U.K. : Be the First to Enter Phase III Trials and have Received the Most Pre-Orders

In September, the world is likely to officially usher in the first new coronavirus vaccine. At this time, it was less than 10 months since the first known case of new coronary pneumonia was discovered. This speed far exceeds the 8-10 years required for general vaccine development.

Global developers are racing against time and 170 vaccine candidates flood the track.

Among them, a total of 7 candidate vaccines from China (4), the United States (2), and the United Kingdom (1) are the first to enter the final sprint of Phase III clinical trials. The sudden emergence of the Russian vaccine 'Sputnik-V' has also attracted attention.

At the same time, global buyers represented by governments of various countries have also preemptively placed orders, and the 'vaccine battle' is about to start.

Surging international launched the 'Global Vaccine Road' series of reports to comprehensively analyze the 'racers' on the vaccine development track.

On August 3, the British government and the Indian pharmaceutical company Wockhardt reached an agreement to purchase the exclusive rights to a production line of Wockhardt's plant in North Wales, U.K. for the next 18 months. Once the candidate vaccines ordered by the British government are on the market, a large amount of vaccine potions will be shipped to this factory, filled into vials or syringes, and then shipped to hospitals, clinics and consumers in the U.K. and even around the world.

The production line at the Wockhardt plant is not expected to hang for too long. Among the existing orders of the British government, the highly anticipated research and development team led by Sarah Gilbert, a professor of vaccinology at the Jenner Institute of Oxford University, and AstraZeneca Pharmaceuticals Co. The vaccine AZD1222 is expected to be put into use as early as September.

According to an article in the July issue of the medical journal 'The Lancet', the Phase I/II clinical trial of AZD1222 on 1,077 subjects conducted from April 23 to May 21 showed that this new coronavirus vaccine candidate was subject to all evaluations. All the subjects were tolerated and produced a strong immune response against the new coronavirus. In addition, it did not cause serious side effects.

As early as the end of May before the public release of this result, AZD1222 has gradually started Phase II/III clinical trials in the U.K., Brazil, South Africa and other places, becoming the world's first new coronavirus vaccine candidate to enter Phase III trials. In August, the scope of this test was also extended to the United States, where the number of new coronaviruses diagnosed and deaths was the highest.

'It is really shocking that Sarah and her team will be able to start clinical trials of the vaccine in less than 100 days after obtaining the gene sequence of the (new coronavirus) virus.' John Bell, senior professor of medicine at Oxford University, at the end of July commented in an interview with the Financial Times.

The British Broadcasting Corporation (BBC) stated that the AZD1222 (formerly known as ChAdOx1 nCoV-19) project progressed beyond expectations. Kate Bingham, Chair of the British government's vaccine working group, said in early July that the vaccine team led by Gilbert is far ahead of the world and that they are developing 'the most advanced vaccine in the world'.

However, Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases, warned of the Oxford team’s leadership in vaccine development. He told the BBC that 'whether it is a temporary lead or already has a really effective vaccine must be carefully evaluated.'

At present, this new coronavirus vaccine candidate developed by the Oxford team and issued by AstraZeneca has won the world's largest number of pre-orders.

Get Started

Gilbert, 58, often wakes up at four in the morning because of 'a lot of problems in her mind'. After waking up, she usually works at home for a few hours, then rides a bike to the Institute, where she will work until at night.

The Gilbert team was invited to interview in April, stating that the team of researchers are intensively developing a new coronavirus vaccine and cannot respond to the media during this period. A Bloomberg reporter also pointed out in a report on July 15 that Gilbert showed a super efficient and serious style. The team may be at a critical moment in making breakthroughs, and there is not a single minute to spare.

This race against time stems from Gilbert’s previous unsuccessful vaccine development experience. In 2014, Gilbert’s Jenner Institute led the first trial of an Ebola vaccine. However, when the vaccine is successfully developed, the epidemic will be over. This experience made Gilbert and her team realize the importance of speed.

Gilbert began to pay attention to the outbreak of new coronary pneumonia in Wuhan. 'At that time, we didn't know the early spread of the (epidemic), but when I chatted with my colleagues, we thought that once the gene sequence came out, we would do something.'

On January 7, the Chinese Center for Disease Control and Prevention successfully isolated the new coronavirus strain. After China submitted the new coronavirus genome sequence information to the WHO on the 12th, Gilbert and her team immediately began work. Since then, the number of people in the team has expanded from the first few people to about 250 people.

