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COVID-19 Monthly Update: Current COVID-19 Treatment Options as Bridges Toward a Vaccine
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to propagate across the United States and worldwide. At the time of this writing, global cases are approaching 50 million, with increases of more than 500,000 new cases per day, and global deaths have exceeded 1 million, according to the Johns Hopkins Coronavirus Resource Center. A recent Morbidity and Mortality Weekly Report (MMWR) article showed a 5-fold increased risk of in-hospital death and increased risk for 17 various complications, including some involving body systems other than the respiratory tract, among hospitalized Veterans Administration patients compared with patients hospitalized with influenza.1 Another report showed nearly 300,000 excess deaths from January to October 3, 2020, compared with the same period from 2019, with nearly 70% of these excess deaths attributed to COVID-19 and affecting primarily young Hispanic or Latinx persons.2
In the more than 300 days since the U.S. Centers for Disease Control and Prevention (CDC) first activated up to 7,400 federal workers to address the emerging coronavirus disease 2019 (COVID-19), the numbers of cases and deaths have ebbed and flowed depending on a number of factors. As the colder months are beginning in the Northern Hemisphere, cases are increasing worldwide, including Europe and nearly all states in the United States. A number of factors are involved, including growing restriction fatigue of citizens that has led to riskier activities, mixed and inconsistent messaging about masks and other preventive measures, colder weather forcing more indoor activities where increased transmissibility is more likely, and eased restrictions in certain districts.
While this news is not optimal, some silver linings are evident and more are likely to come. First, as we learn more about this disease, mortality rates in the United States have decreased in recent months (current case fatality rate of 2.7%); younger and healthier patients have composed most of the newer identified cases; improved and expanded testing and tracing have allowed more mild or even asymptomatic cases to be detected and isolated, with quarantining of those with potential exposure; and peer-reviewed data from higher quality studies have been published on a number of treatment options, allowing health professionals taking care of patients with COVID-19 to make better, informed decisions on appropriate management including nonpharmacologic therapies (e.g., proning patients on a mechanical ventilator) and pharmacologic treatments. Because of these data, treatment guidelines from the National Institutes of Health and other authoritative organizations have provided the most up-to-date recommendations for these agents. Additionally, emerging data are being reported — albeit not in peer-reviewed manuscripts at this point — on a number of novel therapies. And finally, the best news is that approximately 170 vaccine candidates are in development per the World Health Organization (WHO).
This article provides the most recent and relevant information on the various treatment options as well as potential vaccine candidates as the world moves hopefully closer to a long-term, viable solution for both treating and preventing COVID-19. The U.S. Food and Drug Administration (FDA) recently approved the first agent for COVID-19, and data are imminent for the well-publicized COVID-19 vaccines now in phase 3 trials.
Current State of Therapeutic Options for COVID-19
We have learned a lot about COVID-19 treatment options since the virus was first identified in December 2019. While a number of treatment options have not panned out, a select number have provided some form of benefit based on changes in morbidity and/or mortality; these are recommended in guidelines as well as used frequently worldwide to treat patients infected with SARS-CoV-2. This program updates information from prior Power-Pak programs about each medication (and if applicable medication class) with the most current information and recommendations.
On October 22, remdesivir became the first medication to be approved by FDA for use in adult and pediatric patients 12 years of age and older and weighing at least 40 kg for the treatment of COVID-19 requiring hospitalization. A nucleotide analogue, remdesivir has broad-spectrum antiviral activity in vitro and in vivo against a number of viral pathogens, including SARS-CoV-2. It inhibits viral RNA replication via antagonism of RNA-dependent RNA polymerase. It was studied extensively during the Ebola outbreak with mixed results.
Remdesivir is being studied in a number of ongoing, international phase 3 trials evaluating both efficacy and safety for COVID-19. While its FDA-approved indication covers pediatric patients and adults aged 12 years or older, an Emergency Use Authorization (EUA) issued previously was revised by FDA to cover use of remdesivir for treating hospitalized pediatric patients under 12 years of age weighing at least 3.5 kg or hospitalized pediatric patients weighing 3.5 kg to less than 40 kg with suspected or laboratory confirmed COVID-19 for whom use of an intravenous (IV) agent is clinically appropriate.
