Halting the Oxford vaccine trial doesn’t mean it’s not safe – it shows they’re following the right process

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Nigel William Crawford, Murdoch Children’s Research Institute and Jim Buttery, Monash University

Only days after the federal government announced a A$1.7 billion vaccine deal to roll out COVID-19 vaccines to Australians in 2021, one of the two candidates has halted its phase 3 trials after a participant became ill.

The AZD1222 vaccine, considered one of the frontrunners in the global race for a COVID-19 vaccine, was developed by the University of Oxford and has been undergoing testing with British-Swedish pharmaceutical company AstraZeneca.

Melbourne-based biotechnology company CSL has committed to producing and supplying more than 30 million doses of the vaccine to Australians if it’s found to be safe and effective.

But this pause in the trials doesn’t necessarily mean it’s not safe. Rather, it indicates the testing is progressing as it should, with due consideration of safety.

What happened?

There’s been no official statement on the nature of the incident that caused the trial to be halted. We only know it was a suspected adverse reaction in a participant in the UK. (Phase 3 trials for the AZD1222 vaccine have been taking place in several countries.)

The New York Times has reported the participant was diagnosed with transverse myelitis, an inflammatory condition than affects the spinal cord and can be sparked by viral infections.

Transverse myelitis is very rare, with between one and eight new cases per million people per year.

Most people will recover, but may be left with some symptoms such as weakness.

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In the world of vaccine safety, transverse myelitis is one of several conditions collectively known as a serious acute neurological episode (SANE) temporally associated with vaccination. Others include Guillain-Barré syndrome and acute disseminated encephalomyelitis.

“Temporal” suggests they occasionally occur some time after vaccination, but we don’t know whether the relationship is one of cause and effect. Unfortunately, it’s not always easy to find what caused these conditions, and it’s important to look for other infections that may be associated with the diagnosis.

There are a couple of things worth noting in this case. First, in the UK branch of the trial, not all participants were receiving the AZD1222 vaccine. To ascertain its effectiveness, researchers have given a control group a type of meningococcal vaccine (MenACWY) that has already been licensed. As the trial is double-blinded, we don’t yet know whether the affected participant received the COVID-19 vaccine.

Second, AZD1222 is not a “live-attenuated” vaccine — it’s not made from live SARS-CoV-2 virus. (It does use a chimpanzee adenovirus vector, but this doesn’t replicate or cause disease in humans.) It’s not impossible the transverse myelitis — if confirmed as a diagnosis — was related to the vaccine. But it wouldn’t be possible for the vaccine to cause a COVID-19 infection, which could then spark the myelitis.

Further, phase 2 and 3 trials involve much broader populations than the young, healthy adults who typically participate in early testing. The UK trial of AZD1222 includes people 70 years and older, which naturally increases the risk of temporally associated adverse events.

So what next?

AstraZeneca will already be investigating the incident, with input from external regulatory bodies such as the study’s data safety monitoring board, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).

These independent bodies will review all parts of the investigation, such as an MRI on the participant to confirm the diagnosis, and look at which of the groups the person was in (whether they received AZD1222 or the other vaccine).

They will try to find out what caused the illness, but this may not be possible. It will be particularly hard to prove the vaccine caused the illness with only one case. Illnesses like transverse myelitis, although rare, have a “background rate” of occurrence already in the community.

The World Health Organisation provides a framework to assess the cause of an adverse event following immunisation. AstraZeneca and the independent bodies monitoring their processes will follow this or similar frameworks to evaluate the event.

Once they’ve reviewed the incident, they will decide whether to resume the trial. Given the impetus to move quickly with this, we’d expect this to happen in a matter of days.

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It’s not a bad thing

This halt on the trial doesn’t indicate the vaccine isn’t safe — we’ll need to see further evidence before we can ascertain this.

But it does reflect robust processes for a clinical trial. In a sense, this is what phase 2 and 3 clinical trials are designed for — to pick up any potential safety issues and investigate them further.

These sort of things happen occasionally in other clinical trials too. We just don’t hear about it. There’s perhaps never been so much attention on a single clinical trial as there is on the trial of this and other potential COVID-19 vaccines.

We’re not sacrificing safety for speed

In the course of this pandemic, we’ve often heard that fast can’t be safe in the context of a vaccine. We don’t feel that’s the case here.

The reason these trials are moving so fast is largely because recruitment is happening quickly. The phase 3 trials of AZD1222 will have 40,000-50,000 participants in total.

