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Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone

Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine... Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone Morrison O Jusu, Geoffrey Glauser, Jane F Seward, Mohamed Bawoh, Judith Tempel, Michael Friend, Daniel Littlefield, Michael Lahai, Hassan M Jalloh, Amara Bangali Sesay, Amanda F Caulker, Mohamed Samai, Vasavi Thomas, Nicholas Farrell, Marc-Alain Widdowson Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 The Journal of Infectious Diseases SUPPLEMENT ARTICLE Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone 1 2 3,a 1 4,b 5 4 1 Morrison O. Jusu, Geoffrey Glauser, Jane F. Seward, Mohamed Bawoh, Judith Tempel, Michael Friend, Daniel Littlefield, Michael Lahai, 1 1 1 1 3 3 3 Hassan M. Jalloh, Amara Bangali Sesay, Amanda F. Caulker, Mohamed Samai, Vasavi Thomas, Nicholas Farrell, and Marc-Alain Widdowson 1 2 3 College of Medicine and Allied Health Sciences, University of Sierra Leone, Freetown, Sierra Leone; Conceptual Mindworks, Washington, D. C.; Centers for Disease Control and 4 5 Prevention, Atlanta, Georgia; Modality Solutions, League City, Texas; and Global Good, Intellectual Ventures, Bellevue, Washington In response to the 2014‒2015 Ebola virus disease (Ebola) epidemic in West Africa, researchers accelerated the development of Ebola vac- cines. e Th Centers for Disease Control and Prevention, in collaboration with local partners, sponsored a phase 2/3 trial in Sierra Leone of a single dose (2 ×  10 plaque-forming units/mL) of a candidate replication-competent recombinant vesicular stomatitis virus–Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). Because of its early development status and limited, critical stability data, the vaccine had to be stored at –60°C or colder. Planning for the trial began in late 2014 on an accelerated timeline with significant challenges, including the lack of –60°C or colder vaccine storage, handling, and transport capability in a country with high year-round ambient temperatures. The supply chain needs for vaccine handling from storage through transport, up to the time of administration, were carefully evaluated, and then the supply chain was designed. Critical equipment that was procured, shipped, installed, and qualified to meet an aggressive timeline for launching the trial included ultracold freezers, custom-developed Arktek DF containers for storage at –60°C or colder, insulated containers for storage at 2°C–8°C, and multiple backup power sources at vaccine storage sites. Local personnel were trained in good clinical practices and trial documentation. During 9 April–12 December 2015, the trial staff vaccinated approximately 8000 participants. Five temperature excursions occurred, but the vaccine manufacturer assessed that vaccine quality was not impaired because of improper storage or transport temperatures. Both the infrastructure and the human capacity developed for the cold chain during the trial will continue to be useful as the country maintains preparedness for ring vaccination responses and future clinical research. Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220]. Keywords. Ebola; rVSVΔG-ZEBOV-GP; vaccine; cold chain; ≤–60°C. The 2014‒2015 Ebola virus disease (Ebola) epidemic in West stomatitis virus–Zaire Ebola virus envelope glycoprotein vac- Africa stimulated global response efforts and accelerated cine (rVSVΔG-ZEBOV-GP). development of Ebola vaccines and therapeutics [1–3]. By late Sierra Leone is on the Atlantic coast of West Africa, bordered 2014, phase 1 studies of candidate Ebola vaccines started in by Guinea to the north and northeast and by Liberia to the south the United States, Europe, and Africa [4, 5]. In collaboration and southeast. The country has sub-Saharan year-round climate with local investigators, international agencies initiated further conditions (temperature, 22.8°C–31.1°C; relative humidity, 75%), clinical studies in Sierra Leone, Guinea, and Liberia [6–8]. In resulting in classification by the World Health Organization Sierra Leone, the Centers for Disease Control and Prevention (WHO) for Stability Studies as climatic zone IV-B (a hot/humid (CDC) sponsored a phase 2/3 trial—the Sierra Leone Trial country, characterized by 2 seasons: one hot and dry and the to Introduce a Vaccine Against Ebola (STRIVE)—in col- other wet or rainy). Sierra Leone has one of the world’s lowest laboration with the College of Medicine and Allied Health gross domestic products and has been undergoing reconstruction Sciences, University of Sierra Leone, and the Sierra Leone to improve its road network and energy distribution following a Ministry of Health and Sanitation (MoHS) [6]. The vaccine decade-long civil war that ended in 2002. However, only 12% of tested was a replication-competent recombinant vesicular the major roads are currently paved, and power interruptions are a daily occurrence. A few major cities, such as Freetown, Makeni, Bo, and Kenema, are connected to the national power grid, which provides intermittent electricity; in some instances, the power Present affiliation. Partnership for Influenza Vaccine Introduction, Center for Vaccine Equity, Task Force for Global Health, Atlanta, Georgia (J. F. S.). supply is rationed to certain parts of these cities on alternate days, Retired. so backup power sources are needed. Other areas of the country Correspondence: G. Glauser, BS, Conceptual Mindworks, Washington, DC (geoffrey. rely on generators and other sources of power. glauser@hhs.gov). The Journal of Infectious Diseases 2018;217(S1):S48–55 e Th rVSV∆G-ZEBOV-GP candidate vaccine had a stability Published by Oxford University Press for the Infectious Diseases Society of America 2018. profile that required storage at –60°C or colder before dilution This work is written by (a) US Government employee(s) and is in the public domain in the US. and at 2°C–8°C aer di ft lution. For STRIVE, we had to transport DOI: 10.1093/infdis/jix336 S48 • JID 2018:217 (Suppl 1) • Jusu et al Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 the vaccine before dilution for up to 120 miles to 2 rural cold –80°C ultracold freezers be acquired to meet the vaccine storage chain depots. Aer di ft lution, vaccine syringes had to be stored requirements; this would also allow some leeway (or increase and transported up to 50 miles to 7 vaccination sites across 5 in temperature) in meeting the required –60°C or colder stor- districts; to retain vaccine potency, filled syringes could be age temperature (Table  1). Because local procurement was not stored at 2°C-8°C for up to 12 hours. The equipment, storage possible, the freezers were purchased in Europe and Asia, and and handling sites, and general conditions needed to meet the owing to the urgency of launching the trial, they were shipped physical handling requirements for vaccine for this trial were via air delivery at significant cost. e Th team selected 3 locations not available in Sierra Leone—a country with no vaccine clin- for housing the freezers: a central depot in Freetown (Sierra ical trial experience. Moreover, STRIVE investigators aimed to Leone’s capital city) and district depots in Port Loko and Makeni launch the trial no more than 3–4 months aer t ft he decision to (Figure 1A); each was colocated adjacent to Expanded Program go ahead in late 2014, leaving little time to establish partner- on Immunization vaccine storage sites. The freezers required ships, regulatory processes, and infrastructure or to recruit and a constant source of electricity to maintain a temperature of train a staff before beginning the study [ 6]. –80°C, and all sites required extensive electrical upgrade work In this article, we describe how we established a cold chain and installation of power backups to ensure this. In addition, system for rVSVΔG-ZEBOV-GP within this short time frame the freezers had to operate in a controlled temperature environ- in the face of an unprecedented Ebola outbreak, and we share ment (range, 20°C–25°C) so their compressors would not fail; lessons learned from implementing a clinical trial under these ensuring controlled temperatures required building or renovat- circumstances in a low-resource tropical setting. ing rooms and installing air conditioners. Because these sites would be used to store potentially life-saving vaccines during STUDY OVERVIEW the Ebola epidemic, security upgrades were required. A private security company provided 24-hour security for the vaccine at STRIVE individually randomly assigned eligible healthcare all depots throughout the trial and also supplied fuel to gen- personnel and frontline Ebola response workers to immediate erators as needed. es Th e security personnel also accompanied (within 7  days) or deferred (within 18–24 weeks) vaccination daily transport of diluted vaccine from the depots to the vacci- and followed them for 6 months for adverse events or the devel- nation sites. Cold chain consultants from Modality Solutions (a opment of Ebola. For STRIVE, we set up 7 trial enrollment cold chain management expert company) accompanied trans- and vaccination sites in 5 districts in Sierra Leone (Figure  1). port of undiluted vaccine vials, which occurred approximately Enrollment and vaccination began on 9 April 2015, and the monthly. last vaccine was administered in the deferred cohort on 12 Global Good, as part of Intellectual Ventures, procured 8 December 2015. An immunogenicity substudy was also con- ultracold freezers (temperature, –80°C) for use in STRIVE; 4 ducted at one site. We obtained ethical and regulatory approvals freezers with a capacity of 500–1000 L were placed at the central from the Sierra Leone Ethics and Scientific Review Committee, depot in Freetown, and 2 freezers with a capacity of 500-L were the CDC Institutional Review Board, the Pharmacy Board of placed at each of the district depots (Figure  