by Reynald Castaneda in London.

AstraZeneca’s Covid-19 vaccine AZD1222 splits experts as to whether its trials restarted too quickly on the heels of a second volunteer having a neurological event. While some said a more in-depth analysis is needed to conclude these events are truly independent of the vaccine, others noted these cases are unprecedented with the vaccine’s adenovirus vector and so could be due to chance.

The split is reflective of recent decisions from the FDA and European Medicines Agency (EMA) around AZD1222. The FDA has broadened its investigations and still has the US trial on hold, as per 30 September media reports. On 1 October, the EMA announced it was starting a rolling review of AZD1222, and all ex-US trials have restarted, including in Brazil, Japan and South Africa, as well as the UK, where two separate late-phase neurological events occurred.

Experience with AZD1222 adenovirus vector is limited and the events occurred during clinical trials where volunteers are highly selected, which supports further investigations. There is limited information to connect the vaccine with the incidents and noted to the dire straits of the trial being conducted in a pandemic.

However, there should be scrutiny over whether the process has had enough time to properly evaluate if more such events could occur later in the trial or in the general population, especially given the Covid-19 vaccine race. Furthermore, there is no diagnostic test to accompany the vaccine if it were to get any Emergency Use Authorization. The cost-benefit ration of AstraZeneca’s Covid-19 vaccine would deserve more scrutiny if there were more of the same events in the trials, some experts noted.

AZD1222 was initially developed by the University of Oxford, which declined to comment. AstraZeneca, which has a £110.35bn ($143.01bn) market cap, did not respond to a comment request.

AZD1222: More detailed analysis needed to ease neurological event concerns

The two neurological events observed in AstraZeneca’s development so far need further investigation because, compared with other technologies in the Covid-19 vaccine race, AZD1222’s adenovirus vector has limited precedence in humans, noted Nikolai Petrovsky, PhD, professor, College of Medicine and Public Health, Flinders University, Adelaide, Australia. Although previously investigated in clinical trials in various infectious diseases, the only AD26-vectored vaccine to garner an approval anywhere is Johnson & Johnson’s Zabdeno (Ad26.ZEBOV) for protection versus Ebola. The EMA greenlit the vaccine on 2 July based on data from approximately 6,500 volunteers. The Russia-developed Sputnik V Covid-19 vaccine features a prime-boost approach comprising a mixture of AD26 and AD5.

During a conference call, AstraZeneca’s CEO Pascal Soriot said the company had temporarily halted vaccinations in July after a participant experienced neurological symptoms, which were later concluded to be undiagnosed multiple sclerosis (MS) and thus unrelated to the Covid-19 vaccine. On 6 September, a second vaccination pause was triggered in all trials due to another event reported by the press as transverse myelitis, with both incidents occurring in UK-based volunteers. Transverse myelitis and MS belong to the same type of neurological condition, with the former being a one-time attack on the myelin sheath, which protects nerve cells; the attack on myelin happens frequently in MS patients, explained Dr Michael Levy, associate professor in neurology, Harvard Medical School, Boston.

Transverse myelitis has not been reported before from the available experience with adenovirus vectors, noted Suresh Mittal, PhD, professor of virology, Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana. A more expected side effect with such a vector is liver toxicity, but this is only anticipated in much higher doses as required in gene therapy, Mittal explained. Still, a detailed sweep of all AZD2111 volunteer data should be done to allow any conclusions, Petrovsky said.

Further investigation is warranted considering the transverse myelitis incident surfaced in a clinical trial setting, where participants are already highly selected, noted Gary Kobinger, PhD, head, Vector Design and Immunotherapy Special Pathogens, Medical Microbiology, University of Manitoba, Canada. The high-level screening achievable in a clinical trial is unlikely to be practical in the wider population, Kobinger added.

