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INTRODUCTION

With summer 2022 here, now is a good time to evaluate the state of coronavirus disease 2019 (COVID-19) 2.5 years into the pandemic. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality around the world and is now becoming an endemic pathogen likely to circulate indefinitely along with the numerous other respiratory pathogens.

As of June 2022, approximately 5 million hospitalizations in the United States have resulted in more than 1 million deaths. Long COVID symptoms have been frequently identified in patients, and this is becoming an increasingly important outcome even as acute pathogenicity of the virus is reduced through herd and individual immunity. Long COVID is resulting in nonspecific fatigue, intermittent headaches, or difficulty concentrating or thinking (“brain fog”). Approximately 13% of patients self-report 1 or more symptoms 1 month after infection, and 2.5% of patients report symptoms at 3 months. In patients who were hospitalized with COVID-19, this increases to about one third of patients 6 months after the onset of COVID-19 symptoms.

Despite these concerns, people are persevering and learning to cope with SARS-CoV-2 and COVID-19 as they return to more normal lives. In this continuing education program, the current status of the pandemic is reviewed, including advances in vaccines and treatments. Particular attention is paid to the omicron variant of SARS-CoV-2 and its mutated substrains that have developed ways of evading the body’s immunological defenses.

WHAT IS THE CURRENT STATUS OF OMICRON VARIANT?

Compared with the original (wild type) SARS-CoV-2 strain identified in Wuhan, China, mutated strains denoted by Greek letters have increased transmissibility. Several of these strains have become predominant as they spread more easily and evade body defenses, resulting in spikes in cases, hospitalizations, and deaths. As people produce antibodies to the variants, cases subside, but further mutations have produced other new strains with increased transmissibility. The cycle then repeats.

Fortunately, strains such as delta and omicron have also produced milder disease. Large upticks in cases with milder illnesses have produced much smaller increases in hospitalizations and deaths. This has been true in recent months, with cases rising but fewer people with severe disease at lower levels than earlier in the pandemic.

With the majority of the U.S. population vaccinated, many people have avoided symptoms and COVID-19 even when they have tested positive for SARS-CoV-2. Innovative treatment options have made the disease more manageable in the ambulatory setting, and the risks of hospitalization and death are lower than in the early days of the pandemic. As of early June 2022, 100% of isolates were the omicron strain and its lineages. The primary subvariant is BA.2.12.1, found in 62.2% of isolates, followed by BA.2, which is found in 24.8% of current isolates and is decreasing.

The next 2 variants, BA.5 and BA.4, have been identified in 23.5% and 11.4% of current isolates and in increasing numbers. These subvariants have a mutation, F486V, not found in BA.2 subvariants. This appears to facilitate immune escape from neutralizing antibodies produced by currently available vaccines. More cases result, and particularly in unvaccinated individuals, some cases produce severe disease, hospitalizations, and death.

Currently, the only monoclonal antibody authorized by the U.S. Food and Drug Administration (FDA) that retains activity against all of these subvariants is bebtelovimab.¹ Sotrovimab had good activity against earlier variants, but it is ineffective against omicron strains and is no longer recommended by guidelines for treatment of COVID-19.² The 2 currently FDA-authorized oral antivirals, nirmatrelvir tablets/ritonavir tablets (marketed as Paxlovid) and molnupiravir, continue to retain activity against the currently circulating variants.

HOW COMMON ARE SARS-COV-2 ANTIBODIES IN THE POPULATION?

A significant “wall of immunity” has been built among Americans, with nearly 83% of people 5 years or older receiving at least 1 dose of COVID-19 vaccine and 70% of people fully vaccinated. Infections of SARS-CoV-2 are the other important source of immunity. A U.S. Centers for Disease Control and Prevention (CDC) study provides insights into the number of American residents who have been infected with SARS-CoV-2.

