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INTRODUCTION

While it is difficult to know for sure what will happen with coronavirus disease 2019 (COVID-19) over the long-term, more and more evidence suggests the United States is slowly shifting its overall strategies with regard to containment of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), progressing from pandemic to endemic status. California, often a bellwether state, has overtly moved into the “next phase of the pandemic,” revealing the SMARTER acronym to describe its new approach: Shots for 200,000 vaccine administrations per day, masks held in a stockpile, awareness, readiness, testing, education, and Rx treatments when illness occurs.

The effect of COVID-19 has been devastating in this country, with nearly 78 million cases and more than 900,000 deaths as of mid-February 2022. In addition, a significant number of cases have resulted in long-term effects, primarily neurologic in nature such as “brain fog,” but new data indicate possible long-term cardiac effects, even in people who were not hospitalized for COVID-19.¹

While essentially 100% of current SARS-CoV-2 isolates in the United States are now omicron variants, overall COVID-19 presentation has been milder than with the delta variant, marked by fewer intensive care unit admissions during the current surge. However, with increased transmissibility, the omicron variant sped through the population, frequently causing disease and overwhelming many emergency departments and hospitals because of the overall sheer number of cases. The good news is that omicron cases have peaked in many areas of the country, hospitalizations are decreasing, and deaths have leveled off and should decrease shortly based on the known lag between cases and hospitalizations/deaths. Two years into the COVID-19 pandemic, we are beginning to approach endemic status, and the country is hopefully beginning a transition to a new normal of learning to live with COVID-19.

This continuing education program focuses on transitioning to this endemic status along with notable updates regarding both COVID-19 vaccines and treatment options for symptomatic disease and high-risk patients.

TRANSITIONING FROM PANDEMIC TO ENDEMIC COVID-19

As with other respiratory viruses, including other coronaviruses, completely eradicating COVID-19 at this point is not likely. The various waves of this pandemic have demonstrated that, even with mass vaccination including boosters and widespread natural infections, “zero COVID” is not a feasible strategy. It is anyone’s educated guess at this time how long immunity endures after previous infection, vaccination, or both. Reservoirs of the virus in other countries with lower vaccination rates also makes eradication impossible. People have also transmitted SARS-CoV-2 to companion animals and other species in contact with people, and this creates reservoirs of the pathogen in homes, zoos, and wildlife sanctuaries; on farms; and in animals such as deer that have contact with people.²

Effective vaccines are now widely available, and a growing number of approved or authorized oral, intramuscular, subcutaneous, and intravenous therapies are useful for prophylaxis, postexposure treatment, and symptomatic infection management. It is therefore logical to move toward policies for establishing a reasonable strategy for living with COVID-19. Two overarching goals during this shift in strategies are to redefine the appropriate national risk level as well as rebuild trust with patients while simultaneously revamping or even overhauling current public health infrastructure.³

A challenge going forward is to determine appropriate risk thresholds for cases as well as hospitalizations and deaths. While thus far COVID-19 has essentially “squeezed” out cases of influenza for the past 2 seasons, that situation will not likely persist as COVID-19 cases decline and people stop wearing masks and practicing physical distancing. Thus, a reevaluation of the resources currently devoted to the pandemic — including testing, treatment, as well as availability of health system resources currently used or prioritized for patients with COVID-19 — is critical in long-term management of SARS-CoV-2 as an endemic pathogen. These discussions and decisions will most likely have to happen at local and regional levels, given the wide variability in disease presentation and spread of contagious viral illnesses among the states and parts of the country.

An up-to-date infrastructure is paramount for better managing the next pandemic threat, as it is “when” and not an “if” that will occur. Allocation of funding and resources toward improving public health data systems is a good start, but a critical mass of workforce is needed to ensure these resources are managed and executed appropriately. Examples of necessary resources include up-to-date, instantaneous compilation of all information related to an outbreak, such as cases, hospitalizations, and deaths along with monitoring of longer term sequalae, including symptoms from long COVID. Historical epidemiological data may be combined with novel approaches to disease monitoring, such as surveillance of wastewater for viral RNA or other components, that can provide a comprehensive picture of a pandemic on a continuous basis and create a system with a proactive rather than reactive posture for continuously managing communicable diseases, beyond the pandemic emergency state.³

