A promising vaccine candidate for coronavirus cleared a major obstacle this week, when Moderna Therapeutics entered phase two of clinical trials. The move signals that the company’s mRNA vaccine has passed its first safety checks and has met an important milestone to bring this drug closer to the public and commercial markets.
After nearly five months of global deaths and financial closures by the COVID-19 pandemic, people are consciously waiting for a glimpse of hope of a return to normal routines. This partly explains the recent frenzy over the results of Moderna and its front-runner candidate, who moved from the company̵
On May 18, the biotech company announced preliminary findings that healthy individuals had responded to their mRNA vaccine by producing “neutralizing antibodies.” Antibodies are the main guarding points of the immune system to prevent infection with the coronavirus. Experts were quick to point out that the results were only for eight people out of 45 in the trial, conducted by the U.S. National Institute of Allergy and Infectious Diseases. The company has not released enough information to measure whether people in phase one had protective immune responses, which immunologists consider to be more than just producing antibodies.
But the details that Moderna presented, in combination with the latest announcement, suggest that the company may be on track to achieve something unparalleled: licensing the first human mRNA vaccine.
“The results are exciting, because they have got phase one data that shows the vaccine is safe, which is a big deal,” said Ali Salem, a drug developer and professor at the University of Iowa College of Pharmacy who is not involved in the Modern Trial.
The phase two study will involve an estimated 600 participants across 10 locations and eight states. These sites began screening for topics this week, and if they qualify based on physical exams, some will receive immunizations starting this coming Monday. After this story was originally published, Moderna confirmed via press release that the first participants in each age group in the trial – adults under and over 55 – received doses from the company’s candidate.
“Our top investigators would easily say that these studies are the most important ones they have done in their lifetime,” said Jaime Farra, marketing director at Alliance for Multispecialty Research, which operates a site in Newton, Kansas.
How mRNA vaccines appeared
When a bacterium infects a body, our immune systems rush to recognize and get a response. Traditional vaccines benefit from this response by injecting whole but inactive viruses, or their entire proteins, into our bodies, triggering an immune response. These vaccines take time to develop, partly because scientists have to grow and inactivate an entire bacterium or its proteins in a specific way.
Messenger RNA is genetic material made of nucleic acid – the same stuff as our DNA – that travels through our cells and gives final instructions on which proteins to build to form the body’s cellular architecture. In the early 1990s, researchers wondered what would happen if they made pieces of viral DNA and mRNA and then injected them into human cells or lab animals. It was hoped that the cells would take in the genetic extracts, make viral proteins and trigger an immune response.
In theory, this method would allow researchers to make vaccines faster; Instead of weeks, a candidate may be ready to test for hours or days. These vaccine candidates would also be more flexible and durable against bacteria that tend to develop through mutation, such as coronavirus, influenza and HIV. This could lead to a universal vaccine that would work against multiple strains of viruses, says Margaret Liu, chair of the board of directors of the International Society of Vaccines.
Thirty years ago, Liu was among the first waves of laboratory scientists trying to use DNA and mRNA vaccines; her early results with a universal DNA vaccine against influenza were the first to show protection and showed the most promise – at least in mice. Taken together, the early days of DNA vaccines and mRNA vaccines showed repeated success in animal models, which are known as the “pre-clinical” stage of drug development, but then could not generate potent immune responses in humans.
“People thought, it must be because people are bigger,” says Liu. But that hypothesis lost support after successful DNA vaccines were developed for horses, fish and California condors.
At the same time, mRNA vaccines struggled with weakened stability. Once inside the body, mRNA from a vaccine breaks down faster than DNA, which also limits the ability of the immune system. In addition, mRNA can aggravate immune cells and cause side effects. For several years, these challenges have included mRNA vaccines and transferred DNA vaccines to veterinary medicine.
The pivot is ongoing
The story began to change in 2005, when researchers at the University of Pennsylvania introduced small chemical modifications to mRNA vaccines. These changes increased durability and made vaccines safer, causing fewer adverse immune responses.
“Many people began to see mRNA as a therapeutic strategy for various diseases,” says the University of Iowa Salem. One of those shippers would be “ModeRNA Therapeutics,” now known as Moderna, a company created in 2010 after Harvard researcher Derrick Rossi used modified mRNA to reprogram stem cells in an attempt to treat cardiovascular disease.
Over the years, the company also came to rely on a popular drug delivery tool called lipid nanoparticles. By packing genetic material inside a slice of skid made of oily lipids, these particles could more easily slip mRNA into cells, where it could go to work. With safer mRNA technology and better drug delivery, the company was able to expand its portfolio and take action against cancer and a number of infectious diseases, including influenza. But the big turning point came with the mosquito-borne Zika virus.
After Zika arrived in 2015, the laboratories rushed to find a suitable vaccine. Justin Richner, now an assistant professor at the University of Illinois at Chicago, was part of a multi-university effort to conduct early research on mRNA vaccine candidates from Modern Therapeutics. Richner says the team attached the mRNA codes, which led one of Moderna’s Zika vaccines to early human trials in 2016 – where it stopped.
Modern Therapeutics did not respond to multiple requests from National Geographic for an interview. But the company’s company updates, which are not peer-reviewed, can give clues about their progress with the COVID-19 vaccine. While, for example, the announcement of Moderna on May 18 did not provide hard figures on how many antibodies were found in humans or mice after immunization. However, it revealed that the first phase of the COVID-19 trial has obviously achieved its primary goal of determining the safest drug dose.
“When conducting a first-person clinical trial, the most important information is to determine whether the vaccine is safe,” said Maria Elena Bottazzi, attorney general at Baylor College of Medicine National School of Tropical Medicine, which is not involved in Modern trial.
She adds that a better sign of success for Moderna may be something that has not yet been addressed by the company’s statements: T-cells. Antibodies are just one branch of an immune response. T cells are another. Both can provide lasting protection on their own, but T cells help to make antibodies appear. This is important because DNA and mRNA vaccines are better targeted at triggering T cells, Bottazzi says, but assessing such a response is cumbersome and typically reserved for later phases of human trials.
Still, Moderna can have a long way to go. Phase two subjects are planned to be monitored for at least 15 months, but if early signs look good, the vaccine candidate may move on to his final steps later this year.
Whether Modern succeeds, the world will need several versions to beat the pandemic. Globally, more than one hundred COVID-19 vaccine candidate trials are underway, and so far several companies are reporting promising peer-reviewed results. Many investments are ultimately an advantage, because if any individual vaccine candidate fails, the others remain to offer continued hope, Bottazzi says.
Editor’s Note: The story has been updated with the news that Moderna has confirmed the beginning of its phase two trial. The story was originally published on May 29.