Fasting for Weight Loss and Longevity: Total energy expenditure (TEE) and the intriguing new science of energy envelopes and fasting
I. The Age-Dependent Energy Envelope
It is widely believed that excess fat on our bodies reflects an imbalance between the amount of energy (measured in calories or kcal) that we consume vs. the amount we burn, and that diet is the driver of energy consumption while activity and lifestyle are the chief drivers of energy expenditure.
According to this line of thinking, if a sedentary person eats the same number of calories as an exerciser, we would expect that the sedentary person would burn fewer calories and store more fat compared to the exerciser.
But new research is showing that, while diet does determine energy intake, activity might not be a critical driver of total energy expenditure (TEE). For one thing, regardless of lifestyle or activity, it has now been established that how many calories we burn each day is highly age-dependent.
TEE ramps up during infancy when our brains and immune systems are developing, then starts to drop until we reach our mid-20s. At that point, it stabilizes throughout early and middle adulthood, dropping again with each decade of life after about age 60.
This lowering of metabolism helps explain the difficulty many of us have trying to lose weight as we age. And this is true regardless of whether we are manual laborers or accountants; exercise addicts or couch potatoes.
It turns out most of our TEE is linked to automatic ‘basal activities’ like digesting food, pumping blood, mediating inflammatory processes in areas of the body under stress, and to other relatively low-exertion activities such as thinking (in humans, brain activity accounts for about 20% of TEE), moving from one room to another, or fidgeting while we work, rather than to occasional larger exertions like taking a run or mowing the lawn.
We now understand that the body regulates energy expenditure according to an internally calculated daily allotment or ‘energy envelope’ which is based on age, and it is hard to burn more or fewer calories than the age-dependent, pre-allotted amount. If we use a lot of energy during a workout, our bodies try to make up for it by spending fewer calories on other things (like generating an inflammatory response) in order to stay within the daily TEE allotment.
Our bodies also adapt physiologically to regular exercise, becoming more efficient over time, burning fewer and fewer calories during exertion. For example, in one study, sedentary women who trained to run a half marathon increased their TEE at first but after a few weeks, gradually dropped back to about the same TEE as before they had started to train. This is hormesis at work. The body is getting stronger and more efficient by repeatedly stressing it in a consistent way over time.
Of course, it is possible to push through the limitations of our energy envelope with more extreme amounts of exertion. People who routinely exercise for many hours per day such as ultramarathon runners, Olympic swimmers, and Ironman triathletes can push their TEE beyond the envelope to induce weight loss. But even during extreme endurance activities, we quickly reach an upper limit to how many calories we can burn–about 2.5 times the basal metabolic rate (BMR) which is the amount we burn at rest.
This has repercussions for health–especially with regard to weight loss. After 35 years in clinical practice, it is abundantly clear to me that while exercise is a critical hormetic practice that strengthens the heart, lungs, and muscles, promoting longer lifespan and healthspan, it is not a good strategy as a monotherapy for weight loss. If, short of dedicating several hours a day to working out, we can’t exercise our way to an ideal body weight, then weight loss must be driven mainly by our diet.
II. Why Diets Fail
The strategy of most weight loss programs like Weight Watchers, Jenny Craig, and even Optavia (the program we use at the office) is to tilt the balance between calories consumed and calories burned. Taking in fewer calories while keeping activity levels constant can, in the short term, induce weight loss.
But calorie restriction diets only work for a while. After about 3-4 months, the weight loss hits a plateau. At this point, even if someone is consuming less than half their normal amount of calories, they will struggle to lose any more weight.
That’s because, over time, our bodies adapt to lower food intake by adjusting down our metabolism. A 30-year-old who spends too much time on a calorie restriction diet can lower her metabolic rate to a level comparable to a 70-year-old, and that’s bad. To make matters worse, when this happens it becomes very difficult to raise metabolism again–sadly, it doesn’t automatically adjust back upward when we resume eating more calories.
