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The race to develop COVID-19 vaccines could well see some Americans vaccinated before the end of 2020 — less than a year after the world first learned a new virus was causing a dangerous new form of pneumonia in China.
The design, testing, and mass production of multiple vaccines has never been attempted on this type of timeline, making this moment a turning point in the development of vaccines to respond to new disease threats.
But the complexity of that work may pale in comparison to what comes next — the rollout of hundreds of millions of doses of never-before-used vaccines across the United States and, eventually, around the world.
Expect snafus. Expect confusion. Despite the best of intentions and months of painstaking planning to figure out how to get vaccines to people in an ethical order, doing so is going to be a gargantuan and sometimes messy task.
“There will be many, many problems with distribution,” warned Bill Foege, a former director of the Centers for Disease Control and Prevention and co-chair of a National Academy of Medicine panel that recently recommended a priority system for vaccine distribution.
Some of the looming problems aren’t foreseeable. But here are some potential hurdles that might complicate this very important effort.
How do you define high-risk health workers? Essential workers?
Settling on the groups of people who should be at the front of the line for vaccines is a challenging enough task. But interpreting the broad directions that distribution guidances lay out is a tougher one still.
A recent report from the NAM panel co-chaired by Foege recommended high-risk health workers and frontline workers should be the first to be vaccinated, in what’s known as Phase 1A, while critical workers should be offered vaccine in Phase 2. A working group set up by the Advisory Committee on Immunization Practices, a group that recommends vaccination policy to the CDC, may be leaning towards having essential workers in Phase 1b, after health workers.
Both the National Academy report and ACIP offer advice about who might fit into these various categories. But at the end of the day, those decisions will be made at the state, local and tribal level. It is very possible a group of workers deemed critical in one state will not be in another. It’s also very likely there could be a significant amount of jostling for places in line.
During the 2009 H1N1 flu pandemic, an association representing bread makers argued its workers were essential, because bread is a staple of the American diet. At an ACIP meeting in late August, Santa Ric Erwin, of the Fraternal Order of Real-Bearded Santas, made a plea for St. Nick impersonators to be vaccinated in Phase 2. “This year Christmas will be more important to the American psyche than ever before,” he argued.
A federal official familiar with the process said while state, local and tribal officials often want highly detailed guidance on who to prioritize, there is no one-size-fits-all approach. National officials cannot anticipate every scenario in every location.
High-risk medical conditions push you to the front of the vaccine line. How do you prove you have them when you get there?
A number of medical conditions put people at higher risk of having severe COVID disease, regardless of their age. The National Academy report recommends that people with two or more high-risk conditions — which include cancer, chronic kidney disease, sickle cell disease, type 2 diabetes and serious heart conditions — should be very close to the front of the vaccine line for vaccine. It put them in Phase 1b, just behind health workers in high-risk roles and first responders.
But how are the people tasked with administering vaccine in the early days, when supplies are scarce, going to know if a person standing before them actually qualifies to be in Phase 1b?
If vaccines are being given by primary care physicians, it will be easy enough for them to call inpatients who fit the requirements. But if they are given at clinics, it’s likely going to come down to an honor system that will undoubtedly be abused in some circumstances, Foege admitted.
“Since there is no easy way to visually detect these people, you have to rely on what people tell you. Sure, there will be people who pushed to the front of the line by saying they have things — that will happen,” he said. “You won’t have the resources to actually screen.”
How do you vaccinate special populations when there are little or no data on how the vaccines work for them?
Children and teenagers are pretty much at the back of the line for COVID-19 vaccines. That’s probably a good thing. Maybe by the time there’s enough vaccine available for them to get in the queue, there will have been research to determine the correct dosage for children and data on whether the vaccines are safe and effective in this precious population.
