/Moderna and Pfizer Are Reinventing Vaccines, Starting With Covid

Moderna and Pfizer Are Reinventing Vaccines, Starting With Covid

The strong early results for two leading Covid-19 vaccines have implications that go far beyond the current pandemic: They suggest the time has come for a gene-based technology that could provide new treatments for cancer, heart disease and other infectious diseases.

The unproven technology, named messenger RNA after the molecular couriers that deliver genetic instructions, has long eluded researchers. An mRNA vaccine has never been cleared by regulators. It is now the basis for Covid-19 vaccines from

Moderna Inc.


MRNA -5.13%

and

Pfizer Inc.


PFE 1.86%

and its partner

BioNTech SE.


BNTX -4.83%

Both have shown in recent days to be more than 90% effective at preventing symptomatic Covid-19. That performance is in line with some older vaccines even though the new shots were developed in a fraction of the time.

“It’s 21st-century science,” said William Schaffner, professor of preventive medicine at Vanderbilt University School of Medicine. The positive data for mRNA-based Covid-19 vaccines bodes well for the technology’s potential to combat future outbreaks of infectious diseases, he said.

Since the new coronavirus emerged as a world-wide threat, health authorities have eyed vaccines as the antidote needed for the world to begin returning to normal. They are crucial to ensure that enough people are protected against the virus so it can’t spread easily, even to those who aren’t immune. Nearly 50 candidates, based on different technologies, are in clinical trials.

A department store in Taipei, Taiwan, Nov. 16.



Photo:

Chiang Ying-ying/Associated Press

Vaccines normally take years to bring to market. With older technologies, researchers spend time developing and growing a virus or proteins from the virus, which generate an immune response when injected. Measles, shingles and other older vaccines use an inactive or weakened virus to coax the body to build up protection.

The manufacturing process, often in eggs or large bioreactors, is laborious and time intensive. Successful shots typically take more than a decade to develop, according to a 2013 study published in the journal PLOSOne.

Messenger RNA promises to cut that time by taking advantage of the body’s own molecular machinery, essentially teaching cells how to make a protein similar to one found on the virus, which then triggers the body’s immune response.

Messenger RNA, one type of RNA found in cells, is a naturally occurring substance. It is a kind of molecular worker bee, carrying instructions encoded in DNA for cells to follow. Given its role, scientists had long theorized it could be repurposed to turn cells into miniature drug or vaccine factories.

How Messenger RNA Vaccines Work

The experimental vaccine from Moderna, as well as the candidate from Pfizer and BioNTech, use a new gene-based technology known as mRNA.

Traditional Vaccines

1. In classic vaccines, such as those against measles and polio, the patient is inoculated with weakened or inactivated versions of the virus. This triggers the immune system to produce specialized antibodies that are adapted to recognize the virus.

2. After vaccination, the antibodies remain in the body. If the patient later becomes infected with the actual virus, the antibodies can identify and help neutralize it.

Scientists have identified the genetic code that coronavirus uses to produce spike proteins. They employ molecules called RNA to ferry this genetic information into our cells. The RNA is protected by a lipid coating.

Instead of using the whole virus to generate an immune response, these vaccines rely on coronavirus’s outer spike proteins, which are what antibodies use to recognize the virus.

RNA

encased

in lipid coating

When injected into a patient, the RNA enters healthy cells where it helps orchestrate the production of coronavirus spike proteins.

Once exported from the cells, the spike proteins prompt the immune system to mount a defense, just as with traditional vaccines.

Vaccine-generated antibody response

1. In classic vaccines, such as those against measles and polio, the patient is inoculated with weakened or inactivated versions of the virus. This triggers the immune system to produce specialized antibodies that are adapted to recognize the virus.

2. After vaccination, the antibodies remain in the body. If the patient later becomes infected with the actual virus, the antibodies can identify and help neutralize it.

Scientists have identified the genetic code that coronavirus uses to produce spike proteins. They employ molecules called RNA to ferry this genetic information into our cells. The RNA is protected by a lipid coating.

Instead of using the whole virus to generate an immune response, these vaccines rely on coronavirus’s outer spike proteins, which are what antibodies use to recognize the virus.

RNA

encased

in lipid coating

When injected into a patient, the RNA enters healthy cells where it helps orchestrate the production of coronavirus spike proteins.

Once exported from the cells, the spike proteins prompt the immune system to mount a defense, just as with traditional vaccines.

Vaccine-generated antibody response

1. In classic vaccines, such as those against measles and polio, the patient is inoculated with weakened or inactivated versions of the virus. This triggers the immune system to produce specialized antibodies that are adapted to recognize the virus.

2. After vaccination, the antibodies remain in the body. If the patient later becomes infected with the actual virus, the antibodies can identify and help neutralize it.

Scientists have identified the genetic code that coronavirus uses to produce spike proteins. They employ molecules called RNA to ferry this genetic information into our cells. The RNA is protected by a lipid coating.

