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INTRODUCTION

Coronavirus disease 2019 (COVID-19) continues to be a significant cause of morbidity and mortality in the United States. Nearly 30 million cases and 500,000 deaths have occurred, and some patients are experiencing “long-term COVID” — symptoms of shortness of breath, fatigue, and joint pain long after convalescence from the initial infection. In addition, several variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are circulating worldwide and have made their way into the United States. Limited data on current vaccines authorized or seeking authorization indicate decreases efficacy against these strains.

As of February 2021, 2 mRNA vaccines have received emergency use authorizations (EUAs) for use in the United States: the Pfizer/BioNTech vaccine, BNT162b2, and the Moderna vaccine, mRNA-1273. Several other candidates — including those from Johnson & Johnson, Novavax, and Astra Zeneca/Oxford — will likely seek approval in the coming months. The single-dose Johnson & Johnson candidate, known as JNJ-78436735 or Ad26.COV2.S, goes before the FDA Vaccines and Related Biological Products Advisory Committee on February 26, and an EUA is expected soon thereafter.

This continuing education program provides an in-depth update on the current state of authorized vaccines, other viable vaccine candidates, and how these vaccines work against currently circulating variants.

CURRENT EXPERIENCES WITH MESSENGER RNA VACCINES

Because of many significant logistical challenges, the initial rollout of vaccines did not go as hoped. This was primarily due to lack of coordinated efforts between the federal government and individual states, leading to confusion and inability to vaccinate patients in a timely fashion. While the U.S. Centers for Disease Control and Prevention (CDC) has issued recommendations concerning which people should be prioritized for vaccine administration, individual states establish their own criteria and distribution strategies. Most states initially prioritized health care workers and residents of long-term care facilities, and now jurisdictions are vaccinating people based primarily on age and comorbidities. From the state level to ultimate vaccination, much of the responsibility has been delegated to individual hospitals, clinics, and local public-health government agencies. A state-by-state guide has been published to help determine best way to obtain information leading to a vaccine.

The federal government had a goal of 20 million vaccinations to be completed by end of 2020, but at the end of the year, only about 3 million Americans had received vaccinations even though 14 million vaccine doses had been shipped to the states by Pfizer and Moderna. West Virginia was a standout exception; by early February 2021, nearly 10% of all West Virginians have received at least 1 dose of an mRNA vaccine, and the state led the country with number of patients who have received second doses and in percentage of doses administered (83%). While the federal government partnered with CVS and Walgreens to handle vaccinations at long-term care facilities, states such as West Virginia and North Dakota chose to use locally owned independent pharmacies and were able to achieve a well-executed rollout.

Solutions to logistical challenges, while not perfect, have significantly improved. More than 50 million mRNA vaccinations have taken place in the United States, with a slightly higher percentage of patients vaccinated with the Pfizer vaccine compared to Moderna. Much of this recent success can be attributed to pharmacists, pharmacy technicians, and pharmacy interns who have significantly increased the number of vaccinations provided at local chains such as CVS, Walgreens, and Kroger. Their experience with other vaccinations, such as those for influenza and shingles, along with easy accessibility of pharmacies to the vast majority of Americans, positions the profession well to help end the pandemic through successful vaccinations. CVS states that it can vaccinate 20 to 25 million people monthly once supplies are obtained. Walmart in early 2021 stated it could vaccinate 10 to 13 million patients monthly. This can be accomplished through online scheduling tools capable of handling a large influx of appointment requests. Concerns over overwhelming pharmacy staff with vaccinations on top of other normal duties have led to some chains working to hire additional staff. Walgreens has stated it plans to hire an additional 25,000 staff nationally to provide vaccines and help alleviate the bottleneck on other pharmacy activities.

The Biden administration had set a goal of 1 million vaccinations per day for the first 100 days of their tenure, and that is already being met or exceeded. In addition, the administration has secured further deals with Pfizer/BioNTech and Moderna to acquire an additional 100 million doses of each product. This increased supply of 50% ensures availability of 600 million doses by end of July 2021, enough to fully vaccinate 300 million Americans. While approximately 260 million people are believed to be eligible for vaccination, current trials enrolling children as young as 12 could allow more children to be vaccinated. In addition, Novartis has signed an agreement with Pfizer/BioNTech to provide manufacturing capacity for that mRNA vaccine, which will boost production and avoid the risk of running out of the product.