When weight loss stops due to slowed metabolism, we lose the feeling of reward that came with the initial good results. This leads most people to (understandably) drop the diet. And when they return to the eating habits developed over a lifetime–only now, in the context of a slower metabolism–they gain weight quickly.
Research shows that roughly 80% of people who lose significant weight on calorie-restriction diets, with or without exercise, will begin to regain their weight within the first year of coming off their diet and will regain, on average, more than half of what they lost within two years.
III. A Better Strategy: The Modern Human Diet
At our clinic, we promote a high-fiber, low-glycemic diet which I have called the Modern Human Diet (MHD) to induce and maintain healthy body weight. The MHD resembles what is commonly referred to as the Mediterranean diet but it adds some science-based twists designed to promote better gut health and avoid sharp rises in blood sugar.
When patients transition from the standard American diet (SAD) or from a calorie restriction diet to the MHD, they report better mental acuity, sleep quality, and overall feeling of wellbeing. Why? The MHD diet keeps blood sugar stable. Most calorie restriction diets drive blood sugar too low and that doesn’t feel good (more about this below).
The MHD also improves the gut microbiome–the trillions of microorganisms that live inside our digestive systems and inform our health in myriad ways ranging from immunity to mood. You can read more about the gut microbiome here. But for the purpose of this post, it is sufficient to understand that diets like the SAD which are low in naturally occurring plant fiber are a key driver of obesity, diabetes, cardiovascular disease, and other forms of chronic illness because they deprive the gut microbiome of their food source: fiber. Without fiber, the healthy bacteria in our gut die-off leaving our health weakened.
Establishing comfort on the MHD diet is the prelude to the second phase of weight loss and makes up half of the blueprint for the style of eating that patients are encouraged to maintain long-term after they’ve reached the weight at which they feel and look their best.
In recent years, intermittent fasting or time-restricted eating (also known as ‘the 16/8 method’) has become a popular weight loss technique. There are many versions of fasting being promoted in books and on the internet. Some make sense scientifically, many do not.
For the purpose of this discussion, fasting refers to taking in no calories for 24 or more continuous hours. This is something I have employed both personally and in my practice for many years. But there is a lot of misinformation regarding how it works and how to do it correctly.
It may seem strange but our bodies respond very differently to calorie restriction than to fasting. Unless we are on a highly carbohydrate-restricted diet (like keto), blood sugar can dip low enough during calorie-restricted diets to cause fatigue, headache, lightheadedness, extreme hunger, and impaired concentration.
When you eat, your pancreas releases insulin to put the body into a state of energy storage. Insulin signals cells in the muscles and liver to take in glucose (sugar) absorbed from food and convert it into glycogen, the stored form of glucose that acts as a ready energy reserve. It also signals fat cells to convert glucose into triglycerides and store those as adipose or body fat. And insulin also directs liver, muscle, and fat cells to shut down the release of stored energy for use by the body. In short, when you eat high glycemic foods that cause blood sugar to shoot up (like baked goods, chips, and sweets) your body makes insulin and insulin is a hormone that promotes calorie storage while blocking calorie-burning. If someone eating a high glycemic SAD with toast and jam or instant oatmeal for breakfast; a burger and fries or a sandwich and chips for lunch, and pizza for dinner, while sipping sweet soft drinks at work to keep their energy levels up, they are constantly over-secreting insulin which hangs around after meals. If they skip a meal, their blood sugar will continue to drop as residual insulin drives it down lower and lower, making them feel ravenously hungry, tired, nauseated, light-headed, even sick.
Let’s imagine that your body’s TEE envelope is 2,000 kcal/day when you begin a calorie restriction diet such as time restricted eating or Weight Watchers. Prior to dieting, you had been consuming 2,500 kcal/day, on average, and had been gaining about 5 lbs. each year. If the new diet involves eating several times each day, that keeps insulin levels relatively high since you release insulin each time that you eat, and the effect of insulin on cells continues for 1-2 hours after a meal. So, even though you are restricting your intake to just 1,000 kcal/day, you don’t have access to the stored calories in glycogen (liver and muscles) or triglycerides (fat) because the regular secretion of insulin which blocks the release of stored energy won’t allow it! The result is a 1,000 kcal deficit that results in extreme hunger, fatigue, and other unpleasant symptoms until, eventually, metabolism slows down to meet the chronically reduced caloric availability of the diet.
