7 New Insights about the Frontrunner U.S. Vaccine Candidate
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.

A vaccine from Moderna could be available as early as January, Fauci recently said.
Earlier this year, biotech company Moderna broke world records for speed in vaccine development. Their researchers translated the genetic code of the coronavirus into a vaccine candidate in just 42 days.
We're about to expand our safety data in Phase II.
Phase I of the clinical trial started in Seattle on March 16th, with the already-iconic image of volunteer Jennifer Haller calmly receiving the very first dose.
Instead of traditional methods, this vaccine uses a new -- and so far unproven -- technology based on synthetic biology: It hijacks the software of life – messenger RNA – to deliver a copy of the virus's genetic sequence into cells, which, in theory, triggers the body to produce antibodies to fight off a coronavirus infection.
U.S. National Institute of Allergy and Infectious Diseases Director Anthony Fauci called the vaccine's preclinical data "impressive" and told National Geographic this week that a vaccine could be ready for general use as early as January.
The Phase I trial has dosed 45 healthy adults. Phase II trials are about to start, enrolling around 600 adults. Pivotal efficacy trials would follow soon thereafter, bankrolled in collaboration with the government office BARDA (Biomedical Advanced Research and Development Authority).
Today, the chief medical officer of Moderna, Tal Zaks, answered burning questions from the public in a webinar hosted by STAT. Here's an edited and condensed summary of his answers.
1) When will a vaccine become available?
We expect to have data in early summer about the antibody levels from our mRNA vaccine. At the same time, we can measure the antibody levels of people who have had the disease, and we should be able to measure the ability of those antibodies to prevent disease.
We will not yet know if the mRNA vaccine works to prevent disease, but we could soon talk about a potential for benefit. We don't yet know about risk. We're about to expand our safety data in Phase II.
In the summer, there is an expectation that we will be launching pivotal trials, in collaboration with government agencies that are helping fund the research. The trials would be launched with the vaccine vs. a placebo with the goal of establishing: How many cases can we show we prevented with the vaccine?
This is determined by two factors: How big is the trial? And what's the attack rate in the population we vaccinate? The challenge will be to vaccinate in the areas where the risk of infection is still high in the coming months, and we're able to vaccinate and demonstrate fewer infections compared to a placebo. If the disease is happening faster in a given area, you will be able to see an outcome faster. Potentially by the end of the year, we will have the data to say if the vaccine works.
Will that be enough for regulatory approval? The main question is: When will we cross the threshold for the anticipated benefit of a presumed vaccine to be worth the risk?
There is a distinction between approval for those who need it most, like the elderly. Their unmet need and risk/benefit is not the same as it is for younger adults.
My private opinion: I don't think it's a one-size-fits-all. It will be a more measured stance.
2) Can you speed up the testing process with challenge studies, where volunteers willingly get infected?
It's a great question and I applaud the people who ask it and I applaud those signing up to do it. I'm not sure I am a huge fan, for both practical and ethical reasons. The devil is in the details. A challenge study has to show us a vaccine can prevent not just infection but prevent disease. Otherwise, how do I know the dose in the challenge study is the right dose? If you take 100 young people, 90 of them will get mild or no disease. Ten may end up in hospital and one in the ICU.
Also, the timeline. Can it let you skip Phase II of large efficacy trial? The reality for us is that we are about to start Phase II anyway. It would be months before a challenge trial could be designed. And ethically: everybody agrees there is a risk that is not zero of having very serious disease. To justify the risk, we have to be sure the benefit is worth it - that it actually shrunk the timeline. To just give us another data point, I find it hard to accept.
This technology allows us to scale up manufacturing and production.
3) What was seen preclinically in the animal models with Moderna's mRNA vaccines?
We have taken vaccines using our technology against eight different viruses, including two flu strains. In every case, in the preclinical model, we showed we could prevent disease, and when we got to antibody levels, we got the data we wanted to see. In doses of 25-100 micrograms, that usually ends up being a sweet spot where we see an effect. It's a good place as to the expectation of what we will see in Phase I trials.
4) Why is Moderna pursuing an mRNA virus instead of a traditional inactivated virus or recombinant one? This is an untried technology.
