The Evolving Virus Against the Vaccines

Larry Corey, MD

For about a month, we were lulled into thinking we had turned the corner and were winning the battle against the virus.

With 95% effectiveness in preventing COVID-19 illness and nearly 100% efficacy in preventing severe disease, we just needed to mass produce these wonderful mRNA vaccines developed by Pfizer / BioNTech and Moderna. Then we could bring an end to this nightmare in a few months.

This illusion can now be called a delusion. We are in a new phase.

Our South African brethren have pointed the way. They had the foresight to set up a genomic surveillance system in a systematic, regionalized way to see how the virus was mutating day by day. This is the way molecular epidemiology and pandemic control should be undertaken.

What they’ve learned has been disturbing. They detected incredibly sudden changes in the virus’s mutational pattern. These were not single nucleotide changes of little consequence. These were multiple sudden changes to the viral RNA code that caused significant structural alterations to several areas of the spike protein on SARS-CoV-2. This has set off alarms in the scientific community. The spike protein is the structure that makes the vaccines work.

The changes we’ve witnessed were in regions of SARS-CoV-2 that were stable over the past year. The mutations were particularly concerning because they affect the Receptor Binding Domain (RBD), which defines the part of the spike protein where the virus attaches to the ACE2 receptor in human cells.

The current vaccines elicit neutralizing antibodies to the Receptor Binding Domain. Some of these mutations look so unusual, that scientists began to wonder whether the antibodies induced by the original vaccines can still bind and neutralize as intended. Might this new Receptor Binding Domain structure resist all neutralizing antibodies, from either natural infection or from vaccine-induced immunity? We’ve had to ask and answer that question. There are also changes to the viral RNA that encodes for another area we call N-terminal domain (NTD) that we don’t really understand.

The South Africans reported these changes first to the United Kingdom (UK), because the predominant strains circulating in South Africa in the early parts of the epidemic were similar to the most common one in the UK. It’s no surprise the two countries have similar viral strains, as there is considerable international travel between the two countries.

Once informed of the new strain from South Africa, now known as B.1.351,  UK molecular biologists started to look harder at strains circulating in their own country. They found a new variant that was starting to sweep over the country, called B.1.1.7. That new variant has driven a second wave of infection.

The second wave is worse than the first, as seen by increased rates of transmission and increased rates of hospitalization in the UK. This variant had one of the mutations in the RBD part of the genome, the one that appears associated with increased replication in the nose and transmission to other people, but fortunately not the changes that alter the neutralizing antibodies.

Very quickly, scientists put two and two together. The virus was evolving more rapidly than previously detected. Changes were occurring across two behavioral characteristics. And, the changes to these two characteristics were being detected in the same virus.

We have seen variations pop up over the past year. In June, we had a variation in the US where the original strain from Wuhan was overtaken by what we call the D to G614 strain; that’s what is mainly circulating here now. This strain also increased attachment to the ACE2 receptor, but the newer F105Y mutation enhances these characteristics even more and facilitates an even greater rate of spread.

This B.1.1.7 variant, commonly referred to as the UK variant, has now spread throughout Europe, and is being increasingly recognized in the US. The CDC predicts that this strain, with its evolved advantages, will become the predominant form of the virus circulating in the US over the next few months.

The B.1.351 variant, widely known as the South African variant, also has the increased transmissibility stemming from the mutation in the F105Y gene. But that’s not all. The South African variant has a couple more nasty mutations, one called E484K, that is associated with escape from an important neutralizing epitope that most people have after contracting COVID-19. That neutralizing epitope  is also found on antibodies induced by vaccination. This escape mutation on the part of the virus has been seen in other unrelated strains, so it seems to be a frequent way the virus tries to use to escape from people who have acquired immunity. So, people who have been infected with prior strains and developed immunity to those prior strains appear to be at an increased risk of re-infection with the B.1.351 variant.

We call this escape from neutralization or adaptive immune escape from the virus’s point of view.

This is what RNA viruses do. Influenza does this; HIV does it too.

In retrospect, we were a bit naïve about SARS-CoV-2, thinking that because this subgroup of coronaviruses edits its mutations more efficiently, we might escape from having lots of different strains. But natural selection is very powerful, as Darwin taught us. We have had more than 100 million confirmed cases of COVID-19 worldwide thus far, and the real number is certainly much, much bigger. When a virus spreads to this many hosts, this fast, it creates a lot of opportunity for the virus to adapt against the natural selection pressure placed on it by the human immune system.

The bad news is that we continue to give the virus opportunity to adapt. We’re tired of social distancing. Not everyone wears masks. We have limited supplies of vaccine at the moment. So, we find ourselves in a situation where mathematically, this pandemic is not going to stop anytime soon.

What do we do about it? This week brought us data that says we don’t have to panic. We do really have evidence that our current tools are going to be OK. Moderna reported that its vaccine, in lab tests, continued to produce robust neutralizing antibodies against the B.1.1.7 variant. The Moderna vaccine produced 6-fold lower titers of antibodies against B.1.351, but those antibody levels that are still higher than what are typically seen in cases of natural infection. Importantly, the nature of the mRNA technology makes it possible for Moderna to make a new mRNA construct very quickly to educate the immune system against this new B.1.351 variant, and that new “updated” vaccine can be tested in a small, fast clinical trial to validate its use as a “booster.”

Scientifically, this is the good news. But it’s only a piece of the puzzle. We have to create strategies to get us back up to the optimal state. This means vaccinating everyone globally as fast as possible. What impacts one of us impacts all of us, including here in the US. Ongoing community spread anywhere with this virus means it can spread everywhere in our interconnected world.

Besides findings from lab tests, we now have hard clinical evidence that our current vaccines will work as well against the UK variant as they have for the variants circulating in the US. The best evidence of this is a 14,500-person clinical trial of the Novavax vaccine which showed a 90% efficacy rate in a UK study where the UK variant constituted 30% to 40% of the strains circulating at the time of the trial. The antibody concentration from this two-dose vaccine is pretty similar to what we saw in the Moderna and Pfizer vaccines. Several scientific teams have now shown that sera from people vaccinated with either of these vaccines also neutralize the B.1.1.7 isolate as well as the isolate from Wuhan. That’s good news.

More importantly, we got data from the Johnson & Johnson (J&J) vaccine trial out of South Africa on Friday. We were lucky. We didn’t know when we conducted the J&J trial that there would be marked viral strain differences between South Africa and the US. In fact, when I worked with the company to design the trial, the reason we went to South America and South Africa for an international trial was because J&J is a global company and they wanted a globally developed vaccine. Their vaccine is also tailor-made for global vaccination efforts, since it can be given in a single shot, and shipped to remote parts of the world with standard refrigeration – no need for deep freeze.

My network was already working with J&J on their experimental HIV vaccines and we had great investigators in both South Africa and South America who were tackling the COVID-19 epidemic and wanted to help. We were conducting so many vaccine trials in the US, we felt we could distribute some of the work internationally and everyone would benefit. At the time these decisions were made last summer, we didn’t realize how fortuitous this decision would be. A month ago, after the South Africans noted that the B.1.351 variant was the main circulating strain in the country, we got nervous about whether the vaccine would be effective against this tough new variant.

Fortunately, this anxiety was alleviated when the data arrived from the 43,000-volunteer global trial. The J&J vaccine protected against hospitalization and death in 88% of the enrollees in South Africa! There were zero deaths in the vaccine group; six in the placebo group in South Africa. Overall, the vaccine was 57% effective against moderate and severe disease in South Africa.

The efficacy number in the US was 72%; in Brazil, 71%. Worldwide, the numbers worked out to 66 percent protection against moderate and severe disease.

Yes, we do have an 18% to 20% difference in the effectiveness in the J&J vaccine by region, and this is some source of concern. And I will add that the Novavax vaccine, which was shown to be 90% effective in the UK, showed 55% protection in South Africa. So, here too we saw a reduction in efficacy.

But to put it in perspective: What’s more important, do we develop these vaccines to reduce the frequency and severity of sore throats and cough? Or do we develop vaccines to prevent us from getting hospitalized, being put on supplemental oxygen, put on a ventilator, or dying?

I think all of us would take a vaccine that prevents us from dying, even though it might still mean a case of COVID-19 with a sore throat and a headache and body aches for a couple days. I’d take that deal.

In my next blog, I’ll talk more about the J&J vaccine and where it fits in the vaccine response in the US and globally. We need a bit more data to become public before we tackle this task. There are lots of opinions here and there’s nothing wrong with that. But it’s been a very good week. We now have two new safe and effective vaccines—Novavax and J&J. That can be nothing but great news.

As in all science, all good clinical trial outcomes lead to more good questions that we’ll need to answer to bring an end to this pandemic.

Dr. Larry Corey is an internationally renowned expert in virology, immunology, and vaccine development and a leader of the COVID-19 Prevention Network (CoVPN), which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic. He is a Professor in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center, past President and Director of Fred Hutch, and a Professor of Medicine and Virology at University of Washington.


Ideas for an FDA Reboot

Luke Timmerman, founder & editor, Timmerman Report

The FDA needs to get healthy, and fast.

Its credibility as the world’s No. 1 science-based regulator of food and drugs has been tarnished.

From the start, it had to play catch-up on RT-PCR diagnostic tests in the wake of CDC’s epic screwup. Partly to make up lost ground, it swung open the floodgates for antibody tests. A Wild West debacle ensued. Then came hydroxychloroquine (caving in with a premature Emergency Use Authorization, followed by the embarrassing withdrawal when failure was obvious). Then came the convalescent plasma fiasco.

It’s painful to write those words.

Throughout, there was a failure of leadership to level with citizens and clearly communicate the rationale for its decisions in real-time.

Even when FDA staff were inspired to burn the midnight oil to make sure we got vaccines without delay, and the news was good, the agency was tainted. It wasn’t able to speak with the gravitas needed to shore up confidence in therapies and vaccines. Too many people came away thinking FDA was a bunch of bureaucrats or political hacks, cutting corners, probably engaged in skullduggery.

Anyone who gives a damn about healthcare, and about biopharmaceutical innovation, ought to care about restoring the FDA as the world’s leading scientific regulator. We all ought to focus our prying, skeptical eyes on the agency to hold it accountable and keep it on its toes. But we shouldn’t go overboard into bottomless cynicism.

So, today I’d like to propose a few bold ideas to help the FDA get back on its feet.

  1. Move out of the Washington, DC area. The FDA doesn’t need to be headquartered in Washington, any more than the US Mint. The FDA has about 11,000 employees in 8 million square feet of space. The scientific review teams can do their jobs anywhere – and it’s preferable to do it in a quiet place free from excessive influence from Congressmen, hacks in the White House, or industry lobbyists pushing their own special interest.

By moving out of the Washington, DC metro area, the federal government could reap a real estate windfall. The FDA has valuable land that could be redeveloped by private developers of mixed-use business and residential properties. FDA could take the windfall proceeds and build a reimagined, tightly integrated campus in the middle of the country on cheaper land.

I’m thinking of a place like Wichita, Kansas (pop. 390,000) or Tulsa, Oklahoma (pop. 402,000). These cities offer low cost of living and high quality of life. They have diverse demographics with White, Black, Hispanic and Native American populations that closely reflect the population of the country as a whole. The FDA, operating down the street from healthcare providers in a place like this, could test out lots of cool new initiatives in a “real world” healthcare setting. Done right, the FDA could gain valuable insights into how to operationalize things like telemedicine for clinical trials, remote patient monitoring and more.

A move could also refresh the agency’s staff, by clearing out some people ready for early retirement, and providing an opportunity for an influx of new talent attracted to work on hard challenges. These people could be good scientific citizens in their communities. They would be parents of kids in local schools, and neighbors to ordinary people. FDA staff could weave themselves in with local schools that don’t get enough exposure to the wonders of 21st century medical science.

  1. Double the budget over five years. The FDA has always had to struggle for resources. When it succeeds, no one notices. It doesn’t get to bask in the glory of discovery like the NIH. Its public health mission sometimes puts it crosswise with powerful constituents, like drugmakers or tobacco companies or Big Agriculture. The FDA doesn’t have a lot of natural allies in Congress who understand or enthusiastically support its multi-faceted work. Its budget, at a requested $6.1 billion for 2021, is peanuts for an agency that regulates one-fourth of the economy. How is it supposed to monitor manufacturing facilities and supply chains around the world to keep us safe from contaminated or counterfeit medicines?

For almost 30 years, the agency has long been kept on a tight leash with Congressional appropriations, and has been forced to rely increasingly on industry user fees. That’s one way to be penny-wise. But it also creates a financial dependence on industry, and a closeness that can sometimes get a little too close in ways that are subtle and hard to quantify. I think there’s a place for user fees in the FDA budget, but the lion’s share ought to come from us, the taxpayers. Either we as taxpayers think this work is important, or we don’t. If the COVID-19 pandemic has taught us a few lessons, one is the importance of an independent, nimble, science-based FDA.

With more pandemic threats looming and so many groundbreaking biopharma products coming down the pike, we need to double the budget just to keep with the anticipated demands on this stretched agency. Pay raises should go to agency veterans who have gone above and beyond.

  1. Draft a New Commissioner for the Moment. The FDA acting commissioner is Janet Woodcock. She’s an agency veteran, knows where all the bodies are buried, is a steady hand, and a serious person who knows medical evidence inside and out. She’s thoughtful about how the agency needs to modernize (see this 2017 NEJM editorial on master protocols to generate high-quality medical evidence). She has a backbone, standing with career staff in September against political hacks in a strong USA Today editorial. Woodcock cares about patients through her work on personalized medicines.

But at a moment when the agency needs to restore public trust, and break out of some of limited thinking of the past, it needs a commissioner with excellent communication skills and a vision for a 21st century FDA. The next FDA commissioner needs to communicate to the public and advocate passionately with leaders on Capitol Hill and the executive branch. Scott Gottlieb was skilled at this part of the job, and understood how to strike the balance of protecting public health while facilitating quality development of new products. Margaret Hamburg, who made a great impact as commissioner, wasn’t the kind of public spokesperson the agency needs now.

I’m thinking of someone to lead the FDA who has public health experience, who believes in the FDA mission to the bone, who can communicate scientific risk / benefit equations to a Nobel laureate or your grandma, and who doesn’t have too many industry conflicts. I could imagine a few excellent candidates.

