Get In-depth Biotech Coverage with Timmerman Report.
Today’s guest on The Long Run is Bassil Dahiyat.
Bassil is the CEO of Monrovia, Calif.-based Xencor.
He’s been on a true Long Run.
Bassil co-founded Xencor in 1997 after getting his PhD in chemistry at Caltech. He’s been through a lot of ups and downs in the biotech markets, and taken the company through a couple big strategic shifts.
The company is known for its work on engineering monoclonal antibody drugs, and engineered cytokine therapies. Few people may realize it, but the monoclonal antibody sotrovimab, developed by VIR Biotechnology and GSK as a broadly neutralizing antibody that still works against the Omicron variant of SARS-CoV-2, was made with help from the antibody engineers at Xencor.
Antibody engineering has come a long way over the past 20 years. These treatments are crucial to the present and future of medicine. Bassil has seen the evolution at close range.
Xencor is now aspiring to make a difference for its partners, but also to develop a few drugs of its own.
This is a fun, freewheeling, insightful conversation with a scientific entrepreneur.
Now, before we get started, a word from the sponsor of The Long Run.
Today’s sponsor, Answerthink, has been consistently recognized by SAP, one of the largest enterprise software companies, as a top business partner for delivering and implementing SAP solutions for small and midsized life science companies. Their SAP certified solutions designed for the Life Science Industry are preconfigured, rapidly deployable and address fundamental business and IT challenges such as:
Explore how Answerthink can streamline your business processes to ensure growth.
Visit Answerthink.com/timmerman and get a copy of the e-book- “Top Three Barriers to Growth for Life Science Organizations.“
Now please join me and Bassil Dahiyat on The Long Run.
[Editor’s Note: this is the first in a monthly series with business development executives about some of the surprises, subtleties, and human aspects of biotech dealmaking.]
Cambridge, Mass.-based Constellation Pharmaceuticals lived through the ups and downs of the epigenetic drug discovery field for a decade, before it exited on a high note last year. The company was acquired by Germany-based Morphosys for $1.7 billion, or $34 a share, in June 2021.
The deal gave Morphosys access to Constellation’s two lead product candidates, pelabresib (CPI-0610), a BET inhibitor, and CPI-0209, a second-generation EZH2 inhibitor. At the time of the signing, pelabresib was in Phase III clinical development for myelofibrosis and the EZH2 inhibitor was in Phase II development for hematological and solid tumors. For some of the background on the lead program and the company journey, listen to CEO Jigar Raythatha on The Long Run podcast from December 2019.
One interesting wrinkle in this deal came in the form of a $1.4 billion upfront payment from Royalty Pharma to Morphosys.
I spoke with Brad Prosek, the chief business officer of Constellation at the time, about how this deal came to be.
Why did the deal make sense for the two parties?
Morphosys has a long history of developing antibody and biologics products. They have close to 50 collaborations in their 30+ year history, several of which have started to pay off in terms of approved products, bringing royalties and profit shares back to Morphosys. So under the leadership of their CEO Jean-Paul Kress, they have started to turn the page from that platform basis to a product-oriented company.
I had originally reached out to them (as documented in the transaction’s 14D-9) around July 2020, though my initial outreach was not about partnering Constellation’s lead program. I had seen Morphosys print a deal with Incyte that put them on my map as a fellow traveler in the heme-onc space with money to invest in partnerships. Constellation was considering collaborations around our next generation EZH2 program. We felt our EZH2 inhibitor could be a best-in-class program and we wanted to build a data wall around the program – and we felt that with a partner we could deliver a bigger program faster than we could on our own.
As Morphosys got to know the company, I think we started to check a lot of boxes for them with respect to their growth strategy. They wanted to grow into small molecules to complement their monoclonal antibody base. They wanted to build a Boston research site. And they were looking for additional assets in the hematology and oncology spaces more broadly. So the more they looked, they liked a lot more than just what I had initially reached out to them to talk about.
How did you balance their desire to learn about Constellation more broadly vs. keeping them focused on the EZH2 program, which was your more immediate-term partnering goal?
As you’re going to do in any initial BD discussions, we did present the EZH2 program in some context – we showed our pipeline slide and maybe a strategy slide. But to focus on our objective, we did step off of that very quickly onto what I wanted to talk about. At least that was my initial approach.
Ultimately, in the subsequent discussions Morphosys asked us about pelabresib. [Pelabresib, an inhibitor of BET, was Constellation’s lead program and was in a Phase 3 clinical trial for myelofibrosis at the time of the acquisition]. They had seen some of the data we had presented publicly. We had made a few comments here and there about how excited we were in advancing the program. But I tried really hard not to get distracted by that.
I wanted to avoid the trap of getting onto the slippery slope of even discussing structures of interest. When the topic of pelabresib first came up, I had been pretty clear with them that Constellation was not interested to partner, for example, US rights for pelabresib. I tried to head that off at the pass pretty quickly.
Of course, sometimes the more you say no to someone, the more they want something. As Constellation was a public company, Morphosys had the ability to change the dialogue at any time by throwing in an unsolicited proposal. Which is what they did in October 2020. Morphosys must have done additional work on their side to get comfortable that this does check the boxes for something bigger.
How did you build your relationships within Morphosys?
In my view, you have to build multiplex conviction on the other side and use the relationships you build carefully over time to make sure things work. I got introduced to Barbara Krebs-Pohl [SVP and Head of BD&L and Alliance Management at Morphosys] through Mary Martin Roberts, a dear friend and former colleague at Biogen who had gone on to join Morphosys’ market access organization. Barbara had me talk to some of her team to begin the relationship, including Monika Bӓhner and other folks in Morphosys’ search and evaluation function.
As you know, if the technical team doesn’t have conviction, it doesn’t matter how hard you bang on the senior business leaders to make your case. Given the type of deal that I was focused on with our EZH2 program, it was OK for me to let those senior relationships recede into the background as we focused on technical discussions.
As things evolved, having had a good open relationship with Barbara from the beginning was important as we advanced through the later discussions.
How did you balance your ongoing Morphosys relationship-building with Constellation’s desire to get to the right kind of deal?
That is a constant and regular dialogue with your full management team, and sometimes on a more frequent basis with a subset of the management team.
We had what I liked to call our “Gang of Four” – our CEO Jigar Raythatha, our CFO Emma Reeve, our General Counsel Karen Valentine, and myself – that would get together sometimes a couple of times a week to share how we were thinking about things, what we were seeing, and to calibrate what made the most sense. We also regularly updated a strategy subcommittee of the Board, as well as our broader Board of Directors.
It’s good to be clear as a management team and aligned with your Board as to what your goals are for the company. Then you can use what you’re learning from the market to figure out what’s going to get you closer to your goals. Partnerships and straight financings are just two different strategic options in pursuit of your company goals.
At the end of the day, I believe in having as many options as I can on both the financing and BD fronts running in parallel as much as possible. You can’t always program that. But if you can keep things running in parallel, even if some of those options are not the right situations to pursue, it gives you the ability to really think about trade-offs. You can’t do stuff by remote control or through management consulting decks, sometimes you have to have specific opportunities with tangible trade-offs to really think about your path forward. And oftentimes it can be a bit like Goldilocks to get to the path that is just right.
What was the business situation at Constellation and why did you feel this was the right time to work with Morphosys?
It’s important to note that we had a good cash position at the time when Morphosys approached us. We had not gone out seeking an M&A. And the magic here was we had the ability in this period of time to be incredibly selective due to several other options on the table as part of our work towards 2021 goals. That allowed us to not feel like our back was against the wall to any option. So Morphosys’ proposal to us was sort of an epi-phenomenon on top of what we were already trying to execute.
Our goal was to build Constellation into a biotech company where the research engine could keep sustainably delivering even as the lead programs shifted to commercialization. We were building real conviction around pelabresib’s data and clinical opportunity. We also had a great asset in our EZH2 inhibitor and wanted to go fast with that. But wanting to move our EZH2 program fast could also create resource conflicts with the Phase 3 and additional development work on pelabresib.
As we looked at the plan to get to and through early commercialization, we had some really great options to move Constellation forward and manage our cash raises in a thoughtful way. But ultimately we were going to have to finance the company at some point. And there would be additional risk, particularly technical risk, and dilution.
So when we walked into the Board Meeting where Morphosys’ ultimate Spring 2021 M&A proposal was on the agenda, that certainty for shareholders that emerges out of an M&A process was an important consideration.
Why was Morphosys the right partner for Constellation?
