COVID-19 updates
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COVID-19 Vaccines
A 19,109 patient, British observational study described the effectiveness of COVID-19 vaccines against the Delta variant. The effectives of the Pfizer-BioNTech COVID-19 vaccine was estimated to be 88% after two doses and 67% with two doses of the AstraZeneca vaccine. An analysis of data by Israeli researchers found the effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 91% to prevent severe disease and 88% to prevent hospitalizations. The vaccine had an estimated effectiveness of 41% to protect against symptomatic disease and 39% to prevent infection due to the Delta variant compared to an estimated 64% effectiveness at the beginning of July. COVID-19 Anti-Inflammatories Mesoblast announced that in a 60-day, 222 patient, Phase III trial (NCT04371393), treatment with remestemcel-L added to standard of care (SOC) did not reduce all-cause mortality compared to SOC in ventilator-dependent patients with moderate to severe acute respiratory distress syndrome (ARDS) due to COVID-19. In a pre-specified analysis of 123 patients under age 65, remestemcel-L reduced mortality by 46% by day 60, but not in 94 patients 65 or older. The Data Safety Monitoring Board (DSMB) recommended the trial be stopped when an interim analysis of 30-day data for 180 patients found it unlikely the trial would achieve a 43% reduction in mortality at the target enrollment of 300 patients. The DSMB recommended the trial be completed with the 222 patients already enrolled. COVID-19 Vaccines
The World Health Organization’s Global Advisory Committee on Vaccine Safety found the benefits of mRNA COVID-19 vaccines outweigh the risksin reducing hospitalizations and deaths from COVID-19. The risk for myocarditis and pericarditis is very low. The estimate in patients 12 to 29 is 40.6 cases per million second doses among males and 4.2 cases per million among females. In patients over 30, the rate drops to 2.4 per million second doses in males and one per million second doses in females in patients. The FDA has added Guillain-Barre syndrome to the Warning section of the Fact Sheet for the Johnson & Johnson COVID-19 vaccine. Most cases occurred within 42 days after vaccination. The occurrence is very low at 100 cases per 12.5 million doses. The FDA, CDC, and NIH have issued a joint statement that a booster vaccination is not currently needed for people that are fully vaccinated for COVID-19. A retrospective analysis of the outcomes of 15,060 pregnant women in an Israeli database found the estimated effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 78%. Updated NIH Treatment Summary Current treatment recommendations from NIH are organized by severity of disease in an easy-to-use graphic.
NIH found there is insufficient evidence to recommend either for or against the use of GM-CSF inhibitors (lenzilumab, otilimab, or mavrilimumab) for the treatment of hospitalized patients with COVID-19. COVID-19 Antivirals An analysis of oropharyngeal specimens from 181 patients that were collected during the Norwegian arm of the WHO Solidarity study did not find a decrease in SARS-CoV-2 viral load with remdesivir or hydroxychloroquine compared to standard of care. COVID-19 Vaccines
Researchers have examined the incidence of myocarditis after mRNA COVID-19 vaccine immunization.
