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INTRODUCTION

The day the world has waited for since the emergence of the coronavirus disease 2019 (COVID-19 pandemic has arrived: approval of a vaccine targeting the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After initial approval occurred in the United Kingdom on December 2, 2020, Margaret Keenan, a 90-year-old grandmother, became the first person in the Western world to receive the Pfizer-BioNTech vaccine outside clinical trials when she was vaccinated at University Hospital Coventry. The U.S. Food and Drug Administration (FDA) followed suit by issuing an Emergency Use Authorization (EUA) for the Pfizer-BioNTech mRNA vaccine, BNT162b2, on December 11, 2020, after a 17–4 positive vote by the FDA Vaccines and Related Biological Products Advisory Committee. This same committee reviewed Moderna’s mRNA vaccine candidate (mRNA-1273) a week later and recommended issuing an EUA for this second mRNA vaccine.

The first Pfizer/BioNTech SARS-CoV-2 vaccines were administered on December 14 in the United States, merely 48 hours after initial approval as distribution occurred quickly with 145 locations receiving vaccines. Trucks from FedEx and United Parcel Services transported 500,000 doses of the vaccine from Pfizer’s Michigan plant, stored in Pfizer’s own special container to maintain the ultracold temperature of –70° C (–94° F) required to maintain the integrity of the vaccine. While initial vaccines have been administered, the first half of 2021 will be when the vast majority of Americans will be eligible to receive vaccination.

In this program, answers are provided to 10 of the most important questions regarding these newly approved mRNA vaccines.

1. How do mRNA vaccines work?

Messenger RNA technology, while a new term to many, has been studied for over a decade in the disciplines of gene therapy and cancer treatments. For these vaccines, mRNA technology delivers a small segment of the SARS-CoV-2 mRNA, which prompts host cells to translate the genetic code into viral protein. The immune system reacts to this viral protein by making antibodies that can later respond if presented with the pathogen.

SARS-CoV-2 is made up of 29 main proteins. The primary protein found on the outer membrane is the spike protein, which is one of the virus’s major mechanism for infecting healthy cells. The mRNA vaccines contain the mRNA that encodes for the spike protein (and only the spike protein).

This mRNA is very fragile. Only by encapsulating this molecule in a lipid nanoparticle can it be presented for fusing with human cells after intramuscular injection. Ribosomes translate the mRNA and use amino acids to build the spike protein. The mRNA from the vaccine is eventually destroyed by the cell and contrary to concerns voiced, the mRNA never becomes a part of the host DNA. Some of these spike proteins migrate to the surface of the cell and present themselves to macrophages, which send information to B cells for antibody production and T cells for inducing additional long-term immunity before ultimately destroying the host cells transfected with the mRNA.

2. How efficacious are the mRNA vaccines?

In short, much more effective than predicted. In the pivotal Pfizer trial, nearly 38,000 patients available for data evaluation were randomized 1:1 to receive 2 doses of either the vaccine (BNT162b2 30 mcg) or placebo given 3 weeks apart. Vaccine effectiveness (VE) for the first primary endpoint in patients without evidence of SARS-CoV-2 infection was 95% (credible interval of 90.3%–97.6%), which was measured at least 7 days after dose 2. For the second primary endpoint, VE was 94.6% in participants with and without evidence of SARS-CoV-2 infection before and during the vaccination regimen. Additionally, these benefits were consistent across a number of subgroups including age, sex, race/ethnicity, and comorbidities (including obesity). Of note, only 1 case of severe COVID-19 was documented in the treatment group, while 9 cases occurred in the placebo group, indicating that the vaccine may prevent severe COVID-19 illness as well.¹

For the Moderna vaccine, participants were randomized to mRNA-1273 100 mcg or placebo at 0 and 4 weeks. The VE for the primary endpoint was 94.5% (95% CI: 86.5%–97.8%) as measured at least 14 days after the second dose. Similar to BNT162b2, mRNA-1273 prevented severe COVID-19 illness, with no cases identified in the treatment arm.²

