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In Race for a Coronavirus Vaccine, an Oxford Group Leaps Ahead
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https://www.nytimes.com/2020/04/27/world/europe/coronavirus-vaccine-update-oxford.html
With a head start, Oxford scientists say their vaccine could be available by September. If it works.
As scientists at the Jenner Institute prepare for mass clinical trials, new tests show their vaccine to be effective in monkeys.
I emailed out to NATAP list about this vaccine effort 12 days ago, see below....
In Race for a Coronavirus Vaccine, an Oxford Group Leaps Ahead
As scientists at the Jenner Institute prepare for mass clinical trials, new tests show their vaccine to be effective in monkeys.
By David D. Kirkpatrick, New York Times. April 27, 2020 Updated 4:14 p.m. ET
In the worldwide race for a vaccine to stop the coronavirus, the laboratory sprinting fastest is at Oxford University.
Most other teams have had to start with small clinical trials of a few hundred participants to demonstrate safety. But scientists at the university's Jenner Institute had a head start on a vaccine, having proved in previous trials that similar inoculations - including one last year against an earlier coronavirus - were harmless to humans.
That has enabled them to leap ahead and schedule tests of their new coronavirus vaccine involving more than 6,000 people by the end of next month, hoping to show not only that it is safe, but also that it works.
The Oxford scientists now say that with an emergency approval from regulators, the first few million doses of their vaccine could be available by September - at least several months ahead of any of the other announced efforts - if it proves to be effective.
Now, they have received promising news suggesting that it might.
Scientists at the National Institutes of Health's Rocky Mountain Laboratory in Montana last month inoculated six rhesus macaque monkeys with single doses of the Oxford vaccine. The animals were then exposed to heavy quantities of the virus that is causing the pandemic - exposure that had consistently sickened other monkeys in the lab. But more than 28 days later all six were healthy, said Vincent Munster, the researcher who conducted the test.
"The rhesus macaque is pretty much the closest thing we have to humans," Dr. Munster said, noting that scientists were still analyzing the result. He said he expected to share it with other scientists next week and then submit it to a peer-reviewed journal.
Immunity in monkeys is no guarantee that a vaccine will provide the same degree of protection for humans. A Chinese company that recently started a clinical trial with 144 participants, SinoVac, has also said that its vaccine was effective in rhesus macaques. But with dozens of efforts now underway to find a vaccine, the monkey results are the latest indication that Oxford's accelerated venture is emerging as a bellwether.
"It is a very, very fast clinical program," said Emilio Emini, a director of the vaccine program at the Bill and Melinda Gates Foundation, which is providing financial support to many competing efforts.
Which potential vaccine will emerge from the scramble as the most successful is impossible to know until clinical trial data becomes available.
More than one vaccine would be needed in any case, Dr. Emini argued. Some may work more effectively than others in groups like children or older people, or at different costs and dosages. Having more than one variety of vaccine in production will also help avoid bottlenecks in manufacturing, he said.
But as the first to reach such a relatively large scale, the Oxford trial, even if it fails, will provide lessons about the nature of the coronavirus and about the immune system's responses that can inform governments, donors, drug companies and other scientists hunting for a vaccine.
"This big U.K. study," Dr. Emini said, "is actually going to translate to learning a lot about some of the others as well."
All of the others will face the same challenges, including obtaining millions of dollars in funding, persuading regulators to approve human tests, demonstrating a vaccine's safety and - after all of that - proving its effectiveness in protecting people from the coronavirus.
Paradoxically, the growing success of efforts to contain the spread of Covid-19, the disease caused by the virus, may present yet another hurdle.
"We're the only people in the country who want the number of new infections to stay up for another few weeks, so we can test our vaccine," Prof. Adrian Hill, the Jenner Institute's director and one of five researchers involved in the effort, said in an interview in a laboratory building emptied by Britain's monthlong lockdown.
Ethics rules, as a general principle, forbid seeking to infect human test participants with a serious disease. That means the only way to prove that a vaccine works is to inoculate people in a place where the virus is spreading naturally around them.
If social distancing measures or other factors continue to slow the rate of new infections in Britain, he said, the trial might not be able to show that the vaccine makes a difference: Participants who received a placebo might not be infected any more frequently than those who have been given the vaccine. The scientists would have to try again elsewhere, a dilemma that every other vaccine effort will face as well.