Remdesivir is currently administered only as an IV infusion; a 200-mg IV loading dose is followed by 100 mg IV daily for 5–10 days. A published, randomized, open-label phase 3 trial included patients with confirmed SARS-CoV-2 infection, radiologic confirmation of pneumonia, and oxygen saturation of 94% or less breathing room air; results showed no difference in outcomes between remdesivir durations of 5 days versus 10 days. Patients randomly assigned to the 10-day group had significantly worse clinical status that the 5-day assigned group (P = 0.02), making interpreting these results more difficult.3 Based partly on these findings, the Infectious Diseases Society of America (IDSA) guidelines recommend remdesivir be given for 5 days for most patients but stated 10 days of therapy is appropriate in hospitalized patients with severe COVID-19.
The National Institutes of Health (NIH) treatment guidelines recommend prioritizing the limited supplies of remdesivir for use in patients who are hospitalized with COVID-19 who require supplemental oxygen but who do not require oxygen delivery through a high-flow device, noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) (strength of recommendation, B; quality of evidence, I).4 The panel also recommends use of remdesivir for patients with COVID-19 in these situations:
- Hospitalized and requiring supplemental oxygen: For these patients, remdesivir can be given for 5 days or until hospital discharge (whichever occurs first) (A-I recommendation). Alternatively, dexamethasone (discussed below) can be given in concert with remdesivir therapy (B-III recommendation) or in place of remdesivir therapy (B-III recommendation).
- Hospitalized and requiring supplemental oxygen delivery through a high-flow device or noninvasive ventilation: Remdesivir is not recommended as monotherapy but rather in conjunction with dexamethasone (A-III recommendation).
- Hospitalized and requiring invasive mechanical ventilation or ECMO: Remdesivir is only recommended with dexamethasone in patients who have recently been intubated.
Of note, the WHO SOLIDARITY trial has been made available to the public via preprint.5 This study evaluated remdesivir among a number of options (hydroxychloroquine, lopinavir/ritonavir, interferon) and found little to no impact of any of these agents on in-hospital course or 28-day mortality. Unlike the Adaptive COVID-19 Treatment Trial (ACTT-1), which was a randomized and controlled trial of remdesivir, SOLIDARITY was an open-label trial across 405 hospitals in 30 countries. Until rigorous peer-review and publication are completed, it is difficult to evaluate these results, but it seems that remdesivir does not decrease mortality from COVID-19 infection. New questions are also being raised about how effective remdesivir is at decreasing other endpoints such as time to recovery. Whether remdesivir would work best earlier in COVID-19 presentation when viral replication is highest remains to be seen (and has not been established). A phase 3 trial of IV remdesivir in outpatients with initial COVID-19 infection is currently enrolling. Additionally, a nebulized dosage form is currently in development (phase 1a trial).
In summary, remdesivir is recommended primarily in patients who are receiving oxygen supplementation with benefit most likely in patients who do not have severe COVID-19 disease. In addition, remdesivir to this point has not demonstrated a decrease in mortality from COVID-19. Peer review and ultimate reconciliation of findings within the SOLIDARITY trial may change the current recommendations in national guidelines despite the recent approval of remdesivir by FDA.
Corticosteroids have long been studied and evaluated in a number of infectious diseases, especially those complicated by sepsis syndromes and/or acute respiratory distress syndrome (ARDS) due to anti-inflammatory effects that can decrease immune-mediated lung damage. Historically, these studies have often been conflicting, leaving in question the overall benefits versus known risks of systemic corticosteroid therapy. Fortunately, in the management of COVID-19, there have been clear positive results with corticosteroids.
