Clot concerns with adenovirus COVID-19 vaccines, antibody treatment recommendations and data

Based on reports of cerebral venous sinus thrombosis with the Johnson & Johnson (Janssen) COVID-19 vaccine, federal officials recommended a pause in its use, which will be reconsidered on April 23. The NIH updated its recommendations on monoclonal antibody treatments for outpatients.

The CDC and FDA have recommended a pause in the use of the Johnson & Johnson (Janssen) vaccine. The agencies jointly announced the pause on April 13, and the Advisory Commission on Immunization Practices (ACIP) voted to continue it during an April 14 meeting. According to presentations from the ACIP meeting, as of April 12, the Vaccine Adverse Event Reporting System had received six reports of cerebral venous sinus thrombosis (CVST) among patients who had received the vaccine. All were White women between 18 and 48 years of age, and all were found to have thrombocytopenia (platelet count <150,000 cells/mm3). ACIP officials noted that thrombocytopenia and thromboses are not usually found together but were also both present in patients with reported complications from the AstraZeneca COVID-19 vaccine. In the CVST patients, the median time to symptom onset was eight days (range, 6 to 13 days). One patient died, two were discharged home, and three remained hospitalized. The pause was recommended “out of an abundance of caution,” the agencies' joint statement noted. With six cases after more than 6 million vaccinations, the rate of reported CVST is 0.87 cases per million doses. ACIP presentations noted that the pause could allow experts to determine whether the vaccine is associated with any other types of thrombosis and to develop more specific recommendations for its use, possibly based on age. A virtual emergency meeting of the ACIP is scheduled for April 23.

Details on one case of extensive thrombosis, including CVST, and severe thrombocytopenia in a patient who received the Johnson & Johnson vaccine were provided by a letter to the editor of the New England Journal of Medicine (NEJM), published on April 14. The patient presented with malaise and abdominal pain and was found to have disseminated intravascular coagulation, initially treated with heparin. After an assay for antibodies against platelet factor 4 (PF4)–polyanion was strongly positive, treatment was switched to argatroban, along with IV immune globulin. The patient's platelet count increased, but she remained critically ill at the time of the report. Representatives of Janssen responded to the case report in a letter that was also published by NEJM on April 16. They described how one case of CVST with thrombocytopenia was reported in the vaccine's trial, which included 75,000 participants. Clear causation by the vaccine was not found in that case, and the evidence is still insufficient to establish this connection, according to the letter authors. They also highlighted differences between the Janssen and AstraZeneca vaccines, suggesting that they may have very different biological effects. “More evidence is needed to clarify the observation of thrombotic thrombocytopenia in persons receiving a vaccine against Covid-19,” they wrote.

A study published by NEJM on April 16 described 23 cases of thrombosis associated with the AstraZeneca vaccine. The authors noted that 21 of the patients were positive for PF4 antibodies. They recommended that such patients be treated with nonheparin anticoagulants and IV immune globulin, not platelet transfusions. An editorial also published by NEJM on April 16 addressed the recent reports of thrombotic thrombocytopenia with the COVID-19 vaccines. It noted that there have also been five possible (but unvetted) cases of CVST with the Moderna mRNA vaccine and reviewed the current understanding and outstanding questions regarding this possible complication. “The very low prevalence of this complication of vaccination, however severe, relative to the benefits of preventing Covid-19 (a condition with 1 to 2% mortality and potential long-term sequelae) must be emphasized,” the editorial said. “The questions of whether certain populations can be identified as more suitable candidates for one or another vaccine and who and how to monitor for this rare potential complication will require additional study.”

In other COVID-19 news, on April 16, the FDA revoked the emergency use authorization that allowed for bamlanivimab to be administered alone in treatment of mild to moderate COVID-19. The agency concluded that due to increases in SARS-CoV-2 variants that are resistant to this monoclonal antibody directed against the spike protein of SARS-CoV-2, the risks appear to outweigh the benefits. The use of bamlanivimab and etesevimab, administered together, is still authorized, as is the combination of casirivimab and imdevimab. On April 8, the NIH's COVID-19 treatment guidelines panel updated its recommendations on use of these same drugs. For outpatients with mild to moderate COVID-19 who are at high risk of clinical progression, the panel recommends bamlanivimab, 700 mg, plus etesevimab, 1,400 mg, or casirivimab, 1,200 mg, plus imdevimab, 1,200 mg. The panel no longer recommends bamlanivimab monotherapy.