On 4/23/2021, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended lifting the pause on administering the J&J COVID-19 vaccine that was implemented on 4/4/2021. The pause was established to investigate the occurrence of eight cases of thrombosis with thrombocytopenia among seven million patients that received the vaccine in the U.S. On 4/22/2021, ACIP voted 10-4 to resume immunization with the vaccine. The committee also recommended that a warning about the risks of thrombosis with thrombocytopenia syndrome be added to the vaccine information and that clinicians follow the recommendation from the American Society of Hematology guidance for diagnosis and treatment of the condition. The CDC and FDA recommended lifting the pause in immunizations with the J&J vaccine on 4/23/2021. The FDA revised the vaccine EUA, healthcare professional fact sheet and patient fact sheet to include information on thrombosis-thrombocytopenia syndrome (TTS).
Researchers analyzed data from 35,691 pregnant women, who had received either the Pfizer–BioNTech or Moderna COVID-19 vaccines, that were enrolled in the V-safe Surveillance System and Pregnancy Registry and the Vaccine Adverse Event Reporting System (VAERS). Compared to nonpregnant women the incidence of injection-site pain was more frequent, while headache, myalgia, chills, and fever were less frequent. The rate of spontaneous abortion was 12.6%, which falls within the historical range of 10% to 26%. While not directly comparable, the rate of adverse pregnancy and neonatal outcomes after COVID-19 vaccination were similar to the rates reported before the COVID-19 pandemic. Based on data from the study, the CDC now recommends COVID-19 vaccination for pregnant women.
In the 39,321 patient, Phase III, ENSEMBLE trial (NCT04505722), a single immunization with the J&J COVID-19 vaccine resulted in 66.4% efficacy after 28 or more days after vaccination. The vaccine was 85.4% effective in preventing severe disease. Efficacy was similar across age groups after at least 28 days. In South Africa, efficacy was 64% in South Africa for moderate to severe disease and 81.7% for severe disease. There were eleven cases of venous thromboembolic events in the vaccine group compared to three the placebo group. Only one case of transverse sinus thrombosis with cerebral hemorrhage was seen in in the vaccine group.
The Federal Government contracted Emergent Biosolution to manufacturer the active ingredients for COVID-19 vaccines from J&J and AstraZeneca. In March 2021, Emergent had to destroy millions of doses of the J&J vaccine, due to cross-contamination. An FDA inspection has revealed numerous manufacturing, sterility and training issues. Johnson & Johnson has now taken over responsibility for manufacturing their vaccine at the Emergent plant. Production of the AZ vaccine will be moved to a different facility.
The Federal Government will not fund a Phase III trial of Inovio’s COVID-19 vaccine, but will continue to fund a Phase II trial. Depending on the results of the trial, Inovio may run a Phase III trial with China’s Advaccine and the International Vaccine Institute outside the U.S.
Researchers tested antibodies from recovered COVID-19 patients, fully mRNA (Pfizer-BioNTech and Moderna) vaccinated subjects and who received the Regeneron monoclonal antibody combination in neutralizing the B.1.526 (New York) variant. The B.1.526 variant, decreased titers, but was still neutralized by all four types of antibodies.
NIH has determined there is not enough evidence to recommend for or against the use of fluvoxamine to treat COVID-19.
NIH has determined there is not enough evidence to recommend for or against the use of colchicine to treat COVID-19 in non-hospitalized patients and colchicine should not be used in hospitalized patients, except as part of a trial.
In the 90-day, 685 patient, Phase III, TOGETHER trial (NCT04403100), neither hydroxychloroquine nor lopinavir-ritonavir reduced hospitalization or death in high-risk, Brazilian outpatients with early symptomatic COVID-19.
On 4/14/2021, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that a pause in administering the J&J COVID-19 vaccine be continued, to give the committee more time to analyze a more complete data set. ACIP plans to vote within seven to 10 days on a recommendation for vaccine.
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) recommended adding a warning regarding a rare adverse event of thrombosis in combination with thrombocytopenia to the product label for the Johnson & Johnson COVID-19 vaccine. PRAC reviewed eight cases of thrombosis with thrombocytopenia among seven million patients that received the vaccine in the U.S. The committee noted that all cases happened within 3 weeks of receiving the vaccine in patients under 60. Most cases occurred in women and were very similar to those seen with the AstraZeneca vaccine.
A retrospective analysis of 513,284 patients, found the incidence of cerebral venous thrombosis to be eight times more common in patients that developed COVID-19 than in patients that received the AstraZeneca vaccine and ten times more common than in patients that received the Pfizer-BioNTech or Moderna vaccine.