Amy Abernethy, deputy commissioner, FDA

How about Bob Wachter of UCSF, one of the most trenchant observers of the pandemic response? Or Julie Gerberding, a former CDC director and now an EVP at Merck with tons of experience in communications? Or Anna Barker, a National Cancer Institute veteran and now the chief strategy officer at the Ellison Institute for Transformative Medicine at USC? Or FDA deputy commissioner Amy Abernethy, who’s spearheading a futuristic data science initiative, and who has credentials from academia (Duke) and industry (Flatiron Health).

Or maybe bring Gottlieb into the Biden Administration, even though he’s a Republican? He’d have to quit his board activities, and work for a Democratic administration, but that would be one way to show that the FDA isn’t a partisan institution.

  1. Get Ahead of the Trends with PDUFA VII. The Prescription Drug User Fee Act, the governing compact that has set the terms of engagement between industry and FDA since 1992, is renewed and updated every five years. The current iteration of PDUFA is due to expire in September 2022. It may seem far off, but now is the time when behind-the-scenes negotiations between industry and the agency pick up. The industry and agency will have to discuss fundamentals like fee rates, support for new initiatives, and allocating resources to keep up with the agency’s mission.

The FDA is staring at a mountain work ahead on cell and gene therapies. About 900 gene therapy INDs were in the pipeline as of February 2020. Former FDA commissioner Gottlieb and Peter Marks, head of the Center for Biologics Evaluation and Research, forecasted in 2019 that if current trends continue, the FDA will have to be in position to approve 10-20 cell and gene therapies a year by 2025.

The FDA has to staff up with people in CBER to keep up with the anticipated workload. This unit of FDA, remember, has been running at full tilt all year.

Besides the obvious need for more staff, there’s always a need to stay current with information technology, and lab technology tools, to keep up with an industry that is well-funded and moving faster than ever. The agency also needs resources for staffing up far-flung field offices so it can adequately do facility inspections, especially with the vast array of generic drug facilities around the world, and the boom in biologic manufacturing here and abroad. If we don’t make this investment, we can expect a slowdown in approvals — an abundance of innovations that can’t get all the way to people. It would be an “innovation pile-up” reminiscent of a Third World country.

If we’re smart, we’ll invest now to get ahead of the curve of the needs for CBER, while also preparing for healthcare and biopharma changes. Consider the FDA’s data science initiatives led by deputy commissioner Amy Abernethy. Or, consider master protocol study designs that could cut down on some of the waste that bogs down clinical trials today.

Neglecting the basics of how we gather medical evidence comes with a cost. There were too many small, single-site, investigator-sponsored studies in this pandemic – small and crappy trials. The FDA is the one agency that can take the lead on demanding new standards, but it needs strong leadership and  adequate funding.

It’s easy to overlook the FDA. It’s easy to criticize. Often, we’re right when we do.

But the FDA also needs our support. It deserves our most creative, constructive ideas on how to fulfill its mission. We shouldn’t take it for granted. The pharmaceutical industry wouldn’t be worth much if it were to wither on the vine.

We can’t allow that to happen. I don’t think it will. Let’s revitalize the FDA, and put it in position to be great at what it does for the next 100 years.

The Evolving Virus
  • Manaus Is Collapsing Again. CNN. Jan. 28. (Matt Rivers)
  • Manaus, the Amazonian City of 2 Million That Hatched the Brazil Variant, Has Been Crushed By It. Washington Post. Jan. 27. (Terrence McCoy and Heloísa Traiano)
  • Three-quarters Attack Rate of SARS-CoV-2 in the Brazilian Amazon During a Largely Unmitigated Epidemic. Science. Jan. 15. (Lewis Buss et al)
  • Virus Variant First Detected in South Africa Now Detected in US for First Time. Associated Press. Jan. 28. (Mike Stobbe and Michelle Liu)
  • UK Variant May be More Deadly. BBC. Jan. 22. (James Gallagher)
SARS-CoV-2 Characteristics
  • Gaithersburg, Maryland-based Novavax reported that its protein-based vaccine candidate was 89 percent effective in a Phase III study in the UK that enrolled 15,000 participants. Jan. 28. (Novavax statement)
  • Tracking COVID-19 Vaccines Across the US. NIH Director’s Blog. Jan. 28. (Francis Collins)
  • Merck Ends COVID-19 Vaccine Development Because of Insufficient Immune Response; Continues COVID-19 Therapeutic Work. Merck Statement. Jan. 26.
  • Moderna Vaccine Retains Neutralizing Antibody Production Against B117, but Less Robust Defense Against B.1.351. Moderna Now Working on a New Construct for Booster Vaccine Against B.1.351. Jan. 25. (Moderna statement).
  • mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. BioRxiv. Jan. 25. (Kai Wu et al, Moderna and National Institute of Allergy and Infectious Disease).
  • Pascal Soriot, CEO of AstraZeneca, Interview With La Repubblica. “There Are a Lot of Emotions on Vaccines in EU.” Jan. 26.
  • As Virus Grows Stealthier, Vaccine Makers Reconsider Battle Plans. NYT. Jan. 25. (Denise Grady, Apoorva Mandavilli and Katie Thomas.)
Collateral Damage of the Pandemic
The Infodemic
  • Anti-Vaccine Activists Peddle Theories That Covid Shots Are Deadly, Undermining Vaccination. Kaiser Health News. Jan. 25. (Liz Szabo)
Treatments for COVID-19
  • Efficacy of Colchicine in Non-Hospitalized Patients with COVID-19. MedRxiv. Jan. 27. (Jean-Claude Tardif, Nadia Bouabdallaoui, Philippe L L’Allier et al at Montreal Heart Institute)
  • Full-Dose Blood Thinners Decreased Need for Life Support and Improved Outcome in Hospitalized Patients. NIH statement on three trials. Jan. 22. (National Institutes of Health)
  • Lilly, Vir Biotechnology and GSK announce first patient dosed in expanded BLAZE-4 trial evaluating bamlanivimab (LY-CoV555) with VIR-7831 (GSK4182136) for COVID-19. Jan. 27. (GSK statement)
  • Lilly’s neutralizing antibodies bamlanivimab (LY-CoV555) and etesevimab (LY-CoV016) together reduced risk of COVID-19 hospitalizations and death among COVID-19 patients considered high-risk. The BLAZE-1 trial found that in 1,035 high-risk patients, there were 11 events (2.1 percent) in patients taking therapy and 36 events (7.0 percent) in patients taking placebo. There were 10 deaths total in the study — all of which were in the placebo group.
Market Chaos

The GameStop retail shareholder attack against hedge funds of Wall Street has prompted a lot of bewildered hot takes. As someone who formerly covered biotech stocks for Bloomberg News, I have some sympathy for the little guy who always gets screwed by the big guys. It’s been going on far too long (for just one example in biotech, see my “Selling Drug Secrets” investigation for The Seattle Times in 2005). At the simplest level, this retail shareholder rebellion makes some sense in a world that’s come unglued and where it appears there are no consequences for people who incite society-wide lawbreaking and mayhem. But when you open a Pandora’s Box of lawlessness and bottomless cynicism and too many people don’t know what’s true and don’t care, terrible damage gets done to innocent victims.

Look at Vir Biotechnology. The San Francisco-based developer of infectious disease therapies scored a fundamental win this week with its hepatitis B treatment. The stock skyrocketed to a high of $135 this week, before falling to as low as $51. There’s no fundamental reason for this much volatility. It had good news for hepatitis B, and some more good news for its combo therapy partnership on COVID-19 with Lilly and GSK. Apparently, part of the volatility can be explained because there’s a large percentage of shareholders who have a short position in the company based on a belief that it’s overvalued for its COVID-19 therapeutic antibody work. It’s fine for people to argue about valuations in the market – that’s what the market is supposed to do. But I think most people would also agree that we don’t want to have a system where it’s fun and profitable to launch manipulative attacks – bearish or bullish – to settle scores against Hedge Fund Bad Guys, if it means companies tackling the world’s biggest health challenges become collateral damage.  

Our Shared Humanity

  • Rob Perez on His Big Idea That Might Change the World. Authority magazine. Jan. 26. (Fotis Georgiadis)

Worth a Listen


Kirk Raab, the former CEO of Genentech, died from complications of COVID-19. He was 85.


San Francisco-based Verana Health struck an agreement with Janssen Pharmaceuticals to curate real-world evidence for data analysis to inform R&D in ophthalmology and urology. Terms weren’t disclosed. (TR coverage of Verana, July 2018)

Data That Mattered

Takeda Pharmaceuticals said that its experimental drug mobocertinib, an oral tyrosine kinase inhibitor, showed positive results in a Phase I/II trial of non-small cell lung cancer patients with EGFR Exon20 insertions. Researchers reported a 35 percent overall response rate, in patients who had previously worsened after platinum-based chemotherapy. Data were presented at the World Conference on Lung Cancer.

Amgen’s sotorasib, the oral KRAS G12C inhibitor, generated an overall response rate in 37 percent of patients with advanced lung cancer, according to data presented at the World Conference on Lung Cancer.

Genentech’s faricimab met the primary endpoint of in a pair of Phase III studies of patents with the wet form of age-related macular degeneration. The Genentech medicine is a bispecific antibody aimed at angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). The drug, administered every 16 weeks, was found non-inferior compared with Regeneron’s aflibercept (Eylea).

Personnel File

San Diego-based Cidara Therapeutics, the developer of antifungal and antiviral therapies, named molecular biologist Bonnie Bassler of Princeton University and Carin Canale-Theakston, founder and CEO of Canale Communications, to its board of directors.

Seattle-based Umoja Biopharma, an in vivo immunotherapy company, added Rob Glassman to its board of directors. He has been a vice chair at Credit Suisse since 2015.

Philadelphia-based Tmunity Therapeutics, the developer of T-cell therapies for solid tumors, said Jeff Leiden has become its new chairman of the board. Leiden is executive chairman of Vertex Pharmaceuticals.

San Diego-based ViaCyte, a regenerative medicine company, named Michael Yang as President and CEO. Brittany Bradrick was promoted to COO and CFO, and Steve White was named chief technology officer.


Waltham, Mass.-based Tscan Therapeutics raised $100 million to advance T-cell receptor engineered T-cell therapies for cancer. BlackRock and RA Capital Management participated.

Cambridge, Mass.-based Nuvalent raised $50 million in a Series A financing from Deerfield Management to work on kinase inhibitors for treatment-resistant cancers.

Seattle-based Lumen Bioscience received funding from CARB-X worth up to $14.5 million to develop orally available monoclonal antibody cocktails for serious diarrheal diseases.

Redwood City, Calif.-based Seer, a proteomics company, said it’s raising $251 million in a stock offering at $67 a share.

Germany-based CureVac, a mRNA therapeutics and vaccine developer, raised $450 million in a follow-on stock offering.

Israel and Palo Alto, Calif.-based Ukko raised $40 million to combat food allergies. Leaps by Bayer led.

Regulatory Action

Alameda, Calif.-based Exelixis won FDA clearance for cabozantinib (Cabometyx) in combo with nivolumab (Opdivo) as a first-line treatment for patients with advanced renal cell carcinoma.


What’s Your DEQ? Why Data Empathy Is Essential For Health Data Impact

David Shaywitz

“Their story — yours, mine — it’s what we all carry with us on this trip that we take, and we owe it to each other to respect our stories and learn from them.” — Dr. William Carlos Williams to Dr. Robert Coles, from Coles’s “The Call of Stories.”

The term “data empathy” is on the verge of entering the mainstream.  It’s about time.

At least in print, the concept of “data empathy” was introduced in a 2014 paper by James Faghmous and Vipin Kumar, on climate science. One of the most significant challenges of working with “big data,” the authors write, is that, “with large datasets where one measures anything and everything, it can be difficult to understand how that data were collected, and for what purpose.”

This matters, the authors eloquently argue, in the most important sentence of the paper: 

“Every dataset has a story, and understanding it can guide the choice of suitable analyses.” 

This understanding, the broader contextual background surrounding the data collection and analysis, is termed “data empathy.”

There are two important reasons to seek out the story behind data, continue Faghmous and Kumar:

“[F]irst, understanding how the data are generated, their purpose, and generation processes will guide your investigation. Second, understanding the inherent biases in the data gives you the chance to correct them or adjust your results and recommendations.”

Yes, yes, a thousand times yes.

The most significant challenge faced in learning from “big data” in health is the disconnect between those generating the data and those trying to apply analytics to learn something from these data. Nearly everything worthwhile in health is complicated and messy, from biology to healthcare delivery (see here, here, here).

It’s appealing (for some) to imagine the intrinsic messiness can be offset by data volume or smart analytics, or that if you just stick all your assorted information in a giant digital vat, you can generate brilliant insights simply by letting data geeks, AI, or both, push and pull at it until it’s tortured into submission.  

Bashing at data you don’t deeply understand is futile at best, and often dangerously misleading, because you can always calculate something. The question is whether what you’re doing is meaningful or simply digital onanism.

I’ve recently discussed in TR why learning from EHR data, challenging under the best of circumstances, requires a sophisticated understanding of the local clinical practices associated with the data you’re examining; absent this knowledge, your conclusions are likely to be naïve, misguided, and quickly dismissed.

This has profound implications for healthcare and pharma organizations building out data science teams, as so many are right now. To cut to the chase: unless you recognize the foundational importance, as an organizing principle, of data empathy, and select your team with this vital and often elusive capability in mind, you’re going to have a really difficult time both gaining critical organizational traction and delivering meaningful insights. You will risk being regarded as just the innovation flavor of what promises to be a very short moment. 

Many supposedly brilliant data scientists, arriving with impeccable technology credentials (think “best of the best of the best, sir”), have enjoyed remarkably short tenures in healthcare organizations – attributable, I’d argue, to a low DEQ – data empathy quotient.

Conversely, leaders who’ve most effectively marshaled health data science to solve organizational challenges – Dr. Amy Abernethy’s work at Flatiron obviously comes immediately to mind – have extremely high DEQs. Other conspicuous examples of high DEQ at work include Dr. Omri Gottesman’s early contribution to Regeneron’s data integration platform, and Dr. Griffin Weber’s work in the academic sector.

The integrative ability at the heart of data empathy must reside in and reflect the philosophy of the entire data science team, as well as be embodied by the team’s leadership. The data science team must recognize, and must, critically (this is the biggest challenge), persuade the organization that data scientists do not and will not succeed by staring at a computer screen and delivering insights on datasets they’ve been handed.

The organization must not be conditioned to expect this over the transom approach, either. Instead, skilled data scientists work closely and collaboratively with front-line colleagues, including physicians and drug developers, who are generating the data, and with colleagues who are seeking greater insight from the data (the two groups might not be the same, but could be).

