Fielding COVID Questions

I haven’t written a COVID blog in a while (too busy chasing my toddler). But I’ve been fielding the same COVID questions from people, so it’s maybe more efficient to put it in writing. First, I thought it would be worthwhile to examine a tough question I received in February 2021, more than year ago. Back then, vaccine was just beginning to roll out and the end of the pandemic was in sight. I was asked to project what life would be like in 2022. Did I miss the mark?

Hi Martha, I hope you’re well! I have greatly enjoyed and appreciated your posting about the pandemic since the spring. I wanted to reach out with a few life updates as well as a question. I graduated from medical school last spring and started my internal medicine training at XXX College of Medicine, and I am loving it! I’m considering cardiology or GI fellowships post-residency, and I’ll be starting cardiology research in the coming weeks. On a personal note, I got engaged about a year ago! XXX (my fiancée) and I have begun wedding planning in hopes of getting married in 2022. We are considering options ranging from May to August for 150 people in NYC. That is where my question comes in. I know no one has a crystal ball and that modeling cannot perfectly capture reality. From a COVID perspective, do you have an opinion as to when is the beginning of an appropriate time period in 2022 to consider having an event that would be indoors for approximately 150 people? We have an option for May 28th that we are considering and also are looking at August 20th. Do you think end of May 2022 is too soon? I am wondering if you think pushing the date to August is likely to significantly decrease any COVID risk? I recognize it’s hard to give answers to these questions, but I felt that getting the opinion of an expert could really help us decide, and I value your opinion. Thank you very much for your any thoughts you may have. I know I owe everyone a more thorough update, but please say hello to everyone from me! All the best, XXX

Hi XXX, It’s great to here from you! Congratulations on….EVERYTHING. You can imagine I get these questions a lot. The big unknown is variants. We can get America’s adults vaccinated by 2022. But could there be a new crop of variants in 2022 that are not as well protected by vaccines? We’re kind of setting the stage for that to happen by having a partially immunized population and a UK highly transmissible variant rising fast that could led [sic] to large numbers of infections in a population with incomplete immunity and strong selection for immune-escape variants. Without a crystal ball here’s how I’d lay out your options: Option 1: Outdoor wedding. Option 2: 50 person wedding. Option 3: 2023 wedding.

I don’t know if my friend took my advice on his 150-person indoor wedding or not. I know the answer I gave him was not the one he wanted. But I know that my mom got infected during an outbreak at an indoor wedding held during spring of 2022 (she’s fully recovered now). The “UK highly transmissible variant” I referred to was alpha, which never caused the massive wave in the US that it did in the UK, but was a harbinger of the delta and omicron variants to come. But I understand where he was coming from. Back in February 2021 most Americans believed the pandemic was essentially over once they got the vaccine in their arm. No one understood why I wasn’t so convinced. In case people are curious what my predictions are today, here are some of the other questions I’ve been answering these past few weeks.

Question: The CDC 5-day isolation rule is confusing. Back when it was 10-day isolation you could be pretty confident that if you “did your time” you were no longer infectious and could go back to life as usual (whatever that is now). Is that still true? Why the shortened isolation? Did the virus really change that much?

Answer: Yes and no. Yes, omicron behaves differently from the original strain. It’s a supercharged virus that replicates really fast, so the timeline of infection and transmission is shorter. But it’s not half. The 5-day isolation period is also a practical compromise with an American economy desperate to get back to work so the trains can run again. The CDC did not state that no transmission occurs after 5 days, only that the *majority* of transmission occurs in the first 5 days. The CDC watered down the policy even more by saying that you needn’t be symptom-free after 5 days, you just needed to have symptoms that were “resolving (no fever within 24 hours.” The CDC also did not require people to test negative before returning to work. They tried to make up for these shortcomings by asking people to mask up for another 5 days (so 5 days isolation + 5 days mask). But this is a pretty leaky set of recommendations.

The upshot is that it’s much easier for Americans to go back to work after a COVID infection, but they’re much more likely to infect other people. So on the plus side, America, if you get infected with COVID, it’s not the 10-day stranglehold it used to be. But on the downside, America, you’re much more likely to encounter still-infectious people wandering around your schools, airline terminals, churches, etc. Is that a good tradeoff or a bad one? You tell me. Practically speaking, if you get infected with COVID, you can still follow the CDC’s 5-day isolation period, but after that don’t just slap on a mask and go back to life as normal (definitely don’t go visit granny at the nursing home). If you still have symptoms, even mild, stay home. Tests aren’t the panacea we once thought they were, but they can give you some indication of whether you’re likely to still be infectious, especially if you test negative multiple days in a row. In the end, just know that you could still be infectious after 5 days and proceed with caution. After 10 days and some negative tests, you can probably relax.

Question: About that “relax”…..at that point I’m like a superhero who can’t get reinfected for at least a few months, right?

Answer: Remember those pesky variants I mentioned back in February 2021 to Mr Wedding? Houston, we still have a variant problem. Omicron is not a single variant, but actually a family of 5 different variants (BA.1-BA.5). If you were infected this spring or early summer you were probably infected with BA.2. Now BA.5 is quickly on the rise and beginning to dominate. Most of the studies done by scientists have been on the BA.1 and BA.2 variants, so the newer BA.5 are not as well characterized. But early data suggests there could be substantial risk of reinfection with BA.5 among those infected with BA.2. The upshot: a period of invulnerability post-infection could be a myth.

BA.5 on the rise in the mid-Atlantic region

Question: Why did it take so long to get the vaccines for young kids approved? Are they safe?

Answer: Vaccine manufacturers like Pfizer knew what kind of volcano would erupt if they made an errors in the kid vaccine. Even if just one kid got seriously ill in clinical trials it would be game over. The wave of vaccine hesitancy made them even more cautious. So it’s understandable why they started their trials with a really low dosage in the under-5 vaccine (3 micrograms, whereas the adult Pfizer dose has 30). Pfizer erred on the side of caution. Well, it turns out they erred a little too far. The vaccine barely made a blip in antibody response. So they had to go back and add a third dose. But the third dose was given 8 weeks after doses 1 and 2, meaning it takes 3 months for a kid getting the Pfizer vaccine to be considered fully vaccinated.

The Moderna under-5 vaccine has 25 micrograms in each shot (the Moderna adult vaccine has 100). When I had to make a personal decision about my own vaccination, I opted for the more potent Moderna vaccine over Pfizer. Moderna does appear to have longer-lasting immune protection than Pfizer.

It’s understandable that American parents are confused about the differences between the Pfizer and Moderna vaccines, the different dosing schedules, and skeptical of a vaccine that seemed to have a number of false starts. But I consider it a good thing that parents have options. Those, like me, who want to get their kid maximally protected in the shortest time possible, can opt for Moderna. Those who are more cautious and prefer a lower-dose regimen over a longer wait-and-see time window can choose Pfizer. This is America, and we have both Coke and Pepsi. The math is pretty straightforward that 2 doses of Moderna (25 + 25) is still much higher than 3 doses of Pfizer (3 + 3 + 3). Like the adult vaccine, the Pfizer vaccine will still protect, but that protecting might wane more quickly.

Speaking of my kid, I need to go pack his lunch pronto! Let me know if I missed any burning questions. We didn’t even get to international travel yet.

Flirting with Normalcy in Year 3 of the Pandemic

Americans’ desire for normalcy is beginning to outweigh fear of the virus. But as we loosen the belt, we need to do so strategically. A guiding principle is to loosen the belt during refractory periods between variant waves and tighten the belt as variants spread like wildfire to “flatten the curve” on explosive growth to keep medical systems intact. The CDC’s recent misfire on the shortened quarantine/isolation recommendations was a case study of how not to do it, loosening policies just as omicron tore through the nation, which flew in the face of common sense and enraged everyone except airline CEOs.

Masks

Where to tighten the belt: Quality matters (especially during omicron). We’ve graduated from the early days of wearing drippy cloth masks and bandanas everywhere we go. If you’re going to wear a mask, use it properly and strategically in high risk settings. Tip: to avoid counterfeit N95 and KN95 masks shop at a reliable source like the non-profit projectn95.org.

Where to keep the belt tight: High risk environments. Wear masks in indoor public places (e.g., while shopping, public transit, airports, church, etc.) As a rule of thumb, wear a mask if you’re indoors around people whose names you don’t know, especially if you can’t socially distance.

Where to loosen the belt: Follow the rest of the world when it comes to young children and masks. Every morning I drop my 3-year old son off at preschool where kids ages 2-5 run around outside wearing masks. The kids are good sports; most keep their masks on. But you wouldn’t observe a scene like this in most of Europe, or most other countries. Do masks reduce transmission? Sure (Probably.) (When worn properly.) (When quality is high, especially against highly transmissible omicron.) But the World Health Organization does not recommend masks for young age groups, reasonably weighing COVID-19 risks for young children against the costs of lost empathy and socialization that comes with learning to read faces at early ages. Most small children realistically can’t wear N95s or KN95s anyway. My son Bjorn is resilient and highly social and will likely bounce back from a short delay in acquiring social skills. But I prefer not to gamble with my son’s future unless it’s absolutely medically necessary. I surreptitiously slip off my mask to sneak tiny Bjorn a goodbye kiss and flash him a big smile before I leave him for the day. It’s against the rules and the strict teacher Megan scolds me. She’s trying to maintain order and safety. But we’re outdoors, 6 feet from other kids, and it’s the last genuine smile Bjorn will see for 8 hours. If a liberal, COVID-wary, science-driven mom like me (who never stopped wearing masks in grocery stores, even in July when everyone else shed them) thinks the mask mandate for young children is a bit draconian, and may do more harm to my child than good, Democrats should brace for a bloodbath at midterm elections.