1A). Supporting Sierra Leone, and the Food and Drug Administration. electrical panels were upgraded to power a minimum of two e m Th anufacturer supplied frozen (temperature, –60°C or –80°C freezers and a refrigerator at each depot. One freezer colder) rVSVΔG-ZEBOV-GP in 1-mL vials at a concentration was used for storing vaccine and the other for preconditioning of 1 ×  10 plaque-forming units (pfu)/mL. The vaccine had to phase-change materials (PCMs) for portable passive vaccine be thawed and diluted with 0.9% normal saline to provide the storage devices (Arktek DF; developed by Intellectual Ventures/ concentration of 2 × 10 pfu/mL required for administration. Global Good [Bellevue, WA] for storage and transport of vac- COLD CHAIN FOR STORAGE AND TRANSPORT OF cines for the Expanded Program on Immunizations and mod- VACCINE ified for the purpose of this clinical trial), and the refrigerator Vaccine Storage was used to cool the 0.9% normal saline vaccine diluent and to Before STRIVE started, a team from the US Government condition coolant packs used for transport of the diluted-vac- Biomedical Advanced Research and Development Authority cine syringes from the depot to the vaccination sites. STRIVE (BARDA), WHO, CDC, and MoHS conducted a needs assess- cold chain staff stored the PCM coolant packs that were used ment to evaluate the infrastructure challenges that had to be in the Arktek DF containers in the freezers used for vaccine addressed and the equipment that would have to be purchased storage. This assisted in stabilizing interior freezer temperatures to establish the cold chain, not only for the vaccine but also for and provided short-term capability to reduce temperature fluc - storing serum specimens collected for the STRIVE immunoge- tuations due to power failures. nicity substudy. Monitoring the power supply 24 hours a day and providing Because there were no specifically manufactured –60°C backup sources of electricity (Table 1) were required for ensur- freezers on the market, the assessment team recommended that ing a reliable electricity supply for the cold chain equipment, Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S49 Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 13˚0´0˝W 12˚0´0˝W Sierra Leone 9˚0´0˝N 9˚0´0˝W LEGEND Central Cold Chain Depot Rural Cold Chain Depot Vaccination Sites (facilities labeled) Vaccine driven in an insulated shipping container with dry ice TM Vaccine in vials transported via Arkteks DF Diluted vaccine in syringes transported via CryoQ’s 10 20 40 Miles 13˚0´0˝W 12˚0´0˝W B C Figure 1. A, The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) cold chain depots for vaccine storage and transport and study sites for vaccine adminis- tration. B, Arktek phase-change material containers and vaccine racks that were modified for use in STRIVE. The Arktek DF container had 3 sets of vaccine carrier racks that filled the space between the phase-change materials. However, the racks were not used to hold vaccines during STRIVE because using them would have meant removing individual vaccine vials from their package carton, which was not feasible without risking the vaccine going out of storage temperature range. Therefore, the vaccines were packed out in Arktek DF containers in their original boxes of 20 vials. C, CryoQ containers packed to show the interior with coolant packs (left), with a close-up view of syringes containing diluted vaccine packed inside (right). A foam pad was then placed on top of the syringes before the CryoQ container was closed. performing daily cold chain activities, and maintaining the low the third, at Port Loko, which is not connected to the national freezer temperatures. Two depot facilities were connected to grid, relied on a generator. The final power configurations the national power grid as their primary source of electricity; at each of the depots were designed to withstand frequent S50 • JID 2018:217 (Suppl 1) • Jusu et al Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 Table 1. Summary of Key Challenges and Resolutions Challenge Resolution No –80°C freezers in country –80°C freezers were procured internationally, shipped, and installed at 3 cold chain depots. No appropriate housing for operating Appropriate building renovations were made at all storage locations, including installation of air conditioning –80°C freezers under necessary units to maintain ambient temperature <25°C for normal operation of –80°C freezers. ambient temperature conditions No reliable electricity Multiple power sources were established at each storage site, including further connections to the national grid, batteries that were charged from the national grid, installation of multiple generators, solar panels for lighting, installation of voltage regulators and of both manual and automatic power switches, and use of security personnel for notification of power failure when all else failed (see below). Monitoring electricity supply to the Power indicator lights were installed, to denote the status of the power supply to the depots and each of the ultracold freezers individual freezers. These were monitored by cold chain staff, and, after hours, they were continuously moni- tored by onsite security guards with indicator lights at the guard post. If the light went on, indicating a power failure, the security staff alerted cold chain staff immediately. How to transport vaccines across the Global Good provided Arktek DF containers, passive cooling carriers that were preconditioned with frozen country at –60°C or colder phase-change materials to maintain the required temperatures. How to transport diluted syringes across Passive containers (CRYO-Q containers) were used as vaccine carriers for diluted vaccines, with programmed substantial distances from depots to TempTales to monitor temperature. vaccination sites and monitor tempera- tures of 2°C–8°C How to track vaccine dilution batches Unique dilution numbers were assigned to each batch of 12 syringe doses. How to label each syringe containing a Preprinted labels were obtained from the manufacturer, with appropriate identifiers. diluted vaccine dose appropriately How to maintain security for candidate Twenty-four–hour security presence was ensured at all storage sites throughout the vaccine storage period. Ebola vaccine in an epidemic context Security guards also monitored electricity supply to the depots, using lights that activated when power was lost. primary power outages by providing at least 2 backup alter- We also used the central vaccine storage site for temporary native power sources; these included generators and batteries. storage of serum samples collected for the immunogenicity sub- Solar panels generated power to run lighting at the Port Loko study, because it had the freezers and trained, experienced sta ff cold chain site. Additional precautions to overcome power sup- needed for safe storage of these samples. We stored the samples ply irregularities included the following, some of which were in a separate freezer from the study vaccine or other pharma- implemented aer t ft he trial started as cold chain staff gained ceutical products and later transported them to US laboratories experience with frequent power outages. First, voltage regula- for testing with a validated assay. tors were installed, to minimize the impact of power surges. Second, automatic power switches were installed, to provide Vaccine Transport smooth and rapid transfer of power from grid to generator e Th STRIVE vaccine was shipped in polyurethane-insulated or battery backup and vice versa when the power supply was containers on pelletized dry ice via air cargo from the United interrupted and again later when it was restored. Initially, States to Lungi International Airport in Sierra Leone. Aer ft STRIVE used manual power switches for transfer of power to customs clearance, the vaccine was transferred by vehicle to backup systems. Third, power indicator lights were installed, to the central depot (3.5 hours by road). Four vaccine shipments denote the status of the power supply to the depots and each occurred during the trial. Because many flights to Sierra Leone of the individual freezers. These were monitored by cold chain were cancelled during the epidemic, the first 3 shipments were staff, and, aer h ft ours, they were continuously monitored by complicated, with itineraries changing before and during ship- onsite security guards with indicator lights at the guard post. If ment, delays occurring because flights were cancelled, and the light went off, indicating a power failure, the security sta ff because the vaccine, as a cargo shipment, was lower priority would alert cold chain staff immediately. than passenger luggage for loading onto planes. The shipping Even with multiple sources of electricity and backup plans in company monitored shipment temperatures, and dry ice had place, power interruptions to the freezers occurred frequently, to be replenished during transit delays. Shipment durations for a variety of reasons, including failure of the grid, mechanical ranged from 3 to 10 days. or electrical faults (eg, malfunction of an automatic switch), and e cen Th tral depot supplied vaccine to the 2 district depots human factors (eg, a guard not adding fuel to the generator or approximately monthly. Without any local source of dry ice, the leaving his watch during the night). Moreover, 2 freezers failed assessment team recommended acquiring Arktek containers to before or during the trial and could not be fixed in Sierra Leone; fill the critical need for transporting the vaccines at –60°C or therefore, new freezers or alternative solutions for temporary colder from the central Freetown depot to the district depots vaccine storage had to be provided. (Figure 1 and Table 1). The Arktek container is a double-walled Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S51 Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 