In a small glimmer of hope in what has been a rapidly deteriorating epidemic in the United States, the FDA yesterday voted 17-4 (with one abstention?) to approve the Pfizer/BioNTech coronavirus vaccine through an Emergency Use Authorization (EUA). This is the same approval process that has brought various testing modalities for COVID-19, including antigen and antibody tests, to market. A full Biologic License Application (BLA) would be much further down the line and require at least six months of follow-up in a substantial number of clinical trial participants. Before today, the Pfizer/BioNTech vaccine had already been approved for use in the United Kingdom, Canada and Bahrain.
I have spent the last several weeks answering questions about this vaccine and other vaccine candidates and will outline the main questions I have been getting below:
How and when can I get the Pfizer vaccine? Will you have it in your office?
This is a difficult question to answer and I have not heard any concrete plans. Distribution of the Pfizer vaccine is complicated and requires an ultracold chain of storage at -70°C. Vaccines will be sent out via a specialized thermal shipping container. Upon opening the shipping container, the vaccine can be stored refrigerated at 2-8°C but must be used within 5 days. GIven that the minimum lot size is 1000 doses, only large medical centers with adequate storage capacity and the clinical infrastructure to deliver 200 doses a day (and then 200 doses to the same individuals three weeks later) will be suitable sites.
Specifics for distribution beyond transportation from Pfizer’s facility in Michigan to distribution sites have not been well articulated. Tweets from Governor Newsom suggest that California had ordered over 300,000 doses of Pfizer’s vaccine (which would effectively vaccine 150,000 individuals – again if distributed without error) Those shots are expected to arrive around Dec. 15, Newsom said Monday. Seven California hospitals will be among the first in the United States to get the vaccine when it becomes available. Cedars Sinai Medical Center, Los Angeles; Mercy Medical Center, Redding; Rady Children’s Hospital, San Diego; UCD Health, Sacramento; UCSF Medical Center, San Francisco; Valley Children’s Healthcare, Madera; and Zuckerberg San Francisco General Hospital are on a list provided by the California Department of Public Health. Health officials are quick to point out that these initial shipments will not be sufficient to vaccine healthcare workers and prioritization will be made for those taking care of vulnerable populations.
It does appear that private industry will also be involved in the distribution of the vaccine. McKesson Corporation, the major source of medical supplies and well known for their logistics and robust supply chain management, has been identified as a “preferred vendor” by the US Government. Pfizer, however, has taken pains to specifically not use McKesson and instead said in press releases that they would deliver the vaccine directly to healthcare providers. Also, there has been some discussion that CVS and Walgreens will store and distribute doses of the vaccine destined for long-term care facilities. Each dose has been estimated to cost about $20 (it will be interesting to see what insurance companies actually reimburse upon delivery).
I do not anticipate having the Pfizer particular vaccine available in my office and have received no communication from our usual vaccine suppliers. In fact, I have not even received communication about how I myself might obtain one as a healthcare worker – not from the State, County or the hospital where I am on staff. But I do think that the Moderna vaccine (detailed below) and potentially the AstraZeneca will be much more viable in-office solutions and, for those over the age of 65, may even be available as early as January.
The other limiting factor in generalized availability of the Pfizer vaccine is that the US government has declined to purchase additional doses beyond the original 100 million doses (which would effectively vaccinate 50 million Americans if distributed perfectly) negotiated in July. In the interim, other countries have stepped in to order the vaccine and would now be prioritized before the US. This includes the UK (40 million doses), Japan (120 million doses in preparation for the Summer Olympics), and the European Union (200 million doses with an option for 100 million more). Additional Pfizer vaccines would most likely not be available to the US until June or July.
For those who are not frontline healthcare workers or long-term care facility residents, the wait for a Pfizer vaccine will likely be considerable. There are at least 18 million health care workers in the US (1.7 million in California). There are 1.3 million long-term care facility residents (400,000 in California). Given that each vaccination series is two doses, separated by three weeks and that clinical studies suggest that protection is attained fully at week 5 from the first dose. I think most realistic estimates suggest that late Spring or early Summer will find the vaccine available for the general population. It is also important to remember that the vaccines have yet to be evaluated for safety in those under 18 or in pregnant or breastfeeding women.
Fortunately, there are other options.
What about the Moderna vaccine? And will you have that available in the office?
Although there has been a general outcry about the US not purchasing additional Pfizer vaccine (spearheaded by Dr. Scott Gottleib, former FDA commissioner and now a Pfizer board member – clearly not an unbiased voice), the good news is that there are other effective vaccine candidates that are also near FDA approval.
The next candidate will be the Moderna vaccine which was developed in partnership with the National Institutes of Health (NIH), It, like the Pfizer vaccine, is also on an mRNA platform and is a series of two injections spaced 3 weeks apart. The FDA will review Moderna’s application on December 17th and a quick approval is expected. Both the Pfizer/BioNTech and Moderna vaccines have been shown in large trials to reduce the risk of developing symptomatic Covid-19 infection by more than 90% and severe disease by 100%.
The Moderna candidate vaccine has far less stringent cold chain requirements. Moderna’s vaccine remains stable for six months at negative 20°C and for 30 days in a standard medical refrigerator. That difference makes Moderna more suited for distribution in individual physician offices as well as rural areas which have been decimated by a preference for large, metropolitan regional hospitals.
Cost? $32-37 per dose.
What about the AstraZeneca vaccine?