Adenovirus vector vaccine is currently one of the main technical routes used by the world's major new coronavirus vaccine research and development teams. This is a relatively mature vaccine technical route, that is safe, efficient, and causes fewer adverse reactions. However, the biggest problem with this type of vaccine is how to overcome the problem of 'pre-existing immunity'. Because adenovirus is spreading in humans, many people are immune. The AZD1222 developed by the Oxford University uses chimpanzee adenovirus as a vector, which is very different from human adenovirus, so most people's immune systems will not immediately respond to it to solve the 'pre-existing immunity' problem.

Oxford University has its own vaccine production facility, which can quickly produce vaccines for the Gilbert team for early trials. These vaccines were then transferred to an Italian manufacturer, planning to produce 1,000 doses for clinical trials in advance. On February 17, Gilbert's team began to vaccinate mice.

Subsequently, the R&D team conducted a trade-off discussion on whether to conduct a human test directly or to look at the results of another monkey test first.

In the 2003 SARS virus vaccine test, some vaccinated animals were more ill than unvaccinated animals. This phenomenon is called antibody dependence enhancement (ADE). Fearing that the new coronavirus vaccine might reappear in this situation, the Gilbert team decided to test it on monkeys at the Rocky Mountain Laboratory in Montana, USA, to rule out this possibility.

At that time, the new coronary pneumonia epidemic has spread to the world, and a large number of patients have died one after another. Waiting for the results of the monkey test means that the team will lose a few critical weeks. But in the end, the Gilbert team decided to proceed with caution.

In mid April, the results of the monkey experiment came from Montana. In mid May, the University of Oxford disclosed the vaccine-related animal experiment data on the website BioRxiv, and criticism followed. The data showed that the rhesus monkeys participating in the vaccine injection were all infected with the new coronavirus. Three of the monkeys were infected with accelerated breathing and obvious symptoms, which were regarded as evidence of the unsatisfactory effect of the vaccine.

William Haseltine, a former professor at Harvard Medical School, subsequently published an article in Forbes magazine, arguing that the Oxford vaccine seems to be only partially protective because it does not produce a protective effect by neutralizing antibodies that protect cells from infection. In an interview with Bloomberg, he said, 'My guess is that the Oxford vaccine is not strong enough for the elderly, so they must improve the effectiveness of the vaccine, and increasing the effectiveness of the vaccine may have side effects.'

Despite the controversy, the research and development team still believes that the results of animal experiments show some signs of optimism. So on the second day after the preliminary results were announced in late April, a team led by Gilbert’s colleague Andrew Pollard began a phase one clinical trial that lasted about a month. The results of the Phase I/II clinical trials of the AZD1222 candidate vaccine that were released on July 20 are quite optimistic.

During this period, Gilbert's triplets, three 21-year-old students studying biochemistry, also participated as volunteers in the first phase of the experiment.

As she was busy developing vaccines, Gilbert did not even discuss the matter with the young team, but she was not worried. 'I know the potential for adverse reactions and the dosage used, because our team has tested countless times and this (vaccine) is very safe, so I am not worried.' Gilbert said.

According to AstraZeneca, the results published in The Lancet confirmed that a single dose of AZD1222 can quadruple the antibody to the new coronavirus spike protein in 95% of participants within one month after the injection. T cell responses were induced in all 1077 participants, peaking on day 14 and maintained for two months after injection. One month after vaccination, 91% of the participants and 100% of the participants who received the second dose saw neutralizing activity against the new coronavirus.

Mene Pangalos, Executive Vice President of AstraZeneca Biomedical Research and Development, said he was 'encouraged' by the above data.

Accelerate

Under normal circumstances, most vaccine development plans take more than five years, and at least 12 to 18 months at the fastest. However, the number of confirmed cases of new coronavirus in the world is still increasing at a rate of 200,000+ per day, and countries are looking forward to a safe and effective vaccine to reverse the situation.

In order to speed up the speed of vaccine development, as early as the same time as the animal test, the Gilbert team began to apply to the regulatory agency for human testing and negotiate with the vaccine manufacturer.

In early March, Gilbert, who raised money everywhere, received a small grant from the Coalition for Epidemic Pretation Innovations (CEPI). But this is not enough. Gilbert's team still seeks to cooperate with large pharmaceutical companies, but repeatedly hits a wall. Professor Adrian Hill, Director of Jenner Institute, said that most funders don't think they can do it (to develop a vaccine).

