Recently, I was asked to comment on the clinical stoppage of phase III trial of the AstraZeneca Oxford Covid vaccine. The oxford vaccine named AZD1222 is a replication-deficient viral vector vaccine (adenovirus from chimpanzees) which has a portion of the Covid-19 virus (spike protein). The trial reported a serious adverse event that was later disclosed as transverse myelitis (inflammation of the spinal cord) in a single female volunteer from the UK. The related media reports also suggested that the patient was recovering and will leave the hospital soon.
Even though this is a single event in a large number of recruited volunteers, there lies a bit of extra concern. The vaccine had a similar transverse myelitis like situation in another patient during the earlier, smaller phase II trial. The patient who experienced this serious adverse event was later diagnosed to have multiple sclerosis. Multiple sclerosis too can also result in a transverse myelitis like scenario.
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Transverse myelitis is a serious condition involving inflammation of the spinal cord. This condition can result in muscle weakness, paralysis, pain and bladder problems. Most of the time, we fail to identify a cause for transverse myelitis. This condition can happen as a result of several viral or bacterial infections. It can also occur due to immune mediated conditions as well. This condition was earlier reported by some other vaccines in very rare instances.
The vaccine is currently under trial in the US, UK, India, Brazil and South Africa. Trials are also planned in Japan and Russia. The US arm alone plan to recruit 30,000 volunteers. Both Adeno viruses (the vector in the current vaccine under trial) and our target (Covid-19) can produce transverse myelitis. Authorities immediately stopped the trail and initiated a process of examining the adverse.
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These stoppages are routine practice in drug/vaccine trials. Usually, the rules are written before the start of the trial and when they reach such situations, the trial is stopped and the DSMB (data safety monitoring board) examines the data in detail to confirm whether the event is due to the drug/vaccine under trial or not. All clinical action will be on hold during such assessments.
Last Sunday, the authorities permitted restarting of the phase III trial of AZD1222 after a fully detailed safety investigation by the DSMB. The statement from the DSMB (data safety monitoring board) goes on to say that the entity has concluded its investigations and advised the Medicines Healthcare Products Regulatory Authority, (UK equivalent of the FDA) that trials in the UK are safe to resume. This brings a huge sigh of relief for all awaiting a successful vaccine against Covid-19. The thousands of volunteers who signed up for the experimental vaccine too can stop worrying about serious adverse events as of now.
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Earlier in July, the results of a preliminary safety and effectiveness study suggested that two out of three people who received the experimental vaccine reported fatigue and headache after test inoculation. Many patients also reported muscle aches and fever, but less in number compared to the other two side effects. The researchers reported at that time that there were no serious adverse reactions among the 500 plus people vaccinated in that phase. As of now, only UK has restarted the trial. The trial is yet to restart in the US. We are yet to know the restart policy for India. It is expected that both the US and India will follow UK in restarting the vaccine trial.
The last seven days were like a roller coaster ride for the team behind the vaccine as the entire global media went freaking out and succeeded in scaring all. Recruitments for other ongoing vaccines too had a hit as fear of complications extended to other candidate vaccines as well.
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The US government awarded the AstraZeneca effort up to $1.2 billion in May this year as part of Operation Warp Speed (OWS), the Trump administration’s push to have a widely available coronavirus vaccine by January. Through OWS, partnerships were established with more than 18 biopharmaceutical companies to accelerate development of drug and vaccine candidates for Covid-19. It is expected that the proposed timelines may be delayed by a month or two given the circumstances.
Researchers across the globe are toiling hard to bring out a vaccine against SARS-CoV-2. Experts expect at least six to nine months from now to see a successful vaccine in the shelves ready to be taken by the public. Currently, at least 46 Covid-19 vaccines are under trial in various stages from preclinical to Phase three. Only seven have reached the final phase three mandatory stage including the Oxford vaccine. To date, just one coronavirus vaccine has been approved. The vaccine named Sputnik V developed by the Gamaleya Research Institute in Moscow was given approval by the Ministry of Health of the Russian Federation on 11 August.
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Several global experts have already raised serious doubts about the vaccine’s safety and efficacy given the fact that this approval was without a mandatory Phase 3 clinical trial. Several researchers have also questioned the recently published data related to this vaccine in the medical Journal “The Lancet” earlier this month. In an open letter to the editor of the journal which published early-stage trial results of the Sputnik V coronavirus vaccine, a group of 27 scientists said the data was definitely incomplete and had shown some unlikely patterns. The Gamaleya Research institute has not responded to these charges yet.
Looks like the road to a successful Covid-19 vaccine is all rickety and the timelines are constantly pushed to later dates. It remains to be seen whether we will see a successful SARS-CoV-2 vaccine by the end of this year or early next year. All we can hope is that at least one of those seven front runners will reach the finishing line in time and bring an end to this long-lasting misery.
(Dr Manu Raj is a paediatrician, clinical researcher and research methodologist based in Kochi.)