A report describes 22 patients with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the AstraZeneca COVID-19 vaccine. As in previous descriptions the patients were positive for antibodies to platelet factor 4 (PF4), unrelated to the use of heparin. The researchers recommend avoiding heparin and platelet transfusions, using a non-heparin anticoagulant and intravenous immune globulin considered. An algorithm is provided for testing and treating patients.
A preprint article describes the immunity response in 165 patients, 80 or older, that received a single dose of either the Pfizer-BioNTech or Astra Zeneca vaccine. Antibodies were elicited in most patients (93% and 87%). Previous infection caused a higher antibody response.
Both Pfizer-BioNTech and Moderna have said that patients that received both doses of the mRNA COVID-19 vaccines will likely need a booster dose within a year.
Merck announced interim results from the 304 patients enrolled in the 29-day, 1,300 patient, Phase II/III, MOVe-IN trial (NCT04575584), where molnupiravir did not improve the percentage of patients that achieved sustained recovery compared to placebo in hospitalized patients with COVID-19. Merck discontinued the MOVe-IN trial, because the interim results did not demonstrate a clinical benefit with molnupiravir.
Merck announced interim results from 302 patients enrolled in the 29-day, 1,850 patient, Phase II/III, MOVe-OUT trial (NCT04575597), where molnupiravir decreased hospitalizations and mortality compared to placebo in outpatients with COVID-19. Merck expects final trial results in September or October.
NIH discontinued enrollment in the 29-day, Phase III, ACTT-4 trial (NCT04640168) after 1,000 patients when an interim analysis found it was unlikely that baricitinib plus remdesivir would reduce the need for mechanical ventilation or death compared to dexamethasone plus remdesivir in hospitalized COVID-19 patients on supplemental oxygen.
On 4/16/2021, Lilly requested the EUA for bamlanivimab be revoked because of the evolving resistance with variants and availability of a superior regimen that combines bamlanivimab with etesevimab. The FDA revoked the EUA for bamlanivimab given alone on the same day. The EUA remains in place for the combination of bamlanivimab and etesevimab for COVID-19 in outpatients. Lilly will only provide the combination for use and the U.S. government has modified contracts with Lilly to only purchase the two antibodies in combination. Any healthcare site that still has bamlanivimab alone can purchase etesevimab to use in combination.
The CDC and FDA are recommending a pause in the use of the J&J vaccine. The FDA, CDC and the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) are investigating six cases of cerebral venous sinus thrombosis in combination with thrombocytopenia that occurred in women between the ages of 18 to 48 with symptoms occurring 6 to 13 days after vaccination. The adverse event is very rare with only six reports after 6.8 million doses. The CDC’s Advisory Committee on Immunization Practices (ACIP) will review these cases and assess their potential significance. The FDA will review ACIP’s report. J&J’s vaccine patients should be advised to monitor for severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after receiving the vaccine. If symptoms occur, the patient should contact their health care provider. Health Care providers are reminded to report adverse events from any COVID-19 vaccine to VAERS.
The Director of the Chinese Center for Disease Control and Prevention said the current Chinese COVID-19 vaccines offer low protection against the coronavirus. He also praised the mRNA vaccines and said China is working on developing mRNA vaccines. Hundreds of millions of doses of Chinese vaccines have been distributed worldwide and 65 million Chinese citizens received at least one dose.
A supply shortage of raw materials, such as bags used to grow cells, has delayed the production target for Novovax until 3Q21.
NIH recommends that either Casirivimab 1,200 mg plus Imdevimab 1,200 mg (Regeneron) or Bamlanivimab 700 mg plus Etesevimab 1,400 mg (Lilly) be used for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of clinical progression. NIH recommends against the use of Bamlanivimab alone, due to resistance from variants, unless the combination products are not available. NIH also recommends against the use of any monoclonal antibodies in hospitalized patients unless they are part of a clinical trial.
Regeneron announced that in a 29-day, 1,505 patient, NAID sponsored Phase III trial (NCT04452318), symptomatic COVID-19 developed in 1.5% of patients that received a single subcutaneous injection of REGEN-COV (casirivimab and imdevimab) 1,200 mg compared to 7.8% of patients that received placebo in COVID-19 negative patients exposed to a COVID-19 positive patient in the same household. In the same trial symptomatic COVID-19 developed in 29% of patients that received REGEN-COV compared to 42% of patients that received placebo in 204 asymptomatic COVID-19 positive patients that did not have anti-virus antibodies and had been exposed to a COVID-19 positive patient in the same household.
