COVID-19 Vaccine Updates: VITT Has High Mortality, Myocarditis Is Benign Short-Term
Executive Summary
Recipients of AstraZeneca’s vaccine hospitalized with vaccine-induced immune thrombocytopenia and thrombosis (VITT) had overall mortality of 22%, NEJM study finds. JAMA reports 15 children who had myocarditis following Pfizer/BioNTech vaccine were mildly affected. Efficacy of Moderna vaccine in adolescents and durability of Pfizer vaccine in cancer treatment recipients is also reported.
As stakeholders await regulatory decisions related to the COVID-19 vaccines, a batch of journal articles published this week offered additional safety and efficacy data to add to the conversation in the meantime.
One of the articles looked at the incidence of vaccine-induced immune thrombocytopenia and thrombosis (VITT) with AstraZeneca PLC’s COVID-19 vaccine. While occurrence of the syndrome is rare, it is deadly. UK researchers found that in 220 cases of definite or probable VITT following the first dose of the vaccine, overall mortality was 22%.
In an article published 11 August in the New England Journal of Medicine, the researchers report the results of a prospective cohort study involving patients with suspected VITT – brain blood clots accompanied with low levels of platelets – who were hospitalized in the UK between 22 March and 6 June 2021. They found that the high mortality rate associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial bleeding.
The authors, led by Sue Pavord of Oxford University Hospitals, found that the syndrome usually manifests five to 30 days after the first vaccinations with AstraZeneca’s adenovirus-based vaccine, ChAdOx1 nCoV-19. They report that in their cohort 85% of patients were younger than 60 years of age.
Concerns about increased risk of VITT with AstraZeneca’s adenoviral vector vaccine arose in March. A dozen European countries limited its use to people over 50, 60, or 65, and Denmark stopped use altogether. It has not been authorized by the US Food and Drug Administration. (Also see "J&J COVID-19 Vaccine Rollout Resumes In EU With New Rare Blood Clot Warning" - Scrip, 21 Apr, 2021.)
The incidence of VITT, also referred to as thrombosis with thrombocytopenia syndrome (TTS), also has occurred following administration of Johnson & Johnson’s COVID-19 vaccine. The FDA and US Centers for Disease Control and Prevention called for a pause in administration of the vaccine on 13 April after reports of six cases, including one death, in women between the ages of 18 and 48. Ten days later, the CDC’s Advisory Committee on Immunization Practices voted to reaffirm its use in persons 18 and older based on a positive risk-benefit analysis, and the agencies lifted the pause on 23 April. (Also see "With J&J’s COVID Vaccine Pause Now Lifted, The Question Is How Well The System Worked" - Pink Sheet, 23 Apr, 2021.)
The UK study provides further information on the incidence of the syndrome with AstraZeneca’s vaccine. The researchers note that by 6 June, approximately 16 million first doses had been administered to persons 50 years of age or older and eight million had been administered to those younger than 50 years of age.
The researchers said they did not find any individual risk factors for VITT, but found increased mortality among patients with severe thrombocytopenia, cerebral venous sinus thrombosis, intracranial hemorrhage, laboratory markers of severe coagulation activation, or all these variables. They noted that anti-PF4 antibodies were present in 198 of 220 patients.
Myocarditis May Have ‘Benign Short-Term Course In Children’
The VITT study was one of several studies on the safety and efficacy of COVID-19 vaccines reported in NEJM and JAMA on 10 and 11 August.
Researchers at Boston Children’s Hospital and Harvard Medical School looked at another adverse event of concern, myocarditis associated with Pfizer Inc./BioNTech SE’s mRNA COVDI-19 vaccine, BNT162b2, in children. They studied a case series of 15 patients age 12 to 18 who were admitted to Boston Children’s Hospital for management of acute cases of myocarditis, inflammation of the heart muscle, within 30 days of receiving the vaccine. The admissions occurred between 1 May and 15 July.
Their study, published online 10 August in JAMA Cardiology, found that boys were most often affected after the second dose. No patient required admission to the intensive care unit, and the median hospital stay was two days. At follow-up one to 13 days after hospital discharge, 11 patients (73%) had resolution of symptoms. One patient had persistent borderline low LV systolic function on echocardiogram (EF 54%), troponin levels remained mildly elevated in three patients, and one patient had nonsustained ventricular tachycardia on ambulatory monitor.
“COVID-19 vaccine-associated myocarditis may have a benign short-term course in children; however, the long-term risks remain unknown,” concluded the researchers, led by Audrey Dionne, of Boston Children’s Hospital.
The authors noted that to date, there have been 1,226 reports of myocarditis after messenger RNA vaccination submitted to the Vaccine Adverse Event Reporting System (VAERS). It is estimated that the highest rate is among males aged 12 to 17 years. Pfizer’s vaccine was initially authorized by FDA in December 2020 for those aged 16 and older. On 10 May, the agency lowered the age of authorized use to 12 years.