The point is that whether in a pharma company or a healthcare system, only by deeply understanding the nuance of how the data were generated, and having a sense of the anticipated use — and by being innately curious about both — can health data scientists function effectively, and deliver relevant results and meaningful insights. 

Fortunately, there are at least two reasons for real hope: first, data scientists, as I’ve described in both a recent Wall Street Journal book review and in TR, are increasingly attuned to the shortcomings in their datasets, and are (now) exceptionally attuned to issues of bias and equity. The idea that even – especially – large datasets need to be scrutinized with particular care is now dogma among leading data scientists, who recognize data doesn’t exist, and can’t be assumed to exist, on some pure, objective plane. The increased attention to how data are generated will be especially valuable for healthcare data science.

Second, and perhaps most importantly, there are ever-more inquisitive physicians and biomedical scientists who are captivated by, and often trained in, data science. I grew up running gels in traditional wet labs (how quaint), but today’s inquisitive physicians and scientists are as likely to be crunching data at multiple desktop monitors.

These emerging health data scientists are more apt to recognize that all data aren’t equally suitable for all analyses, and to realize how important it is, as you’re collecting and organizing your data, to have a clear sense of what sort of things you hope to learn from it. Done right, in collaboration with providers and scientists who are closest to the problems, it’s possible to create a positive feedback loop in which data scientists get more clarity on the problems to solve, and front-line stakeholders appreciate the insights and values high DEQ data scientist teams can bring.

Bottom line

The successful application of data science to healthcare delivery and drug development requires a high DEQ, an awareness of, and innate curiosity around the context in which data are generated. Data science teams in healthcare organizations foundationally require data empathy. The increased humility and self-reflection within the field of data science, and the increased focus of inquisitive biomedical researchers on data science questions, both represent hopeful signs for the future of health data science.


A Bold Idea for the NIH

Luke Timmerman, founder & editor, Timmerman Report

Too many people don’t believe anymore in the American dream.

But if you can’t dream big, you can’t accomplish big things.

Today, I’d like to propose a bold idea for the future of biomedical research.

Let’s triple the National Institutes of Health budget over the next decade.

Impossible? Hear me out.

We know the NIH, with a $41.7 billion a year budget, is a force for human health and the economy. It has catalyzed the economy for decades.

Think about the Human Genome Project. Criticized as a costly boondoggle in the 1990s, it morphed into a seed investment for the ages. It cost $3.8 billion between 1990-2003. What did we get? Through 2010, the estimated economic impact was $796 billion, according to Battelle.

That’s $141 of economic activity for every $1 invested by the US government. That’s right — a 141x return on investment!

The dividends don’t stop there. That calculation was made in 2010. Biotech would be in the dark ages today without that DNA code on every desktop, and the ability to sequence DNA at high speed and low cost. You can draw a straight line between that catalytic investment by the US government (and to a lesser extent the UK, France, Japan and others), and biopharma’s invention of mRNA vaccines for COVID-19.

That is one success story. There are many others.

The NIH, composed of 27 institutes, supports the best work in cancer, infectious disease, neuroscience, mental health and other fields.

Ordinary citizens in the US have no idea that our taxpayer dollars can have this kind of impact. They have no idea that when we send our $41.7 billion to Washington for the NIH, 85 percent of that money comes right back to the states that are home to so many vibrant universities.

People have no idea that the NIH money is divvied out on a competitive, merit-based grant review system. Often, they are surprised to learn it doesn’t go in the pocket of some Congressman’s son-in-law.

They have no idea that the institutes themselves are led and staffed by brilliant hard-working people like Tony Fauci. They are surprised to learn he’s more than a good talker on TV. They are surprised to learn he got his job because he was the 13th most cited scientist in the world from 1983-2002.

People have no idea that you and me — the US taxpayer — are by far the most powerful investors in biomedicine. No country in Europe invests at this magnitude. China? It has ambition. But it envies the NIH system, seeks to copy it, and knows it has a long way to go.

Citizens in the US tend to have an exaggerated view of what billionaires like Bill Gates and Warren Buffett can do. Drinking from the poisoned chalice of political entertainment media for far too long, we’ve internalized the idea that government is full of screw-ups, and business titans like Gates and Buffett are the true wellsprings of science and innovation.

Generous as they are, their impact pales by comparison to the US taxpayers. The Bill & Melinda Gates Foundation, the world’s largest philanthropy, invests $5 billion a year across all its programs that include education, global development and global health. The NIH pumps $41.7 billion into biomedical research alone for the American people. The Gates Foundation knows this, and it’s why they are always talking about partnerships. They know the NIH is the beating heart of biomedical research.

We as a country just don’t fully appreciate what a gem we have in the NIH.

In my state of Washington, the late Sen. Warren Magnuson brought home the bacon that built the University of Washington Health Sciences Center and the Fred Hutchinson Cancer Research Center. These are sparkling stars in my community, and in the global scientific enterprise.

Sen. Magnuson operated in the optimistic post-WWII era, guided by FDR’s science advisor, Vannevar Bush. It’s worth re-reading that seminal document “Science, the Endless Frontier.”

It’s worth noting that in 1945, when Bush wrote that visionary document, we hadn’t even discovered the double helix structure of DNA.

So what could we do with a reinvigorated NIH?

A couple thoughts:

  1. A new NIH intramural campus, located West of the Mississippi. The NIH campus in Bethesda, Maryland currently has about 6,000 research scientists. I’m thinking of a new 5,000 or 6,000-scientist campus in a Midwestern or Western city. It could be an attractive place for young families, a place with affordable housing, cultural amenities, existing biomedical building blocks, and good transportation bones to handle an influx of newcomers. St. Louis would work. It’s the home of Washington University in St. Louis, it’s the Gateway to the West, and a major American city that has lost 65 percent of its population since its peak in 1950.

Why do this? Planting a major research stake in the ground, outside of Washington DC, New York, San Francisco or Boston could have multiple benefits. We would get good bang for our taxpayer investment, with lower operating and capital expenses. A new NIH campus would spur surrounding economic development with housing, transportation, small business. It would send a powerful cultural message that this 21st century industry creates shared prosperity, not just prosperity for a few coastal cities.

Putting an NIH campus in St. Louis would give young scientists a place to spread their wings and get established – where they could make the same wage as in a place like Bethesda but where their salary would support a higher standard of living. Not only that, but a fresh new campus would create some healthy competition for Bethesda, and help bust out of moldy Groupthink patterns of thought.

A St. Louis NIH campus could attract fresh new thinkers. I’m reminded of Nobel Laureate Mario Capecchi, who left Harvard University to go to the University of Utah to get away from some of the suffocating aspects. At Utah, free to do his own thing, he invented knockout mouse technology. (Capecchi, by the way, is a Holocaust survivor, and orphan, who found refuge in the US. He’s a poster boy for immigration reform, but that’s another column.)

  1. Build up four new cornerstone institutes of the NIH. We could support areas that need more basic research. I’m thinking of a reborn National Institute of Infectious Disease ($5.8 billion annual budget), a beefed-up National Institute of Mental Health ($2 billion), and a more generously funded National Institute of Neurological Disorders and Stroke ($2.4 billion). The “allergy” part of Fauci’s group at NIAID could be reorganized under a new, independent National Institute of Immunology. This is worth housing in an independent institute because immunology is so full of possibility, and we need more young people growing up in the field.

Why do this? These institutes are traditionally underfunded, especially compared with the big dog at NIH – the National Cancer Institute ($6.6 billion annual budget). But look at the future of disease burden. There’s SARS-CoV-2 and flu and malaria, TB and HIV. Then depression and anxiety and schizophrenia and bipolar disorder. Then Alzheimer’s and Parkinson’s and multiple sclerosis.

We’re talking about diseases affecting tens of millions of people worldwide.

Biopharma invests little in these areas because these fields are less mature than cancer, and because there’s less government-funded basic research to build on. There simply are not a lot of promising, short-term angles for industry R&D to attack. That was true for cancer in 1970. But then President Nixon and leaders in Congress (including Sen. Magnuson) made a big bet on the National Cancer Institute. That investment is paying dividends today.

This week, while mulling the state of our divided country, I listened to a podcast with former Sen. Bill Frist (listen here). He’s a Republican from Tennessee, a heart surgeon by training. NIH director Francis Collins was his guest. Frist, reminiscing about the Human Genome Project, marveled at how it came in ahead of schedule and under budget.

Then he asked Collins about the NIH budget.

Collins rattled through the basics. The NIH budget doubled in a bipartisan push from 1998-2003. Then things stalled. Only one-fifth of grant proposals get funded, leaving a lot of worthy projects on the cutting-room floor, Collins said. By 2015, Congress took notice, setting aside cash for “inflation-plus 5 percent” budgets. Collins sounded happy with this progress.

Certainly, “inflation plus 5 percent” is better than the 25 percent annual budget cuts that President Trump proposed. Congress, wisely, overruled him.

Francis Collins, NIH director

But we can do better than “inflation plus 5 percent.” We are in a biology renaissance. The needs for human health are enormous, and growing. The US government is by far the most powerful force in the world for this kind of catalytic investment. The NIH is capable of creating entirely new industries, like genomics.

With NIH as the foundation, along with a vibrant biotech industry, the US should be able to create hundreds of new drugs and diagnostics and vaccines over the next 100 years. We have a generation of talented young people that are yearning for purpose and meaning in work.

Let’s shake off the cynicism, pessimism and stale thinking that has infected our country in recent years.

Let’s triple the NIH budget. Let’s continue to lead the world in biomedical research.


  • Moderna on Track to Make 100 Million Doses of Vaccine by End of March, CEO Says. WSJ. Jan. 19. (Peter Loftus)
  • Model-informed COVID-19 vaccine prioritization strategies by age and serostatus. Science. Jan. 21. (Kate Bubar et al)
  • How Fast Can Vaccination Make a Difference? Look at Israel. The Economist. Jan. 23.
  • Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine. JAMA Insights. Jan. 21. (Tom Shimabukuro, Narayan Nair)
  • SARS-CoV-2 Vaccines: Much Accomplished, Much to Learn. Annals of Internal Medicine. Jan. 19. (Mark Connors, MD, Barney S. Graham, MD, H. Clifford Lane, MD, Anthony S. Fauci, MD)
  • Let’s Not Forget, We Have a Phase III COVID-19 Vaccine Readout Coming Soon from J&J.
Science of SARS-CoV-2
  • SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. BioRxiv. Jan. 19. (National Institute for Communicable Diseases of the National Health Laboratory Service, Johannesburg, South Africa team)
  • Severely ill COVID-19 patients display impaired exhaustion features in SARS-CoV-2-reactive CD8+ T cells. Science Immunology. Jan. 21. (Anthony Kusnadi et al)
  • Sex Differences in Immune Responses to COVID-19. Science. Jan. 22. (Takehiro Takahashi and Akiko Iwasaki)
  • Effect of Bamlanivimab as Monotherapy or in Combination With Etesevimab on Viral Load in Patients With Mild to Moderate COVID-19. JAMA. Jan. 21. (Robert L. Gottlieb et al)
  • The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome. PNAS. (Brett Finlay et al)
  • mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. BioRxiv. Jan. 15. (Zijun Wang et al)
  • Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study. The Lancet Immunology. Jan. 18. (Fang Li et al)
Public Health
  • Outgoing CDC Director Warns We’re Heading Into the ‘Worst of it.’ NPR. Jan. 15. (Mary Louise Kelly)
  • Europe’s Growing Mask-Ask: Ditch the Cloth Ones for Medical-Grade. Washington Post. Jan. 20. (Loveday Morris)
  • Another Way to Protect Against COVID-19, Beyond Masking and Social Distancing. Indoor Humidity. Scientific American. Jan. 19. (Akiko Iwasaki)
  • Patients Fend for Themselves To Access Touted Antibody Therapeutics. Kaiser Health News. Jan. 20. (JoNel Alecia)
  • Rogue Antibodies Could Be Driving Severe COVID-19. Nature. Jan. 19. (Roxanne Khamsi)
Policy & Politics
  • A ‘Tsunami of Randoms’: How Trump’s COVID Chaos Drowned the FDA in Junk Science. Vanity Fair. Jan. 19. (Katherine Eban)
  • Signs of Hope in Joe Biden’s Science Advisor. The Bulwark. Jan. 16. (David Shaywitz)
  • National Security Directive on United States Global Leadership to Strengthen the International COVID-19 Response and to Advance Global Health Security and Biological Preparedness. WhiteHouse.gov. Jan. 21. (The White House)
  • New CDC Director Pledges to Speed Vaccination, Restore Trust in Agency. WSJ. Jan. 19. (Betsy McKay)
  • COVID-19 Vaccine Leaders Waited Months to Approve Distribution Plans. WSJ. Jan. 15. (Betsy McKay, Rebecca Ballhaus and Stephanie Armour)
  • Mark Cuban Is Going to Help Pharma’s Image. Forbes. Jan. 19. (John LaMattina)
Our Shared Humanity
  • If You’re Offered a Vaccine, Take It. NYT. Jan. 21. (Melinda Wenner Moyer)
  • Ideaya, Spelman College Team Up to Provide Young African-American Women a Steppingstone to Biotech Careers. FierceBiotech. Jan. 19. (Amirah Al Idrus)

Cambridge, Mass.-based Beam Therapeutics, the developer of DNA base editing for drug development, raised $260 million in a stock offering at $93 a share. The developer of this early-stage technology is now valued at more than $5 billion. It has been buoyed in part by intriguing results by one of its partners, Verve Therapeutics, which uses base-editing for a single-shot gene therapy that has shown an ability to lower cholesterol in non-human primates.

Speaking of base-editing, Cambridge, Mass.-based Verve Therapeutics raised $94 million in a Series B venture financing led by Wellington Management and co-led by Casdin Capital. The company plans to enter the clinic in 2022 with its gene-editing therapy aimed at PCSK9 for patients with heterozygous familial hypercholesterolemia. It’s a genetic disease that causes extremely high levels of cholesterol that raises the risk of heart attack, stroke and death. (Listen to CEO Sek Kathiresan on an upcoming episode of The Long Run podcast).  

South San Francisco-based Vera Therapeutics, the developer of treatments for autoimmune and inflammatory diseases, raised $80 million in a Series C deal. Abingworth led. The company is developing atacicept, in-licensed from Merck KGaA, and is being run by a team of drug developers formerly with Gilead Sciences.

Plymouth Meeting, Penn.-based Inovio, the DNA vaccine developer, raised $150 million in a stock offering at $8.50 a share.

