These Covid-19 vaccine candidates could change the way we make vaccines — if they work

As urgency mounts for a Covid-19 coronavirus vaccine, a key question for scientists is whether this pandemic will be the watershed moment for two new technologies that have never before seen widespread use in humans. If proven effective, these approaches could dramatically speed up the development of other new vaccines and drastically lower costs, heralding a new era in the fight against infectious disease.

The main technologies gaining traction are vaccines that use an adenovirus vector and mRNA. Rather than construct a new vaccine from scratch, the idea behind these technologies is to use a standard set of parts, like a repurposed virus or a nanoparticle, to carry genetic material into a cell. That material — DNA or RNA — can then code for specific proteins from a virus.

Once one of these delivery platforms are proven safe, it’s just a matter of tweaking DNA and RNA strands. That’s much faster than conventional vaccines, which involve culturing large quantities of viruses that are then weakened, inactivated, or separated into tiny fragments and purified — processes that require years of cumbersome trial-and-error and safety testing.

“If the new platforms work in a way, that may actually change how other vaccines are produced,” Rahul Gupta, senior vice president and chief medical and health officer at the March of Dimes, told reporters during a National Press Foundation webinar on August 7. “So we may be at the cusp of very much a new technology that we’re going to see for the first time in over a century, basically.”

Researchers using these new platforms have recently posted some encouraging results. On Thursday, the pharmaceutical giant Pfizer published results of its phase 1 and phase 2 clinical trials for its mRNA-based vaccine platform in the journal Nature. Moderna is now entering phase 3 trials for its mRNA platform for Covid-19.

Meanwhile, Oxford University’s Jenner Institute is partnering with AstraZeneca to develop a vaccine using an adenovirus vector platform. It has also published some early promising results.

But there is a lot of competition, with more than 200 coronavirus vaccine candidates under investigation around the world. Two dozen are undergoing testing in humans, and six are in phase 3 clinical trials as of August 13.

A vaccine effort of this scale is astonishing for a disease that was discovered less than a year ago. But the immense health and economic devastation of the Covid-19 pandemic has prompted an unprecedented level of collaboration among scientists, as well as funding from governments, private companies, and philanthropists. That’s why some scientists expect there will be enough data proving 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 a major step toward ending the pandemic.

However, there is no guarantee that any of these candidates will succeed, let alone whether a new vaccine technology will triumph over tried-and-true methods. Although companies working with the new platforms have readily cleared the earlier stages of clinical trials, they are now at the mercy of larger, slower phase 3 trials, where a lot can happen to derail their progress.

That’s why it’s important to understand how these novel strategies for preventing infection work, what they bring to the table, and the critical caveats to consider.

How most older vaccines work

Vaccines work by coaching the immune system to fight off a specific pathogen. When you get one, your white blood cells are being introduced to a potential threat, such as a virus or bacterium. That gives the immune system time to start mounting a response so that if the pathogen shows up another time, the body can quickly neutralize it.

Vaccines have been around in various forms for centuries, but the 20th century saw a boom in new ones for diseases such as polio, anthrax, pneumonia, meningitis, Hepatitis A, and influenza.

The conventional strategies for constructing vaccines that offer 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 live form of the virus or bacterium is cultivated in such a way that it is weakened when given to a human. The pathogen can reproduce somewhat, 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 of a bacterium or virus. Toxoid vaccines, like those for diphtheria and tetanus, are 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 deliberately killed by heat or with a chemical treatment. This is the approach behind vaccines for diseases like Hepatitis A and rabies. Inactivated pathogen vaccines also often require more than one dose or boosters to retain immunity.

But instead of using whole-virus or bacterium particles, scientists can also use purified fragments of a pathogen — known as antigens — to trigger an immune reaction. These subunit vaccines tend to be stable, but they’re tricky to do right and often generate a weaker immune response than whole-pathogen vaccines.

Developing a vaccine using any of these methods, however, is time-consuming, often taking more than a decade to demonstrate that they’re safe and effective. That’s far too long during a pandemic like the one sweeping the world right now.

The new Covid-19 vaccine platforms harness human cells to make key 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 common subunit of interest is the spike protein.

This protein is the business end of the virus. It’s what the coronavirus uses to dock with the ACE2 receptor on a human cell in order to enter the cell, make copies of itself, and then spread to other cells.

Scientists reason that they can coax the immune system to generate antibodies to this spike protein. Antibodies are proteins made by the immune system that attach to specific parts of a pathogen, thereby disabling it or marking it for destruction by other immune cells. If antibodies bind to the spike protein of a live SARS-CoV-2 virus, they could prevent it from causing an infection.

But with these new platforms, it’s not the spike protein of the virus that’s being injected, it’s the genetic instructions for making 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 inside the cell, the cell’s machinery reads them to manufacture the spike protein of the virus. The newly minted spike proteins are either secreted from the cell or attached to its surface, where other cells from the immune system can identify the spike protein and begin manufacturing antibodies to it.