Summing up to this point: calorie restriction in the context of a SAD means high insulin levels which block access to stored energy and low blood sugar which feels terrible. And having access to just the 1,000 kcal that you are eating causes metabolism to adjust downward, setting you up for weight gain once you come off the diet and go back to consuming a more normal amount of calories.
So, if eating fewer calories than we burn is how we get rid of fat, how can we lose weight feeling miserable and slowing our metabolism? At our practice, the weight loss journey begins by transitioning from a SAD to the MHD. There are no blood sugar spikes on the MHD and once you are used to it (about a month), calorie restriction becomes easy. Without all that extra insulin hanging around from blood sugar spikes, we feel tolerably hungry when we eat less without feeling tired or irritable. But prolonged calorie reduction diets, including time-restricted eating, can lead to slowing of our metabolism so once we find we are able do with less, we introduce the second piece of the puzzle: fasting.
It is counterintuitive that fasting does not slow our metabolic rate–in fact it slightly boosts it! In addition, fasting causes the body to halt the release of insulin. Dropping insulin levels during fasting signals cells in the liver and muscles to start breaking down glycogen into glucose and releasing it into the blood for energy. It also signals fat cells to do the same with regard to their stored triglycerides, breaking them down into glycerol and free fatty acids which are carried to the liver and converted into ketone bodies which serve as an alternative energy source to sugar.
Lowering insulin through fasting enables us to maintain our normal TEE, keeping metabolism high while burning fat, losing weight, and feeling well on a steady supply of energy supplied from mobilized glycogen and triglycerides (glucose and ketone bodies).
Summing up further: when you fast, you lower insulin and your body starts to eat its own stored energy, keeping metabolism high and inducing weight loss.
More Benefits To Fasting: Hormesis
In a recent briefing, I discussed the concept of hormesis, the physiological process whereby we grow stronger in response to repeated exposure to a particular stressor. I discussed how regular exercise and other practices such as sauna bathing have been shown to improve both lifespan and healthspan. Fasting is another hormetic practice. How does it work?
The cells of our body contain several distinct membrane-bound structures called organelles, each of which acts like a miniature organ doing its own special work inside the cell that ensures proper functioning. For example, the mitochondrion is an organelle that has the function of producing energy; the lysosome has the function of breaking large molecules down into smaller ones; and phagosomes are organelles that capture and eliminate foreign or toxic material such as viral proteins.
As we age, organelles like mitochondria and lysosomes start to lose energy and become less efficient. We also make fewer phagosomes as we age which lowers our self-protection. These organelles can collect toxins and defective old proteins that are unusable, mucking up their ability to perform their specialized jobs. Cells containing significantly dysfunctional organelles are referred to as senescent cells.
After about 24 hours without taking in any calories, we enter the hormetic fasting state which induces the production of a special kind of phagosome called an autophagosome.
Autophagosomes help repair or digest dysfunctional organelles within senescent cells as a way of extracting needed energy from them during fasting. They swallow up waste, attach themselves to lysosomes whose job is to break big molecules down into smaller ones, and then feed the cell by degrading these senescent organelles to release energy–a process known as autophagy.
Autophagy can be thought of as the body’s way of keeping energy levels high during cellular starvation and also as a way of getting healthier and stronger by clearing out toxic and dead materials to improve the quality and function of organelles within our cells. This is why people who fast regularly often look much younger than their age.
Fasting dramatically increases the number of autophagosomes within cells, driving autophagy. The longer we fast, the more autophagosomes we make, and the healthier and ‘younger’ our cells become. Of course, there are limits to fasting as there are to all hormetic practices. I personally fast for 26 - 28 hours 2 times per week and for 48-72 hours about once every 2-3 months. Many studies have demonstrated that fasting extends lifespan.