Where to loosen the belt: Outdoors.

Vaccines

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Where to tighten the belt:

– Update CDC definition of “fully vaccinated” in light of omicron. Less than 50% of Americans considered “fully vaccinated” have had a booster.

America, the country that pioneered mRNA vaccines, lags countries like Vietnam and Uruguay in vaccination rates.
This UK data is mostly on the AstraZeneca vaccine and is not fully translatable to the US, but the overall patterns are similar.

– Increase booster uptake by correcting misleading narrative that omicron is “mild.” The death rate from omicron is higher than delta in the US.

So much for omicron being “mild”

Isolation and quarantine.

Where to tighten the belt: Isolating at first sign of cold symptoms, especially during variant waves: Back in 2020 the key COVID symptoms were fever, cough, shortness of breath, loss of taste, but omicron symptoms have shifted to common cold symptoms like runny nose, headache, fatigue, sneezing and sore throat. Isolating (hard and early) is even more important for omicron, where transmission occurs at earlier stages of infection. Your sore throat is also not likely to be not flu. Other respiratory viruses like influenza have continued to be repressed during the pandemic. In fact, one of the 4 influenza virus strains in the quadrivalent flu vaccine (B/Yamagata lineage) seems to have gone extinct globally simply because people move around less, reducing opportunities for transmission.

Influenza continues to be in retreat during the pandemic’s 2nd winter

Where to loosen the belt: I agreed in spirit with the CDC’s recent decision to shorten the isolation period for asymptomatic infections from 10 to 5 days. The policy change was partly based on science (omicron has a shorter incubation period) and partly an effort to keep America operational. During omicron many businesses (notably airlines) lost so many staff to isolation and quarantine they could barely operate. The CDC was trying to be practical and be so not knee-jerk in “safely” picking the most conservative path, to balance disease control with societal functionality. But the timing was awful. Doctors and nurses already felt like sacrificial lambs as omicron cases skyrocketed, overwhelming hospitals. Optically, in tampering with a core component of outbreak control CDC seemed to be favoring business interests over the medical system. It makes sense to shorten the isolation period, but control the tsunami of infections first.

Plus, the CDC protocol has holes. For example, which of these scenarios do you think poses less risk to others?

(A) An unvaccinated person isolating for 5 days and then going to a large indoor concert on Day 6 (wearing a mask).

(B) A vaccinated person isolating for 5 days and then on Day 6 going for a solo run/walk in an uncrowded park (not wearing a mask).

The answer is B.

And which scenario violates CDC protocol?

B again.

This is nothing compared to the flowchart on whether Novak Djokovic could enter Australia.

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The Path Forward: An Interview with Myself

Interviewer: Nice to see you. You haven’t said anything in a while.

Me: I’m burned out.

Interviewer: Join the club. But we’re out of this pandemic hellhole soon, right?

Me: I have no crystal ball. But we’ve been watching respiratory virus pandemics for more than a hundred years. There have been at least five – 1889, 1918, 1957, 1968, 2009 – and each one behaves like the month of March: in like a lion, out like a lamb. The virus rips around the world for a couple years, killing millions, and then settles into a steady endemic state of seasonal outbreaks. 

Interviewer: Why? The virus evolves to be milder?

Me: Possibly, but it’s more of a buildup of human immunity as more people get infected or vaccinated. 

Interviewer: Like Islamic terrorism. Terrorists didn’t lay low after 9/11, we just strengthened our defenses.

Me: Sure. 

Interviewer: There’s this idea that viruses evolve to become milder over time because that helps them transmit better.

Me: Part truth, part myth. Respiratory viruses kill you when they dive deep into the lower respiratory tract and flood the lungs. But they transmit more efficiently from the upper respiratory tract. There are somewhat different cellular receptors for viruses to bind in the upper versus lower tracts, so there’s a degree of tradeoff.

Interviewer: So that’s why Omicron transmits better but isn’t quite as deadly. It shifted its receptor binding more towards the upper airway. 

Me: Exactly. But it’s worth pointing out that Omicron deaths have already exceeded Delta deaths. The rate of mortality may be lower, but when the denominator of infected people is so high, that’s still a surge of deaths. It’s misleading to call Omicron “mild.” 

Interviewer: But plenty of governments have cited Omicron’s lower death rate as justification for lifting restrictions.

Me: Right, that’s why hospitals are overflowing, ambulances are lining up outside hospitals, medical staff are cracking and quitting, and medical systems are being hollowed out. You think the grocery aisle looks bare. 

Interviewer: Really? It’s that bad.

Me: It’s a vicious cycle. As more healthcare workers quit, the remaining staff get overburdened and more likely to fold too. Some proactive states like Maryland have called in the National Guard to help with hospital staff shortages. But many hospital workers who once felt like heroes now feel abandoned and betrayed.

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Interviewer: America is cracking.

Me: People are cracking because there is no light at the end of the tunnel and the goal posts keep moving. Everyone was told to get vaccinated and life would go back to normal. It feels like a bait and switch. 

Interviewer: So when does this magical shift occur where SARS-CoV-2 becomes a normal seasonal virus we treat like influenza? Are we there yet?

Me: I need to be honest here. When we do cross the COVID-19 finish line there will be nothing satisfying like breaking the tape. No confetti. No war armistice and parades in the street, with hero scientists kissed by beautiful girls. It’ll more like when you don’t know if your partner finished but you’re tired and go to sleep anyway and will eventually find out in the morning.

Interviewer: Ha! You mean the end of Omicron wave could be the end of the pandemic. Or not. It’s anyone’s guess.

Me: Yes, and we’ll be fools if we try to have some Fourth of July celebration in February when Omicrons settles down and we prematurely declare a return to normalcy. We already read that book last summer.

Interviewer: So we just keep going in this interminable void? This is torture. How many people have to get naturally infected or vaccinated before we reach herd immunity?

Me: Let’s be real, there will never be herd immunity. Herd immunity is the gold standard where the virus gets wiped out entirely, like what happened to measles and polio in the 1990s in America. We’re not even going to get close for a many reasons: low vaccine uptake, waning immunity over time, pathogen evolution. Three strikes.

Interviewer: You’re killing me.

Me: This is not doomsday. Humans have been coexisting with deadly pathogens since the dawn of civilization. Realistically, we accept a certain level of death by pathogen as the cost of cities, transport ,and modern economies. We made peace with the equilibrium 10,000 years ago, the same way we’ve made peace with a certain number of automobile fatalities so we can cruise around comfortably in cars. Trying to prevent every death will strangle society.

Interviewer: “Strangled” is how many Americans feel right now. How do we decide what the acceptable number of deaths is.

Me: Remember in April 2020 when it was all about “bending the curve?” We had an explicit goal to keep hospitalizations and deaths low enough so our medical system didn’t collapse.

Interviewer: You don’t hear about bending the curve anymore. 

Me: Go figure. Two years later, we still have the same goal of not decimating the medical system.

Interviewer: Two years later we’ve lost the spirit of cooperation. It’s every man for himself. 

Me: Vaccine holdouts crushed any spirit of cooperation. 

Interviewer: Right, if you died from COVID-19 in 2020 you were a victim. Now you’re just an idiot.

Me: But we’ve forgotten the hospital workers who have to tend to those sick people. The same nurses we desperately need as Baby Boomers age. Our medical system was broken going into COVID-19; god knows what shipwreck we’ll have coming out.

Interviewer: So what should our strategy be right now?

Me: Flattening the curve has been the strategy from day 1. When a wave hits, everyone mobilizes into a new wartime mindset and makes small sacrifices. I was supposed to go on vacation in mid-January as Omicron was surging. I could (a) stick to my travel plans, enjoy my vacation triple-boosted and with low risk to myself; or (b) delay my travel plans by 3-6 weeks to a time when Omicron is not spreading like wildfire. You have a choice. You can throw gasoline on the fire, or you can be the kid that didn’t immediately grab for the marshmallow. We all knew Omicron was coming, we saw the havoc it wrecked in South Africa, we just lost our will.

Interviewer: Bad timing before the holidays.

Me: Yes. But Omicron is starting to go down and there will be a better time to travel soon.

Interviewer: When it’s safer.

Me: It’s not just about personal safety. It’s about not being a vector.

Interviewer: So why exactly is Omicron going down right now? 

Me: Million dollar question. We obviously haven’t reached herd immunity, but we met some immunity threshold that just tips the scales for the virus. And you can see different states reach that Omicron peak at different times based on when the wave started.

Interviewer: By now aren’t all Americans either vaccinated or have been infected? Shouldn’t it be getting much harder for the virus to transmit in America? 

Me: In theory, yes. But immunity wanes. So if you were infected in 2020 your antibodies may have dipped to levels that won’t provide much protection in 2022, particularly to a strain like Omicron that has so many spike protein mutations and looks so different to the immune system. 

Interviewer: But isn’t it good to have a sharp Omicron peak, meet that immunity threshold sooner rather than later, so the Omicron wave is one short big spike and we can go back to our lives sooner. Let’s rip the bandaid fast.

Me: That’s a nice theory, but during a pandemic healthcare workers are like firefighters. It’s better to have a manageable situation even if it lasts a little longer than a dangerous situation spiraling out of control.

Interviewer: How are we going to figure out when the pandemic peters out if we can’t even figure out why the Omicron wave ends?

Me: We need to be square with people. Yes, we will at some point reach an equilibrium with SARS-CoV-2. SARS-CoV-2 is here to stay, but the pandemic will end.

Interviewer: What does that even mean? Is there some arbitrary number of deaths that make something pandemic versus endemic?