The Jenner Institute's coronavirus efforts grew out of Professor Hill's so-far unsuccessful pursuit of a vaccine against a different scourge, malaria.
He developed a fascination with malaria and other tropical diseases as a medical student in Dublin in the early 1980s, when he visited an uncle who was a priest working in a hospital during the civil war in what is now Zimbabwe.
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"I came back wondering, 'What do you see in these hospitals in England and Ireland?'" Professor Hill said. "They don't have any of these diseases."
The major drug companies typically see little profit in epidemics that afflict mainly developing countries or run their course before a vaccine can hit the market. So after training in tropical medicine and a doctorate in molecular genetics, Professor Hill, 61, helped build Oxford's institute into one of the largest academic centers dedicated to nonprofit vaccine research, with its own pilot manufacturing facility capable of producing a batch of up to 1,000 doses.
The institute's effort against the coronavirus uses a technology that centers on altering the genetic code of a familiar virus. A classic vaccine uses a weakened version of a virus to trigger an immune response. But in the technology that the institute is using, a different virus is modified first to neutralize its effects and then to make it mimic a targeted virus - in this case, the virus that causes Covid-19. Injected into the bloodstream, the harmless impostor can induce the immune system to fight and kill the targeted disease, providing protection.
Professor Hill has worked with that technology for decades to try to tweak a respiratory virus found in chimpanzees in order to elicit a human immune response against malaria and other diseases. Over the last 20 years, the institute has conducted more than 70 clinical trials of potential vaccines against the parasite that causes malaria. None have yet yielded a successful inoculation.
In 2014, however, a vaccine based on the chimp virus that Professor Hill had tested was manufactured in a large enough scale to provide a million doses. That created a template for mass production of the coronavirus vaccine, should it prove effective.
A longtime colleague, Prof. Sarah Gilbert, 58, modified the same chimpanzee virus to make a vaccine against an earlier coronavirus, MERS. After a clinical trial in Britain demonstrated its safety, another test began in December in Saudi Arabia, where outbreaks of the deadly disease are still common.
When she heard in January that Chinese scientists had identified the genetic code of a mysterious virus in Wuhan, she thought she might have a chance to prove the speed and versatility of their approach.
"We thought, 'Well, should we have a go?'" she recalled. "'It'll be a little lab project and we'll publish a paper.'"
It did not stay a "little lab project" for long.
As the pandemic exploded, grant money poured in. All other vaccines were soon put into the freezer so that the institute's laboratory could focus full-time on Covid-19. Then the lockdown forced everyone not working on Covid-19 to stay home altogether.
"The whole world doesn't usually stand up and say, 'How can we help? Do you want some money?'" Professor Hill said.
"Vaccines are good for pandemics," he added, "and pandemics are good for vaccines."
Other scientists involved in the project are working with a half dozen drug manufacturing companies across Europe and Asia to prepare to churn out billions of doses as quickly as possible if the vaccine is approved. None have been granted exclusive marketing rights, and one is the giant Serum Institute of India, the world's largest supplier of vaccines.
Donors are currently spending tens of millions of dollars to start the manufacturing process at facilities in Britain and the Netherlands even before the vaccine is proven to work, said Sandy Douglas, 37, a doctor at Oxford overseeing vaccine production.
"There is no alternative," he said.
But the team has not yet reached an agreement with a North American manufacturer, in part because the major pharmaceutical companies there typically demand exclusive worldwide rights before investing in a potential medicine.
"I personally don't believe that in a time of pandemic there should be exclusive licenses," Professor Hill said. "So we are asking a lot of them. Nobody is going to make a lot of money off this."
The Jenner Institute's vaccine effort is not the only one showing promise. Two American companies, Moderna and Inovio, have started small clinical trials with technologies involving modified or otherwise manipulated genetic material. They are seeking both to demonstrate their safety and to learn more about dosing and other variables. Neither technology has ever produced a licensed drug or been manufactured at scale.
A Chinese company, CanSino, has also started clinical trials in China using a technology similar to the Oxford institute's, using a strain of the same respiratory virus that is found in humans, not chimps. But demonstrating the effectiveness of a vaccine in China may be difficult because Covid-19 infections there have plummeted.
Armed with safety data from their human trials of similar vaccines for Ebola, MERS and malaria, though, the scientists at Oxford's institute persuaded British regulators to allow unusually accelerated trials while the epidemic is still hot around them.