Some pharmacy businesses are working creatively to try and meet early demand. While some pharmacies are using online scheduling, others are providing wait lists in case of an open opportunity for vaccination. Others, such as Hy-Vee Inc., are working with a local universities to set up mass vaccinations in large facilities. They also plan to use greenhouses to ensure temperature stability for larger groups. In addition, Hy-Vee plans to deploy recreational vehicles to help immunize staff when it goes to manufacturing plants.

While the pharmacist job market has been saturated over the last several years, pharmacists and pharmacy technicians are in demand from various companies to try to meet vaccination goals. Compared with 2020, pharmacy job listings are up 35%, including positions available with major chains and independent pharmacies. In addition to more job openings, 5-figure sign-on bonuses for pharmacists of up to $20,000 are being offered in some areas of the country. Pharmacy interns are also benefitting since they are trained to provide vaccines, earning significant pay. The COVID-19 pandemic is demonstrating pharmacists’ and pharmacy technicians’ skills and value to the public as they work the frontlines to help end the pandemic.

VACCINE HESITANCY

It is unprecedented what scientists and vaccine companies have accomplished in the last 12 months, developing not 1 but 2 mRNA vaccines and conducting the clinical research needed for obtaining EUAs from the FDA. While this is a remarkable feat, vaccines must lead to vaccinations in order for the COVID-19 pandemic to end.

A recent Morbidity and Mortality Weekly Report (MMWR) provided some good news with regards to American’s intent to receive a COVID-19 vaccine. From September to December 2020, the percentage of Americans who said they were “very likely” or “absolutely certain” to receive the vaccine rose from 39% to 49%. This was most pronounced in the older adult (65 years or older) demographic, increasing from 49% to 66%. Essential workers who intended to get vaccinated also increased, from 37% to 46%. Black people were most likely to state they did not intend to get vaccinated (down from 56% to 47%). Other groups that were more likely to report not getting vaccinated were those without insurance, adults in nonmetropolitan areas, those with lower educational levels or lower incomes, and younger adults. Overall, in the 18–64-year-old age group, about half of respondents said they would ultimately be vaccinated.¹

A January 2021 U.S. Census Bureau survey revealed approximately 51% of Americans definitely will get the vaccine, while 26% state they “probably will,” 14% state the probably will not, and 10% stating they definitely will not. The most common reasons for considering not vaccination included side effect concerns, planning to wait for more data, and allowing other people who are higher risk to receive their doses first. Most studies and experts believe that in order for true population herd immunity to occur, between 70% to 80% of the population must develop immunity, making every vaccine critical to achieve this overarching goal. COVID-19 vaccinations in general would be more likely to occur if health care providers stated the products are safe, no out-of-pocket costs were incurred, people could get back to school or work safely and quickly, and the vaccine was easily obtainable.

Vaccine hesitancy is not an issue solely among patients; it is all too common among health professionals as well. As of October 2020, an American Nursing Foundation survey showed that 63% of nurses were somewhat or very confident that the vaccine would be safe and effective. Only 34% would voluntarily receive the vaccine, and about half of those surveyed would be comfortable discussing COVID-19 vaccines with potential recipients. Nearly 70% of staff at a hospital in Florida refused the vaccine, which led to a high number of unused vaccine doses that were diverted for administration to the general public. Nearly 30% of health care workers in a Kaiser Permanente survey stated they want to “wait and see” how the vaccine is working for other people before getting it themselves. All of these survey results are giving public health officials concern as many patients look to health professionals for guidance when deciding whether to get vaccinated.

Establishing vaccine confidence is critical to encourage successful COVID-19 vaccinations. Given pharmacy’s role in the immunization neighborhood, pharmacists and pharmacy technicians have important roles to play in this process. Vaccine confidence is defined as the trust that patients, parents, or providers have in the following: 1) recommended vaccines; 2) providers who administer vaccines; and 3) processes and policies that lead to vaccine development, licensure, manufacturing, and recommendations for use. Three primary strategies for vaccinating with confidence have been advocated by the CDC. These included building trust, engaging communities and individuals, and empowering health care personnel. Trust is built by sharing clear, complete, and truthful messages about COVID-19 vaccines and taking visible and demonstrable actions to build trust in the COVID-19 vaccine, vaccinator, and system, including all stakeholders at each level of government. Communities should be engaged in a sustainable, equitable, and inclusive manner. This is accomplished through increased collaboration and listening to concerns from those who are vaccine hesitant.