Me: No. And I understand the confusion. What defines endemic versus pandemic is seasonality. Influenza is now endemic because it only causes winter epidemics. The virus doesn’t have enough traction to rip through America during summer, even if travelers from the Southern hemisphere bring it in. Seasonal flu needs environmental conditions like temperature and humidity to be just right. A pandemic virus has no rules and can tear through any place, any time, regardless of season. Eventually SARS-CoV-2 will settle into regular predictable cycles, like a menstrual period.

Interviewer: And there will be fewer total deaths each year?

Me: Likely. A virus that isn’t fit enough to transmit during summer also won’t be quite so transmissible during winter.

Interviewer: I think I’m getting it. So we won’t know until this spring and summer if the pandemic is really over.

Me: At least. More importantly, we need to watch what happens in other countries. We can’t keep taking arbitrary victory laps in America while the virus is still ripping through the rest of the world. The pandemic will not end in America before it ends everywhere else. We have this silly notion that because America manages to keep out other plagues in developing countries (parasites, malaria, Ebola, drought, widespread starvation, diarrhea, etc.) with clean water and technology, America is also fortressed against COVID-19. Respiratory viruses play by different rules. That’s why we still have flu, RSV, seasonal colds, and a ton of other viruses, even if we vaccinate a lot more. Flu is no worse most years in Tanzania than in America. Respiratory viruses are the great equalizers.

Interviewer: So not vaccinating the world as fast as possible really was a miss.

Me: Undoubtedly.

Interviewer: So realistically, how do we live with this virus?

Me: When Omicron peters out, we should relax some restrictions. If you ask people to enter a wartime mindset during the Omicron wave, you need to press the release valve when it’s over. 

Interviewer: That’s what people hate, the whiplash. We’re creatures of habit, we hate having the rules constantly changing.

Me: I hear that. Personally, I’d rather the rules follow the science, just as I modulate my driving speed based on the weather conditions. But I get that we are creatures of habit. My toddler can adapt to wearing masks all day at school, but probably would be less compliant if the mask rules changed every couple weeks. 

Interviewer: We can see weather with our own eyes and judge for ourselves. COVID-19 is different. When you commented earlier that our spirit of cooperation was eroded by vaccine holdouts, you could add that people lost faith in government. No one follows a leader spinning you in circles. 

Me: There’s a communication breakdown here. These natural cyclical waves of new variants are signatures of pandemics. All past pandemics experienced atypical waves that strayed from standard seasonal disease patterns, the proverbial snowstorms in June. The patterns seem topsy-turvy, but these pulses are totally expected.

Interviewer: But amazing mRNA vaccines weren’t available for past pandemics. Aren’t they a game changer?

Me: Americans love magic bullets. Ask anyone who’s written a diet book. Science is more complicated than that.

Interviewer: But American leadership seemed to drink the vaccine kool-aid too.

Me: They sure did. 

Interviewer: You care to comment on that?

Me: Not really. But it’s not surprising. America loves winners, ask any Yankees or Dallas Cowboy fan (okay, I’m a child of the 1990s). A vaccine that prevents illness is a bonafide winner. We’ll throw resources at that, and rightly so. But a test that tells you if you’re sick or not, that sometimes gives the wrong result, which usually comes too late anyway, and you’re probably not going to contact trace anyway, is not a proven winner anyone wants to touch. Unsurprisingly, when HHS was asked to write a national strategy testing strategy, they passed. Maybe they thought it unnecessary since vaccines were saving the day. Maybe it was wishful thinking. Maybe bureaucrats hate getting barbecued when programs hit snags for reasons outside their control. But it’s a vicious cycle. If you don’t invest in testing, the tests won’t perform so well, so they’ll be less interest in using testing.

Interviewer: This pandemic is chock full of vicious cycles.

Me: Data collection and surveillance are equally messy and convoluted, sapping the will to even try. Bureaucracy can be a bear, even for people trying really hard to get things done. Especially for people trying to get things done.

Interviewer: You care to comment on that?

Me: Pass.

Interviewer: This has been great. Is there any last thing you want to tell people?

Me: Final plea: be civil. Our minds are all wavering under duress. Cut people slack. The pandemic will end, maybe sooner than later, but that’s not when everything goes back to normal, just when the healing begins.

Another Round of COVID Confusion

You heard: Breakthrough infections are uncommon.

What that means: Breakthrough infections are uncommon when you look at the totality of data spanning from when vaccines began to be rolled out in December 2020. The New York Times and other papers often cite a Kaiser Family Foundation report that states Almost all (more than 9 in 10) COVID-19 cases, hospitalizations, and deaths have occurred among people who are unvaccinated or not yet fully vaccinated, in those states reporting breakthrough data (see Figure 2). But data from last spring does not necessarily capture the current picture.

We expect breakthrough infections to become more frequent as more Americans get vaccinated.

We expect breakthrough infections to become more frequent as COVID cases rise, driven by explosive growth in unvaccinated people.

The US is beginning a major Delta wave.

Moreover, there appears to be a higher rate of breakthrough cases since Delta variants ripped across the country this summer, even controlling for the larger population of vaccinated people compared to last spring. See the figure below from Dane County, Wisconsin (yes, it would be useful to have this kind of figure for nationwide data but America has crippling data collection problems). The 7-day rate of infection for unvaccinated residents is almost 3x times higher than fully vaccinated residents (29.1 versus 10.5 per 100,000), showing that vaccines do work. Still, with 68% of the population vaccinated (including 79% of eligible people), this still means many of the cases will be breakthrough (43% breakthrough/57% unvaccinated).

But it’s important not to conflate rising breakthrough cases with reduced effectiveness of the vaccine. It’s always compared to what?

Data from Dane County, Wisconsin. Breakthrough cases per 100,000 of the vaccinated population surge following the emergence of Delta

You heard: Protection from the vaccine is waning and I need a third shot booster.

What that means: Israel was supposed to be the poster child for an effective vaccine campaign that beat back COVID. The country not only received an early supply of Pfizer vaccine but benefits from a highly monitored health system to track the vaccine’s impact. Over 78% of the eligible population was vaccinated by July 1, 2021 and COVID deaths had sunk to zero for the first time since the start of the pandemic. Data was showing that COVID-19 vaccines were not only effective in preventing hospitalization and death, but also in blocking infection and transmission. The feared spring wave of UK Alpha variants never materialized in Israel or the US the way it did in European countries with lower vaccine rates. Vaccine offered salvation. Until it didn’t.

There has been a lot of handwringing about vaccines not working anymore. It sounds bad when of the 515 patients currently hospitalized with severe cases in Israel nearly 60% are vaccinated. Media outlets have quoted this figure to suggest that vaccine effectiveness has waned and third shot boosters are needed.

A helpful COVID-19 Data Science post explains step-by-step how appropriately stratifying by age can change the interpretation of vaccine effectiveness (VE) data. If you’re reading oversimplified VE percentages in the media that are not age-stratified, you should just ignore them. Here’s why:

  1. Nearly all older people were vaccinated (>90% of residents >50yr) while the vast majority of unvaccinated are younger people (>85% of unvaccinated <50yr)
  2. Older people are orders of magnitude more likely to be hospitalized than young people. Those >50yr are >20x more likely to be hospitalized compared to <50yr and for 90+ are the difference is >1600x more. These are enormous confounders.
Israeli data on severe hospitalized COVID cases split into crude age groups (below and over 50 years)

If you estimate VE without taking into account age you get 67.5%, which means 2/3 of severe cases are prevented by vaccine. Pretty good, but not as good as the previously touted 90-95% range.

But….if you take into consideration the fact that more vaccinated people are old and much more likely to get hospitalized in the first place (91.9 versus 3.9 in unvaccinated group = 23x more likely) things start to look a lot better. VE for younger people is 91% (1 – 0.3/3.9) and VE for older than 50 is 85% (1 – 13.6/91.9). VE is expected to be lower for older people who don’t mount as good immune responses. In fact, VE might drop quite a bit for 70+ and 80+ if you further stratify by age (bumping up the VE for 50-59). But overall these are good numbers and the vaccine is performing well against Delta in protecting people against severe disease. It may seem statistically impossible that 85% VE + 91% VE = 67% VE (combined), but that just shows how important the age-stratification is.

How well the vaccine protects against mild infection with Delta is another question that requires deeper data.

Later in September the FDA is expected to approve third shot boosters of mRNA vaccines for everyone and the shots will be available 8 months from the date of your second dose (since I got my second shot in May, the third shot would not be until January). In the mean time I recognize that vaccines are not 100% effective and do not give me license to party like it’s 2019. I am grateful that I live in a country where vaccine supply is plentiful and all the adults in my family are well protected against severe disease, allowing grandparents to see their grandchildren. I have no problem wearing a mask inside public spaces for as long as it takes for COVID to become managed. Personally, unless there is irrefutable data that vaccine effectiveness has plummeted I would rather give my booster shot to someone at high risk in a developing country who hasn’t even gotten one dose. Beating COVID in America requires altruist behavior: people acting not just in immediate self-interest but making sacrifices for the larger community, including the vulnerable and children. How can we expect Americans to behave altruistically when the country itself is not acting altruistically towards other countries? When will we begin modeling the behavior we desperately need to promote? Moreover, helping other countries is not just altruistic; containing COVID in other countries will reduce the likelihood of new variants emerging overseas. The more viruses circulating, the more opportunity for new mutants to arise. Not only are SARS-CoV-2 viruses capable of evolving by mutation, but they can swap entire stretches of genetic material with each other through recombination (a version of viral “mating”).

Delta is the most recent variant to takeover globally but other alarming variants are already circulating. So far nothing has emerged that outpaces Delta, but it could be a matter of time.

You heard: Delta variants are as contagious as chickenpox.

