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COVID-19 Monthly Update: Comprehensive COVID-19 Vaccine and Treatment Update


Nearly 20 months into the coronavirus disease 2019 (COVID-19) pandemic, more than 200 million cases resulting in at least 4 million deaths worldwide have occurred as of the middle of August 2021. The delta variant of SARS-CoV-2 is now common around the world, and specifically in the United States, the hopefulness of early summer has waned a bit as the 4th wave has increased cases and subsequently hospitalizations and deaths nationally. Some southeastern states are reporting increased numbers of COVID-19–related pediatric hospitalizations though rates still low compared with other age groups. Mask mandates by the U.S. Centers for Disease Control and Prevention (CDC), which had been removed for fully vaccinated patients, have been reinstated to recommend wearing a mask indoors in public if in an area of substantial or high transmission.

There are some silver linings at the time this program was prepared (mid-August 2021). The United States may be a couple of weeks behind the United Kingdom, where a sharp decrease in cases appears to be underway. Based on U.K. data from the Office for National Statistics, more than 90% of U.K. adult residents have some antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) either through infection or vaccination. There is hope that the United States will follow with a similar trend in decreased cases, but time will tell. This pattern appears to be beginning in the United States, where southeastern states with low overall vaccination rates and high numbers of cases, such as Arkansas and Missouri, are seeing declines in cases.

Another factor is the rebound in vaccination rates, which have slightly increased over the past few weeks, likely due to concerns over the delta variant. Despite some risk of breakthrough infections, full vaccination remains the best intervention for preventing COVID-19 and most importantly decreasing the risk of severe COVID-19 manifestations that can lead to hospitalization and death. Full approval of available COVID-19 vaccines by the U.S. Food and Drug Administration (FDA) — which began on August 23 with the Pfizer/BioNTech product (Comirnaty) — could accelerate vaccinations by reducing vaccine hesitancy and increasing mandates by employers, schools and other institutions, and businesses.

Even in the midst of high case counts and increased hospitalizations in some areas, especially among the unvaccinated, deaths are significantly lower compared with earlier in the pandemic. This is likely due to high vaccination rates among individuals at greatest risk of severe disease. As of August 2021, 70.1% of the adult population has received at least 1 dose of a COVID-19 vaccine, with 90% of adults 65 years or older receiving at least 1 dose.

This continuing education program addresses major updates in the fields of vaccines against SARS-CoV-2 and treatments of COVID-19.


The question of vaccine mandates is on the forefront as schools and colleges/universities begin fall classes and employees return to offices after months of working remotely, all in the midst of rising case counts caused by the delta variant.

Hundreds of colleges and universities have mandated fully vaccinated status for students, while other institutions of higher learning have avoided these mandates. Concerns over litigation and previous lack of a fully approved vaccine have given some K–12 schools pause when considering mandates of COVID-19 vaccination. However, recent FDA approval of the Pfizer/BioNTech vaccine for ages 16 and older should provide further leverage for organizations to mandate COVID-19 vaccination, especially as the Moderna vaccine will likely be approved as well.

New York City will require workers and customers to demonstrate proof of at least 1 dose of a COVID-19 vaccine for indoor dining, gyms, and performances as announced by Mayor Bill de Blasio. This requirement takes effect in August, and enforcement begins on September 13. A $100 incentive has been offered to the public to encourage vaccine-hesitant citizens to receive at least 1 dose of a COVID-19 vaccine.

Many companies — including Google, Facebook, and Twitter — have delayed the return of many workers to the office in hopes that the cases will again subside and unvaccinated workers will obtain a COVID-19 vaccine. Many of these employees are able to work remotely, but some jobs are not as easily transferred to remote work. A number of companies have also stated that they will mandate vaccines for any employee returning to the office. In addition, President Joe Biden announced that federal workers, as well as federal contractors, will be required to sign forms confirming they have received COVID-19 vaccination. If employees have not been vaccinated, they will be forced to comply with mandatory masking, physical distancing, weekly or twice weekly screening tests, and subject to official travel restrictions.