stainless steel vacuum-assisted insulated drum that was devel- was preconditioned to use to transfer vaccine between depots oped for storage of Expanded Program on Immunizations vac- and for storage in the event of freezer failure. At the Port Loko cines at 2°C–8°C for up to 1  month. The device was modified depot, preconditioned Arktek containers were rotated for use, (and designated as “ Arktek DF”; hereaer r ft eferred to as “ Arktek”) to permanently store the vaccine owing to failure of one of the to handle –80°C (as with the ultracold freezers, to allow some ultracold freezers. leeway in maintaining the required vaccine storage temperature of –60°C or colder) for the Ebola vaccine trials, with a poten- Providing Vaccine to Vaccination Sites tial payload of approximately 200 vials of vaccine (Figure  1B) Because the manufacturer provided the vaccine in 1-mL vials [9]. This was accomplished by substituting a combination of at a concentration of 1 ×  10 pfu/mL, it had to be diluted to phase-change proprietary denatured alcohols that were titrated the required concentration of 2 ×  10 pfu/mL before admin- to freeze and thaw at –80°C for the water/ice contained in the 8 istration. Because no traditional pharmacies were located at crescent-shaped plastic or metal containers inside the 35-pound study locations, the cold chain sites served that purpose. The drum. The filled phase-change containers were preconditioned Freetown site functioned as the central study pharmacy, and in the ultracold freezers at –85.5°C to reach the solid crystalliza- trained pharmacists handled study vaccine dispensation at all tion threshold. Once this temperature was reached, the liquids the sites. We developed facilities to allow for vaccine dilution at changed to solids, and the interior temperature was efficiently all 3 depots. Following standard operating procedures and ster- maintained in the ultracold freezers. When needed, the PCMs ile transfer techniques, trained pharmacy staff thawed the vac - were loaded into the Arktek containers. Because STRIVE lead- cine at ambient temperatures of <25°C and then diluted 2.7 mL ers were concerned that repeated opening of an Arktek con- from three 1-mL vials of vaccine into a vial containing 10.8 mL tainer in sub-Saharan temperatures over several days would of 0.9% normal saline. This resulted in the required 5-fold vac - compromise its ability to maintain a temperature of –60°C or cine dilution and sufficient vaccine in the diluent vial to draw colder, Intellectual Ventures conducted laboratory qualifica - up (allowing for wastage) 12 syringes, each with 1  mL of the tion tests in which the Arktek containers were opened 8 times correct vaccine dose. The use of vial adapters to draw up vaccine a day (to simulate removal of vaccine) at ambient temperatures into syringes from the diluent vial helped promote sterile con- of 32°C and 42°C. es Th e tests showed that temperatures colder ditions and significantly streamlined the dilution process with than –60°C could be maintained for >6  days in those condi- Leur-Lok connections. e Th manufacturer provided preprinted tions [9] (Figure  2). Eight Arktek containers were provided syringe labels with appropriate identifiers, and the syringes for STRIVE; 5–6 were used regularly, and the remaining 2–3 were maintained at a temperature of 2°C–8°C for up to 12 hours were on standby. Under field conditions, temperatures in the before administration to participants. Arktek containers remained in the range of –74°C to –70°C for Passive insulated reusable containers (CryoQ; Lisaline about 5 days, well below the required temperature of –60°C or Lifescience Technologies, Thane, India), were used to transport colder. Each depot always had at least 1 Arktek container that vaccine from depots to vaccination sites at a temperature of −55 −60 −65 −70 −75 −80 −85 0123 4 56 7 Time, days Figure  2. Temperature of the vaccine compartment of the Arktek DF container during laboratory qualification testing. During the testing, the Arktek DF container was opened 8 times a day, 1 hour apart, and the temperature in the vaccine compartment was continuously monitored. The phase-change material (PCM) appears to have fully melted by 5 days, but since it took approximately 1.5 days after PCM melting for the system to warm to –60°C, the hold time of the –78° PCMs was just under 6.5 days. S52 • JID 2018:217 (Suppl 1) • Jusu et al Temperature, °C Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 2°C–8°C. The WHO provided 15 of these containers in Sierra QUALITY CONTROL AND MONITORING SYSTEMS Leone on very short notice, and Intellectual Ventures/Global Temperature Monitoring Good flew in another 20 containers later. Engineers from We put systems in place to ensure that cold chain standards and BARDA and Modality Solutions tested and qualified the CryoQ requirements were maintained and recorded according to good containers to ensure they could maintain a temperature of 2°C– clinical practice, to monitor rVSVΔG-ZEBOV-GP at 2 tem- 8°C for 12 hours despite repeated opening to retrieve vaccine peratures, –60°C or colder before dilution and 2°C–8°C aer ft syringes. To achieve and maintain this temperature range, the dilution. If temperature excursions occurred outside these spec- CryoQ containers had to be preconditioned with 1 frozen gel ifications, we immediately quarantined the vaccine, investigated pack and 3 refrigerated ice packs. The CryoQ container was the excursion, and reported the excursion to quality experts at then closed with fitted-in foam packs to keep syringes secure NewLink Genetics (the vaccine manufacturer; the vaccine was and the enclosed temperature monitoring device from touching later licensed to Merck). These experts reported the final dispo - the inside walls of the CryoQ container (Figure 1C). sition of the vaccine, based on the temperature excursion profile To minimize wastage and plan daily vaccine dilutions for par- and stability data. ticipants randomly assigned to the immediate group, STRIVE We used 2 types of devices to monitor vaccine at tempera- cold chain depot staff maintained regular communication with tures of –60°C or colder: the TempTale4 device (Sensitech; enrollment and vaccination sites regarding the expected and Beverly, MA) and the HOBO device (Onset Computer; Bourne, actual number of participants. Participants randomly assigned MA). During vaccine shipment from the United States to Sierra to the immediate vaccination group were not given appoint- Leone, a TempTale4 device recorded the temperature in transit. ments, because of the unpredictability of their work schedules Upon the shipment container’s arrival at the Freetown central during the Ebola epidemic, so vaccinators did not know in depot, we downloaded the temperature profile from the moni - advance the exact number of participants who would be vac- toring device to a computer and sent it to the vaccine manufac- cinated each day. Therefore, based on estimates from previous turer for review. The storage freezers were set at –85.5°C but were days, pharmacists diluted and provided syringes to start vacci- programmed to alarm at temperatures warmer than –70°C. We nation at each site and then communicated with the site manag- used 2 independent methods to monitor freezer temperatures: ers during the day to assess whether additional vaccines would (1) twice-daily manual recording of temperatures from built-in be required. Because each dilution required 3 vaccine vials to temperature displays on the freezers and (2) continuous elec- produce 12 doses, such planning and ongoing communication tronic temperature monitoring via a HOBO device, which had were important for reducing vaccine wastage. thermocouple probes that monitor the interior temperatures of In contrast, for the participants in the deferred vaccination the equipment to which it is connected; their outputs can be group, schedulers set up visits in advance and made telephone read on the HOBO display. We programmed the HOBO device calls reminding participants to come for vaccination on their to display a visual indicator (alarm bell icon) when freezer tem- appointed days. This contributed to a reduction in wastage of peratures went outside limits. When depot staff saw the alarm vaccine doses across all the sites, from 32% during immediate indicator, they immediately noted a deviation and initiated an vaccination to 22% during deferred vaccination (Table 2). investigation. HOBO devices were also tfi ted for each Arktek Table 2. Vaccine Doses Prepared and Wastage per Vaccination Site, by Study Phase Immediate Vaccination Deferred Vaccination Doses Prepared, Doses Administered, Doses Wasted, Doses Prepared, Doses Administered, Doses Wasted, Site No. No. % No. No. % Connaught Hospital, 2290 1553 32 1736 1391 20 Freetown COMAHS Library 1174 902 23 1060 852 20 Port Loko Government 626 423 32 516 399 23 Hospital St. John of God Hospital, 319 194 39 288 170 41 Lunsar St. John of God Health 312 150 52 216 143 34 Center, Lungi Holy Spirit Hospital, 870 595 32 744 546 27 Makeni Magburaka District 528 366 31 384 338 12 Hospital Total 6119 4183 32 4944 3839 22 Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S53 Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 container. Cold chain staff also recorded storage depots’ ambi - transporting vaccine between depots, diluting and transporting ent temperatures twice daily. vaccines in syringe doses to vaccination sites, and maintaining To monitor the temperature of diluted vaccine in syringes ancillary supplies. Unused syringes were returned to the depot at a temperature of 2°C–8°C, we initialized programmable at the end of each day for incineration, along with any damaged TempTale4 devices and included one in each CryoQ pack or rejected syringes, and wastage was closely monitored. We sent to vaccination sites. At days’ end, we downloaded, saved, documented vaccine