Just over 40 COVID vaccines are in clinical trials, but very few are being tested yet in children or teens. One Phase 2/3 study in the United Kingdom enrolled 60 children aged 5 to 12 to receive the AstraZeneca vaccine. A Phase 3 study of the Pfizer/BioNTech vaccine is enrolling U.S. teens aged 16 to 18, as well as healthy adults. Two clinical trials of a COVID-19 vaccine candidate in China were open to children as young as 6 months, according to the clinical trial registry ClinicalTrials.gov. A trial of a vaccine in India was allowing people aged 12 to 65 to enroll.
There are no data yet from any of these trials.
Moncef Slaoui, co-chair of Operation Warp Speed, the U.S. government effort to fast-track COVID vaccines, said it made a decision to wait until it was clear that vaccines worked in adults before testing them in children.
“As you get into pediatric [testing] you have to go age bracket by age bracket. It takes a while, appropriately, to make sure safety is there,” he told STAT.
Another problematic evidence gap is whether it’s safe to use any of the vaccines in pregnant people, who have so far been excluded from all of the trials.
Historically, vaccine development has been a vexing Catch-22 for pregnant people. No one wants to give them an untested vaccine, so they aren’t enrolled in clinical trials. Then, when the vaccine is authorized for use, there are no data on which to determine if it’s safe to use during pregnancy. This well-known pattern of neglect has been recognized and discussed in the development of OWS-sponsored vaccines. An yet, when vaccines become available, there will be no data on their safety and efficacy in pregnancy.
“While pregnant women are not included in the Operation Warp Speed-supported trials at this time, the Administration is working tirelessly to ensure every vulnerable American has access to a safe and effective vaccine as soon as possible,” a spokeswoman for the Department of Health and Human Services said.
This time, the lack of data is even more critical because of who is at the very front of the vaccine priority line: health workers. Those of childbearing age make up a large portion of the health-care workforce.
“I think with this infection in particular, if we don’t have a vaccine that we can feel confident giving to women of childbearing age, we don’t have a vaccine for health care workers and first responders,” said Katherine Neuzil, director of the University of Maryland’s Center for Vaccine Development and Global Health.
There’s also not going to be much data on which to gauge how well the vaccines work in the people who are at highest risk from COVID-19 — people age 85 and older. All the vaccines being developed with assistance from Operation Warp Speed have to enroll seniors in their trials, but some have a cut off around the mid-80s.
At least two vaccine manufacturers, Moderna and Novavax, are enrolling people living with HIV in vaccine trials — so at some point there will be data to show whether those vaccines are safe and effective in the HIV population.
How widely can Pfizer and BioNTech’s vaccine be used, given its taxing storage requirements?
Before any vaccine can start being rolled out, manufacturers have to be able to produce enough doses and get the vaccine where it needs to go. As it stands, the vaccine that currently seems poised to make it across the finish line first is also the one that will be the most difficult to put into use, if clinical trials show it is effective.
Pfizer and BioNTech’s candidate, which uses messenger RNA technology, must be shipped and stored at -70 Celsius.
The drug maker developed its own thermal shipping boxes that can hold up to 5,000 doses for up to 10 days. But the containers should not be opened more than twice a day and should not remain open for more than one minute at a time.
The boxes need dry ice to keep cold — 23 kilograms of dry ice pellets, to be precise, which must be replenished within 24 hours after the shipper is first opened, and then five days after.
This is far more complex than standard vaccine distribution. And if it’s not done properly, there could be enormous waste of limited doses.
“I think from our members’ perspective, that’s not feasible. You might say it’s possible, but it’s not feasible. To actually train providers to use dry ice — to get them dry ice — you’re really going down a path that’s not feasible,” said Claire Hannan, executive director of the Association of Immunization Managers.
“You’ve got to trust that where you’re sending it has some experience with this. To send a package with dry ice — to a nursing home?” she asked, her voice conveying skepticism.
How will Pfizer and BioNTech’s ordering system affect the potential rollout of its vaccine?
