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INTRODUCTION

Significant progress has been made in the effort to minimize the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the disease it causes, coronavirus disease 2019 (COVID-19). Three vaccines are approved or authorized by the U.S. Food and Drug Administration (FDA) based on their safety and efficacy against COVID-19 disease, especially severe disease as defined by hospitalization, intensive care, need for mechanical ventilation, and/or death. Several FDA-authorized treatment modalities, including oral and intravenous therapies, reduce the risk of hospitalization and death in patients with COVID-19 who are at high risk of complications, most of whom have not been vaccinated.

These factors, combined with the high transmissibility of various waves of SARS-CoV-2, including most recently omicron and other emerging variants, have resulted in a significant “wall of immunity” 2+ years after the pandemic began. Attention is now shifting to long-term strategies of how to live with COVID-19 as an endemic disease in the United States and most likely the rest of the world. Dr. Anthony Fauci, chief medical advisor to the Biden administration, said this in early April about COVID-19: “It’s going to be a person’s decision about the individual risks they’re going to take” as “this is not going to be eradicated and it’s not going to be eliminated.”

This continuing education program focuses on updates related to recent developments regarding COVID-19 including the current predominant variant (BA.2) as well as SARS-CoV-2 vaccines and treatments.

WHAT TO DO WITH BA.2?

BA.2 has now become the dominant SARS-CoV-2 strain in most geographical regions of the world, including the United States. An omicron subvariant, BA.2 accounts for nearly 75% of currently circulating variants (as of the second week of April 2022) with the remainder BA.1.1 and B.1.1.529. It comes from the same ancestor strain as the BA.1 omicron variant which had significantly more transmissibility than previous strains, such as delta, but fortunately less severe disease including pneumonia. BA.2 contains 8 unique mutations in the spike protein compared to the previous omicron subvariant, BA.1. While data are still being gathered, it does not appear that BA.2 has any increased risk of severe disease compared to the more recent omicron variant despite its likely enhanced ability to infect.

In much of February and March 2022, BA.2 was responsible for increasing numbers of cases with some increase in hospitalizations as well. Previous waves of SARS-CoV-2 infection that occurred in Europe typically have preceded increased cases and morbidity several weeks later in the United States. The percentage of U.S. cases caused by BA.2 did occur,, but thus far, cases have not increased. This could be the result of a number of factors. First, the availability of in-home testing likely has decreased the number of cases that are being officially reported to state and federal tracking agencies.¹ Every home in the United States continues to be eligible to order 2 sets of 4 at-home tests for delivery by the U.S. Postal Service. Second, previous COVID-19 infections combined with full vaccination (with or without boosters) have led to preserved T-cell immunity and B-cell memory, which could be lessening the number and impact of BA.2 infections.^2,3 Time will tell how large the increase in BA.2 cases will be, but early data indicate that this wave will be nothing like previous ones caused by earlier variants.

SECOND BOOSTER SHOT AUTHORIZED

On March 29, 2022, FDA authorized a second booster dose of either mRNA vaccine (Pfizer/BioNTech or Moderna) for specific populations and with caveats. First, any individual 50 years of age and older may receive a booster dose of either the Pfizer or Moderna vaccine after receiving any authorized or approved COVID-19 vaccine. For immunocompromised patients 12 years of age and older, a Pfizer COVID-19 booster may be administered to those patients who have already received any authorized or approved COVID-19 vaccine. For immunocompromised patients 18 years of age and older, a Moderna COVID-19 booster may be administered to similar immunocompromised patients. The timing of the booster is the same regardless of type of mRNA vaccine in that it may be administered at least 4 months after receiving the first booster vaccine injection. The rationale behind these recommendations relates to waning of protection from severe COVID-19 outcomes observed in these populations. It is not clear if or when FDA will authorize a second booster injection in other age groups or patient populations.

SOTROVIMAB NO LONGER AUTHORIZED FOR TREATING SARS-COV-2

As of April 5, 2022, sotrovimab is no longer authorized by FDA for treating SARS-CoV-2. Previous variants were susceptible to sotrovimab because of their uniquely preserved epitope binding site for this agent compared to other monoclonal antibodies. This is not the case with BA.2. Since the BA.2 subvariant was circulating in more than half of all U.S. regions, the sotrovimab authorization was removed by FDA.