“Despite the risks of myocarditis associated with vaccination, the benefits of vaccination likely outweigh risks in children and adolescents,” the authors stated. “It is estimated that COVID-19 vaccination in males age 18 to 29 years can prevent 11,000 COVID-19 cases, 560 hospitalizations, 138 intensive care unit admissions, and 6 deaths compared with 39 to 47 expected myocarditis cases."
CDC’s Advisory Committee on Immunization Practices considered reports of myocarditis following administration of both Pfizer and Moderna, Inc.’s mRNA vaccines at a meeting last month. ACIP reaffirmed that the benefit-risk profile of the vaccines remains positive and the FDA added warning language to COVID-19 mRNA vaccine fact sheets about the risk of myocarditis and pericarditis. (Also see "mRNA COVID-19 Vaccines To Add Warning Language On Myocarditis Risk" - Pink Sheet, 23 Jun, 2021.)
The ACIP also is meeting on 13 August to consider additional vaccine doses for immunocompromised individuals.
Positive Data On Moderna Vaccine In Adolescents
Two other studies looked at the efficacy of mRNA vaccines in adolescents and the durability of response in patients undergoing cancer treatment.
In an article published in NEJM on 11 August, researchers reported interim results of an ongoing Phase II/III placebo-controlled trial of Moderna’s mRNA-1273 vaccine in those 12 to 17 years old, the Teen COVE trial. Between 9 December 2020 and 28 February, a total of 3,732 adolescents were randomly assigned in a 2:1 ratio to receive mRNA-1273 (2,489 participants) or placebo (1,243 participants) at 26 sites in the US.
The primary immunogenicity analysis was based on noninferiority of neutralizing antibody titers in adolescents in the trial compared with young adults in the Phase III Coronavirus Efficacy (COVE) trial. The FDA’s emergency use authorization of the vaccine in adults 18 and older was based on the COVE trial. The study showed the noninferiority of immune response based on both the geometric mean titer and serologic response in adolescents compared to young adults. The safety and reactogenicity of mRNA-1273 was similar to that observed in adults 18 to 64 in the Phase III COVE trial.
In addition, the authors found that vaccine efficacy in 12 to 17-year-old adolescents was 93%, according to CDC’s less stringent case definition of COVID-19 with an onset 14 days after the second injection. They said a precise efficacy measure was difficult because of the low incidence of COVID-19 in the trial (four cases in the placebo group and none in the mRNA-1273 group).
“However, it appears that the mRNA-1273 vaccine safely induced levels of antiviral antibodies that should be protective against SARS-CoV-2 infection,” the authors, led by Kashif Ali, Kool Kids Pediatrics in Houston, concluded.
They said it is difficult to compare their results with those for Pfizer/BioNTech’s mRNA vaccine in which the neutralizing antibody titers in adolescents were higher than those in young adults because the neutralizing antibodies for mRNA-1273 were measured in a pseudovirus assay while those for BNT162b2 were measured in a live virus neutralization assay.
The most common solicited adverse reactions after the first or second injections were injection-site pain, headache, and fatigue. No serious adverse events related to the vaccine or placebo were noted. No cases of myocarditis or pericarditis had been reported to date. The authors said they did not expect to detect those events in this trial since the reported incidence in young men has been estimated to be in the range of 13 cases per million doses of vaccine.
Moderna plans to expand the safety database of its vaccine study in children age five to 11 to increase the likelihood of detecting rare events. (Also see "Rare Or Common Events? COVID Vaccine Trials In Children Boost Safety Databases, Triggering Fears Of Heart Events" - Pink Sheet, 26 Jul, 2021.)
Duration of Antibody Response In Cancer Patients
Initial findings of a study of the durability of Pfizer/BioNTech’s vaccine in patients receiving cancer treatment were described in a letter published online 11 August in JAMA Oncology. Israeli researchers conducted a prospective cohort study evaluating the antispike IgG antibody response to the vaccine in patients with solid tumors on active anticancer treatment versus healthy controls.
The analysis included 95 patients and 66 controls. The authors, from Beilinson Hospital in Petah Tikva, Tel Aviv University, and Sheba Medical Center in Tel Hashomer, reported that after a median of 123 days from the second vaccination, 83 cancer patients (87%) and all the controls were seropositive for anti-S IgG antibodies. The median titer levels in the patients with cancer were significantly lower than those in the control group. They noted that the median IgG titer in the patients and the controls decreased over time.
Evaluating IgG titers by tumor type and anticancer treatment, they found that the lowest titers were observed with immunotherapy plus chemotherapy/biological therapy.
The researchers also noted that interim results from a Phase III trial of Moderna’s mRNA-1273 vaccine in 33 healthy adults demonstrated that the antibody activity remained high in all age groups after approximately seven months.
“Although the correlation between antibody levels after vaccination and clinical protection is yet to be proven, the accumulating evidence supports antibody response as a potential correlate of disease protection. Long-term cellular memory could call into question the need for a third BNT162b2 booster dose,” Noa Eliakim-Raz, et al, stated.