On 5/17/2022 the FDA approved a booster dose for children 5 to 11 with the Pfizer-BioNTech COVID-19 vaccine. The CDC updated their COVID-19 vaccine recommendations to include a booster for this age group five months after the primary series. The CDC also recommends a second booster (fourth vaccination) for immunocompromised patients 12 and older and everyone older than 50, at least four months after their first booster (third vaccination).
In a review of VAERS data, the CDC found no increase in the occurrence of myocarditis with the Pfizer-BioNTech COVID-19 vaccine in males 5 to 11.
Pfizer-BioNTech announced that in a 1,678 patient, Phase II/III trial, vaccine efficacy after three 3mcg doses of their COVID-19 vaccine in children six months to five years was 80.3%. Antibody titers were similar in young children as in patients 16 to 25 years. The third dose was given two months after the second and the trial was done when Omicron was the dominant variant.
The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) will meet on 6/14/2022 to discuss use of the Moderna COVID-19 vaccine in patients 6 years through 17 years of age. On June 15 VRBPAC will discuss use of the Pfizer-BioNTech COVID-19 vaccine in patients 6 months through 4 years of age.
In the WHO sponsored, open-label 8,275 patient, Phase III SOLIDARITY trial (NCT04315948), treatment with remdesivir did not improve mortality compared to placebo in the hospitalized patients with COVID-19. There was no statistical difference in mortality in patients who already required ventilation but mortality was lower in patients not on a ventilator (11.9% vs. 13.5%). Among patients not requiring mechanical ventilation at treatment initiation, fewer remdesivir patients progressed to a ventilator than those who received placebo (14.1% vs 15.7%).
Clazakizumab, is an interleukin-6 (IL-6) inhibitor being evaluated by CSL Behring as a treatment for hospitalized patients with severe or critical COVID-19 disease accompanied by hyperinflammation.
ICER provided a review of drugs for outpatient treatment of COVID-19. ICER found that compared to symptomatic treatment:
All three drugs were found to be cost effective, with a quality-of-life year gained (QALY) < $100,000. The cost of an averted hospitalization was also < $100,000.
In the 4,016 patient, Phase II/III KidCOVE trial (NCT04796896), two 50 mcg doses of Moderna’s COVID-19 vaccine, given 28-days apart, elicited immunogenicity in children 6 to under 12 years of age that was similar to young adults, age18 to 25 years, who received two 10 mcg doses. Vaccine efficacy was estimated to be 88% during a period when the delta variant was dominant.
A CDC test-negative, case-control study, using data from December 2021 to February 2022, estimated the Pfizer-BioNTech COVID-19 vaccine effectiveness against symptomatic infection for children 5 to 11 years as 60% one month after the second vaccine dose and 29% after two months. Vaccine effectiveness for adolescents 12 to 15 years of age was 60% one month after the second dose and 17% after two months. Vaccine effectiveness for adolescents who received a booster dose was 71%.
The FDA expanded the EUA for the Pfizer-BioNTech COVID-19 vaccine to include a single booster dose, at least five months after completion of a primary series, for children 5 to 11 years. Only the Pfizer-BioNTech vaccine is approved for use in this age group.
Based on the review of available scientific evidence the FDA declined to approve an emergency use authorization (EUA) for fluvoxamine for the treatment of COVID-19 because the data was insufficient to support use of the drug in the treatment for COVID-19.
NIH has provided a reference page to describe drug interactions and their management for Paxvolid (ritonavir-boosted nirmatrelvir).
The FDA limited the authorized use of the J&J COVID-19 Vaccine to when mRNA vaccines are not accessible or clinically appropriate or for patients who choose to receive the vaccine and would otherwise not receive a COVID-19 vaccination. The FDA considers the known and potential benefits of the vaccine to outweigh the known and potential risks of receiving it. The restriction was due to the rare occurrence of thrombosis with thrombocytopenia syndrome (TTS). TTS is estimated to have an incidence of 3.23 cases per million vaccinations and 0.48 deaths per million. Risk factors for TTS associated with the J&J vaccine have not been identified and prompt diagnosis and treatment of TTS may not prevent deterioration of the condition.
A pre-print draft of an Israeli analysis examining SARS-CoV-2 antibodies during pregnancy, found antibodies levels were too low to provide protection by delivery in 34.6% of patients who experienced a first trimester infection and 9.1% who experienced a second trimester infection. A single dose of the Pfizer COVID-19 vaccine induced protective antibody titers for both mother and infant with modest adverse effects.
The FDA has provided additional information about use of Paxlovid in a new posting. The FDA addresses reports of rare infection recurrences after completing a course of the drug combination. A re-analysis of Paxlovid data found that while 1-2% of patients may test positive after treatment, it was unclear whether this was a drug effect, because the same results were seen in placebo patients (tested negative, then tested positive). However, the FDA stated there is no evidence to support use of the drug beyond five days.