Studies vary in terms of how long a fast is required to increase the production of autophagosomes to induce autophagy. Some studies indicate autophagy may begin as soon as 16-20 hours without any calories. Most studies suggest it takes closer to 24 hours of fasting to induce autophagy. And it looks like the rate of autophagy continues to increase during prolonged periods of fasting, reaching peak levels at about 2 - 3 days. It also seems that fasting during the night may promote more autophagy than daytime fasting so, for example, fasting from breakfast to breakfast may induce more autophagy than from lunch to lunch or dinner to dinner.
Fasting is part of our evolution
Humans evolved over a period of about 6 million years, during which time we lived by a rhythm of feasting and fasting that was necessitated by our natural environment. During cold seasons, floods, droughts, or other environmentally hostile periods when little plant food was available for consumption, humans would often go days or longer before they were able to kill an animal and feast for a day or two, surviving in the interim on just water and whatever calories they had been able to store in their bodies. Animal migration and hibernation added to the food scarcity issue, especially during wintertime.
Because of this feasting-and-fasting pattern of eating, our bodies evolved to become excellent at storing fat. That served us well throughout most of our evolutionary history when calories were often scarce. But now, amidst unprecedented abundance, both in terms of the density of calories in today’s extremely carbohydrate-rich processed foods and the ever present availability of things to eat in advanced societies like ours, this evolutionary advantage today is working against us. For nearly all of our history as a species, getting enough to eat was our greatest day-to-day challenge. Now, one of our greatest challenges is learning how to eat less!
Autophagy is an evolutionary adaptation. A way of promoting health and self-preservation by utilizing the reserve energy of intracellular toxins, senscent proteins and other debris to feed starving cells while cleaning them and bringing them back to optimal functioning.
When modern societies conceived of the ‘three square meals a day’ pattern of eating, this represented an attempt to ensure that all citizens were afforded adequate nutrition. We didn’t know it then, but this rhythm of feeding, designed to put an end to malnutrition, closed us off from the hormetic practice of fasting which had been part of human societies for millions of years.
And today, with food not only exceedingly available but also manufactured to be hyper-delicious (to the point of driving ‘soft addictions’), most people eat more than three times per day, supplementing their meals with snacks–some of which are taken strictly for pleasure. And many of us now habitually eat throughout the day to soothe anxiety, loneliness, boredom, or stress. Snack food manufacturers have succeeded in promoting this as part of a lifestyle and have even invented the concept of ‘healthy snacking’ as though supplementing meals with better quality food could make snacking a health practice. But we now know that the opposite is true. Snacking drives up insulin and insulin blocks fat burning. Snacking is making us fat.
Fasting is more than a tool for weight loss, it’s a health practice
When we lose weight through fasting, we maintain our metabolic rate, burn fat, and enjoy good energy and mental clarity. Fasting turns on autophagy, reversing our biological age, and induces the production of hormones called sirtuins that have been shown to protect against cancers and extend lifespan. Weight loss achieved through fasting is less likely to result in rebound weight gain, feelings of misery during the weight loss period, or the development of stretch marks once the fat goes away.
Fasting, it can be said, is a tool for health and happiness. It stresses the body hormetically, making it stronger and healthier when done consistently over time. It has been a traditional practice among many cultures and a spiritual practice among many different religions. It promotes a kind of physiological cleansing at the cellular level, the benefits of which can be felt almost immediately among those who commit to doing it.
C19 Weekly Briefing Supplement on the importance of maintaining high circulating levels of neutralizing antibodies through vaccine boosters.
The new wave of the pandemic is being driven by Delta which bypasses prior immunity at a higher rate than any previous variant. How is Delta managing to do this? It appears likely that some combination of mutations allow it to escape key neutralizing antibodies while affording it the ability to generate more viral copies (viral titers among people infected with Delta are 1,000 times higher than those of people infected with the original strain of the virus), combined with timing. People have the highest level of neutralizing antibodies shortly after getting vaccinated or infected and then those levels wane gradually over months until they are low enough to allow for breakthrough infections. It is likely that those who were vaccinated or infected several months ago have less immune protection against getting infected than those who were vaccinated or got infected more recently.
