News update, Sept. 15, 2020—U.S. regulators paused AstraZeneca’s vaccine trial in the U.S. while the National Institutes of Health (NIH) launches an investigation of its own into a serious side effect in an unnamed patient in Britain. “The highest levels of NIH are very concerned,” said Dr. Avindra Nath, intramural clinical director and a leader of viral research at the National Institute for Neurological Disorders and Stroke, an NIH division. A great deal of uncertainty remains about what happened to the patient. AstraZeneca “need[s] to be more forthcoming with a potential complication of a vaccine which will eventually be given to millions of people,” said Dr. Nath. “We would like to see how we can help, but the lack of information makes it difficult to do so.”19 Enrollment of new patients and other trial procedures were being rescheduled until at least midweek although studies might take a month or two. The status of the South African and Indian trials remains unknown, but the trial in Brazil has also restarted.20
Multinational pharmaceutical company AstraZeneca announced on Sept. 8, 2020 that it was putting a hold on a Phase 3 clinical trial testing its experimental AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine due to a suspected very serious adverse reaction in a female participant in the United Kingdom.1 In a private conference call on Sept. 9, AstraZeneca chief executive Pascal Soriot stated that the woman suffered symptoms consistent with a rare but serious neurological disorder called transverse myelitis, which causes inflammation of the spinal cord.2
Soriot also confirmed that the participant was injected with the company’s COVID-19 vaccine and not a placebo. Four days later, AstraZeneca released a statement3 that the trial in the U.K. would resume following confirmation by the Medicines Health Regulatory Authority (MHRA) (Britain’s equivalent of the U.S. Food and Drug Administration) that it was safe to do so. They provided no further details. Researchers running other clinical trials are now looking for similar cases of neurological reactions by combing through databases.4
“What we have here is a special set of circumstances where the whole world becomes involved in the conduct of a clinical trial,” Soriot said. “The reality is we all have to be very patient and see how it unfolds.”5
Another AstaZeneca COVID-19 Vaccine Trial Participant Developed Multiple Sclerosis
AstraZeneca’s public statements about the temporary pause in its COVID-19 vaccine clinical trial contain few details, and drug company officials will not publicly confirm that this is the second time it has stopped trials to investigate potential adverse health events occurring among participants.6 A woman in the U.K. trial was diagnosed with multiple sclerosis in July, but the company said that serious adverse event, which triggered the first clinical trial pause, was not related to the vaccine.7
AstraZeneca’s clinical trial is the first Phase 3 COVID-19 vaccine trial publicly acknowledged to have been put on hold. According to the National Institutes of Health (NIH), such holds are not uncommon. Francis Collins, MD, director of the NIH, told a U.S. Senate panel last week:
To have a clinical hold, as has been placed on AstraZeneca as of yesterday, because of a single serious adverse event is not at all unprecedented. This certainly happens in any large-scale trial where you have tens of thousands of people invested in taking part, some of them may get ill and you always have to try to figure out: Is that because of the vaccine, or were they going to get that illness anyway?8
AstraZeneca Seeks 30,000 Participants for U.S. Phase 3 Trial
In April, Oxford University’s Jenner Institute and Oxford Vaccine Group partnered with AstraZeneca to develop, manufacture, and distribute ChAdOx1 nCoV-19, which uses a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein.9
AstraZeneca, which sponsors the clinical trials, began Phase 3 trials in the U.S. in late August. Phase 3 trials confirm and expand the evidence base for safety and efficacy of Phase 1 and 2 trials. The U.S. trial, which aims to enroll about 30,000 participants, is currently taking place at 62 sites across the country, according to clinicaltrials.gov, a government registry, though some sites have not yet started enrolling participants. Simultaneously conducted Phase 2/3 trials were previously started in the U.K., Brazil, and South Africa.10
Transverse Myelitis Is A Rare But Serious Neurological Disorder
Transverse myelitis involves inflammation of the spinal cord, which carries signals to and from the brain through nerves that extend from each side of the spinal cord and connect to nerves elsewhere in the body. Symptoms of transverse myelitis include pain that can be sharp or blunt and may shoot down arms and legs or wrap around the trunk or chest; sensory problems such as tingling, numbness, pricking, coldness, burning and sensitivity to touch or temperature; weakness in the legs and possibly the arms causing loss of balance, difficulty walking, and loss of function, which may develop into paralysis; bladder and bowel problems such as constipation, incontinence, or frequent need to urinate; and sexual dysfunction. These problems may develop suddenly over a period of hours, or over days or weeks.11
About 1,400 new cases of transverse myelitis are diagnosed each year in the United States. Although some people recover from transverse myelitis with minor or no residual problems, the healing process may take months to years. Others may suffer permanent impairments that affect their ability to perform ordinary tasks of daily living. There is no cure for transverse myelitis.12
A 2018 study published in the journal Neurology, which examined evidence for a causal relationship between transverse myelitis and vaccination, concluded that: “the unbalanced distribution of these cases in the first 6 weeks after vaccination suggests that the association between vaccination and some cases may not be coincidental. Work is in progress to determine association of individual vaccine types with the course of TM.”13
High Percentage of Local and Systemic Side Effects in AstraZeneca COVID-19 Vaccine Trial
Preliminary results of the AstraZeneca’s Phase 1 and Phase 2 trials were published in The Lancet14 in July 2020. There were 1,077 healthy adults ages 18 to 55, who were randomly given either the ChAdOx1 nCoV-19 vaccine or the meningococcal conjugate (MenACWY) vaccine. Local and systemic reactions were more common in the trial group given the experimental COVID-19 vaccine, and a portion of both groups received prophylactic paracetamol (acetaminophen) before vaccinations were administered.