South San Francisco-based CytomX Therapeutics, the developer of antibody drugs for cancer, raised $100 million in a stock offering at $7 a share.

Cambridge, Mass.-based Editas Medicine, the genome editing therapeutics company, raised $231 million in a stock offering at $66 a share.

Waltham, Mass.-based Dyne Therapeutics raised $168 million in a stock offering at $28 a share. The company is developing treatments for muscle diseases.

Durham, NC-based Chimerix raised $100 million in a stock offering at $8.50 a share.

Bothell, Wash.-based Athira Pharma raised $90 million in a stock offering at $22.50 a share. It’s working on small molecule drugs for neurodegenerative diseases.

San Francisco-based Invitae said it’s raising $400 million in a stock offering to support its genetic testing.

Lexington, Mass.-based Aldeyra Therapeutics raised $75 million in a stock offering at $9.50 a share. It’s working on immune-mediated diseases.

Cambridge, Mass.-based Syros Pharmaceuticals raised $75.6 million in a stock offering at $14 a share. It’s working on medicines based on controlling gene expression.

Cambridge, Mass.-based TCR2 Therapeutics, the developer of T-cell therapies for cancer, raised $140 million in a stock offering at $30.50 a share.

Cambridge, Mass.-based Fulcrum Therapeutics raised $44 million in a stock offering at $11 a share. (TR coverage of Fulcrum, September 2018).

San Diego-based Plexium raised $35 million in a Series B financing to develop protein degrading drugs. Lux Capital and Pivotal BioVentures led, with participation from The Column Group.


South San Francisco-based Twist Bioscience, the DNA synthesis company, struck a pair technology partnerships. One, with Serotiny, allows it to make Chimeric Antigen Receptors for CAR-T cell therapies. Another deal with Applied StemCell provides access to Chinese Hamster Ovary cell technology for making antibody therapeutic candidates.

Emeryville, Calif.-based Gritstone Oncology, a personalized neoantigen therapeutics developer, secured a licensed from the La Jolla Institute for Immunology to incorporate additional epitopes into a new SARS-CoV-2 vaccine candidate, potentially making it harder for the virus to develop escape mutations. The National Institute for Allergy and Infectious Disease and Bill & Melinda Gates Foundation are supporting the work.

Servier and MiNA Therapeutics agreed to work together on small activating RNA therapies for neurological diseases.

Thermo Fisher Scientific agreed to acquire Mesa Biotech for $450 million in cash upfront. The small company does PCR point of case testing for infectious diseases.

Eli Lilly agreed to work with Netherlands-based Merus on T-cell engaging bispecific antibodies for cancer. Merus will get $40 million in upfront cash, plus a $20 million equity investment from Lilly.

Personnel File

Eric Lander, the leader of the Broad Institute, was appointed to be science advisor to President Joe Biden, and head of the Office of Science and Technology Policy. The OSTP was also elevated to a Cabinet-level position, increasing the clout of science in the new administration. Read Biden’s letter to Lander, filled with questions on important scientific matters for the years ahead. (Science coverage)

BIO CEO Michelle McMurry-Heath announced her new team, and leadership structure.

Cambridge, Mass.-based Foundation Medicine said CEO Cindy Perettie is moving over within the Roche group of companies to lead the Molecular Lab Solutions business at Roche Diagnostics in Pleasanton, Calif. Brian Alexander, the chief medical officer, will lead Foundation Medicine until a permanent CEO takes over at Foundation Medicine.

Bristol-Myers Squibb’s head of hematology, Nadim Ahmed, left the company after the company failed to win FDA approval of its liso-cel CD-19 directed cell therapy by Dec. 31. Reported by FiercePharma.

Cambridge, Mass.-based Cerevel Therapeutics, the developer of drugs for neurodegenerative diseases, named Deval Patrick and Deborah Baron to its board of directors.

South San Francisco-based Trishula Therapeutics named Anil Singhal as its new CEO. The company is developing a CD39-directed antibody for cancer.

San Diego-based Avidity Biosciences, the developer of antibody-oligonucleotide drugs, named Michael Flanigan as its chief technical officer.

Cambridge, Mass.-based Black Diamond Therapeutics named Kapil Dhingra to its board of directors.

Regulatory Action

Daiichi Sankyo and AstraZeneca won FDA approval for fam-trastuzumab deruxtecan-nxki (Enhertu), a treatment for locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.

Janssen Pharmaceuticals won FDA approval for daratumumab and hyaluronidase-fihj (Darzalex Faspro) for newly diagnosed light chain amyloidosis. It’s a subcutaneous form of Darzalex.

Merck won FDA approval for vericiguat (Verquvo) for heart failure patients.


Science is back in the saddle, and serious people are back in charge at the top of the US government. Thank God.


Gene Editing for Transplants and Cell Therapy: Luhan Yang on The Long Run

Today’s guest on The Long Run is Luhan Yang.

Luhan is the founder and CEO of Hangzhou, China-based Qihan Biotech.

Luhan Yang, founder and CEO, Qihan Biotech

Qihan is using genome editing technology to engineer pigs with organs that can be safely transplanted into humans. This is what scientists call xenotransplantation. The concept has been around a long time, but new CRISPR-based gene editing technologies make it more feasible to overcome some of the challenges, including the likelihood that the human immune system will reject an organ transplant from a pig. If this turns out to be feasible at scale – still a big IF – then Qihan could be position to tackle the shortage of available organs for transplant.

Besides xenotransplantation, Qihan is also seeking to leverage its precise gene editing capabilities to engineer off-the-shelf, allogeneic cell therapies that won’t be rejected by the immune system.

Luhan is a native of China, and one of the leaders in CRISPR gene editing. She made her name in George Church’s lab at Harvard, and was the first author on a landmark paper in Science in 2013 that was the first demonstration that CRISPR could make precise gene edits in mammalian cells. She went on to co-found Cambridge, Mass.-based eGenesis to advance the xenotransplantation application of CRISPR, before leaving the US to take the helm of Qihan in China.

Luhan is a bright young scientific entrepreneur, in the hunt for the first big medical applications of a groundbreaking technology. I think you’ll enjoy this conversation.

Now, please join me and Luhan Yang on The Long Run.


Two Doses or One? Let’s Stick To the Data

Chris Beyrer, MD, MPH, Desmond Tutu Professor in Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health

With COVID-19 surging and a chaotic political situation, we still have reasons to consider ourselves fortunate.

We have two safe and effective COVID-19 vaccines authorized for emergency use by the U.S. Food and Drug Administration. While the rollout has been frustratingly slow thus far, these vaccines and others under study hold our best promise of pandemic control.

Both products, the Pfizer-BioNTech and the Moderna vaccines, are based on novel mRNA technology, and both were shown to be highly effective in large clinical trials in preventing COVID-19 illness and severe COVID-19 disease.

Larry Corey, MD, leader of the COVID-19 Prevention Network (CoVPN) Operations Center; Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division, Fred Hutch

Both were studied as two-dose regimens. The Pfizer vaccine is given as two doses 21 days apart, and the Moderna vaccine is given as two doses 28 days apart.

The two products work remarkably similarly as two-dose vaccines. 

With both vaccines, the goal was to be well above the antibody levels of persons who recovered from the natural SARS-CoV-2 infection. Essentially, we were aiming to show that vaccines could trigger the production of even more antibodies than the body would normally produce from a natural infection.

That is exactly what we saw with these vaccines.

The Phase I trials showed it took two doses of mRNA to get above these natural levels. This is the basis for the two-dose regimens that were eventually tested, and shown to be so effective at preventing illness. 

Both scientific papers on the Pfizer/BioNTech and Moderna vaccines show the vaccines appear to start working 10-12 days after the first dose. These trends, which show protection for people on vaccine compared with people who got a placebo, are extended out for the next four months.

Over time, protection increases. The data after 21 days for the Pfizer vaccine or after 28 days for the Moderna vaccine, however, show the results of the second dose, since everyone in these trials received two doses.

Since no large trials have been run with a single dose, we simply don’t know how effective a single dose might be.

There’s a reason why the first big trials looked at two-doses, not just one. Vaccine regimens are selected based on empirical studies of immune responses, first in animals, and then eventually, if the products pass safety and immune response tests, in human volunteers.

Both the dose (how much of a vaccine is given) and the regimen (one, two, or three doses, and how far apart) are carefully selected based on these kinds of studies. Then, we go into the field with our best estimate of dose and regimen, and study how the vaccines work in real people with real exposures to the diseases we are trying to prevent.

In the case of the mRNA COVID-19 vaccines, we studied two-dose regimens, spaced by 3 or 4 weeks. That is what we know from the data from the vaccine efficacy trials.

That said, we are learning more about these products every day. Safety data continue to be gathered. Each day, we understand more about the ‘real world’ logistical challenges of using these products.

The pressure to get more people immunized is driving some decision-makers to move toward single-dose use, or to stop withholding vaccines – as U.S. Department of Health and Human Services Secretary Alex Azar announced last week – which has an impact on the certainty of available second doses for all who have had their first doses.

President-Elect Joe Biden has also stated he would press for release of all available doses and no longer hold back vaccine doses to make certain that everyone who got a first dose will be able to get the second dose on schedule. Neither is suggesting that one dose is enough – but both approaches are gambling that product manufacturing will keep up with demand, and that by extension it would be acceptable to have some persons vaccinated with second doses after longer windows than the current FDA-approved 21 or 28 days.

To be clear, the findings from the clinical trials in tens of thousands of volunteers is that these vaccines work as two-dose regimens with tight time intervals between doses.

Everything else is speculation.

Until we have the empirical evidence to suggest it would not reduce safety or efficacy to make a change in the dosing and regimen, two spaced doses are what has shown such high efficacy.

While there is urgency to accelerate the COVID-19 vaccine rollout, and to immunize more Americans who want and need these vaccines, there are real risks to the effectiveness in changing anything about their current recommended and authorized use.

A corollary of the two-dose response to the mRNA vaccines that is also increasingly being asked is how closely to 21 or 28 days does one need to be to give the second dose? The answer is another unknown. But in general, waiting for a boost is often associated with higher responses.

So getting a boost at 2 months, while unproven, would compare well with other vaccine platforms and will likely be able to spur the kind of antibody production we know is sufficient to protect against illness. The key issue with delaying the second vaccination is really how good, and how long, a first vaccination alone will work. That answer is unknown. Getting the second dose, from a policy point of view, is imperative.

With the AstraZeneca-Oxford vaccine candidate, the trials in the US, UK and elsewhere have also studied two-dose regimens. This two-dose regimen was what the UK approved for Emergency Use Authorization in December. But again, some decision-makers in the UK are pressing to deliver this product as a single-dose vaccine.

The argument from policymakers is that a single-dose represents a reasonable trade-off. If you give a single dose to a larger percentage of the population, it might be better at blunting the spread of the pandemic than giving a two-dose regimen to a smaller group of people.

But this too is a problematic framing of the issues.

We don’t know that one dose is effective, or for how long. Having a large number of people partially protected, particularly during periods of high COVID-19 transmission, could end up benefiting variants of the viruses that can bypass the weak or partial protection from incomplete immunizations.

The combination of partial protection, and loosening of social distancing precautions, could end up undermining the effort to control the pandemic. A decision of this gravity has to be made based on empirical data from human vaccine trials, not on modeling or other speculative approaches, and certainly not on political considerations or expediency. 

The current COVID-19 vaccines that we have developed so quickly are precious resources. We must use them wisely and protect their efficacy. This calls for fidelity to the science, ongoing and rigorous research, and the great patience that COVID-19 has demanded of us all.

We need to ramp up immunizations as quickly as is humanly possible, and we need to get many more vaccines into people’s arms. But for a two-dose vaccine regimen, that means getting two doses, spaced apart as our data suggest, to ensure that people are truly protected.

Chris Beyrer, MD, MPH is the Desmond Tutu Professor in Public Health and Human Rights at the Johns Hopkins Bloomberg School of Public Health. A professor of Epidemiology, Nursing, and Medicine, he now serves as Senior Scientific Liaison to the COVID-19 Vaccine Prevention Network, and as co-editor of this blog series.

Dr. Larry Corey is the leader of the COVID-19 Prevention Network (CoVPN) Operations Center, which was formed by the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health to respond to the global pandemic and the Chair of the ACTIV COVID-19 Vaccine Clinical Trials Working Group. He is a Professor of Medicine and Virology at University of Washington and a Professor in the Vaccine and Infectious Disease Division and past President and Director of Fred Hutchinson Cancer Research Center.


Our Communities, and Biotech, Need Local Journalism

Luke Timmerman, founder & editor, Timmerman Report

National traumas force us out of our comfort zones. They can force us to search, to ask new questions, to think deeper about our world.

This week, my first real journalism job came to mind.

One day, when I expressed surprise to my editor in Madison, Wisconsin that the tiny Grand Forks Herald in North Dakota had won the Pulitzer Prize for Public Service for its coverage of a 100-year flood, he said:

“One of the great things about journalism is that you can look at newspapers in all 50 states, and there are editors there who know their communities, know all the elected officials, have institutional memory,” he told me. “Every one of these places has the potential, under the right circumstances, to win a Pulitzer.”

“Then I guess we just need a natural disaster to hit Madison,” I joked.

Twenty years later, I see this conversation in a different light. My editor was telling me something important. Maybe more important than he and I realized at the time.

The newspaper industry was the primary fact-gathering engine of American journalism and the town hall for political discourse. Newspapers were the thing, for more than 200 years, that set the agenda for conversations across the country. These community organs, in the second half of the 20th century, were especially profitable and stable. Radio, TV, and everyone else followed the lead.

Newspapers often had local owners and publishers with backbones, editors who had seen and heard it all, and a small group of tireless young reporters working for starvation wages (watch “Spotlight” with Michael Keaton and Mark Ruffalo to get a feel).

Newspapers were a carefully curated bundle of news, information you could use, sports, entertainment. The content was meant to appeal at least a little to everyone in the community – there’d be something from last night’s city council meeting, high school sports recaps, and human-interest features about the local Girl Scout troop fundraiser. There was the crime blotter, the weather, and what our US Senator might have said about dairy policy that week.

Occasionally, we would dig up a scandal about a crooked local politician. The ensuing outrage would force change, like a resignation.

Maybe even more important than what we did publish was what we chose NOT to publish. When a neo-Nazi skinhead or some other extremist called to complain, or wrote a racist letter to the editor, we tossed that in the trash. Before we did, we might turn to a colleague and say “can you believe this guy?”

Seven days a week, with metronomic consistency and community sensibility, the family newspaper arrived on the doorstep.