Beyond the AZD1222 vaccine, we’re seeing open disclosure of processes and transparency around any issues. This includes a pledge from the major pharmaceutical companies to keep safety at the forefront when evaluating COVID-19 vaccines.

Of course, there are exceptions to this — notably the Russian vaccine, which has published some phase 1 data but reportedly gone into widespread use before completing all of the standard safety and effectiveness checks.

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In Australia, we follow certain steps to assess the safety of new vaccines. If the trial of the Oxford/AstraZeneca vaccine resumes and it proves safe and effective, Australia’s Therapeutic Goods Administration (TGA) will see the data and interact closely with regulatory bodies around the world to ensure it’s safe to use.

The TGA is also responsible for post-marketing surveillance, which we regard as phase 4. When the vaccine is being rolled out, we continue to monitor for adverse events, and follow these up using both jurisdictional vaccine safety units, such as SAEFVIC in Victoria, and active surveillance systems, such as Smartvax and Vaxtracker.

Nigel William Crawford, Associate Professor, Murdoch Children’s Research Institute and Jim Buttery, Professor of Paediatric Epidemiology, Monash University

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Oxford immunologist on coronavirus vaccine: our early results look highly promising

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Rebecca Ashfield, University of Oxford

A vaccine against COVID-19 is urgently needed if we’re to stop the virus spreading and prevent potentially millions of further deaths. We’re now one step closer to that goal.

Today, we published early results from our clinical trial of the vaccine ChAdOx1 nCoV-19 (also known as AZD1222), designed by the University of Oxford and developed in partnership with AstraZeneca. The preliminary data shows that it is safe and induced a strong antibody response in all vaccinated volunteers, suggesting that an effective vaccine could be within reach.

This trial was the first time that the vaccine had been given to humans: 543 healthy adults aged 18-55 were vaccinated with a single dose of ChAdOx1 nCoV-19. A further 534 people were given a control vaccine that gives similar minor reactions, including injection site redness and mild pain. Volunteers are having their immune response (both antibodies and T cell levels) monitored for at least 12 months, and will also be observed to see whether or not they develop COVID-19.

The preliminary data from the trial clearly demonstrates that the vaccine induces an antibody response within 28 days. This response is in a similar range to that in individuals who have recovered from COVID-19, providing encouragement that the vaccine will be able to protect the majority of people against infection.

Ten volunteers were also given a second “booster” dose of the vaccine. This increased the antibody response to even higher levels, and 100% of blood samples from this group showed neutralising activity against COVID-19 infection in a laboratory setting.

The vaccine also induced T cells that specifically recognise SARS-CoV-2, the virus that causes COVID-19. It’s encouraging to see both antibody and T cell responses, as together this is the right kind of immune response that could lead to protection against the virus. Importantly, the vaccine demonstrates an acceptable safety profile, with no vaccine-induced severe adverse events – that is, no major side-effects.

We were confident testing the vaccine in humans after encouraging trials with mice and rhesus macaque monkeys. These had shown that the vaccine was safe and induced a robust immune response. Significantly, the vaccinated monkeys were protected from severe disease after they were challenged with a much higher dose of SARS-CoV-2 than humans would encounter through natural exposure.

How does this vaccine work?

Vaccines work by training the immune system to recognise and fight off infectious agents (pathogens), such as bacteria and viruses. Vaccines do this by presenting the immune system with a readily identifiable part of a pathogen, which the immune system remembers so that it can quickly respond should it encounter that same pathogen in the future.

Most vaccines in development for SARS-CoV-2 – including this one – focus on presenting the spike protein that decorates the surface of the virus. It’s this protein that allows the virus into human cells by binding to a molecule on their surface called ACE2.

The coronavirus SARS-CoV-2, with its spike proteins shown in red.
US Centers for Disease Control and Prevention/Wikimedia Commons

There is a broad range of approaches to vaccine design; ChAdOx1 nCoV-19 is what’s known as a viral vector vaccine. To make this vaccine, particles of a different, harmless virus (called ChAdOx1) are loaded with the portion of SARS-CoV-2 DNA that instructs cells how to build the spike protein.

When these ChAdOx1 particles infect human cells, the coronavirus DNA is then “expressed”, building the spike protein for the immune system to respond to. Importantly for vaccine safety, the viral vector can’t replicate and cause an ongoing infection.

The ChAdOx1 viral vector has been used to make eight vaccines already in clinical trials for other human diseases, including Mers (Middle Eastern respiratory syndrome), a coronavirus that is related to SARS-CoV-2.

What happens now?