Researchers from NIAID and their academic partners found that while virus neutralization from antibodies from 15 persons who had received the Moderna COVID-19 vaccine and 10 persons who had received the Pfizer–BioNTech vaccine were reduced the antibodies retained 79% of activity against the B.1.617.1 (India) variant and 96% of activity against the B.1.617.2 (India, Delta) variant. COVID-19 Anti-inflammatories A meta-analysis, by the World Health Organization, of 27 trials involving 10,930 patients, evaluated IL-6 inhibitors in the treatment of COVID-19. At 28-days the mortality risk in tocilizumab or sarilumab patients was 22% compared to 25% with usual care or placebo. The mortality benefit was maintained in patients receiving corticosteroids (21% vs 25%). The data supporting tocilizumab was more robust than sarilumab due to the larger patient population and the trials being conducted later in the pandemic, when use of corticosteroids became more common. There was not enough data (one trial) to estimate the effect of using siltuximab. Based on the data, the WHO now recommends that either tocilizumab or sarilumab be added to corticosteroids for the treatment of severe or critical COVID-19 infections. COVID-19 Vaccines
The CDC provides advice on myocarditis and pericarditis in adolescents and young adults who received an mRNA COVID-19 vaccine. Most cases have occurred in male patients 16 and older and patients responded well to treatment. The CDC continues to recommend vaccination of all patients 12 years and older due to the greater risk for complications from COVID-19. A preliminary FDA review found reported cases of myocarditis/pericarditis have been consistent with the Pfizer-BioNTech COVID-19 vaccine clinical trials. The reported cases were greater than expected in patients 16 to 24. After the second dose, the incidence is estimated to be 16 cases per million doses. At least 81% of affected patients fully recovered. HHS, CDC and several professional societies published a statement in support of continued vaccination of all eligible patients 12 and older. Oxford University is examining the safety and efficacy of giving two different COVID-19 vaccines to provide evidence for when the use of two different vaccines is unavoidable and to determine optimal use of the vaccines. A preprint draft provides results from the first phase of the 830 patient, Com-COV trial, where the elicited immune response was measured after different combinations of Comirnaty (Pfizer/BioNTech COVID-19 vaccine) and Vaxzevria (AstraZeneca COVID-19 vaccine) were given 4 weeks apart and antibody levels measured 28-days after the second dose.
A preprint draft provides results from a study examining antibody levels after a delayed second dose or third dose of the AstraZeneca COVID-19 vaccine. Antibody titers were higher with longer intervals. A third dose of the vaccine produced higher antibody titers and T-cell response. COVID-19 Antibodies HHS and the FDA are pausing distribution of Lilly’s monoclonal antibody combination bamlanivimab and etesevimab and etesevimab alone, due to concerns over resistance with COVID-19 variants. Distribution of bamlanivimab had been paused in April 2021. COVID-19 Anti-inflammatories Emricasan is a pan-caspase inhibitor being developed by Histogen for the treatment of nonalcoholic steatohepatitis. Because of emricasan ability to reduce inflammation, Histogen is evaluating the drug for the treatment of COVID-19.
The FDA granted an EUA for tocilizumab (Actemra, Roche) to treat hospitalized adults and pediatric patients two years of age or older, with COVID-19 and who are receiving a systemic corticosteroid and require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). COVID-19 Vaccines
Curevac announced interim data from the 36,500 patient, Phase IIb/III, HERALD trial (NCT04652102), where the mRNA COVID-19 vaccine CVnCo demonstrated 47% efficacy after 134 cases of COVID-19 developed in the European and Latin American study population. An analysis of COVID-19 cases found all but one infection was from COVID-19 variants. COVID-19 Antibodies In a pre-print draft of the 28-day, 9,785 patient RECOVERY trial (NCT04381936), treatment with Regeneron’s REGN-COV2 monoclonal antibody combination of casirivimab and imdevimab added to standard-of-care reduced all-cause mortality compared to placebo in hospitalized patients with COVID-19. In the placebo group, mortality was 30% in seronegative patients and 15% in seropositive patients. When all patients were compared regardless of antibody status, there was not a benefit with REGN-COV2 (20% vs 21%). However, in patients that were seronegative (had not developed antibodies), mortality was 24% with REGN-COV2 compared to 30% with placebo. Hospital stay was shorter (13 vs 17 days), the chance of being discharged greater (64% vs 58%) and use of mechanical ventilation or death was lower (30% vs 37%) in the seronegative group of patients. GSK and Vir announced that in the 29-day, 1,057 patient, Phase III, COMET-ICE trial (NCT04545060), treatment with VIR-7831 reduced the risk for hospitalization or death by 79% compared to placebo in patients with mild to moderate COVID-19 who are at high risk of progression to severe disease. COVID-19 Anti-inflammatories Tofacitinib (Xeljanz, Pfizer) is a JAK1 and JAK3 inhibitor with partial JAK2 inhibition. It is theorized that JAK inhibition may reduce cytokine storm associated with COVID-19 infection and decrease viral reproduction.