Over the 6-month period of September 2021 through February 2022, blood specimens were obtained nationally and submitted to CDC for testing. The seroprevalence of SARS-CoV-2 antibodies in February 2022 was 63.7% of adults aged 18–49 years, 49.8% among adults aged 50–64 years, and 33.2% in adults 65 years of age or older. Approximately 75% of children and adolescents demonstrated serologic data consistent with previous infection —not surprising considering those age groups were the last to be vaccinated and their vaccination rates are lower than those of older people.³ This also speaks to the transmissibility of the omicron variant (B.1.1.529) compared to previously identified variant strains. The seroprevalence of B.1.1.529 significantly increased during study period, with an approximate 25% to 30% increase in prevalence.

Important to note is that previous infection does not necessarily confer protection from further infection and vaccination remains the best way to ultimately prevent severe disease among both children and adults. Patients should understand that vaccine recommendations apply to everyone; they are not different among patients who previously had COVID-19. This is a question likely to come up given the number of patients who have had COVID-19 illness or asymptomatic detections of SARS-CoV-2.

WHAT LONG-TERM COMPLICATIONS ARE COMMON AFTER COVID-19?

As the COVID-19 pandemic continues to shift toward endemic status, long-term consequences of COVID-19 infection are being documented in the adolescent and adult populations. While vaccinations have significantly decreased severe disease manifestations of COVID-19, they are less effective for protecting against breakthrough infections. This puts people at risk for long-term symptoms. Because SARS-CoV-2 can infect cells, tissues, and organs from head to toe, a number of long-term and sometimes debilitating symptoms can occur for months, including fatigue, shortness of breath, “brain fog,” fever, and gastrointestinal complaints. In addition, a number of new mental health diagnoses or worsening of preexisting mental health conditions, such as depression, anxiety, or sleep disorders, have been documented.

A recently published report sheds light on the prevalence of 26 of these long-term conditions. In a case–control study of electronic health records of adults (18–64 years, ≥65 years), long COVID symptoms 30 to 364 days after the enrollment encounter were grouped as cardiovascular, pulmonary, renal, hemolytic/vascular, gastrointestinal, neurologic, mental health, musculoskeletal, and endocrine. At least 1 long-term symptom was documented in 38% of participants with confirmed COVID-19 compared with 16% of controls, for an overall absolute difference of 22%. That figure is similar to previous studies that reported long COVID-19 symptoms in approximately 1 of 5 survivors.³

In that study, long COVID-19 symptoms occurred in a larger percentage of older adults, with an absolute difference of 26.9%. The most common condition present regardless of age was respiratory symptoms, followed by musculoskeletal pain. Pulmonary embolism was the most frequently documented pulmonary condition, irrespective of age group. All incident conditions were higher for cases than controls in the 65 years or older age group; 22 of 26 conditions were more prevalent in the 18–64 years of age group. For this younger age group, no differences between cases and controls were identified for cerebrovascular disease, other mental health conditions, mood disorders, or substance-related disorders.³

The National Institutes of Health (NIH) has created the Researching COVID to Enhance Recovery (RECOVER) Initiative to learn about the long-term effects of COVID-19 disease. This initiative connects patients, caregivers, clinicians, community leaders, and scientists from across the United States to “understand, prevent, and treat post-acute sequelae of SARS-CoV-2, including Long COVID.” Through the RECOVER consortium, more than 100 researchers are leading long COVID studies in more than 200 areas around the country and enrolling a diverse population of participants, including children and pregnant women.

DO COVID-19 VACCINES PREVENT LONG-COVID SYMPTOMS AFTER INFECTION?

The benefits of full vaccination in preventing severe COVID-19 disease (related hospitalizations or deaths) are well documented. Not well known is the ability of vaccines to prevent long-COVID symptoms in patients with breakthrough infection.

A recent study from the U.S. Department of Veterans Affairs (VA) attempted to answer this question. Using the VA national database, a case–control study evaluated a cohort of 33,940 patients with breakthrough infection after COVID-19 vaccination (cases) as well as 3 control cohorts without evidence of SARS-CoV-2 infection: contemporary (n = 4,983,491), historical (n = 5,785,273), and vaccinated (n = 2,566,369). Vaccinated individuals with breakthrough infections had a 34% reduction in risk of mortality, compared with unvaccinated people from the control cohorts who had SARS-CoV-2 infections during the study period. However, the reduction in risk of postacute sequelae was smaller at 15%, indicating only partial protection of vaccination against long COVID with pulmonary and/or extrapulmonary manisfestations.⁴

Global health strategies continue to emphasize primary prevention of SARS-CoV-2 infection as the best way of reducing the risks of long-COVID while balancing risks of “social distancing” and lockdowns, which can have significant mental health ramifications. A recent brief by the World Health Organization demonstrated a 25% increase in anxiety and depression worldwide in the first year of the pandemic, most likely the result of isolation, work constraints, and decreased support/engagement within local communities along with fear of infection and illness or death in loved ones.

