The AstraZeneca/Oxford University Phase 3 COVID-19 Vaccine Trial – Why Was It Paused?

by Helen Stillwell

Recently, a Phase 3 trial investigating a COVID-19 vaccine (AZD1222) being developed by AstraZeneca and the University of Oxford was put on hold in the US following a report of an adverse event in a study participant in the U.K. (Feuerstein 2020). One of the predominant vaccine candidates against SARS-CoV-2, AZD1222 is a chimpanzee adenovirus-vectored vaccine expressing the SARS-CoV-2 spike protein. This technology has yet to be used in an FDA-approved vaccine; however, it has been widely tested in early phase trials for a variety of viruses, such as Ebola virus. 

The UK participant that triggered the study’s hold presented with neurological symptoms that were diagnosed as transverse myelitis (TM). TM is a rare inflammatory disorder that involves the spinal cord and manifests as rapid onset weakness, sensory deficits, and bowel/bladder dysfunction (Simone & Emmady 2020). The disease can persist for as little as 3 to 6 months or result in permanent debilitation. 

TM typically arises idiopathically — without a known cause; however, it can also arise post-infection. TM has been reported following infection with enteroviruses, West Nile virus, herpes viruses, HIV, human T-cell leukemia virus type I (HTLV-1), Zika virus, and others (Simone & Emmady). TM is an autoimmune condition that results when one’s immune system is unable distinguish between ‘self’ antigen and infectious antigen. In eliciting a host immune response through the presentation of a viral antigen, in some cases, vaccines initiate the autoimmune cascade, resulting in diseases such as TM (Levin et al. 2009). Indeed, a systematic review of the literature citing TM associated with vaccination identified 37 reported cases between 1970 and 2009.

Viral infection may induce autoimmunity through several mechanisms: molecular mimicry between viral antigens and ‘self’ antigens, epitope spreading by which viral antigens accelerate an existing autoimmune response through increased inflammation, or the polyclonal activation of B lymphocytes or bystander activation resulting in increased cytokine production and the expansion of self-reactive T-cells (Levin et al. 2009).

Clinically, however, it is difficult to say for certain whether an environmental stimulus such as vaccination is the direct cause of an autoimmune condition. In some cases, an autoimmune condition may have been developing slowly overtime and had yet to present symptoms. 

The AstraZeneca trial was halted following this incident to allow for a comprehensive examination of the case, something that is not uncommon in Phase 3 clinical trials. In any clinical trial, unexpected illness emerges among study participants – whether that illness is a result of the study drug is subject to an extensive review of the case and whether there were any other factors involved that might have contributed to the outcome. Therefore, the fact that the study was paused due to an adverse event does not necessarily say anything in particular about the vaccine’s safety or efficacy at this point in time. While another study participant also reported neurological symptoms earlier this summer, the patient was later diagnosed with multiple sclerosis which was found to be unrelated to vaccine administration (Feuerstein 2020). 

An evaluation of the case by an independent safety committee and regulatory officials determined that it would be safe to resume the trial in the UK (Loftus 2020). No specific information on the decision was offered to protect the confidentiality of the affected participant; however, the review must have revealed information that compelled officials to conclude that the likelihood that the vaccine had caused the patient’s TM was very low.

References

Simone CG, Emmady PD. Transverse Myelitis. [Updated 2020 Aug 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan.

Feuerstein A. COVID-19 Vaccine Trial Participant Had Serious Neurological Symptoms, But Could Be Discharged Today, AstraZeneca CEO Says. STAT News. (2020). https://www.statnews.com/2020/09/09/astrazeneca-covid19-vaccine-trial-hold-patient-report/.

Levin NA, Kivity S, Szyper-Kravitz, Shoenfeld Y. Transverse myelitis and vaccines: a multi-analysis. Lupus. (2009) 18: 1198-1204. 

Loftus P. AstraZeneca COVID-19 Vaccine Trials Resume in U.K. WSJ. (2020). https://www.wsj.com/articles/astrazeneca-covid-19-vaccine-trials-resume-in-the-u-k-11599922981.

Comments on this entry are closed.

  • Phil HALPER 28 September 2020, 6:13 pm

    Any thoughts on why the FDA has not let it resume? If I recall correctly apparently the patient was discharged from hospital quite quickly, is that normal in TM case? Lastly how can scientists determine if a potential adverse reaction is caused by the vaccine or not ?