Redhill Biopharm announced that in a 14-day, 40 patient, Phase IIa U.S. trial (NCT04414618), 50% of patients treated with opaganib did not require oxygen compared to 22% with placebo in hospitalized patients with severe COVID-19 pneumonia requiring supplemental oxygen. 86.4% in the opaganib group were discharged by Day 14 compared to 55.6% with placebo. Most patients received dexamethasone and/or remdesivir. Redhill is evaluating the effect of opaganib on the need for mechanical ventilation in a 475 patient, Phase II/III trial (NCT04467840). COVID-19 Vaccines
The WHO released simplified names for COVID-19 variants of interest and concern to make it easier to report and talk about these virus mutations in non-scientific reports and articles. The simplified labels use Greek letters to identify a variant. The CDC has added these new designations to its tables of variant classifications and definitions. The WHO lists both the new simple names along with scientific names on its variant tracking page. The current list of variants being tracked by the CDC and WHO include (Pango lineage designation, Region first detected, WHO label):
Researchers from Johnson & Johnson and academia evaluated the efficacy of antibodies from 25 participants in a Phase I/IIa trial of J&J’s Ad26.COV2-S COVID-19 vaccine (NCT04436276) to neutralize COVID-19 variants. While there were decreased neutralization activity, functional activity was maintained for the Alpha variant, Gamma variant and Beta variant. A preliminary FDA review found reported cases of myocarditis/pericarditis have been consistent with the Pfizer-BioNTech COVID-19 vaccine clinical trials. The reported cases were greater than expected in patients 16 to 24. After the second dose, the incidence is estimated to be 16 cases per million doses. At least 81% of affected patients fully recovered. The FDA extended the shelf life of the Johnson & Johnson COVID-19 vaccine from 3-months to 4.5 months at refrigeration temperature (2-8 C). Researchers in Scotland examined COVID-19 cases and found the Delta variant as the dominant variant in the country. The researchers estimated the effectiveness of the Pfizer-BioNTech COVID-19 vaccine to be 92% for the Alpha variant and 73% for the Delta variant. The Astra Zeneca COVID-19 vaccine was 73% effective for the Alpha variant and 60% effective for the Delta variant. A pre-publication draft of a similar study in England found the effectiveness of the Pfizer-BioNTech to be 95% for the Alpha variant and 96% for the Delta variant with the AZ vaccine being 86% effective for the Alpha variant and 92% effective for the Delta variant. In a 30 patient case series from Johns Hopkins, researchers examined the effect of a third mRNA COVID-19 vaccine dose on transplant patients. Antibody levels were measured before the third dose and most patients had negative antibody levels with six having low levels. The booster dose was given 67 days after the second vaccine dose. Half of the patients received the J&J vaccine, while the rest received one of the mRNA vaccines. All six low antibody level patients developed high antibody titers. In the 24-patient, negative antibody level group, 25% developed high titers, 8% developed low titers and 67% remained negative. COVID-19 Antibodies NIH recommends that either Casirivimab plus Imdevimab (Regeneron), Bamlanivimab plus Etesevimab (Lilly) or Sotrovimab (Vir) 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. Use of Bamlanivimab plus Etesevimab may be restricted in areas with high prevalence of the Beta and Gamma variants. NIH also recommends against the use of any monoclonal antibodies in hospitalized patients unless they are part of a clinical trial. Celltrion announced that in a 28-day, 1,315 patient, Phase III trial (NCT04602000), 3.1% of patients treated with regdanvimab were hospitalized or died compared to 11.1% with placebo in patients with mild-to-moderate COVID-19 at high risk of progressing to severe disease. High risk patients recovered in 9.3 days compared to 14 days with placebo. Astra Zeneca announced that in the 30-day, 