COVID-19 Monthly Update: Nuts and Bolts About mRNA Vaccines: Distribution, Storage, and Administration
In the latter half of December 2020, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began reaching the U.S. market. Two mRNA vaccines indicated for prevention of coronavirus disease 2019 (COVID-19) have been authorized for administration in the United States. On successive Friday afternoons, the U.S. Food and Drug Administration (FDA) issued emergency use authorizations (EUAs) for the Pfizer/BioNTech vaccine, BNT162b2, and the Moderna vaccine, mRNA-1273.
Logistics of vaccine distribution, storage, and administration now take center stage as the hard work begins to work toward herd immunity through mass vaccination efforts as COVID-19 cases, hospitalizations, and deaths continue to rise in the United States. Pharmacists are in a unique position to be at the forefront of ending the pandemic by administering potentially millions of doses of these mRNA vaccines as well as more candidates that may be approved in first or second quarter of 2021. As of December 21, more than 500,000 people in the U.S. have received BNT162b2 with Moderna expected to produce 20 million doses in the U.S. by year end, a number of which will be administered. To respond to the challenge of administering hundreds of millions of doses of COVID-19 vaccines as quickly as possible, recruitment of additional pharmacists and pharmacy technicians has begun.
This article seeks to provide a framework for how distribution of these 2 COVID-19 vaccines will occur along with pertinent information related to both storage and administration.
With logistics planning in process for months in eager anticipation of final vaccine authorization, the first trucks left Kalamazoo, MI, with supplies of BNT162b2 vaccine in tow heading toward airports and distribution centers. From there, the vaccine was transported to thousands of hospitals and health systems to allow for vaccination of some of the highest priority groups outlined by the CDC: long-term care facility residents and healthcare providers, including many pharmacists.
While this sounds like an easy process on its surface, cold-chain logistics were critical, as this vaccine must be maintained at –80° C during its storage and transport. Unlike Moderna’s distribution, which is being managed primarily by Operation Warp Speed partner McKesson, Pfizer is leading this effort for BNT162b2.
First, specially made containers with temperature sensors that provide feedback on real-time conditions including temperature, light exposure and significant movement house BNT162b2 vials as they traverse to various settings for ultimate administration. Trays carrying nearly 200 vials are packed in boxes filled with dry ice weighing 80 pounds each; once reconstituted, these vials yield nearly 1,000 doses. Pfizer has been simulating these exercises for months, shipping them across continents via air travel to ensure viability.
Several deliveries in California and Alabama were returned back to Pfizer to determine viability because the vaccines arrived at even colder than recommended temperatures. Overall delivery of the vaccines has gone well with few issues reported nationally, and many vaccines already administered.
Moderna’s vaccine is being distributed with a similar framework used for H1N1 pandemic vaccines in 2010. Unlike BNT162b2, mRNA-1273 does not require storage in ultracold temperatures but can be maintained at –20° C, which is standard for freezers already present in hospitals and pharmacies. This vaccine can also be shipped and stored at this same temperature, making transportation logistics much easier.
Because the federal government has had significantly more time to plan the rollout, more than 3,000 sites were scheduled to receive shipments of mRNA-1273 during the initial wave, per Gen. Gustave Perna, chief operating officer of Operation Warp Speed. Commercial shipping companies, such as FedEx or UPS, primarily delivered the vaccines to administration sites from “fill/finish” Moderna facilities to local distribution centers and commercial pharmacy networks. The U.S. government decides which states/jurisdictions received vaccine, and orders fulfilled under direction of McKesson distribution.
STORAGE: FROM DELIVERY TO VACCINE PREPARATION
Once vaccines are delivered, proper planning is required to maximize vaccination based on individual properties of BNT162b2 and mRNA-1273, which differ significantly in logistics for storage at individual sites.
The vaccine made by Pfizer has the most difficult logistics of 2 approved mRNA vaccines. While the vaccine may be stored in the original Pfizer thermal shipping container with dry ice, traditional freezer or refrigerator stability is much shorter depending on the device used.