Importantly, Morphosys’ proposal valued the full Constellation portfolio. We had worked to build a really exciting company with a broad drug portfolio. What Morphosys was emphatic about and has been very public about since the deal is that they came for more than just pelabresib.
Agreeing to a company sale is a multifactorial analysis, but we’re all in this business to get new therapeutic options to patients as fast as possible with as much data as possible. If that’s your lodestar and where your compass points, then the analysis of any option crystalizes around whether it helps with your goal and is it fair to shareholders. And that’s where we got comfortable with Morphosys.
Paraphrasing Jigar’s commentary, we had this vision of being a fully integrated commercial-stage company acting on a global scale with an ability to work in parallel across our portfolio. Partnering with Morphosys accelerated that vision.
Was there any dataset in particular that drove Morphosys’ interest to acquire you?
At ASH 2019, we revealed data showing proof of concept with pelabresib in front-line, JAK-naive, myelofibrosis patients. We had previously shared data in second line patients, but this first-line activity was the watershed dataset.
We knew the first-line efficacy was going to be a key dataset and we wanted the data to speak for itself. That’s part of why we did the PIPE in October 2019. The PIPE followed by the data enabled our December 2019 follow-on offering that enabled us to be choosy about where to go next.
Given you were publicly traded, how did you get comfortable that the Morphosys proposal would be attractive to your investors?
We spent a fair amount of time over the years that led up to this making sure we knew what sentiment was around all of our programs, including our lead program. So we weren’t starting from square one when Morphosys sent in their initial proposal.
There is this constant tension between looking at your company plans, the cash needs to fund that plan, the options available to raise that cash, and what taking any of those options might mean for your shareholders. Our bankers at Centerview were particularly helpful at boiling that analysis down to the potential risk versus the reward.
As a CBO, you’re not doing your job unless you have these pieces ready at hand. When the game changes as the CBO, you need to be able to confidently sit down with your CEO and your Board and say, “Here’s how we can think about this.”
How did the deal process go with Morphosys?
Every deal has lots of near-death moments. Part of what being in this CBO chair is about is thinking about and trying to anticipate what you can, having the ability to react fluidly in real-time, and always having back-ups to the back-ups to your back-up plans.
Again, you never want to end up against a wall.
One thing with respect to this deal is Morphosys had a very creative and transformational financing that they had to pull together to make this deal happen. When we started the journey with Morphosys’ first proposal in October 2020, from just looking at their financial statements, it was not clear where Morphosys would get the cash to pull off the acquisition.
This ended up becoming effectively a three-party deal with Royalty Pharma coming in with significant funding to Morphosys.
A two-handed deal is already hard to close, and a three-handed deal is very hard to pull off. This was really Morphosys’ problem and not ours, and we didn’t really see any of this come together until the very end, but a lot of this was evolving in parallel on Morphosys’ side. At the end, Jigar and Jean-Paul were communicating regularly so we did know what we needed to.
One thing I felt confident about on the BD side was that whoever Morphosys was going to talk to about their financing needs, we had probably also talked to them. Again, to keep our options open, I wanted the royalty funding groups to have a perspective on Constellation and our programs.
Deal competition also helps to signal that things are moving along, but we didn’t use that card until necessary.
When and why did you bring in Centerview?
Long before anything got hot and before anything like the deal we did with Morphosys was even apparent, I prioritized introducing Eric Tokat [a Partner at Centerview] to Jigar and the Board. An important thing to realize is that bankers like Eric and his team are not just in it for the immediate deal that you might be able to transact right now. Good bankers would far rather help you think about what your options are, would prefer you generate the best return for shareholders over the broad horizon, and ultimately may help you be acquired for more money later on instead of a deal that may be on the table today.
The Centerview team is tremendous. Eric had a long relationship with Jean-Paul Kress, which no doubt helped during the deal process. But having a good banking partner around the table will help a young company. Nobody has a monopoly on relationships, and different folks bring different perspectives and specialize in different types of deals.
You’ve done many transactions over your career – was there anything about this one that was just different?
Feedback can be a gift. I had done a lot of buy-side deals over my career, and one of my goals when joining Constellation was to do more sell-side. One of my learnings was to be incredibly diligent about asking for feedback from counter-parties, seeking clarifications, and really understanding what is happening on their side. We got a ton of free consulting from these discussions. And there is always your vision for the asset versus what is in the eye of the beholder.
And it’s important for any sell-side process to integrate the feedback you’re getting. This helped us understand what partners might have considered as warts in our programs, think of plans to maximize the value of each of our assets, and know when to come back to re-engage and update counter-parties. I really believe that this super-diligent approach to getting and integrating feedback from partners led to us having the multiple options that we did.
In December, a team led by two University of Pennsylvania scholars, psychologist Angela Duckworth (best known as author of Grit) and behavioral economist Katy Milkman published in Nature the results of a colossal study on behavior change.
The researchers evaluated the impact of a huge range of behavioral interventions – 54 – that were thought to potentially influence gym attendance after four weeks.
The research – termed a “megastudy” – involved 61,293 participant subjects, and 30 scientists from 15 different U.S. universities; each of the 54 conditions were studied in groups of at least 455 participants; the average group size was over 1,000 participants.
The authors’ main area of emphasis in the paper was methodological. Successfully executing such massive a field experiment encourages other scientists to take advantage of this powerful approach, the authors contend. “By enabling direct comparisons of diverse intervention ideas,” they write, “megastudies can accelerate the generation and testing of new insights about human behavior and the relevance of these insights for public policy.”
What did they learn about their interventions? These data were somewhat disappointing. While nearly half the approaches worked better than the negative control, the effects, while statistically significant, were relatively small. Moreover, few approaches proved discernably better than what was essentially a standard-of-care (active) control, an approach consisting of three, evidence-based elements:
The supplemental intervention that seems to perform the best was offering microincentives (worth 9c) to participants who had missed a workout, as an encouragement to return. This resulted in a 27% improvement over placebo (amounting to an extra 0.4 days of exercise per week), and a 16% improvement over the active control.
Unfortunately, even the relatively modest benefits of interventions dropped off rapidly after the study concluded; in other words, the interventions did not seem to impart to participants improved behavior in a particularly durable fashion.
Harvard business school professors Michael Luca and Max Bazerman summarized (prepublication) these results in their book The Power of Experiments (my WSJ review here): “behavioral interventions that led to short-term gains were less effective when looked at over a multiple-month span.”
As professor Duckworth succinctly told Luca and Bazerman: “Behavior changes are really *#$@ing hard.”
Perhaps the most interesting aspect of the megastudy was the inclusion of predictions of intervention efficacy by a range of impartial assessors, including behavior science professors and practitioners. Not only were there “no robust correlations” between predicted and observed treatment effects, but the predictions anticipated a level of benefit that was “9.1 times too optimistic.” In other words: experts thought the interventions were going to work far, far better than was ultimately observed.
These results are consistent with the large and growing body of literature on the limitations of expert prediction (see this magnificent Louis Menand discussion of Philip Tetlock’s scholarship). The megastudy also supports expansive literature on the epidemic of overconfidence (one of Nobel laureate Daniel Kahneman’s many areas of contribution – see here).
I’ve discussed expert fallacy and the challenge of overconfidence in a number of Wall Street Journal book reviews (including Rosenzweig’s Left Brain, Right Stuff, and The Invisible Gorilla, by Chabris and Simons). I’ve also explored these issues in the context of biopharma – see this Financial Times op-ed with Nassim Taleb, and this piece in Forbes.
Between these biases, and the burgeoning literature on irreproducibility, it’s tempting to embrace the famous William Goldman observation about Hollywood, “Nobody knows anything,” and quickly find yourself in a very dark place.
But, it turns out, cynicism is probably not the right answer either.
You don’t have to spend much time on social media – or in late-night college bullshit sessions – to appreciate the power and appeal of cynicism, defined in an academic paper as “a negative appraisal of human nature, a belief that self-interest is the ultimate motive behind all human actions, even the seemingly good ones, and that people will go to any lengths to satisfy it.”
As Stanford psychologist Jamil Zaki reviews in a fabulous, short TED talk (“How to escape the cynicism trap” – here), while we may not enjoy the company of cynics, we tend to think they are smarter, and that their grim view of others makes them better at detecting dishonesty, for example, and hence less likely to get ripped off (not true, as Zaki reveals).
There’s also the contrasting concern that a less cynical, more hopeful and generally positive attitude, as “Freakonomics” host Steven Dubner notes, “can be seen as a sign of weakness,” and “as something that might be exploited.”