The turning point occurred in late March.

On March 23, British Prime Minister Boris Johnson ordered the nationwide blockade. On the same day, the government announced that it would provide Gilbert's team with a grant of 2.2 million pounds support vaccine testing and production.

In early April, Mene Pangalos, Head of R&D of AstraZeneca Biopharmaceuticals, after learning that the vaccine developed by the Jenner Institute of Oxford University is showing some positive signs, he took the initiative to contact the latter, and finally the two parties reached a cooperation. According to the agreement, AstraZeneca is responsible for the global distribution and production of this unsuccessful vaccine.

Later, the British government once again increased the amount and provided 65 million pounds to the laboratory in order to obtain mass-produced vaccines in September.

In addition to injecting funds into the research and development team to promote vaccine research and development, the British government has also adopted multiple measures to ensure that the vaccine can be put into use as soon as the trial is completed.

According to the BBC report, Professor Hill told reporters at an online briefing in April that they have not only begun small-scale production of the vaccine, which is still in the trial stage, but also have manufacturers in 7 regions around the world. In the United Kingdom, two are in Europe, one in India and one in China. 'Our goal is to have at least 1 million doses of vaccines ready by September, when we have the final test results.'

But the team has never stated that if the clinical results of the vaccine are found to be unsafe and unsuitable for vaccination, and what will happen to the above-mentioned 1 million doses of vaccine.
In addition, the British government, which has been criticized for its ineffective fight against the epidemic and deliberately tried the 'herd immunity' strategy, has taken the vaccine very seriously this time.

According to information on the British government website, just after the Oxford vaccine team announced significant progress on July 20, the government added another 100 million pounds to ensure that the candidate vaccine can be mass-produced in the U.K. in the future. This investment will be used to build a new innovation center capable of producing millions of doses of vaccines per month, which will be officially opened in December 2021.

In early August, an agreement with Wockhardt for production line-specific agreements ensures that vaccines will be produced in the U.K. before the opening of the above-mentioned innovation centers. It is also the latest step taken by the British government for future vaccine supply 'logistics'. In addition, on August 28, the British government stated that it intends to adopt a series of new measures, including amendments to relevant regulations, to allow regulatory agencies to temporarily authorize the emergency use of the new coronavirus vaccine with proven safety and effectiveness in order to speed up the market.

In addition to ensuring the development, production and marketing of vaccines in the country, the British government has also ordered vaccine candidates from vaccine research and development teams in many countries, and established a Vaccine Working Group (VTF) in May to find a promising portfolio of vaccine candidates and to ensure that British people get clinically effective and safe vaccines as soon as possible.

Up to now, the British government has ordered 6 different candidate vaccines entering clinical trials, totaling 340 million doses. If all transactions are made, the equivalent of 66.65 million British people can get 5 doses of new coronavirus vaccine per person. In addition, a vaccine (DIOS-CoVax2), developed jointly by Cambridge University and the National Health System Trust of the University of Southampton Hospital in the United Kingdom, has also received 1.9 million pounds of financial support from the British government. It is planned to be in clinical trials will begin early next year.

At present, most of the vaccines being developed in the world have not received final approval. Despite this, Gilbert has shown great confidence in the success rate of her team. She believes that the Oxford vaccine has an 80% probability that it can effectively prevent people exposed to the new coronavirus virus from being infected. In early July, when a British MP asked her if the world would have to survive the next winter if there is no vaccine, Gilbert said, 'I hope our team will rush to achieve results and save this situation.'

Bidding

Today, AZD1222, one of the most eye-catching projects in the first echelon of global new coronavirus vaccine research and development, has received orders from many countries.

According to incomplete statistics, Oxford-AstraZeneca vaccine has received a total of more than 2.5 billion doses of orders, becoming the world's most booked candidate vaccine. The company has also promised to simultaneously establish multiple supply chains around the world and provide more than 2 billion doses of the new coronavirus vaccine globally.

As early as mid-May, the United States ordered 300 million doses of vaccines from AstraZeneca, providing up to 1.2 billion US dollars in funding. In addition, AstraZeneca has pledged to the British government to provide a total of 100 million doses of vaccines, of which 30 million doses will be distributed to the British people as early as September.