For many weeks, the need for booster injections has been debated by officials at regulatory agencies worldwide. Third doses of the mRNA COVID-19 vaccines have now been recommended and/or approved in a number of countries, including the United States. Israel, which has one of the highest percentage of citizens vaccinated worldwide, has seen a significant increase in cases due to the delta variant. Booster injections, initially approved for patients 60 years or older by the Israeli health ministry division, are now authorized for anyone 50 years of age or older as well as health care workers. To date, more than 700,000 citizens of Israel have received their 3rd injection, including Israeli President Isaac Herzog, and an initial survey shows similar or better tolerability compared with previous injections.

On August 12, 2021, the FDA amended the emergency use authorization for both the Pfizer/BioNTech and Moderna COVID-19 vaccines to allow an additional 3rd dose in some immunocompromised patients. Unlike the Israeli strategy of targeting patients by age, the CDC’s Advisory Committee on Immunization Practices (ACIP) focused on immune status based primarily on small studies demonstrating that a high number of hospitalized breakthrough cases involve immunocompromised patients who could further transmit SARS-CoV-2 to household contacts. As accepted by CDC, this new booster recommendation applies to a number of patient groups as listed in Table 1. No booster recommendations or authorizations have been made for the Janssen/Johnson & Johnson vaccine, but data are beginning to emerge that could support such actions.

Table 1. CDC Recommendations for Booster Doses of Currently Available mRNA COVID-19 Vaccines
Patients receiving active treatment for blood or solid tumors/cancers
Organ transplant recipients currently receiving immunosuppressive medications
Recipients of stem-cell transplants within last 24 months who are receiving immunosuppressive medications
Patients with moderate-to-severe primary immunodeficiency
Advanced or untreated patients living with HIV
Patients on active treatment with high-dose corticosteroids or other drugs that may suppress the immune response
Abbreviations: CDC, U.S. Centers for Disease Control and Prevention; COVID-19, coronavirus disease 2019; HIV, human immunodeficiency virus

Listed last in the CDC recommendations, those on high-dose corticosteroids and other immunosuppressive regimens could end up being a very large group, considering the many patients in the United States on medications such as tumor necrosis factor alpha inhibitors for a number of a wide variety of conditions such as Crohn’s disease or psoriatic arthritis. There will be no definitive way to document immunosuppression; administration of a third dose will essentially be on the honor system from the patient seeking vaccination.

Daily numbers of vaccines administered in the United States peaked in spring 2021 at more than 4 million daily; this had dropped to a nadir of around 450,000 daily before rebounding as the delta variant spread. When this program was prepared in August 2021, this figure was approaching a 7-day average of nearly 650,000 for the first time since mid-June. These increases in vaccinations represented not only in adults but also adolescents seeking immunization against COVID-19.

Pharmacies will see increased immunization workloads and patient volumes with the new booster recommendations and full vaccine approvals. This will put more demand on staff to provide these important injections. The number of patients receiving booster vaccinations could increase in the near future, as the Biden administration is expected to expand this recommendation to most Americans who are 8 months out from being fully vaccinated. On August 18, the U.S. Department of Health and Human Services released a statement that the vaccines currently authorized on a 2-dose schedule continue to be remarkably effective in reducing the risk of severe disease, hospitalization, and death, even in those infected by the widely circulating delta variant. However, the department said, “Based on our latest assessment, the current protection against severe disease, hospitalization, and death could diminish in the months ahead, especially among those who are at higher risk or were vaccinated during the earlier phases of the vaccination rollout.” In addition the statement read, “For that reason, we conclude that a booster shot will be needed to maximize vaccine-induced protection and prolong its durability.”

Data supporting this statement have yet to be released, and the FDA, ACIP, and CDC must consider the situation and make definitive recommendations. Concerns include possible added or more severe adverse effects of a third injection (especially for younger adults), definitive benefit in decreasing severe disease with morbidity and mortality, and the consideration that boosters take away from the supply of vaccine for first and second doses worldwide. It remains to be seen how much uptake there will be for this recommendation, even though President Biden himself states he will get the booster injection.


Cases of myocarditis, pericarditis, or myopericarditis have been associated with administration of the 2 available mRNA vaccines by Pfizer/BioNTech and Moderna. Characterized by inflammation of the heart muscle, myocarditis most commonly presents with chest pain, heart palpitations, and/or shortness of breath. Pericarditis is an inflammation of the pericardial sac around the heart, while myopericarditis represents inflammation of the muscle and pericardial sac. A patient with myocarditis can have increased troponin concentrations or have typical findings on an echocardiogram, magnetic resonance imaging, or even the less expensive electrocardiogram.