inventory and chain of custody in com- printed, and attached the recorded temperature data from the pliance with STRIVE standard operating procedures. We also TempTale4 device to the other records of the respective diluted strictly accounted for manufacturer-supplied syringe labels, per vaccine set. good clinical practice. During STRIVE, 5 temperature excursions occurred. Three Because needed materials were not available locally, we of these were associated with frozen concentrated vaccine. Two monitored and replenished satisfactory inventories of ancillary of the excursions were a result of catastrophic failure of key elec- supplies (ie, syringes, syringe caps, needles, and vial adapters) trical equipment. The first of these was a short circuit in the through international purchasing arrangements with suppliers junction box feeding power to the central depot cold chain stor- in Europe, both before and during the trial. age facility. e Th second was a catastrophic short circuit in a plug HUMAN RESOURCE CAPACITY AND MANAGEMENT that contributed to overload of the battery/automatic transfer OF COLD CHAIN system at the central depot. This was the worst excursion, last - Fifteen staff members were directly involved in STRIVE cold ing 5 hours 50 minutes, with the freezer temperature reaching chain activities throughout the trial; 3 were rotating interna- –53°C. The third excursion occurred at Port Loko, when the tional cold chain experts from BARDA and Modality Solutions, main generator went offline and the guard assigned to start up and 12 were national staff members (8 pharmacists and 4 cold the backup generator was absent from his post. Two excursions chain officers). e Th latter 12 staff members were divided among were associated with the diluted vaccine. Both resulted from the 3 depots. The local staff received role-specific trainings improper preconditioning of the refrigerated gel packs used in according to the protocol and standard operating procedures the CryoQ packs. In one instance, the gel ices were too warm, for cold chain activities needed for STRIVE, as well as general resulting in higher temperatures (up to 18°C) for the vaccine training on International Conference on Harmonization guide- for as long as 3 hours 5 minutes. In the second instance, the lines on good clinical practice, human subjects protection, and refrigerated gel packs were too cold, allowing the vaccine tem- good documentation practice. International cold chain experts perature to drop to 0°C, although it did not freeze. For all excur- provided the initial and refresher trainings, supervision, and sions, the vaccine manufacturer determined that the duration onsite oversight for cold chain activities throughout the trial. and magnitude were small enough that the vaccine quality was Aer vaccin ft ation ended, local staff managed oversight of stor - not adversely ae ff cted. age of the remaining vaccine vials, with remote backup from Electronic Alert Systems international consultants. Implementing STRIVE, we learned that having a system for alerting cold chain staff members about power failures and SUMMARY AND CONCLUSIONS potential temperature excursions was essential but also chal- In just 3  months, STRIVE staff successfully established and lenging, owing to unreliable power, Internet, and cellular ser- maintained a cold chain for storing the candidate Ebola vac- vices. Initially, we installed temperature signaling devices in cine at a temperature of –60°C or colder for the phase 2/3 trial each –80°C freezer that would send a text message to cold chain of rVSV∆G-ZEBOV-GP vaccine in Sierra Leone. The staff suc - staff ’s cell phones when an alarm-associated temperature of cessfully administered about 8000 doses of vaccine, with 28% –70°C was reached. However, this system proved to be unreli- of doses wasted overall at the vaccination sites and <0.1% of able because of inconsistent cellular connectivity at the central doses rejected or damaged. Challenges encountered and over- depot, and we replaced it with a WiFi Internet–based system. come included poor infrastructure for cold chain facilities, lack This system also was eventually abandoned owing to unreliable of highly specialized equipment needed for storing vaccine connectivity. Ultimately, we relied on continuous monitoring by at extremely low temperatures, high ambient temperatures, security guards, who notified the cold chain staff via text mes - 24-hour temperature monitoring for vaccine, interruptions and sage or telephone call when they discovered an alarm light trig- surges in the power supply, and freezer equipment failure. The gered by power failure. modified Arktek devices, capable of maintaining extremely low Inventory Management temperatures without power, proved invaluable and reliable Trained study pharmacists managed vaccine dispensation at for transporting the vaccines and as backup vaccine storage at each cold chain site. Inventory management included monitor- all 3 storage sites during temporary periods of power loss or ing each of the following: storing frozen vaccine at the depots, freezer malfunction. Overall, despite frequent interruptions S54 • JID 2018:217 (Suppl 1) • Jusu et al Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 Financial support. This work was supported by the Centers for Disease of the power supply to the ultracold freezers, significant tem - Control and Prevention (CDC), the Biomedical Advanced Research and perature excursions (warmer than –60°C) for undiluted vaccine Development Authority, and the National Institutes of Health, with addi- occurred only 3 times during the trial, and excursions outside tional support from the CDC Foundation. the temperature range of 2°C–8°C for diluted vaccine occurred Supplement sponsorship. This work is part of a supplement sponsored by the Centers for Disease Control and Prevention. only twice. In all these instances, product stability data con- Potential conifl cts of interest. M.  F.  has patents (8 377 030 and 8 887 firmed that the excursion had no effect on product quality, and 944) licensed to Aucma Global Medical. D. L. reports that he was contracted no vaccine doses had to be discarded. This was possible because to the work for the study. All other authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential of the excellent monitoring processes and rapid emergency Conflicts of Interest. Conflicts that the editors consider relevant to the con - response to deviations that we put in place for the trial. tent of the manuscript have been disclosed. e G Th uinea Ebola ça Suffit trial of rVSV∆G-ZEBOV-GP References vaccine reported 100% vaccine efficacy, paving the way for use of this vaccine in response to confirmed Ebola cases [ 10–13]. 1. Gostin LO, Lucey D, Phelan A. The Ebola epidemic: a global health emergency. JAMA 2014; 312:1095–6. One lasting legacy of STRIVE is that the cold chain infrastruc- 2. World Health Organization. Meeting summary of the WHO consultation on ture, specialized equipment, and local staff expertise are now potential Ebola therapies and vaccines. Geneva, Switzerland: 4–5 September, 2014. http://apps.who.int/iris/bitstream/10665/136103/1/WHO_EVD_Meet_ available in Sierra Leone for handling, according to good clin- EMP_14.1_eng.pdf. Accessed 2 August 2017. ical practice, storage at a temperature of –60°C or colder, dilu- 3. Lee BY, Moss WJ, Privor-Dumm L, Constenla DO, Knoll MD, O’Brien KL. Is the world ready for an Ebola vaccine? Lancet 2015; 385:203–4. tion of vaccine, and transport of vaccine at a temperature of 4. Agnandji ST, Huttner A, Zinser ME, et al. Phase 1 trials of rVSV Ebola vaccine in 2°C–8°C, under the challenging conditions frequently encoun- Africa and Europe. N Engl J Med 2016; 374:1647–60. 5. Regules JA, Beigel JH, Paolino KM, et al. A recombinant vesicular stomatitis virus tered there. This will facilitate use of the rVSV∆G-ZEBOV-GP Ebola vaccine. N Engl J Med 2017; 376:330–41. vaccine under emergency access protocols in ring response to 6. Widdowson MA, Schrag SJ, Carter RJ, et  al. Implementing an Ebola Vaccine future Ebola cases both in Sierra Leone and elsewhere [14]. The Study—Sierra Leone. MMWR Suppl 2016; 65:98–106. 7. Kennedy SB, Neaton JD, Lane HC, et al. Implementation of an Ebola virus disease central depot facilities also were able to store several thousand vaccine clinical trial during the Ebola epidemic in Liberia: design, procedures, and immunogenicity specimens that were collected during STRIVE. challenges. Clin Trials 2016; 13:49–56. 8. Ebola ca Suffit Ring Vaccination Trial Consortium. e Th ring vaccination trial: Building local human resource capacity for conducting clini- a novel cluster randomised controlled trial design to evaluate vaccine efficacy cal trials and, in particular, for managing the cold chain means and effectiveness during outbreaks, with special reference to Ebola. BMJ 2015; 351:h3740. that these newly acquired knowledge and skills can be used to 9. Friend M, Stone S. Challenging requirements in resource challenged environment benefit the country in future clinical trials and routine national on a time challenged schedule: a technical solution to support the cold chain for the VSV-Zebov (Merck) Ebola vaccine in Sierra Leone and Guinea. Technical immunization activities. paper F2: Health. In: Technical program series. 2015 Global Humanitarian Technology Conference, Seattle, Washington, 9–12 October 2015. New York, NY: IEEE, 2015. http://sites.ieee.org/ghtc/event-2015/technical-program-sessions/. Accessed 2 August 2017. Notes 10. Lyon DJ, Cheng AFB, Norrby SR. Mechanisms of cefotaxime resistance in Acknowledgments. We thank Mark Feinberg and Swati Gupta from blood culture isolates of Enterobacter high prevalence of extended-spectrum Merck, for providing vaccine and technical support; Tom Monath and Jay β-lactamases [abstract C43]. In: Program and abstracts of the 35th Interscience Ramsey from NewLink Genetics, for advice on dilution, vaccine manage- Conference on Antimicrobial Agents and Chemotherapy, San Francisco, ment during temperature excursions, vaccine shipping, and consumables; California, 17–20 September, 1995. Washington, DC: American Society for Simone Zipursky, Souleymane Kone, Theo Grace, and Argimiro (Miro) Microbiology, 1995:47. 