As a newspaper reporter, I got to learn about the community, and on better days, hopefully helped the community better understand itself. In the newsroom, we kept ourselves and our viewpoints out of our copy. It was our job to gather the facts, lay them out in the proper context, and let the readers decide. We weren’t in the entertainment business. We were trying to make the important stuff interesting to read for a busy reader who might give us 5-10 minutes out of their day.

Today, local newspapers are dead, or shells of their former selves. Most of the jobs are gone. The Internet enabled a great “unbundling.” For most surviving newspapers, ownership is distant, usually some nameless private equity firm fixated on cost-cutting. Communities now get hardly any real news about what’s happening close to home. If they do, it’s not always from people committed to traditional standards of fairness and accuracy.

There’s no more town square, no campfire to sit around and tell each other stories.

It would be a mistake, of course, to indulge in too much sepia-toned nostalgia about local newspapers. These newspapers sometimes would write in hackneyed cliches, show bad judgment, or blow things out of proportion on slow news days. They’d make errors. Sometimes the editorial board would endorse a certain politician, and readers would seethe. Old white men were in charge, and they were too often blind to racial and ethnic injustices.

Imperfect as these outlets were, they were bound by facts and ethics and professional codes of judgment. They were staffed by people who loved their communities.  

Now, instead of relying on local newspaper bundles, news has been both nationalized and fragmented into ever-narrower niches. There are bright spots on today’s Internet, but a serious information seeker has to do a lot of work to find the signal and avoid the noise.

There’s no mystery tens of millions of Americans believe false conspiracies such as QAnon, or that the Presidential election was stolen.

The Internet, over the past 20 years, has come to be dominated by outrage, cable TV infotainment distractions, and partisan rat poison that’s been algorithmically jackhammered into our minds. Opportunists know this, and have seized the advantage. In a pandemic, when millions of people are isolated and genuinely stressed, it adds up to a frightening level of mass radicalization.

As we come to terms with what we have wrought, I’d like to try to think big and bold about better ideas for how we communicate. Local communities, long considered an afterthought, deserve to be brought back in to the conversation.

Biotech, this includes you. Biotech is a thriving industry in the US for many reasons. Strong local communities are one reason. This industry has taken root in local clusters like Boston, San Francisco, San Diego, Seattle, Raleigh-Durham, Washington DC, New York / New Jersey.

Local newspapers are integral parts of those communities. In the early days of biotech – the Boston Globe, San Francisco Chronicle, Seattle Times, San Diego Union-Tribune among others – helped educate the public and tell the stories of this nascent industry. First-generation executives running companies like Genentech, Amgen, Biogen and Genzyme understood this. They read, and spoke with, their hometown papers in addition to the financial press. Their employees read these papers, and so did elected officials that biotech companies wanted to keep in touch with. (I remember ex-Amgen CEO Kevin Sharer calling my cell phone more than once to complain about my coverage in The Seattle Times).

We all live in local communities, and benefit from local investments. Subscribing to your local newspaper is one such small investment.

If a newspaper is too old-school for you, there is a new generation of online outlets – text, audio, and sometimes video. The important thing is to support outlets committed to traditional values of the journalism craft. There’s The Frisc and KQED in San Francisco, Crosscut and KUOW in Seattle, and the Texas Tribune, to name a few. ProPublica, the investigative journalism outlet, is expanding into regional communities. Each place does good work that could help stitch back together the bonds that hold our communities together. It won’t happen overnight, but it’s worth doing.

If we don’t get to work on repairing our democracy, our institutions, our social bonds, our communities, then we all have a lot to lose.

I’ll leave you with a quote from Thomas Jefferson on press freedom. It’s about more than just free speech, and more than just newspapers. The newspaper itself isn’t the important part — it’s the need for a shared set of facts, a shared reality, from which citizens could educate themselves to hold government accountable and make wise decisions in a representative democracy.

Jefferson said:

“The people are the only censors of their governors: and even their errors will tend to keep these to the true principles of their institution. To punish these errors too severely would be to suppress the only safeguard of the public liberty. The way to prevent these irregular interpositions of the people is to give them full information of their affairs thro’ the channel of the public papers, & to contrive that those papers should penetrate the whole mass of the people. The basis of our governments being the opinion of the people, the very first object should be to keep that right; and were it left to me to decide whether we should have a government without newspapers or newspapers without a government, I should not hesitate a moment to prefer the latter. But I should mean that every man should receive those papers & be capable of reading them.”

Responding to Insurrection

The Biotechnology Innovation Organization said it would pause all political giving, as many trade groups have done, in the wake of the insurrection against Congress incited by President Trump. BIO’s statement  noted that the industry is based in science, and that “it is very concerning that some elected leaders last week chose to ignore facts and embrace widely discredited conspiracies.” It’s a start. I want to see the industry issue a permanent ban against funding members of Congress that supported the violent mob insurrection.


The Rockefeller Foundation said it made a $30 million advance market commitment to support COVID-19 testing to help safely reopen communities. The deal enables Thermo Fisher Scientific to move buy necessary supplies, in $30 million chunks at time, with guaranteed demand.

South San Francisco-based DiCE Molecules raised $80 million in a Series C financing led by RA Capital. The company is developing small molecule drugs based on a DNA-encoded library. The lead program is a first-in-class attempt at an oral small-molecule aimed at IL-17, an inflammatory cytokine that’s been well-validated by injectable biologic drugs for psoriasis, psoriatic arthritis and other autoimmune diseases.

Baltimore-based Delfi Diagnostics raised $100 million in a Series A financing to advance a pan-cancer early detection test. OrbiMed led.

Boston-based Atalanta Therapeutics started up with $110 million to develop RNA interference therapies for neurodegenerative diseases. The company said it has partnerships with Biogen and Genentech. Alicia Secor is the CEO.

Cambridge, Mass.-based Vedanta Biosciences, the microbiome therapeutics company, secured a $25 million investment from Pfizer. The company plans to use the cash to advance a Phase II study of a treatment for inflammatory bowel disease.

Cambridge, Mass.-based Generation Bio raised $225 million in a stock offering at $24.50 a share. The company is working on non-viral delivery of gene therapy. (TR coverage, August 2020).

Boston-based Valo Health raised $190 million in a Series B financing led by Public Sector Pension Investment Board. It’s using machine learning for drug discovery.

New York-based Lexeo Therapeutics, a gene therapy developer, raised $85 million in a Series A financing co-led by Longitude Capital and Omega Funds.

San Francisco-based Earli raised $40 million in a Series A financing to advance its platform for early cancer detection. Khosla Ventures led.

Seattle-based Altpep raised $23 million in a Series A financing led by Matrix Capital Management. It’s working on treating amyloid disorders. David Goel of Matrix, Joel Marcus of Alexandria Real Estate Equities, and Chad Robins of Adaptive Biotechnologies are on the board of directors.

Waltham, Mass.-based Mana Therapeutics said it raised a $35 million Series A financing to develop off-the-shelf allogeneic cell therapies for cancer. Cobro Ventures and Lightchain Capital co-led.

Seattle-based Sana Biotechnology, the cell therapy company led by former Juno Therapeutics executive Steve Harr, filed an S-1 prospectus to raise up to $150 million in an IPO.

Monmouth Junction, NJ-based Elucida Oncology raised $44 million in a Series A-1 financing.

Red Bank, NJ-based Provention Bio raised $100 million in a stock offering at $16 a share to continue work on immune-mediated diseases.

Chatham, NJ-based Tonix Pharmaceuticals raised $40 million in a registered direct offering.


Tarrytown, NY-based Regeneron Pharmaceuticals said the US government agreed to purchase up to 1.25 million more doses of its therapeutic antibody cocktail for non-hospitalized COVID-19 patients. The deal is worth up to $2.625 billion.

Beijing and Cambridge, Mass.-based BeiGene formed a partnership with Novartis to further develop and commercialize a PD-1-directed antibody therapy for cancer. BeiGene is getting $650 million upfront.

Cambridge, Mass.-based Bluebird Bio said it will spin off its oncology business into a new company, while the original company will focus on severe genetic diseases. Nick Leschly will be CEO of the oncology newco, and executive chairman of Bluebird Bio.

Seattle-based Adaptive Biotechnologies, which does sequencing of immune system B and T cells for diagnostic and therapeutic applications, struck a deal with AstraZeneca that combines the company’s sequencing and mapping capabilities to map T-cell receptors (TCRs) to antigens, across AstraZeneca’s oncology portfolio. Adaptive didn’t disclose specific financials, but said it will receive quarterly payments plus sequencing and data mapping fees.

Cambridge, Mass.-based KSQ Therapeutics agreed to work with Takeda on novel immuno-oncology therapies. KSQ stands to collect up to $100 million in upfront and preclinical milestones. (See TR coverage of KSQ, October 2017).

Ann Arbor, Mich.-based Evoq Therapeutics formed a deal with Amgen to work on autoimmune therapies. The little company stands to collect up to $240 million in upfront and milestone payments.

Germany-based Boehringer Ingelheim struck a deal with Enara Bio, a UK-based company working on cancer antigen discovery. The upfront payment was undisclosed, but Enara said it stands to collect up to 876 million Euros in milestone payments.

Cambridge, Mass.-based Biogen, the developer of treatments for Alzheimer’s disease, agreed to team up with Apple to use the Apple Watch and iPhone to collect digital biomarker data on cognitive performance for a multi-year observational study starting in 2021.

Menlo Park, Calif.-based Grail, the developer of a methylation-based test for early detection of cancer, formed collaborations with Amgen, AstraZeneca, and Bristol-Myers Squibb. These deals are focused on detecting Minimal Residual Disease, in patients who have been treated for cancer, and might have lingering malignancies not easily seen with other measurements. Separately, Grail said it plans to introduce its Galleri early-detection test before the end of June.

The Broad Institute, Verily and Microsoft said they are working together to expand Terra, a platform the Broad and Verily have been working on for some time, and which they described as “secure, scalable, open-source platform for biomedical researchers to access data, run analysis tools and collaborate.” The new partnership brings Microsoft’s cloud, data and AI technologies to the table.

  • Biden Will Release Nearly All Vaccine Doses, in Break With Trump Administration that Had Been Holding Back 2nd CNN. Jan. 8. (Sara Murray)
  • J&J Single-Dose Vaccine Candidate Phase I/II Data Published in New England Journal of Medicine. Jan. 13. (NEJM article and J&J statement).
  • Moderna Says it Believes It Can Update its Vaccine Without a Big New Trial. Tech Review. Jan. 13. (Antonio Regalado)
  • Messenger RNA Vaccines Against SARS-CoV-2. Cell. Jan. 13. (Eric Topol)
  • Immune determinants of COVID-19 disease presentation and severity. Nature Medicine. Jan. 13. (Peter Broddin)
  • Neuroinvasion of SARS-CoV-2 in human and mouse brain. Journal of Experimental Medicine. Jan. 12. (Eric Song et al)
  • The CDC was damaged by marginalization and politicization. This is how Biden can fix it. NBC News. Jan. 14. (Four former CDC directors)
  • As CDC Director, I’ll Tell You the Truth. NYT. Jan. 11. (Rochelle Walensky)
The Viral Evolution Story
  • Pfizer / BioNTech Vaccine Appears Effective Against Mutation in New Variants. Jan. 8. (Reuters)
  • Still going to the grocery store? With new variants spreading, it’s probably time to stop. Jan. 14. Vox. (Julia Belluz)
  • We lost to SARS-CoV-2 in 2020. We Can Defeat B117 in 2021. STAT. Jan. 9. (Kevin Esvelt and Marc Lipsitch)
  • Why Epidemiologists Are So Worried About the New Variants. Vox. Jan. 8. (Brian Resnick)
  • Germany Plays Catch-Up in Bid to Monitor Coronavirus Mutations. Reuters. Jan. 14. (Ludwig Burger)
  • How Worried Should We Be About SARS-CoV-2 Mutations? Timmerman Report. Jan. 14. (Mara Aspinall)
  • Genomic characterization of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. Virological.org. Jan. 12. (Nuno Faria et al CADDE Genomic Network)
SARS-CoV-2 Features
  • After aborted attempt, sensitive WHO mission to study pandemic origins is on its way to China. Science. Jan. 13. (Kai Kupferschmidt)
  • COVID Reinfections Are Unusual, But Can Still Help Spread the Virus. Nature. Jan. 14. (Heidi Ledford)
Science Features
  • An Algorithm May Soon Help People Make Babies. Future Human. Jan. 13. (Emily Mullin)
  • COVID Measures Also Suppress Flu – For Now. Science. Jan. 15. (Kelly Servick)
Our Shared Humanity
Biotech Strategy
Personnel File

Janet Woodcock, the veteran FDA leader, is expected to be named acting FDA commissioner in the Biden Administration. Joshua Sharfstein is reportedly a leading contender for the top job, according to BioCentury.

Moncef Slaoui, the leader of Operation Warp Speed, is resigning. He will reportedly be available as a consultant to the Biden Administration for about four weeks.

Andy Slavitt, the former acting CMS director under President Obama, will join the Biden Administration as a COVID-19 advisor. He’s been the host of the excellent “In the Bubble” podcast this year.

A former Merck cancer researcher was arrested and charged in federal court with theft of trade secrets.

Cambridge, Mass.-based Beam Therapeutics, the DNA base editing company, named Kate Walsh to its board of directors.

Stamford, Conn.-based Sema4 hired William Oh as chief medical science officer. He was most recently Chief of the Division of Hematology and Medical Oncology at the Mount Sinai Health System and Deputy Director of The Tisch Cancer Institute.

Data That Mattered

BioMarin said it met all primary and secondary endpoints in a Phase III study of its gene therapy for hemophilia A, evaluated for one year. The FDA has held up that product candidate, asking for more follow-up data.

Cambridge, Mass.-based Verve Therapeutics, the developer of gene editing therapies for cardiovascular disease, released updated data from non-human primates which said its experimental therapy was able to reduce LDL-cholesterol levels for six months after a single infusion. The treatment targets the PCSK9 gene, in a lipid nanoparticle delivery package. (Learn more in a few weeks, as CEO Sek Kathiresan is an upcoming guest on The Long Run podcast).


How Worried Should We Be About Emerging Strains of SARS-CoV-2?

Mara Aspinall, managing director, BlueStone Venture Partners; professor of the practice, biomedical diagnostics, Arizona State University

All virus strains mutate continuously. That’s normal. There’s nothing inherently concerning about that word, “mutation.”

Unless, of course, the mutations give an evolving virus new properties that make it more transmissible or more pathogenic. That’s trouble.