To empower health care personnel, several different tactics should be employed. First, professional organizations, associations, health systems, and health-system personnel should be engaged early and often to ensure a clear understanding of vaccine development and approval, newer vaccine technologies (e.g., mRNA), and vaccine benefits. In addition, health systems and medical practices should be equipped to create a culture through leadership that builds confidence in COVID-19 vaccination. Motivational interview training techniques when needed are great tools to increase empathic vaccine conversations, address myths and common questions, and provide tailored vaccine information to patients based on various socioeconomic populations.

Patients have questions about the COVID-19 vaccines and myths that are circulating about their efficacy and safety. Listed below are common questions and information to help address them.

Is it safe to receive a COVID-19 vaccine if I have allergies? Most patients with allergies can safely receive the COVID-19 vaccine. The CDC recommends that people with a history of severe allergic reaction not related to vaccines or injectable medications — such as to foods, pets, or latex — should be vaccinated. People with a history of allergies to oral medications or a family history of allergic reactions (including severe) are eligible for COVID-19 vaccination. People who have had immediate allergic reactions to other vaccines or injectable therapies should discuss with their physician if they should receive the mRNA vaccine.

Do the mRNA vaccines have a high risk of allergic reactions, including severe ones? A recent report from the CDC in MMWR evaluated reports to the Vaccine Adverse Event Reporting System (VAERS) for anaphylaxis to the Moderna vaccine over a 3-week period. Ten cases of anaphylaxis were reported with 4,041,396 first doses (2.5 cases per million doses administered). In addition, a similar report found that the Pfizer COVID-19 vaccine had a rate of 11.1 cases per million first doses.²

A recently published report in JAMA evaluated both mRNA vaccines. Data from VAERS demonstrated that the reported cases of anaphylaxis were 4.7 and 2.5 per million doses administered for the Pfizer/BioNTech and Moderna vaccines, respectively. This analysis included more than 17 million doses and revealed that the median time to onset was 10 minutes; 89% of anaphylaxis cases occurred within 30 minutes of administration. Patients with any history of anaphylaxis or severe allergic reaction to a previous vaccine or injectable therapy should be monitored for 30 minutes after the initial dose, as this will capture nearly everyone at risk for anaphylaxis. All other patients can be monitored for 15 minutes after receiving their first dose. Of note, nearly every case of anaphylaxis reported in the JAMA study (94% and 100% of Pfizer/BioNTech and Moderna, respectively) occurred in women. More studies are ongoing to determine etiology of these reactions.³

People who are allergic to polyethylene glycol (PEG) or polysorbate should not receive either mRNA COVID-19 vaccine. People who have any immediate allergic reaction to their first mRNA COVID-19 vaccine dose should not receive the second dose.

An interesting local reaction has been observed with the Moderna vaccine consisting of itching, erythema, edema, and swelling. These sometimes large, local reactions can appear late (>5 days after injection) and can last up to several weeks. Treatment is symptomatic, consisting of ice, acetaminophen or nonsteroidal anti-inflammatory drugs, and possibly antihistamines. This reaction is not considered harmful and demonstrates a response to the vaccine. Patients experiencing this reaction should receive their second injection but may want to rotate sites to the other arm. A number of consumers are referring to this reaction as “COVID arm,” and photographs are rampant across various social media outlets.

I am currently pregnant but considering an mRNA vaccine. Should I receive one? The EUAs by the FDA for both the Pfizer-BioNTech and Moderna mRNA vaccines indicate that data are currently insufficient to explicitly recommend mRNA vaccines for pregnant women, as neither agent was strategically studied in this population. Data from the Developmental and Reproductive Toxicity animal studies for the Pfizer-BioNTech vaccine do not indicate damage to the mother or fetus. A number of patients were discovered to be pregnant after receiving an mRNA vaccines. Long-term data in this population will be key to determining long-term safety, as there is a strong possibility that a yearly COVID-19 vaccine may be required similar to annual influenza vaccination. Pfizer/BioNTech have started a 4,000-participant study of the safety, tolerability, and immunogenicity of BNT162b2 in preventing COVID-19 in healthy pregnant women 18 years of age and older.

Until then, the American College of Obstetricians and Gynecologists recommends that pregnant women should not be prevented from receiving COVID-19 vaccines as long as they meet criteria for vaccination based on priority groups recommended by the CDC’s Advisory Committee on Immunization Practices. A discussion between the pregnant woman and her health care team is encouraged but not required prior to vaccination.