11. Henao-Restrepo AM, Longini IM, Egger M, et al. Efficacy and effectiveness of an Garcia Montes from the WHO, for their technical assistance in advising on rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from cold chain facilities and equipment; Sandra Pizzaro from the US Embassy in the Guinea ring vaccination cluster-randomised trial. Lancet 2015; 386:857–66. Freetown, for assistance with packages, notifications, and general STRIVE 12. Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of support; the staff of eHealth, for support in coordinating and supporting an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the renovation and sourcing supplies; and Joerg Ropel, Chief of Operations, for Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!). generous assistance and expertise, and other staff from the German Federal Lancet 2017; 389:505–18. Agency for Technical Relief. 13. Meeting of the Strategic Advisory Group of Experts on immunization, October Disclaimer. The findings and conclusions in this report are those of 2015—conclusions and recommendations. Wkly Epidemiol Rec 2015; 90:681–99. the author(s) and do not necessarily represent the official position of the 14. Gulland A. Ebola vaccine will be made available for emergency use. BMJ 2016; 532:i386. Centers for Disease Control and Prevention. Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S55 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone

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Oxford University Press
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Copyright © 2022 Infectious Diseases Society of America
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0022-1899
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10.1093/infdis/jix336
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Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone Morrison O Jusu, Geoffrey Glauser, Jane F Seward, Mohamed Bawoh, Judith Tempel, Michael Friend, Daniel Littlefield, Michael Lahai, Hassan M Jalloh, Amara Bangali Sesay, Amanda F Caulker, Mohamed Samai, Vasavi Thomas, Nicholas Farrell, Marc-Alain Widdowson Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 The Journal of Infectious Diseases SUPPLEMENT ARTICLE Rapid Establishment of a Cold Chain Capacity of –60°C or Colder for the STRIVE Ebola Vaccine Trial During the Ebola Outbreak in Sierra Leone 1 2 3,a 1 4,b 5 4 1 Morrison O. Jusu, Geoffrey Glauser, Jane F. Seward, Mohamed Bawoh, Judith Tempel, Michael Friend, Daniel Littlefield, Michael Lahai, 1 1 1 1 3 3 3 Hassan M. Jalloh, Amara Bangali Sesay, Amanda F. Caulker, Mohamed Samai, Vasavi Thomas, Nicholas Farrell, and Marc-Alain Widdowson 1 2 3 College of Medicine and Allied Health Sciences, University of Sierra Leone, Freetown, Sierra Leone; Conceptual Mindworks, Washington, D. C.; Centers for Disease Control and 4 5 Prevention, Atlanta, Georgia; Modality Solutions, League City, Texas; and Global Good, Intellectual Ventures, Bellevue, Washington In response to the 2014‒2015 Ebola virus disease (Ebola) epidemic in West Africa, researchers accelerated the development of Ebola vac- cines. e Th Centers for Disease Control and Prevention, in collaboration with local partners, sponsored a phase 2/3 trial in Sierra Leone of a single dose (2 ×  10 plaque-forming units/mL) of a candidate replication-competent recombinant vesicular stomatitis virus–Zaire Ebola virus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP). Because of its early development status and limited, critical stability data, the vaccine had to be stored at –60°C or colder. Planning for the trial began in late 2014 on an accelerated timeline with significant challenges, including the lack of –60°C or colder vaccine storage, handling, and transport capability in a country with high year-round ambient temperatures. The supply chain needs for vaccine handling from storage through transport, up to the time of administration, were carefully evaluated, and then the supply chain was designed. Critical equipment that was procured, shipped, installed, and qualified to meet an aggressive timeline for launching the trial included ultracold freezers, custom-developed Arktek DF containers for storage at –60°C or colder, insulated containers for storage at 2°C–8°C, and multiple backup power sources at vaccine storage sites. Local personnel were trained in good clinical practices and trial documentation. During 9 April–12 December 2015, the trial staff vaccinated approximately 8000 participants. Five temperature excursions occurred, but the vaccine manufacturer assessed that vaccine quality was not impaired because of improper storage or transport temperatures. Both the infrastructure and the human capacity developed for the cold chain during the trial will continue to be useful as the country maintains preparedness for ring vaccination responses and future clinical research. Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220]. Keywords. Ebola; rVSVΔG-ZEBOV-GP; vaccine; cold chain; ≤–60°C. The 2014‒2015 Ebola virus disease (Ebola) epidemic in West stomatitis virus–Zaire Ebola virus envelope glycoprotein vac- Africa stimulated global response efforts and accelerated cine (rVSVΔG-ZEBOV-GP). development of Ebola vaccines and therapeutics [1–3]. By late Sierra Leone is on the Atlantic coast of West Africa, bordered 2014, phase 1 studies of candidate Ebola vaccines started in by Guinea to the north and northeast and by Liberia to the south the United States, Europe, and Africa [4, 5]. In collaboration and southeast. The country has sub-Saharan year-round climate with local investigators, international agencies initiated further conditions (temperature, 22.8°C–31.1°C; relative humidity, 75%), clinical studies in Sierra Leone, Guinea, and Liberia [6–8]. In resulting in classification by the World Health Organization Sierra Leone, the Centers for Disease Control and Prevention (WHO) for Stability Studies as climatic zone IV-B (a hot/humid (CDC) sponsored a phase 2/3 trial—the Sierra Leone Trial country, characterized by 2 seasons: one hot and dry and the to Introduce a Vaccine Against Ebola (STRIVE)—in col- other wet or rainy). Sierra Leone has one of the world’s lowest laboration with the College of Medicine and Allied Health gross domestic products and has been undergoing reconstruction Sciences, University of Sierra Leone, and the Sierra Leone to improve its road network and energy distribution following a Ministry of Health and Sanitation (MoHS) [6]. The vaccine decade-long civil war that ended in 2002. However, only 12% of tested was a replication-competent recombinant vesicular the major roads are currently paved, and power interruptions are a daily occurrence. A few major cities, such as Freetown, Makeni, Bo, and Kenema, are connected to the national power grid, which provides intermittent electricity; in some instances, the power Present affiliation. Partnership for Influenza Vaccine Introduction, Center for Vaccine Equity, Task Force for Global Health, Atlanta, Georgia (J. F. S.). supply is rationed to certain parts of these cities on alternate days, Retired. so backup power sources are needed. Other areas of the country Correspondence: G. Glauser, BS, Conceptual Mindworks, Washington, DC (geoffrey. rely on generators and other sources of power. glauser@hhs.gov). The Journal of Infectious Diseases 2018;217(S1):S48–55 e Th rVSV∆G-ZEBOV-GP candidate vaccine had a stability Published by Oxford University Press for the Infectious Diseases Society of America 2018. profile that required storage at –60°C or colder before dilution This work is written by (a) US Government employee(s) and is in the public domain in the US. and at 2°C–8°C aer di ft lution. For STRIVE, we had to transport DOI: 10.1093/infdis/jix336 S48 • JID 2018:217 (Suppl 1) • Jusu et al Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 the vaccine before dilution for up to 120 miles to 2 rural cold –80°C ultracold freezers be acquired to meet the vaccine storage chain depots. Aer di ft lution, vaccine syringes had to be stored requirements; this would also allow some leeway (or increase and transported up to 50 miles to 7 vaccination sites across 5 in temperature) in meeting the required –60°C or colder stor- districts; to retain vaccine potency, filled syringes could be age temperature (Table  1). Because local procurement was not stored at 2°C-8°C for up to 12 hours. The equipment, storage possible, the freezers were purchased in Europe and Asia, and and handling sites, and general conditions needed to meet the owing to the urgency of launching the trial, they were shipped physical handling requirements for vaccine for this trial were via air delivery at significant cost. e Th team selected 3 locations not available in Sierra Leone—a country with no vaccine clin- for housing the freezers: a central depot in Freetown (Sierra ical trial experience. Moreover, STRIVE investigators aimed to Leone’s capital city) and district depots in Port Loko and Makeni launch the trial no more than 3–4 months aer t ft he decision to (Figure 1A); each was colocated adjacent to Expanded Program go ahead in late 2014, leaving little time to establish partner- on Immunization vaccine storage sites. The freezers required ships, regulatory processes, and infrastructure or to recruit and a constant source of electricity to maintain a temperature of train a staff before beginning the study [ 6]. –80°C, and all sites required extensive electrical upgrade work In this article, we describe how we established a cold chain and installation of power backups to ensure