3. What are the notable adverse effects associated with mRNA vaccines?

The most common side effects reported with BNT162b2 were similar to other common vaccines but with increased frequency. Local adverse effects occurred in nearly 85% of patients (pain, swelling, erythema). Fatigue (63%) and headache (55%) were the most common systemic side effects reported, followed by muscle pain (38%), chills (32%), joint pain (24%), and fever (14.2%). Adverse effects were more frequent in the second dose compared to the first and tended to occur less often in older patients (³55 years of age). Serious adverse effects were rare and seen in both the treatment and placebo arms of the study.³

Of note, numerically more patients receiving BNT162b2 developed Bell’s Palsy (4 vs. 0) and displayed lymphadenopathy (64 vs. 6). “Allergic reactions” were reported in 2 patients receiving BNT162b2 in the United Kingdom, prompting regulatory agencies to recommend that patients with a severe history of allergic reactions not receive the vaccine. Both of the affected patients had a history of severe unspecified reactions for which they carried epinephrine auto injectors with them at all times in case of reaction. The causative factor in these adverse reactions is likely not the mRNA vaccine itself but more likely the product’s polyethylene glycol component.

In the United States, the Centers for Disease Control and Prevention also recommends that people with a history of severe allergic reaction to any component of the BNT162b2 not receive the vaccine; the agency lists a precaution in patients who have had severe allergic reactions to other vaccines or other injectable medication. Patients with a history of anaphylaxis should be monitored for 30 minutes post vaccination, and all other patients should receive 15 minutes of monitoring. Close monitoring of these adverse effects will be important going forward as greater numbers of patients receive these mRNA vaccines.

Pharmacists have a critical role to play in educating the public about the most common side effects and rare events so that patients can be fully informed and be more likely to complete their vaccination with the second dose.

Speaking of the second dose…

4. What happens if the second dose is not received? How effective is a single dose of mRNA vaccine? Can a different mRNA vaccine be used for the second dose when the product used for the first dose is not available?

BNT162b2 yields a VE of approximately 52% within 12 days after a single dose.³ In fact, some have advocated that in order to maximize vaccinations early on, focusing on giving more patients 1 dose instead of 2 might be best. However, this is not optimal as vaccine efficacy approximates 95% with the second dose, and single-dose efficacy has not been systematically evaluated in a comparator study.

While both BNT162b2 and mRNA-1273 are mRNA vaccines, they are structurally different. The Advisory Committee on Immunization Practices (ACIP) states that the Pfizer-BioNTech vaccine is not interchangeable with other potential COVID-19 vaccine products that may be approved due to lack of safety and efficacy studies. Patients should receive both doses from the same manufacturer.

In the scenario where a patient receives 2 doses from different manufacturers, no additional doses should be administered.⁴ Any SARS-CoV-2 vaccine should be separated by 2 weeks from any other vaccination.

5. Which populations were not well represented in the mRNA vaccine studies?

Several populations that commonly receive vaccinations not included in the mRNA studies were pediatric, adolescent, pregnant, and immunocompromised patients.

While the EUA for BNT162b2 included use in patients aged 16 years or older, few participants who were 16 or 17 years old (n = 283 participants) were included in the safety analyses. This is the reason for at least one of the negative votes from the FDA advisory committee as it was felt that BNT162b2 should be authorized only for patients who had reached 18 years of age. Moderna did not include participants younger than 18 years of age; the EUA issued by FDA for mRNA-1273 was for patients aged 18 years or older.

Pregnancy was an exclusion criterion in the pivotal trials, and thus no participants who were known to be pregnant were admitted. Some patients became pregnant during the study and are being monitored for long-term outcomes. Immunocompromised patients were not included in the trials in enough numbers to make any meaningful conclusions regarding safety and efficacy in this important population. Both of these populations may be vaccinated when based on a discussion between an individual patient and their healthcare provider, overall benefits of a COVID-19 vaccine are deemed to exceed its risks. This is likely to be the case for pregnant women who are healthcare providers and otherwise would be recommended to receive vaccination.