The vaccine immediately on the heels of the Moderna vaccine is AstraZeneca’s candidate developed in conjunction with Oxford University. It is also given in a two shot series, separated by four weeks. Unlike the Pfizer and Moderna vaccines, AstraZeneca says its vaccine can be stored, transported and handled at normal refrigerated conditions for at least six months and administered within existing health-care settings. Also, unlike the other two vaccines which were developed on an mRNA platform, the Oxford–AstraZeneca vaccine is made from the common cold-causing adenovirus that was modified so that it no longer replicates in cells.
Its cost is expected to be $2.50 per dose.
The raging controversy, however, with this vaccine candidate is that its efficacy is quite different depending on the strength of inoculation given. One dosing regimen showed an effectiveness of 90% when trial participants received a half dose, followed by a full dose at least one month apart. The other showed 62% efficacy when given as two full doses at least one month apart.
The combined analysis from both dosing regimens found an average vaccine effectiveness of 70%. No hospitalizations or severe cases of the disease were reported in participants receiving the vaccine. The difference in the two dosing regimens was not deliberate, but was actually a manufacturing mistake. It is still not clear why there is such a difference in effectiveness – some have suggested it may simply be a statistical fluke in the data (the half dose/full dose group did not include anybody over the age of 55). However, others have suggested that the lower initial dose may actually ‘prime’ the immune system making it a more effective way to vaccinate. I wonder if then the first half strength dose would only be $1.25.
What sort of timeline are we looking at?
This is a good question and one subject to all sorts of conjecture. In my search for something concrete, the timeline most easily understood came from the State of Massachusetts pictured below (Figure 1)
On their website, the Massachusetts Department of Public Health notes that “the timeline reflects several priorities: protecting our most vulnerable, maintaining health care system capacity, and addressing inequities in health care access and COVID-19 burden.” Unknowingly their timeline also reflects an essential public health underpinning which is that you want to prioritize those settings responsible for continued spread of the virus such as congregate care settings (corrections and shelters). Each phase will undoubtedly be broken down further. For example, in Phase One: healthcare workers and support staff working in ICUs should be prioritized before those working in an outpatient setting. In Phase Two, it is more likely that age groups will be subtiered as 85+, 75+, 65+ and so on.
But in general, I think this timeline will hold with much of the US public having vaccine availability in late Spring or early Summer. But that’s still a very long time away, particularly as the pandemic accelerates in our community.
What about vaccine side effects?
Two healthcare workers in the United Kingdom who received Pfizer’s newly approved COVID-19 vaccine did develop a severe allergic reaction after their first dose. Of interest, both have a history of significant allergies (perhaps to medications or to an environmental trigger like a bee sting), and both carry EpiPen injectors at all times. Although these individuals are recovering well, the UK NHS has advised that those with a history of significant allergic reactions not receive the vaccine at this time as further investigation is undertaken.
It is important to note that vaccine trials rely on the participation of healthy adults and individuals with a significant allergy history would have not been eligible for participation. Similarly, the medications have yet to be studied in adolescents (although those clinical investigations are now ongoing), or among pregnant or breastfeeding women.
The good news for the general public is that healthcare workers will function as a large scale trial before the vaccines are distributed more widely. A diverse workforce with (presumably) a close connection to healthcare providers, they should be able to identify and manage any adverse effects from the vaccine and reliably pass that information on to the public.
How do you think things will go from here?
To have any vaccine within a year’s time from the start of the pandemic is an astonishing accomplishment – and even better we now have one approved, one that is nearly approved and one that seems to be a viable candidate. Taking a moment to reflect on the collaborative steps that were required – from the identification of the viral genome, to a narrowed focus on the viral spike protein as a vaccine target, to the recruitment and participation of tens of thousands of volunteers – gives us a sense of just how massive of an undertaking this has been. Typically, vaccine development takes about a decade.
Unfortunately, we are now experiencing an absolutely massive and unprecedented (even by US standards) surge in cases. Some epidemic modeling experts (covid19-projections.com) have estimated that the post-Thanksgiving surge will be 2-3 times our July peak. I actually think that this is an underestimate and that we will see 10 times the cases we had over the summer with a real potential to overwhelm our medical system.
Although there have been improvements in in-hospital care leading to decreased mortality, there have not really been any significant advances in outpatient treatment. And, as we learned from Italy’s experience in March, an overwhelmed health care system significantly worsens survival rates. Just yesterday in Los Angeles there were over 12,000 reported cases – and only a few months ago there was discussion that if the County could drop below 700 daily cases, that we could move into a less restrictive tier. Governor Newsom’s careful planned tier system is moot when we now have extensive and accelerating community spread.
Adding onto this already perilous situation is the upcoming Holiday season where, again, we will see Americans traveling and visiting family. This isn’t smart, it isn’t right and will only serve to flare cases again. I have not yet seen numbers for expected travel over the winter holidays but would expect these to be in line with what we saw over Thanksgiving.
It will be some time before a large enough percentage of the American public is vaccinated to begin to slow community spread. President Elect Biden has promised 100 million doses in his first 100 days – an ambitious goal. Even if achieved, 100 million doses covers 50 million Americans or 15% of the population. Add to that an estimated 15% of the US population that has natural immunity (assuming here that we do not vaccinate those who have already recovered from COVID-19 which we most certainly would and should do), a maximum of 30% of the population would then be immune to the virus. Most estimates expect that a necessary population threshold to significantly impact community viral spread is a 60-70% “herd” immunity. Day 100 of a Biden administration takes us to the first week of May – by then we would only be halfway to our goal population immunity threshold
We still have a very long road ahead of us. Most of it along depressing landscape that we have seen before.