Considerable research has explored the notion of “depressive realism,” the idea that those with a negative view of the world are the ones who are seeing it most clearly, as Stephanie Bucklin nicely discusses here.
Fortunately – at least for the many optimists and aspiring optimists – the dismal view may not be right either. A fascinating 2018 study, for example, examining global data from over 200,000 people, found that while most of us “tend to believe in cynical individuals’ cognitive superiority,” the numbers don’t bear this out.
Rather, the data show that “cynical (vs. less cynical) individuals generally do worse on cognitive ability and academic competency tasks.”
Moreover, across a range of cultures examined, “competent individuals held contingent attitudes and endorsed cynicism only if it was warranted in a given sociocultural environment. Less competent individuals embraced cynicism unconditionally.”
In other words, it’s the people who know less who tend to be reflexively cynical, while those who know more are selectively cynical.
As the authors suggest, this could represent an adaptive posture, preventing those most vulnerable from getting taken advantage of. Causality might also work in the other direction, and those who are reflexively cynical might not open themselves up to opportunities that could expand their knowledge base.
It’s this last point – the receptivity to opportunity – that represents perhaps most compelling argument for resisting the “cynicism trap.” It’s something I’ve heard tech VCs, in particular, emphasize – the importance of being receptive to possibility, and to the outsized potential of radical new ideas. You might be wrong, they say, but you can’t lose more than the value of the investment; yet if you’re right, your upside can be almost unlimited, a return that reflexive cynics will never realize.
As VC Balaji Srinivasan points out here, every significant advance in the technology revolution was originally dismissed by cynical industry experts. There’s a reason for the popular Silicon Valley aphorism, “pessimists sound smart; optimists make money.”
The advantages of an optimistic mindset extend far beyond the financial.
A more positive, less cynical view also enables us to derive greater joy from engagement with other people, to share in their happiness and embrace their possibility.
Both cynical and hopeful stories, Zaki points out, can “can become self-fulfilling,” and he urges us to deliberately choose the more optimistic path. “We can be skeptical,” he says, “demanding evidence before we believe in people — but hopeful, knowing they can change for the better.”
Similarly, as Penn’s Duckworth notes in a (captivating) discussion with Steven Dubner (here), she isn’t advocating for reflexive optimism, sometimes called “toxic positivity.”
Instead, she says, “It’s both possible to have a high center of gravity when it comes to positive emotion and to be pretty stable around that, and I think it’s possible to allow your attentional field to encompass these other things.”
What’s critical for both optimists and pessimists to recognize, Duckworth argues, is that we have choices:
“There are virtuous and vicious cycles; being unhappy, being negative, and always being hyper-critical can really be a spiral downward. If you do pay attention to that, you could say, ‘Hey, look over here, it’s this virtuous upward spiral. I think I’m going to join that one.’”
In essence: happiness is a choice – so choose it.
The vast majority of people in the US have at least partial immunity to many forms of SARS-CoV-2, either from prior infection, vaccination, or both.
The past few weeks have shown us that the Omicron variant transmits faster than any of its predecessors. That essentially guarantees that the unvaccinated plus early vaccinees (last dose/boost more than 6 months ago) will contract COVID-19 over the next few weeks and months.
Early reports from hospitals are telling us that people with Omicron infections are suffering less severe symptoms. If this phenomenon — the combination of airborne transmissibility and mild lower airway symptoms holds up over time — then it is likely that COVID-19 will join the common cold, Influenza and Respiratory Syncytial Virus (RSV) among endemic infectious diseases.
We aren’t going to eradicate COVID. We’re going to have to live with it.
Let’s consider a couple key questions in some depth:
Omicron has become the dominant variant of concern in an even shorter time than Delta, the previous record holder. Because of its plethora of mutations on the Spike protein, Omicron has effective resistance to most previously developed antibody drug cocktails and substantially reduces vaccine effectiveness.
On the good news front, Omicron is causing far fewer hospitalized, ICU or ventilated patients per infection. Laboratory work suggests several compelling hypotheses of why this might be so. Our confidence is mounting that Omicron has higher transmission but lower morbidity and mortality than prior variants of concern: perhaps to the level of seasonal flu.
However encouraging that may be, influenza fatality rates can be tragically high (e.g. 61,000 deaths in 2017-18 in the US). A world with both flu and COVID circulating at the same time will inevitably increase respiratory distress mortality and morbidity, and put tremendous pressure on hospitals.
The best data on Omicron comes from South Africa and the UK, where Omicron developed the earliest and where surveillance has been the most comprehensive. The UK is running about 4 weeks behind South Africa, where the drop in Omicron’s death rate was particularly striking.
The UK pre-existing Delta death rate was already much lower than South Africa, but that too has more than halved in the Omicron era.
The rate of asymptomatic Omicron cases is much higher than prior variants, according to a Dec. 27 study from South African researchers and colleagues at the Fred Hutchinson Cancer Research Center. Researchers found that almost one-third (31 percent) of people with HIV who enrolled in a Moderna vaccine study in South Africa in December were found to already have COVID. That’s up from about 1-2 percent of people who showed up in a comparable vaccine study months ago, when the Beta variant was circulating. These asymptomatic carriers were shown to have high levels of viral shedding based on samples from nasal swabs.
This high rate of hidden cases, and the high levels of viral shedding, means that many people will inevitably transmit their infections to others. Some of these people will end up with severe symptoms.
That’s a glimpse at the biology. Now let’s take a look at the clinical implications.
Researchers at Imperial College London looked at data from the first two weeks of December, when Omicron rose to prominence. The team reported 40-45% lower hospital admissions for Omicron versus Delta (Table 1: note UK “hospitalization” includes emergency department visits, admissions is more representative of severity). Prior infection and vaccination reduced the risk of Omicron hospital admission risk by ~70% (Table 2).
By the end of December, with more data coming in every day, the hospital admission rate in London was about 80 percent lower during this Omicron wave than the prior Delta wave.
The UK Health Security Agency has published an update on vaccine effectiveness after 198,348 UK Omicron cases (Omicron update 12/31/2021).
Bottom-line, a two-dose mRNA vaccination series confers essentially no protection against Omicron infection after 6 months, whereas the two-dose mRNA vaccine retained ~60% effectiveness against Delta (down from 98% initially). A subsequent booster increases Omicron immunity at the 9-10 week point from a rapidly declining ~40% back up to ~50% (Pfizer boost), or ~70% (Moderna boost).
There has not yet been enough time to evaluate longer term effectiveness versus Omicron.
Prior infection, current vaccines and boosters do reduce severity, but cannot be considered effective against infection beyond 6 months. The saving grace of the vaccines, however, can be seen in the hospitalization data referenced above. They are keeping people out of the hospitals.
There hasn’t been enough time yet to fully evaluate the US clinical experience, at least compared with the UK and South Africa. But all the signs are that it will be consistent here (for an always helpful US perspective, see Paul Sax MD’s blog of Dec. 30)
Over the past month, there have been many excellent studies (I have 16 on file currently and more arrive every day) examining the pathology of Omicron infection in animal models and human cell cultures. There are two arenas contributing to a consensus on why Omicron is demonstrating lower morbidity and mortality (see Eric Topol’s excellent “Ground Truths” newsletter on Substack):
Omicron infects primarily the upper respiratory tract – especially the nose and throat. That’s likely causing more coughing and viral aerosol dispersion and transmission. The virus appears to be less able to migrate further the lower respiratory tract, deep into the lungs where prior variants dramatically damage the cells – alveoli – responsible for clearing carbon dioxide and transferring essential oxygen to the bloodstream. This is an evolutionarily favorable path for viral mutation, as evidenced by Omicron’s competitive advantage over Delta, which is more efficient at getting deep into the lungs. This does not preclude a more virulent future path for Omicron, but it does reduce its likelihood.
See the following studies below for more detail:
Although neutralizing antibody counts from prior infection or vaccination do decline toward zero after 6 months, memory B cells (the cells that produce these antibodies) and memory T cells (that mobilize the immune system and attack pathogens directly) both become more broadly effective against unencountered variants after repeated prior exposures.
Generally speaking: the more exposure the better, especially with longer delays between encounters (implies minimum 12-16 week spacing of each initial and booster dose). One of the key early findings of the Omicron wave is that T-cell immunity from prior infection and vaccination appears to be longer-lasting, and this second-line of immune defense is likely a big reason why so many people are getting mild infections that don’t end up sending them to the hospital.
See a few key studies that look beyond neutralizing antibody assays below:
First, let’s look at this in the short term to mitigate the damage from an ongoing airborne threat.