Instead of using the whole virus to generate an immune response, these vaccines rely on coronavirus’s outer spike proteins, which are what antibodies use to recognize the virus.

RNA

encased

in lipid coating

When injected into a patient, the RNA enters healthy cells where it helps orchestrate the production of coronavirus spike proteins.

Once exported from the cells, the spike proteins prompt the immune system to mount a defense, just as with traditional vaccines.

Vaccine-generated antibody response

1. In classic vaccines, such as those against measles and polio, the patient is inoculated with weakened or inactivated versions of the virus. This triggers the immune system to produce specialized antibodies that are adapted to recognize the virus.

2. After vaccination, the antibodies remain in the body. If the patient later becomes infected with the actual virus, the antibodies can identify and help neutralize it.

Instead of using the whole virus to generate an immune response, these vaccines rely on coronavirus’s outer spike proteins, which are what antibodies use to recognize the virus.

Scientists have identified the genetic code that coronavirus uses to produce spike proteins. They employ molecules known as RNA to ferry this genetic information into our cells. The RNA is protected by a lipid coating.

Lipid coating encasing

RNA

When injected into a patient, the RNA enters healthy cells where it helps orchestrate the production of coronavirus spike proteins.

Once exported from the cells, the spike proteins prompt the immune system to mount a defense, just as with traditional vaccines.

Vaccine-generated antibody response

With mRNA, vaccine development becomes an engineering issue, rather than a scientific challenge. Companies can design mRNA vaccines relatively quickly once they know the genetic sequence of the pathogen. Researchers use the genetic sequence of a targeted virus to program the mRNA that can fight it.

In the journal Nature Reviews Immunology last November, the National Institute of Allergy and Infectious Diseases’ Anthony Fauci and John Mascola wrote, “MRNA has the potential to be a rapid and flexible vaccine platform. Starting from gene sequence, mRNA vaccines can be produced in a few weeks.”

Fast development

Moderna, founded in 2010 to focus on mRNA, made more than enough doses for about 45 people to start the first human study of its Covid-19 vaccine within two months of learning the sequence for the so-called spike protein found on the surface of the coronavirus.

With a platform in place, Moderna could quickly design new drugs or vaccines by inserting the relevant snippet of mRNA, said Moderna Chief Executive Stephane Bancel. He calls mRNA “the software of life.”

Ugur Sahin, co-founder of Germany’s BioNTech, was able to sketch out a version of 10 possible mRNA vaccines on his home computer on Jan. 25, days before the illness was first seen in Germany, after reviewing the freshly-decoded genome of the new coronavirus virus. One served as the basis for the current Covid vaccine.

He turned to Pfizer, which had first joined with BioNTech in 2018 to work on an mRNA-based flu vaccine that’s still in development. Mr. Sahin and his wife, Özlem Türeci, started BioNTech in 2008, and have spent more than 25 years studying mRNA.

Özlem Türeci co-founded BioNTech with her husband, Ugur Sahin.



Photo:

Marzena Skubatz for The Wall Street Journal

Pfizer was drawn to mRNA for how quickly any vaccines using the technology could be manufactured, and for its potential for generating stronger immune responses than traditional vaccine platforms, said Kathrin Jansen, who leads Pfizer’s vaccine research.

Dr. Jansen said RNA appears to provide more stimulation of the immune system than other vaccine technologies both by generating antibodies and by inducing responses from T-cells, white blood cells that recognize and eliminate infected cells.

“The mRNA platform is essentially fully synthetic. It’s a defined molecule that can be made very, very quickly, so you don’t need anything live—no live virus, no live cell culture, no eggs, no anything,” Dr. Jansen said.

Messenger RNA is one of a number of new technologies drug companies are using in what is emerging as a once-in-a-generation test of human ingenuity.

How far along each of the vaccines are

Testing stages typically move from ‘preclinical,’ before the vaccine is deemed appropriate to test in people, to the three phases of human clinical trials.

So far, 48 candidates have made it to clinical trials.

Type of vaccine

Viral vector

Genetic code,

including mRNA

Eleven of these have advanced into phase 3, which tests whether the dose that would be given to the public works safely.

Vaccines from

AstraZeneca

PLC and from

Johnson & Johnson

are based on a technology that uses a common-cold virus to deliver genetic instructions that teach the human immune system to mount a defense. The common-cold viruses are modified so they don’t cause infections.

This type of vaccine technology forms part of J&J’s Ebola vaccine regimen that was cleared by European regulators this year. The J&J and AstraZeneca vaccines are in large, late-stage clinical trials that could yield results in the coming weeks or months.

Merck

& Co. is taking a more traditional approach by pursuing vaccines with proven technologies that employ a weakened virus that multiplies to generate an immune response. Merck said its vaccines could produce more lasting protection against the coronavirus than other technologies, but its research takes longer to develop than mRNA versions.

Despite the positive early results for the Pfizer and Moderna vaccines, a lot remains unknown, including how long any apparent protection from Covid-19 lasts and how effective the vaccines are in certain high-risk populations such as the elderly.