Findings from research performed by the ACIP Vaccines Safety Technical (VaST) and COVID-19 Vaccines Work Groups were presented at the June 23, 2021, ACIP meeting. As of June 11, 2021, nearly 296 million mRNA vaccines had been administered in the United States, with 52 million of these doses administered to those ages 12–29 years. Of these, 30 million were first doses and the rest second doses. There were 1,226 reports of myocarditis captured by the Vaccine Adverse Event Reporting System (VAERS) over approximately a 6-month period. The median age of people reporting myocarditis was 26 years, with a median onset of symptoms at 3 days after vaccination. Among the 1,194 reports with documented patient age, 687 involved patients younger than 30 years of age and 507 occurred in people 30 years or older. The vast majority of reported cases were in males (923 out of 1,212 of reports with documented sex) and occurred after the second dose (76% of cases).

A subset of CDC-prioritized rapid-review patients (484 records) identified 323 individuals meeting case definitions for myocarditis, pericarditis, or myopericarditis. Most cases were mild, with no mortality reported in this subgroup and 95% of patients who had been hospitalized subsequently discharged at the time of the review.1 While treatment was poorly documented within VAERS, nonsteroidal anti-inflammatory medications were typically used for treating myocarditis.

In order to provide guidance regarding these adverse effects, calculated crude reporting rates have been reported in Table 2.

Table 2. Expected Number of Cases of Myocarditis by Sex and Age Group per Million mRNA Vaccine Doses
Age Ranges (years) No. Expected Cases Among Males No. Expected Cases Among Females
12–29 39–47 4–5
12–17 56–69 8–10
18–24 45–56 4–5
25–29 15–18 2
³30 3–4 1

Another recent study conducted in the Pacific Northwest documented a similar pattern of myocarditis and pericarditis, although at a slightly higher incidence, suggesting possible underreporting. In addition, pericarditis was much more common in older adults compared with myocarditis.2


Guillain-Barré syndrome (GBS) is a rare neurologic syndrome characterized by symptoms of tingling and weakness. In severe cases, GBS can rapidly progress, suppressing diaphragmatic function and requiring mechanical ventilation to ensure respiration. Influenza vaccine has been rarely associated with GBS, although viral infections such as influenza may also induce GBS.

The ACIP met on July 22, 2021, met to discuss recent VAERS reports indicating a potential association between GBS and the Janssen/Johnson & Johnson vaccine. As of June 30, 2021, 100 total cases of GBS had been reported to VAERS in association with receipt of the Janssen/Johnson & Johnson vaccine. Nearly all of these cases were considered serious; 95 of the patients were hospitalized and 10 patients required intubation and/or mechanical ventilation. The typical patient was 57 years old and male (61%), and the median onset of symptoms after vaccination was almost 2 weeks, with 98% of cases reported within 6 weeks of vaccination. One patient who required mechanical ventilation and subsequently died 25 days post-vaccination had comorbidities of hypertension, heart failure, previous stroke, and diabetes. Facial paresis (24 patients), unilateral Bell’s palsy (12 reports), and recent illness (6 reports) were reported. No concomitant vaccines were reported to VAERS. The highest risk age group was the 18–64 years of age, with a rate ratio of 6.16 per 100,000 person-years compared to a background rate of 1.22 per 100,000 person-years in the population at large. The Moderna and Pfizer/BioNTech vaccines have crude VAERS reporting rates of 1.21 and 1.05, respectively, which is similar to the overall population.

Based on these findings, the FDA added language to fact sheets in the warnings and precautions section related to risk of GBS, noting that the risk of GBS is increased during the 6 weeks following Janssen/Johnson & Johnson COVID-19 vaccination. This is in addition to the previously added risk of thrombosis with thrombocytopenia syndrome (TTS), including cerebral venous thrombosis.