WHY HAS FDA LIMITED THE USE OF JANSSEN COVID-19 VACCINE?

While the Janssen/Johnson & Johnson adenovirus COVID-19 vaccine has been administered much less frequently than either mRNA vaccine, the FDA took further action on May 5, 2022, to limit its use in the general population. A recent analysis indicated an increased risk of thrombosis with thrombocytopenia syndrome (TTS) associated with use of that vaccine. This led FDA to limit the emergency authorization use (EUA) of the vaccine to specific populations. TTS is a rare syndrome with low concentrations of platelets and potentially fatal blood clots. The onset of TTS has generally been 1 to 2 weeks after vaccine administration.

Because of this FDA action, use of the Janssen/Johnson & Johnson vaccine is now limited to adults for whom other authorized or approved COVID-19 vaccines are not accessible or clinically appropriate, and to adults who elect to receive the Janssen COVID-19 vaccine because of allergy or intolerance to 1 or both of the mRNA vaccines or because of hesitancy regarding the mRNA vaccines.

WHAT IS THE STATUS OF VACCINATION IN INFANTS AND CHILDREN?

The process of making COVID-19 vaccines available to infants and children younger than 12 years of age has been a relatively slow and deliberate one. Infants and children initially did not seem to be infected by SARS-CoV-2 at the same rate as adolescents and adults. As testing became more widespread, it turned out that children were infected but did not develop symptoms or have moderate or severe COVID-19 as often as older individuals. Given the sensitivity about conducting clinical research in children and the focus of parents on the number of vaccines children receive, vaccine manufacturers and public health officials carefully and deliberately developed vaccines for infants and children.

At this point, COVID-19 is recognized as the fifth most common disease-related cause of death in infants and young children (it is eighth overall when homicides and other assaults, accidents, and suicides are included). COVID-19 is the most common cause of death from infectious/respiratory pathogens.⁵ While COVID-19 symptoms are usually mild in younger children, rare severe manifestations, including multisystem inflammatory syndrome (MIS-C), have been reported. In addition, long COVID symptoms have developed in children after infection.

Clinical studies have shown efficacy and safety of the mRNA vaccines in infants and children, and these are now available for infants as young as 6 months of age. On May 17, 2022, the FDA amended its previous EUA for the Pfizer/BioNTech COVID-19 vaccine to allow for children ages 5–11 years to receive a single booster dose (this product is fully approved for adolescents and adults ages 16 years or older). The booster authorization comes after authorization of a single booster dose in ages 12–15 years in January 2022. Children within these age groups may receive the single booster dose as long as it has been 5 months since completion of the primary 2-shot series.

While mixing and matching of various manufacturers’ COVID-19 vaccines (heterologous administration) in adult patients is appropriate, this practice has not yet developed in the pediatric population. Long-term monitoring is currently being conducted to ensure safety.

In June 2022, both mRNA vaccines received an EUA from FDA and were recommended by CDC for infants and children 6 months through 4 years of age. Vaccine effectiveness for the Pfizer product was 80.3% in more than 1,500 trial participants during a period of omicron dominance in the general population. Available in a 10-mL multidose vial, the Pfizer COVID-19 vaccine is administered in a primary series of 3 doses (vaccine effectiveness with 2 doses was considered too low). Each dose is 3 mcg — which is one-tenth that of adults. This dose was selected based on safety, tolerability, and immunogenicity studies. The first 2 doses are administered 3 weeks apart and the third dose at least 8 weeks after the second dose in children 6 months through 4 years of age.