The arriving thermal shippers are meant only to be temporary storage units, as they require numerous administrative duties, such as continually monitoring the Controlant temperature monitoring device and reviewing daily email(s) on the status of the container. Dry ice pellets should be replaced 24 hours after arrival (sent by manufacturer) and replaced every 5 days if still maintained in thermal shippers (not provided by manufacturer).
Whoever is accessing the container must know ahead of time how many BNT162b2 vials will be removed, as these containers can be only opened twice daily, and only for 3 minutes at a time in order to preserve the ultracold temperatures. Once accessed, the containers should be resealed with packing tape. This should be repeated each time the container is opened.1
For more permanent storage, ultracold freezers with a temperature of –80° C and –60° C may be used. These are most likely to only be an option at large urban hospitals, as most rural hospitals are already struggling mightily from decreased income due to lost revenue during the pandemic and cannot afford these freezers. Nearly half of U.S. rural hospitals were operating at a loss in April 2020, demonstrating that these hospitals have less leverage to purchase this particular vaccine.
Options for hospitals without storage for BNT162b2 vaccine would include use of mRNA-1273 or one of the non-mRNA vaccines still in testing, as these would be more logistically appealing. The CDC has advised specifically against buying special freezers for ultracold storage, as each of these costs as much as $15,000. Most hospitals buying their own freezers are academic medical centers.
If storage is available, BNT162b2 may be stored in the ultracold freezer until the product’s expiration date, assuming vials are kept upright and protected from light. The U.S. Centers for Disease Control and Prevention (CDC) has indicated that the labeled expiration dates could be extended if the manufacturers demonstrate longer periods of viability in their ongoing tests. Facilities storing this product should use a digital data logger with a temperature probe specific for ultracold temperatures to keep a chart of minimum and maximum temperatures over the prior 24 hours at the start of each workday. Alternatively, the current temperature could be logged at the start and end of each workday if the digital devices do not record minimum/maximum temperatures.1
The storage with the shortest shelf-life for BNT162b2 is under refrigeration. BNT162b2 is only viable for 120 hours (5 days) upon refrigeration (prior to mixing) and therefore careful planning must be undertaken to ensure that all available vaccines are given. Each thermal shipping container holds 5 trays. Each tray contains 195 vials with 5 doses per vial. Temperature logs must be maintained similar to those for the ultra-cold freezers. Beyond-use date labels should be used to verify and track how long the BNT162b2 vaccines have been refrigerated. If the refrigerated vaccine is not used within 5 days, per the CDC it must be discarded and disposed.1
Storage options for mRNA-1273 are much simpler as the vaccine will arrive frozen between –25° C and –15° C, similar to most commercial freezers. Therefore, storage for a higher number of facilities should be feasible in either a traditional freezer or refrigerator.
The Moderna vaccine should be stored at similar temperatures at which it arrived as listed above. While mRNA-1273 can be stored in similar freezers as other approved frozen vaccines for other infectious diseases, the recommended range (–25° C and –15° C) is much narrower for mRNA-1273. Therefore, careful monitoring of freezers used to house these vaccines is important to ensure appropriate storage. A digital data logger along with similar procedures to those listed for BNT162b2 should be performed daily to document proper storage.2
Under standard refrigeration, mRNA-1273 vaccine has a much longer shelf-life than BNT162b2. Moderna’s vaccine may be stored at 2° C to 8° C unopened or unmixed for up to 30 days. Beyond-use date labels should be used similar to BNT162b2 in order to ensure no vaccine is used past the 30-day refrigeration date. If vials are not used after 30 days of storage in the refrigerator, they should be discarded using proper disposal procedures established by the manufacturer and jurisiction.2
ADMINISTRATION: VACCINES BECOME VACCINATIONS
The endgame of this long, winding process is ultimately administration of the vaccines into patients. Pharmacists and pharmacy technicians are among the primary administrators of vaccines in pharmacies and within nursing homes. This will be even more common in 2021 as the vaccine supply increases. Tens of thousands of pharmacists and pharmacy technicians are being hired in order to provide enough staffing to administer COVID-19 vaccines as well as provide/maintain other continuous pharmacy services. Pharmacists are well trained to lead this effort with significant experience storing and ultimately administering a number of vaccines. Additionally, pharmacists’ expertise regarding common side effects associated with COVID-19 vaccines — such as headache, injection site pain, and fever — is critical to ensure patients are adherent with their second dose in 3 weeks (BNT162b2) or 4 weeks (mRNA-1273) by providing sound patient education.