1,121 patient, Phase III STORM CHASER trial (NCT04625972), 3% of patients (23/749) treated with the AZ COVID-19 monoclonal antibody combination, AZD7442 developed symptomatic COVID-19, a non-significant difference compared to 4.6% of patients (17/372) treated with placebo in healthy patients exposed to a patient with COVID-19. COVID-19 Anti-inflammatories In a pre-publication draft of the 28-day, 520 patient, Phase III, LIVE-AIR trial (NCT04351152), treatment with Humanigen’s lenzilumab improved ventilator-free survival by 54% in the mITT population and by 90% in the ITT population compared to placebo in hospitalized hypoxic COVID-19 patients not requiring invasive mechanical ventilation. In the trial, 93.7% of patients received a corticosteroid, 72.4% received remdesivir, and 69.1% received both. Ventilator-free survival was improved by 92% in patients where lenzilumab was added to both corticosteroids and remdesivir. Humanigen requested an Emergency Use Authorization (EUA) for lenzilumab for the treatment of patients hospitalized with COVID-19, based on results from the LIVE-AIR trial COVID-19 Antivirals
Merck has entered an agreement with the U.S. government that if molnupiravir receives an EUA or is approved for the treatment of COVID-19, Merck will supply the U.S. with 1.7 million doses of molnupiravir for $1.2 billion. COVID-19 Antibodies The FDA updated the EUA for Regeneron’s monoclonal antibody combination, REGEN-COV. The dose had been lowered to 1,200 mg (600 mg casirivimab and 600 mg imdevimab). REGEN-COV is administered by intravenous infusion but can now be given subcutaneously when intravenous administration is not feasible. In the 11,558 patient, open-label, convalescent plasma arm of the British RECOVERY trial (NCT04381936), treatment with convalescent plasma did not decrease 28-day mortality compared to usual care (24% in both groups) in patients hospitalized with COVID-19. COVID-19 Anti-inflammatories In a 10-day, 86 patient, Iranian study, treatment with methylprednisolone 2 mg/kg/day improved the 9-point WHO ordinal scale (0 - uninfected to death 8) compared to dexamethasone 6 mg/day at five days (4.02 vs. 5.21) and 10 days (2.90 vs. 4.71) in hospitalized COVID-19 patients. Methylprednisolone also decreased the length of hospital stay (7.43 vs 10.52 days) and the need for mechanical ventilation (18.2% vs 38.1%). It should be noted the relative dose of methylprednisolone was higher than dexamethasone. COVID-19 Vaccines
A pre-print draft of a 12,675 patient, British observational study described the effectiveness of COVID-19 vaccines against the B.1.617.2 (Indian) variant. The effectives of the Pfizer-BioNTech COVID-19 vaccine was estimated to be 87.9% after two doses and the AstraZeneca vaccine was estimated at 59.8% efficacy in a cohort of 1,054 patients with an infection with the B.1.617.2 variant. The CDC provides advice on myocarditis and pericarditis in adolescents and young adults who received an mRNA COVID-19 vaccine. Most cases have occurred in male patients 16 and older and patients responded well to treatment. The CDC continues to recommend vaccination of all patients 12 years and older due to the greater risk for complications from COVID-19. An analysis of patients with immune-mediated inflammatory diseases who were receiving immunomodulatory treatments found that use of methotrexate decreased the immune response from the Pfizer-BioNTech COVID-19 vaccine. Over 90% of patients that were receiving a TNF blocker achieved a robust antibody response compared to only 62.2% of patients that were receiving methotrexate that achieved an adequate response. The FDA may not review additional COVID-19 vaccines for emergency use if the sponsoring company is not already in discussions with the FDA. Novavax, Medicago and Astra Zeneca have discussed approval with the FDA. Other vaccine developers would need to seek full authorization. In a 2,260 patient, Phase III trial (NCT04368728), no cases of COVID-19 developed in patients immunized with the Pfizer-BioNTech COVID-19 vaccine compared to 16 cases in the placebo