this. In addition, system for rVSVΔG-ZEBOV-GP within this short time frame the freezers had to operate in a controlled temperature environ- in the face of an unprecedented Ebola outbreak, and we share ment (range, 20°C–25°C) so their compressors would not fail; lessons learned from implementing a clinical trial under these ensuring controlled temperatures required building or renovat- circumstances in a low-resource tropical setting. ing rooms and installing air conditioners. Because these sites would be used to store potentially life-saving vaccines during STUDY OVERVIEW the Ebola epidemic, security upgrades were required. A private security company provided 24-hour security for the vaccine at STRIVE individually randomly assigned eligible healthcare all depots throughout the trial and also supplied fuel to gen- personnel and frontline Ebola response workers to immediate erators as needed. es Th e security personnel also accompanied (within 7  days) or deferred (within 18–24 weeks) vaccination daily transport of diluted vaccine from the depots to the vacci- and followed them for 6 months for adverse events or the devel- nation sites. Cold chain consultants from Modality Solutions (a opment of Ebola. For STRIVE, we set up 7 trial enrollment cold chain management expert company) accompanied trans- and vaccination sites in 5 districts in Sierra Leone (Figure  1). port of undiluted vaccine vials, which occurred approximately Enrollment and vaccination began on 9 April 2015, and the monthly. last vaccine was administered in the deferred cohort on 12 Global Good, as part of Intellectual Ventures, procured 8 December 2015. An immunogenicity substudy was also con- ultracold freezers (temperature, –80°C) for use in STRIVE; 4 ducted at one site. We obtained ethical and regulatory approvals freezers with a capacity of 500–1000 L were placed at the central from the Sierra Leone Ethics and Scientific Review Committee, depot in Freetown, and 2 freezers with a capacity of 500-L were the CDC Institutional Review Board, the Pharmacy Board of placed at each of the district depots (Figure  1A). Supporting Sierra Leone, and the Food and Drug Administration. electrical panels were upgraded to power a minimum of two e m Th anufacturer supplied frozen (temperature, –60°C or –80°C freezers and a refrigerator at each depot. One freezer colder) rVSVΔG-ZEBOV-GP in 1-mL vials at a concentration was used for storing vaccine and the other for preconditioning of 1 ×  10 plaque-forming units (pfu)/mL. The vaccine had to phase-change materials (PCMs) for portable passive vaccine be thawed and diluted with 0.9% normal saline to provide the storage devices (Arktek DF; developed by Intellectual Ventures/ concentration of 2 × 10 pfu/mL required for administration. Global Good [Bellevue, WA] for storage and transport of vac- COLD CHAIN FOR STORAGE AND TRANSPORT OF cines for the Expanded Program on Immunizations and mod- VACCINE ified for the purpose of this clinical trial), and the refrigerator Vaccine Storage was used to cool the 0.9% normal saline vaccine diluent and to Before STRIVE started, a team from the US Government condition coolant packs used for transport of the diluted-vac- Biomedical Advanced Research and Development Authority cine syringes from the depot to the vaccination sites. STRIVE (BARDA), WHO, CDC, and MoHS conducted a needs assess- cold chain staff stored the PCM coolant packs that were used ment to evaluate the infrastructure challenges that had to be in the Arktek DF containers in the freezers used for vaccine addressed and the equipment that would have to be purchased storage. This assisted in stabilizing interior freezer temperatures to establish the cold chain, not only for the vaccine but also for and provided short-term capability to reduce temperature fluc - storing serum specimens collected for the STRIVE immunoge- tuations due to power failures. nicity substudy. Monitoring the power supply 24 hours a day and providing Because there were no specifically manufactured –60°C backup sources of electricity (Table 1) were required for ensur- freezers on the market, the assessment team recommended that ing a reliable electricity supply for the cold chain equipment, Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S49 Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 13˚0´0˝W 12˚0´0˝W Sierra Leone 9˚0´0˝N 9˚0´0˝W LEGEND Central Cold Chain Depot Rural Cold Chain Depot Vaccination Sites (facilities labeled) Vaccine driven in an insulated shipping container with dry ice TM Vaccine in vials transported via Arkteks DF Diluted vaccine in syringes transported via CryoQ’s 10 20 40 Miles 13˚0´0˝W 12˚0´0˝W B C Figure 1. A, The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE) cold chain depots for vaccine storage and transport and study sites for vaccine adminis- tration. B, Arktek phase-change material containers and vaccine racks that were modified for use in STRIVE. The Arktek DF container had 3 sets of vaccine carrier racks that filled the space between the phase-change materials. However, the racks were not used to hold vaccines during STRIVE because using them would have meant removing individual vaccine vials from their package carton, which was not feasible without risking the vaccine going out of storage temperature range. Therefore, the vaccines were packed out in Arktek DF containers in their original boxes of 20 vials. C, CryoQ containers packed to show the interior with coolant packs (left), with a close-up view of syringes containing diluted vaccine packed inside (right). A foam pad was then placed on top of the syringes before the CryoQ container was closed. performing daily cold chain activities, and maintaining the low the third, at Port Loko, which is not connected to the national freezer temperatures. Two depot facilities were connected to grid, relied on a generator. The final power configurations the national power grid as their primary source of electricity; at each of the depots were designed to withstand frequent S50 • JID 2018:217 (Suppl 1) • Jusu et al Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 Table 1. Summary of Key Challenges and Resolutions Challenge Resolution No –80°C freezers in country –80°C freezers were procured internationally, shipped, and installed at 3 cold chain depots. No appropriate housing for operating Appropriate building renovations were made at all storage locations, including installation of air conditioning –80°C freezers under necessary units to maintain ambient temperature <25°C for normal operation of –80°C freezers. ambient temperature conditions No reliable electricity Multiple power sources were established at each storage site, including further connections to the national grid, batteries that were charged from the national grid, installation of multiple generators, solar panels for lighting, installation of voltage regulators and of both manual and automatic power switches, and use of security personnel for notification of power failure when all else failed (see below). Monitoring electricity supply to the Power indicator lights were installed, to denote the status of the power supply to the depots and each of the ultracold freezers individual freezers. These were monitored by cold chain staff, and, after hours, they were continuously moni- tored by onsite security guards with indicator lights at the guard post. If the light went on, indicating a power failure, the security staff alerted cold chain staff immediately. How to transport vaccines across the Global Good provided Arktek DF containers, passive cooling carriers that were preconditioned with frozen country at –60°C or colder phase-change materials to maintain the required temperatures. How to transport diluted syringes across Passive containers (CRYO-Q containers) were used as vaccine carriers for diluted vaccines, with programmed substantial distances from depots to TempTales to monitor temperature. vaccination sites and monitor tempera- tures of 2°C–8°C How to track vaccine dilution batches Unique dilution numbers were assigned to each batch of 12 syringe doses. How to label each syringe containing a Preprinted labels were obtained from the manufacturer, with appropriate identifiers. diluted vaccine dose appropriately How to maintain security for candidate Twenty-four–hour security presence was ensured at all storage sites throughout the vaccine storage period. Ebola vaccine in an epidemic context Security guards also monitored electricity supply to the depots, using lights that activated when power was lost. primary power outages by providing at least 2 backup alter- We also used the central vaccine storage site for temporary native power sources; these included generators and batteries. storage of serum samples collected for the immunogenicity sub- Solar panels generated power to run lighting at the Port Loko study, because it had the freezers and trained, experienced sta ff cold chain site. Additional precautions to overcome power sup- needed for safe storage of these samples. We stored the samples ply irregularities included the following, some of which were in a separate freezer from the study vaccine or other pharma- implemented aer t ft he trial started as cold chain staff gained ceutical products and later transported them to US laboratories experience with frequent power outages. First, voltage regula- for testing with a validated assay. tors were installed, to minimize the impact of power surges. Second, automatic power switches were installed, to provide Vaccine Transport smooth and rapid transfer of power from grid to generator e Th STRIVE vaccine was shipped in polyurethane-insulated or battery backup and vice versa when the power supply was containers on pelletized dry ice via air cargo from the United interrupted and again later when it was restored. Initially, States to Lungi International Airport in Sierra Leone. Aer ft STRIVE used manual power switches for