The process ends up not only mimicking a key structure of the virus but also imitating how the virus works during an infection, which could potentially generate a stronger immune response and yield better protection compared with other approaches. And because these proteins are produced from within cells rather than injected from the outside, they may be less likely to provoke adverse reactions in the recipient.

How mRNA vaccines work

On August 11, President Donald Trump announced that the US government would buy 100 million doses of Moderna’s mRNA coronavirus vaccine in a deal valued at $1.53 billion, bringing the country’s total investment in the company to $2.48 billion. (The Department of Health and Human Services previously said it would buy 100 million doses of Pfizer’s mRNA vaccine.)

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These are just a couple of the big bets the federal government has placed on different vaccine manufacturers, but the fact that it’s investing so much in a new approach like mRNA signals how much promise it holds.

mRNA stands for messenger ribonucleic acid. It’s a molecule that’s copied from DNA in a cell’s nucleus and used as the code for making a specific protein. If you think of the DNA in the nucleus as a giant cookbook containing all the recipes for all the meals you’ll ever eat, mRNA is the notecard you use to jot down instructions for making your favorite banana bread.

Compared to DNA, mRNA is shorter in length, less stable, and designed to be disposable. Your cells are making and breaking down mRNA strands all the time.

With an mRNA vaccine, the idea is to get a segment of mRNA that codes for a specific viral protein into a cell. For vaccine developers, that means that instead of going through the tedious process of isolating and purifying subunits of a virus, they can just change the code in a strand of mRNA. That makes the development process much faster than conventional approaches, which can take months or years.

“mRNA can literally be completed in days to weeks to create a brand-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 an mRNA-based Covid-19 vaccine.

One of the challenges with using mRNA is that your body can perceive it as a threat, as many viruses use RNA to encode their genomes. There are a lot of enzymes in the body that can readily digest RNA before it gets into a cell. (There are even RNA-digesting enzymes on your skin.) Free-floating mRNA strands in the body can trigger inflammation, so to shield the mRNA until it gets into a cell, developers encase it inside a lipid nanoparticle — a tiny oil bubble. The RNA strand itself is also modified to make it less inflammatory.

Once the mRNA is coded, modified, and encapsulated, it can then be injected. “All modified RNA vaccines for Covid are given intramuscularly, just like old-fashioned flu shots,” Weissman said.

While mRNA is getting a lot of attention, similar approaches are also undergoing tests. Inovio is developing a coronavirus vaccine that uses a double-stranded ring of DNA known as a plasmid. It requires a hand-held device to induce an electric current near the injection site, causing pores within the cell to open, which allows the plasmid to enter. The instructions in the plasmid can then be used to make viral proteins. The company expects to start phase 3 trials in September.

How recombinant adenovirus vector vaccines work

The other new vaccine platform technology for Covid-19 is the adenovirus vector. This is the approach companies such as CanSino Biologics and Johnson & Johnson are using for their vaccines. It’s also the basis for the famous vaccine candidate from Oxford University’s Jenner Institute, which is being developed with AstraZeneca and is now in phase 3 clinical trials.

The Russian government announced this week that it has an adenovirus vector vaccine for Covid-19, too. Dubbed Sputnik V, the vaccine has been registered for use, though many researchers outside of Russia are concerned that the vaccine gained approval without going through the full battery of clinical trials.

Adenoviruses are a family of viruses that usually cause mild illnesses with symptoms resembling those of a common cold or influenza, though an infection can be dangerous for people who have compromised immune systems or certain preexisting conditions.

“This suggests that they are less pathogenic and they can inherently induce protective immunity through nasal routes for respiratory infections,” University of Alberta Faculty of Medicine and Dentistry professor Babita Agrawal, who studies the immune system, said in an email. “Therefore, a vaccine based on [an adenovirus vector] could be certainly a good vaccine candidate against SARS-CoV-2.”

The virus itself is usually less than 100 nanometers in diameter and shaped like an icosahedron — a 20-sided shape with triangle faces, similar to D20 dice. At its corners, it has fibers that stick out.

The adenovirus is very efficient at getting into cells. Researchers have experimented with the adenovirus for years as a tool for gene therapy but are now applying it to vaccines.

Scientists figured out they could modify the virus to harness its breaking-and-entering skills without causing an infection. Instead, the virus can deliver a piece of genetic material inside a cell, serving as a vector.

In the case of Covid-19, researchers are again looking at getting the instructions for making the spike protein of SARS-CoV-2 into the cell.

The way it works is that researchers take the genome of the adenovirus and cut out the section that allows it to reproduce. Then they splice in a section of DNA that codes for the spike protein, turning the adenovirus into a recombinant vector.