In July 2021, ACIP published in MMWR a report related to the overall risk/benefit of the 3 authorized vaccines for COVID-19, taking into account vaccine efficacy and side effect profiles. For the Janssen/Johnson & Johnson vaccine, the risk of GBS and TTS were assessed, while myocarditis was evaluated for the mRNA vaccines. Based on all data available through the end of June 2021, ACIP concluded that all recommended age groups should continue to be vaccinated as the potential harms of vaccines is outweighed by overall benefit of vaccine efficacy preventing cases, hospitalizations, intensive care unit admissions, and mortality. Continued monitoring for long-term safety signals is imperative along with continued education of the public and health care providers regarding vaccine benefits.3

People are exposed to substantial amounts of misinformation regarding adverse effects that have not been proven, such as infertility, and this may dissuade patients from receiving COVID-19 vaccination. In addition, benefits are likely underestimated in the MMWR report, as this analysis did not include any potential long-term symptoms known as “long COVID,” and this condition is being diagnosed significantly more frequently, including in children; the delta variant tends to be more transmissible in this age group compared with the original SARS-CoV-2 strain. One international cohort study demonstrated persistence of symptoms 7 months after infection, primarily from neurological/cognitive effects, with significant loss of productivity at work.4


The incidence of allergic reactions is still being estimated, but has been as high as 2% in one study; anaphylaxis has occurred at a rate of 2.5 per 10,000 patients vaccinated with either the Pfizer/BioNTech or Moderna mRNA vaccine.

A recent multicenter, retrospective, 3-month study at 4 centers in Massachusetts, Tennessee, Connecticut, and Texas examined the safety of a second dose of either vaccine in those patients with a history of immediate and potentially allergic reaction to the first dose. Tolerance was defined as no immediate symptoms after the second dose or symptoms that were mild, self-limited, and/or resolved with antihistamines alone. Patients who were not observed directly by allergy or immunology practitioners were contacted by telephone for details related to vaccination. Most of the 189 patients evaluated were women (86%) and received the Moderna vaccine (69%).5

The most common reactions reported with the first dose were flushing or erythema (28%), dizziness or lightheadedness (26%), tingling (24%), throat tightness (22%), hives (21%), and wheezing/shortness of breath (21%). Of note, 17% of patients met anaphylaxis criteria. Of the 189 patients who participated, 159 received a second dose without any intolerance. Approximately 20% reported immediate/potentially allergic symptoms that were mild, self-limiting, and/or resolved with antihistamine therapy.5

These results show that most patients who report an allergic reaction to a first COVID-19 vaccine dose may not have had a true allergic or an immunoglobulin (Ig) E–mediated reaction to the vaccine.5 This is extremely important, as full vaccination is the goal in protecting patients as much as possible against COVID-19 disease, especially with regard to severe clinical presentations leading to hospitalization and/or death.


The question of whether people can get booster doses of a different vaccine product than their initial dose or doses has been of interest recently for a number of reasons. First, some data suggest increased breakthrough infections with the delta variant in fully vaccinated patients, but this is difficult to quantify, as cases are generally not captured unless the patient is hospitalized or intensive screening is done, as occurs with professional athletes. While breakthrough infections are generally mild, there is evidence that fully vaccinated individuals may harbor enough virus to spread to someone else, although their length of contagious time is shortened compared with an unvaccinated patient. There is also increased interest to see if various combinations of vaccines may elicit a greater immune response over time to help potentially extend immunity.

At the Zuckerberg San Francisco General Hospital vaccination clinic, reports of increased risk of breakthrough infections in those who received the single-dose Janssen/Johnson & Johnson vaccine led to a decision that these individuals should be eligible to receive a supplemental dose of either mRNA vaccine. Mixing different types of vaccines has been performed in other studies, including experimental human immunodeficiency virus vaccines as well as the authorized Ebola vector vaccine.

A recent study published in the Lancet Infectious Diseases evaluated a strategy of giving a dose of ChAdOx1 nCoV-19 (not available in United States) followed by a boost vaccination with BNT162b2 (Pfizer/BioNTech) 9–12 weeks later. This strategy provided a significant increase in neutralization activity against SARS-CoV-2 compared with 2-dose homologous vaccination regimens of either product alone.6

A second study evaluated heterologous priming with the ChAdOx1 nCOV-19 followed by boosting with either BNT162b2 or mRNA-1273 (Moderna). This observational study in healthy adult volunteers demonstrated higher or comparable IgG to spike protein, neutralizing antibodies, and spike-specific CD4 T cells, compared with homologous mRNA 2-dose vaccine series. Overall strong humoral and cellular responses with good tolerability were demonstrated compared to homologous vector regimen.7

