With the growing urgency for a Covid-19 coronavirus vaccine, an important question for scientists is whether this pandemic will be the turning point for two new technologies that have never been widely used in humans. If proven effective, these approaches could dramatically accelerate the development of other new vaccines and cut costs, ushering in a new era in the fight against infectious diseases.
The main technologies gaining momentum are vaccines using an adenovirus vector and mRNA. Rather than making an entirely new vaccine, the idea behind these technologies is to use a standard set of parts, such as a recycled virus or a nanoparticle, to deliver genetic material into a cell. That material – DNA or RNA – can then code for specific proteins of a virus.
Once one of these delivery platforms has been proven to be safe, all you need to do is adjust the DNA and RNA strands. This is much faster than conventional vaccines, which grow large amounts of viruses, which are then attenuated, inactivated, or separated into small fragments and purified – processes that require years of trial and error and safety testing.
“If the new platforms work in a certain way, it could actually change the way other vaccines are produced,” Rahul Gupta, senior vice president and chief medical and health officer at the March of Dimes, told reporters during a webinar from the National Press Foundation on August 7. “So we may be on the cusp of a whole new technology that we will actually see for the first time in more than a century.”
Researchers using these new platforms have recently had some encouraging results. Thursday, pharmaceutical giant Pfizer published results of its Phase I and Phase II clinical trials for its mRNA-based vaccine platform in the journal Nature. Moderna is now entering Phase III trials for its Covid-19 mRNA platform.
Meanwhile, the University of Oxford’s Jenner Institute is working with AstraZeneca to develop a vaccine using an adenovirus vector platform. It has also published a few early promising results.
But there is a lot of competition, with more than 200 coronavirus vaccine candidates in research around the world. Two dozen are being tested in humans and six are in phase III clinical trials on Aug. 13.
A vaccination effort of this magnitude is amazing for a disease discovered less than a year ago. But the immense health and economic devastation of the Covid-19 pandemic has resulted in unprecedented levels of collaboration between scientists, as well as funding from governments, private companies and philanthropists. Therefore, some scientists expect that there will be sufficient data to prove the safety and efficacy of a Covid-19 vaccine in record time, possibly by the end of the year or early 2021. An effective, widely available vaccine would be an important step in direction of vaccine discontinuation. pandemic.
However, there is no guarantee that any of these candidates will succeed, let alone whether a new vaccine technology will triumph over proven methods. While companies working with the new platforms have easily got through the earlier stages of clinical trials, they are now at the mercy of larger, slower Phase III trials, where much can happen to derail their progress.
That’s why it’s important to understand how these new infection prevention strategies work, what they entail, and the critical caveats to keep in mind.
How Most Older Vaccines Work
Vaccines work by coaching the immune system to fight a specific pathogen. When you get one, your white blood cells are exposed to a potential threat, such as a virus or bacteria. That gives the immune system time to build up a response, so the body can quickly neutralize it should the pathogen appear another time.
Vaccines come in different forms for centuries, but in the 20th century there was a boom in new diseases such as polio, anthrax, pneumonia, meningitis, hepatitis A and the flu.
Conventional strategies for making vaccines that provide strong, long-lasting immunity involve mimicking the target. One of the most effective ways to do this is with a live attenuated vaccine. Here, a living form of the virus or bacteria is grown in such a way that it is weakened when given to a human. The pathogen can reproduce to some extent, but rarely enough to make the recipient sick. The most common vaccines – against smallpox, measles, mumps and rubella – use live attenuated viruses.
Vaccines can also target toxic products from a bacteria or virus. Toxoid Vaccinesare, like those for diphtheria and tetanus, stable and safe, but often require multiple doses.
Another approach is to use an inactivated version of the pathogen, usually a live pathogen that has been intentionally killed by heat or chemical treatment. This is the approach behind vaccines for diseases like hepatitis A and rabies. Inactivated Pathogenic Vaccines also often need more than one dose or boosters to maintain immunity.
But instead of using whole virus or bacteria particles, scientists can also use a purified fragment of the pathogen known as a antigen to cause an immune response. This one subunit vaccines are usually stable, but they are difficult to do well and often generate a weaker immune response than whole pathogenic vaccines.
However, developing a vaccine using one of these methods is time consuming and often takes more than a decade to demonstrate that they are safe and effective. That is far too long for a pandemic like the one that is now sweeping the world.
The new Covid-19 vaccine platforms use human cells to make important components
Both mRNA vaccines and adenovirus vector vaccines build on the idea of a subunit vaccine. In the case of SARS-CoV-2, the virus that causes Covid-19, the most abundant subunit is the spike protein.
This protein is the business side of the virus. It’s what SARS-CoV-2 uses to couple with the ACE2 receptor on a human cell to enter the cell, make copies of itself, and then spread to other cells.
Scientists reason they can coax the immune system to generate antibodies against this spike protein. Antibodies are proteins made by the immune system that attach to specific parts of a pathogen, turning off the pathogen or marking it for destruction by other immune cells. When antibodies bind to the spike protein of a live SARS-CoV-2 virus, they can prevent it from causing infection.