Because the adenovirus is a DNA virus, it has to get its genetic material not just into a cell but into the cell’s nucleus.

“It goes into the nucleus, but it does not insert into the genome,” said 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 coding for the spike protein is transcribed into mRNA and then transported out of the nucleus into the cell’s cytoplasm, where it’s translated into protein.

So if the modified virus can’t reproduce, how do scientists make more of them? William Wold, chair of the molecular microbiology and immunology department at the Saint Louis University School of Medicine, explained that recombinant viruses are cultured in cell lines that provide the missing hardware to allow them to make copies of themselves. “It’s easy to make large batches of the virus,” said Wold. But without these engineered cells, the virus can’t spread.

However, there are some drawbacks. Because versions of the adenovirus spread in humans, there are many people who have immunity. To get around this, groups like the team at Oxford are using a chimpanzee adenovirus as a vector, which is different enough from human adenoviruses that most people’s immune systems won’t react to it right away.

But once a vaccine is delivered using a chimpanzee adenovirus, it’s likely that many people would develop immunity to the new vector. That would make it difficult to use the same platform again for another vaccine.

The new Covid-19 vaccine platforms still face the same hurdles as conventional approaches: Phase 3 clinical trials and manufacturing

While new vaccine approaches have helped speed up early development, they are now entering phase 3 trials, where tens of thousands of people are randomly selected to receive either the vaccine or a placebo. Simply recruiting enough suitable participants can take weeks. Many vaccine candidates, including those using the new platforms, require two doses, often several weeks apart. Concluding the trials depends on waiting and seeing how the virus spreads among those who received the vaccine and those who didn’t. That can take months.

“The one thing you can’t truncate are these phase 3 trials,” Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, told reporters during the National Press Foundation webinar. “The proof is in the pudding. Phase 3 is the pudding.”

The main challenge will be demonstrating that the vaccines actually provide protection against the coronavirus. In clinical trials, researchers have found that both mRNA and adenovirus vaccines can make the body produce antibodies to the virus and trigger a response from immune cells.

Those are good signs, but they don’t guarantee that the vaccine recipient is shielded from infection. For Covid-19, the specific combination of responses from the body that indicate whether someone is immune to the virus remains unknown. This combination is called the correlate of protection, or the correlate of immunity.

Without knowing the correlate of protection for Covid-19, researchers can find out if a vaccine is effective only when it’s tested against the actual virus. That means waiting to see how vaccinated people respond when they’re exposed.

Phase 3 trials also provide an important final safety check. Most side effects related to these new vaccine platforms — fever, muscle pain, soreness, chills — have been pretty minor in early clinical trials. But more significant and less-frequent complications could emerge during large-scale testing, when people with imperfect health or preexisting conditions start receiving the vaccines. It’s important to ensure that such problems are rare, since a Covid-19 vaccine would potentially have to be given to billions of people.

If a new vaccine platform does get approval, making enough vaccines will be the next challenge. The world has decades of experience producing conventional vaccines, but companies are still learning how to manufacture the new platforms in large quantities.

“The starting line is a little further back. We don’t have the reassurance from the widespread use of the same technology in a different vaccine,” said Jesse Goodman, a professor of medicine at Georgetown University and former chief scientist at the Food and Drug Administration. “For example, when we had the 2009 [H1N1] influenza pandemic, those vaccines were made using the technology and facilities and manufacturing processes that we used every year for flu vaccines.”

It’s one thing to make small batches of an mRNA or adenovirus vaccine in a laboratory. It’s quite a different endeavor to make billions of doses on multiple assembly lines in different parts of the world. Such large-scale production would need a global supply chain and validation to ensure that the facilities provide a consistent product. That infrastructure has yet to be built.

And since the majority of the world remains vulnerable to the disease, any coronavirus vaccine will need to be deployed on a much larger scale than existing vaccines in order to limit the spread of the virus.

That’s pushing governments and institutions to take some unprecedented steps to prepare. “The one thing that’s happened with this vaccine that I’ve never seen happen before is that pharmaceutical companies have already started making vaccines for people, even if they haven’t been approved yet,” Weissman said.

But there’s still no guarantee that any coronavirus vaccine will come to fruition. The first vaccine across the line may not be the best one; multiple vaccines for different population subsets, such as the elderly, will likely be needed. So even if an mRNA vaccine or adenovirus vaccine for Covid-19 gains approval, it may be prudent to continue pursuing a conventional vaccine as well.

And vaccines alone are not enough. Ending the Covid-19 pandemic will still demand measures like social distancing until sufficient numbers of people are vaccinated to create herd immunity. Although the timing of when a phase 3 trial for a Covid-19 vaccine might conclude is largely out of our hands, we can set the stage for the end of the pandemic now by limiting the spread of this deadly disease.

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