On June 4, AstraZeneca announced that it had reached a US$750 million agreement with the Global Access Mechanism for New Crown Vaccines (COVAX), which was participated by WHO, the Alliance for Epidemic Prevention Innovation (CEPI), and the Vaccine Alliance GAVI, to support 300 million of production, procurement and distribution of vaccines, and delivery began at the end of this year. This is also the first order of COVAX since its establishment.

On the same day, the Dutch Ministry of Health announced that the Netherlands, Italy, Germany and France will form the 'European Inclusive Vaccine Alliance' (IVA) to jointly develop a vaccine against the new coronavirus. Their first order bet on AstraZeneca and purchased 300 million doses of vaccine, including the option to purchase an additional 100 million doses of vaccine from AstraZeneca if the vaccine is ultimately proven safe and effective. The Wall Street Journal reported that this supply of no more than 400 million doses of vaccine will be at zero interest rate.

On August 7, the Serum Institute of India (SII) signed a contract with AstraZeneca to be responsible for some human trials of the vaccine in India, and promised to produce 1 billion doses in India for the Indian market after the vaccine has been identified, and provided to the Vaccine Alliance (GAVI) for use in poor countries, covering 57 countries and regions. Since Oxford University and AstraZeneca have stated that they will sell the vaccine at cost, the Indian Medical Research Council estimates that the price of each dose of the vaccine in the Indian market will be around 1,000 rupees or less than 15USD.

At the same time, AstraZeneca also reached agreements with Japan and Australia in August. The company plans to supply 120 million vaccines to Japan from January 2021, of which 30 million will be supplied in the first batch from January to March. The Australian government, after signing the intent with AstraZeneca, promised on August 18 that once the vaccine is successfully developed, it will be provided to the country's 25 million people free of charge.

On August 12, Mexico and Argentina also reached an agreement with AstraZeneca to obtain the technology transfer of the vaccine and the production license of 150 million to 250 million doses of the vaccine for use throughout Latin America (except Brazil). Delivery in the first half of 2021.

On August 27, the European Commission stated that it had signed a new coronavirus vaccine purchase agreement with AstraZeneca and paid a deposit. This is the first new coronavirus vaccine candidate order agreement signed by the European Union. A spokesperson for the European Commission said that the EU has paid a deposit of 336 million euros (about 396 million US dollars) to order at least 300 million doses of vaccines from AstraZeneca.

Not long ago, China Kangtai Biotech also reached a cooperation with AstraZeneca. According to the terms of the cooperation framework agreement, Kangtai Biotech, as the technology transferee, will ensure that the annual production capacity of at least 100 million doses of the new coronavirus vaccine will be reached by the end of 2020. By the end of 2021, the vaccine design capacity will be expanded to at least 200 million doses per year to meet the needs of the Chinese market.

However, although countries are intensively 'buying, buying' and striving to be the first to order candidate vaccines, after the successful development of future vaccines, the smooth production and transportation of billions of vaccines may also be the biggest challenge in the history of the pharmaceutical industry.

AstraZeneca’s Chief Technology Officer James Miskin described the vaccine production process to Bloomberg reporters : first cultivate a few milliliters of human embryonic kidney cells, and then store them in a frozen vial that needs to be gradually thawed. When cells are fed a sugar solution, they reproduce in a controlled environment of oxygen and carbon dioxide. Over the course of a week, the mixture was transferred to larger and larger vessels and finally into a 200-liter stainless steel bioreactor. The main seed bank of the vaccine -- the adenovirus containing ear protein is added to this viscous mixture, which is then stirred, purified, concentrated and filtered.

Matthew Duchars, CEO of VMIC, a UK government-funded vaccine manufacturing and innovation center (VMIC), said that the process of scaling up to millions of doses is full of big unknowns.
More than that, an article on the website of 'Business Insider' on July 25 pointed out that when the vaccine bottle leaves the factory, the last mile of its journey may be the biggest challenge. Many vaccines need to be stored in the freezer or refrigerator. In this respect, adenovirus-based vaccines such as AZD1222 have advantages over other candidate vaccines : they only need to be refrigerated rather than frozen, which makes them easier to spread globally.

'If the Oxford University vaccine is successful, other vaccines will be successful,' Gilbert said in a UN speech in May this year. 'One of the lessons we learned from Ebola is that multiple vaccines must be licensed, instead of eventually forming a monopoly.'