But with these new platforms, it is not the peak protein of the virus that is being injected. Rather, it’s the genetic instructions to make it. The main differences between mRNA vaccines and adenovirus vector vaccines are the genetic material they use and how they get it into the cell. The mRNA vaccines use mRNA, while adenovirus vaccines use DNA.
Once the instructions are in the cell, the cell’s device reads them to produce the virus’s peak protein. The newly minted spike proteins are either secreted from the cell or attached to the surface, where other cells of the immune system can identify the spike protein and start making antibodies against it.
The process not only mimics a key structure of the virus, but also mimics how the virus works during an infection. This could potentially generate a stronger immune response than other approaches and provide better protection. And because these proteins are produced from the inside out rather than injected from the outside, they are less likely to cause a side effect in the recipient.
How mRNA Vaccines Work
The US government announced this week that it will buy 100 million doses of Moderna’s Covid-19 mRNA vaccine, a $ 1.53 billion deal, bringing the government’s total investment in the company to $ 2.48 billion. (The Ministry of Health and Human Services also said it would buy 100 million doses of Pfizer’s mRNA vaccine.)
These are just a few of the big bets the federal government is placing on various vaccine manufacturers, but the fact that it is investing so much in a new approach like mRNA shows just how much promise it holds.
mRNA stands for messenger ribonucleic acid. It is a molecule that is copied from DNA in the cell nucleus and used as the code for making a specific protein. If you think of the DNA at its core as a gigantic cookbook with all the recipes for all the meals you’ll ever eat, mRNA is a notecard you use to write down the instructions for making your favorite banana bread.
Compared to DNA, mRNA is shorter in length, less stable and designed to be discarded. Your cells are constantly making and breaking mRNA strands.
With an mRNA vaccine, the goal is to get a segment of mRNA encoding a specific viral protein into a cell. For vaccine developers, this means that instead of the tedious process of isolating and purifying subunits of a virus, they can simply change the code of a strand of mRNA. That makes the development process much, much faster than conventional approaches that can take months or years.
“MRNA can literally be completed in days to weeks to make a whole new vaccine,” said Drew Weissman, a professor of medicine at the University of Pennsylvania. He noted that it took only 66 days from when the genome of the SARS-CoV-2 virus was sequenced to when the first patient was injected with a Covid-19 mRNA vaccine.
One of the challenges with using mRNA is that your body may perceive it as a threat, as many viruses use RNA to encode their genomes. There are many enzymes in the body that can easily digest RNA before it enters a cell. There are even RNA digesting enzymes on it your skin. And free-floating strands of mRNA in the body can cause inflammation. So to shield the mRNA until it gets into a cell, developers enclose it in a lipid nanoparticle – a tiny oil bubble. The RNA strand itself has also been modified to make it less anti-inflammatory.
Once the mRNA has been encoded, modified, and encapsulated, it can be injected. “All of the modified RNA vaccines for Covid are given intramuscularly, just like old-fashioned flu shots,” said Weissman.
While mRNA is receiving a lot of attention, there are similar approaches that are also being tested. Inovio is developing a Covid-19 vaccine that uses a double-stranded ring of DNA known as a plasmid. It requires a handheld device to generate an electrical current near the injection site, which opens the pores in the cells, allowing the plasmid to enter. The instructions in the plasmid can then be used to make viral proteins. The company expects to start Phase III Studies in September.
How Recombinant Adenovirus Vector Vaccines Work
The other important new vaccine platform technology for Covid-19 is the adenovirus vector. This is the approach that companies like CanSino Biologics and Johnson & Johnson are taking for their vaccines. It is also the basis for the famous Oxford University Jenner Institute vaccine produced with AstraZeneca, which is now in phase III clinical trials.
The Russian government announced this week that it also has an adenovirus vector vaccine against Covid-19. The vaccine, called Sputnik V, has been registered for use, although many researchers outside of Russia are concerned that the vaccine has received approval without going through the full line of clinical trials.
Adenoviruses are a family of viruses that usually cause mild illnesses with symptoms similar to a cold or flu, although infection can be dangerous for people with compromised immune systems or certain pre-existing conditions.
“This suggests that I). they are less pathogenic and ii). they can inherently induce protective immunity through nasal pathways for respiratory infections, ”Babita Agrawal, a professor in the University of Alberta’s Faculty of Medicine and Dentistry who studies the immune system, wrote in an email. “That’s why a vaccine is based on [an adenovirus vector] could certainly be a good candidate vaccine against SARS-CoV2. “
The virus itself is usually less than 100 nanometers in diameter and is shaped like an icosahedron, a 20-sided shape with triangular faces, like D20 dice. At the corners it has fibers sticking out.
The adenovirus is very efficient at getting into cells. Researchers have been experimenting with the adenovirus as a gene therapy tool for years, but are now applying it to vaccines.
Scientists found they could modify the virus to take advantage of its hacking skills without causing an infection. Instead, the virus can deliver a piece of genetic material into a cell and act as a vector.
In the case of Covid-19, researchers are again looking at the instructions for making the SARS-CoV-2 spike protein in the cell.