Crucially, we need to demonstrate that the vaccine is effective – that it results in significantly lower (ideally zero) cases of COVID-19 in the ChAdOx1 nCoV-19 vaccinated group versus the control group. Falling infection rates in the UK are an excellent outcome for the health of the nation, but may compromise the ability to show this.

If there are no cases of COVID-19 in the group receiving the control vaccine, comparing that group to the vaccinated group would be meaningless. Deliberately infecting people with the virus may be possible in future (after careful consideration of the ethical implications), but is not currently allowed.

For this reason, a second trial has been launched in approximately 10,000 UK individuals, focusing on health workers, and further trials are being conducted in Brazil and South Africa, where infection rates are much higher. The expanded UK trial will include children and older adults to estimate vaccine efficacy in these age groups. Immune responses in people over 70 are often lower than those in younger adults.

It’s essential to follow the vaccine-induced immune response over a period of at least one year, to estimate whether booster injections will be required, and if so how often. My personal prediction – based on decreases in antibody levels in individuals infected with other types of coronavirus, rather than data from the current vaccine trial – is that we’re likely to need yearly boosters, similar to annual flu jabs.

Finally, if the vaccine proves effective, rapid manufacture of potentially billions of doses would be required to supply the world. To facilitate this, AstraZeneca has already initiated a large-scale vaccine manufacturing programme, aiming to have hundreds of millions of doses with delivery starting by the end of 2020. Agreements are in place to provide the vaccine to low-income and middle-income countries and also to the UK, Europe and the US.

Rebecca Ashfield, Senior Project Manager, Jenner Institute, University of Oxford

This article is republished from The Conversation under a Creative Commons license. Read the original article.

Despite Democracy, Christians in Bhutan Remain Underground

Open practice of faith could lead to more persecution, they fear.

THIMPHU, Bhutan, January 25 (CDN) — In this distant and isolated nation in the eastern Himalayas, known as the “Land of the Thunder Dragon,” almost everything looks uniformly Buddhist.

Most men and women in the landlocked country between India and China wear their national dress, and all the buildings – with their sloping walls, trefoil-shaped windows and pitched roofs – look alike, as if they were Buddhist monasteries.

There are no visible signs of Christians’ tiny presence, but they do exist. Christians, whose only official identity falls in the “others” category in the census, are estimated to range in number between 3,000 and 6,000. And they live out their Christian lives underground – no church buildings, Christian cemeteries or Christian bookstores are yet allowed.

Of Bhutan’s more than 670,000 people, 75 percent of them practice Buddhism, according to the 2005 census. Around 22 percent are Hindu, mostly of Nepali origin.

An absolute monarchy for over 100 years, Bhutan became a democratic, constitutional monarchy in March 2008, as per the wish of the former King of Bhutan, Jigme Singye Wangchuck, who served from 1972 to 2006. It has been nearly two years since democracy arrived in Druk Yul, as the country is known in its national language, Dzongkha. But little has changed for Christians.

If there is anything open about Christianity, it is the acknowledgement of Christians’ presence in the national press, which was born after the advent of democracy.

“A journalist telephoned and asked me if I was converting local people,” said a middle-aged pastor clad in Gho, the men’s national uniform, a knee-length gown woven with colorful wool. “I wondered how she got my phone number. Maybe a Christian friend of mine passed it on.”

The pastor requested anonymity – the same request that high government officials made, no matter how trivial the matters they divulged.

The pastor said he told the journalist he did not pay people to convert. “People choose to become Christians out of their own free will,” he said. “I am working within the constitution of the country.”

Still a Monarchy

Asked why the church remained underground in spite of a provision for religious freedom in the new constitution, the pastor replied, “Virtually, Bhutan is still a monarchy. The time is yet to come when we have the assurance of protection.”

His wife, wearing the ankle-length woollen skirt or Kira that is the national dress for women, smiled at what was perhaps a naïve question – the power of the monarchy is beyond question. By law all Bhutanese citizens wear the national dress in schools and certain public, government and religious places. Non-compliance can result in fines or imprisonment.

Asked what would happen if authorities found out about their underground church, the pastor said that before 2008 they would have been arrested because Christianity was banned.

“Even now, there will be serious repercussions,” he said. “What exactly will happen, I do not know. But no Christian worker will take the risk to find it out the hard way.”

To construct any building, Bhutanese citizens require a licence from the government.

“As far as the governance is concerned, the Royal Government of Bhutan is very caring,” he said. “We get free education and free medicine and hospitalization, and there is a sense of security because the crime rate is very low. But asking for a licence for a church is beyond our imagination as of now.”