Overall risk of severe disease from SARS-CoV-2 has been drastically decreased because of the availability of safe and effective vaccines, especially the 2 mRNA COVID-19 vaccines. This latest wave of infections caused by the omicron variant has demonstrated that even fully vaccinated individuals are susceptible to breakthrough infections, but their risk of severe disease as manifested by hospitalization and death is much less than for the unvaccinated individual, especially among fully vaccinated people who also received booster vaccinations.⁴

Messaging to the general public regarding the value of vaccination in protection against omicron has been mixed at best and often incomplete. Future health promotions efforts targeting COVID-19 vaccination education should emphasize the tremendous benefit of vaccination for decreasing severe disease rather than focusing on decreasing overall cases. In addition, laboratory testing strategies should be maximized, allowing for early identification of cases by patients with widespread in-home testing that is sensitive and specific for SARS-CoV-2. This allows for treatment to be initiated as soon as possible with proven, safe therapies such as nirmatrelvir/ritonavir (Paxlovid, Pfizer) or sotrovimab that can further decrease the risk of severe disease manifestations, particularly when used in the early phase of SARS-CoV-2 infections.

Rebuilding public health trust is critical. In this era of social media and the internet, misinformation is rapidly and rampantly propagated through a number of media, platforms, and influential individuals. At times, U.S. regulatory bodies have provided mixed messaging with regard to COVID-19, especially in recommendations for vaccines and masking; these have confused and frustrated people who were trying to take the best actions for avoiding SARS-CoV-2. In addition, nearly every citizen is weary from the pandemic and looking for respite from the many requirements that most have honored during the pandemic. At time of this article, a growing number of states were announcing plans to roll back requirements for masking in indoor venues, including schools in some places. Some locations may elect or be required to continue masking, such as schools, hospitals and health facilities, or public transit. Many of these changes began in states in the Northeast where requirements have been the strictest, such as New York. In addition, a number of major metropolitan areas, such as Chicago, were dropping the requirement for proof of full vaccination in restaurants and other indoor locations. The major airlines have asked the Biden administration to drop COVID testing requirements prior to international flights to further boost global travel. These and other measures, along with education on the benefits of vaccinations and availability of safe and effective COVID-19 treatments, will be key in the transition from pandemic to endemic status of COVID-19.

MODERNA’S VACCINE TRANSITIONS FROM AUTHORIZED TO APPROVED

On January 31, 2022, Moderna’s mRNA vaccine, which has the tradename Spikevax, received full approval from the U.S. Food and Drug Administration (FDA) for the prevention of COVID-19. This approval is for the primary 2-dose series given 1 month apart in patients 18 years of age and older.

Pfizer’s mRNA vaccine (Comirnaty) was approved by FDA last year as a 2-dose series 3 weeks apart in patients 16 years of age and older. The Pfizer vaccine also has emergency use authorizations (EUAs) permitting use in children age 5 to 15 years of age. Other EUAs for the COVID-19 vaccines remain intact, including heterologous (mix and match) administration of booster doses.

To date, the only COVID-19 treatment option that has received full FDA approval is remdesivir (Veklury). Other treatments are available under EUAs.

NOVAVAX SUBMITS EUA REQUEST FOR FDA FOR NANOPARTICLE COVID-19 VACCINE

After a longer-than-anticipated timeframe, Novavax requested in late January that FDA approve an EUA for its COVID-19 vaccine candidate in patients 18 years of age or older. The vaccine is administered as a 2-dose series 3 weeks apart, similar to Comirnaty. The vaccine candidate is currently named NVX-CoV2373 and is different from currently authorized or approved vaccines. This protein-based vaccine uses the Novavax recombinant nanoparticle technology to deliver nanoparticles containing antigen derived from the coronavirus spike (S) protein based on the genetic sequence of the original (wild type) SARS-CoV-2 from the beginning of the pandemic. It is formulated with the company’s saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies.