What that means: The Delta variant is estimated to have a higher R (reproductive number) than prior COVID strains, which means each infected persons pass on the virus to more people. The SARS-CoV-2 virus has been evolving rapidly since it emerged in humans into progressively fitter and more contagious forms. Prior to Delta, Alpha was considered the most transmissible variant, but has now been displaced by Delta.

Keep in mind that R is an average. Since SARS-CoV-2 is a good superspreader there will be a lot of variation in transmission. Many infected people will pass the virus on to no one. A small number will infect dozens. That’s why large gatherings are so problematic. If the infected person was capped out at passing the virus to only 7 people there would not be such a problem. But when a person who happens to be a superspreader (some people just shed a lot of virus) finds themselves in a densely packed gathering, the virus can rip through and infect numbers much, much larger than 7.

Being an average, R can also vary geographically based on local contact patterns. R in rural farm country where no mass gatherings occur will be a lot lower than in urban neighborhoods or tourist destinations that get densely packed. It is an open question the extent to which the elevated estimations of R for Delta reflect intrinsic properties of the virus versus sudden changes in human contact patterns in July and August when Americans loosened social distancing and stopped wearing masks.

You heard: Viral loads are similar in vaccinated and unvaccinated people.

What that means: Viral loads represent the amount of replicating virus. Higher viral loads can lead to more symptomatic disease and/or higher likelihood of transmitting the virus to another person.

There is data showing similar viral loads in vaccinated and unvaccinated people.

But you get a more complete picture when you look at the time course of viral load. There are similar loads early in the infection when transmission occurs. But eventually an immune system primed by a vaccine is able to bring down the viral load much faster than a naive immune response, reducing the risk of severe disease and curtailing the period of infectiousness to other people. There is still a lot we need to learn about Delta, vaccines, and transmission, but in the mean time vaccinated people should recognize that the vaccine is good at protecting you but does not necessarily remove the risk of infecting others. That is why it is particularly important for vaccinated people to continue distancing when possible and wearing masks in dense or poorly ventilated spaces.

You heard: The Delta wave is primarily a problem in the South.

What that means: The Delta wave has spread everywhere. This summer’s epicenter in Southern states mirrors what happened last summer when COVID defied the expectation of being a winter disease that would fade as temperatures warmed, instead during in hot states where people crowd into air-conditioned buildings and spend less time outdoors during summer months. Lower vaccination rates and less social distancing in the South exacerbates the problem, but we saw this same pattern last year when vaccine was not a factor. Wildfire and smoke that keep people indoors in Western states could also drive up transmission in those areas.

The top-10 states with most new daily confirmed COVID cases per 100k population are all located in the South

The surge appears driven by younger people who tend to have lower and more variable vaccination rates across US states.

Highest rates of infection are in young adults.
Vaccination rates are generally high in older people in every state, but gulfs emerge in younger people.

You heard: The current wave is not a big deal because old people are protected so it’s just mild infections.

What that means: Louisiana, Florida and Oregon have reported record hospitalizations in recent weeks as the Delta variant spreads. Recall that hospitalization and death are lagging indicators which means that we won’t observe the real toll of the current surge in cases for several weeks.

Delta wave in Oregon (blue is hospitalizations)

COVID becomes even more lethal when heart attack and car accident victims can’t get a hospital bed. Even pediatric wards are filling up. I challenge anyone who doesn’t think COVID is a big deal right now to volunteer one hour’s time in an over-crowded ICU. Our doctors, nurses, and staff were already seriously burned out going into the summer. August is supposed to be the quiet before the storm when flu season hits in the fall. Exhausted medical staff are more likely to make mistakes. Overtaxing our medical systems has serious knock-on effects.

Oregon’s hospitals are reaching capacity

You heard: Mild cases are okay. In fact, mild infections in vaccinated people could serve as a natural booster.

What that means: There is a tendency in the press to downplay “mild” COVID cases. Yes, a week or two fevering in bed is something we can all tough out. But we all know healthy people who have had seemingly mild cases turn into long-running complications, either cardiovascular, neurological, or pulmonary. Mild breakthrough infections also appear to be able to cause “long COVID” but of course we need better longitudinal data for Delta. Our health tracking systems are not well designed to study long-term COVID complications so methodologically there is a lot we still don’t know.

You heard: Delta is sending more kids to the hospital.

What that means: The rate of hospitalization of kids with COVID is increasing, but the overall risk is still low. But kids are more susceptible to a range of respiratory viruses, including RSV and flu. RSV and flu were both suppressed by school closures last year and there is a risk when school starts of kicking off outbreaks of other respiratory infections in kids whose immune systems have been dormant for a year. A big concern that pediatric wards filled with kids with other respiratory infections might not have capacity for the additional kids that enter with COVID. Even more reason for schools not to be complacent prepared this year. A lot of schools are drawing on last year’s experience to assume that transmission will be low in kids. But Delta is more transmissible and strategies that worked last year may be less effective this year. We owe it to our kids to bring our A game this fall. That means routine testing in schools (pooled if necessary), intensive contact tracing, tents for outdoor lunches, extra teachers for smaller class sizes, mandatory vaccination of teachers and staff, extra staff for facilitating online learning for kids that have to be temporarily isolated at home (any kid with a sniffle could miss school until they get a negative COVID test — just wait until cold season hits).

Why is it taking so long for vaccine to become available for kids <12? The clinical trials for young kids are much smaller, enrolling one-tenth the number as were in the adult trials, which means they require a longer period of data-gathering to achieve sufficient power. Contrary to widespread perception that COVID trials in adults were “rushed”, the trials simply benefited from “blank check” cash influxes that allowed enormous numbers of volunteers to be enrolled to power the study. Not having to wait around for people to get infected also sped up the trials (the *one* benefit of letting COVID rip through the globe).

You heard: COVID vaccines cause sterility.

What that means: You get your news from the wrong sources.

Here’s an example of a rare side effect of the COVID vaccine in children that legitimately occurs and has received attention. An outsized number of vaccinated people (particularly boys ages 18-24) experienced myocarditis (inflammation of the heart). However, the rate of myocarditis is still very rare even in the highest risk category (219 out of >4 million) and the condition generally recedes after a few months. Media headlines about heart inflammation in kids naturally cause anxiety in parents, but this is an exceedingly small risk compared to getting naturally infected with COVID.

You heard: CDC recently changed its guidance on mask wearing for vaccinated people.

What that means: Effectively, that Americans now have no idea when they are supposed to wear masks.

What prompted the change? The CDC changed the mask guidance for vaccinated people after seeing the data from an outbreak in Provincetown, Massachusetts during Fourth of July festivities. The vast majority (74%) of the 469 COVID-19 cases from the Provincetown outbreak were in fully vaccinated people. Most of this population was adult males (average age 40). Almost all the viruses were Delta (90%). Overall, 274 (79%) vaccinated patients with breakthrough infection were symptomatic (although asymptomatic cases were likely missed). Measures of viral load in vaccinated people who got infected were similar to those who were unvaccinated (viral load is often used as a proxy for contagiousness). Five COVID-19 patients were hospitalized, four who were fully vaccinated; no deaths were reported. The data was difficult to interpret because it was not age-stratified.

What are the changes for fully vaccinated people?

CDC addition: Wear a mask in public indoor settings in areas of “substantial or high transmission”.

My translation: At first I thought this meant “settings with high transmission” like bars, restaurants, buses, but if you click the link it means US counties with high COVID activity. Which includes almost all counties, even in Vermont. So really this is just: “Wear a mask in all public indoor settings“. What does “public” encompass? My interpretation includes any place you encounter strangers, including private businesses.


CDC addition: Wear a mask regardless of the level of transmission, particularly if they are immunocompromised or at increased risk for severe disease from COVID-19, or if they have someone in their household who is immunocompromised, at increased risk of severe disease or not fully vaccinated.

My translation: You should already be doing this (see above)


CDC addition: Fully vaccinated people who have come into close contact with someone with suspected or confirmed COVID-19 to be tested 3-5 days after exposure, and to wear a mask in public indoor settings for 14 days or until they receive a negative test result.

My translation: You should already be doing this (see above).


CDC addition: CDC recommends universal indoor masking for all teachers, staff, students, and visitors to schools, regardless of vaccination status.

My translation: You should already be doing this (see above).

The Day I Got Harassed For Jogging Without a Mask

“Wear a mask!”

I stopped running and wheeled around. A middle-aged woman ambled towards me on DC’s Glover-Archibald hiking trail. She was alone and walked with a long stick. “Wear a mask!” she repeated, closing to within five yards of me.

“Don’t judge me,” I glowered.  

“I’m not judging you, I just want you to wear a mask,” she prattled on, continuing to approach me. She was overweight and walked with a staff. “What are you, a Trumpie?”

“You know nothing about me.” I stared into her grey eyes.

“You’re the reason 300,00 people are dead. Selfish people like you who don’t care.”

“You don’t think I care?”

“No. You’re selfish!” She caught up to me on the trail and we now walked side-by-side. It was a brisk November day, just a few days after Biden was elected President, and my sweat was already giving me a chill.

I smirked. “I thought you weren’t judging me.”

“I AM judging you!” she decided. “You deserve to be judged.”

I tried describe what she could not see: that I posed no threat. I was the least likely person to transmit COVID to her. I rarely left my house except to jog. I always wore a mask during my once-a-month shopping trips to the grocery store. I knew the science, being an infectious disease epidemiologist working every day for the nation’s premier research institute to save people from COVID and other pandemic threats. Threats she never even knew about. I spent nights writing my COVID blog to help people navigate confusing times without losing their minds, even after getting a concussion after falling off a horse. I answered readers’ COVID questions until my headaches made it impossible. I was not the bad guy. The world was not that simple.

