The November announcement by Pfizer and BioNTech of promising interim data in their COVID-19 vaccine trial represented the first breakthrough in a series of world-changing developments surrounding the efficacy of COVID-19 vaccines. While other successful trials and subsequent approvals followed, one particular challenge with the Pfizer vaccine in particular is that it must be kept at -70 °C (-94 °F) during storage and distribution, which requires new equipment and protocols beyond the refrigerated supply chains used for vaccines currently (the vaccine “cold chain”).
COVID-19 vaccine development continues to be dynamic. For example, Moderna also unveiled an effective vaccine that does not have such extreme temperature requirements, and AstraZeneca has also shown promising efficacy for its vaccine which also does not come with such stringent cold storage requirements. With nearly 60 vaccines in some stage of human clinical trials as of early 2021, developments in this area will continue at a rapid clip. However, in this article, we’ll be focusing on the cold storage needs for the Pfizer vaccine, as it represents the most intense test of the advanced vaccines thus far in terms of cold storage logistics.
What We Know About the Vaccine
According to Pfizer, at -70 °C, the vaccine has an expected shelf life of 6 months. At 2-8 °C, a more common vaccine storage temperature range, it can be safely stored for 5 days before degradation. Other vaccines typically have a shelf life of 1-3 years at the recommended storage temperature, and from hours to weeks if improperly held at higher temperatures.
The reason for the lower storage temperature of the Pfizer vaccine is the fragility of the mRNA used in it. Research into using mRNA for vaccines is relatively new, with a great deal of progress having been made in the last 10 years. (There are other vaccines being developed that don’t rely on mRNA, we’ll discuss some of those later in this article.)
Are Such Low Temperature Requirements Unusual?
For vaccines that are distributed to the general public, yes. The majority of common vaccines require storage between 2 and 8 °C to maintain potency. The H1N1 vaccine, for example, falls into this category. A smaller number of vaccines require storage between -50 and -15 °C (these are usually mixed with a diluent before administration which is not frozen). The CDC has guidelines and training for this type of storage, and the lower temperature storage of the Pfizer COVID vaccine would be a significant shift.
Typical vaccine distribution involves refrigeration at the point of manufacture, which is maintained through distribution with a network of refrigerated warehouses and shipping containers. At the administration site (doctors offices, hospitals, pharmacies) cold storage is maintained, and rigorous protocols are used to track inventory and storage conditions. For more information on how these various stages work in the case of common vaccines, please see our white paper on this topic.
What Will Be Some of the Major Cold Storage Challenges?
There are a number of challenges to the distribution of any vaccine, which are made more severe by a low temperature requirement.
- Geography. Refrigeration must be maintained through areas with unpredictable, dramatic swings in outside temperature. For example, in the 2013-2014 flu season, the outdoor temperature was found to correlate with effectiveness of the H1N1 vaccine, probably because of its high degree of temperature sensitivity combined with temperature variability during truck loading and unloading.
In areas with less developed transportation and electrical grid infrastructure, higher frequency of unpredictable transportation delays adds to the challenge.
- Scale. The scale of the planned COVID-19 vaccine distribution is unprecedented in modern times, and will require significant addition to the existing network.
- Equipment availability. As of today, the primary plan to maintain the temperature of the Pfizer vaccine is to pack it in dry ice. We’ll talk about this in greater detail in the next section. This bypasses many of the problems with mechanical freezers, but requires a reliable source of dry ice, which is in short supply in some areas due to a combination of COVID-related causes.
Ultra-cold freezers, which are used to maintain biological specimens at -70 °C or below, could theoretically be used for distribution and storage. However, they are usually only found at large research facilities and not currently used for vaccine storage. Using them in all stages of the cold chain is probably not feasible, because they aren’t available in large supply, are expensive and complex, and require a large amount of power (10 to 30 kWh per day, roughly 10X the power used by a normal refrigerator).
- Training. As recognized by the CDC, a robust training program is one of three components of a reliable cold chain (the other two being storage/monitoring equipment and inventory management). Storing and handling ultra low temperature vaccines will require new procedures, regardless of what kind of equipment is used. In the case of dry ice, additional safety hazards are present that staff must be aware of.
- Emergency response. Similar to staff training, new response procedures in the case of emergency situations like equipment or power failures that are unique to ultra-low temperature storage will be needed.
What Type of Equipment Is Needed to Manage This Type of Cold Chain?