Dexamethasone was recently studied in the RECOVERY Trial, which evaluated 6,425 patients hospitalized for COVID-19 in the United Kingdom.6 This was a randomized, controlled, open-label adaptive study. By evaluating a number of treatment options, agents could be dropped if this or other studies showed a lack of benefit, thereby increasing the focus on the most promising agents.
Dexamethasone 6 mg once daily intravenously or by mouth was administered for 10 days and compared with usual care. The patients receiving dexamethasone therapy had an overall decrease in 28-day mortality (22.9% vs. 25.7%; P <0.001), with the benefit most pronounced in patients who were receiving invasive mechanical ventilation at time of enrollment (29.3% vs. 41.4%; 0.64; 95% CI 0.51–0.81). This equates to a number needed to treat of 25 patients receiving oxygen or 8 patients receiving mechanical ventilation to prevent 1 death.
Based on the RECOVERY trial outcomes, the newly updated NIH guidelines made these recommendations regarding dexamethasone in patients with COVID-19 at studied dosages (in order of preference)4:
- Hospitalized or hospitalized with SARS-CoV-2 without requiring supplemental oxygen (moderate disease): Panel recommends AGAINST dexamethasone use.
- Hospitalized and requiring supplemental oxygen: Dexamethasone can be given concurrently with remdesivir therapy (B-III recommendation) or in place of remdesivir therapy (B-III recommendation).
- Hospitalized and requiring supplemental oxygen delivery through a high-flow device or noninvasive ventilation: Dexamethasone plus remdesivir therapy (A-III recommendation) or dexamethasone (A-I recommendation)
- Hospitalized and requiring invasive mechanical ventilation or ECMO: Dexamethasone (A-I recommendation) or dexamethasone plus remdesivir (C-III recommendation) in patients who have been recently intubated.
Use of hydrocortisone in patients with COVID-19 has been evaluated in 2 published studies. Dequin et al. randomized critically ill patients with respiratory failure to low-dose hydrocortisone (200 mg/d as continuous infusion titrated down based on response for total of 8–14 days of therapy) or standard care. Unfortunately, little can be gleaned from this study due to the trial ceasing early and therefore being too underpowered to detect any significant differences between the groups.7
The REMAP-CAP study was an open-label, adaptive-platform trial that evaluated IV hydrocortisone as a 7-day fixed-dose course (50 or 100 mg intravenously every 6 hours for 7 days) or hydrocortisone 50 mg intravenously every 6 hours when patients with COVID-19 had clinical shock versus standard of care for the disease. The probability of superiority (Bayesian cumulative logistic model) in patients with severe COVID-19 was 93% and 80% for fixed-dosing and shock-dependent–dosing strategies, respectively, versus standard of care for organ support-free days. However, the study was halted early when results from the RECOVERY trial were released demonstrating dexamethasone’s reduced mortality.8
In a prospective meta-analysis of 1,703 patients randomized to a corticosteroid (dexamethasone, hydrocortisone, or methylprednisolone) or placebo/usual care, 28-day all-cause mortality was lower in the active intervention group, with an overall summary odds ratio (OR) of 0.66 (95% CI 0.53–0.82). Values for the corticosteroids were dexamethasone (3 trials; OR 0.64; 95% CI 0.50–0.82 with P <0.001), hydrocortisone (3 trials; OR 0.69; 95% CI 0.43–1.12 with P = 0.13), and methylprednisolone (1 trial; OR 0.91; 95% CI 0.29–2.87 with P = 0.87). Therefore, it appears that most of this cumulative finding was driven by dexamethasone.9
The available guidelines vary on recommendations for corticosteroids other than dexamethasone, which is supported uniformly by the NIH, IDSA, and WHO for use in patients with severe critical or severe noncritical COVID-19. The WHO specifically recommends hydrocortisone 50 mg intravenously every 8 hours for 7–10 days as an alternative option to dexamethasone in patients with severe/critical COVID-19. The NIH and IDSA guidelines allow for use of other corticosteroids (e.g., prednisone, methylprednisolone, hydrocortisone) when dexamethasone is not available. However, because of the lack of effectiveness of other corticosteroids demonstrated thus far in the RECOVERY trial, dexamethasone should be preferentially used. Fortunately, this agent has intravenous and oral dosage forms, allowing for optimized use based on patients’ ability to tolerate oral therapy.