COVID-19 Convalescent Plasma
In a 28-day, 1,181 patient, Phase II trial (NCT04373460), 2.9% of patients treated with high titer convalescent plasma, within nine day of symptom onset, were hospitalized for COVID-19 compared to 6.3% with placebo in outpatients with recent onset of COVID-19. Over 80% of patents were unvaccinated.
The FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) will meet on June 8, 21 and 22 to review use of Moderna and Pfizer/BioNTech COVID-19 vaccines in children under six.
The FDA expanded approval for remdesivir, on 4/25/2022, for children 28 days and older, who weigh at least 3 kg (7 lbs), if they are hospitalized or outpatients at high risk for progression to severe COVID-19.
Pfizer announced that in the 14-day, 2,597 patient, Phase II/III, EPIC-PEP trial (NCT05047601), prophylactic treatment with nirmatrelvir plus ritonavir did not reduce the risk of developing symptomatic COVID-19 compared to placebo in healthy patients exposed to a patient that developed COVID-19.
COVID-19 Monoclonal Antibodies
NIH does not recommend using bamlanivimab plus etesevimab, casirivimab plus imdevimab, nor sotrovimab for the treatment of COVID-19 due to lack of activity for the Omicron variant. NIH only recommends use of bebtelovimab when ritonavir-boosted nirmatrelvir (Paxlovid) or remdesivir are not available.
COVID-19 Convalescent Plasma
NIH recommends against the use of convalescent plasma that was collected prior to the emergence of the Omicron (B.1.1.529) variant. Convalescent plasma should not be used for treatment of COVID-19 in hospitalized, immunocompetent patients. NIH did not find sufficient evidence to recommend either for or against the use of high-titer convalescent plasma, collected after the emergence of Omicron for the treatment of immunocompromised patients and nonhospitalized, immunocompetent patients with COVID-19.
Pfizer and BioNTech announced immunology data from a 140 patient, Phase II/III trial, where a booster dose of their COVID-19 vaccine, given six-months after the initial series, produced a six-fold increase in antibodies one month after the booster compared to antibody titers one month after the second dose in children 5 through 11 years of age. A sub-analysis of 30 patients found that the Omicron variant was neutralized by the antibodies.
A pre-print draft describes an 895 patient, open-label, Phase II/III trial, where a bivalent COVID-19 vaccine developed by Moderna was tested against its approved vaccine. The bivalent vaccine consisted of the original vaccine with the addition of mRNA for the Beta variant spike proteins. Compared to original vaccine, the bivalent vaccine elicited increased antibody titers for the original virus and Beta, Omicron and Delta variants after 28 days. Antibody titers levels were still elevated for the bivalent vaccine at 180 days for the original Beta, Omicron variants. The bivalent vaccine was given as a booster about nine months after the primary series. Moderna is also developing a bivalent vaccine that combines the original vaccine with mRNA for the Omicron variant spike proteins. A blinded randomized trial for this vaccine will be reported in 2Q22. Moderna feels the Omicron bivalent vaccine will be chosen for use as a booster in the fall.
A systematic review and meta-analysis of 29 studies involving 11,713 solid organ transplant patients identified risk factors for decreased antibody titers. The risk factors included older age, recent transplantation, deceased donor status, active use of antimetabolites, and recent exposure to antithymocyte globulin or rituximab. Receiving additional doses of an mRNA vaccine increased the chance of developing higher antibody titers.
British researchers analyzed the vaccine effectiveness (VE) for the Omicron variant for COVID-19 vaccines from Pfizer-BioNTech and AstraZeneca.
In the six-month, 5,197 patient, Phase III, PROVENT trial (NCT04625725), 0.3% of patients who received a prophylactic dose of tixagevimab plus cilgavimab developed symptomatic COVID-19 compared to 1.8% who received placebo in adults at increased risk of an inadequate response to COVID-19 vaccination.
The FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) did not develop a plan for COVID-19 vaccine booster composition or timing of additional boosters. In addition to attempting to predict which variant will be dominant, half of the U.S. population has not received a booster dose, so how to optimize protection for everyone will be more of a challenge. VRBPAC members agreed the goal for booster doses should be prevention of hospitalization and death in at least 80% of patients. Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research, said the fourth dose vaccine dose was a reasonable approval until a new booster, that would preferably have longer-lasting protection, was available. He felt frequent use of boosters was not a strategy that should be continued. VRBPAC will meet again to discuss more specific details of a booster program for COVID-19.
The CDC endorsed the FDA’s approval of a second booster vaccination and recommended certain immunocompromised individuals and people over the age of 50 who received an initial booster dose at least 4 months be eligible for a second booster (fourth dose) or an mRNA COVID-19 vaccine.