I am concerned that this whole vaccine approval process for the mRNA viruses was rushed. Didn’t this authorization happen fast compared to other vaccines? There are a number of reasons that this appears like an overly quick process, but once all components are evaluated and explained, patients can hopefully be put at ease. The overarching reason for the rapid development and testing of these vaccines is that due to the nature of the COVID-19 pandemic, it was the first and most important priority for the FDA, CDC, and many researchers. This culminated in Operation Warp Speed, which brought stakeholders from the government and private industry together to accomplish these goals together.

The process began with researchers using existing clinical trial networks to conduct trials on COVID-19 vaccine candidates. While clinical trials were ongoing, manufacturers were already generating product with the intent that if approved, these vaccines would be ready to ship and administer. The government funded at-risk, large-scale manufacturing of the most promising vaccine candidates during phase 3 clinical trials to ensure this availability.

While this is first successful use of mRNA technology for vaccines, the underlying science has been studied for a decade, often in cancer therapies. In addition, mRNA vaccines are much easier to produce in large quantities compared to traditional vaccine candidates such as the influenza vaccine.

It is also important to point out that the FDA and CDC are prioritizing review, recommendation, and ultimately authorization of all COVID-19 vaccines. These vaccines are authorized through EUAs but not fully approved by FDA, as intensive monitoring is currently under way to ensure both safety and efficacy of the products. There are known, serious risks of COVID-19 diseases including hospitalization and death, justifying the vaccines’ availability through the EUA process.

The safety of mRNA vaccines, which had been administered to more than 50 million Americans at the time this program was prepared, are well tolerated, with tolerable adverse effects such as arm soreness, fever, chills, and fatigue. As more and more vaccines are administered, any rare events or long-term trends will be quickly investigated to determine whether they are related to 1 or more of the COVID-19 vaccines.

UPDATES ON THE JOHNSON & JOHNSON COVID-19 VACCINE CANDIDATE

Janssen Biotech Inc. (subsidiary of Johnson & Johnson) has a COVID-19 vaccine candidate known as JNJ78436735 or Ad26.COV2.S. This vaccine candidate is an adenovirus-based vaccine — essentially double-stranded DNA placed inside Adenovirus 26, which enters a host cell after inoculation but cannot replicate or cause disease. These adenoviruses travel to the nucleus of the cell, where the DNA is transcribed to produce mRNA. The mRNA leaves the nucleus and is translated in the cytoplasm to yield viral spike proteins. After assembly, these proteins migrate to the surface and are recognized by the immune system — similar to the process used by mRNA vaccines — eventually providing immunity through a number of mechanisms.

This candidate could be a significant game changer for several reasons. First, because it is a DNA and not an RNA vaccine, it can be refrigerated for up to 3 months safely, which would allow for significant distribution to a wider number of areas and locations in comparison with the freezer requirements for long-term storage of the mRNA vaccines. Second, it is being studied as a single dose, which would facilitate administration to a larger number of people, avoid the challenges of recalling people for second doses, and freeing up the time of health professionals to vaccinate other people. Third, a non-mRNA vaccine option might be acceptable to people who are hesitant about the Pfizer/BioNTech and Moderna vaccines because they use a novel vaccine platform.

Janssen Biotech recently announced the overarching results from their studies. The single-dose vaccine was 66% effective at protecting patients from moderate-to-severe disease across 43,783 participants 18 years and older. There was significant variability among different regions ranging from 57% efficacy in South Africa to 72% in the United States. Most importantly, the product was 85% effective in protecting against severe disease, with no hospitalizations or deaths in the vaccine arm of the trial. Based on these data, Ad26.COV2.S will go before the FDA Vaccine and Related Biological Products Advisory Committee on February 26, 2021, and FDA is likely to issue an EUA soon thereafter. Delivery of 100 million to the U.S. government is required by June 2021, but at the time this program was prepared, news reports centered on later rather than earlier delivery of this product and on possibly altering its composition to address variant SARS-CoV-1 strains emerging around the world.

UPDATES ON THE NOVAVAX VACCINE CANDIDATE

Novavax, which has been supported by the federal government’s Operation Warp Speed, recently announced initial results from a British trial. The vaccine candidate (NVX-CoV2373) works differently from the products discussed previously. A modified gene for the viral spike protein is inserted into a baculovirus, which is allowed to infect moth cells. The cells produce spike proteins, which are harvested and formulated into nanoparticles resembling the COVID-19 structure. These spike nanoparticles and an immune-enhancing compound extracted from the soapbark tree are injected into the patient, ultimately leading to immunity through a number of mechanisms. Thus, this product is similar to influenza, human papillomavirus, and other older vaccines in that it works by presenting antigenic viral proteins to the host but different in the way the proteins are produced and formulated.