Passive antibody therapy in the form of convalescent plasma infusion is thought to potentially prevent infection with SARS-CoV-2 or minimize the severity of COVID-19. A typical regimen involves administration of 1 or 2 infusions of 200 mL each.
While the FDA issued an EUA in mid-August for convalescent plasma, the data supporting its use are difficult to interpret. Many of the studies of convalescent plasma were stopped early because of lack of plasma availability; studies that were completed are mostly of poor quality. The NIH guidelines do not recommend either for or against routine administration of convalescent plasma because of this lack of data evaluating its overall benefit or potential harm. The Surviving Sepsis Campaign and IDSA guidelines also do not recommend routine use; IDSA specifically recommends use only within the confines of a clinical trial.
A recent open-label, parallel, multicenter, randomized controlled trial across 39 public and private hospitals in India found no benefit for the primary outcomes of progression to severe disease or 28-day all-cause mortality.10 At this point, the role of convalescent plasma in the management of COVID-19 remains unknown, pending completion of higher quality studies.
Unlike previously discussed therapeutic agents discussed that are used primarily in the inpatient setting, newer monoclonal antibodies are being evaluated in the outpatient setting as infusions given to patients with mild to moderate symptoms of COVID-19. The idea is that these agents provide passive immunity for patients with known SARS-CoV-2 infection who have not yet mounted an immune response against the pathogen. These antibodies bind to different regions of the SARS-CoV-2 spike protein, which plays a major role in receptor recognition and eventual infection. Four products are in various stages of clinical trials. These include REGN-COV-2 (Regeneron), LY-CoV555 and LY-CoV016 (Lilly), and AZD7442 (AstraZeneca).
REGN-COV-2 is a combination of two different monoclonal antibodies, REGN 10933 and REGN 10987. Results of a descriptive analysis were recently announced by the company but have not yet been peer reviewed. In the first 275 patients enrolled, patients were randomized 1:1:1 to receive placebo, a single infusion of 2.4 g of REGN-COV-2, or a single infusion of 8 g of REGN-COV-2. Nearly half of patients enrolled had developed SARS-CoV-2 antibodies (45%), and 41% remained seronegative. In the key virologic outcome, the higher doses of REGN-COV-2 significantly decreased viral load through day 7 in seronegative patients compared with placebo (P = 0.03); the decrease in viral load among patients on the lower dose failed to reach significance (P = 0.06). The greatest viral load reductions occurred in those patients with the highest baseline viral loads. Among the seronegative patients, median times to mild symptoms or asymptomatic were not changed significantly: 13 days with placebo, 6 days in the 2.4-g group (P = 0.09), and 8 days in the 8-g group (P = 0.22). From a side effect standpoint, infusion reactions were seen in 4 patients (2 each in the placebo and REGN-COV-2 groups). More than 2,000 participants have been enrolled to this point with no signal indicating unexpected safety issues. No deaths have occurred.
REGN-COV-2 is also being studied as well as part of the RECOVERY trial (phase 3) and also in a phase 3 prophylaxis trial with the National Institute of Allergy and Infectious Diseases (NIAID), a unit within the NIH.
Regeneron has submitted a request to the FDA for an EUA. If granted, the company has contracted to sell up to 300,000 treatment doses to the U.S. Government for a reported $450 million; the product would then be available to United States citizens at no cost.
Ultimately, peer review of these and additional data will determine the ultimate role of REGN-COV-2 within the management of COVID-19. There are obvious logistical concerns with any of these antibodies because they must be administered intravenously. Who exactly will administer these agents? How exactly will costs be covered by the government? The process will have to be well defined as the monoclonal antibodies have most benefit early in the infectious process; infusions would ideally occur early after infection and before seroconversion.