A detailed copy of the US-based trial’s protocol was made public on 19 September, showing the trial excludes people with a history of Guillain-Barré syndrome or any other demyelinating condition. This exclusion criterion would be hard to execute in people who are undiagnosed but susceptible to a condition like transverse myelitis, Petrovsky added. Any effort to detect susceptibility may be moot, Levy agreed. Only one gene has been identified as linked to transverse myelitis risk and, in his patients, only 3% are carriers of this gene, he explained.

This exclusion criterion is not noted on the pages of the UK, Brazil and South Africa-based trials investigating AZD2111, nor is it in Moderna’s or Pfizer and BioNTech’s respective detailed mRNA vaccine trial designs. However, while not listed, this is a common exclusion criterion in any vaccine trial, noted a US-based investigator in Pfizer/BioNTech’s Phase II/III BNT162b2 trial. Statistically, if there is one case of transverse myelitis in any trial, there could be about five to 10 cases of Guillain-Barré syndrome in other volunteers, Levy added.

Based on available information, it is challenging to tell if the transverse myelitis incident is vaccine-related or could have been due to chance, said Dr Hildegund Ertl, professor, Vaccine and Immunotherapy Center, The Wistar Institute, Philadelphia. Transverse myelitis occurs in less than one in every 100,000 people, so one such event is not surprising due to the huge scale of these vaccine trials, added Levy. Still, while the MS case was concluded to be unrelated to the vaccine, it is still nebulous if the participant’s pre-existing condition was exacerbated in some way by AZD1222, noted Don Diamond, PhD, professor, Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, California.

Diagnostic test with vaccine unlikely

Details such as background rates of transverse myelitis in the general population versus rates in the vaccine group in the trial would be helpful to judge the vaccine’s cost-benefit ratio, a Moderna Phase III mRNA-1273 trial investigator said. While one transverse myelitis case should reflect population rates, a second event in the same patient or another volunteer would be higher than statistically expected, Levy added. Any more comparable side effects with the vaccine would be a significant blow to its development prospects, particularly considering it is a crowded field, Diamond said.

There is no available diagnostic test to find people at-risk of transverse myelitis, the Moderna investigator said. The gold standard in diagnosing transverse myelitis is a magnetic resonance imaging (MRI) scan, which is triggered by never-subtle symptoms, Levy explained. The classic features of transverse myelitis are a weakness of the arms and legs, pain, sensory alterations and bowel and bladder dysfunction.

Even if screening procedures were added, there are no clear benchmarks on what would qualify to define an at-risk person, Diamond said. Undiagnosed people are likely to be rare, as such patient’s symptoms would already have triggered a specialist diagnosis, Mittal said. People with underlying autoimmune tendencies would be investigated for such a condition, added Ertl.

It is not unusual for a serious medical condition to surface during vaccine investigations, especially at this huge scale, the Pfizer/BioNTech investigator said. The more volunteers there are, the higher the risk of the vaccine running into side effects due to pre-existing conditions, noted Gordon Dougan, PhD, professor, Department of Medicine, Cambridge University, UK. Since the event was acknowledged and the trial was paused, it means the system is working in finding potential issues, the Moderna investigator said.

There is concern about how the highly publicized trial pause could add fuel to vaccine hesitancy, Mittal said. Since AstraZeneca has been giving mixed messages on the transverse myelitis event, which erodes public confidence on the vaccine’s development, increased investigations should be done to ease concerns, Kobinger noted. AstraZeneca has previously dismissed media reports about the transverse myelitis event despite there being an internal safety report detailing the incident obtained by the press.

While there is concern regarding AZD2111’s potential side effects, some experts were also pragmatic. There is an ongoing pandemic, and any vaccine would be valuable if it is able to reduce the risk of severe disease in thousands of people, said Ertl. While Norbert Pardi, PhD, research assistant professor, Department of Medicine, University of Pennsylvania, Philadelphia, agreed, he noted more information is needed to judge the vaccine’s cost-benefit ratio.