Both Moderna and Pfizer are waiting for more safety data on the shots. The U.S. Food and Drug Administration wants to see if any serious side effects arise during the two months after a vaccine was given.

The mRNA vaccines have other limitations that aren’t common among widely used vaccines for other diseases.

Part of Pfizer’s ‘freezer farm,’ a football field-sized facility for storing finished Covid-19 vaccines in Puurs, Belgium.



Photo:

Pfizer/Associated Press

The vaccines must be stored at subzero temperatures, which has sent some health authorities and hospitals racing to find special freezers. Pfizer created a special container to keep shots cold during distribution and set up its own supply chain for distribution.

The vaccines require two doses three to four weeks apart to create the right immune response, so subjects will need to be tracked to make sure they get both doses.

New understanding

Efforts to engineer mRNA to fight diseases began decades ago, pushed by rapid advances in genetics.

Drew Weissman, an immunologist, and Katalin Karikó, a molecular biologist, started working on mRNA more than 20 years ago in laboratories at the University of Pennsylvania.

Dr. Weissman said he was intrigued not only by RNA’s potential to trigger the production of disease-fighting proteins but also its potential safety.

“It didn’t integrate into the genome. There was no chance you could have an adverse genomic event,” Dr. Weissman said. In contrast, he said, a different type of gene-based therapy was found in a study in France in the early 2000s to cause leukemia-type illnesses in patients who had immune system disorders.

Dr. Karikó, who started working on mRNA in her native Hungary in the late 1970s, said peers were skeptical of her work for more than three decades.

At her first research institute in the city of Szeged, then behind the Iron Curtain, she had to frequent local abattoirs to extract biological material from bovine brains because her agency lacked funding.

“The technology has not had a chance to prove itself until now—but now it is proving itself,” Dr. Karikó said.

Dr. Weissman got mRNA material from Dr. Karikó, who had been testing it in tumor cells. He tested the samples in certain immune cells. “The results were off the wall,” he said.

Problems emerged when the researchers began testing mRNA in animals, where injecting it triggered immune responses that in turn caused inflammation. In testing, high doses would kill mice.

Drs. Weissman and Karikó set out to overcome the inflammation problem by making modifications to mRNA.

They found that making a change to a nucleoside—a building block of RNA—could help RNA injected into the body sidestep the immune reaction that would cause inflammation, while still allowing the RNA to get into human cells to deliver instructions to start producing the desired protein.

Drs. Weissman and Karikó patented their work, and Penn later licensed the technology to both Moderna and BioNTech, including through intermediary companies. In 2014, Dr. Karikó joined BioNTech and serves as a senior vice president.

An antibody production line for Moderna’s Covid-19 vaccine in Visp, Switzerland.



Photo:

olivier maire/EPA/Shutterstock

Moderna spent several years honing its technology. A hurdle was finding the right shell that could carry mRNA toward their target in human cells without getting destroyed by the body’s naturally occurring enzymes during the journey.

The company encloses its mRNA into a protective envelope made of fatty substances called lipid nanoparticles. The company began testing mRNA in humans in 2015.

Moderna also started collaborating several years ago with researchers at the National Institutes of Health on making shots against certain infectious diseases. That collaboration paved the way for teams at both organizations to quickly begin collaborating in January on a Covid-19 vaccine.

A Shot in the Dark

A look at how effective each vaccine is against the illness it was designed to fight.

Vaccine efficacy

The mRNA vaccines’ early success “gives us some encouragement for the technology for other vaccine targets in the future,” said Dr. Mark Mulligan, director of the Vaccine Center at NYU Langone Health.

Moderna is testing several preventive mRNA vaccines in human studies, including one against cytomegalovirus, a common virus that can cause health problems in babies whose mothers caught it during pregnancy. The vaccine was generally safe and induced the desired immune responses in early studies. Testing continues.

Moderna is also testing with Merck whether an mRNA-based therapeutic vaccine can treat cancer. The treatment is custom-made for each patient based on mutations found in their tumor cells. The shot, when given with Merck’s cancer drug Keytruda, showed promise in some patients with head and neck cancer in a small, early-stage study, Moderna said this month.

BioNTech continues advancing potential mRNA vaccines to treat cancer, including tumors for breast, skin and the pancreas. The company has several cancer shots in development, including one for a type of skin cancer in mid-stage testing.

One of the advantages of mRNA vaccines, Dr. Sahin said, is that they can be quickly adjusted so vaccines can better respond to an eventual decline in immunity or virus mutations, which could render other vaccines less effective.

Dr. Sahin said that regulator authorization could potentially lead to a “whole new category of medicines.”

Files for Covid-19 vaccinations at the Research Centers of America in Hollywood, Fla.



Photo:

CHANDAN KHANNA/Agence France-Presse/Getty Images

Write to Peter Loftus at peter.loftus@wsj.com, Jared S. Hopkins at jared.hopkins@wsj.com and Bojan Pancevski at bojan.pancevski@wsj.com

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