The news has been worrisome in recent weeks with reports on the B.1.1.7 strain first detected in the UK, and other new strains of SARS-CoV-2, such as the E484K strain first identified in South Africa.

Before getting into the particulars of those new strains, let’s go over some background. Large numbers of silent mutations are accumulated over time with all viruses. These silent mutations, which don’t cause meaningful change in the clinical sense, are helpful to us because they create a viral fingerprint. This unique code can be used to track the spread of particular versions over time and by geography — the data that tells us how and where a particular virus emerged. 

When a mutation persists and grows as a cause of infection there are two possible reasons: pure chance — that mutation just happened to be in the right place at the right time (aka founder effect); or, more worryingly, because it is more virulent or fitter than its ancestors. The vast majority of mutations do not persist, but a very few do, and when that happens, we have to quickly figure out how concerned to be, and what to do to outmaneuver the fast-spreading virus.

All mutations that are incorporated into virus strains that spread out geographically and grow faster than their predecessors are a “smoking gun”. This is exactly what has happened in the United Kingdom over the past three months and may be happening again in South Africa. The most recent analysis of the UK strain (B.1.1.7; aka VOC-202012/01; aka 20B/501Y.V1) combines prior laboratory findings (Scott 2020) and animal data (Gu 2020) that the N501Y spike enhances the critical spike protein’s ability to bind its human receptor (ACE2).

This finding has serious real-world implications. We see it in the recent explosive growth of UK cases of this strain (rapidly approaching complete dominance). The conclusion is that the UK strain is 50% to 75% more infective than the earlier strains in circulation, boosting its reproduction number Rt from ~1 towards 2.

At the very least, that means that the clock has sped up, and our time window to react effectively is closing. We must dramatically speed up our response – more and more frequent testing; better mask/distance/ventilation/handwashing compliance; faster vaccine roll-out than achieved to date.

The UK and South Africa strains are not the first major variant strains we have faced, but they are the most serious – direct evidence we are living on borrowed time. There have been four major strains of concern since early 2020: the D614G mutation in February; the UK strain in September; the Danish Mink crisis in November; and in December – the South Africa strain (E484K). Each strain is comprised of a number of variants, what follows is a brief summary of the key mutations believed to underly our greatest threat:

February – variant D614G

Extensive in-vitro and mouse work (Plante 2020) confirmed that this strain was more highly transmissible than the original Wuhan strain, most likely because this specific mutation created a more “open” and therefore more infective spike protein. This mutation is now globally dominant as a result and is the common ancestor of more recent strain emergence, against which they are evaluated.

September – UK strain N501Y spike variant

The UK has a national and comprehensive sequencing initiative (the US has a decentralized approach). Ironically, this greater effort at genomic surveillance in the UK may amplify concern in the absence of good data elsewhere. Since its identification in the UK, many other countries, including the US, have found it locally.

This strain comprises 17+ protein-altering variants, six of which are in the Receptor Binding Domain (RBD) of the spike protein, one of which (N501Y) is known to increase virus binding affinity and infectivity. Highly specific monoclonal antibodies may show less therapeutic binding and may be less effective.

The vast majority of new cases in London and the south east UK are of this strain. Higher rates of infection in children are being reported. Population transmission fitness is about 47-75% greater. Spike-based PCR tests are reporting spike negative results, and this is being used as a biomarker of strain prevalence. It is unlikely this strain is dominating only by chance. 

November – Danish Mink Y453F variant (aka “Cluster 5”)

It is a little unfair to label this the Danish strain since it was also found in Dutch, Spanish, Swedish and US mink. Among the four spike mutations comprising this strain, Y453F was found (Scott 2020) to be second only to N501Y in ability to enhance spike binding. There is no evidence that this strain is either more severe or transmissible. No increase in human cases accompanied the emergence of this strain, so the current hypothesis is that its emergence is more likely a chance-driven event. However, it is most concerning since an animal-to-human pathway (i.e. via mink) is a potential avenue for further threatening mutations to arise.

December – South Africa strain E484K and K417N plus N501Y (aka 501.V2; aka B.1.351)

The least is known about this strain, which has only recently been identified. It consists of 21 mutations, nine of which are in the spike protein. It appears to share the UK strain’s greater transmissibility, but this has not been reliably quantified, and there is no evidence today of enhanced severity.  However, this is the strain which presents the most concern with respect to the current vaccines, given in-vitro studies have suggested some decreased efficacy of neutralizing antibodies in the presence of the E484K mutation (Weisblum 2020; Adreano 2020)

Although we have very limited reliable data on which to evaluate the impact of each of these individual strains, action cannot wait.

Specifically, there are five areas of concern.

Will these emerging variants:

  1. Make tests less accurate, threatening our ability to contain the pandemic?
  2. Make the COVID-19 pandemic worse by increasing cases and deaths?
  3. Make emerging treatments ineffective?
  4. Make vaccines ineffective?
  5. Make the vaccination threshold for achieving herd immunity higher?

The best current answers are:

  1. Make tests less accurate? No for antigen tests because all antigen tests cleared via the FDA’s Emergency Use Authorization target the abundant N (nucleocapsid) protein, not the spike protein. PCR and serology tests are more vulnerable since they rely on short stretches of RNA for primers and probes, or limited antigen protein segments, respectively, either one of which may by rendered less effective in the face of novel mutations. However, only a very few target spike RNA at all, and those that do sample additional regions and genes in combination (e.g. Thermo-Fisher Taqpath PCR assay). Few manufacturers publish which antigens are utilized in serology tests –  so more investigation is needed to determine the efficacy of serology assays. Overall, PCR and antigen based active-disease testing is likely minimally affected.
  2. Increase cases and deaths? Almost certainly. None of the known variants have been shown to increase case fatality rates (CFR, percent of infected who die). However, if the greater transmissibility of UK variant associated mutations is confirmed, then the resulting rise in new cases will threaten to overwhelm hospital capacity at an even faster rate, which will lead to more total deaths.
  3. Render treatments Ineffective? Convalescent serum — less likely; monoclonal antibodies — some yes. Convalescent serum has a broad spectrum of antibodies, and although its utility may be limited, it is less likely to be affected than cloned single epitope monoclonals if directed at epitopes directly modified by the new variants. It’s worth noting here that the Regeneron antibody cocktail was specifically designed to hit two epitopes, making it more difficult for the virus to evolve an escape mechanism.
  4. Will vaccines remain effective? Yes, current vaccines are likely still effective. Both currently authorized vaccines in the US invoke immunity against the entire spike protein, i.e. polyclonal responses, so a few changes among all 1,273 amino acids in the protein are unlikely to reduce vaccine effectiveness. Recent unpublished work (Xie 2021) confirms that the Pfizer vaccine (BNT162b2) raises comparable levels of antibodies to the N501Y mutated (Y) virus as to the prior (N) virus. Testing of the Moderna vaccine is underway. All our current data comes from laboratory work on single mutations. It is possible that a novel group of mutations (e.g. the South Africa strain) may have the potential to enable immune escape by the strain. The good news is that even if current vaccines do need to be modified, a new generation of mRNA vaccines can be quickly created (months not years) to adapt.
  5. Will increased vaccination be needed? Likely yes. Achieving herd immunity – the ultimate objective of pandemic control – is a function of both viral contagiousness and vaccine efficacy.[1] If more transmissible strains become widespread, the proportion of global population vaccination required for herd immunity increases, and with it the number of vaccines that must be distributed and administered. The SARS CoV2 vaccine roll-out has to be even quicker and broader than has been previously assumed, and we are falling behind even those more modest expectations. Time is not on our side.

Mara Aspinall is co-founder and managing director of BlueStone Venture Partners and a professor of the practice, biomedical diagnostics, at Arizona State University.


[1] Herd immunity for highly contagious measles requires 95% of children to receive the 97% effective vaccine; but for the less contagious influenza, herd immunity is achieved with only 50% being vaccinated with at most a 60% effective vaccine (e.g. the 2010/11 season) or 80% for more typical 30-40% effective annual vaccines.


The Politics of Speaking Up

Paul Hastings, CEO, Nkarta Therapeutics; vice chair, BIO

We thought we had lived through the most difficult year of our lives in 2020, from the deadly COVID-19 pandemic to the delusional and autocratic ambitions of a sitting President of the United States.

Then we were shocked once more, by deadly mob violence and ominous threats of more to come at the U.S. Capitol in the days before the inauguration of a new President.

The social fabric of our country is in bad shape. Our sense of shared values as a country seems to have gone missing. Many of us in the biotech community were stunned in 2020 to learn that we had to FORCE many people to become educated about the novel coronavirus, including basic mitigation strategies such as social distancing and mask wearing.

These are common-sensical, even self-evident, concepts to those of us who embrace material reality and scientific facts. Even today, with 381,000 Americans dead from COVID-19, we still see certain lawmakers who refuse to wear masks in Congress. Last week, in a shocking display of arrogance, ignorance or callous disregard for their fellow citizens, some of them insisted on remaining maskless while in secure holding rooms at the Capitol. They were there as a safety precaution, after hundreds of unmasked thugs illegally entered the Capitol in a grotesque and seditious act of political violence.

Then, shortly afterwards, still without regard for the gravity of this attack on our democracy, many of these same elected officials immediately resumed their attempt to overturn the outcome of a free election. Their speeches on the House floor were filled with the very same repeated lies that brought the angry mob into the heart of the Capitol.

The treachery and immorality of these actions will haunt our nation for many years to come.  

I’ve noticed that few CEOs, industry leaders, or trade associations are speaking up loudly about this cataclysm. WHY? The facts are clear, our moral compass is intact. Our democracy is at stake. It is time for leaders to LEAD. Our employees are looking to us to help lead the way back to normalcy, so we can focus on our crucial mission of delivering vaccines and therapeutics to the patients who need them. The US provides us with a vibrant, free operating environment to do all the things we do. When our country is in peril, our industry is in peril.

This week, I was surprised to hear from a group of folks concerned about making a public statement about the insurrection. Comments about the atrocities at the capital could anger the California Republican congressional delegation, and we can’t “afford” that.

Really? We, as an industry, should cower on the sidelines and avoid saying anything of substance about a violent mob attack on our democracy, because doing so might anger an elected official? I know professional politicians on both sides of the aisle, and I do not fear angering them. Neither should any self-respecting life science leader or citizen.

If one thinks attempting to overturn a free and fair election with violent insurrection is wrong, and anti-American, one should say so. I do think it is wrong, and anti-American.

If a person, president or otherwise, incites the kind of violence we have seen, that act demands accountability. Actions have consequences. Lawmakers should apply those consequences, period. Our democracy is at stake. Without a democracy, nothing else matters.

Paul Hastings is President and CEO of Nkarta Therapeutics and Vice Chairman of the Biotechnology Innovation Organization.


A Moment of Truth

Jeremy Levin, CEO, Ovid Therapeutics; chairman, BIO

Democracy is fragile.

Its stability depends on the acceptance of its principles by the population as a whole, the resilience of the institutions that support it, an independent judiciary, a free press, free and open elections and, in the United States, the foundation laid by the Constitution.   

The struggle to balance those critical pillars has been waged across the globe in modern times. Despite the terrible lessons of the last century, we see the basic principles supporting democracy under attack, and the ascendency of authoritarian and dictatorial governments around the world. 

Few Americans have believed, until perhaps Jan. 6, that the fabric of our democracy could be stretched in a similar fashion and that we might follow a similar path.

And yet here in the greatest democracy that the world has ever seen, we saw a violent attempt to interfere with the peaceful transfer of power determined by the voters in a national election.

The stress on our democracy has been building for some time. A president who knew he would lose the election, proceeded to undermine its legitimacy before a single vote was cast. Then when he lost, he lied about the results and proceeded to try and undermine the electoral process.

This sustained attack on democracy culminated with a physical assault on the core of our government, our Congress. This assault was deliberate and deadly. It was planned and executed with the intent not only to overturn a legitimate electoral process and deprive the nation of its right to choose its President but also to destroy the foundation of that process and our democratic constitution.

Americans are used to assuming that checks and balances will allow for a robust political dialogue while ensuring a smooth, peaceful political transition in keeping with the Constitution. On this occasion we are witnessing — in real-time — an attempt by a sitting president to formulate an insurrection and impose on the nation a form of dictatorship seen elsewhere in the world.

These attempts will fail. But they will fail not only because of the bravery of those overseeing the elections in battleground states, or the barriers put up in courts around the nation where facts matter, but because the attempt was so blatant and obvious that suddenly the real intent of a President who had been supported by so many for so long, was revealed in stark relief. 

The want-to-be emperor has no clothes. Stripped naked, the lies, the malign intent and complete lack of compassion were laid bare. Instead of a leader who had been given the mandate to lead the nation in 2016, and who could have built so much, we saw what has been seen in so many other lessor nations. We saw the raging of someone who never cared for the nation, surrounded by sycophants and glory seekers, attempting to overthrow democracy.

Elected leaders, who should know better, did not take action to stop the insurrection. Indeed, while the mob attack was ongoing, a few leaders in the Senate and many members of the House continued to fan the flames – spreading the myths and lies of an illegitimate election. 

It was a brutal and disgraceful display of cynicism, craven political cronyism and unthinking fealty.

Instead it was left to brave, outnumbered and ill-equipped individual police officers to protect the Capital. It is they who mitigated what could be one of the greatest terror attacks in our history.

Have egged the mob on to attack Congress and then throughout this terrible episode as mayhem unfolded, as with the horror and devastation by COVID-19, the president remained silent. When, hours later, he released a video telling the mob to “go home,” he continued to repeat his lies about a stolen election and called members of the crowd “very special people.”

Not a word of care was spoken by the President about the Vice President and his family, who may well have ended up on a gallows erected in the Mall, exactly as the crowd who stormed Congress made clear was its intent. 

This was a display worthy of the worst excesses of nations ruled by despots.

But despite this, there is hope. Our nation has reacted in horror. Business leaders have reacted by cutting off donations to those who persist in politically supporting the president’s lies and insisting that the election was “stolen”. Importantly, Twitter, Facebook, Google, Amazon and others have finally stepped forward. They are preventing some, but not all, of the lies and propaganda that are being spread as insidious as a cancer across the psyche of the American population.

It’s a start.

What we witnessed leading up to and including this last week was not a dispute between Republicans or Democrats. It was a clash between democracy and demagoguery. Dictatorship and freedom.

We need legal consequences for those who incited, and participated in, this dangerous attack on America.