Fatigue and headache were the most commonly reported systemic reactions. Fatigue was reported in the ChAdOx1 nCoV-19 group by 70 percent of the participants, who were not give paracetamol prior to vaccination, and in the MenACWY group by 48 percent of the participants without paracetamol. Headaches were reported in the ChAdOx1 nCoV-19 group by 68 percent of the participants without paracetamol and 61 percent with paracetamol and in the MenACWY group by 41 percent of the participants without paracetamol and 37 percent of the participants with paracetamol.
Other systemic adverse reactions were common in the ChAdOx1 nCoV-19 vaccine group: muscle ache—60 percent, malaise—61 percent, chills—56 percent, and feeling feverish—51 percent. In the ChAdOx1 nCoV-19 vaccine group, 18 percent of participants without paracetamol and 16 percent of participants with paracetamol reported a temperature of at least 100.4°F, and two percent of patients without paracetamol had a temperature of at least 102.2°F. In comparison, less than one percent of those receiving MenACWY reported a fever of at least 100.4°F, none of whom were receiving prophylactic paracetamol.
The severity and intensity of local and systemic reactions was highest on the first day after vaccination.
Hold on AstraZeneca COVID-19 Vaccine Trial Coincides with Historic Safety Pledge by Vaccine Companies
AstaZeneca put its trial on hold on Sunday, Sept. 6, but it was only made public following a news leak15 late on Tuesday, Sept. 8, the same day as nine pharmaceutical companies, including AstroZeneca, signed an historic pledge “to make the safety and well-being of vaccinated individuals the top priority in development of the first COVID-19 vaccines.”16 According to STAT News, the pledge was “an apparent attempt to provide public reassurance despite the widely held view that the COVID-19 vaccine development process is politically tainted.”17
U.S. Government Commits $1.2 Billion to Buy AstraZeneca COVID-19 Vaccine
In May the U.S. government pledged to commit up to $1.2 billion to AstraZeneca to develop a coronavirus vaccine and to obtain at least 300 million doses of any COVID-19 vaccine the corporation gets licensed in 2020. The arrangement with AstraZeneca is labeled a public-private partnership and the Biomedical Advanced Research and Development Authority (BARDA) will provide technology transfers and scaled-up manufacturing.18
1 Robbins R, Feuerstein A, Branswell H. AstraZeneca Covid-19 vaccine study put on hold due to suspected adverse reaction in participant in the U.K. STAT News Sept. 8, 2020.
2 Feuerstein A., Covid-19 vaccine trial participant had serious neurological symptoms, but could be discharged today, AstraZeneca CEO says. STAT News Sept. 9, 2020.
3 AstraZeneca COVID-19 vaccine AZD1222 clinical trials resumed in the UK. Sept. 12, 2020.
4 See Footnote 1.
5 Ring S, Paton J. AstraZeneca Still Aiming for Oxford Covid Vaccine by Year-End, CEO Says. Bloomberg Sept. 10, 2020.
6 See Footnote 2.
7 Branswell, H. AstraZeneca resumes Covid-19 vaccine trials in the U.K. STATNews Sept. 12, 2020.
8 See Footnote 2.
9 See Footnote 3.
10 Footnote 2.
11 University of San Francisco. Transverse Myelitis USFC Health Dec. 22, 2019.
12 National Institute for Neurological Disorders and Stroke Transverse Myelitis.
13 Shah S, Patel J., et.al. Development of Transverse Myelitis after Vaccination, A CDC/FDA Vaccine Adverse Event Reporting System (VAERS) Study, 1985–2017. Neurology (p5.099) Apr. 9, 2018.
14 Folegatti PM, Ewer KJ, et.al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS CoV-2: a preliminary report of a phase ½ single-blind, randomized, controlled trial. The Lancet (pp 467-478) Aug. 15, 2020.
15 Cookson C, Oxford and AstraZeneca resume coronavirus vaccine trial Financial Times Sept. 12, 2020.
16 Business Wire. Biopharma Leaders United to Stand with Science. Sept. 8, 2020.
17 Facher L, Amid broad mistrust of FDA and Trump administration, drug companies seek to reassure public about Covid-19 vaccine safety STAT News Sept. 8, 2020.
18 Silverman E, U.S. gives up to $1.2 billion to AstraZeneca for Covid-19 vaccine STAT News May 21, 2020.
19 Allan A. and Szabo L. Regulators in the United Kingdom allowed the AstraZeneca vaccine trial to resume, but U.S. regulators are continuing to investigate. The Daily Beast Sept. 14, 2020.
20 Steenhuysen J, Taylor M. Exclusive: AstraZeneca COVID-19 vaccine trial in U.S. on hold until at least midweek – sources. Reuters Sept. 14, 2020.