COVID-19 Vaccines
FDA reviews of the Moderna and Pfizer- BioNTech mRNA COVID-19 vaccines found them to be as effective for children 6 months to 5 years as in older children and young adults. No cases of myocarditis were experienced in this age group during trials.
• 76.8% for children 6 to 11 years • 36.8% for toddlers 2 to 5 years • 50.6% for infants 6 to 23 months Note: Only the results for children 6 months to 5 years were during an Omicron dominant period. The results are based on preliminary results and may not represent the actual effectiveness. The FDA expanded use of both mRNA vaccines to all patients 6 months and older. The CDC expanded their COVID-19 vaccination recommendations to include the same age groups.
An analysis of data from a Qatar healthcare database found effectiveness against the Omicron BA.2 variant to be:
Sanofi and GSK announced that in the 247 patient, Phase III, COVIBOOST trial (NCT05124171), a booster dose after two doses of the Pfizer-BioNTech COVID-19 vaccine resulted in a 10-fold increase in antibody titers in:
Pfizer announced that in the 28-day, 1,153 patient, Phase II/III, EPIC-SR trial (NCT05011513), treatment with nirmatrelvir plus ritonavir did not increase resolution of symptoms compared to placebo in patients with COVID-19, who were at standard risk for developing severe COVID-19. COVID-19 Vaccines
The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 21-0 with one abstention to recommend an EUA for Novavax’s two-dose COVID-19 vaccine for patients 18 years and older. An FDA review and the discussion by the VRBPAC expressed concern about myocarditis, although the adverse effect appears to be rare. Moderna announced interim data from a Phase II/III trial where an investigational bivalent COVID-19 vaccine containing a combination of the original vaccine and an Omicron variant specific vaccine elicited higher antibody levels for both the original SAR-COV-2 virus and the Omicron variant. COVID-19 Vaccines
A systematic review and network meta-analysis of 38 WHO COVID-19 databases comprising 53 studies found that a three dose regimen of an mRNA COVID-19 vaccine is most effective for prevention of COVID-19. This includes patients who are immunocompromised and/or older than 65 years. COVID-19 Antivirals The FDA has provided additional information about use of Paxlovid in a 5/4/2022 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). Based on limited information, the CDC found that COVID-19 rebound usually occurs 2 to 8 days after initial recovery and include COVID-19 symptoms or a new positive viral test after having tested negative. The natural course of COVID-19 may include a brief return of symptoms, regardless of treatment or vaccine status. Current cases of rebound COVID-19 rebound after Paxlovid have been mild. There is no evidence to support use of the Paxlovid beyond five days, but the CDC recommends following Guidance on Quarantine and Isolation. COVID-19 Anti-inflammatories In the 29-day, 1,047 patient, Phase III, ACTT 4 trial (NCT04640168), mechanical ventilation-free survival was similar between baricitinib plus remdesivir and dexamethasone plus remdesivir (87% vs 87.6%) in hospitalized patients with COVID-19. There were more treatment related adverse events and severe or life-threatening adverse events with dexamethasone plus remdesivir. COVID-19 Vaccines
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. COVID-19 Antivirals 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%). COVID-19 Anti-inflammatories 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. COVID-19 Antivirals 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). COVID-19 Vaccines
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. COVID-19 Antivirals 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. COVID-19 Vaccines
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. COVID-19 Antivirals 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. COVID-19 Vaccines
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.
COVID-19 Antibodies 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. COVID-19 Vaccines
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.
COVID-19 Antibodies 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. COVID-19 Antivirals 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:
COVID-19 Antibodies 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). COVID-19 Vaccines 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. |
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