There has been massive demand in the US for rapid testing. Individuals have become more familiar with self-testing. This is not about to decline. The industry needs to develop expanded availability of rapid tests to allow self-diagnosis to distinguish among the broad range of respiratory diseases – tests that can discriminate among both bacterial and viral respiratory infections – COVID-19, Influenza, RSV, tuberculosis, pneumonias etc.
Without adequate testing and surveillance, it’s hard to answer a key question — how will we know if it is “over” (at least in its current form)?
Official counts of cases are becoming less reliable. Few of the rapid self-test results are reported to public health authorities who manage the official databases. Omicron’s increased asymptomatic cases will largely go untested — people will have COVID and walk around infecting other people without ever knowing they were positive.
In this context, reported case numbers understate the reality, even as the total number is rising exponentially. Given this reality, some have suggested we should primarily track hospital admissions since this is generally a reliable indicator of serious disease (although COVID deniers are advocating ignoring the hospitalized with COVID and only counting the hospitalized for COVID).
Unfortunately, we now know that viral loads and hence transmission can be just as high in the asymptomatic – we cannot afford to lose track of the total number of cases.
A continuing unknown is the long-term effect of past infection. We do know that virus is found in many organs on autopsy; a trend likely exacerbated by Omicron as a result of its reduced ACE2/TMPRSS dependency. A 1/2/2022 University of Waterloo Canadian paper suggests that executive function is significantly affected during post-acute COVID-19 recovery, but we do not yet know what circumstances drive vulnerability to Long COVID-19, nor what types of infection cause it.
This is one of the big research questions that will take time to answer – to what extent does Omicron infection lead to various forms of Long COVID? What biological phenomena are driving the chronic symptoms? How many people will be affected, and for how long? What kind of symptoms will they have to endure?
It will take time to gather data to help us understand what’s going on.
It has been 100 years since the devastating 1918-1921 Influenza pandemic. That avian H1N1 virus infected one-third of the global population, with nearly 5% mortality among younger adults. We have been fortunate that COVID-19 has had a relatively low mortality rate of 1-2%, but it is clear that 21st century travel and COVID-19 show that infection can spread quickly to more than just one third of the global population – by the time this pandemic is over, 70-80% of the global population will have been exposed, infected and/or vaccinated.
We have been negligent preparing for inevitable waves of epidemic infections. We have few effective viral therapies in hand. We are rapidly exhausting the antibiotics that have protected us from bacteria scourges for the past 70 years.
Given that it is highly unlikely that COVID-19 disappears, we are beginning the transition to an influenza-like endemic COVID: a continuing threat of more virulent mutation-fueled outbreaks driving ever-present danger to the respiratory impaired and those with compromised immunity.
The last 50 years have taught us that animal reservoir pathogens can mutate and spread without warning — we cannot allow ourselves to fall under the spell of complacency ever again.
My phone buzzed with alerts about record-setting case numbers as I rushed between patients. A pile of tiny bottles with swabs floating in pink liquid accumulated while awaiting PCR testing.
Patients with coughs and sniffles lined up outside the door, waiting to be seen.
My shift as an internal medicine physician yesterday in MGH Chelsea’s urgent care facility reminded me of the early days of the pandemic.
The first wave was scary. The disease moved so fast. It was so severe. We knew so little.
We are certainly in a much better place this time around. But in terms of the raw numbers of people affected, the current wave is even worse.
On Monday, two days after Christmas, my clinic set a record for the number of patients seen. Shockingly, the rate of positive COVID tests has been 60-70% this week. That’s higher than I ever remember from the first wave. I tried to avoid eye contact with the people in the packed waiting area, as many patients waited over 3 hours to be seen.
It’s daunting as a healthcare worker to see this many people in line with COVID. But the feeling on the ground is different. Thanks to the vaccines and our familiarity with the disease, the illness severity is far less than before. We are seeing more patients with non-respiratory illnesses now than we saw in the first wave. And, after nearly two relentless years of pandemic pressure, fatigue has clearly set in among both healthcare workers and patients.
First, some numbers: I saw 19 patients during my 8-hour shift yesterday—about 3 or 4 more than I’d be able to get through in a busy shift before COVID. Of these patients, 11 had respiratory symptoms and 8 had other issues.
Remarkably, 10 of the 11 with respiratory symptoms had previously been vaccinated for COVID—6 had received 2 doses and 4 had received 3 doses. Only one of my respiratory patients, a young person who had very recently emigrated from Central America, was unvaccinated. Four of the patients I saw tested positive for COVID, below average for what my clinic has seen over the past week. These patients were mostly in their 20s to 40s, but in our clinic we are seeing patients with COVID spanning a full spectrum from infants to the elderly, with and without comorbidities.
Of all the differences during this wave compared with prior COVID waves, the vaccination rate is the most important. The fact that all but one of my respiratory patients yesterday were vaccinated is both good and bad. This reflects the ability of the Omicron variant to at least partially escape immunity built up from prior rounds of vaccination or infection. That’s the bad news.
Now for the good news – these vaccinated patients with COVID had mild respiratory symptoms. They are not getting so sick that they develop Acute Respiratory Distress Syndrome (ARDS) — the kind of serious illness that requires mechanical ventilators.
Here’s what I mean by mildly ill. Almost all 11 of these patients had cold symptoms – runny nose, stuffy nose, sore throat, fatigue — but no shortness of breath. Only one patient, who was vaccinated, was slightly short of breath. None of my patients needed to be referred to the emergency department. They all went home.
The story was different in the first wave. There were days when we sent every third patient by ambulance to the emergency room—in March and April 2020, MGH had contracted with an ambulance company to keep an ambulance waiting at all times outside our front door.
Chelsea is an impoverished community of about 40,000 people, just across the Mystic River from Boston. The people who live here are mostly immigrants from Latin America. They do a lot of low-wage jobs and have limited access to healthcare. Despite these challenges, Chelsea has a vaccination rate substantially higher than the state average—an accomplishment featured in October in the Boston Globe.
Now, during the Omicron surge, it appears Chelsea is reaping the rewards. Its residents are mostly protected from severe illness and death from COVID.
The prevalence of vaccination completely changes how I take care of each patient. The patients I am seeing are uncomfortable, with stuffy nose and sore throat. But their vital signs are usually stable. They are not struggling for air.
My risk assessment for these patients’ progression is also dramatically different. In the past, I was unable to speculate about whether a patient was likely to turn the corner soon or whether the illness would worsen. Now, I can reassure the vast majority of patients that, thanks to the vaccine, their illness is unlikely to get much worse. Usually, this means they can go home, get some rest, drink plenty of fluids, and stay away from other people until they are no longer infectious.
There are people out there disparaging the vaccines, wondering why anyone should bother if they can be vaccinated and still get sick. But the vaccines are clearly getting the job done. They are keeping people out of the ER and the ICU and the funeral home.
Our familiarity with COVID and how to manage its effects has progressed dramatically. In the spring of 2020, aside from a few case reports from China and Italy, we were almost flying blind. We did not know precisely how the illness was spread, who was at highest risk, and how to treat patients who were sick.
The CDC told us we did not need to wear N95 masks when seeing COVID patients (we should have). We debated whether to keep patients in negative pressure rooms (probably overkill). We worried too much about fomites—passing the virus through direct contact—and not enough about airborne aerosol spread. Protective equipment was scarce and an enormous source of anxiety for many healthcare workers.
For months, we were forced to sift through a flood of weak evidence and inference to determine how best to treat patients. For a while, ibuprofen was strictly avoided and atorvastatin and hydroxychloroquine were the mainstays of therapy (wrong on all counts).
Today, while access to outpatient treatments is still severely limited, as I’ll discuss later, we have greatly improved inpatient treatment protocols with a combination of prone positioning, tailored oxygen therapy, dexamethasone, remdesivir, and prophylactic anticoagulation. If I ever have to admit a patient to the hospital, I feel confident that they will receive care that improves their chances of recovery.
Early on, while COVID cases shot up, patients with non-COVID conditions seemed to vanish. Of course, they did not truly go away; they just stayed home, which put them at risk of deterioration without proper medical care.
That has changed. While I saw 11 respiratory patients yesterday, I also saw 8 patients without respiratory issues. I saw a patient with substance use disorder, one with a nasty nosebleed, patients with urinary infections, gastrointestinal issues, and more.
Our clinic is not just dealing with the current COVID wave. We’re dealing with our usual steady flow of sick people, plus a COVID wave on top. This makes our days busier. In the bigger picture, though, it is a relief that our patients with non-respiratory issues are getting the help they need. As long as hospitals aren’t overwhelmed with COVID patients, this will remain true.