LY-CoV555 and LY-CoV016
Two investigational monoclonal antibodies, LY-CoV555 and LY-CoV016, are being studied by Lilly. Both were isolated from a blood sample from a patient with COVID-19 who had recovered from their illness early in the pandemic. LY-CoV555, also known as bamlanivimab, is a neutralizing IgG-1 monoclonal antibody that binds to the SARS-CoV-2 spike protein region, thereby blocking viral attachment and passage into cells with the potential to both prevent and treat SARS-CoV-2. LY-CoV016, also known as JS016 and etesevimab, also binds SARS-CoV-2 spike protein but in a different region that blocks the binding of the virus to the well-known angiotensin converting enzyme 2 (ACE2) host cell surface receptor. This antibody, like LY-CoV555, has potential for both prevention and treatment of SARS-CoV-2.
A number of studies of these antibodies are planned or ongoing, primarily with LY-CoV555. The ACTIV-2 study is a phase 2 trial being sponsored by the NIH that will compare LY-CoV555 to placebo in approximately 200 outpatients with mild-to-moderate COVID-19 who have symptoms for 10 days or less. The NIH is also studying LY-CoV555 versus placebo in approximately 300 patients who are hospitalized with mild-to-moderate COVID-19 who have symptoms for fewer than 13 days.
Initial results were published for the BLAZE-1 study, an ongoing phase 2, randomized, double-blind, placebo-controlled trial evaluating various dosages of LY-CoV555 (700 mg, 2800 mg, or 7000 mg) versus placebo. Additionally, a dual therapy cohort of LY-CoV555 (2800 mg) plus LY-CoV016 (2800 mg) versus placebo was also evaluated.11
In the LY-CoV555 monotherapy treatment group, decrease in viral load was statistically significant only for the 2800 mg dose, with complete clearance documented by day 11 in most patients. Most patients in the placebo group also had documented clearance by day 11. In secondary analyses, emergency department visit or hospitalization occurred in 1.7% of patients receiving LY-CoV555 group, compared with 6% of placebo patients. Treatment-emergent side effects were comparable to placebo.11
For the dual therapy cohort, a statistically significant (P = 0.011) reduction in viral load was demonstrated compared with placebo by day 11. Like the monotherapy cohort, complete clearance was demonstrated for most patients in both the treatment and placebo arms. The combination group also reduced viral levels at day 3 (P = 0.016) and day 7 (P <0.001) as well as reducing symptoms versus placebo. Like the monotherapy group, SARS-CoV-2–related emergency department visits and hospitalizations were decreased versus placebo (0.9% vs. 5.8%), but these were overall low numbers of patients to make any meaningful statistical analysis. Treatment-emergent side effects were comparable to placebo.11
Lilly is focused on the 700 mg dosage of LY-CoV555 since “similar clinical effects were seen across all dose levels tested in BLAZE-1.” This is a bit surprising considering the statistically significant effects were seen primarily with the 2800 mg dose. The manufacturer estimates that it will have as many as 1 million doses of LY-CoV555 monotherapy available during quarter 4 2020. Combination therapy will increase significantly in the first quarter of 2021 because of expanded capacity based on a manufacturing partnership with Amgen. Further manufacturing resources are being sought for resource-limited developing countries internationally.
Based on these initial findings from the BLAZE-1 study, Lilly has submitted a request to the FDA for an EUA for LY-CoV555 monotherapy in higher-risk patients with COVID-19 of mild-to-moderate severity. If clinical trial enrollment continues to increase and no signals are seen for significant side effects with either antibody, a planned submission to the FDA for an EUA for combination therapy should be completed in November 2020. If an EUA is approved, Lilly is contracted to sell the U.S. Government 300,000 doses of LY-CoV555 for $375 million.
In October 2020, the NIH/NIAID paused and then terminated the ACTIV-3 trial because an interim data assessment indicated that LY-CoV555 is unlikely to be of benefit to patients hospitalized with COVID-19. Also during October, the FDA cited the Branchburg, New Jersey, Lilly facility on 2 counts of “inadequate control of computer systems,” which included deleted data on the company’s manufacturing processes and failed quality control over audit paper trails.