A CDC analysis of COVID-19 vaccine effectiveness (VE) from 12/16/2021 to 3/7/2022 found that for preventing emergency department/urgent care visits VE was 24% for one J&J vaccination, 54% after two J&J doses, 79% after one J&J vaccination followed by one mRNA dose, and 83% after three mRNA doses. VE for the same vaccine regimens to prevent COVID-19 associated hospitalizations was 31%, 67%, 78%, and 90% respectively.
In a 2,812 patient, case–control, test-negative trial, vaccine effectiveness (VE), of the Pfizer-BioNTech COVID-19 vaccine, for the Omicron variant was 20% for non-critical COVID-19, 40% to prevent COVID-19 hospitalizations and 79% for critical COVID-19 in adolescents 12 to 18 years of age with a median interval since vaccination of 162 days. VE was 68% to prevent COVID-19 hospitalizations in children 5 to 11 years of age, with a median interval since vaccination of 34 days.
A CDC analysis of EHR data from 40 health systems found the risk for myocarditis, pericarditis, or multisystem inflammatory syndrome to be 2 to 6 times higher in 12 to 17 year old boys who experienced a COVID-19 infection compared to receiving an mRNA COVID-19 vaccine. In young men 18 to 29 years, the risk is 7 to 8 times higher with infection over vaccination.
An analysis of EHR data from 1,252,331 Israeli patients, who were 60 and older, found that a fourth vaccination with an mRNA COVID-19 vaccine lowers the risk by half for a confirmed infection. But the protection wanes and only lasts about eight weeks. Protection against severe cases of COVID-19 were three times lower and did not appear to decrease over time. The study was too short to estimate the duration of protection against severe disease.
NIH Outpatient Treatment Update
NIH recommend that nonhospitalized patients with mild to moderate COVID-19 who are at high risk of disease progression, be treated with (in order of preference):
Alternative Therapies if nirmatrelvir boosted with ritonavir or remdesivir are not available or an inappropriate choice for the patient, then one of the following therapies can be used.
The FDA no longer authorizes sotrovimab to treat COVID-19 in the U.S. due to the Omicron BA.2 sub-variant becoming the dominant variant. The CDC reports that BA.2 now accounts for 72.2% of all COVID-19 cases with BA.1.1 accounting for most of the remaining cases.
In a 28-day, 1,181 patient, Phase II trial (NCT04373460), 2.9% of patients treated with high titer convalescent plasma were hospitalized for COVID-19 compared to 6.3% with placebo in outpatients with recent onset of COVID-19.
In the 28-day, 3,515 patient, Phase III, TOGETHER trial (NCT04727424), treatment with ivermectin did not reduce COVID-19 hospitalizations or urgent-care visits compared to placebo in high-risk Brazilian outpatients with COVID-19.
The FDA placed a partial hold on leronlimab HIV trials and a full hold on leronlimab COVID-19 trials in the United States. At the same time, CytoDyn decided to place a hold on its leronlimab COVID-19 Brazilian trial pending review of two cardiac events by the data safety monitoring board.
A revised (3/28/2022) ICER review of drugs that are effective to treat the COVID-19 Omicron variant found that compared to no active treatment:
The CDC found that sotrovimab is not active against the BA.2 Omicron subvariant. NIH (ASPR) will stop distributing sotrovimab in stares and territories where BA.2 has reached 50% frequency. This includes HHS Region 1 (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont) and Region 2 (New Jersey, New York, Puerto Rico, and the Virgin Islands).
A Canadian retrospective analysis of 97,590 pregnant patients and a retrospective study of 157,521 singleton births in Sweden and Norway found that COVID-19 vaccination during pregnancy did not increase the risk of adverse peripartum outcomes compared with vaccination after pregnancy and with no vaccination. Most patients received an mRNA vaccine during the second and third trimester in both studies.
On 3/29/2022, the FDA approved a 4th dose (2nd booster) of mRNA #COVID-19 vaccines for patients 50 and older. In cetain immunocompromised patients the age is lowered to12 and older with the Pfizer-BioNTech vaccine and 18 and older with the Moderna vaccine. This decision was made before a scheduled meeting to discuss vaccine boosters. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC), CDC and NIH will meet on 4/6/2022 to discuss additional COVID-19 vaccine boosters and how to select specific SARS-CoV-2 virus strains for COVID-19 vaccines to address current and emerging variants.
Synairgen announced that NIAID had discontinued the Phase II/III ACTIV-2 COVID-19 trial (NCT04518410) in March 2022, due to changes in the pandemic that necessitate a change in how COVID-19 therapies are evaluated. ACTIV-2 was evaluating several drugs in the treatment of COVID-19.