The agency will continue to monitor BA.2 as well as future strains to provide guidance on sotrovimab as well as other previously authorized monoclonal antibodies for the treatment of SARS-CoV-2. If and when sotrovimab is authorized, 2 important updates will be important. Sotrovimab should be used within 7 days of symptom onset (this was previously 10 days) and may be given as a 15-minute infusion when diluted in 50 mL of intravenous fluids. If 100 mL of fluids are used, the infusion should be given over 30 minutes . Patients should continue to be monitored for 1 hour after completion of the infusion.

BEBTELOVIMAB AUTHORIZED FOR TREATMENT OF COVID-19

Bebtelovimab was authorized by the FDA in February 2022 for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients at least 12 years of age who weigh 40 kg or more. These patients should receive therapy only if they have a confirmed positive SARS-CoV-2 test, are at high risk for progression to severe COVID-19, and do not have other accessible or clinically appropriate treatment options.

Currently, bebtelovimab is the only monoclonal antibody recommended for treatment by the Infectious Diseases Society of America and the National Institutes of Health guidelines as well as authorized by FDA for treatment of COVID-19. While bebtelovimab retains in vitro activity against all identified omicron variants and subvariants, clinical outcome data correlating with this in vitro activity are not available at this time. For that reason, its authorization is limited since other authorized agents, such as the combination of nirmatrelvir/ritonavir (Paxlovid), are also authorized and effective. Most of the outcome data for bebtelovimab released to this point were from the BLAZE-4 phase 1/2 trials that demonstrated efficacy versus primarily against delta and alpha variants and have not been published in peer-reviewed journal.

One major advantage of bebtelovimab is that it may be given as a single intravenous push injection of 175 mg over 30 seconds. Infusions are required for all other available monoclonal antibodies for COVID-19.

Outcome data for bebtelovimab are required to make a long-term full assessment of its place in the management of COVID-19.

UPDATED TIXAGEVIMAB–CILGAVIMAB DOSING RECOMMENDATIONS

Because of concerns that the previously authorized tixagevimab 150 mg and cilgavimab 150 mg (Evushield) dosing regimen may not provide optimal activity versus omicron subvariants such as BA.2, FDA has revised initial dosing to 300 mg of each of the long-acting antibodies, tixagevimab and cilgavimab, as 2 individual consecutive intramuscular injections. If patients received the recommended dose more than 3 months previously, then they should be given the 300 mg/300 mg doses of tixagevimab plus cilgavimab. However, if the dose was given within the past 3 months, an additional 150-mg dose of both tixagevimab and cilgavimab is recommended.

At this time, long-term use of tixagevimab–cilgavimab is not authorized by FDA. FDA said the duration of protection provided by Evusheld against symptomatic SARS-CoV-2 infection may not be as long as was shown in the clinical trial supporting the initial authorization because the clinical trial data came from a time period before the emergence of the BA.1 and BA.1.1 subvariants.

MODERNA TO SEEK AUTHORIZATION of mRNA-1273 FOR CHILDREN UNDER 6 YEARS OF AGE

In late March 2022, Moderna announced that they had successfully met their primary endpoint regarding SARS-CoV-2 neutralizing antibody titers in a study of infants and children ages 6 months to under 6 years. Healthy children in the United States and Canada received 2 doses of 25 mcg each 28 days apart and were monitored for immunogenicity and safety. Similar immunogenicity was provided as with the standard 100-mcg, 2-dose series in participants 18–25 years of age. The study was not paused for any adverse effects, and no cases of myocarditis, pericarditis, or multisystem inflammatory syndrome (MIS-C) occurred. These adverse effects have been rarely reported in adult vaccination postmarketing but more commonly can occur with COVID-19 disease, especially MIS-C, which has been reported specifically in children.