group for 100% efficacy in patients 12 to 15. In a 77-day, 40,382 patient, Phase III trial (NCT04510207), efficacy was estimated to be 72.8% with Sinopharm’s WIV04 COVID-19 vaccine and 78.1% with the HB02 vaccine in healthy adults in the United Arab Emirates and Bahrain. COVID-19 Antibodies HHS has paused distribution of Lilly’s monoclonal antibody combination bamlanivimab and etesevimab in Illinois and Massachusetts, Arizona, California, Florida, Indiana, Oregon and Washington because the combined incidence of the P.1 variant (Brazil) and B.1.351 variant (South Africa) exceeds 10% of COVID-19 cases. In vitro data suggest that bamlanivimab and etesevimab administered together are not active against these variants. HHS recommended Regeneron’s REGN-COV2 a combination of casirivimab and imdevimab be used when a monoclonal antibody is needed in these states. The FDA granted an Emergency Use Authorization (EUA) to sotrovimab (VIR-7831) for the treatment of mild-to-moderate COVID-19 in adults and pediatric patients (12 years of age and older weighing at least 40 kg) with COVID-19, who are at high risk for progression to a severe infection. Healthcare providers should review the Fact Sheet for information on the authorized use of casirivimab and imdevimab and mandatory requirements of the EUA. Please see the FDA Letter of Authorization, Fact Sheet for Healthcare Providers, and Fact Sheet for Patients, Parents, and Caregivers. COVID-19 Anti-inflammatories In the 28-day, 146 patient, open-label, Phase III, STOIC trial (NCT04416399), 3% of patients treated with inhaled budesonide added to usual care required urgent care or hospitalization compared to 15% with usual care alone in outpatients with COVID-19. Clinical recovery was also one-day less with budesonide. In the 30-day, 4,488 patient, Phase III, COLCORONA trial (NCT04322682), treatment with colchicine did not reduce hospitalizations or mortality compared to placebo in outpatients with COVID-19 diagnosed by PCR testing or clinical criteria, who were at least 40 years old and had at least one risk factor for more severe disease. Among the 4,159 patients with PCR confirmed infection there was a small benefit with colchicine with 4.6% of patients requiring hospitalization or dying compared to 6% with placebo. COVID-19 Vaccines
On 5/19/2021, the FDA approved storage of the Pfizer-BioNTech COVID-19 vaccine at refrigerator temperatures for up to 30 days. Moderna announced that in the 3,732 patient, Phase II/III TeenCOVE trial (NCT04649151), no cases of COVID-19 were reported among adolescents ages 12 to 17 years that received two doses of the Moderna COVID-19 vaccine compared to the placebo group in the adult Phase III COVE study. Efficacy was 93% when measured 14 days after the first dose. The vaccine was well tolerated with no serious adverse events. The World Health Organization announced that COVID-19 vaccines currently approved in the U.S. and Europe are effective against virus variants. This includes the B.1.617 (India), B.1.351 (South Africa), B.1.1.7 (U.K.) and P.1 (Brazil). A review of outcomes in British patients over 70, found vaccine effectiveness after one dose, at 28 to 34 days, to be 61% with the Pfizer-BioNTech vaccine and 60% with the Astra Zeneca vaccine. The vaccines provided approximately 80% protection against hospital admission. Effectiveness after a second dose of the Pfizer-BioNTech vaccine was estimated at 90% in patients 80 and older. No estimate was provided for effectiveness after a second dose of the Astra Zeneca vaccine. COVID-19 Anti-inflammatories In the 28-day, 4,116 patient, Phase III, DISCOVERY trial (NCT04381936), adding tocilizumab to usual care resulted in 31% mortality compared to 35% with usual care alone in hospitalized adults with COVID-19 with oxygen saturation < 92% or requiring oxygen therapy and C-reactive protein of 75 mg/L or >. Corticosteroids were used in 82% of the study population. COVID-19 Vaccines