First, speed matters in a pandemic. If you have tech that can move much quicker, that makes a difference. The reason we have broken world records is that we have invested time and effort to be ready. We're starting from a platform where it's all based on synthetic biology.
Second, it's fundamental biology - we do not need to make an elaborate vaccine or stick a new virus in an old virus, or try to make a neutralizing but not binding virus. Our technology is basically mimicking the virus. All life works on making proteins through RNA. We have a biological advantage by teaching the immune system to do the right thing.
Third, this technology allows us to scale up manufacturing and production. We as a company have always seen this ahead of us. We invested in our own manufacturing facility two years ago. We have already envisioned scale up on two dimensions. Lot size and vaccines. Vaccines is the easier piece of it. If everybody gets 100 micrograms, it's not a heck of a lot. Prior to COVID, our lead program was a CMV (Cytomegalovirus) vaccine. We had envisioned launching Phase III next year. We had been already well on the path to scale up when COVID-19 caught us by surprise. This would be millions and millions of doses, but the train tracks have been laid.
5) People tend to think of vaccines as an on-off switch -- you get a vaccine and you're protected. But efficacy can be low or high (like the flu vs. measles vaccines). How good is good enough here for protection, and could we need several doses?
Probably around 50-60 percent efficacy is good enough for preventing a significant amount of disease and decreasing the R0. We will aim higher, but it's hard to estimate what degree of efficacy to prepare for until we do the trial. (For comparison, the average flu vaccine efficacy is around 50 percent.)
We anticipate a prime boost. If our immune system has never seen a virus, you can show you're getting to a certain antibody level and then remind the immune system (with another dose). A prime boost is optimal.
My only two competitors are the virus and the clock.
6) How would mutations affect a vaccine?
Coronaviruses tend to mutate the least compared to other viruses but it's entirely possible that it mutates. The report this week about those projected mutations on the spike protein have not been predicted to alter the critical antibodies.
As we scale up manufacturing, the ability to plug in a new genetic sequence and get a new vaccine out there will be very rapid.
For flu vaccine, we don't prove efficacy every year. If we get to the same place with an mRNA vaccine, we will just change the sequence and come out with a new vaccine. The path to approval would be much faster if we leverage the totality of efficacy data like we do for flu.
7) Will there be more than one vaccine and how will they be made available?
I hope so, I don't know. The path to making these available will go through a public-private partnership. It's not your typical commercial way of deploying a vaccine. But my only two competitors are the virus and the clock. We need everybody to be successful.
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
Probiotic bacteria can be engineered to fight antibiotic-resistant superbugs by releasing chemicals that kill them.
In 1945, almost two decades after Alexander Fleming discovered penicillin, he warned that as antibiotics use grows, they may lose their efficiency. He was prescient—the first case of penicillin resistance was reported two years later. Back then, not many people paid attention to Fleming’s warning. After all, the “golden era” of the antibiotics age had just began. By the 1950s, three new antibiotics derived from soil bacteria — streptomycin, chloramphenicol, and tetracycline — could cure infectious diseases like tuberculosis, cholera, meningitis and typhoid fever, among others.
Today, these antibiotics and many of their successors developed through the 1980s are gradually losing their effectiveness. The extensive overuse and misuse of antibiotics led to the rise of drug resistance. The livestock sector buys around 80 percent of all antibiotics sold in the U.S. every year. Farmers feed cows and chickens low doses of antibiotics to prevent infections and fatten up the animals, which eventually causes resistant bacterial strains to evolve. If manure from cattle is used on fields, the soil and vegetables can get contaminated with antibiotic-resistant bacteria. Another major factor is doctors overprescribing antibiotics to humans, particularly in low-income countries. Between 2000 to 2018, the global rates of human antibiotic consumption shot up by 46 percent.
In recent years, researchers have been exploring a promising avenue: the use of synthetic biology to engineer new bacteria that may work better than antibiotics. The need continues to grow, as a Lancetstudy linked antibiotic resistance to over 1.27 million deaths worldwide in 2019, surpassing HIV/AIDS and malaria. The western sub-Saharan Africa region had the highest death rate (27.3 people per 100,000).
Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
To make it worse, our remedy pipelines are drying up. Out of the 18 biggest pharmaceutical companies, 15 abandoned antibiotic development by 2013. According to the AMR Action Fund, venture capital has remained indifferent towards biotech start-ups developing new antibiotics. In 2019, at least two antibiotic start-ups filed for bankruptcy. As of December 2020, there were 43 new antibiotics in clinical development. But because they are based on previously known molecules, scientists say they are inadequate for treating multidrug-resistant bacteria. Researchers warn that if nothing changes, by 2050, antibiotic resistance could kill 10 million people annually.
The rise of synthetic biology
To circumvent this dire future, scientists have been working on alternative solutions using synthetic biology tools, meaning genetically modifying good bacteria to fight the bad ones.
From the time life evolved on earth around 3.8 billion years ago, bacteria have engaged in biological warfare. They constantly strategize new methods to combat each other by synthesizing toxic proteins that kill competition.
For example, Escherichia coli produces bacteriocins or toxins to kill other strains of E.coli that attempt to colonize the same habitat. Microbes like E.coli (which are not all pathogenic) are also naturally present in the human microbiome. The human microbiome harbors up to 100 trillion symbiotic microbial cells. The majority of them are beneficial organisms residing in the gut at different compositions.
The chemicals that these “good bacteria” produce do not pose any health risks to us, but can be toxic to other bacteria, particularly to human pathogens. For the last three decades, scientists have been manipulating bacteria’s biological warfare tactics to our collective advantage.
In the late 1990s, researchers drew inspiration from electrical and computing engineering principles that involve constructing digital circuits to control devices. In certain ways, every cell in living organisms works like a tiny computer. The cell receives messages in the form of biochemical molecules that cling on to its surface. Those messages get processed within the cells through a series of complex molecular interactions.
Synthetic biologists can harness these living cells’ information processing skills and use them to construct genetic circuits that perform specific instructions—for example, secrete a toxin that kills pathogenic bacteria. “Any synthetic genetic circuit is merely a piece of information that hangs around in the bacteria’s cytoplasm,” explains José Rubén Morones-Ramírez, a professor at the Autonomous University of Nuevo León, Mexico. Then the ribosome, which synthesizes proteins in the cell, processes that new information, making the compounds scientists want bacteria to make. “The genetic circuit remains separated from the living cell’s DNA,” Morones-Ramírez explains. When the engineered bacteria replicates, the genetic circuit doesn’t become part of its genome.
Highly intelligent by bacterial standards, some multidrug resistant V. cholerae strains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut.
In 2000, Boston-based researchers constructed an E.coli with a genetic switch that toggled between turning genes on and off two. Later, they built some safety checks into their bacteria. “To prevent unintentional or deleterious consequences, in 2009, we built a safety switch in the engineered bacteria’s genetic circuit that gets triggered after it gets exposed to a pathogen," says James Collins, a professor of biological engineering at MIT and faculty member at Harvard University’s Wyss Institute. “After getting rid of the pathogen, the engineered bacteria is designed to switch off and leave the patient's body.”
Overuse and misuse of antibiotics causes resistant strains to evolve
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Seek and destroy
As the field of synthetic biology developed, scientists began using engineered bacteria to tackle superbugs. They first focused on Vibrio cholerae, whichin the 19th and 20th century caused cholera pandemics in India, China, the Middle East, Europe, and Americas. Like many other bacteria, V. cholerae communicate with each other via quorum sensing, a process in which the microorganisms release different signaling molecules, to convey messages to its brethren. Highly intelligent by bacterial standards, some multidrug resistant V. choleraestrains can also “collaborate” with other intestinal bacterial species to gain advantage and take hold of the gut. When untreated, cholera has a mortality rate of 25 to 50 percent and outbreaks frequently occur in developing countries, especially during floods and droughts.
Sometimes, however, V. cholerae makes mistakes. In 2008, researchers at Cornell University observed that when quorum sensing V. cholerae accidentally released high concentrations of a signaling molecule called CAI-1, it had a counterproductive effect—the pathogen couldn’t colonize the gut.