Another study also found that heterologous prime-boosted immunization with the ChAdOx1 nCoV-19 vaccine followed by the BNT162b2 vaccine 10–12 weeks later resulted in improved immunogenicity with similar tolerability.8

While initial findings are hopeful, more research is needed to fully establish the appropriate place in therapy of mixing the available COVID-19 vaccines. Future research should focus on timing of mixed vaccines, mixing of the adenovector Janssen/Johnson & Johnson vaccine with mRNA vaccines, and comparison of mixing vaccines with just giving booster shots with the same vaccine, such as those recently approved in the United States by the FDA for immunocompromised patients. In addition, these strategies may be compared with “tweaked” mRNA vaccines that may be developed in the future with enhanced activity against circulating variants, such as the delta variant.


Despite initial enthusiasm for convalescent plasma as a treatment option for COVID-19, randomized trials continue to demonstrate no benefit of this intervention.

The most recent negative trial was published in New England Journal of Medicine in August 2021. In this multicenter, randomized, single-blinded trial, patients in the emergency department were randomized to 1 unit of convalescent plasma or placebo, with all participants 50 years or older and having 1 or more risk factors for disease progression. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission (any reason), seeking emergency or urgent care, or death. Secondary outcomes were severity of illness, hospital-free days within 30 days after randomization, and death from any cause. For the primary outcome among 511 patients enrolled, disease progression occurred in 30% of the convalescent plasma group and 31.9% in the placebo group, not a statistically significant difference. Death occurred in 5 patients in the convalescent plasma group and 1 patient within the placebo group. There were no significant differences between groups for any of the secondary outcomes.9


The role of monoclonal antibodies in treatment of COVID-19 continues to evolve. The need for treatments is real: Millions of Americans remain unvaccinated or not fully vaccinated and people who are immunosuppressed cannot mount a sufficient response to vaccinations even after receiving the full regimens. When such individuals are infected by SARS-CoV-2, some are at high risk of infection-related morbidity and mortality.

On August 17, 2021, the COVID-19 NIH treatment guidelines expanded the use of casirivimab plus imdevimab to allow for postexposure prophylaxis administration. Patients with a recent exposure to SARS-CoV-2 consistent with the CDC definition of close contact and who are not fully vaccinated or are fully vaccinated but have an immunocompromising condition (such as taking antirejection medications such as tacrolimus or mycophenolate mofetil) can receive casirivimab 600 mg plus imdevimab 600 mg. Notably, this may be administered as an intravenous infusion or a subcutaneous injection. The subcutaneous dosage form should be administered as 4 injections at 4 different sites, while the intravenous dosage form is administered as a 1-time infusion over 1 hour. Each dosage form should be monitored for at least 1 hour after injection or infusion and should be given as soon as possible after confirmed exposure, ideally within 7 days. This recommendation also applies to patients who are at high risk of exposure based on location, such as residing in a prison or rehabilitation facility.

This recommendation continues to stress testing of patients with either nucleic acid amplification testing or antigen testing. Patients who test positive for SARS-CoV-2 who meet emergency use authorization criteria for treatment (not prophylaxis) should be considered for treatment with casirivimab plus imdevimab or sotrovimab monotherapy. Intravenous infusions are preferred for casirivimab plus imdevimab unless not feasible or when that route of administration would cause a delay in treatment; sotrovimab is only available as an intravenous infusion.


Numerous medications have been put forth for treatment of COVID-19 but later (and unfortunately) failed to improve outcomes. Research continues with a goal of translating basic science and clinical findings on older medications into clinically useful prophylactic or therapeutic approaches.

Fluvoxamine, a lesser known selective serotonin reuptake inhibitor most often used in the management of obsessive-compulsive disorder, has recently been in the news due to some cautiously optimistic findings regarding COVID-19 management. From a pathophysiologic standpoint, fluvoxamine has antiviral, antiplatelet, and anti-inflammatory activity that is mediated through a number of mechanisms. It also possesses strong activity at the sigma-1 receptor, which could play a role in treating viral infections by modulating innate and adaptive immune responses. But do these basic science mechanisms result in the desired clinical outcome benefits?