The process of getting C19 starts with exposure–a person inhales viral aerosols that stick to mucous membranes in the nose, nasopharynx, or lungs. This is called colonization. If someone has high levels of circulating neutralizing antibodies in the immune system of the mucous membranes (called the "MALT"), they can kill off the virus before it penetrates into the body's interior to cause an infection. This is what happens in most people who were recently vaccinated. However, as circulating neutralizing antibody titers wane over time, the MALT has fewer soldiers to keep colonization contained and this allows breakthrough infections to occur.
There are now sufficiently ample data showing that an additional shot of vaccine boosts circulating neutralizing antibodies to levels much higher than those seen after completion of the initial vaccination regimen. This should provide those who get booster shots with much stronger protection against getting infected (lots of neutralizing antibodies circulating in the MALT). And there have been no reports of adverse events from receiving a third shot of mRNA vaccine or a second shot of Janssen vaccine. So what's the delay and why are so many experts still not recommending booster shots across the board? Three reasons have been given:
The focus of most public health and infectious disease experts has been on the acute viral period of C19. That's largely because, while some other infections can cause long-term health consequences, most do not, and most doctors by training are concerned about preventing severe illness and death. But C19 has shown itself to be different from other common RTIs in so many ways (it's airborne, it's more contagious, it's more deadly, it shape-shifts more quickly than expected, etc.) and the fact that it causes such a high degree of chronic and potentially chronic illness is just one more distinguishing feature of this novel virus. It is not unreasonable to be concerned that in the end, the second and third phases of C19 will wind up taking a larger toll on society than the (sometimes deadly) first phase. If boosters were available today, I'd take one immediately.
943. Iceland recommends booster shots for all citizens who got Janssen at 8 weeks post-vaccination.
944. Moderna seeks authorization of the first variant-specific booster shot; but it's tuned to Beta, not Delta.
945. Pfizer submits data from Phase I clinical trials on booster doses which they now recommend for the general population. Boosters triggered the production of significantly higher levels of circulating neutralizing antibodies against Delta.
946. Dr. Fauci: "Everyone will need a booster shot."
947. Israel is now doing booster shots for all persons 50 and over and for all healthcare workers.
948. Biden Administration to approve booster shots for most Americans at 8 months post-vax, beginning with healthcare workers.
August 16, 2021 Weekly C19 Briefing summary: Cloth and surgical masks are minimally helpful; FDA approves mAb therapy for prophylaxis and approves boosters for immunocompromised (and the booster shots are working); Moderna offers better protection than Pfizer against Delta; new quarantine periods for Delta depend on whether or not the patient has been vaccinated; more data show the vaccines do not impact fertility; if Florida were its own country, it would have the 5th highest rate of C19 in the world; HHS workers must get vaccinated or lose their jobs; higher circulating antibody levels are what prevents infections while durable B and T cells prevent severe disease during the viral phase.
927. The quality of the mask is important. 20% protection with cloth masks, 40% with surgical masks, 95% with the masks we are wearing. Vaccinated people are having a shorter disease period and spreading the disease less than unvaccinated people; they tend not to be superspreaders but confine their spread to household members.
928. The FDA authorizes use of mAbs for prophylaxis in people with known exposure.
929. In a study of more than 50,000 patients in the Mayo Clinic Health System, Moderna's effectiveness dropped from 86% effectiveness against infection against Alpha to 76% against Delta (Jan/Feb vs. July). Over the same time period, the effectiveness of Pfizer dropped from 76% to 42%.
930. Among 198 residents in a long term care home, stronger immune responses were mounted following Moderna than Pfizer, with higher levels of total and neutralizing antibodies after Moderna.
931. More great epidemiological work from the UK: the REACT study evaluates population-level info to reveal where, how, and which variant of Scov2 is spreading. We have no similar effort here. The CDC’s cohort studies are small, narrow, and occasional. We are still not investigating breakthrough cases unless they result in severe disease or death. This website is worth perusing–it's a treasure trove of real time data. One new data point: Delta infections cause longer viral shedding than prior variants.