6. For people who want to receive a COVID-19 vaccine, when can they expect to be vaccinated?

For the initial period when supplies of mRNA COVID-19 vaccines are expected to be limited, ACIP has provided recommendations regarding four distinct groups who should receive priority for vaccination. These ethical principles used to make this decision involved maximizing benefits and minimizing harms, promoting justice, mitigating health inequalities, and promoting transparency.

The four groups decided upon by the committee for inclusion in the first phase of vaccinations include the following: 1) health care personnel 2) other essential workers 3) adults with high-risk medical conditions 4) adults aged 65 years of age or older, including residents of long-term care facilities.⁵ Many of the initial vaccinations were given to health professionals, both because of the role in frontline care of patients and because the BNT162b2 required ultracold storage more commonly available in health systems.

Leaders in specific industries, such as the commercial airlines, are trying to persuade government officials that their workers are truly more essential than others such as food services, restaurant, or utilities. A possible scenario is for about 20 million people (health care personnel and long-term care residents) to receive the vaccine in December followed by about 140 million people (essential workers) in January through March 2021 with higher risk adults (age ≥65 and those with comorbidities) being vaccinated from March onward.

The U.S. government placed an initial order for 100 million doses of BNT162b2 in July 2020 and is currently negotiating with Pfizer to provide an additional 100 million doses in 2021. Through Operation Warp Speed, the U.S. government had already acquired 100 million doses from Moderna earlier this year but now has exercised its option to acquire an additional 100 million doses for about $1.68 billion, which would be enough to vaccinate 100 million people total because of the 2 doses required for full vaccination.

If non-mRNA vaccines are eventually authorized by the FDA, such as those by Astra Zeneca/University of Oxford and/or Janssen, these could help alleviate some of bottleneck with regards to prioritization of vaccine administration. Most patients should be vaccinated by summer 2021 assuming all goes well with currently approved therapies and others are eventually approved.

7. What are some of the major obstacles to successful widespread vaccination leading ultimately to normalcy?

A team effort will be required in order to vaccinate enough patients to result in herd immunity. While the scientists and staff have provided the vaccine and the FDA has authorized their emergency use, it will be the truck drivers, pilots, nurses, pharmacists, and pharmacy technicians who will ultimately help vaccinate patients.

Cold-chain logistics are critical with mRNA vaccines as they must be shipped and stored at freezing temperatures to maintain product viability. BNT162b2 has a shelf life of 15 days in thermal shippers followed by 6 months in ultra-low-temperature freezers (around –70° C). At refrigerated temperatures, the vaccine is viable for 5 days. On the other hand, mRNA-1273 is a bit easier from a storage standpoint, with stability of 6 months in a standard freezer and 30 days once refrigerated. Thorough planning will be the key to successful vaccination.

Adherence to vaccination is another important component of widespread vaccination. While one dose provides some immunity, widespread effective, high-level immunity is provided only by 2 doses either 3 weeks (BNT162b2) or 4 weeks (mRNA-1273) apart. ACIP has recommended a grace period of 4 days for the second dose of BNT162b2. Doses missed by the 21-day mark for BNT162b2 should still be administered “at earliest opportunity” .³

It is important to remember that vaccines do not save lives — only vaccinations do. The most important obstacle to vaccination may be the patients themselves. According to a Pew Research Center, approximately 63% of Americans would be willing to receive the COVID-19 vaccine, up from 50% in September. Some concerns include the rapid nature of the approval as well as the new technology of mRNA vaccines. Additionally, because these vaccines are new, long-term data on side effects must be accumulated. Continual education and strong recommendations from all healthcare providers involved are necessary to allay vaccine fears and ultimately encourage vaccination.

8. After vaccination, do people need to follow recommendations to maintain physical distances or wear a mask?

Yes. While the mRNA vaccines so far have been very efficacious, including preventing severe COVID-19, they aren’t 100% effective. It is also unclear if vaccination prevents SARS-CoV-2 transmission even if the vaccinated patient shows no symptoms. This is why it is important to encourage overall vaccination so that herd immunity occurs. This is believed to be when approximately 70% of the population have immunity from a vaccine or have recovered from their COVID-19 illness. Restrictions should loosen once these milestones are reached.