Simultaneously, FDA approved EUAs for the Moderna mRNA-1273 vaccine for a 2-dose regimen of 100 mcg/dose for adolescents aged 12–17 years of age, a 2-dose regimen of 50 mcg/dose for children ages 6 through 11 years old, and a 2-dose series of 25 mcg/dose in infants and young children ages 6 months through 5 years of age. The Moderna mRNA-1273 vaccine is administered as a primary series of 2 doses, 1 month apart, to individuals 6 months through 17 years of age. The vaccine is also authorized to provide a third primary series dose at least 1 month following the second dose for individuals in this age group who have immunocompromising conditions. These pediatric doses are also available in a 10-mL multidose vial.

While parents may be attracted to the Moderna product because of its 2-dose series, its vaccine effectiveness was lower than that of the 3-dose Pfizer series. The vaccine was 50.6% and 36.8% effective for preventing COVID-19 in study participants ages 6–23 months and 2–5 years of age, respectively.

Both of the mRNA vaccines were relatively safe in clinical trials of infants and children. For Pfizer, the most commonly reported side effects in clinical trial participants 6 through 23 months of age who received the vaccine were irritability, decreased appetite, fever and pain, and tenderness, redness, and swelling at the injection site. These side effects were also reported for the vaccine recipients 2 through 4 years age, in addition to fever, headache, and chills.

For the Moderna vaccine, the most commonly reported side effects in clinical trials in the 6–17-year-old age groups included pain, redness and swelling at the injection site, tiredness, headache, muscle pain, chills, joint pain, underarm swollen lymph nodes in the same arm as the injection, nausea and vomiting, and fever. For participants 2–5 years of age, the most commonly reported side effects included pain, redness and swelling at the injection site, fever, and underarm (or groin) swelling/tenderness of lymph nodes in the same arm (or thigh) as the injection. In clinical trial participants 6–36 months of age, the most commonly reported side effects also included irritability/crying, sleepiness, and loss of appetite. In clinical trial participants 37 months through 5 years of age, the most commonly reported side effects also included fatigue, headache, muscle ache, chills, nausea/vomiting, and joint stiffness.

The FDA and CDC safety surveillance systems have previously identified increased risks of myocarditis and pericarditis following vaccination with either of these vaccines. The observed risk has been highest in males 18 through 24 years of age for the Moderna COVID-19 vaccine and in males 12 through 17 years of age for the Pfizer/BioNTech COVID-19 vaccine. Patients who have these adverse events usually recover quickly with conservative management, with no impact on quality of life in the following 90 days.

WHERE CAN PHARMACISTS FIND INFORMATION ON NIRMATRELVIR/RITONAVIR DRUG INTERACTIONS?

The oral antiviral combination nirmatrelvir/ritonavir, better known by its trade name Paxlovid, is finally being used commonly in the community. The combination is indicated for people with mild-to-moderate COVID-19 symptoms who test positive for SARS-CoV-2 and are at high risk of progression to severe COVID-19. A few examples of higher risk include people with diabetes mellitus, chronic obstructive pulmonary disease, or cirrhosis.

In the EUA labeling, limitations on authorized use of Paxlovid are emphasized:

• Paxlovid is not authorized for initiation of treatment in patients requiring hospitalization due to severe or critical COVID-19.
• Paxlovid is not authorized for pre-exposure or postexposure prophylaxis for prevention of COVID-19.
• Paxlovid is not authorized for use longer than 5 consecutive days.

The ritonavir component of Paxlovid is associated with a number of significant drug interactions. These must be managed appropriately, as ritonavir is a potent enzyme inhibitor and could cause accumulation of other drugs and subsequent harm.

FDA has a published tool for prescribers that divides medications into a “red” category of medications that are contraindicated with Paxlovid therapy as well as a “yellow” category for medications that should be avoided, held, dose adjusted, or monitored more frequently if given with Paxlovid therapy. The Pfizer website explains that Paxlovid is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated concentrations are associated with serious or life-threatening reactions (elevated concentrations of these drugs could result). Paxlovid is also contraindicated for use with drugs that are potent CYP3A inducers (reduced nirmatrelvir and ritonavir concentrations could result) and in patients with a history of clinically significant hypersensitivity reactions.

