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The coVID-19 vaccine is still a long way off

Six months after the COVID-19 outbreak, the world is hungering for a vaccine.

On June 28, statistics from Johns Hopkins University showed that the number of confirmed coVID-19 cases in the world has passed the 10 million mark, and the number of deaths has reached nearly 500,000. The epidemic shows no sign of stopping its expansion.

In the past week, new cases rose in 81 countries and fell in only 36.
With the US, Brazil and India “leading the way”, the COVID-19 pandemic is accelerating into a “new phase of danger”.

Globally, the coVID-19 pandemic has brought the worst economic crisis since the Great Depression of the 1930s.
Global manufacturing supply chain disruption;
Industries such as aviation, tourism, leisure and hotels have been hit hard;
Schools and businesses closed in droves.
These changes are having a profound impact on human society.

In the long battle with Novel Coronavirus, vaccine becomes the ultimate weapon of human and the best way to restore normal life.

In the history of vaccine development, the average age of a vaccine is 10 to 15 years, and the record to date is four years.
Still, this is bad news for the world — no one wants to wait four more years in the shadow of a coronavirus — and it means the death of millions and total economic and social paralysis.

More than 100 teams are racing to develop the Novel Coronavirus vaccine worldwide, with the fastest progress being made in the UK, China and the US.
At least five vaccines are in or about to enter the most critical phase 3 clinical trials.
Developers say they hope to have a record first batch of vaccines produced by the end of this year and early next year.

Behind the optimistic forecasts lies the hard truth: vaccine development has traditionally been an extremely complex undertaking, with a far greater chance of failure than of success.
Although the world’s top scientists are doing their best, it is only less than 6 months since novel Coronavirus began to be introduced to and understood by human beings. Despite the incomplete knowledge of this novel virus, there are still many unsolved mysteries puzzling us.

What part of the immune system can novel Coronavirus strike a deadly blow?
Why do different individuals react so differently to the virus?
Will the constant mutation of the virus render the vaccine ineffective?
How long will immunity last?

Even if a vaccine is developed, the greater challenge is to produce billions of doses in a short time, distribute them fairly and reach each country safely.
This will be a challenge unprecedented in human history.

Vaccines are only the beginning of a novel coronavirus battle. We are entering into more uncharted territory.

This autumn could be a turning point for the coVID-19 pandemic: we may wait for positive news about the vaccine, and we will know if a second wave hits.
In 1918, the influenza pandemic broke out in three waves, with the second wave in the fall being the deadliest.

Can the COVID-19 vaccine be the savior?
In past battles between humans and viruses, optimists and pessimists have their reasons.
The pandemic of 2020 is destined to be one of the deepest memories of our time.

Visit family members with confirmed COVID-19 in Spain

The challenge of phase III clinical testing

At the time of writing, at least two vaccines in the race to the finish line are in phase III clinical trials, and three will be in phase III trials by July.

Human trials of vaccines are generally divided into three phases. The first phase is to ensure that the vaccine will not cause harm to humans.
A second phase (which will involve hundreds of people) will demonstrate the vaccine’s efficacy and further verify its safety.
The phase III trial, which will require tens of thousands of participants, is the gold standard for testing whether the vaccine is truly protective.

Good results in the first two stages of a vaccine do not necessarily mean it is effective in preventing infection.
Only a large, well-controlled phase III study will show whether the vaccine is truly effective at preventing infection and saving lives.

“The number of people in a phase III trial would have to be large to show whether the vaccine is effective.”
Beate Kampmann, director of the Vaccine Centre at the London School of Hygiene and Tropical Medicine (LSHTM), told The paper (www.thepaper.cn) that “the first two trials can be conducted anywhere and the third trial, which aims to determine the effectiveness of the vaccine, can only be conducted in areas where the virus is still circulating.”

Participants in the phase III trial will be divided into a vaccine group and a placebo control group, kampman said.

For example, Kampman said, suppose that among 10,000 vaccinated people, over a period of time, 1,000 people from a novel Coronavirus and 5,000 people from a control group of 10,000 vaccinated people from a novel Coronavirus showed that the vaccine effectively protected the majority from infection.

If the formula for vaccine efficacy is used – vaccine efficacy =1- vaccine group incidence/control incidence – the vaccine efficacy in the above example is 80%.

“Normally phase III trials require an observation period of six to 12 months.
But it also depends on how high the infection rate is, and if the infection rate is very high in the population, the duration of the trial can be shortened.
If you don’t have that high infection rate, the trial time will be longer because it will take more time to accumulate cases.”
She said.