So the group, led byJohn March, professor of biological and environmental engineering, developed a novel strategy to combat V. cholerae. They genetically engineered E.coli toeavesdrop on V. cholerae communication networks and equipped it with the ability to release the CAI-1 molecules. That interfered with V. cholerae progress.Two years later, the Cornell team showed that V. cholerae-infected mice treated with engineered E.coli had a 92 percent survival rate.
These findings inspired researchers to sic the good bacteria present in foods like yogurt and kimchi onto the drug-resistant ones.
Three years later in 2011, Singapore-based scientists engineered E.coli to detect and destroy Pseudomonas aeruginosa, an oftendrug-resistant pathogen that causes pneumonia, urinary tract infections, and sepsis. Once the genetically engineered E.coli found its target through its quorum sensing molecules, it then released a peptide, that could eradicate 99 percent of P. aeruginosa cells in a test-tube experiment. The team outlined their work in a Molecular Systems Biology study.
“At the time, we knew that we were entering new, uncharted territory,” says lead author Matthew Chang, an associate professor and synthetic biologist at the National University of Singapore and lead author of the study. “To date, we are still in the process of trying to understand how long these microbes stay in our bodies and how they might continue to evolve.”
More teams followed the same path. In a 2013 study, MIT researchers also genetically engineered E.coli to detect P. aeruginosa via the pathogen’s quorum-sensing molecules. It then destroyed the pathogen by secreting a lab-made toxin.
Probiotics that fight
A year later in 2014, a Nature study found that the abundance of Ruminococcus obeum, a probiotic bacteria naturally occurring in the human microbiome, interrupts and reduces V.cholerae’s colonization— by detecting the pathogen’s quorum sensing molecules. The natural accumulation of R. obeumin Bangladeshi adults helped them recover from cholera despite living in an area with frequent outbreaks.
The findings from 2008 to 2014 inspired Collins and his team to delve into how good bacteria present in foods like yogurt and kimchi can attack drug-resistant bacteria. In 2018, Collins and his team developed the engineered probiotic strategy. They tweaked a commonly found bacteria in yogurt called Lactococcus lactis.
Engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut. --José Rubén Morones-Ramírez.
More scientists followed with more experiments. So far, researchers have engineered various probiotic organisms to fight pathogenic bacteria like Staphylococcus aureus (leading cause of skin, tissue, bone, joint and blood infections) and Clostridium perfringens (which causes watery diarrhea) in test-tube and animal experiments. In 2020, Russian scientists engineered a probiotic called Pichia pastoris to produce an enzyme called lysostaphin that eradicated S. aureus in vitro. Another 2020 study from China used an engineered probiotic bacteria Lactobacilli casei as a vaccine to prevent C. perfringens infection in rabbits.
In a study last year, Ramírez’s group at the Autonomous University of Nuevo León, engineered E. coli to detect quorum-sensing molecules from Methicillin-resistant Staphylococcus aureus or MRSA, a notorious superbug. The E. coli then releases a bacteriocin that kills MRSA. “An antibiotic is just a molecule that is not intelligent,” says Ramírez. “On the other hand, engineered bacteria can be trained to target pathogens when they are at their most vulnerable metabolic stage in the human gut.”
Collins and Timothy Lu, an associate professor of biological engineering at MIT, found that engineered E. coli can help treat other conditions—such as phenylketonuria, a rare metabolic disorder, that causes the build-up of an amino acid phenylalanine. Their start-up Synlogic aims to commercialize the technology, and has completed a phase 2 clinical trial.
Circumventing the challenges
The bacteria-engineering technique is not without pitfalls. One major challenge is that beneficial gut bacteria produce their own quorum-sensing molecules that can be similar to those that pathogens secrete. If an engineered bacteria’s biosensor is not specific enough, it will be ineffective.
Another concern is whether engineered bacteria might mutate after entering the gut. “As with any technology, there are risks where bad actors could have the capability to engineer a microbe to act quite nastily,” says Collins of MIT. But Collins and Ramírez both insist that the chances of the engineered bacteria mutating on its own are virtually non-existent. “It is extremely unlikely for the engineered bacteria to mutate,” Ramírez says. “Coaxing a living cell to do anything on command is immensely challenging. Usually, the greater risk is that the engineered bacteria entirely lose its functionality.”