An additional resource is the COVID-19 treatment guidelines from the NIH. It details various management strategies for potential Paxlovid drug interactions. These strategies include prescribing alternative COVID-19 therapy when the interacting drug cannot be safely stopped (e.g., amiodarone or phenytoin), temporarily withholding concomitant medication if deemed clinically appropriate (e.g., atorvastatin or alfuzosin), adjusting concomitant medication dose and/or frequency with monitoring for adverse effects (e.g., apixaban or digoxin), and continuing concomitant medication with subsequent monitoring (e.g., amlodipine or warfarin).

While not new resources, the Liverpool COVID-19 Drug Interactions website and the Ontario COVID-19 Science Advisory Table are also useful for specific drug modification strategies, including dose adjustments.

IS PAXLOVID THERAPY ASSOCIATED WITH COVID-19 REBOUND?

Recent anecdotal reports are circulating about “COVID-19 rebound” after finishing Paxlovid therapy for confirmed COVID-19. With the increased transmissibility of the omicron variant and increased availability of Paxlovid therapy, more courses are being prescribed (these increased by more than 300% in a recent 4-week period) and administered to patients. Because of its antiviral actions, Paxlovid treatment should be initiated as soon as possible after confirmation of SARS-CoV-2 and definitely within 5 days of symptom onset.

In late May 2022, the CDC issued a health advisory about case reports of rebound symptoms after completion of a course of Paxlovid for COVID-19. Paxlovid was studied in unvaccinated patients, but rebound symptoms have been reported both in vaccinated and unvaccinated patients. Recurrent illness has been reported from 2 to 8 days after completion of therapy. Of note, these people had negative COVID-19 test results after completing their Paxlovid course with subsequent positive test results at the time of rebound symptoms. In these case reports, rebound symptoms resolved within a median of 72 hours after onset.

The cause of these symptoms is unclear. Affected patients have had COVID-19 reinfection or Paxlovid antiviral resistance. Bacterial or other viral coinfections have not been detected in patients with rebound COVID-19 symptoms. In addition, with more patients using Paxlovid to treat COVID-19, the symptoms could be a manifestation of the currently circulating omicron strain. Rebound symptoms were rarely reported in clinical trials; further study will be required to delineate the cause of the rebound symptoms as well as risk factors for its development.

Patients experiencing COVID-19 rebound after Paxlovid therapy should not seek additional treatment unless the symptoms worsen to the point that medical evaluation is needed. If COVID-19 rebound is confirmed with a positive test, patients should restart isolation for another 5-day period and wear a mask for a total of 10 days after the reappearance of symptoms.

WHEN IS MOLNUPIRAVIR AN APPROPRIATE CHOICE FOR TREATING COVID-19?

Molnupiravir is an oral antiviral agent with an FDA-approved EUA. It is indicated for treatment of people with mild-to-moderate COVID-19 who are at high risk of progression to severe disease. According to the NIH COVID-19 treatment guidelines, molnupiravir is recommended only when other options (e.g., Paxlovid or remdesivir) are not available, feasible for use, or appropriate for the specific patient presenting with COVID-19.²

In a post hoc evaluation of data from the Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002), better known as the MOVe-OUT trial, outcomes not included in the primary analysis were assessed. These included changes in C-reactive protein levels and oxygen saturation, need for respiratory interventions (e.g., mechanical ventilation), and need for medical service through day 29. In addition, within the subset of patients who were hospitalized for COVID-19, need for respiratory interventions and time to discharge were also evaluated for molnupiravir compared with placebo.⁶

Results showed that participants who received molnupiravir had more rapid normalization of C-reactive protein concentrations and oxygen saturation compared with placebo. The molnupiravir group also had a decreased need for respiratory interventions compared with placebo, with a relative risk reduction (RRR) of 34.3% [95% CI, 4.3%–54.9%]. In participants who were hospitalized for COVID-19, the RRR was 21.3% (95% CI, 0.25%–38%). Of particular interest, among the 115 patients who were hospitalized for COVID-19, those receiving molnupiravir had a 49.2% RRR (CI, –49.9% to 82.8%) in the need for invasive mechanical ventilation compared with placebo; with a smaller number of patients in this group, this reduction was not statistically significant. Participants receiving molnupiravir were discharged a median of 3 days before those receiving placebo, decreasing the average hospital stay from 12 days to 9 days. Compared with the placebo group, those receiving molnupiravir needed about 3.4% fewer acute care visits and COVID-19–related acute care visits.⁶