But the trail narrowed and suddenly I was the one who felt unsafe, realizing I was in the blast radius of a stranger who was spitting as she yelled, not paying attention to her physical distance, and not wearing her mask properly. It was askew. I wanted to say more, but I decided it was best to move on. I shouted a cheerful “Well, have a good day!” over my shoulder as I trotted away, adding “Try not to judge people!”

As I trotted home I knew our country was screwed. The mask issue had gone too far. People were no longer rational. I understood why the woman yelled at me; she was scared. She wanted to feel safe and my naked face seemed threatening. The pandemic was ripping through America, mowing down older, overweight people like her. A mask had become a shorthand barometer for evaluating who was safe and who was not. America had found a new marker to divide sinner from saints, our culture wars bleeding into our pandemic response. Which was bad news for everyone.

The Coming COVID-19 War: Vaccinating Children

If you thought controversies over masks and lab-leaks were fever pitched, just hold your hats until the COVID-19 vaccine is licensed for kids under 12 this fall. Nothing gets Americans lathered up like policies that affect the safety of their kids. The diversity of opinions on this matter is about to skyrocket because the cost-benefits of vaccinating America’s 50 million kids ages 0-11 for COVID-19 is not nearly as straightforwards as it would be for pandemic influenza, for which kids are one of the highest risk groups for severe disease. Here’s a sneak peak of what’s to come.

Universal recommendation for vaccinating kids with underlying conditions. There will be scientific consensus on vaccinating kids with underlying conditions (asthma, obesity, diabetes, autoimmune disorders, etc.) who are at higher risk for hospitalization and death. This is not a small group of kids. Obesity has been surging in children for decades and BMI is over the 95th percentile in age/sex-specific growth charts for 13.4% of 2- to 5-year-olds and 20.3% of 6- to 11-year-olds.

Percentage of US children obese. Obesity is body mass index (BMI) at or above the 95th percentile from the sex-specific BMI-for-age 2000 CDC Growth Charts.
SOURCES: National Center for Health Statistics, National Health Examination Surveys II (ages 6–11), III (ages 12–17); and National Health and Nutrition Examination Surveys (NHANES) I–III, and NHANES 1999–2000, 2001–2002, 2003–2004, 2005–2006, 2007–2008, 2009–2010, 2011–2012, 2013–2014, 2015–2016, and 2017–2018.

Should healthy US kids get vaccine before high-risk adults in countries with low vaccine supply? Honestly, I don’t know what my answer would be if given the option to voluntarily donate my child’s COVID-19 to an at-risk adult in an African country being ravaged by COVID-19 and desperately in need of vaccine. If I put on my economist hat and weigh costs and benefits, of course I should rationally and ethically donate the vaccine. There is a vanishingly small chance of COVID-19 killing my two-year old. Moreover, controlling SARS-CoV-2 overseas makes it less likely that an even more dangerous variant will evolve and make its way to America, just as India’s Delta variant is now. But wearing my mom hat I do everything in my power to ensure my son’s safety, even if it means setting aside high-minded principles. The long-term sequelae of infection in kids (“long-haul COVID”) is unknown and voluntarily leaving him exposed presents an ethical conundrum. As his parent I have also observed that making toddlers wear masks is particularly disruptive at a vulnerable stage of development where children are just learning to read peers’ social cues. Foregoing vaccine with the reasoning that kids can just continue wearing masks at school under-recognizes those developmental costs. And of course there is the issue of herd immunity. Kids have not been the community superspreaders for COVID-19 to the same extent as flu, but they still transmit (particularly for more transmissible delta variants) and the more unvaccinated kids there are in America the longer it will take for the country to fully reopen and normalize.

Washington Post op-ed from May 12, 2021

Mixed messaging around kids, COVID-19 risk, and vaccines will reduce rates of vaccination in kids and waste precious vaccine doses. My prediction is that America will get the worst scenario possible. No politician has the nerve to tell his constituency that American kids are being bypassed for vaccine to save people in other countries. But the mixed messaging from reputable scientific sources is going to scare parents and reduce vaccine uptake in kids under 12. The end result will be large volumes of wasted doses, continued mask-wearing in schools, not reaching herd immunity thresholds in most communities, and ongoing outbreaks. Score one for the Yanks!

How to Weigh COVID-19 Risks in a Brave New (Vaccinated) World

TL;DR: Everything is in place for the COVID-19 pandemic to end in America. The vaccines are working beautifully, even against new variants. But vaccine hesitancy remains a stubborn barrier to full normalcy, putting American on course to reach equilibrium, not eradication.

Ahead of last summer I was telling everyone they were fools for declaring the pandemic over and reopening too soon. Not this time. Unless new variants emerge that reduce vaccine effectiveness, the US trajectory is in good shape to continue a steady process of normalization. I’m bullish about the future.

The mRNA vaccines are rockstars. The data just gets better and better for the mRNA vaccines (Moderna and Pfizer). In a large study of breakthrough infections in vaccinated healthcare workers, only 1% got infected after one dose, and only 0.05% got infected after two doses*. The vaccines perform well against variants. No vaccine for any disease manages to protect everyone, but the COVID vaccines are similarly effective as the smallpox vaccine, which managed to eradicate the disease not just from America, but from the entire planet. In theory, if we could vaccinate enough people, we could eradicate SARS-CoV-2 not just from America but from the entire world, and never have to think about it again.

We won’t even reach herd immunity in America. For reasons that I explained last year, plenty of America is simply not interested in taking the COVID-19 vaccine, even with bribery. We all have friends and family who have explained to us why they are not getting vaccinated. Vaccine hesitancy is likely to be even stronger for kids. My son will get vaccinated as soon as it is available for his 2-year old age group, barring any new questionable data coming out of ongoing clinical trials. But a lot of parents are going to want to wait and see. I doubt school administrators will have the spine to require COVID vaccination for public schoolchildren the way they do for vaccines for other diseases like measles, mumps, rotavirus, and chickenpox. This could delay a return to normalcy for kids at school and potentially extend the wearing of masks and elements of social distancing. It is a tragedy that children continue to be the ones paying the biggest price for the mistakes of adults in mishandling the pandemic response and forgoing vaccination.

Kids do not need to wear masks playing outdoors. Given the delay in vaccine availability for young of schoolchildren, we need to begin seriously weighing risks of disease against normal freedoms to be kids. The time has come for kids to stop wearing masks when they play outdoors. The risk of COVID transmission is so low in outdoor settings AND kids are at low risk for symptomatic COVID infections. We have to get over our natural tendency to err on the side of maximum caution with children. It could be another six months or more before COVID vaccines are available for all kids over two. For those of us who live in Washington, DC where July humidity makes it suffocating to breathe under normal conditions, we cannot keep children bubble wrapped out of an undue abundance of parental caution.

As context, there were 279 reported COVID-19 deaths in US kids over the last year (5/21/20-5/20/21). Most were in teenagers.

Keep wearing masks indoors in public places even if vaccinated. No, vaccine was not the get-out-of-jail-free card some expected. You still have to wear a mask when you buy your groceries, ride public transit, go to work, or take your dog to the vet. It’s not a bait and switch, it’s just that practically speaking businesses have no way to tell who is vaccinated or not and have no option other than to enforce mask wearing among everyone that comes through the door. This is the reality: as long as large swathes of the country’s adults remain unvaccinated business owners have no other choice.

What happens if we do not reach herd immunity? Strictly speaking, herd immunity is a number. But population immunity operates on a spectrum. Even if America does not meet the magical herd immunity threshold that will completely eradicate COVID within our borders, each additional person who is vaccinated helps cut off possible paths of COVID transmission and brings community cases down. Already we can see the impact of vaccination on the rapid fall of COVID cases nationwide, resulting in fewer opportunities for transmission to the individuals who remain vulnerable. We may never vaccinate enough people to exterminate COVID, but we can aim for an equilibrium where the virus percolates at such low levels that most American life is unaffected and spontaneous outbreaks are rapidly dealt with. Getting vaccinated is not just about protecting yourself, but the entire community. Americans who decide whether to get vaccinated based purely on cost-benefits to themselves are either missing the big picture or don’t particularly care for their neighbors.

Technically this is not showing ‘herd immunity’, which is the precise threshold at which a high enough proportion of people are immunized (yellow people in the left column) that there are zero infected people (red people in the right column). But the general concept here is that vaccinated people serve as firewalls that block transmission within a community so fewer people get sick.

Variants present a threat to unvaccinated people. New variants emerging globally transmit at high rates, exploiting pockets of low vaccination. This has been evident in the UK where the India B.1.617.2 variant is currently exploding despite vaccination driving down cases of the previously circulating lineage B.1.1.7. This new epidemic is being driven by unvaccinated people and could threaten the country’s return to normalcy. The India variant has only begun to reach the US, but it has the potential to similarly exploit pockets with unvaccinated people.

Courtesy John Burn-Murdoch
https://twitter.com/jburnmurdoch/status/1397995388267810818

Are there any activities vaccinated people should still avoid? The risk of breakthrough infection is so low (particularly for the 2-dose vaccines) that the path to normalization for vaccinated people is really a matter of personal comfort. That said, as the country begins to normalize there is a need to be respectful of friends and family re-socializing at different rates. Some vaccinated people will be ready to party like it’s 1999 and others will barely change their lifestyle. Neither group is crazy. We’re entering a new phase where the most important act of social responsibility is simply to get vaccinated. What people do after that is largely up to their own weighting of personal risk and proclivities. I happen to be an outdoors person who is in no hurry to return to indoor dining, museums, cinema, or shopping malls. Even if I know the risk of breakthrough infection is small, I know that the CDC is primarily tracking breakthroughs associated with hospitalizations and deaths. I’m acutely aware that a ‘mild’ COVID infection is still nothing to trivialize. The other day I ran with a friend who had a mild COVID infection six months ago and still is struggling to run normally. It is unknown how long it will take for lung function to recover. I derive so much happiness from outdoor activities that I am more than willing to forego most indoor exposures to eliminate even a small risk. But I openly accepted that others whose enjoyment derives from indoor sources will make entirely different risk calculations that better suit their proclivities. Given the natural variability in risk tolerances, it is best to ask direct questions, explicitly request permissions, and avoid assumptions. Can I get a hug? Have you been vaccinated? Just for the record, asking colleagues, associates, or friends about vaccination status is not an invasion of privacy or protected by HIPAA. It is a valid question in a society experiencing a deadly pandemic for which there are strictly different protocols for vaccinated and non-vaccinated persons.