It’s been almost two years of this. It feels longer. It’s natural for us all to be tired. Healthcare workers have had a particularly difficult couple of years, having seen so many sick people with so little that we could do for them. We have put our own health on the line, especially in the days before the vaccines. Some of us feel that our employers haven’t fairly recognized that sacrifice. Many healthcare organizations have experienced a higher rate of turnover than usual. That has compounded the fatigue for the people who have stayed put and had to pick up the slack.
Scared as we all were in the early days, I was exhilarated by being able to help on the front lines.
I still look forward to my clinical shifts, but my level of excitement has moderated over time.
The fatigue is not just among the healthcare workers. Our patients are also tired. Yesterday, I saw some patients who seemed nonchalant about possibly having COVID. In part, this makes sense. For low-risk, vaccinated people, COVID infection is very unlikely to be severe. But being infected with COVID still warrants more than a shrug.
There is also increasing fatalism. It’s understandable that some people would question why they should bother adhering to public health recommendations when they still have not been able to avoid getting infected. That attitude was palpable in some of my patients.
In spite of the frustrating circumstances, it is important to weigh the risks and benefits of one’s actions. For most healthy, vaccinated people, it probably doesn’t make sense to go back to a full lockdown. But it also doesn’t make sense to throw caution to the wind by abandoning masks and basic precautions.
We still have very few treatments to offer outpatients with COVID.
With Omicron, we took a big step back in our therapeutic options for outpatients. The monoclonal antibodies from Regeneron and Eli Lilly were helpful against earlier variants, but don’t work against the new variant. There have been important treatments authorized by the FDA in recent weeks. But availability is limited.
Here’s the latest status for therapeutic options at my hospital:
Over the next month or two, access to sotrovimab, Paxlovid, and Evusheld will hopefully improve and make a significant dent in COVID. For now, your best bet is to get a vaccine booster and wear a high-quality mask.
I was naïve enough to think that under Biden the CDC would regain scientific independence, but unfortunately that does not seem to have happened, at least not to the extent I had hoped.
Earlier this week, the CDC, with no data to support the decision, shortened the duration of quarantine for COVID patients from 10 days to 5 days. This news was a hot topic of conversation on the front lines. I spoke with about half a dozen patients yesterday about the CDC’s announcement. Some were uncomfortable with the change, and others were happy that they would be able to return to work sooner. In all cases, I had to discuss what the data actually show. (My advice to those patients: test before ending quarantine if possible, shorter quarantine for vaccinated than unvaccinated, and in no case less than 7 days.)
In spite of these challenges, I am confident that we are in a good position to get through this wave. Most of us are vaccinated and strongly protected against severe illness. For those who do get sick, we know how to take care of them. Hopefully, we will soon have new treatments available that will dramatically protect those who do get sick.
Vaccine misinformation has put millions of people unnecessarily at risk, but it is not too late to fix that.
Get boosted, wear a mask, and stay strong. Together, we’ll make it.
As we start to think about 2022 and improving our health and wellness in the New Year, we make ambitious resolutions and urgently try to identify the optimal diet and best exercise program to achieve our health goals.
As intuitive as this approach sounds, it’s almost certainly the wrong mindset.
What behavior change experts, including Brad Stulberg and Steve Magness (best known for their books and for “The Growth Equation” website and podcast) as well as John Berardi (author of Changemakers, discussed here) and others all emphasize is that there generally isn’t a magic diet or exercise routine that’s intrinsically better than others. There is no fitness program that rules them all.
While healthy eating (essentially, avoiding highly processed foods) and regular movement (get off the couch) are clearly good for you, the best routine is one you are most likely to stick with over time.
As tempting as it might be to pick some elaborate, ambitious exercise program, say, you need to ask yourself what are you truly likely to stick with; otherwise, you are just setting yourself up for the inevitable disappointment once life intervenes.
As Magness says (podcast quote edited slightly for clarity), “If you look at the research, and you look at the data on successful diets especially, there isn’t any that shows that one specific diet works better than anything else over the long haul. When it comes to diet, what you can consistently adopt over a very long time works best.”
Magness cautions against wasting your time seeking the “one answer” — the “magic bean” — and says if you do, “you’re just setting yourself up for failure.”
The same advice holds for exercise, Magness says. “Are there specific types of movement activity that might be slightly better or slightly worse?” he asks. “Sure. But in general, if you move sometimes long, sometimes hard, sometimes strong, you’re going to be good.”
What’s critical, Magness adds, is not to “get caught in the details, like ‘Oh, is this workout with 15 second intervals better than this one with 60 second intervals. It doesn’t freaking matter.”
Can tech tools – like wearables – help us become healthier over the long term?
Well, maybe. To the extent a tracker can serve as prompt to remind you to exercise, and a community on Strava, say, can motivate your participation – great.
But, as we’re increasingly recognizing, trackers also bring a series of challenges. One concern is the tendency to rely on the wearable and begin to lose touch with your own body, reducing your confidence in your ability to understand the feedback your body is giving you.
Another problem: the quality of the output of these devices depends on the quality of the input (see we discussed this summer); so if a PPG device, say, struggles to detect and measure heart rate accurate especially during physical activity, then measures derived from these measurements – independent of the intention and quality of the algorithm applied – will be suspect.
A third problem, described eloquently by Stulberg, is when “tracking becomes a religion,” an “ideology.” He adds,
“You get all these secondary effects. Much like someone that is an evangelical devout Christian or an Orthodox Jew, you get someone that becomes an Orthodox Tracker, where their community becomes other trackers, and their whole life is dictated by eating during certain windows, breathing in certain ways, only eating certain foods, uploading everything to a computer, and pretty soon, you have no time and energy for anything else.”
He points out that while “these extreme communities” may “represent themselves publicly like the healthiest people in the world,” the reality is “unless they show me that they are living longer with higher function, they simply look like adherents to a very fervent religion to me.”
Other advice from experts relates to the nature of goals. While we’re tempted to focus on performance goals (an 8-minute mile, say, or 8 hours of sleep a night), experts like Stulberg, Magness, and Berardi all advise focusing instead on behavior goals, specific actions you can do, with the long-term mindset of achieving “mastery.”
Also important: pick goals and select actions that are small, realistic, and which you believe you are highly likely to consistently do; you can build on these. Also important: being kind to yourself, celebrating the progress you make and not beating yourself up when life inevitably happens.
To support yourself in pursuing the actions you plan to take, remember that your best chance of success happens when you don’t rely on will power (almost universally now believed to be inadequate to the task), but instead, modify your environment, where possible, to help you out. If you don’t want to eat candy bars, don’t keep them around the house. If you want to get to the gym in the morning, leave your stuff out and ready to go the night before.
Community can play an important role in promoting your health and well-being, at a number of levels. For one, we’re happier when we’re part of communities and engaging with others – one of the reason the pandemic has been especially devastating. Seeking out opportunities to engage in communities, to connect in person with other people authentically, can enhance your wellbeing – and theirs.
For all the discussion of sensors and AI, I suspect the most significant contribution from digital fitness platforms – as I’ve repeated discussed in the context of Peloton – is the potential to create and nourish a sense of community.
The huge opportunity I see here is for a wellness platform to perhaps initially attract users through sexy technology like a connected bike, rower, strength machine, or wearable, but then to view the platform as far more than a supportive environment for already fit cyclists, rowers, lifters, or gadget hounds.
Instead, the real win (and it seems that at least Peloton may be pursuing this) is to create and nourish a far broader and more inclusive community, one that attracts and sustains individuals with a diverse range of fitness abilities, and interests, providing a range of attractive on-ramps to a range of offerings that collectively support an expansive conception of wellness.
On the other hand, there are things I’d urge you not to do in the new year, and they generally boil down to avoiding quick fixes, even (I’m tempted to say especially) if pitched as “natural.”
I tend to be skeptical about supplementation in general, and exceptionally skeptical about the increasingly-popular idea of “precision supplementation,” which strikes me as bullshit squared.
I’m also wary of pseudo-medical “hyperwellness” products – although a company offering a range of highly dubious offerings (including a range of “IV drip therapies”) just raised $140M from a top PE firm. As Quizzify CEO and wellness guru Al Lewis observed, “I don’t know which of these is scariest and what went wrong with evolution that we need IV drips and intramuscular shots in order to thrive,” adding “how is half this stuff even legal?”
Transitioning from the overutilization of pseudo-medical treatments to underutilization of actual medical treatments, let’s spend a few minutes taking (another) hard look at the problem of severe obesity, once again benefiting from the insight of MGH physician and obesity scholar Fatima Cody Stanford.