An additional constraint of Pfizer’s vaccine relates to how much you have to order if you’re going to use it. The smallest possible order is 975 doses.
That vaccine has to be used up pretty quickly after it is thawed — within five days, as long as it’s kept at fridge temperature, 2 to 8 Celsius. A well-equipped teaching hospital in a large city could easily manage to round up that many high priority staff to use up that much vaccine within a few days. But for hospitals and clinics in smaller towns? Nursing homes? Doing so is a much bigger challenge.
“A large part of our country is rural. And to prioritize vaccine to essential workers or health care personnel and make sure that you’re reaching them in rural areas with this vaccine — extremely tough,” Hannan said.
Large academic medical centers would have ultra-low temperature freezers in which to store the vaccine. Those that do could split up the vaccine doses — which come in five-dose vials — using some vials to give people their first dose, and saving the rest for the second, booster shot that is needed 28 days after the first.
Smaller places would have to buy special storage units, or store the vaccine in Pfizer’s thermal shippers. Pfizer’s thermal shippers can only store the vaccine doses frozen for 10 days.
All this means the Pfizer vaccine will only really be useful in select settings, said Foege. “That particular vaccine will have to almost invariably be given in hospitals. It’s not something you can do in clinics or in pharmacies.”
With air travel slowed, can vaccines get where they need to go quickly?
The pandemic has dramatically slowed down commercial air traffic, which the pharmaceutical industry has long relied on to shuttle their products around the world. or the past three decades or so, drug makers shipped about half of their products in the bellies of passenger planes, but as much as 80% of that capacity has disappeared, according to Neel Shah Jones, global head of air carrier relationships at Flexport, a freight forwarder.
“We’ve never tried to vaccinate the world in a matter of 12 months,” said Shah Jones. Flexport and Pharma.Aero, another industry organization, have formed a task force to find ways to safely and efficiently move COVID-19 vaccines in and out of airports.
DHL, a major player in transporting pharmaceutical products, says transporting COVID-19 vaccines globally will require about 200,000 pallet shipments and 15 million deliveries in cooling boxes — and about 15,000 flights to make those deliveries possible.
Even shipping containers pose a challenge, because the millions of vaccine doses that are expected to be produced will need to be transported in a relatively short amount of time. Even with companies ramping up their manufacturing of refrigerated shipping containers, there are still concerns that supplies may be inadequate.
“We’re seeing increased demand for containers that can store product at low temperatures and longer transport duration,” said Joachim Kuhn, the chief executive officer of Va-Q-Tec, a manufacturer that’s ramping up its production of containers by 50% this year.
How can officials keep a highly coveted resource safe from theft — and prevent counterfeits?
Any COVID-19 vaccine will be extremely valuable — and as such, at high risk of being stolen. Everyone from airport officials to drug makers are taking precautions to protect future doses.
Pfizer is adding extra security and background checks on everyone involved in each step of the process for transporting vaccines. The company will also place a GPS tracker inside every box of vaccines — an escalation from the usual practice of only tracking delivery trucks.
Security and distribution challenges will only grow more complicated as drug makers look to distribute vaccines to other parts of the world.
“Each country may work differently. Therein lies another wrinkle – where is the governance model for allocation of vaccines? And is that federal or state level? In some countries, ministries decide where the vaccine is going,” said Roddy Martin of TraceLink, which develops technology to mitigate diversion and counterfeiting.
The same holds true for confirming whether a vaccine is legitimate, or whether it’s a counterfeit product, Martin said. Every part of the supply chain has a different way of confirming whether a product is authentic.
“There are many systems that are used for scanning, but there may also be different versions of the truth,” he said.
Helen Branswell is Senior Writer, Infectious Disease for STAT. Helen covers issues broadly related to infectious diseases, including outbreaks, preparedness, research, and vaccine development. Ed Silverman is Pharmalot Columnist, Senior Writer for STAT. Ed covers the pharmaceutical industry.