Pfizer’s mRNA vaccine failed to demonstrate noninferiority regarding immunogenicity in this age group, age 2 to under 5-year-old population (noninferiority was shown in the 6- to 24-month age group). Pfizer has been testing a 3-dose regimen in children under 5 years of age, and results are expected at FDA in early May. If Moderna’s vaccine is authorized first, it would become the first COVID-19 vaccine available to children under 5 years of age in the United States, but there has been some discussion of approving both products at the same time to avoid confusion.

LONG-TERM PLAN FOR COVID-19 VACCINATION?

With the approval of a second COVID-19 vaccine booster dose for some groups, many people are beginning to ask, “What will long-term COVID-19 vaccination look like?” Because this pandemic is playing out in real time, it is difficult to know exactly what long-term COVID-19 vaccination strategy will prove best. Antibody levels clearly wane over time, but with vaccines providing T-cell immunity that can last for extended periods of time, the number of vaccines required over time is yet to be determined.

In addition, Moderna and other companies are evaluating modified versions of their vaccines that would cover multiple strains of COVID-19, similar to what is currently done with seasonal influenza vaccinations. There are also current discussions among FDA advisors about vaccines to potentially target specific strains, such as omicron, for the upcoming fall immunization campaign. Moderna has announced clinical data for a bivalent COVID-19 booster platform that would cover multiple known strains, including beta, delta, and omicron variants. Other studies would require initiation by May to evaluate the vaccine and have enough time logistically to manufacture and distribute enough doses for those who would benefit.

While more than 80% of the population 5 years and older has received at least 1 COVID-19 vaccine dose, fewer than half of the adults have received a booster dose, suggesting that vaccine fatigue has set in, especially with continued approvals of multiple booster doses. A common question from patients is, “How often will I need a COVID-19 vaccine?” The answer currently is we don’t know, as it will ultimately depend on a number of factors. Dr. Anthony Fauci, the White House chief medical advisor, recently stated in an article, “It will depend on who you are, but if you are a normal, healthy 30-year-old person with no underlying conditions, you might need a booster only every 4 or 5 years.” Chief scientist at the World Health Organization, Soumya Swaminathan, recently stated, “I don’t think the entire population is going to need annual vaccines.” This statement does not address the needs of special populations, such as older adults and people who have immunocompromising conditions or drug regimens.

SARS-CoV-2 has produced new variants at a much faster rate than common respiratory viruses such as influenza, which makes definitive timing of doses even more difficult to determine. One major advantage of the mRNA vaccine technology is that abrupt, necessary changes can be made within available vaccines to better target variants in an efficient manner compared with historical vaccine technology, which relied on “best guesses” to predict which influenza strains would be circulating nearly a year later.

IVERMECTIN RANDOMIZED TRIAL DEMONSTRATES NO SIGNIFICANT BENEFIT

Ivermectin has elicited great controversy over whether it should be used in the treatment of COVID-19. A highly informative opinion blog summarizing the controversy can be found on the NEJM Journal Watch site. Much of the data to date have been of lower quality. The research comes from nonrandomized studies with methodologic flaws, including a study that was retracted due to data discrepancies and plagiarism concerns.

A study recently published in the New England Journal of Medicine was well done. The investigators randomized adult outpatient participants with symptomatic COVID-19 to either ivermectin (400 mcg/kg) or placebo once daily for 3 days in an adaptive platform trial across 12 public health clinics in Brazil. While the trial was designed initially to provide a single dose of ivermectin similarly that used for parasitic diseases, the trial organizers responded to advocacy groups by increasing the treatment duration to 3 days at a higher dose than typically used with other ivermectin COVID-19 studies. Patients could not have had COVID-19 symptoms for more than 7 days, and approximately half of participants had symptoms for 3 days or less. The primary outcome in this trial consisted of COVID-19 hospitalization or emergency department visit due to COVID-19, both within 28 days of randomization. Ivermectin did not statistically significantly reduce the primary outcome compared with placebo (14.7% vs. 16.3%; relative risk, 0.90; 95% Bayesian credible interval, 0.70 to 1.16).⁴

LONG COVID AND DIABETES?

A number of long-term effects have been documented after the initial COVID-19 infection. Because of the expression of the ACE2 receptor in most body tissues, SARS-CoV-2 entry into cells is facilitated. “Long COVID” symptoms can occur within a number of organs and cause significant morbidity, including “brain fog,” headaches, and other sequelae.