What I’ve taken away from a long conversation with Stanford, as well as from many of her lectures, talks, and podcast appearances, is that while we’re collectively obsessed with weight loss, we really haven’t yet come to terms with obesity as a medical condition, preferring to consider it a regrettable life-style choice, rather a chronic disease such as hypertension or diabetes.
As a result, patients who suffer from severe obesity, or who are progressing in that direction, rarely receive the medical care they require, and often getting little more than vague and tepid “diet and exercise” advice, offered half-heartedly. While doctors tend to be quick to treat the hundreds (UpToDate, as I discussed, lists over 230) of conditions associated with obesity, obesity itself tends to languish.
This is especially unfortunate, Stanford argues, because in addition to emphasizing the foundational role of diet and exercise, there are increasingly well-described roles, she says, for pharmacological treatments — which she’d like to see deployed comfortably and routinely by primary care doctors — as well as surgery (as I discussed in Forbes in 2012).
As Stanford sees it, we don’t use a teaspoon to clean up after a Boston blizzard – we use a snowplow, a tool suited to the demands of the job. Similarly, she argues patients suffering from severe obesity deserve access to appropriate tools and modalities.
The issues around medication were captured in a very thoughtful exchange with an audience member at a talk Stanford gave in 2018 at the Radcliffe Institute (video here).
The questioner noted that years ago, when she studied nutrition in college, “nobody gave drugs. Never.” Even more recently, she continued, “it was like a no-no. It’s like, ‘Well, why would you take amphetamines? You know, it’s really an artificial thing.’”
But Stanford’s perspective, the questioner observed, seemed strikingly different, viewing medication as a way to manage a “physical problem the person has with absorption or energy expenditure or whatever. So that’s a whole new thing.”
Finally, she asked, when patients start medicines, “do they have to take them for life or and how much weight do you lose? And then do they plateau out? How does it really work over a long period of time?”
On the use of medicines, Stanford explained,
“I see these medications as complementary to someone that has improved already their diet quality and physical activity. These are the patients that come in and they’re doing everything right. I love what they’re doing and I’m like, ‘there’s not anything else I can do. But we do need to modify how your brain sees its weight set point.’”
In Stanford’s view, medicines for obesity, a chronic condition, need to be viewed the same way as medicines for other chronic conditions – when necessary and appropriate, they can make a difference, but typically need to be maintained for life, otherwise the condition they are treating reverts. In a sense, it’s like you’re keeping the obesity in remission, rather than “curing” it.
“I’m sorry,” Stanford explained. “It’s the reality for patients, you know, and that’s what I tell patients before we commit to it. Because if the medicine works, then I’m going to keep you on.”
In addition to emphasizing the need for primary care doctors to become more comfortable offering medical therapies for obesity, Stanford also highlights the value of comprehensive obesity care centers like the one she’s in at MGH – and which has a waiting list of nearly 2,000 patients.
Stanford stresses the need to democratize comprehensive obesity care, and serves on the advisory board of what seems like a promising startup, Calibrate, with this medical mission; the company raised a $100M series B in late August.
As we find ourselves still dealing with the challenges of the pandemic, the need for a healthy workplace – as I’ve recently discussed – has only become more urgent.
Many employers have sought to address these challenges by increasing the buffet of wellness offerings; yet useful as these may be to some individuals, these offerings, although abundant, may not really address the core issue.
More promising, I suspect, is an evidence-driven approach, distilled into a toolkit, that has been developed by the Work and Well-Being Initiative, a “joint research-for-action” effort from the Harvard School of Public Health and MIT’s Sloan School of Business.
The basic thesis goes as follows:
“Many employers, increasingly concerned about rising health care costs, have implemented corporate wellness programs that use workplaces as venues for promoting individual health behaviors (such as healthy eating and increased exercise). However, recent research demonstrates that these programs are not very effective and have only limited positive influence on employee health outcomes, medical costs, and productivity.
In contrast to wellness programs, the approach we offer in this toolkit emphasizes the importance of targeting and changing work conditions—that is, how workplace practices and relationships are designed and organized. Ample research has demonstrated that these are often the real root causes of employee ill health and stress.”
The initiative contends that “three work dynamics—job control, job demands, and social relationships at work— are root drivers of many forms of worker health,” and emphasizes that by addressing these issues organizationally, with employee/management partnership (which should be in the enlightened self-interest of both), and by also focusing on the emerging principles of promoting positive health (vs avoiding negative health; see my discussion here), healthier workplaces are possible.
What a hopeful vision for the upcoming year.
Best wishes for a healthier, happier, and more positive 2022.
Note to readers: reflecting the evolving focus of both my work and writing, the column will now be called “KindWellHealth.” It will concentrate on health, wellness, flourishing, and entrepreneurship. The core principles and priorities are unchanged: I remain firmly grounded in science, cautiously optimistic about technology, and centered, as always, on people. Column-related inquires can now be sent to me here: Writing@KindWellHealth.com.
Over the past week I have been reflecting on what we know now, two years into a seemingly unending pandemic.
One of the biggest failures has been with testing.
At first, our only effective defenses were masking and social distancing. We were slow to ramp up testing, unable to give most people the timely information they could use to isolate and curb the spread.
As the first year went on, we got better and better at testing. First came PCR, then rapid antigen tests.
At the start of 2021, we began to think that testing was less necessary. Vaccination, many hoped, would bring the end of COVID all on its own. Masking became inconsistent and despised. Testing declined – to the extent that a major US rapid test antigen company began to wind down a manufacturing plant in the summer of 2021.
Now at the end of 2021, it is clear that the virus has continued to evolve in dangerous ways.
It has kept pace, and in some ways is outpacing our best efforts. Rapid antigen tests are now reportedly in short supply in many parts of the country, right at the time they are needed most. New more transmissible variants are emerging every ~100 days. The newly emergent Omicron variant contains all the best/worst mutations of earlier variants that contribute to transmissibility and immune escape, plus an unprecedented number of mutations of which we know little or nothing.
Today, the CDC reported that Omicron makes up about 73 percent of new US cases. It took two weeks to reach that threshold. Delta needed four weeks to reach that level, and Alpha took 12 weeks. [Clarification, 12:40 pm PT Dec. 28: On Dec. 28, the CDC revised this estimate of Omicron incidence downward from 73 percent to 23 percent of new cases for the week ending Dec. 18.–LT]
In 2022, we will add effective treatments for the more seriously ill. But instead of putting all our eggs in one basket, we must mobilize all the tools at our disposal to return to “normal”, whatever that will turn out to be. Masking, vaccination, improved indoor ventilation, and the fast, low-cost and frequent self-testing that empowers individuals to manage their own health, their family health, and their community health.
Effective testing depends on how, when and where the virus replicates and the natural progression of resulting infections. A major challenge to our early understanding was that all our data came only from the sickest patients in hospital.
How did testing become so much easier, simpler and cheaper?
We have decent answers to four key scientific questions that put us in much better position than we were in two years ago:
Stopping the chain of transmission requires tests that identify the infectious subset of the infected. If the upper respiratory viral load is high enough, secondary aerosol transmission can occur, especially in closed spaces where vocalization is happening (e.g. choirs, basketball arenas, bars and restaurants).
High viral loads have been identified in all infectees: vaccinated or not; asymptomatic, pre-symptomatic, peak symptomatic, or early post symptomatic. This is to be expected, as the vaccines were designed to stimulate systemic immunity to save lives – they weren’t designed to prevent infection and transmission (although some scientists hoped they might do it all).
Optimizing the testing protocols for increasingly available rapid antigen tests depend on studies of the end-to-end natural history of disease in the same individuals over time (i.e. longitudinal, not cross-sectional) — from pre-infection, first positive test, peak infection, through viral clearance across all degrees of illness severity. This data is harder to find, mainly because it’s harder to collect than cross-sectional data.
But we do have some data to help guide us here.
A July 2021 Singapore study of hospitalized patients with Delta variant infections, who were previously given mRNA vaccines, showed that peak viral loads were similar between vaccinated and unvaccinated patients, but that the vaccinated had less severe illness and cleared the virus consistently faster (see adapted study Fig. 1).
One caveat: only the seriously symptomatic were included in this study.
A December 2021 letter in the New England Journal of Medicine confirms these insights in the National Basketball Association’s 2020/2021 longitudinal screening program in a group of 173 healthy individuals (60% players/40% staff), PCR tested 19,941 times (before Omicron emerged):
Based on these data, we can conclude a few things.