The CDC’s Advisory Committee on Immunization Practices (ACIP) recommended use of the Pfizer-BioNtech vaccine to adolescents 12 to 15 on 5/14/2021. Researchers from Pfizer, BioNTech and the University of Texas tested antibodies from the Pfizer-BioNTech COVID-19 vaccine against the new COVID-19 variants, B.1.526, B.1.429, and B.1.1.7+E484K. In the lab tests the antibodies were able to neutralize all three variants. A pre-publication draft describes an analysis by British researchers of 175 patients, who were 80 or older and received the Pfizer-BioNTech COVID-19 vaccine. Patients received the second dose at the standard 3-week interval or at an extended 12-week interval. The 12-week interval produced antibody titers that were 3.5-fold higher, but the cellular immune responses was 3.6-fold lower. The EMA recommended extending the storage time for the Pfizer-BioNTech COVID-19 vaccine from five days to 31 days at normal refrigerator temperatures. In the U.S. the vaccine may be kept at standard freezer temperature for up to two weeks. A retrospective study by Yale identified 16 patients that developed a delayed localized cutaneous reactions 2 to 12 days after receiving the Moderna COVID-19 vaccine. The reaction was near the injection site and was pruritic and painful with edematous pink plaques. The reaction developed in 11 of the patients with the second dose. The reaction was also seen in a small number of patients during the pivotal COVE trial. The reaction had a duration of five days. Researchers examined data from 30 pregnant, 16 lactating, and 57 non-pregnant/non-lactating patients and found the mRNA vaccine response was equivalent for pregnant and lactating women compared to non-pregnant/non-lactating women. Further, the immune transfer to neonates occurred via placental and breastmilk. Pregnant and lactating women also developed neutralizing antibodies that were active against the B.1.1.7 (U.K.) and B.1.351 (South African) variants. CDC researchers analyzed the outcomes in 1,843 health care professionals and found the mRNA vaccines’ efficacy to be 82% in preventing COVID-19 after one dose and 94% after two doses. Animal studies suggest that an influenza-COVID-19 combination vaccine would elicit antibodies for both viruses at levels similar to that seen with the individual vaccines. The vaccine also prevented infection from a virus challenge. Novavax will delay seeking an EUA for its COVID-19 vaccine to July 2021 due to manufacturing issues that include a quality control assay and problems with supplies needed to grow cell cultures. On 5/12/2021, the CDC announced it had identified 28 cases of thrombosis with thrombocytopenia among 8.7 million patients that received the J&J COVID-19 vaccine and considers the relationship between the vaccine and the adverse event to be a "plausible causal association". Sanofi and GSK announced interim results from a 722 patient, Phase II trial (NCT04762680), where the companies’ COVID-19 vaccine elicited antibody levels comparable to recovered patients following a second dose in all age groups (18 to 95 years old) of patients from the U.S. and Honduras. Based on the interim results from the Phase II trial, Sanofi and GSK are planning to initiate a 35,000 patient Phase III trial with the goal of submitting data for an emergency use authorization (EUA) in 4Q21. A pre-publication draft describes interim results from a 588 patients enrolled in the Phase II portion of a Phase II/III trial (NCT04636697), where the Medicago COVID-19 vaccine (CoVLP) with GSK’s AS03 vaccine adjuvant elicited antibody titers after a second dose in all adult age groups that were ten times higher than a panel of recovered COVID-19 patients. COVID-19 Antivirals Due to the volume of press releases from CytoDyn, the FDA provided a “Statement on Leronlimab” stating that neither an 86 patient trial in mild-to-moderate COVID-19 infection, nor a 394 patient trial in patients with severe disease provided evidence to support a benefit in using leronlimab in the treatment of COVID-19. The FDA does not feel that a positive finding in a sub-group supports use of the drug, rather it suggests design parameters for a new trial. |
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