In a small, double-blind, randomized trial in the greater St. Louis, Missouri, metropolitan area, outpatient participants were randomized to either fluvoxamine or placebo starting at a dose of 50 mg the evening of the baseline assessment and eligibility confirmation. Doses were titrated to 100 mg twice daily for 2 days and then to 100 mg 3 times daily through day 15. After day 15, fluvoxamine was tapered over a maximum of 15 days and then discontinued. The primary outcome was clinical deterioration within 15 days of randomization defined by both shortness of breath or hospitalization for shortness of breath or pneumonia and oxygen saturation of 92% or less on room air or need for supplemental oxygen to achieve oxygen saturation of 92% or more.10

Results showed clinical deterioration in none of 80 patients in the fluvoxamine group and 6 of 72 patients in the placebo group (8.7% [95% CI 1.8%–16.4%]; P = 0.009). Tolerability was similar, with 12 adverse events in the fluvoxamine group and 18 in the placebo group, and more serious adverse events reported in the placebo group.10

A second real-world trial was published in Open Forum Infectious Diseases in the setting of a mass outbreak at a horse racing track in which 65 patients opted into fluvoxamine therapy (50 mg twice daily) and 48 declined. Hospitalization incidence was 0% in the fluvoxamine group and 12.5% of the observation group alone. At 14 days, symptoms persisted in none of the patients on fluvoxamine and 60% of patients on observation alone.11 Thus, while early returns on these small studies are hopeful, larger studies are needed to better determine the ultimate role of fluvoxamine.

Interim results from the TOGETHER adaptive platform trial were recently presented through the National Institutes of Health. This multinational study, conducted primarily in Brazil and Canada, uses an adaptive study design to evaluate a number of repurposed drugs for outpatient management of COVID-19 to prevent disease progression. A number of these agents have not proven fruitful, such as lopinavir/ritonavir and metformin and ivermectin. However, among 1,480 participants, those randomized to fluvoxamine 100 mg twice daily for 10 days (n = 739) demonstrated a statistically significant 19% decrease in need for emergency department observation (6 hours or more) or hospitalization compared with placebo (relative risk, 0.71 [0.54–0.93]). Final publication is pending, but fluvoxamine could offer a very inexpensive agent with potentially significant benefits, including decreases in emergency department visits and hospitalizations.


Currently, all authorized COVID-19 vaccines in the United States are administered intramuscularly, which is providing outstanding immunity clinically against severe disease as manifested by hospitalizations and death. However, with increased reports of breakthrough infections or even SARS-CoV-2 nasal carriage leading to spread via fully vaccinated individuals, researchers are looking at booster doses and possible additional administration methods, including an intranasal dosage form that could block SARS-CoV-2 both systemically and in the nasal passage.

A recent animal study in Science Translational Medicine evaluated administration of intranasal versus intramuscular vaccines in hamsters. Both routes of administration produced high levels of antibodies in the blood after a single dose. Concentrations were higher after intranasal administration compared to intramuscular administration. Hamsters were then exposed to SARS-CoV-2 through either direct inoculation or infected hamster close contact. While both routes of vaccine administration provided protection from serious illness, intranasally administered hamsters had less infectious virus in their nasal passages. Similar findings were seen in a small number of rhesus macaques inoculated with both dosage forms. A clinical study through the University of Oxford is currently evaluating this dosage form in human volunteers.12


As clinicians continue looking for the best interventions for preventing SARS-CoV-2 infections and treating COVID-19, researchers are also looking for oral therapies useful against this pathogen. FDA has neither authorized nor approved any oral agents, but their development and availability would be a breakthrough management strategy for limiting progression to moderate or severe disease and the associated morbidity and mortality.

Three leading candidates are being developed individually by Pfizer, Merck, and Shionogi. The Pfizer product (PF-07321332), is an orally active small-molecule inhibitor of the main protease of SARS-CoV-2. It has demonstrated activity in a mouse-adapted SARS-CoV-2 model and achieved plasma concentrations after oral administration exceeding in vitro antiviral cell potency in a phase I clinical study.