In initial trial results, the overall efficacy of NVX-CoV2373 was 89.3%, similar to mRNA vaccines. However, efficacy was much lower in the South African patient population — 49.4% — likely because of mutated variants of SARS-CoV-2 circulating in that country at the time of the study. More data across 100 sites and 30,000 total patients are being evaluated for eventual presentation to FDA. Current estimates are that Novavax will not request an EUA until late April 2021.

Having a novel vaccine candidate that works through protein as opposed to adenovirus vector (Janssen) or mRNA technology (Pfizer/BioNTech or Moderna) will provide an additional option for COVID-19 immunizations and would help alleviate any potential supply/demand bottleneck that might occur with more acceptance of COVID-19 vaccinations and expansion of the immunization program into other parts of the world.

VACCINES AND SARS-COV-2 VARIANTS

A number of SARS-CoV-2 variants have been identified in the United States and internationally that are causing concern and worth monitoring. The 3 variants currently of most concern are the following: B.1.1.7 or 501Y.V1, first identified in the United Kingdom; B.1.351 or 501Y.V2, identified in South Africa; and P.1 or 501Y.V3, identified in Brazil. Emerging variant cases in the United States are tracked on a CDC website, which stood at more than 1,500 cases in nearly every state when this program was prepared in late February 2021. Each variant consists of nearly 10 spike protein mutations and are rapidly becoming dominant strains in a number of geographic areas.

The B.1.1.7 strain has an established increased transmissibility (~40%) compared with the parent strain but does not demonstrate immune escape or evade the current mRNA vaccines. Post hoc analysis demonstrates a slight drop-off of the Novavax candidate versus the B.1.1.7 variant. While the South African and Brazil variants have not yet been demonstrated to be more transmissible, they have sufficient antigenic drift to reduce effectiveness of the Novavax and Janssen vaccines in trials conducted in those geographic areas, especially the South African variant. Data are unclear currently on how efficacious the mRNA vaccines are versus the South African variant, but initial data on 26 patients suggests greater levels of antibodies needed for neutralization with the Pfizer/BioNTech vaccine.

What are the implications of the emergence of these SARS-CoV-2 variants? First, only the B.1.1.7 strain has demonstrated increased transmissibility. Second, scant evidence suggests that these variants cause increased COVID-19 disease severity including mortality. In fact, based on data from the more than 70,000 participants who received active vaccine in the Moderna, Pfizer/BioNTech, Novavax, and Janssen studies, not 1 patient was hospitalized for COVID-19, died from COVID-19, or died from administration of the vaccine. This is an important message to deliver to the public in order to demonstrate that the most important outcomes are best met through mass vaccination leading to herd immunity. The alternative – letting the virus run its course through the population — will only result in more morbidity and mortality, and viral mutations will increase the likelihood of COVID-19 becoming an endemic disease in much or all of the world. Third, mRNA technology allows tweaking and modifying the current vaccines in order to better cover for these variants, similar to what is done to maximize coverage versus different strains of influenza. According to Kizzmekia Corbett, PhD, scientific lead for the Coronavirus Vaccine Program at the National Institutes of Health, it is possible to replace a sequence of mRNA in a vaccine for another in just a matter of weeks. This would allow a booster dose to be ready for distribution in the fall if the South African strain became the dominant strain in the United States.

Mass vaccination efforts are the key to ultimately ending this pandemic, even if variants become the dominant strains across the United States. Maximizing successful vaccinations of all authorized vaccines will be critical. Involvement and strong support of health professionals —in particular pharmacists, pharmacy technicians, and pharmacy interns —are vital to ensure vaccinations happen with minimal friction as possible to encourage patients to make the decision to vaccinate.

REFERENCES

1. Nguyen KH, Srivastav A, Razzaghi H, et al. COVID-19 vaccination intent, perceptions, and reasons for not vaccinating among groups prioritized for early vaccination — United States, September and December 2020. MMWR Morb Mortal Wkly Rep. 2021;70:217–222. doi: http://dx.doi.org/10.15585/mmwr.mm7006e3
2. CDC COVID-19 Response Team, Food and Drug Administration. Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine — United States, December 21, 2020–January 10, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(4):125–129. doi: http://dx.doi.org/10.15585/mmwr.mm7004e1
3. Shimabukuro TT, Cole M, Su JR. Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14,2020–January 18, 2021. JAMA. Published online February 12, 2021. doi: 10.1001/jama.2021.1967.

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