At the London School of Hygiene and Tropical Medicine

Web site

Here is a list of almost all the vaccine trials currently under way worldwide and the stages they are in.
Kampman says international cooperative trials abroad are complex and expensive, and the vaccine’s effectiveness is a major concern.
At the same time, data from large-scale trials will gather more information on vaccine safety.

Leading the way in the vaccine marathon is a collaboration between Oxford’s Jenner Institute and AstraZeneca.
It is the first vaccine in phase III trials in the world.
About 10,000 people are currently involved in phase III trials of the vaccine in the UK and Astrazeneca says the results so far are safe.

The Oxford-Astrazeneca vaccine also plans to recruit 30,000 people in the US and thousands more in Brazil and South Africa for phase iii trials.
Astrazeneca said the first vaccines would be available to the UK and US as early as September or October this year if the trials go well.

It was followed by a vaccine from China’s national medicine.
On June 23, Sinopharmacology group announced on its official website that the novel Coronavirus inactivated vaccine, jointly developed by Wuhan Institute of Biological Products and Wuhan Institute of Viruses of Chinese Academy of Sciences, will begin phase III international clinical study (hereinafter referred to as Sinopharmacology vaccine) in the United Arab Emirates.

Xia Shengli, director of the Vaccine clinical Research Center of the Henan Provincial Center for Disease Control and Prevention, is in charge of phase I and PHASE II clinical trials of the inactivated sinopharma vaccine, which had shown good results.
He told thepaper.cn that foreign phase III clinical trials of the vaccine have not yet officially started, and many uncertainties remain.

A number of experts told Thepaper.cn that the international cooperation in phase III clinical trials is facing considerable difficulties.
The additional challenges of conducting clinical trials during a pandemic, the high cost of the trials, the communication with foreign partners, the uncertainty of policy, the uncertainty of implementation in different cultural contexts, and the ethical acceptance of conducting trials using placebos are all significant challenges.

Meanwhile, the other two vaccines that will enter phase III trials in July are US-BASED Moderna’s mRNA vaccine and China’s Inactivated vaccine.
The former plans to recruit 30,000 people and the latter 9,000 in Brazil.
In addition, a number of vaccines in China, the United Kingdom, the United States, Germany and other countries are or will be in phase II clinical trials.

One of the main lessons of the previous fight against the virus was that vaccine development accelerated dramatically during an outbreak, but the outbreak was still missed.
This happened with SARS in 2003 and ebola in West Africa in 2014.

When the Ebola outbreak broke out in West Africa in the spring of 2014, although the virus had been identified more than four decades earlier and there had been several previous outbreaks, there had been no vaccine, no drugs, limited diagnostic products and much of the product development remained at the pre-clinical stage.

Ervebo, the first vaccine for Ebola, submitted an accelerated application to the European Medicines Agency in 2016 after an emergency clinical trial began in guinea in 2015, just as the outbreak in West Africa was ending.
The world’s first Ebola vaccine was finally not approved by European regulators until 2019.

This time, the lessons of the past seem to have been learned.
As soon as novel Coronavirus appeared, researchers were already engaged in vaccine development.

“In the past 50 years, the discovery of a variety of new infectious diseases and related pathogens has accumulated rich experience in vaccine development.
We believe that the progress of vaccines for SARS, MERS and Ebola can provide a guide to the pace of vaccine development for COVID-19.”
Zhao Yingxi, a global health researcher and PhD from The University of Oxford, told thepaper.cn.

This time, perhaps the last thing people want is for the vaccine to arrive after the outbreak is over.

The two sides signed the clinical trial approval document

How the vaccine works

If avirus is a novel coronavirus that wants to invade the human body, the role of a vaccine is to train the immune system to read a novel coronavirus and fight it off.

At present, more than 100 vaccines with different research and development routes can be roughly divided into four categories according to the principle and technology: inactivated virus vaccine, protein vaccine, recombinant virus vector vaccine and nucleic acid vaccine.

The first three have all had successful, widely used vaccines, while the nucleic acid vaccine has never been approved.

Vaccines from different technical routes have their advantages and disadvantages.

Most traditional inactivated vaccine regimens use weakened or inactivated viruses to stimulate an immune system response.
The developed process route is relatively mature, but a large number of viruses need to be cultured in production, which requires a higher level of laboratory protection.

Protein vaccine USES viral protein fragments to stimulate human immune response. The advantages are good safety, small side effects and good stability. However, the preparation process is complex, the technology is difficult, and the immunogenicity is often weak.