The way it works is for researchers to take the adenovirus genome and cut out the part that allows it to reproduce. They then split into a piece of DNA encoding the spike protein, turning the adenovirus into a recombinant vector.
Since the adenovirus is a DNA virus, it must not only get its genetic material into a cell, but also into the cell nucleus.
“It enters the nucleus, but it is not introduced into the genome,” says Hildegund C.J. Ertl, a professor at the Wistar Institute’s Vaccine & Immunotherapy Center. “It’s a fairly transient effect.”
Once in the nucleus, the DNA encoding the spike protein is transcribed into mRNA that is transported from the nucleus to the cell’s cytoplasm. There it is converted into protein.
So if the modified virus can’t reproduce, how can scientists make more of it? William Wold, a professor and chair of the molecular microbiology and immunology department at Saint Louis University School of Medicine, explained that the recombinant viruses are grown in cell lines that provide the missing hardware that allows them to make copies of themselves. “It’s easy to make large batches of the virus,” says Wold. But without these developed cells, the virus cannot spread.
However, there are some drawbacks. Since versions of the adenovirus spread in humans, there are many people who have immunity. To get around this, groups like Oxford use a chimpanzee adenovirus as a vector, which is sufficiently different from human adenoviruses that most people’s immune systems won’t respond to it right away.
But once a vaccine is delivered using a chimpanzee adenovirus, many people are likely to develop immunity to the new vector. That would make it difficult to reuse the same platform for a different vaccine.
The new Covid-19 vaccine platforms still have to overcome the same hurdle as conventional approaches: Phase III clinical trials and manufacturing
While new vaccine approaches have helped accelerate early development, they are now moving into Phase III trials, where tens of thousands of people are randomly selected to receive the vaccine or a placebo. Simply recruiting enough suitable participants can take weeks. Many vaccine candidates, including those using new platforms, require two doses, often with several weeks between doses. And the completion of the studies depends on waiting and seeing how the virus spreads among those who have received the vaccine and those who have not. That can take months.
“The one thing you can’t cut off is these Phase III trials,” Paul Offit, director of the Vaccine Education Center at Children’s Hospital in Philadelphia, told reporters for the National Press Foundation. “The proof is the pudding. Phase III is the pudding.”
The main challenge is to demonstrate that these vaccines actually protect against Covid-19. In clinical trials, researchers have found that both mRNA and adenovirus vaccines can cause the body to produce antibodies to the virus and trigger a response from immune cells.
These are good signs, but they do not guarantee that the recipient of the vaccine will be protected from infection. For Covid-19, the specific combination of the body’s responses that indicate a person is immune to the virus remains unknown. This combination becomes the correlate of protection or the correlate of immunity.
Without knowing the correlation of protection for Covid-19, researchers can only find out whether a vaccine is effective when tested against the actual virus. That means waiting to see how vaccinated people react when exposed.
Phase III studies also provide an important final safety check. Most side effects from these new vaccine platforms were quite minor in early clinical studies: fever, muscle aches, aches, chills. But more significant and less frequent complications can arise during large-scale testing when people with imperfect health or pre-existing conditions begin to receive the vaccines. It’s important to make sure such problems are rare, as a Covid-19 vaccine may need to be given to billions of people.
When a new platform vaccine does get approval, the next challenge is to make enough of it. The world has decades of experience making conventional vaccines, but companies are still learning how to produce these new vaccine platforms in large quantities.
“The starting line is a bit further back. We don’t have the reassurance of the widespread use of the same technology in another vaccine, ” said Jesse Goodman, a professor of medicine and infectious diseases at Georgetown University and former chief scientist for the Food and Drug Administration. “For example, when we got the 2009 [H1N1] flu pandemic, those vaccines were made using the technology, facilities and manufacturing processes that we use every year for flu vaccines. “
It is one thing to make small batches of an mRNA or adenovirus vaccine in a lab. Making billions of doses on multiple assembly lines in different parts of the world is a completely different pursuit. Such large-scale production requires a global supply chain and validation to ensure the facilities deliver a consistent product. That infrastructure has yet to be built.
And since most of the world remains vulnerable to the disease, any Covid-19 vaccine will need to be deployed on a much larger scale than existing vaccines to limit the spread of the virus.
That is forcing governments and institutions to take some unprecedented steps to prepare. “The only thing that has happened with this vaccine that I’ve never seen happen before is that pharmaceutical companies have already started making vaccines for humans, even if they haven’t been approved yet,” Weissman said.
But there is still no guarantee that a vaccine against the coronavirus will come out. The first vaccine across the street may not be the best; multiple vaccines for different population subgroups, such as the elderly, are likely to be needed. So even if a Covid-19 mRNA vaccine or adenovirus vaccine gets approval, it may be wise to go ahead with a conventional vaccine as well.
And vaccines alone are not enough. Ending the Covid-19 pandemic still requires measures such as social distance until enough people have been vaccinated to create herd immunity. While the time when a phase III study for a Covid-19 vaccine could be completed is largely not in our hands, we can now pave the way for the end of the pandemic by limiting the spread of this deadly disease.
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