932. Viral loads decline more rapidly in vaccinated (mRNA) vs. unvaccinated people infected with Delta. Vaccinated reached a Ct value of 30 on day 9 post-diagnosis vs. day 15 for unvaccinated. If we use Ct as a surrogate for infectiousness with the assumption that a Ct value of 30 or more means viral titers have dropped low enough to make the disease no longer transmissible, we should consider amending our current quarantine instructions as follows: 10 days for vaccinated; 16 days for unvaccinated (from on set of illness covid-19-science-news-and-research-weekly-briefings-august-16-2021.html or date of positive test).
933. Neither infection nor mRNA vaccination causes any harm to eggs or ovarian follicles.
934. As Delta rips through Florida (one in every five cases in the country is currently taking place in Florida), the Governor of that state has issued an executive order banning mask mandates for kids in schools and threatening to withhold teacher salaries if schools require masking. The CDC, the American Academy of Pediatrics, and other major health organizations and leading experts are all in agreement that masking is critical for safety as the case rates among kids rises exponentially due to Delta. Now, >800 doctors sign a letter criticizing what is clearly a political–not rational, science-based–anti-masking position.
935. The WHO is conducting a clinical trial in 52 countries to study 3 anti-inflammatory drugs as potential treatments for hospitalized C19 patients: artesunate, imatinib and infliximab. The primary endpoint will be death. This will be part of the Solidarity PLUS trial. Artesunate is already used for malaria, imatinib for certain cancers, and infliximab for autoimmune diseases such as Crohn's Disease and RA. The original Solidarity trial last year found that all 4 treatments evaluated - remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon - had little or no effectiveness against C19. Unfortunately, they did not include colchicine which has shown a strong signal from the data that it could prevent hospitalizations....
936. HHS Secretary Xavier Becerra announced today that vaccinations will be mandated for its workforce. This will include employees of NIH and will affect > 25,000 employees, contractors, trainees, and volunteers whose duties put them in contact or potential contact with patients at an HHS medical or clinical research facility. This comes on the heels of the Pentagon announcement earlier this week that by mid-September all 1.3 million military members would have to get vaccinated. The U.S. Department of Veterans Affairs also announced a similar move last month and various airlines are moving in the same direction.
937. From NEJM: Confronting the catastrophe of long-covid/PCS. C19 is not the first microorganism to cause long-term clinical sequelae but, perhaps because it is so much more widespread or perhaps because Scov2 enters cells through ACE2 and ACE2 is so ubiquitous, it is doing so at a much higher prevalence rate. How will we deal with what looks very much like ME/CFS on a widespread scale? Will we continue to marginalize these patients or treat their debilities as purely psychogenic? My take: We will need more longitudinal studies like the one from the UK biobank showing a consistent pattern of gray matter destruction among C19 infected patients to help validate the suffering of long-haulers if they are going to be taken seriously by many healthcare providers. If we do not do this, their care and management will be overseen by allied providers and fringe providers who are less well trained and less well equipped to take care of them.