Results of a phase 3 trial of NVX-CoV2373 (PREVENT-19) was recently published in the New England Journal of Medicine. NVX-CoV2373 was tested in nearly 30,000 patients from December 2020 until February 2021 in the United States and Mexico. The vaccine efficacy was 90.4% (95% CI 82.9–94.6; P <0.001) compared with placebo. With no moderate or severe cases occurring in the treatment arm of this trial, the vaccine efficacy was 100% for protection against COVID-19 of that severity. Adverse effects were generally mild, typically occurred more often after the second dose, and were short lasting (<24 hours). Of note, because of the timing of this study, no delta or omicron strains were isolated among participants, meaning more data will be needed to assess its vaccine efficacy against these variant strains.⁵

Similar findings were also found in a clinical trial of NVX-CoV2373 completed in participants in the United Kingdom.⁶

A study that is not yet peer reviewed found that a booster dose of NVX-CoV2373 approximately 6 months after primary series resulted in increased reactogenicity for both the parent strain and all variants evaluated, including delta and omicron.⁷ More data are needed regarding the vaccine’s effect on patient outcomes, specifically severe outcomes resulting in hospitalization and death, as these have been a strong point for the mRNA vaccines.

WAITING PERIODS ENDED FOR COVID-19 VACCINES AFTER MONOCLONAL ANTIBODY ADMINISTRATION

The CDC has revised its guidance on the timing of vaccines after monoclonal antibody administration. Previously COVID-19 vaccines were deferred for 30 days if the antibody was administered for postexposure prophylaxis and 90 days if the antibody was used for COVID-19 treatment. Now, there is no deferral period — COVID-19 vaccines can be administered immediately except for 1 specific product, as discussed below.

This change was made for a number of reasons. First, antibody response, while lower in patients who received monoclonal antibodies, was still considered high. There also was no correlation between timeframe between COVID-19 vaccination and neutralizing antibody titers in patients receiving monoclonal therapies.⁸

This new recommendation makes it easier to vaccinate as many patients as possible and thereby decrease the overall risk of infection and most importantly hospitalization and death when breakthrough infections occur. The exception is for administration of tixagevimab/cilgavimab, which should be deferred for 2 or more weeks after COVID-19 vaccination. This product, available under the trade name Evusheld (AstraZeneca), is used in adolescents and adults who are not currently infected with and have no known exposure to SARS-CoV-2 and either have moderate-to-severe immunocompromise or are not able to receive COVID-19 vaccines because of a history of severe adverse reactions or prior adverse reactions to COVID-19 vaccines or their components.

PFIZER/BIONTECH SUBMIT AMENDMENT TO EUA FOR CHILDREN YOUNGER THAN 5 YEARS OF AGE

Pfizer and BioNTech on February 1, 2022, initiated a rolling submission requesting extension of the currently authorized EUA to include children 6 months of age through 4 years of age. The application was for 2 doses of 3 µg/dose in a planned 3-dose series, with the assumption a submission for approval of the third dose would follow after data become available in late March 2022. After scheduling an advisory committee meeting to review this rolling submission, FDA precipitously postponed that meeting. The reasons for that delay and any implications they might have for emergency authorization for use of this vaccine in young children were not immediately apparent.

Currently, a 2-dose series of 10 µg/dose is authorized for children 5–11 years of age, and a 2-dose series of 30 µg/dose is authorized for those 12–15 years of age. Data for the third dose in the 6 month to 4 year olds will continue to be compiled and included with a new EUA application. If approved by FDA, this would be the first authorization of a COVID-19 vaccine in this age group.

NEW OMICRON VARIANT EMERGING?

Some news outlets have reported identification and spread of an omicron variant known as BA.2. It remained under investigation at the time this program was finalized. BA.2 has been called by some the “stealth” variant, as it is difficult to distinguish from other circulating variants, such as delta, using currently available polymerase chain reaction tests.

Early reports showed a 120% increase in growth over the current omicron variant, indicating greater transmissibility. However, this is much less than the nearly 500% growth advantage of omicron over the delta strain. Currently, BA.2 makes up approximately 4% of isolates in the United States, with the rest belonging to the omicron B.1.1.529 strain. The stealth omicron variant could spread somewhat more efficiently that the currently dominant omicron strain, but it is too early to tell what clinical effects, especially on severity of disease, may result if it becomes the dominant strain.