Recombinant vector vaccine is made by using the novel Coronavirus protein gene as the carrier of a harmless modified adenovirus.
S protein is the key “key” of novel Coronavirus invading human cells. A harmless adenovirus wearing the “hat” of S protein enables the human body to produce immune memory and stimulates antibodies.
A vaccine jointly developed by the Chinese Academy of Military Sciences and Consino Bio falls into this category.

Adenovirus vector vaccine is a relatively mature vaccine technology route.
It is safe, efficient and causes few adverse reactions.
The biggest problem with such vaccines, though, is overcoming the problem of “pre-stored immunity” : most people grow up infected with adenovirus type 5 and may have antibodies that neutralise the adenovirus vector, potentially attacking it and reducing its effectiveness.
In other words, the vaccine is safe but may not be effective enough.

Nucleic acid vaccine (including mRNA vaccine and DNA vaccine) is to directly inject the encoded S protein gene, mRNA or DNA into the human body, synthesize S protein in the human body, and stimulate the human body to produce antibodies.
This is equivalent to giving the body’s immune system a detailed record of the virus.
Merck’s mRNA vaccine falls into this category.

The biggest advantage of nucleic acid vaccine is that it does not need to synthesize protein or virus, the process is simple and the development speed is fast.
The biggest problem is that the technology is so new that it has not yet been approved anywhere in the world, and most countries cannot produce on a large scale, making it too expensive to reach low-income countries.

Some scientists are also exploring the possibility of “new USES” for old vaccines.
Novel Coronavirus is the novel coronavirus that scientists in the United States and Australia are testing to see if the novel Coronavirus can provide preventative protection.

“Vaccines from different routes have different technical and development characteristics.
Countries and companies choose different routes mainly based on their technological strengths and past research and development experience.”
Kim Dongyan, a virologist and professor of medicine at the University of Hong Kong, told thepaper.cn.

According to the paper, among the vaccine development plans that have been made public, many teams choose protein vaccine, recombinant virus vector vaccine and nucleic acid vaccine (especially mRNA vaccine), while relatively few choose the route of inactivated vaccine.

Jin dongyan believes that this is mainly because the development of inactivated vaccine is relatively slow, while the development of recombinant vaccine and nucleic acid vaccine is relatively fast.
On the other hand, the research and development of inactivated vaccine has higher requirements on the safety protection level of production site.
However, mass production of traditional vaccines is relatively easy, while large-scale production of new vaccines is challenging.

Danny Altmann, professor of immunology at Imperial College London, believes more detailed discussion of different vaccine technologies is needed.

“This is not an easy race to the finish.
All vaccines in a number of different parameters on the performance is different, including the antibody response, cell (here refers to the T cells, lymphocytes, plays an important role in the immune response) reaction, cell factor, the nature of persistence, increase the number of required, whether you need adjuvant to large-scale production, storage, security, and it is the ease of the supply chain, etc.
We need to compare these factors carefully, or we may make some wrong choices.”
“He told thepaper.cn.

Altman further explained that many of the vaccines that did well in phase 1 and phase 2 trials would not have a chance to test for potential safety problems until they moved to larger phase 3 trials.

He cites the example of an antibody – dependent enhancement (ADE) effect that is of great concern to immunologists and vaccine experts.
In 2017, a dengue vaccine called Dengvaxia was widely administered to more than 800,000 schoolchildren in the Philippines, some of whom reported serious illness or even death.

Altman notes that this is a rare phenomenon, but not a groundless concern.
At the heart of the tragedy is an unsolved scientific mystery: in a small number of people, vaccines don’t boost immunity, but instead exacerbate infection.

“I don’t want to overstate the risks, but there is no 100 per cent guarantee that it won’t happen.
If that happens this time, it will be a very serious challenge.”
Kampman, director of the Vaccine Center at the London School of Hygiene and Tropical Medicine.

“So far, animal and human trials of coVID-19 vaccines have not sent a worrying signal, but we must tread carefully,” she explained.
The key to the antibody-dependent enhancement effect is what happens when a former infected person encounters the virus again, because we haven’t.
From this point of view, Wuhan, where the outbreak first occurred, is an important place to observe.
It would be very worrying if anyone got sicker.”

Some cases of severe hyperimmune syndrome in young children linked to coVID-19 have been reported in the UK, Europe, the US and Japan, Kampman said.
“These children tested positive for antibodies indicating that they had a previous infection with novel Coronavirus but had no symptoms.
Now they are in hospital with severe inflammation of multiple organs.
It worries me because it could be an ADE signal.”
She said.

In the final analysis, our understanding of novel Coronavirus is still in progress.
Although some vaccine research institutions and governments continue to report positive developments, it is difficult to select the most promising coVID-19 vaccine at this time, given the early stage of development and lack of scientific data.