transfer of power to customs clearance, the vaccine was transferred by vehicle to backup systems. Third, power indicator lights were installed, to the central depot (3.5 hours by road). Four vaccine shipments denote the status of the power supply to the depots and each occurred during the trial. Because many flights to Sierra Leone of the individual freezers. These were monitored by cold chain were cancelled during the epidemic, the first 3 shipments were staff, and, aer h ft ours, they were continuously monitored by complicated, with itineraries changing before and during ship- onsite security guards with indicator lights at the guard post. If ment, delays occurring because flights were cancelled, and the light went off, indicating a power failure, the security sta ff because the vaccine, as a cargo shipment, was lower priority would alert cold chain staff immediately. than passenger luggage for loading onto planes. The shipping Even with multiple sources of electricity and backup plans in company monitored shipment temperatures, and dry ice had place, power interruptions to the freezers occurred frequently, to be replenished during transit delays. Shipment durations for a variety of reasons, including failure of the grid, mechanical ranged from 3 to 10 days. or electrical faults (eg, malfunction of an automatic switch), and e cen Th tral depot supplied vaccine to the 2 district depots human factors (eg, a guard not adding fuel to the generator or approximately monthly. Without any local source of dry ice, the leaving his watch during the night). Moreover, 2 freezers failed assessment team recommended acquiring Arktek containers to before or during the trial and could not be fixed in Sierra Leone; fill the critical need for transporting the vaccines at –60°C or therefore, new freezers or alternative solutions for temporary colder from the central Freetown depot to the district depots vaccine storage had to be provided. (Figure 1 and Table 1). The Arktek container is a double-walled Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S51 Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 stainless steel vacuum-assisted insulated drum that was devel- was preconditioned to use to transfer vaccine between depots oped for storage of Expanded Program on Immunizations vac- and for storage in the event of freezer failure. At the Port Loko cines at 2°C–8°C for up to 1  month. The device was modified depot, preconditioned Arktek containers were rotated for use, (and designated as “ Arktek DF”; hereaer r ft eferred to as “ Arktek”) to permanently store the vaccine owing to failure of one of the to handle –80°C (as with the ultracold freezers, to allow some ultracold freezers. leeway in maintaining the required vaccine storage temperature of –60°C or colder) for the Ebola vaccine trials, with a poten- Providing Vaccine to Vaccination Sites tial payload of approximately 200 vials of vaccine (Figure  1B) Because the manufacturer provided the vaccine in 1-mL vials [9]. This was accomplished by substituting a combination of at a concentration of 1 ×  10 pfu/mL, it had to be diluted to phase-change proprietary denatured alcohols that were titrated the required concentration of 2 ×  10 pfu/mL before admin- to freeze and thaw at –80°C for the water/ice contained in the 8 istration. Because no traditional pharmacies were located at crescent-shaped plastic or metal containers inside the 35-pound study locations, the cold chain sites served that purpose. The drum. The filled phase-change containers were preconditioned Freetown site functioned as the central study pharmacy, and in the ultracold freezers at –85.5°C to reach the solid crystalliza- trained pharmacists handled study vaccine dispensation at all tion threshold. Once this temperature was reached, the liquids the sites. We developed facilities to allow for vaccine dilution at changed to solids, and the interior temperature was efficiently all 3 depots. Following standard operating procedures and ster- maintained in the ultracold freezers. When needed, the PCMs ile transfer techniques, trained pharmacy staff thawed the vac - were loaded into the Arktek containers. Because STRIVE lead- cine at ambient temperatures of <25°C and then diluted 2.7 mL ers were concerned that repeated opening of an Arktek con- from three 1-mL vials of vaccine into a vial containing 10.8 mL tainer in sub-Saharan temperatures over several days would of 0.9% normal saline. This resulted in the required 5-fold vac - compromise its ability to maintain a temperature of –60°C or cine dilution and sufficient vaccine in the diluent vial to draw colder, Intellectual Ventures conducted laboratory qualifica - up (allowing for wastage) 12 syringes, each with 1  mL of the tion tests in which the Arktek containers were opened 8 times correct vaccine dose. The use of vial adapters to draw up vaccine a day (to simulate removal of vaccine) at ambient temperatures into syringes from the diluent vial helped promote sterile con- of 32°C and 42°C. es Th e tests showed that temperatures colder ditions and significantly streamlined the dilution process with than –60°C could be maintained for >6  days in those condi- Leur-Lok connections. e Th manufacturer provided preprinted tions [9] (Figure  2). Eight Arktek containers were provided syringe labels with appropriate identifiers, and the syringes for STRIVE; 5–6 were used regularly, and the remaining 2–3 were maintained at a temperature of 2°C–8°C for up to 12 hours were on standby. Under field conditions, temperatures in the before administration to participants. Arktek containers remained in the range of –74°C to –70°C for Passive insulated reusable containers (CryoQ; Lisaline about 5 days, well below the required temperature of –60°C or Lifescience Technologies, Thane, India), were used to transport colder. Each depot always had at least 1 Arktek container that vaccine from depots to vaccination sites at a temperature of −55 −60 −65 −70 −75 −80 −85 0123 4 56 7 Time, days Figure  2. Temperature of the vaccine compartment of the Arktek DF container during laboratory qualification testing. During the testing, the Arktek DF container was opened 8 times a day, 1 hour apart, and the temperature in the vaccine compartment was continuously monitored. The phase-change material (PCM) appears to have fully melted by 5 days, but since it took approximately 1.5 days after PCM melting for the system to warm to –60°C, the hold time of the –78° PCMs was just under 6.5 days. S52 • JID 2018:217 (Suppl 1) • Jusu et al Temperature, °C Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 2°C–8°C. The WHO provided 15 of these containers in Sierra QUALITY CONTROL AND MONITORING SYSTEMS Leone on very short notice, and Intellectual Ventures/Global Temperature Monitoring Good flew in another 20 containers later. Engineers from We put systems in place to ensure that cold chain standards and BARDA and Modality Solutions tested and qualified the CryoQ requirements were maintained and recorded according to good containers to ensure they could maintain a temperature of 2°C– clinical practice, to monitor rVSVΔG-ZEBOV-GP at 2 tem- 8°C for 12 hours despite repeated opening to retrieve vaccine peratures, –60°C or colder before dilution and 2°C–8°C aer ft syringes. To achieve and maintain this temperature range, the dilution. If temperature excursions occurred outside these spec- CryoQ containers had to be preconditioned with 1 frozen gel ifications, we immediately quarantined the vaccine, investigated pack and 3 refrigerated ice packs. The CryoQ container was the excursion, and reported the excursion to quality experts at then closed with fitted-in foam packs to keep syringes secure NewLink Genetics (the vaccine manufacturer; the vaccine was and the enclosed temperature monitoring device from touching later licensed to Merck). These experts reported the final dispo - the inside walls of the CryoQ container (Figure 1C). sition of the vaccine, based on the temperature excursion profile To minimize wastage and plan daily vaccine dilutions for par- and stability data. ticipants randomly assigned to the immediate group, STRIVE We used 2 types of devices to monitor vaccine at tempera- cold chain depot staff maintained regular communication with tures of –60°C or colder: the TempTale4 device (Sensitech; enrollment and vaccination sites regarding the expected and Beverly, MA) and the HOBO device (Onset Computer; Bourne, actual number of participants. Participants randomly assigned MA). During vaccine shipment from the United States to Sierra to the immediate vaccination group were not given appoint- Leone, a TempTale4 device recorded the temperature in transit. ments, because of the unpredictability of their work schedules Upon the shipment container’s arrival at the Freetown central during the Ebola epidemic, so vaccinators did not know in depot, we downloaded the temperature profile from the moni - advance the exact number of participants who would be vac- toring device to a computer and sent it to the vaccine manufac- cinated each day. Therefore, based on estimates from previous turer for review. The storage freezers were set at –85.5°C but were days, pharmacists diluted and provided syringes to start vacci- programmed to alarm at temperatures warmer than –70°C. We nation at each site and then communicated with the site manag- used 2 independent methods to monitor freezer temperatures: ers during the day to assess whether additional vaccines would (1) twice-daily manual recording of temperatures from built-in be required. Because each dilution required 3 vaccine vials to temperature displays on the freezers and (2) continuous elec- produce 12 doses, such planning and ongoing communication tronic temperature monitoring via a HOBO device, which had were important for reducing vaccine wastage. thermocouple probes that monitor the interior temperatures of In contrast, for the participants in the