It will be painful, and some will make political arguments against accountability. But it’s a necessary first step toward protecting and strengthening our cavalierly maligned democracy.

Once the insurrection has been put down, we will need to heal the fractured relationship between the parties and those who know that together, as a country, we are stronger. If we do not do so, many abroad will take advantage to diminish and / or harm our nation. Some have started to take advantage of the perceived turmoil — including Russia, North Korea, Iran and China.

In the face of this, our allies in Europe, Asia and elsewhere need to feel confident of our support. We will have much work to do to stabilize the erosion of global confidence in America and rebuild its credibility, economic strength and political standing around the world.

More importantly, we have rebuilding to do here at home. We need to ensure that the domestic terrorists who, encouraged and egged on by the delusions of a president who refuses to except facts and persists in lying, are not able to continue to incite violence, and that they are no longer able to undermine institutions of democracy which we all count on. 

The strongest way to do this is for our leaders to acknowledge the pain and anguish the nation is experiencing economically, politically and medically. Each is a huge challenge. All pillars need to be strengthened at all levels and across all social and racial groups. We know we are stronger together.

The healing that needs to take place now will need to happen against the backdrop of the miasma and horror of the COVID-19 pandemic. But there is hope at the end of this tunnel. The biopharmaceutical industry united to tackle the onslaught of the virus, delivering in record time vaccines which will stop the pandemic in its tracks. That example of pivoting, uniting, and focusing on solving an existential threat is one that our political leadership can, and hopefully will, emulate.

I believe we should hope and expect of our leaders come together to forge a stronger, more robust democracy out of the chaos and mayhem.

But let us make no mistake, if our leaders cannot find common ground, then what we saw on Jan. 6 is not an instance of horror and despicable behavior but the beginning of what has been seen in so many other nations — the dissolution of a dream. To prevent that, there can be no compromising at all with the behaviors that led up to the insurrection. There must be an absolute guarantee that those who involved themselves in this despicable act of insurrection are prosecuted fully.

At the end of the day, I believe the American dream is stronger than anything we have witnessed over the last four years and in the immediate last six days. Ours is a nation built to stand tall and strong: because of the fundamental good nature and values of the vast majority of our citizens we have the capacity to be even stronger. And we will be.

Jeremy M. Levin is the chairman and CEO of Ovid Therapeutics, and chairman of the Biotechnology Innovation Organization.


Biotech Is Radiant In a Dark Moment

Luke Timmerman, founder & editor, Timmerman Report

The virus, at the start of a New Year, has arrived on all seven continents. Even Antarctica.

An estimated 2 million people have died worldwide from the SARS-CoV-2 virus, and that’s surely an undercount. About 4,000 people are dying per day in the US. About 255,000 new people are being diagnosed with this dangerous and mysterious invader every day in the US.

We see a few new variants circulating. We are seeking to understand what that means.

The pandemic is causing Biblical levels of suffering. Hospital staff are exhausted, reduced in many instances to operating in battleground triage mode.

Millions of people are jobless. Many are homeless or living on the brink of eviction. Millions are starving.

A violent mob, incited by a twisted individual still in place as President of the United States, attacked the heart of the nation’s capital. The mob attempted to overturn an election. They took selfies, gleefully thumbing their noses at democracy. Police were either unable or unwilling to stop the mayhem.

It’s the logical result that follows from years of mass radicalization by cynical political leaders and entertainment / media personalities.

These are sad, cold truths. I get angry and frustrated sometimes.

But we won’t get anywhere by wallowing in the horror, averting our gaze, hoping it will all just go away, or lashing out at the “Others.” We must get swift justice for those responsible for the domestic insurrection. Then we have to do a lot of long, hard work in rebuilding our communities.

Ugly as this week has been, there is beauty out there. We can allow ourselves to open our eyes and see it.

Biopharma is one of the bright spots. This industry, in partnership with government and academic researchers, has produced two remarkably effective vaccines. We knew they would be supply-constrained from the start, and we’d have to be patient. Yet the rollout is more painful than it had to be. Too many of the vaccines we have – 95 percent effective vaccines, remember! — are sitting around on freezer shelves instead of getting injected into arms.

Only 5.9 million first doses have been administered out of the 21.9 million doses delivered to states, according to the CDC on Jan. 7. Systemic failure on multiple levels explains this situation. There’s vaccine hesitancy, aided by firehoses of misinformation. There’s no serious federal plan, never has been. The state agencies are chronically underfunded and understaffed.

Local stay-at-home orders and social distancing requirements remain intact. People are struggling without the social contact we all need. No surprise, we are seeing waves of depression, apathy, suicide, homicide.

Much of what’s described above is beyond our control. But look around in biopharma, especially at the list of financings and deals this week. The capacity for good — the industrial horsepower that can be channeled into progress that will end this pandemic — it’s palpable. This community has tremendous capacity for good work. The beating heart is on display for anyone who cares to look.

We should be thankful to be alive in this biotech renaissance. What we are witnessing, and participating in, isn’t an accident or a lucky break. The foundation has been laid for decades with government and industrial investments in enabling technologies, better understanding of basic biology, vibrant capital markets with an appetite for high-risk / high-reward propositions, a growing pool of experienced executives, savvy and independent regulators, and a talented, committed, increasingly diverse workforce.

People of ability and good will, over decades, cultivated the biopharma community we live in today.

You can’t take the pulse this January at San Francisco’s Union Square, but everything I see and hear says the industry is adapting and improving in the pandemic. Some old bad habits and craft attitudes are being shed. The industry is moving faster. It’s rediscovered the power of single-minded, intense focus — rather than trying to sometimes be everything to everyone. It’s getting more productive. It’s getting more inclusive. More empathetic. More understanding of industry’s role in the wider world.

We have a chance, if we finally decide to deliver universal healthcare to US citizens, to enter a truly great age of progress in improving the health of individuals and society.

It would be easy to snicker at the above paragraph, and say this has been tried before. But now that the world has seen a once-in-a-century mobilization of the scientific enterprise pay off in spades, why not think universal healthcare is possible? Why not imagine a tripling of the NIH budget over the next 10 years? Why not build an entirely new NIH campus west of the Mississippi, in a place with some strong biomedical assets already in place, like Missouri, Nebraska, or Utah? Why not dream of a world in which the most talented young people are drawn like moths to careers in science, instead of investment banking or management consulting?

What might be possible if that were to happen?

I’ve been covering biotech for 20 years. I’m confident that what I’ve been fortunate to witness thus far will pale in comparison to what I’ll get to see in the next 20 years.

We are a dynamic, flexible country. We have been gifted with a system of democratic self-governance, quite intentionally the opposite of a monarchy or authoritarian regime. It’s our job to maintain it as active participating citizens. If we accept that challenge, then we can be confident we will continue to live in a system that is sometimes volatile, but rebalances and recalibrates every so often. Our representative democracy has its flaws, but it has proven durable in its ability to unleash human flourishing while generally resisting the various idea viruses circulated by factions and mobs.

We still have it within us to strive for greatness.

I grew up poor on a small family farm in Grant County, Wisconsin. I got to attend the flagship state university about 90 minutes away, in Madison. I now own and operate a successful small business, where I get to interview the smartest scientific entrepreneurs in the world on a daily basis. Many of the people I interact with are brilliant immigrants who have overcome all sorts of obstacles to come here and do amazing things.

This kind of thing can, and does, happen so often that we sometimes take it for granted. We shouldn’t. 

We will find our North Star again as a country as we correct the catastrophic errors of the past and present.

I look forward to hearing your ideas on what you’re doing, however small it may seem, to make a positive contribution. We all have a part to play.

Let’s think big. I’m listening. luke@timmermanreport.com.


Venrock raised its ninth fund, worth $450 million, to invest in early stage tech and healthcare companies.

Boston-based Scorpion Therapeutics raised $162 million in a Series B financing co-led by Boxer Capital of Tavistock Group, EcoR1 Capital, Omega Funds and Vida Ventures. It’s a precision oncology company led by Gary Glick, the star serial entrepreneur. (Read my interview with Glick when he stepped down from the CEO role at his last startup, December 2019.)

Cambridge, Mass.-based LifeMine Therapeutics raised $50 million in a Series B led by Rick Klausner and Milky Way Investments. The company is working on a fungi-based drug discovery platform. (See TR coverage of LifeMine, including my interview with CEO and CSO Greg Verdine.)

Cambridge, Mass.-based Werewolf Therapeutics raised $72 million in a Series B financing. Its lead product candidates are engineered IL-2 and IL-12 protein therapies for cancer. RA Capital led.

South San Francisco-based Senti Bioscience raised a $105 million Series B financing to develop programmable cell therapies for cancer. Leaps by Bayer led. (See TR coverage of Senti, including interview with co-founder and CEO Tim Lu.)

Cambridge, Mass.-based Myeloid Therapeutics said it raised “over $50 million” in startup funding to develop engineered myeloid cells for cancer. NewPath Partners led. (See TR coverage of Myeloid, including interview with co-founder Siddhartha Mukherjee).

Newton, Mass.-based Abcuro raised $42 million in a Series A-1 deal co-led by co-led by Mass General Brigham Ventures and Sanofi Ventures. The company is engineering cytotoxic T and NK cells.

Boston-based Ikena Oncology raised $120 million in a Series B financing led by Omega Funds. The company is working on biomarker-directed cancer drugs. Otello Stampacchia, a TR contributing writer par excellence, is joining the board.

Cambridge, Mass.-based Immuneering raised a $62 million Series B financing, led by Cormorant Asset Management. The company is focusing on drugs that target the RAS/MAPK pathway.

San Diego-based Iconovir raised $77 million in a Series A financing co-led by Nextech and Vida Ventures. It’s developing oncolytic virus therapies for cancer. Mark McCamish was named the CEO.

Philadelphia-based Aro Biotherapeutics, the developer of what it calls “precise receptor-mediated delivery of RNA drugs to address intracellular gene targets,” said it raised $88 million in a Series A financing. Northpond Ventures and Cowen Healthcare Investments co-led the round.

San Francisco-based Color, a genomic testing company, raised $167 million in a Series D financing led by General Catalyst and T. Rowe Price Associates.


Durham, NC-based Ribometrix received a $25 million upfront from Genentech as part of a deal to work on small molecules directed against RNA targets.

Cambridge, Mass.-based Dewpoint Therapeutics, a company working on a biomolecular condensate-based platform for drug discovery, formed a deal with Pfizer to work on drugs for myotonic dystrophy type 1, DM1. Dewpoint is getting an undisclosed upfront payment and milestones worth as much as $239 million. (TR startup profile of Dewpoint, Apr. 2019).

Netherlands-based argenx, an immunology-based drug developer, formed a deal with Shanghai-based Zai Lab to develop and commercialize efgartigimod in China, Taiwan, Hong Kong and Macau. Argenx is getting $75 million upfront in Zai Lab equity. The drug is designed to tamp down excessive production of disease-causing IgG antibodies.

Switzerland and California-based Myovant Sciences forged a deal with Pfizer to work on relugolix – a once-daily, oral gonadotropin-releasing hormone (GnRH) receptor antagonist – for cancer and women’s health indications in the U.S. and Canada. Myovant is collecting $650 million upfront.

Waltham, Mass.-based Morphic Therapeutic, the company developing small molecules against integrin targets, said its partnership with Janssen Pharmaceuticals has expanded to include a third integrin target. The deal was struck in Feb. 2019. (See TR coverage of Morphic, Oct. 2018, and listen to scientific founder Tim Springer on The Long Run podcast, Nov. 2019).

Tokyo-based Sosei Heptares said it regained worldwide rights to its muscarinic agonist programs, after getting them handed back from its partner, Allergan (now part of AbbVie.) The programs are being studied against Alzheimer’s disease and schizophrenia. (Listen to Karuna Therapeutics CEO Steve Paul on The Long Run podcast for more on muscarinic receptor modulation for schizophrenia.)

Vaccine Rollout. Not. Good.



  • Four Ways to Fix the Vaccine Rollout. Make it a Lottery. NYT. Jan. 7 (Bob Wachter and Ashish Jha)
  • Britain Takes a Gamble with COVID-19 Vaccines, Raising the Stakes for the Rest of Us. STAT. Jan. 4. (Helen Branswell)
  • The Politics of Covid Just Got Even More Hellish. New strains of the virus mean the world is about to face some of the most difficult trade-offs yet. Bloomberg Opinion. Jan. 4. (Tyler Cowen)
  • Johnson & Johnson corporate blog update on COVID-19 vaccine work. Jan. 5. (Matthai Mammen)
  • Novavax initiates COVID-19 vaccine Phase III trial with 30,000 volunteers. Dec. 28. (Company statement)
  • How the Novavax Vaccine Works. NYT. Dec. 31. (Jonathan Corum and Carl Zimmer)
  • The Risks of the COVID-19 Vaccine, In Context. NYT. Dec. 30. (Aaron Carroll)
  • We Came All This Way to Have Vaccines Go Bad in the Freezer? NYT. Dec. 31. (Editorial Board)



  • Thermo Fisher Scientific Joins Amazon and CVS Health in Coalition to Promote Expanded Workplace Testing. Thermo Fisher corporate blog. Dec. 24. (Mark Stevenson)

Science – COVID-19

  • Viral Mutations May Cause Another Very, Very Bad COVID-19 Wave, Scientists Warn. Science. Jan. 5. (Kai Kupferschmidt)
  • Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies. BioRxiv. Jan. 4. (Jesse Bloom, Helen Chu et al)
  • Estimated transmissibility and severityof novel SARS-CoV-2 Variant of Concern 202012/01 in England. Preprint manuscript. Dec. 23. (Nicholas Davies et al at Centre for Mathematical Modelling of Infectious DiseasesLondon School of Hygiene and Tropical Medicine).
  • Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion ΔH69/V70. BioRxiv. Dec. 21. (SA Kemp, et al)
  • Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife. Oct. 28. (Hans-Heinrich Hoffmann)
  • COVID-19 virus enters the brain, research strongly suggests. Science Daily. Dec. 17. (UW Medicine)

Science (Non-COVID)

The Business of Biotech

  • Year in Review. A Biotech Paradox. LifeSciVC. Jan. 4. (Bruce Booth)
  • Drug Prices Increase in New Year and Biopharma Bashing Returns. Forbes. Jan. 5. (John LaMattina)
  • Drugmakers to Hike Prices in 2021 as Pandemic, Political Pressure Put Revenues at Risk. Reuters. Dec. 31. (Michael Erman and Carl O’Donnell)
  • Haven, the Healthcare Joint Venture from Amazon, Berkshire and JP Morgan, is Shutting Down. Jan. 4. CNN Business. (Paul La Monica)
  • Medicare Payment Reform’s Next Decade: A Strategic Plan For The Center For Medicare And Medicaid Innovation. Health Affairs. Dec. 18. (Amol S. Navathe, Ezekiel J. Emanuel, Sherry Glied, Farzad Mostashari, Bob Kocher)

Science Features

  • We Know Almost Nothing About Giant Viruses. The Atlantic. Jan. 5. (Sarah Zhang)
  • How HIV Research Laid the Foundation for COVID Vaccines. WSJ. Dec. 24. (Gregory Zuckerman and Betsy McKay)
  • Must-Read Stories of the Pandemic. Pocket. (Ed Yong)
  • The World’s Most Loathed Industry Gave Us a Vaccine in Record Time. Bloomberg News. Dec. 23. (Drew Armstrong)

Managing in a Pandemic

Our Shared Humanity

  • Pastor, Can White Evangelicalism Be Saved? NYT. Dec. 19. (Nicholas Kristof)
  • Health tech’s Newest Unicorn is Running Toward Medicaid Patients Long Marginalized in Medicine. STAT. Dec. 22. (Casey Ross)

Personnel File

Boston-based Jnana Therapeutics, a company working on metabolite transporter therapies, added Annie C. Chen, the chief medical officer of Cambridge, Mass.-based Nimbus Therapeutics, to its board of directors.