AstraZeneca is early in its studies of a monoclonal antibody product, a combination of AZD8895 and AZD1061 that work in concert to bind to distinctly different portions of the COVID-19 spike protein. These antibodies were discovered at the Vanderbilt Vaccine center in partnership with AstraZeneca and could provide a prevention and treatment option for SARS-CoV-2. Proprietary technology is being used in an attempt to extend the half-lives of the molecules. One unique aspect of the clinical evaluation is an intramuscular dosage form in phase 1 trials. This would provide a unique dosage form and make logistics of administration much easier if comes to fruition, allowing for scaling of doses and administration in a much broader manner. However, these studies are in extremely early stages, making it difficult to know whether this dosage form will pan out as an option.
In conclusion, while much fanfare has been made about monoclonal antibodies and initial news releases have been positive overall, initial peer-reviewed evaluations of clinical studies are being published, and the ultimate roles for the agents within therapy have yet to be defined. As evidenced by the termination of the ACTIV-3 trial with LY-CoV555, data are needed before conclusions can be reached. Even if the data are supportive, significant logistical concerns concerning storage and administration could be limiting.
Janus Kinase Inhibitors
Inhibiting Janus kinase (JAK) enzymes could lessen the effects of SARS-CoV-2–mediated inflammation and lung damage in severely infected patients by decreasing signaling responsible for pro-inflammatory cytokines, such as interleukin-6. While some are approved by FDA for the treatment of rheumatoid arthritis, none are currently recommended routinely for treatment of COVID-19. The NIH guidelines do not recommend JAK inhibitors outside of a clinical trial; the risk of significant adverse effects is high because of the drugs’ wide immunosuppressive effects, resulting in the potential for opportunistic infections such as tuberculosis. The two primary JAK inhibitors currently being evaluated for treatment of COVID-19 are baricitinib (Olumiant) and ruxolitinib (Jakafi). Most reported data so far have been with baricitinib.
Baricinitib was included as part of the adaptive ACTT-2 study, which was a phase 3 randomized, double-blind, placebo-controlled trial comparing remdesivir (standard dosing up to 10-day course) versus remdesivir (standard dosing up to 10-day course) plus baricitinib 4 mg orally daily for the duration of hospitalization up to 14-day course. The mean recovery time was approximately 1 day shorter in the combination group (7 vs. 8 days; P = 0.04), with greater odds of clinical improvement with the combination (OR 1.3; 95% CI 1.0–1.6; P = 0.04). Mortality was lower through day 29 with the combination but not statistically significant (5.1% vs. 7.8%; P = 0.09); the greatest benefit was observed in patients receiving supplemental oxygen therapy.
These results, while appearing favorable, have not been peer reviewed or published, and in light of the SOLIDARITY findings, they should be interpreted with caution. Additionally, study participants must be monitored closely for potential adverse reactions, including new infections, for the overall risk-to-benefit ratios to be meaningful.
THERAPIES OF LIMITED POTENTIAL BENEFIT
While a large number of therapies have been evaluated since the beginning of the pandemic, most have not shown benefit, and large registry trials through government organizations are no longer enrolling patients on those agents so that the adaptive format being used in the registries can be focused on the most promising regimens. Multiple studies with hydroxychloroquine with or without azithromycin and lopinavir/ritonavir have shown no benefit and some with potential harm (i.e., QTc prolongation), and therefore use of these agents is not supported by NIH guidelines.4
Two recent studies have cast doubt on future utility of interleukin-6 antagonists, specifically tocilizumab (Actemra). Used frequently early in the pandemic, this agent has produced mixed data (at best), often of poor quality (primarily case reports and case series). Stone et al. reported in the New England Journal of Medicine that tocilizumab was not effective for preventing intubation or death in moderately ill, hospitalized patients with COVID-19 with nearly 50% of patients Hispanic or Latinx.12 Salvarani et al., writing in JAMA Internal Medicine, also demonstrated no benefit of tocilizumab in hospitalized patients with COVID-19 early in their course in an open-label, randomized trial.13 The lack of benefit demonstrated in these higher quality studies in conjunction with significant immunosuppression conferred by these agents likely will lead to recommendations against routine use of interleukin-6 antagonists when treating COVID-19.