There is still plenty of COVID-19 going around (Pennsylvania shown here, for example), more daily cases than during the first wave last April. The pandemic is not ‘over’.

When can I hold my 200-person indoor wedding? It is not crazy to expect life to continue to improve and normalize as more Americans get vaccinated and COVID levels recede. I encourage vaccinated people to be bullish about planning events and travel. At the same time, there is a need to be realistic. The path to normalcy is underway, but without reaching herd immunity there will be no flip of the switch. COVID will still be around in 2022 and lots of people will still be unvaccinated. Even if I am personally vaccinated, along with my family, would I invite 200 people of unknown vaccination status to a densely packed indoor event? How confident would I be that enough people would be vaccinated to prevent a superspreading event? Will the city even permit an indoor event that size? How much COVID will be circulating at that time? Would I be uncomfortable mixing unvaccinated guests from across the country with my elderly relatives who may not respond to vaccine as well? Will antibodies from vaccine have waned by next spring? Would it not be better to hold the event outdoors so the bride has one less thing to worry about?

What about the rest of the world? The world is being divided into tiers of rich countries with access to vaccine and many countries, rich and poor, without access to vaccine. While the top tier speeds towards normalcy, the lower tier burns. Even Japan is not on track to host the Summer Olympics in Tokyo. I cannot emphasize how important it is to get vaccine to every country as fast as possible. That is why it is doubly infuriating that millions of Americans are foregoing vaccines and precious doses are increasingly going to waste. If we could get America to herd immunity quickly we could turn our attention to other countries in need of supply. The longer Americans stubbornly hold out, the longer it will be before we can get vaccine to countries that desperately need it.

* These data should be interpreted within the context that a lot of COVID was circulating at the time of the study, but on the other hand this was a young population that tends to mount a strong antibody response following vaccination and less prone to breakthroughs.

Why We Will Never Know the Real Origins of SARS-CoV-2

COVID-19 slashed red tape and poured in government funding to spark giant leaps forward in scientific innovation, most prominently in vaccinology but also behind-the-scenes in genetic sequencing to track a fast-evolving virus generating new variants. These developments set the stage for promising new strategies for a range of infectious disease threats, from malaria to influenza. In contrast, it should be lost on no one what minuscule progress has been made in figuring where the virus came from in the first place — and why.

Decades from now, when we sit the dinner table, regaling our grandchildren with sordid tales of the great Pandemic of 2020, we will recount the fear of touching doorknobs, the great run on toilet paper, and finally the joy of receiving the miracle vaccine that saved everyone and let kids go back to classrooms. But when our descendants ask where the virus came from and how it got into people, we will just have to take a long, slow swig of beer and admit that some things, like who shot JFK, are just never known.

We will list the various theories that got batted around, filling the airwaves with media fodder. Pangolin soup. Lab accidents in Wuhan. In contrast to other unsolved mysteries of science – why did the dinosaurs vanish? – the absence of a proven COVID-19 origins story presents a real practical problem going forward. The next pandemic virus is already out there, somewhere, circulating in an animal. The next global pandemic could blow in twenty years, or twenty months. Any global strategy for preventing future pandemics hinges on knowing whether to invest in shoring up lab vulnerabilities worldwide or massively expanding disease surveillance of ‘viral chatter’, which refers to the thousands of viruses that pass between animals and humans every year but in most cases never establish in humans. The absence of a resolved origins story saps the political will to do either.

As a scientist with a decade of experience studying how pathogens transmit between animals and humans I have a strong hunch about where SARS-CoV-2 came from, at least in principle. Strong enough to bet my career on. But science is not about hunches, and there is no point dissecting the conjectures, coincidences, and scraps of evidence that provide little more than tea leaves at the moment.

Tragically, it need not be this way. Conspiracy theories about global pandemics caused by scientists mishandling pathogens rise and recede every time an outbreak occurs, like a tide. When the 2009 H1N1 pandemic broke an Australian scientist propagated a theory that the virus contained genetic signatures that suggested it arose during an error in commercial production of influenza vaccines for US swine. A decade earlier, a Rolling Stone article outlined the evidence that HIV jumped to humans by way of a contaminated oral polio vaccine campaign in central Africa in the 1950s. The theory was researched in more detail in another journalist’s compelling 1000-page book. The page-turner was eloquent and a great read. The only problem: it was dead wrong. After a period of capturing the media’s attention, the theories were eventually put to rest by accruing scientific evidence.

It is a great deal easier to draw together a compelling lab origins theory based on conjectures and coincidences than it is to debunk one with hard scientific evidence. Tracking down the real source of HIV required arduous expeditions deep into Congolese jungles to sample viruses from apes. The team of Oxford researchers had to navigate rebel forces and swarms of mosquitoes (one famous professor died of malaria) during a needle-in-a-haystack search for simian viruses related to HIV. The search for the origins of the 2009 H1N1 pandemic in Mexico’s swine herds was tame by comparison. But my collaborators and I spent seven years painstakingly swabbing the noses of tens of thousands of pigs from farms to extract and sequence the genetic material of disease-causing pathogens to resolve the virus’s perplexing origins. An unusual amount of detective work was required to trace how swift globalization of swine farming in the 1990s led to pigs being moved across continents via commercial air travel that spread influenza viruses found in pigs in Europe, Asia, and the United States into Mexican farms, creating a new hotspot for influenza virus evolution and eventually a virus that could jump to humans.

The fact that the lab origins theories of the 2009 H1N1 pandemic and HIV did not hold up does not mean that human error never plays a role in disease outbreaks. One of my first scientific papers as a graduate student included genetic evidence that the 1977 H1N1 ‘Russian flu’ pandemic had been a lab escape (although it was not the focus of the paper). The H1N1 virus had circulated in humans from 1918 – 1957 before vanishing, only to surprisingly reappear twenty years later and cause a pandemic that mostly infected children, since most adults had already been infected when they were younger. The 1977 pandemic virus was nearly genetically identical to the virus that had circulated in the 1950s, a pattern that would not be seen if the virus had just been circulating in nature unobserved in humans or an animal reservoir.  Combined with knowledge that Soviets had been conducting experiments with a vaccine that included a live H1N1 virus that may not have been properly attenuated, we concluded that the 1977 pandemic was caused by human error and was a lab virus, which was supported by subsequent analyses. The lab-escaped virus caused recurring epidemics worldwide for forty years before it vanished a second time, replaced by a newer strain during the 2009 pandemic.

Despite technological revolutions in disease surveillance driven by advances in genomic sequencing and mobile phones, it is possible that we will know even less about the origins of SARS-CoV-2 than we know about influenza pandemics that occurred 10-40 years ago, or even a HIV pandemic that began a century ago. It is obviously not a a question of scientific capacity, but of access to samples. And not just samples from the Huanan Seafood Market where the pandemic was first detected in humans. The lack of SARS-CoV-2 virus detected in animals at the seafood market has been cited as evidence for a lab leak, but the argument is specious. The market is not where the original animal-to-human transfer occurred. The market merely amplified transmission in humans because many people congregate there, providing easy routes of human-to-human transmission. Certainly, a wet market presents an environment that is conducive to zoonotic transmission because humans and densely packed animals intermingle. But the first human case of SARS-CoV-2 was detected weeks before the major Huanan market outbreak. The original jump from animals to humans likely occurred 1-2 months before the Wuhan outbreak. Sampling from animals from a larger swathe of China would be helpful in piecing together where the virus traveled prior to the Wuhan explosion.

There is a long history of sensitivity about specific countries being blamed for pandemic pathogens that emerged within their borders. For that reason the 2009 H1N1 pandemic was termed ‘Swine Flu’ instead of ‘Mexican Flu’, breaking a centuries-old tradition of naming ‘Spanish Flu’, ‘Russian Flu’, and ‘Hong Kong Flu’ after the locations of origin (although there was equal backlash from swine farmers after a panicking public stopped buying bacon). During COVID-19 there has also been resistance against naming variants after the country where they are first detected (e.g., South Africa variant, India variant), which disincentivizes countries from performing rigorous surveillance so another country detects the variant earlier. Early references to the COVID-19 pandemic as ‘China flu’ had the same scapegoating effect that incentivizes plausible deniability when it comes to whether the pandemic originated in a specific country. Heroically brave Chinese scientists released early SARS-CoV-2 genome data in January 2020 to alert the international community when the pandemic was rapidly unfolding and authorities were still scrambling. The Chinese government is no longer on its heels.