deferred vaccination the equipment to which it is connected; their outputs can be group, schedulers set up visits in advance and made telephone read on the HOBO display. We programmed the HOBO device calls reminding participants to come for vaccination on their to display a visual indicator (alarm bell icon) when freezer tem- appointed days. This contributed to a reduction in wastage of peratures went outside limits. When depot staff saw the alarm vaccine doses across all the sites, from 32% during immediate indicator, they immediately noted a deviation and initiated an vaccination to 22% during deferred vaccination (Table 2). investigation. HOBO devices were also tfi ted for each Arktek Table 2. Vaccine Doses Prepared and Wastage per Vaccination Site, by Study Phase Immediate Vaccination Deferred Vaccination Doses Prepared, Doses Administered, Doses Wasted, Doses Prepared, Doses Administered, Doses Wasted, Site No. No. % No. No. % Connaught Hospital, 2290 1553 32 1736 1391 20 Freetown COMAHS Library 1174 902 23 1060 852 20 Port Loko Government 626 423 32 516 399 23 Hospital St. John of God Hospital, 319 194 39 288 170 41 Lunsar St. John of God Health 312 150 52 216 143 34 Center, Lungi Holy Spirit Hospital, 870 595 32 744 546 27 Makeni Magburaka District 528 366 31 384 338 12 Hospital Total 6119 4183 32 4944 3839 22 Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S53 Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 container. Cold chain staff also recorded storage depots’ ambi - transporting vaccine between depots, diluting and transporting ent temperatures twice daily. vaccines in syringe doses to vaccination sites, and maintaining To monitor the temperature of diluted vaccine in syringes ancillary supplies. Unused syringes were returned to the depot at a temperature of 2°C–8°C, we initialized programmable at the end of each day for incineration, along with any damaged TempTale4 devices and included one in each CryoQ pack or rejected syringes, and wastage was closely monitored. We sent to vaccination sites. At days’ end, we downloaded, saved, documented vaccine inventory and chain of custody in com- printed, and attached the recorded temperature data from the pliance with STRIVE standard operating procedures. We also TempTale4 device to the other records of the respective diluted strictly accounted for manufacturer-supplied syringe labels, per vaccine set. good clinical practice. During STRIVE, 5 temperature excursions occurred. Three Because needed materials were not available locally, we of these were associated with frozen concentrated vaccine. Two monitored and replenished satisfactory inventories of ancillary of the excursions were a result of catastrophic failure of key elec- supplies (ie, syringes, syringe caps, needles, and vial adapters) trical equipment. The first of these was a short circuit in the through international purchasing arrangements with suppliers junction box feeding power to the central depot cold chain stor- in Europe, both before and during the trial. age facility. e Th second was a catastrophic short circuit in a plug HUMAN RESOURCE CAPACITY AND MANAGEMENT that contributed to overload of the battery/automatic transfer OF COLD CHAIN system at the central depot. This was the worst excursion, last - Fifteen staff members were directly involved in STRIVE cold ing 5 hours 50 minutes, with the freezer temperature reaching chain activities throughout the trial; 3 were rotating interna- –53°C. The third excursion occurred at Port Loko, when the tional cold chain experts from BARDA and Modality Solutions, main generator went offline and the guard assigned to start up and 12 were national staff members (8 pharmacists and 4 cold the backup generator was absent from his post. Two excursions chain officers). e Th latter 12 staff members were divided among were associated with the diluted vaccine. Both resulted from the 3 depots. The local staff received role-specific trainings improper preconditioning of the refrigerated gel packs used in according to the protocol and standard operating procedures the CryoQ packs. In one instance, the gel ices were too warm, for cold chain activities needed for STRIVE, as well as general resulting in higher temperatures (up to 18°C) for the vaccine training on International Conference on Harmonization guide- for as long as 3 hours 5 minutes. In the second instance, the lines on good clinical practice, human subjects protection, and refrigerated gel packs were too cold, allowing the vaccine tem- good documentation practice. International cold chain experts perature to drop to 0°C, although it did not freeze. For all excur- provided the initial and refresher trainings, supervision, and sions, the vaccine manufacturer determined that the duration onsite oversight for cold chain activities throughout the trial. and magnitude were small enough that the vaccine quality was Aer vaccin ft ation ended, local staff managed oversight of stor - not adversely ae ff cted. age of the remaining vaccine vials, with remote backup from Electronic Alert Systems international consultants. Implementing STRIVE, we learned that having a system for alerting cold chain staff members about power failures and SUMMARY AND CONCLUSIONS potential temperature excursions was essential but also chal- In just 3  months, STRIVE staff successfully established and lenging, owing to unreliable power, Internet, and cellular ser- maintained a cold chain for storing the candidate Ebola vac- vices. Initially, we installed temperature signaling devices in cine at a temperature of –60°C or colder for the phase 2/3 trial each –80°C freezer that would send a text message to cold chain of rVSV∆G-ZEBOV-GP vaccine in Sierra Leone. The staff suc - staff ’s cell phones when an alarm-associated temperature of cessfully administered about 8000 doses of vaccine, with 28% –70°C was reached. However, this system proved to be unreli- of doses wasted overall at the vaccination sites and <0.1% of able because of inconsistent cellular connectivity at the central doses rejected or damaged. Challenges encountered and over- depot, and we replaced it with a WiFi Internet–based system. come included poor infrastructure for cold chain facilities, lack This system also was eventually abandoned owing to unreliable of highly specialized equipment needed for storing vaccine connectivity. Ultimately, we relied on continuous monitoring by at extremely low temperatures, high ambient temperatures, security guards, who notified the cold chain staff via text mes - 24-hour temperature monitoring for vaccine, interruptions and sage or telephone call when they discovered an alarm light trig- surges in the power supply, and freezer equipment failure. The gered by power failure. modified Arktek devices, capable of maintaining extremely low Inventory Management temperatures without power, proved invaluable and reliable Trained study pharmacists managed vaccine dispensation at for transporting the vaccines and as backup vaccine storage at each cold chain site. Inventory management included monitor- all 3 storage sites during temporary periods of power loss or ing each of the following: storing frozen vaccine at the depots, freezer malfunction. Overall, despite frequent interruptions S54 • JID 2018:217 (Suppl 1) • Jusu et al Downloaded from https://academic.oup.com/jid/article/217/suppl_1/S48/4999139 by DeepDyve user on 14 July 2022 Financial support. This work was supported by the Centers for Disease of the power supply to the ultracold freezers, significant tem - Control and Prevention (CDC), the Biomedical Advanced Research and perature excursions (warmer than –60°C) for undiluted vaccine Development Authority, and the National Institutes of Health, with addi- occurred only 3 times during the trial, and excursions outside tional support from the CDC Foundation. the temperature range of 2°C–8°C for diluted vaccine occurred Supplement sponsorship. This work is part of a supplement sponsored by the Centers for Disease Control and Prevention. only twice. In all these instances, product stability data con- Potential conifl cts of interest. M.  F.  has patents (8 377 030 and 8 887 firmed that the excursion had no effect on product quality, and 944) licensed to Aucma Global Medical. D. L. reports that he was contracted no vaccine doses had to be discarded. This was possible because to the work for the study. All other authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential of the excellent monitoring processes and rapid emergency Conflicts of Interest. Conflicts that the editors consider relevant to the con - response to deviations that we put in place for the trial. tent of the manuscript have been disclosed. e G Th uinea Ebola ça Suffit trial of rVSV∆G-ZEBOV-GP References vaccine reported 100% vaccine efficacy, paving the way for use of this vaccine in response to confirmed Ebola cases [ 10–13]. 1. Gostin LO, Lucey D, Phelan A. The Ebola epidemic: a global health emergency. JAMA 2014; 312:1095–6. One lasting legacy of STRIVE is that the cold chain infrastruc- 2. 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Meeting of the Strategic Advisory Group of Experts on immunization, October Disclaimer. The findings and conclusions in this report are those of 2015—conclusions and recommendations. Wkly Epidemiol Rec 2015; 90:681–99. the author(s) and do not necessarily represent the official position of the 14. Gulland A. Ebola vaccine will be made available for emergency use. BMJ 2016; 532:i386. Centers for Disease Control and Prevention. Cold Chain of –60°C or Colder for Ebola Vaccine Trial • JID 2018:217 (Suppl 1) • S55

Journal

The Journal of Infectious DiseasesOxford University Press

Published: May 18, 2018

Keywords: ebola virus; ebola virus disease; sierra leone; vaccines; temperature; ebola vaccines; vaccination; Storage and handling; disease outbreaks

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