The Department of Health and Human Services has authorized pharmacy technicians to administer COVID-19 vaccines under certain conditions. They must be supervised by a qualified, licensed pharmacist with vaccines provided under the Advisory Committee on Immunization Practices (ACIP) recommendations. They must have a current basic cardiopulmonary resuscitation certificate and must complete 2 hours of Accreditation Council for Pharmacy Education (ACPE) continuing education on immunization practices during the relevant period of COVID-19 vaccinations. Pharmacists supervising pharmacy technicians should comply with recordkeeping and all reporting requirements including ensuring submission of all pertinent information to the patient’s primary care physician and any state/local vaccine registries.
Administration differs in a number of significant ways between the Pfizer vaccine (BNT162b2) and Moderna vaccine (mRNA-1273). These will be highlighted below for each vaccine.
Depending on the storage method used, BNT162b2 vaccine requires various thawing times prior to administration. Vaccines that have been stored at freezing temperatures may be thawed either in the refrigerator or at room temperature. If placed in the refrigerator, it may take 2–3 hours to thaw completely, with higher numbers of vials taking longer to thaw. For those vials thawing at room temperature, the process is shorter, taking 30 minutes to 2 hours. Vials at room temperature that are not punctured but also not used must be mixed within 2 hours or returned to the refrigerator. Note: Once thawed, BNT162b2 may not be refrozen.1
Once thawed and ready for mixing, multidose vials may be mixed with preservative-free normal saline diluent (ensure date of diluent is valid). Vials are injected with 1.8 mL of this diluent using sterile technique only after initially gently inverting the BNT162b2 vial 10 times. The liquid vaccine should be inspected to ensure it is not discolored; it should be white to off-white color. It is important due to fragility of the molecule to NOT shake the vaccine vial at any time. Once the diluent has been added to the vaccine vial, the mixture should again be inverted gently 10 times, being careful not to shake the vial.
The ready-to-administer BNT162b2 vaccine (labeled for 5 doses per vial) must be used within 6 hours, as the vaccine is preservative-free and may not be placed back into refrigeration or refrozen. Of note, reports have surfaced nationally of more than 5 doses per vial being available, with some vaccinators noting 6 or even 7 doses per vial. The FDA is advising to use “every full dose obtainable…pending resolution of the issue.” Of course, this is common knowledge to pharmacists who when drawing up intravenous medications see overfill with many other medications, not just vaccines.1
Before administering the BNT162b2 dose, ensure the patient has no contraindications to vaccination and is the appropriate age (16 years or older). Document both the name of vaccine and the lot number. Using sterile technique, draw up 0.3 mL (30 mcg) of BNT162b2 and inject into the deltoid muscle, similar to an influenza vaccination. After vaccination, patients should be observed for 15 minutes for any immediate adverse reaction. If patients have a history of anaphylaxis, observation should be extended to 30 minutes. Those centers administering vaccinations should have life-saving medications and supplies for administration on hand in case of anaphylaxis; cases of this serious reaction have been reported in rare circumstances during initial rollout of BNT162b2.1
For those tolerating the vaccine normally, education should be provided about common adverse effects and a card reminding them of their second vaccine dose due 3 weeks from initial vaccination (must be same manufacturer). A 4-day grace period may be given in which to receive the second dose; patients thus may receive the second dose as soon as 17 days after the initial vaccination. Should the second dose be administered earlier than 17 days, it does not need to be repeated. As no maximum time to the second dose has been established, patients presenting later can still receive the second dose.1