While these findings are reassuring, it is important to remember that these were post hoc analyses, sponsored by the manufacturer, and not the primary outcomes of the MOVe-OUT trial.⁵ Future research into any COVID-19 treatment modality including molnupiravir should include these outcomes and possibly evaluate long-COVID symptoms.

WHAT IS THE RISK OF BREAKTHROUGH COVID-19 INFECTIONS IN ADULTS WITH HIV?

While most people need a primary series of 2 doses of an mRNA vaccine followed by 1 or 2 booster doses, those who are moderately or severely immunocompromised receive a 3-dose primary series and 2 booster doses. This group includes some but not all patients with HIV (PWH). The CDC currently categorizes adolescents and adults as moderately or severely immunocompromised when they have advanced or untreated HIV infection and CD4 counts less than 200/mm³, history of AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV.

Breakthrough infections are a particular concern in moderately or severely immunocompromised individuals. A recently reported cohort study added to the little that is known about this risk. The Corona-Infectious-Virus Epidemiology Team (CIVET)-II, a component of the International Epidemiology Databases to Evaluate AIDS, used 4 prospective, electronic health record-based cohorts to compare outcomes in adults with HIV to matched controls without HIV based on vaccination date, age, race/ethnicity, and gender through the end of 2021. Breakthrough COVID-19 infections were defined as laboratory evidence confirmed with SARS-CoV-2 or COVID-19 diagnosis after a patient received full vaccination.⁷

In this study of 113,994, the number of people with breakthrough infections was small overall (3.8%), but a significantly larger percentage of PWH had this outcome (4.4%) compared with those without HIV (3.5%). In PWH, younger age, history of COVID-19, and not receiving an additional vaccine dose were associated with increased risk of breakthrough COVID-19 infection. HIV viral load suppression was not associated with breakthrough infections, but those with very high CD4 counts (≥500 cells/mm³) had fewer breakthrough infections. The investigators concluded that the current recommendation of providing booster doses only to moderately or severely immunocompromised PWH should be reconsidered in view of the elevated risk associated with all but highest CD4 counts.⁷

WHAT NEW AT-HOME TESTING OPTIONS ARE AVAILABLE?

An important new home test became available in May 2022 when FDA authorized the LabCorp Seasonal Respiratory Virus RT-PCR DTC Test. This unique at-home sample collection kit enables consumers to test simultaneously for 3 commonly circulating pathogens: COVID-19, influenza virus, and respiratory syncytial virus (RSV).

Individuals with presumed symptomatic respiratory viral infection can self-collect a nasal sample and send it to LabCorp for testing. An order from a medical practitioner is not required. Samples can be self-collected by adults 18 years and older, self-collected by individuals 14 years and older with adult supervision, or collected by adults for children 2 years or older. Patients are notified through an online portal. A health care provider follows up on invalid or positive test results.

ARE COVID-19 VACCINES FOR VARIANTS OF SARS-COV-2 UNDER DEVELOPMENT?

Since authorization of the mRNA vaccines developed for the original (wild type) SARS-CoV-2, mutations have occurred with the virus as expected, including several within the spike protein. A major advantage of mRNA vaccines is the ease of modifying and adapting the vaccine product relatively quickly as circulating strains change. This is analogous to the annual updating of influenza vaccine to match the strains expected during the next season, but the process is easier and faster with mRNA vaccines.

Moderna, manufacturer of the COVID-19 vaccine mRNA-1273, announced recently its research comparing this original vaccine to a new investigational, bivalent candidate, mRNA-1273.211. The phase 2/3 trial tested 50- and 100-mcg doses containing equal amounts of wild type and beta variant mRNA coding for the spike protein. The product was used as a booster dose administered 8.8–9.8 months after primary mRNA-1273 series.

mRNA-1273.211 demonstrated statistically significant greater neutralizing ability (approximately 2-fold) against the beta, delta, and the currently circulating omicron strains compared with the parent vaccine booster within 1 month after administration. This superiority was maintained out to 6 months for all strains except delta. Both doses of the bivalent vaccine were well tolerated, but a greater incidence of local and systemic adverse reactions occurred with the higher dose, including injection site pain and fatigue.

