over six months hinders overall vaccine availability so that only 62% of arriving patients can receive vaccines. Increasing the target population from 25% to 100% progressively worsens these bottlenecks, while increasing influenza vaccination time-frame from 1 to 6 months decreases these bottlenecks. CONCLUSION: Since the choice of target populations for influenza vaccination and the time-frame to deliver this vaccine can substantially affect the flow of all vaccines, policy-makers may want to consider supply chain effects when choosing target populations for a vaccine.

The optimal number of routine vaccines to order at health clinics in low or middle income countries.

In a low or middle income country, determining the correct number of routine vaccines to order at a health clinic can be difficult, especially given the variability in the number of patients arriving, minimal vaccination days and resource (e.g., information technology and refrigerator space) constraints. We developed a spreadsheet model to determine the potential impact of different ordering policies, basing orders on the arrival rates seen in the previous 1, 3, 6, or 12 sessions, or on long-term historical averages (where these might be available) along with various buffer stock levels (range: 5-50%). Experiments varied patient arrival rates (mean range: 1-30 per session), arrival rate distributions (Poisson, Normal, and Uniform) and vaccine vial sizes (range: 1-dose to 10-dose vials). It was found that when the number of doses per vial is small and the expected number of patients is low, the ordering policy has a more significant impact on the ability to meet demand. Using data from more prior sessions to determine arrival rates generally equates to a better ability to meet demand, although the marginal benefit is relatively small after more than 6 sessions are averaged. As expected, the addition of more buffer is helpful in obtaining better performance; however, this advantage also has notable diminishing returns. In general, the long-term demand rate, the vial sizes of the vaccines used and the method of determining the patient arrival rate all have an effect on the ability of a clinic to maximize the demand that is met.

Replacing the measles ten-dose vaccine presentation with the single-dose presentation in Thailand.

Introduced to minimize open vial wastage, single-dose vaccine vials require more storage space and therefore may affect vaccine supply chains (i.e., the series of steps and processes involved in distributing vaccines from manufacturers to patients). We developed a computational model of Thailand's Trang province vaccine supply chain to analyze the effects of switching from a ten-dose measles vaccine presentation to each of the following: a single-dose measles-mumps-rubella vaccine (which Thailand is currently considering) or a single-dose measles vaccine. While the Trang province vaccine supply chain would generally have enough storage and transport capacity to accommodate the switches, the added volume could push some locations' storage and transport space utilization close to their limits. Single-dose vaccines would allow for more precise ordering and decrease open vial waste, but decrease reserves for unanticipated demand. Moreover, the added disposal and administration costs could far outweigh the costs saved from preventing open vial wastage.

Maintaining vaccine delivery following the introduction of the rotavirus and pneumococcal vaccines in Thailand.

Although the substantial burdens of rotavirus and pneumococcal disease have motivated many countries to consider introducing the rotavirus vaccine (RV) and heptavalent pneumococcal conjugate vaccine (PCV-7) to their National Immunization Programs (EPIs), these new vaccines could affect the countries' vaccine supply chains (i.e., the series of steps required to get a vaccine from their manufacturers to patients). We developed detailed computational models of the Trang Province, Thailand, vaccine supply chain to simulate introducing various RV and PCV-7 vaccine presentations and their combinations. Our results showed that the volumes of these new vaccines in addition to current routine vaccines could meet and even exceed (1) the refrigerator space at the provincial district and sub-district levels and (2) the transport cold space at district and sub-district levels preventing other vaccines from being available to patients who arrive to be immunized. Besides the smallest RV presentation (17.1 cm³/dose), all other vaccine introduction scenarios required added storage capacity at the provincial level (range: 20 L-1151 L per month) for the three largest formulations, and district level (range: 1 L-124 L per month) across all introduction scenarios. Similarly, with the exception of the two smallest RV presentation (17.1 cm³/dose), added transport capacity was required at both district and sub-district levels. Added transport capacity required across introduction scenarios from the provincial to district levels ranged from 1 L-187 L, and district to sub-district levels ranged from 1 L-13 L per shipment. Finally, only the smallest RV vaccine presentation (17.1 cm³/dose) had no appreciable effect on vaccine availability at sub-districts. All other RV and PCV-7 vaccines were too large for the current supply chain to handle without modifications such as increasing storage or transport capacity. Introducing these new vaccines to Thailand could have dynamic effects on the availability of all vaccines that may not be initially apparent to decision-makers.

Single versus multi-dose vaccine vials: an economic computational model.

Single-dose vaccine formats can prevent clinic-level vaccine wastage but may incur higher production, medical waste disposal, and storage costs than multi-dose formats. To help guide vaccine developers, manufacturers, distributors, and purchasers, we developed a computational model to predict the potential economic impact of various single-dose versus multi-dose measles (MEA), hemophilus influenzae type B (Hib), Bacille Calmette-Guérin (BCG), yellow fever (YF), and pentavalent (DTP-HepB-Hib) vaccine formats. Lower patient demand favors fewer dose formats. The mean daily patient arrival thresholds for each vaccine format are as follows: for the MEA vaccine, 2 patients/day (below which the single-dose vial and above which the 10-dose vial are least costly); BCG vaccine, 6 patients/day (below, 10-dose vial; above, 20-dose vial); Hib vaccine, 5 patients/day (below, single-dose vial; above, 10-dose vial); YF vaccine, 33 patients/day (below, 5-dose vials; above 50-dose vial); and DTP-HepB-Hib vaccine, 5 patients/day (below, single-dose vial; above, 10-dose vial).