VACCINES: WHERE WE STAND
Current treatment options for COVID-19, based on available published data, are limited in their effectiveness. Only one treatment to date (dexamethasone) has demonstrated a mortality benefit in the sickest of COVID-19 patients. Research continues into therapeutic approaches that can attenuate the SARS-CoV-2 at earlier stages of infection and limit potential longer-term adverse effects associated with COVID-19. The hope is that antiviral agents, antibodies, and passive immunity products can provide a bridge from the widespread pandemic to an effective vaccine.
Given recent reports of isolated reinfection and limited treatment options in the outpatient setting where earlier treatment could be provided more easily, vaccine therapy provides the greatest opportunity to effectively provide herd immunity and move society closer to normalcy going forward. However, no vaccine is currently approved in the United States, and it is important to ensure that vaccines are indeed safe and effective before widespread administration. FDA in late October gave renewed assurances that only those vaccines that are demonstrated to be safe and effective will be licensed for use.
This is critical as data show that many Americans would not get vaccinated even if FDA approved a product deemed to be safe and effective. A Pew Research study performed in September 2020 showed that among all adults, only 51% would definitely or probably get the vaccine, while 24% would definitely not get the vaccine, limiting the overall effectiveness toward the ultimate goal of herd immunity. The number of those willing to get the vaccine was down nearly 20% from a similar survey performed in May 2020. Only 43% of Black Americans, a group whose socioeconomic disparities and other factors place them at highest risk for significant morbidity and mortality, now say they will receive the COVID-19 vaccine once available per a recent Harris poll. This figure has decreased by 22 percentage points since August.
As of this writing, 48 vaccines are in clinical trials on humans and nearly 90 are in preclinical evaluation in animals. Of the vaccines in clinical testing, 15 vaccine candidates are in expanded phase 2 safety trials, and 11 candidates are in phase 3 large-scale efficacy testing. Six vaccines are approved for early or limited use, all outside of the United States — primarily in Russia and China. At the opening address of IDWeek 2020 on October 21, Dr. Anthony Fauci of the NIAID stated, “Looking at the number of infections in the country and the distribution of the trial sites, we feel confident that we will have an answer likely in mid-November to the beginning of December as whether we have a safe and effective vaccine.”
The phase 2 and 3 vaccine candidates are generally divided into nucleic acid (Moderna and BioNTech/Pfizer), viral vector (AstraZeneca, Janssen/Johnson and Johnson) and protein subunit (Novavax) platforms. Moderna announced on October 22 completion of enrollment in its phase 3 trial with more than 30,000 participants, including more than 30% representing minority participants. Approximately 25% of population studied was 65 years of age or older, one of the highest risk patient groups for morbidity and mortality if infected with SARS-CoV-2.However, Johnson and Johnson has paused its trial due to an “unexplained illness” in one of the volunteers. It is unknown if the patient received the experimental vaccine or not. AstraZeneca had initially placed their trials on hold globally on September 6 because of a report of transverse myelitis; within a week, the trials restarted outside the United States. The FDA authorized a restart of trials within the United States in late October.. A study participant who died in Brazil is believed to have not received the vaccine.
A major concern going forward is how vaccines will be distributed and administered in an organized, widespread manner to ensure fair and efficient allocation. Logistical concerns such as having enough freezers to store large quantities of vaccine as well as prioritization of patient populations are major factors to work through as we work toward an approved vaccine in the United States. Pfizer so far has spent $2 billion on developing the vaccine as well as the distribution network, with a goal of delivering up to 100 million doses in 2020 and 1.3 billion doses in 2021. The company could apply for an EUA for this vaccine by late November if key milestones within the trials are met.