The Merck product, the ribonucleoside analog molnupiravir, inhibits replication of multiple RNA viruses including SARS-CoV-2. It has demonstrated activity against SARS-CoV-2 in multiple models as both a prophylactic and treatment modality. In a phase 2 trial among 202 participants, virus isolation was significantly lower in patients receiving molnupiravir (1.9%) at a dose of 800 mg daily versus placebo (16.7%) at day 3 (P = 0.02). Time to viral clearance was also statistically significantly better in the molnupiravir group (P =0.01). In a different phase 2 double-blind study, outpatients receiving molnupiravir were less likely to be hospitalized and/or die from moderate COVID-19 disease. Merck has a contract with the federal government to supply nearly 2 million doses at a price tag of $1.2 billion if molnupiravir is authorized by FDA.

Shionogi is somewhat behind Merck and Pfizer in progressing toward an approved agent. The company recently initiated a phase 1 study in Japan of S-217622 as a treatment for mild-to-moderate COVID-19 in the outpatient setting. SARS-CoV-2 possesses an enzyme called 3CL protease that is necessary for viral replication. S-217622 selectively inhibits this enzyme, leading to a quick, significant decrease in viral load in animal studies. While data are limited with regard to efficacy and toxicity with S-217622, the medication is expected to be tested as a once-daily oral therapy, which is different from the twice-daily Pfizer product.


  1. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 vaccine after reports of myocarditis among vaccine recipients: update from the Advisory Committee on Immunization Practices—United States, June 2021. MMWR Morb Mortal Wkly Rep. 2021;70:977–982. doi: 10.15585/mmwr.mm7027e2
  2. Diaz GA, Parsons GT, Gering SK, et al. Myocarditis and pericarditis after vaccination for COVID-19. JAMA. Published online August 4, 2021. doi: 10.1001/jama.2021.13443
  3. Rosenblum HG, Hadler SC, Moulia D, et al. Use of COVID-19 vaccines after reports of adverse events among adult recipients of Janssen (Johnson and Johnson) and mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna): update from the Advisory Committee on Immunization Practices—United States, July 2021. MMWR Morb Mortal Wkly Rep. 2021;70:1094-1099. doi: 10.15585/mmwr.mm7032e4
  4. Davis HE, Assaf GS, McCorkell L, et al. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. 2021(Aug 1);38:101019. doi: 10.1016/j.eclinm.2021.101091
  5. Krantz MS, Kwah JH, Stone CA Jr, et al. Safety evaluation of the second dose of messenger RNA COVID-19 vaccines in patients with immediate reactions to the first dose. JAMA Intern Med. Published online July 26, 2021. doi: 10.1001/jamainternmed.2021.3779
  6. Tenbusch M, Schumacher S, Vogel E, et al. Heterologous prime-boost vaccination with ChAdOx1 nCOV-19 and BNT162b2. Lancet Infect Dis. 2021;21(9):1212–1213. doi: 10.1016/S1473-3099(21)00420-5
  7. Schmidt T, Klemis V, Schub D, et al. Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination. Nat Med. Published online July 26, 2021. doi: 10.1038/s41591-021-01464-w
  8. Hillus D, Schwarz T, Tober-Lau P, et al. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation wth ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study. Lancet Resp Med. 2021 (Aug 12). doi: 10.1016/S2213-2600(21)00357-X
  9. Korley FK, Durkalski-Mauldin V, Yeatts SD, et al. Early convalescent plasma for high-risk outpatients with Covid-19. N Engl J Med. Published online August 18, 2021. doi: 10.1056/NEJMoa2103784.
  10. Lenze EJ, Mattar C, Zorumski CF, et al. Fluvoxamine vs placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial. 2020;324(22)2292–2300. doi:10.1001/jama.2020.22760
  11. Seftel D, Boulware DR. Prospective cohort of fluvoxamine for early treatment of coronavirus disease 19. Open Forum Infect Dis. 2021;8(2):ofab050. doi: 10.1093/ofid/ofab050
  12. van Doremalen N, Purushotham JN, Schulz JE, et al. Intranasal ChAdOx1 nCoV-19/AZD1222 vaccination reduces viral shedding after SARS-CoV-2 D614G challenge in preclinical models. Sci Transl Med. 2021;13(607):eabh0755. doi: 10.1126/scitranslmed.abh0755

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