Vaccines are still extremely valuable tools, but they are one layer of protection out of many.
To curb the rate of spread and keep our hospitals from being overwhelmed, we need to massively increase both the number of people who test, and how often we test, while being highly diligent in masking – even for the vaccinated and boosted. Otherwise, we’ll continue to fly blind during another very long and painful winter.
Today’s guest on The Long Run is Vineeta Agarwala.
Vineeta is a general partner with Andreesen Horowitz’s bio fund.
Vineeta has spent a lot of time on the front lines of an explosion in biological data, and efforts to analyze it to develop better therapeutics, diagnostics and digital health applications. Before coming to A16Z, she worked at GV and Flatiron Health, among other stops.
I first spoke with Vineeta in 2019 when she, along with colleagues at Flatiron Health and Foundation Medicine, published a paper in the Journal of the American Medical Association. The paper focused on non-small cell lung cancer outcomes for patients, based on their tumor genomic characteristics. It’s a fascinating piece of work, offering a glimpse into what might be possible for personalized medicine and a “learning” health data system.
See the full JAMA article here.
In this episode, Vineeta talks about her career journey this moment of possibility in biotech, how to make more use of engineering and computation in biotech, and some of the other challenges on her mind as she considers investments in early-stage startups.
Today’s sponsor, Answerthink, has been consistently recognized by SAP, one of the largest enterprise software companies, as a top business partner for delivering and implementing SAP solutions for small and midsized life science companies. Their SAP certified solutions designed for the Life Science Industry are preconfigured, rapidly deployable and address fundamental business and IT challenges such as:
Explore how Answerthink can streamline your business processes to ensure growth.
Visit Answerthink.com/timmerman and get a copy of the e-book — “Top Three Barriers to Growth for Life Science Organizations.”
Absci is all about creating new possibilities in the realm of protein-based therapeutics. What does this mean?
Absci has a fundamentally different approach to drug discovery. It designs and develops next-gen biologics of any modality, from antibodies to T-cell engagers to completely novel protein scaffolds, including a futuristic format it calls “Bionic Proteins.”
Because Absci conducts its screens in its scalable production cell line, it collapses several steps of biologics discovery into one integrated, efficient process. Absci also has a unique computational antibody and antigen discovery approach for isolating fully-human antibodies from disease tissues and using these antibodies to identify novel drug targets.
Absci does all this with a powerful combination of deep learning AI and synthetic biology technologies. Absci is already helping some of the best partners in biopharma translate their ideas into drugs. Check them out at absci.com and absci.ai.
Now please join me and Vineeta Agarwala on The Long Run.
I think I have seen enough. We cannot fight an exponential rise with linear thinking and processes. And yet, this is what we keep doing.
On that optimistic note, some background for those of you who are new to my cranky musings. As many of you know, I wrote here on Nov. 26 about the emergence of Omicron as an ominous new Variant of Concern.
What follows is a (fairly wonky) post to discuss how serious this new threat is. There were many “known unknowns” at the time: in the intervening period, some of them are now much clearer. I thought of sharing the evidence, completely unprompted by my gracious editor as well as by the (many) emails from readers.
If you want the TL;DR version: get a third dose of a vaccine as soon as possible (and I mean now, really). And be very, very careful this winter in the Northern Hemisphere, and keep layering non-pharmaceutical interventions (masks, tests) to stay safe.
Previous unknown #1: is Omicron much more transmissible than Delta?
The circumstantial evidence was already fairly strong: S. Africa’s commendable genome surveillance effort noticed a rapid spread in a predominantly Delta background (over a very short period of time). There is now incontrovertible evidence that this is indeed the case: (FT coverage) in both the UK and Denmark, also countries performing an admirable job in genome surveillance and sequencing of viral infections, Omicron is going to be the predominant variant within a few days (again, on a Delta prevalent background).
The doubling time in cases in both UK and Denmark seems to track around 2 days. That’s shocking. The Rt for the virus (a measure of transmissibility) is estimated at ~6 with Omicron, which is (very roughly) a 400-500% increase over Delta (also a shocking statistic).
As I type this in the evening of Dec. 14, the Washington Post is reporting on the CDC warning that their modelling is showing worst-case scenario of Omicron spreading could overwhelm health systems by January, particularly in under-vaccinated communities. More on the un-vaccinated below.
Answer: yes, way more transmissible.
Previous unknown #2: Is Omicron able to evade previous immunity more effectively than Delta? AND: Previous unknown #3: Will the vaccine protect against Omicron?
Again, here the circumstantial evidence from South Africa was fairly strong: Omicron spread in the background of a population having undergone a massive Delta wave just several months prior, leaving an estimate of ~70% of the population recently exposed to Delta and therefore having (presumably) some meaningful level of pre-existing immunity. We now have more consistent data (still more to come) that show just how much is Omicron capable of evading the immune system.
Quoting from one of the many papers published over the last few days in pre-print servers:
“Using isolates of SARS-CoV-2 WT, Beta, Delta and most importantly Omicron we studied the capability of the BNT162b2 vaccine given in two or three doses to neutralize major SARS-CoV-2 variants of concern (VOC). We demonstrate low neutralization efficiency against delta and wild-type for vaccines with more than 5 months following the second BNT162b2 dose, with no neutralization efficiency against Omicron. We demonstrate the importance of a third dose, by showing a 100-fold increase in neutralization efficiency of Omicron following a third dose, with a 4-fold reduced neutralization compared to that against the Delta VOC. The durability of the effect of the third dose is yet to be determined.” (59425721 (medrxiv.org).
Another recent study using Pfizer/BioNTech vaccine showed that protection against hospitalization fell to 70% (from 93% with Delta) and against infection to 33% (from 80% with Delta).
Now, there is a lot to unpack here, so let me elaborate. Vaccine-induced antibody levels from two doses of the Pfizer/BioNTech COVID-19 vaccine, seems to drop substantially against Delta after 5 months from the second dose and to practically completely drop against Omicron.
Some caveats are in order: antibodies are not the only defense the body has against a viral infection (there are other arms of the immune system which are more difficult to monitor that have a significant role, see Dec. 14 Timmerman Report article from Harlan Robins). It is expected that some protection against hospitalizations and deaths will still be in place with a two-dose vaccine. Efficacy from therapeutic antibodies also seems to drop significantly against Omicron, with many losing their neutralizing effect against this new version of the virus. The good news is that a third dose of the vaccine restored very high level of neutralizing antibodies against both Delta and Omicron.
Answer: yes, able to evade existing immunity way more effectively than Delta. Vaccines (three doses, less so for two) appear to still be strongly protective against severe disease. A two-dose regimen seems to still show substantial reduction in efficacy against hospitalization (down to ~70% from >90% previously) at least in the few months following the last dose administered.
Still unknown #1: is Omicron “milder” than Delta or the other variants (or will it cause more severe disease)?
That is definitely still unclear. However, dark clouds loom on the horizon. Many people are pointing to data on hospitalizations from S. Africa in the current Omicron wave vs the previous Delta wave to state that, individually (crucial word, that one: we will come back to that), Omicron does not seem to cause more severe infections than Delta.
I would like to spare you the (by now routine) reminders that increase in cases precede increases in hospitalizations by 2-3 weeks, and hospitalizations precede increases in fatalities by 2-3 weeks. But these facts bear repeating.
South Africa might also provide us with a misleading comparison. It has a very young general population (average age of 27-28), it is in its late spring-early summer (with less mixing in indoor / poorly ventilated spaces), and it just had a massive Delta wave just a few months prior (during the end of their winter). All those factors could be contributing to a lower proportion of severe infections requiring hospitalization. As a counterbalancing argument, S. Africa has ~20% of its population infected with HIV, which should increase the severity of Omicron infections.
So, if South Africa might not be the right comparator, where should we look? The UK and Denmark should be considered the canary in the coal mine here: both have excellent genomic surveillance and sequencing (see above), they are now in winter, and have older population than S. Africa (~40.5 in UK and 42 in Denmark, thanks Wikipedia: the US is at roughly 37).
There are, of course, differences in public health measures between these two countries. The UK started its vaccination campaign with AZ’s vaccine, which does not confer the same level of protection as early as the mRNA ones (they are now boosting with mRNA). I do not know also the various % of people in vulnerable populations vaccinated in each country. Caveats abound.
Therefore, there is a gradient, or sliding scale if you will, to consider, when looking at the data coming in from those two countries in the coming days. That said, it is absolutely clear that the Omicron’s spread has taken authorities by surprise (not many virologists / epidemiologists, I have to say, but then, if the world listened to them, we would not be here). On Dec. 13, the UK reported an estimated 200,000 cases, with 20% attributed to Omicron, as well as the first death related to the variant. I am afraid this is only the beginning.
