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Adrian

                      Adrian Baskir                      and                           Dylan Liew

COVID-19 Actuaries Response Group – Learn. Share. Educate. Influence.

Summary

Whilst the world rejoices at the news of the approved SARS-CoV2 vaccines, many countries are realising there is another major hurdle to overcome: logistics. How can we ensure the vaccines are administered quickly enough to beat the spread of the virus?

Global vaccine distribution will be fraught with practical and logistical challenges with particular regard to the low-temperature environment required for some of the vaccines – and this will need to be maintained throughout shipping (the “cold chain”). We need to consider mundane issues such as box sizes, space, ice, rubber stoppers , and glass production – on top of the detailed planning to ensure sufficient personnel as well as suitable locations to administer mass-scale vaccination.

As we all know, the SARS-CoV2 virus has thrown up many unprecedented challenges to the world. But “it’s not how you start that matters, it’s how you finish”. With the swift approval of vaccines from Pfizer BioNTech^[1], Moderna^[2], Oxford/AstraZeneca^[3], and Sinovac^[4] (along with others such as Sputnik V^[5]) the focus is now on the logistics for rollout.

Supply chains are already stretched and challenged

Vaccines fall into three temperature categories: Ultra-cold (-70°C); Frozen (-20°C) and Refrigerated (+2 to +8°C)^[6]. The Ultra-cold (e.g. Pfizer BNT162b2) and Frozen (e.g. Moderna) vaccines present unique logistical challenges with the Pfizer vaccine having some additional requirements highlighted later. A particular challenge is temperature maintenance and monitoring, as the vaccines could be rendered ineffective if not maintained at the correct temperature throughout their journey.

International transportation poses additional challenges. Air transport plays a central role, and temperature control on aircrafts is difficult. More than half of air cargo is actually shipped via passenger aircraft in the ‘underbelly’ section of planes^[7] rather than in dedicated cargo planes. However, passenger demand is at an all-time low, meaning fewer planes are available for shipping and there is less capacity in the system (so also increasing costs).

Many aircraft have been put into ‘storage’, and many airlines have cut staff. Retro-fitting passenger aircraft for cargo use will be costly and airlines would need an incentive to do this (especially as the conversion costs might be incurred twice, if planes were to be eventually converted back for normal use). The alternative, of flying passenger aircraft without (or with very few) passengers, would be extremely expensive and inefficient.

We are reminded of some of the challenges the world already faced in shipping PPE – which, compared with vaccines, can be stored relatively easily and without specialist equipment.

Furthermore, only select airports are capable of receiving vaccine shipments. They must be able to unload, store, and ship in controlled environments under tight timelines, and ideally located near their final destination. A starting point may be to look at airports with the IATA’s CEIV Pharma certificate^[8].

Customs and regulatory requirements also need to be considered, given the heterogeneous nature of pharmaceutical regulation worldwide.

The Cold Chain is a small but complex subset of this stretched Supply Chain

Even if airline capacity was restored, we would face challenges in temperature control. Vaccines can degrade quickly at the wrong temperature. In every step of the journey from vaccine deployment, they must be kept cold^[9].

Every step from the production plant, to intermediate storage facilities, to hospitals and clinics requires cold storage. The world has never faced such demand for cold chain capacity. Few warehouses, for example, will have faced the need to be built to ensure precisely maintained cold temperatures, from the point of receiving through to shipping goods.

Pfizer temperature requirements go even further –

Ultra-Cold

The incredibly rapid development of the Pfizer vaccine means that it hasn’t had time to be adequately “stress tested” at different temperatures. This simply wasn’t at the top of Pfizer/BioNTech’s priorities. They planned to first establish that the vaccine worked and then consider viability at different temperatures. They are still collecting data on thermostability^[10], but the current stable temperature is recognised as -70°C.

RNA is a notoriously unstable molecule that can be easily broken down, but this harsh requirement has been described as more of a “matter of caution” by Pfizer/BioNTech rather than an ironclad  requirement^[11]. But it is also important to remember that absence of evidence does not imply evidence of absence.

Nevertheless, this requirement is staggering. The coldest temperature ever recorded in the entire history of the Northern Hemisphere is -68°C^[12]. Medical refrigerators typically found in GP surgeries and hospitals are designed to operate between 2 °C and 8 °C^[13] – orders of magnitude hotter. These kinds of temperature would usually be found only in expensive “Ultra-Low Temperature” freezers^[14] more common in laboratory rather than medical settings^[15]. It is challenging to imagine how other components of the supply chain such as airplane and warehouse storage could adapt to meet these requirements.

Specialised boxes

Pfizer has developed a highly specialised box as a quick solution, capable of maintaining the required temperature for up to 10 days if the box remains unopened (or 30 if replaced with dry ice every 5 days^[16]), but this too is not without challenge.