The real challenge, According to Kampman, is not to pick one vaccine candidate but to ensure that multiple promising candidates are invested in, thereby increasing the likelihood of success.

If a vaccine has good data from phase III trials, WHO will prequalify the data, Kampman said.
If the product is prequalified by WHO, drug regulators in many countries, especially in developing countries, will approve it more quickly.

“I don’t think we can really shorten the process significantly because we have to carefully review the data.
“My biggest concern is that we rush into a product that may not be safe and effective in the long run, and that ultimately will do a lot of harm and damage the credibility of other vaccines.”
She said.

Oxford-astrazeneca said it expected the clinical trials to run concurrently with production, an unprecedented move for a drugmaker.

Gates Foundation founder Bill Gates has said he will fund all seven vaccine plants funded, although only one or two may end up being used.
“So we don’t waste time.”
He said.

“It’s like a gamble.”
Kampman said.

Covid-19 vaccine development

A bigger challenge

Even if a proven vaccine is successfully developed, it does not mean all problems will be solved.
On the contrary, it is only the first step.

Zhang Li, director of the Gavi Centre for Strategic Innovation and New Investors, said at a recent Gates Foundation media workshop on global health and development that there are four key links from development to use: research and development, production, procurement and vaccination.

Zhang pointed out that the first practical challenge after successful research and development is the capacity.

“We know that vaccine development has a low success rate. There are at least 126 vaccine candidates now registered with the WHO, and only 7 percent succeed.
Once a vaccine is developed for clinical trials, the success rate can only improve to 17 per cent.
How can it be put into production after successful development?
Many manufacturers don’t have enough capacity right now.”
She said.

Making and distributing vaccines on an unprecedented scale will be a huge challenge, especially packaging and transporting them to every corner of the world at low temperatures.
Imagine considering just one seemingly simple step: putting the vaccine into vials would require manufacturers to procure billions of vials and billions of plugs. Accurately filling and sealing with machines would be a daunting task.

“The methods of vaccination vary enormously.
Some products are easier to produce and deliver than others.
Overall, however, the scale of operations needed to produce, transport, manage and monitor billions of doses of vaccine would be greater than anything attempted, from two world wars to a mission to the moon.
We need scientists, medical experts, policymakers and administrators to work together to meet such a huge challenge.”
Altman, professor of immunology at Imperial College London.

On the procurement side, Zhang li said, which country will supply the vaccine first?
How do you prioritize vaccination groups within a country?
Who should be immunized first and who should be immunized first?
Where does this plan come from?
These are challenges.

“On a macro level, I think the first thing to avoid in this process is what’s called vaccine nationalism.
“If every country is going to be the first to sign bilateral agreements with all the manufacturers at this point, then you end up with low-income countries and countries that don’t have the resources to get the vaccine, especially the initial vaccine.”
She said.
“And that would have a serious impact on equitable access to vaccines.”

The last piece is vaccination.
Zhang li said that how to make the overall price of the vaccine affordable, the final realization of equitable distribution also needs coordination.

Faced with the threat of novel Coronavirus, The words of Richard Hachter, CEO of The Alliance for Epidemic Prevention Innovation (CEPI), hit the right note: “We have all witnessed the devastating impact of this epidemic on human life, health and the global economy.
Everyone hopes that the epidemic will end soon.
The only hope for an end to the epidemic is for countries to work together.

“In the face of epidemic prevention and control, governments are under great pressure.
However, we should not view the epidemic in a way that puts national and international interests in opposition.
This cannot happen if governments go their own way.
Relying solely on the market carries the risk of vaccine development failure, loss of public confidence and soaring vaccine prices.
Each of these risks is exposed if countries support different vaccine manufacturers.
We should think of vaccine development as a race between humans and viruses, not between countries.
This will ultimately benefit all countries.”
“Hatchet said.

The history of global pandemics tells us that such pandemics can last for years, with countries likely to experience multiple outbreaks that return when they are contained.
The world needs an equitable global distribution system that will work for years after a vaccine is developed, Hatchet said.
This system requires funding, management, and global support and collaboration.

“It won’t be a perfect system, but we’ll try to be fair.”
He said.

Kampman says most of the people around her are ready for the coVID-19 vaccine.
“I initially thought, as a health professional, ‘The sooner I am infected with novel Coronavirus, the better so I will be immune.
I dont think so any more.
I’m in my 50s, and I see people my age on ventilators.
I hope to have a safe and effective vaccine as soon as possible.”

“Despite the risks, we really don’t have much choice.”
She said.

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