939. According to Shane Crotty at La Jolla Institute for Allergy and Immunology, after each exposure to a pathogen, the immune system conducts a kind of cost/benefit analysis on how robust and how durable post-infection immunity should be. [My thought: The two-shot regimen is superior to the single dose regimen in part because the second exposure informs the immune system that the pathogen (or spike protein antigen) in question is highly prevalent. We now know that the ideal spacing between doses for Pfizer is 8 weeks (see #901 from a previous briefing) and this could be one reason why Moderna, whose second shot is given at 4 weeks, is holding up better than Pfizer, whose second shot is at three weeks.] Shane Crotty: A third exposure some months later via a booster is likely to make the immune response not only bigger (about twice the level of neutralizing antibodies is seen following the booster compared to that following the second dose of a two shot regimen) but also more durable as it informs the immune system that the pathogen (the spike protein) is prevalent and durable in the environment. What's the best way to understand the relative roles of circulating antibody levels, memory B cells, and T cells? Circulating neutralizing antibody levels are the line of defense that protects against infection. With sufficient exposure, the virus will colonize in the mucous membranes of the nose, throat, mouth, and nasopharynx. High levels of circulating neutralizing antibodies can quickly attack those (technically external) cells and stop the colonization from penetrating into the interior to cause an infection. This, in my opinion, is the chief argument in favor of booster shots. Memory B and T cells, on the other hand, form the primary arsenal of defenses once infection has occurred. When the virus breaks through the epithelial level to enter the body's interior, helper T cells alert memory B cells and plasma cells to produce antibodies while killer T cells destroy infected cells and viruses contained therein. This cell-mediated response takes a few days to mount, however, and with Delta replicating more quickly with a shorter incubation time, many breakthrough infections are symptomatic. So far, we have seen that antibodies wane some months after infection or vaccination but T and B cells persist. The durability of immune cells is what ensures that most vaccinated people will not progress to severe illness if they get infected; the waning of antibody titers over time means that months after primary vaccination or primary infection, the risk of breakthrough infections and reinfections increases. If our focus is exclusively on the viral phase of C19, we do not need boosters yet. If, however, we are also focused on the post-viral phase, then we need boosters to increase circulating antibody levels to help prevent infections. Notice how Carlos Del Rio has to evade direct questions from Bob Wachter about what is clearly a need for boosters among those of us who got vaccinated half a year ago. The focus is exclusively on the viral phase, as though the very subject of long-covid/PCS or the growing impressive data showing brain injury among those with even mild or asymptomatic infection, are taboo.
940. After a third shot (using Moderna) patients with organ transplants had a 71% neutralizing antibody protection against Scov2 compared with 13% among those who received the standard two dose regimen followed by placebo. https://www.nejm.org/doi/full/10.1056/NEJMc2111462?query=featured_home941. Elderly patients who waited 11-12 weeks for their second shot developed triple the antibody response compared to those who took the second shot at three weeks (Pfizer).
942. FDA approves boosters for limited group of immunocompromized patients under EUA, ahead of the CDC. It looks like it will be a standard dose of either mRNA vaccine. They are expected to give full certification of the vaccines (at least Pfizer and Janssen) in the next two weeks. This would allow physicians to make their own decisions about when, which, how much, and to whom to give booster shots. As yet, there is not guidance on timing in relation to other vaccines but I anticipate the recommendation will be to give at least a 30 days window.
August 9, 2021 Weekly C19 Briefing summary:
Local and national case rates continue to climb with 2,750 cases in one day (yesterday); vaccination protects against getting infected, lowering risk of catching C19 by 3-10x depending on the source; the FDA is expected to approve booster shots and certify Pfizer and Janssen very soon; herd immunity now estimated to be 90% of population immunized; the case rate among children is going up very fast; review of what we know about children and C19 and what we should be recommending; review of the new VOCs coming after Delta; the concept of 'leaky vaccines' is validated through a very well done new study.
906. There were 2,754 new cases yesterday in San Diego with a weekly average of more than 1,400/day. This is almost certainly a significant undercount since Delta can cause a clinical picture that looks just like allergies or a cold with runny nose, sneezing, sore throat, and many people assume they have something that they "get all the time" or their doctors assume they have a cold.
907. Although the MA team has doing PCR testing for some time, with new team members, I thought it would be good to review the technique for performing the swab which can make the difference between a positive test and a false negative test. The key is to advance the swab along the floor of the nose toward the throat, not upward toward the brain. Joyce, please make sure the entire team knows how to do this properly.
908. Vaccinated are 3x less likely to get infected than unvaccinated by the most current estimate from the REACT1 Study, in this paper from Imperial College London:
909. But 8x less likely to get infected according to Covid Tracker (Johns Hopkins University).
910. And about 10x less likely to get infected according to the SDCDPH COVID-19 Watch.
911. Two-thirds of people with mild or moderate viral periods (non-hospitalized) are still symptomatic 30-60 days after OOS: fatigue, SOB, and brain fog were the most common symptoms. Yet another name for the syndrome is introduced in this paper as well: post-acute sequelae of SARS-CoV-2 or PASC.