The present king, Jigme Khesar Namgyel Wangchuck (selected in 2006 but not crowned until 2008) rules absolutely, said local Buddhists, though not with any regret.

“It’s democracy, but still not a democracy,” said a civil government employee requesting anonymity. “It’s the king who makes all important decisions.”

Asked about the Christian presence, he said Christianity grew even at a time when it was banned. “There are many secret Christians. They meet in secret locations for prayer.”

The clean-shaven, medium-built 31-year-old king, an avid soccer fan who studied at Phillips Academy and Wheaton College in Massachusetts in the United States and the University of Oxford in the United Kingdom, is seen as a progressive person but conservative in matters of religion and culture.

According to the new constitution, the king is the head of state, though the parliament has the power to impeach him by a two-thirds majority vote – a provision not likely to be used anytime in the future, according to popular sentiment.

Banned

Suggesting that Christian fears are warranted, a pastor from Pheuntsholing town near the India border explained that memories of a period of severe crackdown on underground churches were still fresh in the minds of local Christians.

“I was picked up from a house where I was conducting Sunday worship in Tsirang district in September 1995 and put in a prison,” said the pastor. “I was asked to leave the district with immediate effect, and I had to move to another location.”

His voice trembling as he spoke by telephone, he said, “Once the government discovers that you are a Christian, nothing will be free for you.”

The pastor said that although there are no violent attacks on Christians, they do face discrimination by the government and society.

According to the government-run weekly Kuensel of Nov. 4, 1992, the National Assembly banned Christianity in 1969 and in 1979. The edicts against Christians were said to have passed due to reports of conversions to Christianity in south Bhutan, inhabited mostly by people of Nepali origin.

In the early 1990s the government of Bhutan began a massive crackdown on Christians, mainly in southern parts, and intensified it towards the end of the decade.

The authorities identified Christians in government or business and took their signatures on a form pledging compliance with rules and regulations governing practice of religion. There were several reports, though unconfirmed, of violence against Christians by police and village heads during the period.

In April 2001, international media reported on persecution of Christians in Bhutan when police stormed churches on Palm Sunday to register Christians, many of who were detained and threatened.

Almost a decade later, the legal standing of the Christian minority under the new constitution remains unclear.

Ambiguous Laws

In May 2009, the national daily Bhutan Times quoted Interior Minister Lyonpo Minjur Dorji as saying, “It was absolutely okay if people were born Christian … The constitution supports them. But it is unlawful to convert. If we get proof of proselytization in the country, we shall definitely take action.”

The newspaper noted that there are no official churches in Bhutan. “And most of the Sunday masses and gatherings are held in the homes of pastors and converts,” noted the daily, which occasionally criticizes government policies, though mildly and without taking aim at any particular official.

The new Constitution of the Kingdom of Bhutan, drafted in 2005 and officially adopted in 2008, gives religious freedom to all the citizens of the country but also contains a virtual “anti-conversion law” as found in neighboring India.

The exotic, official website of the constitution – which displays the national emblem of two dragons and a lotus surmounted by a jewel symbolizing harmony between secular and religious powers and sovereignty of the nation – states that all Bhutanese citizens “shall have the right to freedom of thought, conscience and religion” in Article 7.

But Article 7 adds: “No person shall be compelled to belong to another faith by means of coercion or inducement.”

What the terms “coercion” and “inducement” mean is not clear. Whether “proselytization,” which the home minister recently suggested was illegal, means propagation of Christianity or conversion by “coercion or inducement,” is also left unclear.

The Supreme Court of Bhutan, whose judge appointments have yet to be completed and are not yet functional, is likely to have the prerogative to interpret the constitution.

What is unambiguous, however, is that the government of Bhutan will continue to preserve the uniform culture of the country, which, it maintains, is based on Buddhist values. Article 3 of the constitution says that “Buddhism is the spiritual heritage of Bhutan, which promotes among others the principles and values of peace, non-violence, compassion and tolerance,” and “it is the responsibility of religious institutions and personalities to promote the spiritual heritage of the country while also ensuring that religion remains separate from politics in Bhutan.”

Article 4 mandates the government to “endeavour to preserve, protect and promote the cultural heritage of the country,” adding that “parliament may enact such legislation as may be necessary to advance the cause of the cultural enrichment of Bhutanese society.”

According to Article 8, it is a fundamental duty of all citizens to “preserve, protect and respect the culture and heritage of the nation.”

“Apart from religious restrictions, we are happy to be in Bhutan,” said a pastor from Thimphu. “Look at the unrest India, China and Nepal have from time to time. We are happy and thankful to God for this nation.”

Report from Compass Direct News