The mRNA-1273 vaccine can be thawed in the refrigerator (2.5 hours for thawing) or at room temperature (1 hour for thawing). Vials that are unpunctured may be kept between 8° and 25° C for up to 12 hours before placing back into the refrigerator. NOTE: Thawed vaccine may not be refrozen under any circumstances and must be used in an appropriate timeframe or discarded.2
Once patients are screened for precautions and contraindications to mRNA-1273, aseptic technique should be followed to prepare the vaccine. Unlike BNT162b2, which requires inversion and diluent addition, mRNA-1273 is ready for administration once thawed and inspected to ensure no particulate or discolored matter is present. The vaccine vial should be swirled before drawing up the initial as well as subsequent doses. The pharmacist or pharmacy technician should withdraw 0.5 mL (100 mcg) and inject into the deltoid muscle. Similar to BNT162b2, patients should be monitored for 15 minutes after vaccination unless they have a previous history of anaphylaxis, in which case observation for 30 minutes is required. Those centers administering vaccinations should have life-saving medications and supplies for administration on hand in case of anaphylaxis.2
Once tolerated, patients should be educated on common adverse effects and provided a card to remind patients of their second vaccine dose due 4 weeks from initial vaccination (must be same manufacturer). A 4-day grace period may be given in which to receive the second dose.2
BRIEF UPDATE ON OTHER VACCINE CANDIDATES
More non-mRNA vaccine candidates are expected to be fully evaluated in early 2021. The 2 most promising candidates will be much easier to transport, store, and administer at mass immunization sites with limited infrastructure (e.g., parking lots or other outdoor locations that more easily permit physical distancing) from a logistics standpoint if they are authorized by the FDA. In addition, one of these vaccines requires only a single dose, eliminating the complexity of tracking patients and products used.
Astra Zeneca and Oxford’s candidate, known as AZD1222, is a weakened version of an adenovirus that was 62.1% effective in patients who received 2 standard doses but 90% in patients who receive an initial half dose followed by the standard dose.3 The higher response rate in those receiving the initial half dose — which occurred by accident4 — was puzzling to scientists; they theorize that potentially the immune system is being “primed” more gradually by the initial half dose. Astra Zeneca officials said this “dosing error” involved doses produced in Italy, and the trial is being followed until completion for full evaluation of all findings. Additionally, regulators allowed trials to resume following independent evaluations of a case of transverse myelitis that was possibly related to the vaccine. Further monitoring will be required to determine if this is indeed associated with AZD1222. It may be stored, transported, and handled at refrigerated temperatures for at least 6 months.
Johnson and Johnson’s vaccine candidate, known as Ad26.COV2.S, recently finished enrolling patients into its primary phase 3 trial of 45,000 participants (ENSEMBLE trial). If the product is effective in this trial, an emergency use authorization should be submitted to the FDA in February 2021. This candidate is unique in that unlike the mRNA vaccines and AZD1222, it is administered in only 1 dose, which would eliminate issue of missed second doses. From a logistics standpoint, this product is expected to be stable for 2 years in a typical freezer environment (not ultracold) and could be stored refrigerated for upward of 3 months.
- Centers for Disease Control and Prevention. Vaccines and Immunizations. Pfizer-BioNTech COVID-19 vaccine. December 22, 2020. Accessed December 24, 2020. https://www.cdc.gov/vaccines/covid-19/info-by-product/pfizer/index.html.
- Centers for Disease Control and Prevention. Vaccines and Immunizations. Moderna COVID-19 vaccine. December 22, 2020. Accessed December 24, 2020. https://www.cdc.gov/vaccines/covid-19/info-by-product/moderna/index.html
- Voysey M, Costa Clemens SA, Madhi SA. Safety and efficacy fo the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. 2020 December 8. doi: 10.1016/S0140-6736(20)32661-1
- Knoll MD, Wonodi C. Oxford-AstraZeneca COVID-19 vaccine efficacy. 2020 December 8. doi: 10.1016/S0140-6736(20)32623-4.
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