The institute last week began a Phase I clinical trial involving 1,100 people. Crucially, next month it will begin a combined Phase II and Phase III trial involving another 5,000. Unlike any other vaccine project now underway, that trial is designed to prove effectiveness as well as safety.
The scientists would declare victory if as many as a dozen participants who are given a placebo become sick with Covid-19 compared with only one or two who receive the inoculation. "Then we have a party and tell the world," Professor Hill said. Everyone who had received only the placebo would also be vaccinated immediately.
If too few participants are infected in Britain, the institute is planning other trials where the coronavirus may still be spreading, possibly in Africa or India.
"We'll have to chase the epidemic," Professor Hill said. "If it is still raging in certain states, it is not inconceivable we end up testing in the United States in November."
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In Lancet today: "The best-case scenario is that by the autumn of 2020, see full text below.
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Professor Sarah Gilbert, a vaccinologist at Oxford, has said she is "80 per cent" confident it will be a success.
There is now hope that the jab, developed by the clinical teams at the Jenner Institute and Oxford Vaccine Group, could be ready from as early as September.... https://www.independent.co.uk/news/science/coronavirus-covid-19-vaccine-oxford-university-human-trials-a9467061.html
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Coronavirus vaccine could be ready by September, says Oxford professor working on trials
https://www.independent.co.uk/news/uk/home-news/coronavirus-vaccine-september-oxford-professor-sarah-gilbert-trials-a9460481.html
An Oxford professor has claimed that a vaccine for Covid-19 could be ready by autumn.
Sarah Gilbert is a professor of vaccinology at the University of Oxford and leads a team of researchers in developing a vaccine for the coronavirus, which has so far infected more than 1.7 million worldwide.
The global Covid-19 death toll passed 100,000 on Friday, according to data from John Hopkins University.
Professor Gilbert told The Times she was "80 per cent confident" the vaccine being developed by her team would be successful in protecting people against the disease.
She was quoted as saying: "I think there's a high chance that it will work based on other things that we have done with this type of vaccine. It's not just a hunch and as every week goes by we have more data to look at."
Developing a working vaccine by September was "just about possible if everything goes perfectly", added Professor Gilbert, but she warned that nobody could promise it would work.
The government is poised to spend millions of pounds for a viable vaccine to have it ready for use and the team is in talks with the government about starting production of the vaccine before the final results become available.
Professor Gilbert said: "We don't want to get to later this year and discover we have a highly effective vaccine and we haven't got any vaccine to use."
Other experts have expressed confidence in Professor Gilbert's claim, and said the Oxford team is highly advanced.
Professor of microbial pathogenesis at the London School of Hygiene and Tropical Medicine, Brendan Wren, said: "The Oxford vaccine group are among the most advanced groups in the world and have been working on vaccine biopreparedness for several years.
"This means that they can test and evaluate Covid-19 vaccine candidates rapidly (even in human volunteers). A strong vaccine candidate available by September would not be surprising."
However, Professor Brendan warned that because the UK lacks manufacture capabilities, it might be "at the back of the queue" if it depends on other countries with manufacturing capacity, such as Germany, Belgium and France.
"Desperate times require desperate measures, so upscaling and manufacture would be justified before data is fully known," he said.
"Even if the vaccine didn't prove effective this would be a useful trial run for the manufacture of alternative Covid-19 vaccines and vaccines against other viral and bacterial diseases."
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Gilbert is understandably cautious when asked to map out a timetable for the trial, but hopes to have vaccinated 500 volunteers by mid-May; this will be followed by an extension of the maximum age of trial volunteers from 55 to 70 years, later moving on to the over-70 age group. Phase 3 expansion is expected to involve 5000 volunteers; results from the earlier trials will be included in the efficacy follow-up. "The best-case scenario is that by the autumn of 2020, we have an efficacy result from phase 3 and the ability to manufacture large amounts of the vaccine, but these best-case timeframes are highly ambitious and subject to change", Gilbert says. "Our ability to determine vaccine efficacy will be affected by the amount of virus transmission in the local population over the summer, and we are also beginning to think about initiating trials with partners in other countries to increase our ability to determine vaccine efficacy", she says.