Seattle-based TwinStrand Biosciences, a next-generation DNA sequencing company, added Gary Gilliland to its board of directors. He’s the former president of the Fred Hutchinson Cancer Research Center, and former head of cancer research at Merck. (TR coverage of TwinStrand and other next-gen sequencing startups, June 2020).

Seattle-based Sana Biotechnology, the cell therapy company, hired Ke Liu as head of regulatory affairs and strategy. He’s a 17-year veteran of the FDA, and former associate director of the cell and gene therapy unit within the Center for Biologics Evaluation and Research.

Boston-based Entrada Therapeutics added Peter Kim, the Stanford biochemistry professor and former head of Merck Research Laboratories, to its board of directors.

Waltham, Mass.-based TScan Therapeutics, the developer of T-cell therapies, added Brian Silver to its board of directors.

Newton, Mass.-based Abcuro, a T-cell and NK-cell engineering company, named John B. Edwards as the Executive Chair of the board and David de Graaf as CEO.

Watertown, Mass.-based Forma Therapeutics named Selwyn Vickers to its board of directors. He’s the senior vice president of medicine and dean of the School of Medicine at The University of Alabama at Birmingham (UAB). He’s a pancreatic cancer researcher and leader in health disparities research.

Cambridge, Mass.-based Aura Biosciences, the developer of conjugated biologic therapies for cancer, named David Johnson to its board. He’s the CEO of VelosBio.

Boston-based Karuna Therapeutics, the developer therapies for neuropsychiatric disorders, named Denise Torres to its board.

A Scientific Nation That Can Do Better

While the world grapples with the rise of the B117 and E484K variants of SARS-CoV-2, and the implications for the pandemic response, the US – the world leader in DNA sequencing – is behaving like a corrupt, impoverished country.

Somehow, we are unable to leverage the strengths we have in genomic surveillance to provide better early warnings for our citizens in a pandemic that’s killing almost 4,000 people a day.

See the tweets below from Pavitra Roychoudhury and Trevor Bedford, genomic surveillance experts, which sparked a somewhat incredulous and angry tweet from me.

With a strong leader and probably less than $50 million – a drop in the bucket – we could take this bull by the horns. It’s no panacea, but it is an important aspect of the pandemic response we need now and in the future. It would not only protect our citizens in the immediate here and now, but would radiate world leadership of the sort we used to take for granted.

This is just one of many, many aspects of the pandemic response that must be improved as we turn the page on this nightmare chapter in American history and begin to re-imagine what we can do when we attempt to mobilize to achieve a shared objective.


mRNA Vaccines Inspire Hope for Emerging Technologies; Is Digital Pharma Next?

David Shaywitz

The mRNA vaccines for COVID-19, developed by Moderna and BioNTech/Pfizer, were a conspicuous bright spot in a generally devastating year. Besides giving us a chance to bring the pandemic to an end, they remind us more generally of the profoundly transformative potential of emerging technologies. 

Audacious scientific and entrepreneurial ambitions can take years of grinding persistence, often sounding unrealistic or absurd to outsiders along the way, before suddenly they become generally accepted wisdom.

Moderna’s stock, which IPO’d at $23 a share in December 2018 and struggled to maintain this level in 2019, now sits at north of $100. The company was valued at $7.5 billion at the time of its IPO. Many considered the valuation staggering at the time. As MarketWatch reported, “no mRNA-based drug has ever been approved by the FDA nor any other regulatory agency, so it will be years before Moderna will be able to bring anything to market.” 

Three years later, the company is now valued at over $40 billion. 

It took a solid decade of sweat and capital before Moderna could truly take flight. As Crunchbase notes, 10 years earlier, “it was just a concept-stage company in the earliest stages of formation at Boston area biotech venture firm Flagship Pioneering.”

Stephane Bancel, CEO, Moderna.

While success always requires a prodigious amount of luck, it’s also clear – especially from this fascinating January 2018 Long Run interview with Moderna CEO Stephane Bancel – how much intentionality and deliberate choice were involved as well.

There was a compelling vision that thoroughly captivated founding VC Noubar Afeyan, subsequently shared by Bancel, who Afeyan recruited from Bancel’s previous role as CEO of French diagnostics company bioMérieux. (Fun fact: Bancel actually started his career as a sales rep for bioMérieux in Asia.) 

Of course, not everyone bought into this vision, especially after repeated disappointments, nicely chronicled by STAT here. Many wondered if the perennially-hyped promise of mRNA therapeutics would ever been meaningfully realized. (To be fair, outside of vaccines, which conveniently don’t require chronic dosing, many still worry.)

But it’s not only mRNA vaccines that delivered; as I wrote in the context of JPM2018 (remember JPM?), we’re living through a remarkable moment in biotech, where the promises made decades ago (effective gene therapy, increasingly customized cell therapy, ever more elegant molecular editing) are at last being realized. 

Which raises the question: what’s next?  Who are the Moderna’s of today? What are the nascent concepts or embryonic startups of today, that will revolutionize medicine tomorrow? 

If I was certain of the answer, of course, I would have already founded the company. But I know a few things.

First, there is exceptional and largely unrealized promise that will emerge from the intersection of biopharma and digital/data. Yes, there’s also extraordinary hype and extravagant expectation; in his always-essential year-end review, life science VC Bruce Booth calls out (not unfairly) “AI and machine learning in drug discovery” as the “most prominent” area that’s “over-hyped relative to [its] practical application.” 

Yet from all this heat, I’m confident some real light will emerge. Three of the “V’s” associated with big data are plainly abundant in healthcare: volume, velocity, variety. Two others – veracity, value – would seem to be more of a work in progress. 

There’s also ever-more powerful computers, and smarter (and perhaps even more ethical) algorithms.  Misaligned incentives remain a pervasive problem, especially in healthcare delivery, but the essential opportunities to deliver better medicines more rapidly to the right patients, and to help healthy people remain healthy so they don’t require medicines — remain fundamentally compelling, even if aligning these objectives with durable business models represents an underappreciated, pervasive challenge.

And as for the breathless promises – I’m less worried about them. After all, mRNA vaccines were dismissed as ludicrously overhyped until about, oh, two minutes ago.

A second reason for optimism reflects the lessons we’ve learned about the implementation of emerging technology from successful leaders of innovative biotech companies. In many ways, Bancel may represent the very model of modern integrative CEO, combining the attributes of authentic intellectual curiosity about emerging technology with deep domain expertise in developing approvable drugs. 

Bancel, after completing his MBA at Harvard, joined Lilly and deliberately chose to focus on understanding manufacturing (a famously unglamorous, yet, as Bancel had learned at Harvard, absolutely vital function), then worked on resolving a range of regulatory-related corporate challenges, first at Lilly, then [as CEO] at bioMierieux.

All told, Bancel spent years (Long Run listeners will recall) learning the fundamentals of biotech, a grounding ended up positioning him well for what came later.

The point is that Bancel’s success wasn’t driven by a lifelong passion for mRNA technology, but rather by the ability to recognize the potential of the technology, and then to have the wherewithal — operational sophistication plus situational awareness — to gainfully apply it to a relevant problem.  

While the successful application of digital and data advances to drug development will similarly require both an appreciation for and a facility with emerging technologies, I would bet on – and invest in – the thesis that success is far more likely to be driven by savvy implementation driven by a deep understanding of the critical business problems to be solved, rather than by whether a particular algorithm is powerful enough to go to 11.

It’s a difficult time to be optimistic, but I couldn’t feel more encouraged by the promising future I see at the intersection of biopharma and digital technology. This vision is inspired by patients, powered by data, and enabled by computation, yet will be realized only by pragmatic implementation, by investors and executives who value but are not distracted by dazzling technology, and maintain a relentless focus on the critical problems constraining the core business.


The Vaccine Rollout Could Prompt Real Reform to the US Health System

Alex Harding, MD. Entrepreneur in Residence, Atlas Venture

When I received the COVID vaccine on Dec 24, it was the end of a tense, frustrating two-week period.

Thousands of healthcare workers like me — doctors, nurses, physician assistants and more — at the Mass General Brigham health system were eager to get vaccinated, and antsy about whether we’d get the shot as soon as it was available.

The rollout at Mass General Brigham had problems from the beginning. There was a delayed start in announcing the process for scheduling vaccine appointments. Then came confusion about who was prioritized for the vaccine. Technological flaws caused the scheduling system to crash multiple times. One night, we experienced a tense free-for-all where thousands of staff raced each other to see who could click through a complicated online scheduling site to grab one of the coveted vaccine slots before they were all taken.

I was lucky, and thankful, to get my first dose of vaccine on Christmas Eve. Many of my colleagues, people who have also treated their share of COVID patients this year, had to wait longer.

This tale, for the time being, has a happy ending. All of the top-priority staff in our health system—those who care for known COVID patients—have had the opportunity to receive the first of two doses of the vaccine. But the sluggish and confusing vaccine rollout at Mass General Brigham isn’t unusual. We saw other hospitals around the country struggle with running an efficient and fair vaccination program (Stanford’s debacle is a more extreme example).

As we look beyond the current rollout to healthcare workers and nursing home residents to much larger swaths of the population, such as essential workers and the elderly, I worry my experience is a microcosm for what is to come.

The consequence on that larger scale is not just confusion and frustration. People could be waiting for months longer than necessary to receive their vaccine. When thousands of people are dying every day from COVID, delays in the vaccine campaign come with an enormous toll of suffering and death.

The COVID vaccination campaign, the largest ever attempted, is off to an alarmingly slow start across the country. As of Tuesday, the CDC said that over 17 million doses of the vaccine had been distributed but only 4.8 million doses had actually been administered. These doses are primarily being used for hospitals and clinics to vaccinate their own staff.

When the rollout shifts gears and larger groups of people become eligible, the complexity of administering the vaccine will only increase. It will be more difficult to allocate the right number of doses to specific sites. It will also be more tricky to determine patient eligibility, schedule patients, and make sure everyone is getting their second dose of vaccine on time.

The Unites States is likely to struggle with the vaccination logistics more than other developed countries. First, there has been minimal coordination at the federal level, aside from determining how many doses each state would receive and the CDC making high-level vaccine prioritization recommendations. Instead of taking responsibility for overseeing the rollout, the federal government has passed that task to the 50 state departments of health. These are chronically underfunded institutions that need far more resources to effectively carry out such an important responsibility.

Most problematic for the vaccine rollout is the decentralized manner in which care is provided to patients in this country. Patients in the US receive care through an archipelago of hospitals and clinics that compete with one another instead of collaborating. While most countries in the world have healthcare funded and administered by the government, the US has long favored a decentralized, privately-run model.

The US approach to healthcare can work wonderfully for individual patients in need of acute care. If I needed a heart transplant, knee replacement, or intensive care for a COVID infection, and I had access to good insurance, there is no place on Earth I’d rather be than the US. But when it comes to primary, preventive, and population healthcare, America’s approach does not deliver good results.

The failure of the US healthcare system for primary, preventive, and population healthcare is not news. Although the US spends far more on healthcare as a share of our GDP than any other country, we have one of the lowest life expectancies of any of the 36 countries in the OECD. According to the Commonwealth Fund, compared to 10 peer countries, the US had the highest number of hospitalizations from preventable causes and the highest rate of avoidable deaths.

These failures disproportionately affect the poor and vulnerable members of our society who cannot afford health insurance and struggle to navigate the enormously complex maze of entities that administers and pays for care in this country.

What’s new is that, suddenly, a population health measure has captured the entire nation’s attention. As thousands of people die each day, lack of coordination will lead to chaotic and slow vaccination efforts. Delays of weeks or months could end up costing tens of thousands lives in a pandemic that is killing more than 2,000 people every day.

It is no coincidence that Israel and the UK are two of the countries furthest ahead in the race to vaccinate. In Israel, healthcare is universal and every citizen must join one of four integrated healthcare organizations. In the UK, healthcare is even more consolidated through the National Health Service, which guarantees care to every UK citizen through a single public entity.

Similarly, I anticipate that integrated care organizations like Kaiser Permanente and Geisinger Health, because they handle both paying for and providing care at a very large scale, will be more successful than most clinics and hospitals in the US at vaccinating their patients.

Could the emerging crisis of the delayed vaccination rollout in the US be the catalyst to prompt real reform in our health system? Dysfunction in Washington may make any major legislative effort appear improbable. But we have already demonstrated the ability to achieve highly improbable goals during this pandemic. Creating and developing vaccines with 95 percent efficacy against a novel infectious disease, in less than 12 months, is nothing short of breathtaking. This country’s scientific and biopharma sectors (with the help of German collaborators at BioNTech) have delivered the two most effective COVID vaccines so far. There could be more to come, thanks to our scientific and industrial efforts.

We discovered and developed the vaccines that have the power to end this plague. Now, we are faced with an equally difficult task. Will we be able to efficiently deliver the vaccine to protect people from infection?

Our health system, as currently configured, is not able to execute well on this crucial job.

We can use this moment as an opportunity to catalyze reforms that will deliver the vaccine more quickly by fostering integrated care models and ensuring universal coverage through a public insurance option—reforms that will leave us with a health system that provides better, more equitable health outcomes for all Americans during this pandemic and beyond.