As mentioned, this storage box relies on dry ice, the solid form of carbon dioxide, which is in increasingly short supply^[17] with demand now surging^[18]. It is also classed as a “dangerous good” for many shipping companies which makes handling difficult and reduces capacity while increasing costs. The Federal Aviation Administration, for example, limits dry ice packages to 2.5kg^[19] owing to the risk of low pressure in the aircraft causing more sublimation and hence the crew breathing in dangerous levels of carbon dioxide^[20]. Exceptions to these limits are being granted given the importance of the payload^[21].

Avoiding wastage

Not only will the Pfizer vaccine need to be shipped fast, it will also need to be administered fast, with a reliable number of patients.

As there are constraints on how many times (and for how long) the boxes can be opened, opening the box for each patient as they arrive would not be feasible. Administrators would have to plan on treating (say) 975 patients on Monday and unboxing that number of vaccines in advance, as once unboxed they will only last 5 days in medical refrigerators.

If they unbox any more in anticipation of extra patients arriving without a booking, these potentially lifesaving vaccines could go to waste. A Californian hospital recently successfully scrambled to administer 800 doses in 2 hours after a refrigerator broke^[22]. Israel, currently storming ahead in their vaccination race^[23], are allowing for vaccine “walk-ins” at the end of each day for lower priority groups (willing to queue and wait) to receive any surplus doses about to spoil^[24].

Clearly in many parts of the world, particularly in developing countries, the other vaccines will be more logistically viable. The Pfizer vaccine is a vaccine suited to large and dense metropolitan areas. DHL estimates only 25 countries have the infrastructure in place to deal with a stringent temperature-controlled vaccines^[25]. Oxford’s ChAdOx1 and other vaccines with less stringent demands may instead be the vaccine of choice for harder to reach places.

Infection, symptoms, and problems may still spread

Whilst the virus still spreads exponentially, the rate of vaccinations is a linear process – non-pharmaceutical interventions will still be required. The Pfizer vaccine was observed to provide a form of immunity from symptomatic illness 7 days after the 2^nd dose, with that being administered 21 days after the 1^st, leaving a potential 28-day window (from the first injection) to get infected^[26].

However, the studies do not show that the vaccine stops someone from spreading the virus as a carrier (transmission was not considered as an endpoint in the trial design^[27]). And even if it did, we would need follow-up studies to confirm how long the effects of the vaccine persist.

We don’t know if the vaccine still provides immunity say one year from the second dose (so the logistical challenges may be ongoing rather one-and-done). Other vaccines have similar untested properties.

After delivery how can the vaccine be administered at scale?

A major challenge in the speed and scale of administering the vaccine is the personnel to administer the vaccine and the locations for administration. This will require using retired and allied healthcare workers, and training people with no previous experience. Additionally, such personnel will require PPE, and systems will be needed to facilitate rapid and accurate record-keeping of those vaccinated, dose, and immediate side effects, and an effective follow-up appointment booking system.

Social distancing will be needed at vaccination sites. In order to give enough space for patients to keep safe, pharmacists have suggested using large “off-site” venues such as sports stadiums^[28]. Similar to testing, vaccinations could be given via “drive-in” sites (already seen in Israel^[29]) and cars used as pre-and-post waiting rooms^[30] to maintain distance. “Pop-up” vaccine centres or roving mobile vaccine units may be deployed to reach more remote communities.

It is also worth considering that whilst vaccine side-effects have been described as “mild” or “moderate” e.g. headaches, injection site pain etc.^[31] the scale of the programme means these will affect a lot of people so treating these side effects on a large scale should also not be overlooked.

Whilst most developed countries will have struck bilateral agreements with the manufacturers, COVAX^[32] (a combined CEPI GAVI and WHO initiative) has been established to guarantee fair and equitable access to vaccines for every country in the world.

Apart from manufacturing the vaccine, there are numerous ancillary components requiring mass manufacture – glass vials, needles, inserts.

Surveillance and monitoring will be needed, in many ways

Rigorous surveillance of all vaccines post-approval will be crucial. Across the world, there is a need for post-authorisation safety and efficacy studies. These include monitoring adverse events, disease development, and vaccine uptake, all to be done in real time. A focus on subgroups where the safety of the vaccine has yet to be established (such as pregnant women and immuno-compromised individuals) will be required.

There is a major concern around physical security. Vaccines will be sought after, and illicit markets for medicines already exist^[33], but how could vaccine integrity and administration be guaranteed on the black market? Would criminals have access to an Ultra-cold chain? Interpol have already issued a warning and cautioned there may be scams both physically and online^[34].