Chinese authorities seized control of the COVID-19 outbreak in a way no Western government could, extinguishing the spiraling epidemic with a lockdown of fabled intensity. By February 2020, just as the Wuhan outbreak was winding down, the Chinese government turned its attention to the practice of farming of wildlife for food. Farming exotic wildlife had been promoted by the government for decades to advance the economy of the country’s southern rural regions. In a single edict the authorities wiped out the $70 billion industry and transferred the 14 million employees to new ventures. The destruction of all wildlife on the farms eliminated the potential for pathogen exchange between animals and humans that could spawn future pandemics. Tangentially, it also eliminated an entire vast ecosystem of hosts and pathogens that might have left a valuable paper trail of clues into the origins of SARS-CoV-2. Modern methods of genetic analysis can powerfully reconstruct decades of transmission and evolutionary events in the past from present-day data, as shown by our studies of pandemic H1N1 evolving on Mexican swine farms using data collected 4-5 years following the pandemic. There is no need for a time machine, but there is a need for live animals to sample. The lack of answers about SARS-CoV-2’s origins is no shortcoming of science, only a lack of access to samples in an age where it can be politically expedient to leave some scientific questions unanswered. It is clear by now that China answers to no one on the international stage.  

Agnosticism on the question of where SARS-CoV-2 came from seems logical in the absence of irrefutable scientific evidence to the contrary. But the overwhelming human predilection towards lab origins stories, as observed repeatedly over the history of pathogen outbreaks, particularly for HIV but also for the 2009 H1N1 pandemic, makes pure agnosticism a fiction. It is worth pointing out the enormous public health costs when people believe false lab origins theories. The contaminated oral polio vaccine theory for HIV set back the global campaign to eradicate polio by decades. America is at a juncture where the country desperately needs to shore up confidence in the COVID-19 vaccine, particularly as the campaign expands to younger children. The COVID-19 lab origins theory may seem unconnected to vaccine uptake, but it’s not. They all trace to a deep-rooted fear of government cover-ups, corruption, and arrogant scientists who ignore risks and take advantage of people’s blind trust. Being agnostic on the origins of COVID-19 may seem innocuous, but it’s not. I wish I had the data to prove otherwise. Sadly, I don’t think I ever will. And I dread the day I have to explain that to my grandchildren.

The Smoking Bat: The Quest To Uncover the Origins of SARS-CoV-2

The World Health Organization’s recent probe into the origins of COVID-19 in Wuhan has renewed interest in piecing together when, where, and how the virus jumped from animals to humans during the fall of 2019. The Wuhan Seafood Market outbreak appears to be a red herring, serving as an early amplifier of a simmering outbreak in December 2019, but not the original source of the animal virus, which jumped to humans weeks, or possibly months, earlier (1). The pangolin’s brief moment of fame also appears to have been a red herring, as the pangolin viruses were only distantly related to the human viruses (2). Then again, we know previous little about coronavirus diversity in pangolins and other species. As attention focuses on the first human cases in China, including the unreleased raw data, there has been a notable lack of public interest in what the virus was doing before its grand entrance in humans and how little coronavirus data is available from animals.

Contagion got many things right about outbreak investigations, but the film oversimplified how scientists trace a pandemic’s origins back to animals. At no time in history has an outbreak’s zoonotic source been solved using security camera footage. Anyone who has searched for the animal origins of Ebola outbreaks in bats in West Africa knows how painstakingly laborious the task of sampling wildlife is. Theoretically livestock are easier because at least we know where they are housed. But the politics of getting access to samples can be equally daunting when a wrong bug found in a herd could cost a farmer their lifesavings.

But as humans grapple with the current COVID-19 crisis, the ancestor of the next pandemic virus is already lurking in an animal host somewhere. It could be in a bat in China, a primate in sub-Saharan Africa, or a pig in the Americas. The virus could be a decade away from acquiring the properties needed to transmit to humans, or it could be weeks. Despite the disruptions caused by COVID-19, humans continue to create conditions for zoonotic transfer of viruses from animals to humans, consuming millions of animals every day, congregating in live animal markets, and even holding pig shows. Imagine another pandemic on top of COVID-19.

How can we learn more about a zoonotic event that occurred over a year ago? For approximately the same price tag as what the UK government is currently investing to characterize several thousand SARS-CoV-2 viruses a week (3), researchers could at least begin a sweeping survey of the genetic composition of hundreds of thousands of coronaviruses circulating in wildlife, livestock, and live animal markets across east Asia. A region-wide survey conducted a year following the original animal-to-human transmission event is not guaranteed to produce the ‘smoking gun’ virus or pinpoint which market or farm was responsible. But the descendants of the virus that jumped to humans continue to circulate in animals in China and other Asian countries, and the genetic material of each virus provides important clues about its grandparents. Scientists can reconstruct decades of evolutionary history from gene sequence alone.

Mexico’s response to the 2009 H1N1 influenza pandemic proves how decoding viruses in animals even years after the event can resolve the mysteries of a pandemic’s origins and provide the global community clues for how to prevent the next one. At first, scientists thought the virus that caused the global pandemic in 2009 came from pigs in China, where the most closely related animal flu viruses were found (4). China seemed a logical source, given that the last two influenza pandemics originated in China and the country is home to half of the world’s pigs. Although the first signs of the virus transmitting in humans occurred in Mexico (5), Mexican pigs seemed like an unlikely source because the virus contained genetic material that had never been seen in pigs in any country in the Americas. For seven years it remained a mystery how a virus that seemed to come from Chinese pigs presumably sparked its first human outbreak in Mexico. Had Chinese pigs been smuggled into Mexico? Or had Chinese pig farmers vacationed in Cancun just after acquiring the virus?

Imports of live hogs into Mexico
(Mena I, et al., 2016)

To its credit, Mexico resolved the mystery by embarking after the pandemic on new surveillance of influenza in its swine herds scattered across the northern, central, and far eastern regions of the country. By working with Mexican swine veterinarians our research team uncovered a surprising find: viruses similar in important ways to those in Chinese pigs (6). The story told how Mexico’s rapid modernization of swine production in the 1990s allowed viruses from different continents to be imported and hybridize with each other to create a pandemic in a country assumed to be low risk. While swine farmers care a great deal about keeping deadly pathogens like African swine fever from crossing borders, influenza is already in pigs in every country and newly imported strains are not perceived as a problem worthy of testing or quarantine from an animal health perspective.

Altering food production is economically costly and socially disruptive. Just as COVID-19 lockdowns have become less blunt as key vectors of community transmission were identified, changing how we operate live animal markets, wild animal trade, or bushmeat needs to be grounded in data. Two centuries ago, the grandfather of modern epidemiology John Snow was successful because he used rigorously collected data to pinpoint a single contaminated water pump that was causing the bulk of cholera deaths, and did not ask authorities to disengage every pump in the city. But scientists need a great deal more data to track disease transmission in animals at anything approaching the levels we achieve in humans. We can uncover how coronaviruses get shuttled between countries and continents by trade of wildlife and livestock, as well as by movements of wildlife displaced by habitat loss, and how this relates to human coronavirus outbreaks. Although viruses similar to SARS-CoV-1 in 2003 were identified in civet cats in a live animal market in China (7), we do not know how those viruses wound up in civets in the first place. Are pangolins or other traded wildlife species an important permanent reservoir for coronaviruses connected to human outbreaks? Where did the four coronaviruses that cause common colds in humans come from? Again, the limiting factor is data.

How viruses get shuttled between species and continents. Phylogenetic trees show how influenza viruses sampled from different types of animals and countries are related. We worked with small animal veterinarians in China to show how viruses jump between birds, dogs, and cats and moved from Asia to the US (8)

With over two million COVID-19 deaths it may seem pointless to figure out where the virus came from originally. But fundamental insights into disease systems can have impacts far beyond a single disease event. Although John Snow only asked authorities to turn off a single water pump, the insight that cholera epidemics might be vanquished by cleaning up water supplies transformed the 19th century. The construction of modern sewer systems turned the Industrial Revolution’s squalid, disease-ridden cities in Europe and America into modern economic centers capable of supporting skyrocketing densities. Some day we may back look at the dark ages of 2020 with the same curiosity as ‘night soil men’ pushing carts of human feces and horse dung down Broadway.

TL;DR. Half the world thinks SARS-CoV-2 came from a lab escape. The other half thinks someone ate a bat. Scientists can do a great deal better, and avert future pandemics, but they need data from animals.

References

  1. Pekar J, Worobey M, Moshiri N, Scheffler K, Wertheim JO. Timing the SARS-CoV-2 Index Case in Hubei Province. bioRxiv [Preprint]. 2020 Nov 24:2020.11.20.392126.
  2. Lam TT, Jia N, Zhang YW, Shum MH, Jiang JF, Zhu HC, Tong YG, Shi YX, Ni XB, Liao YS, Li WJ, Jiang BG, Wei W, Yuan TT, Zheng K, Cui XM, Li J, Pei GQ, Qiang X, Cheung WY, Li LF, Sun FF, Qin S, Huang JC, Leung GM, Holmes EC, Hu YL, Guan Y, Cao WC. Identifying SARS-CoV-2-related coronaviruses in Malayan pangolins. Nature. 2020 Jul;583(7815):282-285. 
  3. Nelson MI. 2021. Tracking the UK SARS-CoV-2 outbreak. Science. 371(6530):680-681.
  4. Grantz KH, Meredith HR, Cummings DAT, Metcalf CJE, Grenfell BT, Giles JR, Mehta S, Solomon S, Labrique A, Kishore N, Buckee CO, Wesolowski A. The use of mobile phone data to inform analysis of COVID-19 pandemic epidemiology. Nat Commun. 2020 Sep 30;11(1):4961.
  5. Chowell G, Bertozzi SM, Colchero MA, Lopez-Gatell H, Alpuche-Aranda C, Hernandez M, Miller MA. 2009. Severe respiratory disease concurrent with the circulation of H1N1 influenza. N Engl J Med. 361(7):674-9.
  6. Smith GJ, Vijaykrishna D, Bahl J, Lycett SJ, Worobey M, Pybus OG, Ma SK, Cheung CL, Raghwani J, Bhatt S, Peiris JS, Guan Y, Rambaut A. 2009. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 459 (7250): 1122-5.
  7. Mena I, Nelson MI, Quezada-Monroy F, Dutta J, Cortes-Fernández R, Lara-Puente JH, Castro-Peralta F, Cunha L, Trovao NS, Lozano-Dubernard B, Rambaut A, van Bakel H, García-Sastre A. 2016. Origins of the 2009 H1N1 influenza pandemic in swine in Mexico. eLife 5: e16777. 
  8. Guan Y, Zheng BJ, He YQ, Liu XL, Zhuang ZX, Cheung CL, Luo SW, Li PH, Zhang LJ, Guan YJ, Butt KM, Wong KL, Chan KW, Lim W, Shortridge KF, Yuen KY, Peiris JS, Poon LL. Isolation and characterization of viruses related to the SARS coronavirus from animals in southern China. Science. 2003 Oct 10;302(5643):276-8. 
  9. Chen Y, Trovão NS, Wang G, Zhao W, He P, Zhou H, Mo Y, Wei Z, Ouyang K, Huang W, García-Sastre A, Nelson MI. Emergence and Evolution of Novel Reassortant Influenza A Viruses in Canines in Southern China. mBio. 2018 Jun 5;9(3):e00909-18