Answer: we still don’t know but it might not matter this winter (see below).
OK, skip the technical jargon and take us to the gloomy projections!
Let’s assume for a minute (and I emphatically do not believe this should be our base case) that Omicron does indeed cause mild symptoms and very few breakthrough infections in people who are fully vaccinated (and by fully vaccinated, I mean three doses).
Why am I writing this article in the middle of the night?? There is, shockingly, still a startling amount of misunderstanding about the impact of a fast spreading variant. Let me clarify.
Always known (and always forgotten) #1: a more transmissible / less severe variant is much more dangerous than a less transmissible / more severe variant.
Not to stray too far from the beaten path here, but compare Omicron (or even the original SARS-CoV-2 strain) to SARS-CoV-1 or the MERS virus (all coronaviruses): perhaps a 1-2% Case Fatality Rate versus ~10-15% for the first SARS in 2002-2003 and ~40-50% for MERS in 2012.
The first two coronavirus outbreaks caused an almost infinitesimally small number of deaths compared with SARS-CoV-2. The differences this time: much higher transmissibility and a large number of asymptomatic patients with SARS-CoV-2; and vastly more people travelling (• Global passenger air traffic each year, 2004-2022 | Statista).
The current death toll in the US from the pandemic has just touched 800,000. To put this in perspective, this is more than the US casualties from WWI, WWII, the Korean and Vietnam wars combined.
The latest data from CDC indicates only ~55 million people have been vaccinated with a three-dose regimen (that is ~17% of the population). People who have received two doses are roughly 61% of the US population: A large percentage of these people will be protected (especially if they have gotten their second dose recently).
People who have NOT received a single dose are 28% of the population. And these vaccines refuseniks concentrate in areas with a complete disregard for other mitigating public health measures (masks, no congregating indoor etc.). These are potentially very vulnerable not just to Omicron but to Delta, which is already prevalent. In general, even should Omicron result in a smaller percentage of non-vaccinated people progressing to severe disease, even a small percentage of a very large number is still a very large number!
There is simply not enough time, even assuming everybody who still has to be vaccinated will be miraculously convinced in the next couple of weeks, to vaccinate everybody before Omicron takes over. The US might have 1-2 weeks advantage vs the UK and Denmark but I find it increasingly difficult to believe we will escape this variant unscathed.
The other factor to consider is the following: because of its much higher transmissibility and spread, Omicron might overwhelm healthcare systems just by compressing a lot of cases in a very short period of time. Even with a smaller % of cases requiring hospitalizations, if you compress millions of cases in a period of weeks instead of months, many more people will need treatment.
This tsunami is coming at a vulnerable moment in healthcare. The never-discussed-enough fact is that healthcare professionals are exhausted and despondent after nearly two years of caring for a general population which has taken their selfless sacrifice and abnegation for granted. Nurses are leaving the medical profession in droves. It is frankly shocking how much we are demanding of and taking for granted from these incredible professionals, and how little we are willing to do as a country to support them.
What else is left to say? We have seen this movie already a few times. To quote Jon Levy, Prof. of Environmental Health at Boston University (@jonlevyBU):
“We keep making the same mistakes. We treat a global problem like a domestic one, and a public health problem like a medical one. We localize what should be national and individualize what should be collective. We forget about lags between cases and deaths, and ignore morbidity.”
In doing so, as aptly put by George Santayana, “Those who forget history are condemned to repeat it.”
Stay safe, and Buon Natale to you all. I do wish for all of you a merrier 2022 than what I am expecting.
It’s time to include T cells in the fight against COVID-19.
The scientific community brought novel vaccines to the world in less than a year. That heroic work saved millions of lives. These vaccines were designed specifically to induce antibodies that target the spike protein and disable the virus, blocking it from entering the ACE2 receptor on cells.
Like other vaccines, efficacy was largely measured by using tried and true technology — cheap, simple assays that almost any lab around the world can run — to count the number of neutralizing antibodies against the spike protein.
We knew the target (we thought). This strategy worked brilliantly with the original strain – even better than we had hoped.
But much to our surprise, the virus started to mutate faster. Like other coronaviruses, SARS-CoV-2 is a long RNA virus with an enzyme that self-corrects errors in its genetic code. Therefore, we expected it to evolve slowly. Shorter RNA viruses such as influenza or HIV don’t have this error correction capability. They mutate regularly, which makes these viruses especially difficult moving targets for vaccine developers.
Now we know SARS-CoV-2 is a tough adversary for vaccine development. As the virus started mutating and moved through the Greek alphabet, it successfully evaded much of the neutralizing antibody response induced by vaccines or previous infection-induced immunity.
The neutralizing antibody response has fallen off dramatically – a 40-fold drop against the Omicron variant, according to an early report out of South Africa. But that worrisome development hasn’t yet translated into a real-world drop in vaccine efficacy. How could that be?
The current hypothesis is because of the T cell response, the other primary mechanism by which the adaptive immune system fights viruses. Antibodies prevent the virus from entering cells. T cells locate and kill cells that have been infected by a recognizable pathogen.
Evidence has been mounting in recent months demonstrating that T cells bind to more parts of the SARS-CoV-2 virus than antibodies, which makes it much more difficult for the virus to escape killer T-cells, also known as CD8+ T-cells. In fact, T-cell levels are correlating directly with real-world vaccine efficacy.
Sure, there were breakthrough infections by the time the Delta variant swept the world, but thanks to T cells, hospitalization and death rates among vaccinated individuals were extremely low.
Historically, antibodies have been used as the main measure of vaccine response because they are well-understood and easy to measure. As opposed to a simple blood-based serology test to measure antibodies, the traditional methods for measuring the T cell response require functional assays that use live cells. Since live cells are finicky, these assays are virtually impossible to standardize and run at scale. Also, functional assays require samples to be viably frozen, which is not possible in a global study. As a result, the T cell assessments that have been done on COVID vaccine studies to date have been done by special labs for a small fraction of participants in the vaccine studies.
But we are in a new age of medicine. The tools exist today to measure T-cell response quickly, at scale and cost efficiently. We now have molecular assays that can assess the T cell response using DNA from blood that is compatible with almost any sample handling and shipping protocols.
It’s time to start using them.
Unfortunately, we are now sitting on the edge of efficacy with the present vaccines. With Omicron, we are seeing neutralizing antibody levels drop to less than 10% of the level seen with previous variants. Even T cell levels, which have held steady in vaccinated people for long past six months, are also starting to drop.
We at Adaptive Biotechnologies, along with colleagues at Stanford University, just published last week that the number of circulating T-cells that can kill Omicron has dipped to about 70 percent of the levels seen against the original strain.
This is predicted by determining which T cell epitopes – parts of the Spike gene that T cells bind – are impacted by the Omicron mutations. For each T cell epitope, we have measured the size of the T cell response. So, we can determine how much of the response is lost due to the mutations.
A third shot of an mRNA vaccine six months after the first round of shots will likely provide a reasonable level of protection. But there is still high risk that the protection will drop even farther with the next variant.
It’s time to rethink vaccine design to take advantage of the T-cell response. If we continue to only focus on neutralizing antibodies as the measurement most predictive of vaccine efficacy, we will wind up with new vaccines designed for mutations that are no longer relevant. We cannot afford to make this mistake.
We need to look at both neutralizing antibodies, and T-cells, to get a more comprehensive view of the breadth and depth of immunity being elicited by new vaccine candidates. We need to take these measurements consistently and longitudinally. We need to know how long the protection is likely to last and we need to make sure that a robust T cell response is induced in everyone.
We – and others – have been raising the alarm about the importance of T cells for the last year and our pleas have fallen on deaf ears. As mentioned above, the T cell response was not practical to measure at scale and neutralizing antibodies for other vaccines served as a good correlate of protection. But we now have better measurement tools and SARS-CoV-2 vaccine efficacy is remaining strong even when antibodies are ineffective. The T cell response must be included at scale in all vaccine studies, and now it’s possible to do so.
This has life and death significance. It is imperative to leverage existing technologies to rigorously study the complete immune response to advance vaccine and drug development, inform public health and guide individual decision-making. Companies like Nykode and Gritstone are working on novel vaccines that consider the breadth of the T cell response. More should be following suit.
The world has changed. We should be nervous. We should be acting immediately to develop vaccines that consider both antibody and T cell responses systemically. The time is now.