Gilead Sciences discontinued a 28-day, 1,264 patient, Phase III trial evaluating three intravenous infusions of remdesivir to reduce the development of COVID-19 (NCT04501952), related hospitalization or all-cause death in non-hospitalized COVID-19 patients. The trial was discontinued because the standard of care for outpatient COVID-19 had advanced beyond the need for a multi-day treatment that required administration by intravenous infusion, such as the single dose monoclonal antibodies.
Interim data from the 2,422 patients enrolled in the 28-day, Phase III, PRINCIPLE trial, found that inhaled budesonide added to usual care decreased time to recovery by 3-days compared to usual care alone in outpatients with COVID-19.
The EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) found the AstraZeneca COVID-19 vaccine causes a rare adverse event of thrombosis in combination with thrombocytopenia. PRAC reviewed 62 cases of cerebral venous sinus thrombosis and 24 cases of splanchnic vein thrombosis and concluded the thrombi are most likely to occur within the first two weeks after administration in women younger than 60. PRAC advises the benefits of the vaccine continue to outweigh the risks and the vaccine is effective at preventing COVID-19 and reducing hospitalizations and deaths. The U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA) has recommended that while prompt vaccination with the AZ vaccine outweigh the risk of thrombosis, patients under 30 should be offered an alternative vaccine. The World Health Organization has stated that a causal relationship between the rare event of thrombosis in combination with thrombocytopenia had not been proven, but surveillance and investigation should be continued.
Researchers from NIAID, Emory University, Moderna and others report that antibody titers remained high in 33 patients 200 days after receiving the second Moderna COVID-19 vaccine.
Lilly announced that in the 1,525 patient, Phase III, COV-BARRIER trial (NCT04421027), adding baricitinib to standard of care did not decrease the need for ventilation (non-invasive or mechanical) or death compared to standard of care alone in hospitalized patients with COVID-19.
Pfizer and BioNTech announced that in a 2,260 patient, Phase III trial, no cases of COVID-19 developed in patients immunized with their COVID-19 vaccine compared to 18 cases in the placebo group for 100% efficacy in patients 12 to 15. The companies plan to submit the data to the FDA to expand the EUA to this age group.
Pfizer and BioNTech provided an update for their COVID-19 vaccine trial (NCT04368728) after 927 symptomatic cases of COVID-19 developed after up to six-months of follow-up for 91.3% efficacy. For prevention of symptomatic infection, the vaccine was 100% effective using CDC criteria and 95.3% effective using FDA criteria. There were 800 patients from South Africa in the trial and nine infections developed, six of which were caused by the B.1.351 (South African) variant. All infections developed in the placebo group, suggesting good efficacy, but based on limited data.
A preprint article of a 100 patient study found the Pfizer-BioNTech vaccine elicited high titers of antibodies that provided robust neutralization of the original SARS-CoV-2 virus and the P.1 (Brazilian) variant in healthy patients 80 to 96 years.
In an 8,534 patient, Phase III trial (NCT04400838), 520 patients developed COVID-19. The virus was sequenced in 301 patients. Efficacy in preventing symptomatic infection with the AstraZeneca COVID-19 vaccine was 70.4% against the B.1.1.7 (U.K.) variant and 81.5% against the original SARS-CoV-2 viruses. The vaccine was less efficacious for asymptomatic infection with 28.9% efficacy for B.1.1.7 compared to 69.7% for original viruses.
Novavax has added crossover arms to its studies to allow trial participants that received placebo to get the vaccine without unblinding the trials. A second round of vaccines will be offered for participants in the 15,000 patient, U.K. trial (NCT04583995) and the 30,000 patient, Phase III, PREVENT-19 trial (NCT04611802) in the U.S. and Mexico. Patients that received the vaccine will receive placebo and placebo patients will receive the vaccine. In the 2,905 patient, South African trial (NCT04533399), placebo patients will receive the vaccine, while the original vaccine patients will receive a booster to determine if a booster will improve efficacy for the B.1.351 (South African) variant.
The CoVIg-19 Plasma Alliance (CSL Behring, Takeda, BioPharma Plasma, Biotest, GC Pharma, LFB, National Bioproducts Institute, Octapharma and Sanquin) announced that in the 7-day, 600 patient, Phase III, ITAC trial (NCT04546581), adding anti-coronavirus hyperimmune intravenous immunoglobulin (H-Ig) to remdesivir did not reduce disease progression compared to remdesivir alone in hospitalized patients with COVID-19 who had symptoms for 12 days or fewer without life-threatening organ dysfunction or end-organ failure. NIH sponsored the trial.
The WHO recommended against the use of ivermectin due to inconclusive evidence and felt the drug should only be used to treat COVID-19 as part of a clinical trial.
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