A recent study in The Lancet Diabetes and Endocrinology evaluated the risk of new-onset diabetes within approximately 1 year after COVID-19 infection. This study included U.S. Department of Veterans Affairs patients who survived COVID-19 for at least 30 days. Their outcomes were compared with a contemporary control group during the pandemic (enrolled between March 1, 2020, and September 30, 2021) and a historical control group (March 1, 2018, and September 30, 2019). The outcome of interest, newly diagnosed diabetes, was defined by a hemoglobin A_1C greater than 6.4% or receipt of antihyperglycemic diabetes medications for more than 30 days.⁵

Study results showed that patients with COVID-19 had a 40% increased risk of incident diabetes relative to contemporary control patients (HR 1.4, 95% CI 1.36–1.44) as well as an increased relative risk of incident antihyperglycemic use (HR 1.85; 1.78–1.92). These findings were consistent when compared with the historical control group as well. These findings require duplication in a more diverse population of patients, but if confirmed, they have tremendous implications for monitoring after COVID-19 to ensure that a new diabetes diagnosis is not missed. An estimated 200 million patients worldwide have undiagnosed diabetes, and this new risk would further worsen that statistic if cases are missed.⁵

mRNA VACCINES REMAIN PROTECTIVE AGAINST SEVERE DISEASE

One of the most well-documented benefits of COVID-19 mRNA vaccines is the ability to protect patients from developing severe COVID-19. Hospitalizations have been the defining event in many of these cases. A recent MMWR study sheds light on the effect of these vaccines on the most serious outcomes in severe COVID-19, invasive mechanical ventilation and death.⁶

Overall vaccine effectiveness defined as preventing those outcomes was 90% for people who received 2 mRNA vaccine doses and 94% for those receiving 3 mRNA vaccine doses. For those receiving 2 doses who were 150 days or more after the second dose, vaccine effectiveness decreased from 92% to 84%. In patients with 3 or more chronic conditions, vaccine effectiveness was 84%, and this figure dropped to 74% in those with immunosuppression.⁶

Of note, this study evaluated vaccine effectiveness during time period when a number of different variants were circulating, which demonstrates vaccine effectiveness against both the delta and omicron variants. Specific to the omicron variant, vaccine effectiveness of the 2- and 3-dose series was 79% and 94%, respectively.⁶

These data further confirm the importance of the vital message of COVID-19 vaccination going forward as we transition to endemic COVID-19. The challenge for pharmacists will be to continue to educate patients regarding the benefits of COVID-19 vaccinations while scientists and researchers work to determine the best vaccination schedules for this preventable disease.

REFERENCES

1. Rader B, Gertz A, Iuliano AD et al. Use of at-home COVID-19 tests—United States, August 23, 2021–March 12-2022. MMWR Morb Mortal Wkly Rep 2022;71:489–494.
2. Keeton R, Tincho MB, Ngomti A et al. T cell responses to SARS-CoV-2 spike cross-recognize omicron. Nature. 2022;603:488–492.
3. Goel RR, Painter MM, Lundgreen KA, et al. Efficient recall of omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine. Cell. Published online April 7, 2022. https://www.cell.com/cell/pdf/S0092-8674(22)00456-1.pdf
4. Reis G, Silva EASM, Silva DCM, et al. Effect of early treatment with ivermectin among patients with COVID-19. N Engl J Med. Published online March 30, 2022, with an update on April 5, 2022. https://www.nejm.org/doi/full/10.1056/NEJMoa2115869
5. Xie Y, Zl-Aly Z. Risks and burdens of incident diabetes in long COVID: a cohort study. Lancet Diabet Endocrinol. 2022;10(5):311–321. https://doi.org/10.1016/S2213-8587(22)00044-4
6. Tenforde MW, Self WH, Gaglani M, et al. Effectiveness of mRNA vaccination in preventing COVID-19–associated invasive mechanical ventilation and death—United States, March 2021–January 2022. MMWR Morb Mortal Wkly Rep 2022;71:459–465.

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