Moderna is also evaluating a second booster candidate, mRNA-1273.214, which combines the currently authorized booster with an omicron-specific booster candidate. Per the company, this is the leading candidate for the fall 2022 season in the Northern Hemisphere. Pfizer and BioNTech are also working on an omicron-specific booster injection; it is unknown whether it will be available by fall 2022, but an initial press release reported a respective 12.5- and 19.6-fold increases in neutralizing titers versus omicron BA.1 when administered as an omicron-adapted monovalent 4th booster dose of 30 mcg or 60 mcg. The bivalent vaccine candidate elicited a 9.1- and 10.9-fold increase in neutralizing titers, respectively, with both vaccines demonstrating less neutralization against omicron BA.4 and BA.5.

HOW CLOSE IS THE NOVAVAX VACCINE TO BEING AUTHORIZED IN THE UNITED STATES?

The road has been a long one for Novavax and its COVID-19 candidate in the United States. The World Health Organization and approximately 40 other countries have granted authorization this vaccine. However, the company has struggled in the United States with delays in regulatory approvals and difficulties with distribution. The company requested authorization on February 1, 2022, and FDA action is expected soon.

This vaccine, NVX-CoV2373, is different from the currently approved mRNA vaccines in that it is more of a traditional protein-based vaccine. Recombinant technology is used to generate antigen derived from the COVID-19 spike protein. This antigen is adjuvanted with proprietary saponin-based Matrix-M to improve the immune response and produce high concentrations of neutralizing antibodies. This COVID-19 vaccine candidate is administered as 2 intramuscular injections of 0.5 mL each separated by 3 weeks.

With significant vaccine and case-based immunity demonstrated in the United States, people have asked whether another COVID-19 vaccine is needed. The mRNA products are safe and very effective, especially for prevention of severe disease. About 80% of the U.S. population has received at least 1 dose of COVID-19 vaccine, but nearly one-third are not fully vaccinated and only about one-half of the eligible adult population has received a second booster dose, including just 30% of those 65 years of age or older. Vaccine hesitancy is still present and resulting in low uptake of booster injections, especially with some people concerned about mRNA vaccines being a new technology that was developed and made available quickly.

The CDC has spent significant time and resources to educate the public about the safety and effectiveness of the COVID-19 vaccines and their importance in reducing infections, hospitalizations, and deaths. Since the protein-based vaccine is more of a traditional approach to vaccination (this technique is used in some currently available hepatitis and shingles vaccines), the Novavax vaccine may acceptable to those who have held out to this point based on hesitancy about the mRNA COVID-19 vaccines.

FDA is in the final stages of reaching a decision about an EUA for NVX-CoV2373. Novavax presented clinical data from pivotal trials of the product FDA’s Vaccines and Related Biological Products Advisory Committee during a June 7 meeting, the FDA vaccines advisory committee voted 21–0 with 1 abstention to recommend approval of an EUA of NVX-CoV2373 in the United States. FDA typically but not always follows the advisory committee’s recommendations. The final authorization may not occur for several weeks.

In the phase 3 trial of NVX-CoV2373 conducted in the United States and Mexico, approximately 30,000 adults received an initial 2-dose vaccination series followed by either 2 doses of placebo or 2 doses of NVX-CoV2373. The primary efficacy endpoint was first occurrence of confirmed SARS-CoV-2 with symptoms. It occurred in 17 of 17,272 (0.098%) participants in the NVX-CoV2373 group and 79 of 8,385 (0.942%) placebo recipients, yielding an overall vaccine efficacy of 90.41%. Vaccine effectiveness was 93% and 100% for variants of concern or interest circulating at the time of the study and severe COVID-19, respectively.