9. How much will a COVID-19 vaccine (including mRNA vaccines) cost per patient?

The U.S. federal government has stated that vaccines are “free” for any patient. However, that may not include an administrative fee, which is estimated to be $20–$40 per patient. In an October announcement, federal health officials promised that adults with traditional Medicare, private Medicare Advantage plan patients, or workplace and individual health insurance plans, and those covered under state Medicaid or children’s health insurance plans would have coverage including copays and deductibles when applicable. Additionally, uninsured patients receiving COVID-19 vaccines are covered via federal funding mechanisms.

10. How can pharmacists and pharmacy technicians play a role within the vaccination process?

Pharmacists remain near the top of the list of most respected professionals year after year in Gallup poll surveys. In a recent interview with CNN, Ashish K. Jha, Dean of Brown University School of Public Health, declared, “I think pharmacists are probably are most underutilized health professional. They are very well trained.… We have to make sure pharmacists and pharmacy technicians are part of this vaccination effort.” There are many roles that pharmacists and pharmacy technicians will and should play to make this a successful rollout of the mRNA vaccines (and others that should get approved).

The federal government has taken several actions to be sure pharmacists, pharmacy technicians, and student pharmacists (pharmacy interns) are not underused in the effort to vaccinate hundreds of millions of Americans. Pharmacies and pharmacists are especially critical partners given their accessibility, location (90% of Americans living within 5 miles of a pharmacy), and connection to the community.

Through Operation Warp Speed, the U.S. Department of Health and Human Services contracted with major and regional pharmacy chains and networks of independent pharmacies to expand the network of vaccinators involved in administering vaccines approved by FDA or available through EUAs. Three major pharmacy chains (CVS Health, Walgreens, Wal-Mart) have already committed to hiring a significant number of pharmacists and technicians to help provide manpower to ensure widespread vaccination. In an interview with the Wall Street Journal, CVS executive Chris Cox detailed their plan to hire 90,000 employees (30,000 pharmacists and 60,000 technicians) to provide vaccinations.

Additionally, CVS and Walgreens have a government contract to assist with vaccinations in 74,000 long-term care facilities. Through the Pharmacy Partnership for Long-Term Care Program for COVID-19 Vaccination, pharmacists and pharmacy technicians will actively deploy into these facilities on 3 separate clinic days/facility to ensure both doses are given as well as a make-up day for new admissions and those returning from other care sites.

Pharmacy professionals are very familiar with and serve as experts in the administration and storage of vaccines, including those requiring special temperature conditions. Therefore planning of vaccine schedules for patients including strategic signups will be critical, especially with the Pfizer/BioNTech vaccine, which has a short viability period of 5 days once refrigerated.

Finally, education regarding vaccine efficacy and side effects will be paramount as COVID-19 vaccines roll out. There will be many, many questions by patients as mRNA vaccines are novel. Concerns must be addressed for patients to want to receive their first dose and also return for the second dose, even if they experience common side effects from the vaccine.

References

1. Vaccines and Related Biological Products Advisory Committee Meeting. FDA Briefing Document. Pfizer-BioNTech COVID-19 Vaccine. December 10, 2020. Accessed December 14, 2020. https://www.fda.gov/media/144245/download
2. Vaccines and Related Biological Products Advisory Committee Meeting. FDA Briefing Document. Moderna COVID-19 Vaccine. December 17, 2020. Accessed December 16, 2020. https://www.fda.gov/media/144434/download
3. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020. December 10, 2020. doi: 10.1056/nejmoa2034577.
4. Cohn A, Mbaeyi S. What Clinicians Need to Know about the Pfizer-BioNTech COVID-19 vaccine. U.S. Centers for Disease Control and Prevention. U.S. Centers for Disease Control and Prevention. December 13, 2020. https://www.cdc.gov/vaccines/covid-19/downloads/pfizer-biontech-vaccine-what-Clinicians-need-to-know.pdf
5. McClung N, Chamberland M, Kinlaw K et al. The Advisory Committee on Immunization Practices’ ethical principles for allocating initial supplies of COVID-19 vaccine—United States, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(47).

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