There remain a number of unanswered questions such as:

• Will the vaccine prevent one from getting COVID-19 or simply reduce severity (i.e. can you still be a carrier / transmitter?)
• What is the effectiveness by sub-groups – BAME, age groups etc
• How long will the vaccine afford protection? Will regular vaccination be required and if so, will production ever exceed demand?
• How resilient is the vaccine to new strains and variants?
• Will vaccines be available privately e.g. if airlines institute “no vax no fly policies” as controversially advertised by Ryanair^[35]?
• Will Governments be able to overcome vaccine hesitancy?

8 January 2020

References

[1] https://www.pfizer.co.uk/mhra-grants-temporary-authorisation-for-Pfizer-BioNTech-COVID-19-mRNA-vaccine

[2] https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-COVID-19/moderna-COVID-19-vaccine

[3] https://www.gov.uk/government/news/oxford-universityastrazeneca-vaccine-authorised-by-uk-medicines-regulator

[4] https://www.nature.com/articles/d41586-020-03563-z

[5] https://www.pharmaceutical-technology.com/news/russia-sputnik-senior-citizens/

[6] https://www.cdc.gov/vaccines/imz-managers/downloads/COVID-19-Vaccination-Program-Interim_Playbook.pdf

[7] https://www.iata.org/en/iata-repository/publications/economic-reports/air-cargo-markets-july-update/

[8] https://www.iata.org/contentassets/a94b6b640a404a29b80f18f47a1ff75f/ceiv-pharma_cockpit.pdf

[9] https://ziccum.com/lets-crack-the-cold-chain/

[10] https://www.pfizer.com/news/press-release/press-release-detail/pfizer-investor-day-features-significant-number-pipeline

[11] https://www.lloydsloadinglist.com/freight-directory/news/Delivery-of-COVID-19-vaccine-needs-scaled-up-medical-supply-chains/77325.htm#.X6xYHHd2tuk

[12] https://en.wikipedia.org/wiki/Climate_of_the_Arctic#Temperature

[13] https://www.sussexpartnership.nhs.uk/sites/default/files/documents/refrigerator_monitoring_form_-ver_2-_nov_17.pdf

[14] https://en.wikipedia.org/wiki/ULT_freezer

[15] https://theconversation.com/pfizers-ultra-cold-vaccine-could-be-difficult-to-distribute-149848

[16] https://www.pfizer.com/news/hot-topics/covid_19_vaccine_u_s_distribution_fact_sheet

[17] https://www.bbc.co.uk/news/business-44613652

[18] https://www.cnbc.com/2020/12/09/covid-vaccine-dry-ice-sales-skyrocket-as-hospitals-prepare-to-deliver-shots.html

[19] https://www.faa.gov/hazmat/packsafe/more_info/?hazmat=11

[20] https://www.faa.gov/documentLibrary/media/Advisory_Circular/AC_91-76A.pdf

[21] https://www.freightwaves.com/news/faa-issues-dry-ice-alert-to-airlines-carrying-vaccine

[22] https://edition.cnn.com/2021/01/06/us/california-broken-freezer-vaccines-trnd/index.html

[23] https://www.forbes.com/sites/jemimamcevoy/2021/01/04/why-israel-is-leading-the-world-in-covid-vaccinations-and-the-us-is-trailing/?sh=457241701592

[24] https://www.reuters.com/article/health-coronavirus-israel-idUSL8N2JB0ZW

[25] https://www.dhl.com/content/dam/dhl/global/core/documents/pdf/glo-core-delivering-pandemic-resilience-2020.pdf

[26] https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against

[27] https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-09/C4591001_Clinical_Protocol.pdf

[28] https://www.pharmaceutical-journal.com/news-and-analysis/news/flu-vaccines-could-be-delivered-in-sports-stadiums-town-halls-and-mosques-to-mitigate-COVID-19-risk-says-pharmacy-negotiator/20208142.article?firstPass=false

[29] https://static1.squarespace.com/static/56eddde762cd9413e151ac92/t/5ff3ef69c2ef5e3c22dc8e07/1609822091561/Worth+a+shot+-+James+Lawson%2C+Jonathon+Kitson+and+Matthew+Lesh+-+Final.pdf

[30] https://www.gov.uk/government/publications/health-matters-flu-immunisation-programme-and-COVID-19/health-matters-delivering-the-flu-immunisation-programme-during-the-COVID-19-pandemic

[31] https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-COVID-19/information-for-healthcare-professionals-on-pfizerbiontech-COVID-19-vaccine

[32] https://www.gavi.org/covax-facility

[33] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4318775/

[34] https://www.interpol.int/en/News-and-Events/News/2020/INTERPOL-warns-of-organized-crime-threat-to-COVID-19-vaccines

[35] https://www.independent.co.uk/travel/news-and-advice/ryanair-jab-and-go-advert-coronavirus-b1779849.html