MONOCLONAL ANTIBODIES IN USE AND ON THE HORIZON

A pair of monoclonal antibodies with activity against the omicron variant are now available under EUAs in the United States.

The most recently approved EUA was for Lilly’s bebtelovimab, which has neutralization activity against the omicron variant. Bebtelovimab can be used for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age or older and weighing at least 40 kg) with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progression to severe COVID-19, including hospitalization or death, and for whom alternative COVID-19 treatment options approved or authorized by FDA are not accessible or clinically appropriate. The authorized dose of bebtelovimab is 175 mg given as an intravenous (IV) injection over at least 30 seconds.

Also available for IV administration is sotrovimab, which is authorized by the FDA for the treatment of COVID-19 and has activity against the omicron variant. However, for these and other monoclonal antibody therapies that are administered by IV injection, significant logistical considerations as well as more time required for administration and monitoring make this a less-than-optimal approach. In addition, there are concerns that sotrovimab may have significantly diminished activity against the newest BA.2 omicron variant.

The recently updated COMET-TAIL phase 3 trial (not yet published) evaluated intramuscular (IM) versus IV sotrovimab for early treatment of mild-to-moderate COVID-19 in high-risk ambulatory adults as well as those 12 years of age or older. Participants in both arms of the trial received a 500-mg dose of sotrovimab. The primary endpoint was hospitalization for 24 hours or more or death through day 29 of the study. According to a GlaxoSmithKline media and investor advisory, the composite endpoint was reached in 2.7% of participants receiving IM sotrovimab and 1.3% for IV sotrovimab, with a 1.07% adjusted difference in outcome, which was within the predetermined 3.5% noninferiority margin set in consultation with the FDA (95% CI –1.25% to 3.39%). Both routes of administration were well tolerated, with grade 3 or 4 adverse events occurring in 1% of participants or less.

Authorization of an IM dosage form for sotrovimab would allow for easier and therefore more widespread administration of this therapy, assuming that supply chain demands can be met nationwide. With the omicron variant (B.1.1.529) beginning to wane across many geographical areas in the United States, continued vigilance and monitoring of usage of sotrovimab, bebtelovimab, and other monoclonal antibodies is important to determine appropriateness of treatments, especially as variants continue to mutate and potentially limit the utility of these therapies.

DOES PREVIOUS COVID-19 INFECTION PROVIDE PROTECTION AGAINST THE OMICRON VARIANT?

People previously infected with SARS-CoV-2 have demonstrated protection against reinfection for a number of strains, including the alpha, beta, and delta variants. However, the omicron variant has demonstrated significant immune escape properties, resulting in breakthrough cases, even in fully vaccinated patients.

A recent publication in the New England Journal of Medicine evaluated effectiveness of previous COVID-19 infection in preventing symptomatic new SARS-CoV-2 infection among a number of variants, including omicron. Previous infection with SARS-CoV-2 was associated with an approximately 90% effectiveness in preventing subsequent infection among the alpha, beta, and delta variants. However, for the omicron variant, the effectiveness dropped significantly to 56%, with sensitivity analyses confirming results. Severe COVID-19 illness occurred infrequently in the reinfected patients, with none progressing to critical illness or death.

There are several notable characteristics of this data set. First, the population studied was in Qatar, which has an extremely high vaccination rate. Second, only 9% of its residents are 50 years of age or older, which greatly decreases the proportion of the population that has had severe disease.⁹ While these data are reassuring, the recommendation is for all people to get vaccinated, including those previously infected with SARS-CoV-2, to best protect against severe COVID-19 manifestations.

PHARMACY KEY IN SHIFT FROM PANDEMIC TO ENDEMIC COVID-19

In conclusion, pharmacists and pharmacy technicians across all disciplines and practice settings have been and will continue to be critical in management of COVID-19, and they will be important in the transition to endemic status. Pharmacists are year in and year out near the top of most trusted professionals in the United States, and pharmacy professionals and staff have played a vital role during the pandemic by educating, vaccinating, and providing treatment recommendations to patients and other health care providers. Hopefully, we are heading toward some relief for all health care providers, including pharmacists and pharmacy technicians, as COVID-19 shifts to endemic status.

REFERENCES

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