Local adverse effects of mild-to-moderate pain/tenderness, redness, and swelling were reported primarily by participants receiving NVX-CoV2373; the median duration of local events was 2 days or less. The most common systemic adverse effects reported were headache, fatigue/malaise, muscle and joint pain, fever, and nausea/vomiting, which occurred more often in the NVX-CoV2373 arm and more often in younger participants than among older adults. For both local and systemic adverse effects, the frequency was increased with the second dose compared to the first.

Myocarditis/pericarditis, known rare potential effects with both COVID-19 disease as well as mRNA vaccines, occurred at a rate of 0.02 events/100 person–years in the NVX-CoV2373 group and 0.03 events/100 person–years in the placebo group. The observed rate of 3 cases per 14,513 person–years of myocarditis/pericarditis during the post-crossover period was similar to that demonstrated by the European Medicines Agency when evaluating background rates of COVID-19 vaccine adverse effects. No cases of thrombosis or thrombocytopenia, a well documented risk with the Johnson/Janssen COVID-19 adenovirus vaccine, occurred in this study.

Clinical immunogenicity of NVX-CoV2373 was confirmed with robust anti-SARS-CoV-2 spike protein IgG as well as markedly increased neutralizing antibody concentrations compared with placebo by day 35 in both the 18–64 and 65 years or older age groups. T-cell responses were also demonstrated through CD4+ cells, and if confirmed by longer-term data, this could provide more durable protection against SARS-CoV-2.

WHAT IS THE STATUS OF REMDESIVIR USE IN PEDIATRIC COVID-19 DISEASE?

Remdesivir (Veklury) is approved by FDA for treatment of hospitalized COVID-19 patients (as soon as possible after symptomatic COVID-19 diagnosed) or ambulatory patients with mild-to-moderate COVID-19 who are at high risk for progression to severe disease (within 7 days of COVID-19 symptom onset). The age range of this approval was expanded in April 2022 to include pediatric patients 28 days of age or older weighing at least 3 kg. This is the first medication approved for treating COVID-19 in the pediatric population. Pediatric patients weighing less than 40 kg should receive intravenous doses of 5 mg/kg on day 1 and 2.5 mg/kg on subsequent days. Ambulatory patients should receive remdesivir for 3 days; inpatients may receive therapy for 5–10 days depending on severity of illness.

The pediatric approval was based primarily on efficacy results in phase 3 clinical trials of adults as well as a phase 2/3 single-arm, open-label study of 10 days of remdesivir therapy of 53 pediatric patients with confirmed SARS-CoV-2 with mild, moderate, or severe COVID-19.

All patients on remdesivir should have baseline renal and hepatic panels performed as well as prothrombin time with subsequent monitoring during therapy as clinically appropriate. The primary adverse effects of remdesivir include transaminase elevations as well as hypersensitivity reactions. Remdesivir should be discontinued if transaminase elevation in conjunction with signs and symptoms of liver injury are present as well as any degree of hypersensitivity reaction.

WHICH PATIENTS WITH COVID-19 CAN BE TREATED WITH BARICITINIB?

Baricitinib (Olumiant) was previously authorized by the FDA for the treatment of COVID-19 in hospitalized patients. On May 10, 2022, this authorization for adults was changed to full FDA-approval for hospitalized adult and pediatric patients 2 years or older with COVID-19 and requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation. Patients meeting these criteria may receive baricitinib 4 mg orally daily (with or without food) for 14 days or until hospital discharge, whichever happens first.

Baricitinib therapy should be withheld in patients with COVID-19 whose absolute lymphocyte counts are less than 200 cells/microliter or absolute neutrophil counts are less than 500 cells/microliter until those counts recover. These criteria for holding therapy are different than those for patients with rheumatoid arthritis, which is also an FDA-approved indication for baricitinib.

Janus kinase (JAK) inhibitors such as baricitinib have been implicated in causing secondary serious bacterial infections of various etiologies (e.g., tuberculosis) as well as significant thromboses (e.g., pulmonary embolism). Most of these data are derived from experience treating patients with rheumatoid arthritis, but caution is advised within the COVID-19 population, as serious COVID-19 illness has been associated with similar outcomes.

REFERENCES

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