Eiger BioPharmaceuticals announced that in the 28-day, 4,669 patient, Phase III TOGETHER trial (NCT04727424), 2.7% of patients treated with peginterferon lambda were hospitalized or had an ER visit compared to 5.6% with placebo in non-hospitalized adult Brazilian patients with COVID-19, who were at high risk of progressing to severe illness.
The Vaccines and Related Biological Products Advisory Committee (VRBPAC), CDC and NIH will meet on 4/6/2022 to discuss additional COVID-19 vaccine boosters and how to select specific SARS-CoV-2 virus strains for COVID-19 vaccines to address current and emerging variants.
Based on previously announced data in older children from the 11,700 patient, Phase II/III KidCOVE trial(NCT04796896), Moderna is requesting approval for use of its COVID-19 vaccine in children 6 to 17 years old.
We’d like to thank Emily Stock, TJ Lawall and Randy Haley who helped to update the open-access Prescribe Right COVID-19 web pages as part of their Capstone Project at the University of Health Sciences and Pharmacy in St Louis. Due to the hard work of these talented students, the pages are easier to navigate and contain quick-review summary tables.
In a retrospective analysis or data for 1,164 patients, who had been hospitalized for COVID-19 and received less than 10 days of dexamethasone, continuation of dexamethasone after discharge did not reduce mortality or readmission compared to discontinuing dexamethasone at discharge.
An analysis of COVID-19 antibodies in breast milk of vaccinated mothers found that 96% of lactating women who received the Pfizer-BioNTech vaccine and 97% of mothers that received the Moderna vaccine had detectable IgA antibodies in their milk compared to 39% who received the AstraZeneca vaccine and 48% who received the Johnson & Johnson vaccine.
The CDC now recommends an 8-week interval between the first and second dose of an mRNA COVID-19 vaccine as an option in patients 12 and older, especially males ages 12–39 years to reduce the small risk of myocarditis and increase peak antibody response and vaccine effectiveness.
A CDC analysis of VAERS data, from 21,335,331 patients aged 12–20 years, found the incidence of multisystem inflammatory syndrome in children (MIS-C) to be one case per million individuals receiving one or more doses of a COVID-19 vaccine.
In the 138 patient, Phase IV, CoronavRheum trial (NCT04754698), pausing methotrexate administration for two weeks after each COVID-19 vaccine dose increased IgG seroconversion and neutralizing antibody titers in Brazilian patients with rheumatoid arthritis. The Chinese Sinovac-CoronaVac COVID-19 vaccine was used in the CoronavRheum trial.
A preprint draft describes the New York State Department of Health’s analysis of vaccine effectiveness with two doses of the Pfizer-BioNTech COVID-19 vaccine in children 5 to11 and 12 to 17 years after emergence of the Omicron variant. From December 13, 2021 to January 30, 2022 vaccine effectiveness (VE) in adolescents 12 to 17 years decreased from 66% to 51% and effectiveness against hospitalization decreased from 85% to 73%. In children 5 to 11 years VE decreased from 68% to 12% and against hospitalization from 100% to 48%.
Unlike the New York data, an analysis of data from 10 states by the CDC did not find a rapid decrease in vaccine effectiveness in children 5 to 11 and 12 to 17 years. There was a decrease in VE against the Omicron variant with VE approaching zero at 5 months. Two weeks to ten weeks after the second immunization the CDC found vaccine effectiveness against emergency department or urgent care visits, when Omicron was the predominant variant, to be 76% for adolescents 12 through 15 years, 83% for adolescents 16 to 17 years and 46% for children ages 5 through 11. After 5-months, VE was 38% among adolescents aged 12 to 15 years and 46% among 16 to 17 years. VE increased to 83% in adolescents 16 to 17 years, 7 or more days after a booster dose. Due to the late start of vaccination for the younger age group, data was not available for longer time periods.
In the 101 patient, Phase III, COV-BARRIER trial (NCT04421027), adding baricitinib to standard of care, including corticosteroids, reduced mortality at 28 days (39% vs 58%) and at 60 days (45% vs 62%) compared to placebo in critically ill hospitalized adults with COVID-19 requiring invasive mechanical ventilation or extracorporeal membrane oxygenation.
The FDA limited the EUA for sotrovimab to be used in geographic areas where the disease is likely caused by a susceptible COVID-19 variant.
The FDA increased the initial dose of tixagevimab to 300 mg and cilgavimab to 300 mg, because available data suggests the combination is less active against certain Omicron subvariants. The higher dose may be more likely to prevent infection by the COVID-19 Omicron subvariants BA.1 and BA.1.1 than the original 150mg/150mg dose. Tixagevimab and cilgavimabhave have an EUA for emergency use as pre-exposure prophylaxis (PrEP) for prevention of COVID-19 in patients 12 years of age and older weighing at least 40 kg in patients who may not mount an adequate immune response to COVID-19 vaccination or patients who are allergic or intolerant to a COVID0-19 vaccination.
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