Guidelines for the distribution of ultra-cold vaccines are given by the CDC in their October 2020 COVID-19 Vaccination Program Interim Playbook. These guidelines focus on the use of dry ice (CO2) shipping boxes, which may be shipped directly from the manufacturer to administration sites. Once they arrive, the dry ice is replenished within 24 hours, then once every 5 days after that. During this period, the shipping box should be opened at most two times per day (for one minute, at most). At the end of 15 days, any unused vaccine can be moved to a standard 2-8 °C refrigerator, where it should be used within 5 days.
Pfizer plans to have 100,000 of these boxes ready by December 2020, with more after that. The reusable boxes will contain 1,000-5,000 doses and hold temperature for 10 days during shipping. At this time, the CDC recommends against administration sites purchasing the ultra-cold mechanical freezers we mentioned in the previous section, and instead using the CO2-cooled shipping containers primarily.
However, there are a number of questions around this plan, mainly concerning whether administration sites are equipped to handle the new protocols, whether the time limits on the CO2 storage boxes will allow the vaccine doses to be administered in time, and doubts about whether this plan will allow the vaccine to reach rural areas.
As with present vaccine cold chains, the CDC recommends the use of digital data loggers (DDLs) for temperature monitoring, and that each storage unit or container should have its own temperature probe. Not all temperature sensors are usable at -70 °C, so it’s important to confirm that the DDL being used is fitted with one that is, for example a platinum RTD sensor. Temperature buffering is also a concern at -70 °C, since it is below the freezing point of the typical propylene glycol buffers used in vaccine refrigerators. So the probe must be either suspended in air, or a low-temperature buffer.
Integrating a network of DDLs into a continuous, real-time monitoring system is an important component in protecting and proactively maintaining a cold chain. It becomes even more useful when combining an extremely fragile vaccine with a new, complex refrigeration scheme.
What Happens if There Is a Failure in the Cold Chain?
Cold chain failures can be the result of equipment problems, like a power outage, compressor failure, or loss of refrigerant in the case of a CO2 storage box, or insufficient training, which can lead to frequent opening or inefficient loading of freezers.
For existing vaccines, if any of these failures lead to a temperature excursion (temperatures outside the recommended storage range), the CDC has a detailed response process, which involves quarantining the affected material at the storage temperature, thoroughly documenting the event, and consulting with the vaccine manufacturer on whether the vaccine is still viable. Automatically maintaining a detailed and precise temperature record with a DDL makes this process much simpler.
The consequences of an excursion can be financial, if vaccine batches need to be discarded or recalled after consulting with the manufacturer. They can be far more serious and far-reaching if inactive vaccines were inadvertently administered. In these cases, re-vaccination is recommended, and anyone who is not re-vaccinated may incorrectly believe they have immunity, which is a public health issue.
Of course the best way to safeguard the vaccine supply is to have a cold chain distribution system that can proactively detect and address issues that may lead to an excursion before it happens. An important component of this is a real-time, continuous remote monitoring that can send alerts triggering corrective action when a problem is detected.
What Questions Still Need to Be Answered About the Vaccine?
There are a number of technical and policy-related questions that are still unanswered when it comes to the Pfizer vaccine. For example, one drawback of rapid vaccine development is that long-term safety cannot be established before rollout. Having said this, no safety concerns have been reported by Pfizer, and the CDC will continue to follow trial participants for 2 years.
The initial results announced by Pfizer included 94 participants who became infected with COVID-19. The Phase 3 trial will continue until 164 participants are infected. Pfizer is expected to apply for emergency authorization before the end of November, and the FDA has indicated that it could be granted with only interim Phase 3 data. Emergency authorization will probably involve only limited distribution, targeted at the most at-risk populations, with full approval and distribution in 2021. One of the more difficult questions left to resolve is who should receive the first wave of this vaccine.
There continues to be an unprecedented level of research beyond the Pfizer vaccine, with roughly 54 other COVID-19 vaccines in human trials, 12 of which are in Phase 3, with many others in the earlier stages of animal trials. The partial information available on these other vaccines, some of which do not use mRNA, indicates they will have less severe temperature requirements (including those in development by Johnson & Johnson and AstraZeneca).
In addition, it is possible to modify or formulate mRNA vaccines to have better temperature stability, and in fact, another mRNA vaccine in the pipeline (CureVac) is reported to have shelf stability of three months at +5 °C. For its part, Pfizer hopes to develop a vaccine that can be stored at 2-8 °C by 2022.
In summary, the distribution and storage of the Pfizer vaccine will be technically challenging, and require new equipment and protocols on an unprecedented scale. There are significant components about the distribution that seem uncertain, including the refrigeration equipment that will be used. Even if a vaccine with less severe temperature requirements takes precedence, its distribution will require cold chain coordination on a massive scale.