Palantir Technologies, Inc., a data-mining software company headquartered in Palo Alto, California, has formally partnered with the U.S. government to help organize a system to track manufacturing, distribution, and ultimately administration of COVID-19 vaccines. The system would help “triage” patients to help identify the highest-risk patients who would benefit from vaccination such as older adults (especially those residing in long-term care facilities), health care workers, and immunocompromised individuals. It would allow health authorities to “integrate a wide range of demographic, employment, and public health data sets to identify the location of priority populations,” according to documents reviewed by the Wall Street Journal. This would allow real-time data analysis, including inventory levels and documentation of administration to patients. These analyses and maps created by Palantir will theoretically allow rapid allocation decisions to be made resulting in distribution and ultimate administration to patients. This system would also track delivery of vaccines to hospitals, clinics, and other places of administration.
Pandemic fatigue has limited Americans’ compliance with mitigation strategies that could decrease transmission of SARS-CoV-2, and cases, hospitalizations, and deaths are on the rise as the weather turns colder. While the nation waits for data on investigational COVID-19 vaccines, some beneficial treatment outcomes have been achieved with a repurposed older drug (dexamethasone), but further questions have arisen with remdesivir, which is recommended in current guidelines and recently approved by FDA. Initial data with monoclonal antibodies in patients who are infected with SARS-CoV-2 but not yet seroconverted appear promising, but more studies are required to give a full evaluation.
The light at the end of the tunnel of an FDA-approved vaccine that is safe and effective gives hope that the pre-2020 — or at least a postpandemic — normalcy is within reach, but time will tell whether this is correct. Should an EUA be approved for a COVID-19 vaccine, distribution and administration would likely happen in early 2021, beginning with health care workers and other first responders followed by the highest-risk older adults. That would indeed be the best-case scenario and give everyone hope on the path toward life after the 2020 pandemic.
- Cates J, Lucero-Obusan C, Dahl RM et al. Risk for in-hospital complications associated with COVID-19 and influenza—Veterans Health Administration, United States, October 1, 2018-May 31, 2020. Morb Mortal Wkly Rep. 2020;69:1528–1534.
- Rossen LM, Branum AM, Ahmad FB, et al. Excess deaths associated with COVID-19, by age and race and ethnicity—United States, January 26-October 3, 2020. Morb Mortal Wkly Rep. 2020;69:1522–1527.
- Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med. 2020 May 27. Epub ahead of print. doi: 10.1056/NEJMoa2015301
- COVID-19 Treatment Guidelines Panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. Available at: https://www.covid19treatmentguidelines.nih.gov/. Accessed October 23, 2020.
- WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19; interim WHO SOLIDARITY results. October 15, 2020. doi:10.1101/2020.10.15.20209817
- RECOVERY Collaborative Group. Dexamethasone in hospitalized patient with COVID-19 — preliminary report. N Engl J Med. 2020 July 17. Epub ahead of print. doi: 10.1056/NEJMoa2021436
- Dequin PF, Heming N, Meziani F, et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324:1–9.
- The Writing Committee for the REMAP-CAP Investigators. Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain randomized clinical trial. 2020;324:1317–1329.
- The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19. 2020;324:1330–1341.
- Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P, on behalf of the PLACID Trial Collaborators. 2020;371:m3939. doi: 10.1136/bmj.m3939
- Chen P, Nirula A, Heller B, et al. SARS-CoV-2 neutralizing antibody LY-CoV555 in outpatients with Covid-19. N Engl J Med. 2020 Oct 28. Epub ahead of print. doi: 10.1056/NEJMoa2029849
- Stone JH, Frigault MJ, Serling-Boyd NJ et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020 Oct 21. Epub ahead of print. doi:10.1056/NEJMoa2028836
- Salvarani C, Dolci G, Massari M et al. Effect of tocilizumab vs. standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia. JAMA Intern Med. 2020 Oct 20. Epub ahead of print. doi: 10.1001/jamainternmed.2020.6615
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