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Sarah Gilbert: carving a path towards a COVID-19 vaccine
Lancet Published:April 18, 2020
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30796-0/fulltext
It was the news from Wuhan, China, in the first days of 2020 that made Sarah Gilbert sit up and think. As Professor of Vaccinology at the University of Oxford in the UK, and a leading scientist at the university's Jenner Institute, her research team wasted no time in getting involved. "We had recently started thinking about an appropriate response to Disease X; how could we mobilise and focus our resources to go more quickly than we had ever gone before. And then Disease X arrived", she says. Once the genome sequence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became available in mid-January, Gilbert's team set to work to design a vaccine, using recombinant DNA techniques to create a SARS-CoV-2 antigen and embedding it within a primate adenovirus vector. "At this point it all felt quite theoretical, our goal then being to design a vaccine and to have a paper published showing what was possible in terms of a rapid response to an unknown outbreak, using our adenoviral vectored vaccine technology", she says.
Gilbert's team was awarded a £2·2 million grant from the UK's National Institute for Health Research and the UK Research and Innovation in March, 2020, to scale up her team's efforts to move into coronavirus disease 2019 (COVID-19) vaccine preclinical and clinical trials. "The way various grants have been awarded to different strategic aspects of the project is important, as much of the work can go on in parallel-for example, my colleague Sandy Douglas has received funding for work on scaling up vaccine manufacturing processes at the same time as we are progressing work in developing trials", she says. Preclinical work at Public Health England's Porton Down facility is the immediate priority, complementing parallel initiatives taking place at the US National Institutes of Health and at the Commonwealth Scientific and Industrial Research Organisation in Australia, among others. Gilbert's team has received ethical approval for a clinical trial, and conditional approval from the UK Medicines and Healthcare products Regulatory Agency to screen volunteers for trial enrolment. Another reason for speed is for her team to assess the efficacy of a vaccine in volunteers who have not yet been infected. "Ideally, we need the clinical trial to be taking place when the majority of volunteers have not been exposed to the virus. We will exclude volunteers who have a positive PCR test for SARS-CoV-2, or who have had fever or cough in the past month. Some will inevitably have been exposed, and that is useful too, as we want to know what the vaccine means for people who have been exposed to the coronavirus", she says.
Gilbert's early vaccine work at the University of Oxford started in 1994 with Adrian Hill, who today is Director of the Jenner Institute, with a focus on malaria vaccine research, and, given her particular interest in cellular immunology, the importance of T-cell responses to parasite infection. "From what we were seeing in malaria endemic regions, individuals with a specific HLA type did much better after becoming infected with malaria than others with different HLA profiles. This led us to look at creating vaccine candidates that could trigger favourable T-cell responses, rather than relying solely on antibody responses, the prevailing vaccine model at that time", she explains. This approach coincided with advancements in recombinant DNA techniques, with vaccinologists being able to generate specific antigens that could be safely incorporated in a host virus, as an alternative to the risks associated with using live attenuated vaccines. The ability to create recombinant viral vector vaccines is a core function of Gilbert's research group at the Jenner Institute, which over the past few years has progressed work on many vaccines, including those for influenza and Zika virus and early stage trials for Middle East respiratory syndrome coronavirus vaccine, a helpful template for the work on a COVID-19 vaccine. As Chair of the management committee that oversees initial vaccine production within the University of Oxford, Gilbert and colleagues have suspended all other concurrent vaccine research to prioritise efforts on COVID-19.
Gilbert is understandably cautious when asked to map out a timetable for the trial, but hopes to have vaccinated 500 volunteers by mid-May; this will be followed by an extension of the maximum age of trial volunteers from 55 to 70 years, later moving on to the over-70 age group. Phase 3 expansion is expected to involve 5000 volunteers; results from the earlier trials will be included in the efficacy follow-up. "The best-case scenario is that by the autumn of 2020, we have an efficacy result from phase 3 and the ability to manufacture large amounts of the vaccine, but these best-case timeframes are highly ambitious and subject to change", Gilbert says. "Our ability to determine vaccine efficacy will be affected by the amount of virus transmission in the local population over the summer, and we are also beginning to think about initiating trials with partners in other countries to increase our ability to determine vaccine efficacy", she says.
Sharing knowledge with parallel COVID-19 vaccine efforts worldwide is crucial. "WHO is in the process of creating a forum for everyone who is developing COVID-19 vaccines to come together and present their plans and initial findings. It is essential that we all measure immunological responses to the various vaccines in the same way, to ensure comparability and generalisability of our collective findings. Work is continuing at a very fast pace, and I am in no doubt that we will see an unprecedented spirit of collaboration and cooperation, convened by WHO, as we move towards a shared global goal of COVID-19 prevention through vaccination", Gilbert says.
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