Mutants on the Rise

TL;DR: New variants cropping up globally are headed to America and threaten to overwhelm hospitals. Our highly potent vaccines still protect pretty well against new strains, but we are not rolling out vaccine fast enough to prevent new epidemic spikes.

November’s announcement of highly effective COVID-19 vaccines brought a refreshing break in the otherwise bleak pandemic news cycle. New threats are on the rise, however, as a new contagious UK variant has already made landfall in a dozen US states and could soon lead to new epidemic spikes and overcrowded hospitals. The Brazil and South Africa variants could evade some immune defenses and are headed our way as well. Allowing virus populations to explode globally opened the door to evolution. Each of the 100 million confirmed global COVID-19 cases provides another opportunity for the virus to grow and morph into deadlier, more transmissible forms. Bullets are deadly, but at least they do not use each victim as a personal petri dish.

Fortunately, all is not lost. The COVID-19 vaccines were so good to begin with, inducing such a broad antibody response, they can still protect against a variant capable of evading a certain subset of antibodies. So please tell your grandmother to keep hammering her local vaccination registration page, no matter how many times it loses her data. With mass vaccination still the only option for achieving herd immunity, perhaps by mid-2021, the last thing we need is another news cycle fanning America’s enormous problem with vaccine hesitancy.

As you roll up your sleeve for the syringe, be aware that the COVID-19 vaccine is designed to elicit a large, broad immune response potent enough to protect old people with weak immune systems. In the interest of speeding through clinical trials and vaccine distribution, different formulations were not tested for seniors versus young adults, as they are for influenza jabs. As a result, some young adults may have unusually strong immune responses to the vaccine, particularly to their second dose or if they were naturally infected with COVID-19 previously. Most people will have no reactions to the vaccine, but for those who get a fever or a goose egg-sized swelling on their arm, I’m afraid it is simply the price of admission for protection against the deadliest pandemic in over a century. As more variants emerge that evade certain antibodies, we will be grateful that these potent vaccines activate multiple lines of defense.

Note that more people reported muscle pain who received the placebo (vertical black line) than the Moderna vaccine. People get surprised by new medical problems all the time. As millions (billions!) more people get the COVID-19 vaccines, expect an untick in the number of odd strokes, seizures, and deaths that occur right after vaccination by chance. Merely a coincidence of timing in a giant numbers game. Responsible media will not report such events before scientists have time to figure out if they are related to the vaccine or not. Clickbait media will.

Minor vaccine reactions can be a good sign. I exclaimed Perfect! in response to my son’s three days of snotty nose and malaise after receiving a FluMist vaccine I fought to get this winter instead of the intramuscular version. There are are no clinical studies showing that a two-year old going a year without major immune system challenges because of pandemic isolation is damaging. Just intuition from a evolutionary biologist who did not have to wait for pediatricians to finally update their disastrous advice on early exposure to peanuts.

There is still a lot of uncertainty about these variants, including whether they cause more severe disease in people who get infected and how well they evade detection by the body’s immune defenses. Preliminary data from South Africa indicates that its variant can evade certain antibodies elicited by vaccines, reducing their effectiveness. The UK variant (B.1.1.7) appears to transmit more efficiently between people and has quickly become the dominant virus in the UK and is causing epidemics so severe they must ration oxygen in hospitals. The UK variant has already made landfall in a dozen US states and is will likely become the dominant virus in a matter of months, depending on the particular city or state. High vaccination rates in nursing homes and other vulnerable populations can blunt the mortality rates of epidemic spikes, but as of now we have only vaccinated 17% of the prioritized population. That still leaves a lot of vulnerable people, including those with medical conditions who are not currently in the vaccine queue. COVID-19 cases are beginning to come down after the holiday surge in most states, but a more contagious virus is exactly the kind of tinder on the fire America does not need as it tries to reopen schools. After keeping UK schools open all fall, the variant forced classrooms to shutter again.

Buss et al., Science (2021): Three-quarters of residents in Manaus, Brazil have antibodies to SARS-CoV-2 viruses by October 2020

Why are variants suddenly emerging now? This is all highly speculative, but it may not be a coincidence that South Africa had one of the highest attack rates during the first wave of the pandemic. People with residual immunity from a first infection may now be getting second infections. When a person gets infected a second time, the virus is attacked with primed antibodies, exerting new Darwinian selection pressure on the virus to evolve as a matter of survival. The emergence of a new variant in Brazil could also relate to the extremely high attack rates in the Amazonian city of Manaus, where an uncontrolled virus swept through three-quarters of the population earlier in 2020. Virus evolution may seem random and unexpected, but it is encouraged by human activities. One way to spur the virus to evolve is during repeated treatments of long-term chronic infections in patients with weakened immune systems who are unable to clear the virus. Frankly, if you wanted to design an experiment to spur the virus to evolve, bombarding the virus with one antibody cocktail after another would be a good way to go about it.

Viruses Evolve A Million Times Faster Than Humans. This is the problem: Every time a SARS-CoV-2 virus infects person it replicates. What begins as a family of virus particles in your body explodes into a swarm of viruses, which includes thousands of clones and as well as variants that have new mutations and are slightly different. Since the SARS-CoV-2 virus was already superb at infecting and transmitting between human bodies, most tweaks in its offspring will not be particularly helpful and those mutants will die off. The virus has so many offspring, it can afford to lose most of them, like a kamikaze army. But every now and then, one of the offspring will have a special change that actually makes the virus fitter. Maybe the virus attaches to human cells better. Maybe it escapes cells better to infect more cells. There are a dozen or more steps a virus has to accomplish to successfully invade a human body, replicate en mass, and invade another person. An improvement at any one of those steps makes will make a virus fitter than its brethren.

Evolution is Hard Even For Viruses. In theory, these kamikaze armies of viruses should be evolving like gangbusters. But it’s more complicated than that. Imagine you’re a virus, spreading like wildfire in your poor human’s body, replicating quickly, and you manage to hit the jackpot and one of your offspring lands on a helpful mutation. The problem is that most of the virus swarm does not have a roundtrip ticket. Only a relatively small proportion of offspring will spring from the upper airways to a second unwitting host. Another problem is called epistasis, which is really just a fancy word for bad baggage. Mammals take great care to replicate their DNA with fidelity to avoid costly errors. Even creatures as prolific as rabbits don’t want grotesque mutated offspring and have protein machinery to check for errors in DNA replication. With thousands of progeny, viruses don’t care if some turn out to be the equivalent of a three-headed rabbit. But such levels of sloppiness carry a cost. A good mutation can occur in one of the viruses in the swarm that happens to have a second unhelpful mutation, say the equivalent of the three-headed rabbit mutation. Since beneficial mutations are extremely rare and most mutations make life worse for the virus, it can be difficult to land a good mutation in a problem-free genetic background. Good mutations can get taken down by a faulty ship.

Evolution in one direction incurs tradeoffs in other ways. Just ask the giraffe trying to awkwardly bend down to drink from a river. Coronavirus evolution also incurs tradeoffs. Jailbreaking into human cells is not easy and requires fine-tuned configurations of the virus’s spike protein to attach to cell receptors. Spike proteins that jut out of the virus also happens to be the target of most human antibodies. So the same spike protein mutations that help the virus evade antibodies could impede cell attachment and other functions. The virus may need a second mutation to compensate. Evolution is not necessarily easy for a coronavirus, but we encourage it by creating enormous virus populations across the globe, letting viruses blast through specific populations to create pockets with higher selective pressures, and administer series of therapies to chronically infected patients, creating human petri dishes for evolution. Human cannot necessarily predict how or when the virus will evolve, but we have a degree of control over the conditions that drive it.

Going forward, making a vaccine is a giant leap forward, but there are still hurdles. Vaccine distribution and hesitancy are two big ones. Attaining herd immunity assumes that the vaccine not only protects against illness but also reduces virus shedding and transmission, which is likely but still being assessed. And the virus is a moving target, particularly when we give it plenty of runway and incentive to evolve. The emergence of new variants is also a wakeup call to the global community that we are in this mess together. We can theoretically vaccinate the entire US population, but vaccine escape variants can still emerge in other parts of the world where the virus is not controlled. Funding vaccine efforts in developing countries is not only ethical but in our self-interest.

The take-home message is that viral evolution has constraints, and coronavirus is not going to suddenly turn into Ebola. Still, three new variants serve as a reminder that the SARS-CoV-2 virus capitalizes on our past blunders and is not going gently into the night.