However, the biggest challenge is bringing the curative bacteria to consumers. Pharmaceutical companies aren’t interested in antibiotics or their alternatives because it’s less profitable than developing new medicines for non-infectious diseases. Unlike the more chronic conditions like diabetes or cancer that require long-term medications, infectious diseases are usually treated much quicker. Running clinical trials are expensive and antibiotic-alternatives aren’t lucrative enough.
“Unfortunately, new medications for antibiotic resistant infections have been pushed to the bottom of the field,” says Lu of MIT. “It's not because the technology does not work. This is more of a market issue. Because clinical trials cost hundreds of millions of dollars, the only solution is that governments will need to fund them.” Lu stresses that societies must lobby to change how the modern healthcare industry works. “The whole world needs better treatments for antibiotic resistance.”
Meet Dr. Renee Wegrzyn, the first Director of President Biden's new health agency, ARPA-H
Today's podcast guest, Dr. Renee Wegrzyn, directs ARPA-H, a new agency formed last year to spearhead health innovations. Time will tell if ARPA-H will produce advances on the level of its fellow agency, DARPA.
In today’s podcast episode, I talk with Renee Wegrzyn, appointed by President Biden as the first director of a health agency created last year, the Advanced Research Projects Agency for Health, or ARPA-H. It’s inspired by DARPA, the agency that develops innovations for the Defense department and has been credited with hatching world-changing technologies such as ARPANET, which became the internet.
Time will tell if ARPA-H will lead to similar achievements in the realm of health. That’s what President Biden and Congress expect in return for funding ARPA-H at 2.5 billion dollars over three years.
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How will the agency figure out which projects to take on, especially with so many patient advocates for different diseases demanding moonshot funding for rapid progress?
I talked with Dr. Wegrzyn about the opportunities and challenges, what lessons ARPA-H is borrowing from Operation Warp Speed, how she decided on the first ARPA-H project that was announced recently, why a separate agency was needed instead of reforming HHS and the National Institutes of Health to be better at innovation, and how ARPA-H will make progress on disease prevention in addition to treatments for cancer, Alzheimer’s and diabetes, among many other health priorities.
Dr. Wegrzyn’s resume leaves no doubt of her suitability for this role. She was a program manager at DARPA where she focused on applying gene editing and synthetic biology to the goal of improving biosecurity. For her work there, she received the Superior Public Service Medal and, in case that wasn’t enough ARPA experience, she also worked at another ARPA that leads advanced projects in intelligence, called I-ARPA. Before that, she ran technical teams in the private sector working on gene therapies and disease diagnostics, among other areas. She has been a vice president of business development at Gingko Bioworks and headed innovation at Concentric by Gingko. Her training and education includes a PhD and undergraduate degree in applied biology from the Georgia Institute of Technology and she did her postdoc as an Alexander von Humboldt Fellow in Heidelberg, Germany.
Dr. Wegrzyn told me that she’s “in the hot seat.” The pressure is on for ARPA-H especially after the need and potential for health innovation was spot lit by the pandemic and the unprecedented speed of vaccine development. We'll soon find out if ARPA-H can produce gamechangers in health that are equivalent to DARPA’s creation of the internet.
Show links:
ARPA-H - https://arpa-h.gov/
Dr. Wegrzyn profile - https://arpa-h.gov/people/renee-wegrzyn/
Dr. Wegrzyn Twitter - https://twitter.com/rwegrzyn?lang=en
President Biden Announces Dr. Wegrzyn's appointment - https://www.whitehouse.gov/briefing-room/statement...
Leaps.org coverage of ARPA-H - https://leaps.org/arpa/
ARPA-H program for joints to heal themselves - https://arpa-h.gov/news/nitro/ -
ARPA-H virtual talent search - https://arpa-h.gov/news/aco-talent-search/
Dr. Renee Wegrzyn was appointed director of ARPA-H last October.
Matt Fuchs is the editor-in-chief of Leaps.org and Making Sense of Science. He is also a contributing reporter to the Washington Post and has written for the New York Times, Time Magazine, WIRED and the Washington Post Magazine, among other outlets. Follow him @fuchswriter.