912. The latest update on booster shots is that the FDA will likely approve them for immunocompromised under EUA in the next couple of weeks. The FDA is also expected to approve Pfizer certification by the beginning of September. If that happens, providers will be able to prescribe extra shots to whomever they think needs them.
913. What is the number to reach herd immunity? Because Delta is twice as transmissible as the D614G ancestral strain, the estimated threshold for herd immunity has been increased from 67% to 90%, according to the Infectious Diseases Society of America.
914. A booster dose of Novavax provided 4x the overall antibody levels and 6x greater functional ACE-2 binding inhibition antibodies against Delta than that observed shortly after the primary 2-dose vaccination series.
915. In the last week of July, children represented 19% of C19 cases in the US, representing a 25% jump from the prior average. Cases among children doubled in the last week of July compared to the previous week. This is likely due to Delta which is more transmissible, according to the American Academy of Pediatrics who recommends two things: children should return to school and they should be required to wear masks.
Moderate Dive: Kids and C19 (Summary of the CDC data and guidance)
I. Kids 5 and older can catch it and spread it, just like adults:
In the US through March 2021, the estimated cumulative rates of infections and symptomatic illness in children ages 5-17 years were comparable to infection and symptomatic illness rates in adults ages 18-49 and higher than rates in adults ages 50 and older. Rates of infection and symptomatic illness in 0-4YOs are roughly half of those in 5-17YOs, but comparable to those in adults 65 and older. Children and adolescents can spread Scov2 when they are asymptomatic, presymptomatic, mildly symptomatic, moderately symptomatic, or very sick, just like adults.
II. In-person learning is a good idea. But it's less of a good idea when community transmission is very high and not a good idea without layered risk mitigation measures:
A study comparing C19 hospitalizations between counties with in-person learning and those without in-person learning found no effect of in-person school on hospitalization rates when baseline county hospitalization rates were low or moderate. However, this changes when the community transmission rate goes up and significant secondary transmission has occurred in school settings when prevention strategies are not implemented or are not followed. In Israel, a school was closed less than two weeks after reopening when two students initiated an outbreak of 153 infections among students and 25 among staff members, from among 1,161 students and 151 staff members that were tested. Importantly, prevention strategies were not adhered to–specifically, they lifted the masking mandate. The majority of cases that are acquired in the community and are brought into a school setting result in limited spread inside schools when multiple layered prevention strategies are in place and most studies have shown success in limiting transmission in schools have required that staff and students wear masks. Inconsistent mask use likely contributed to school-based outbreaks.
III. What about distancing and hand-washing?
Distancing is less important with data showing that 1M separation between kids in school was not a higher risk than 6 feet. The recommendation to distance 6 feet was based on a (now understood to be false) assumption that Scov2, like colds and flu, spreads by direct and fomite transmission vectors. Where did the CDC get such an idea? It wasn't from the C19 data but from data on prior common respiratory infections which commonly are spread through touch and droplets from sneezing and coughing up phlegm. Because C19 is a dry respiratory disease (that for a year and a half did not manifest with productive cough or runny stuffy nose), transmission has been primarily through virus-containing aerosols (airborne transmission). My addition: Now, however, with Delta, we are starting to see a new presentation in which C19 in many people looks very much like seasonal allergy or a cold. This could finally make all of that hand washing and surface sanitizing something more than 'hygiene theater.' Let's do it all and add every reasonable layer of protection at our disposal.
IV. If kids are highly unlikely to wind up with severe illness from C19, why vaccinate them or make them wear masks?
917. One reason is that they, like adults, seem to be getting PCS/long-covid at a fairly high rate. Difficulty concentrating, problems with memory, and fatigue are among the most common problems and these things have profound consequences for academics and athletics in the near term. There is as yet no way to know what contracting C19 will mean down the road for children and one could make the case, based on the data so far, that they have the most to lose if the damage (to brain tissue, for example) caused by infections turns out to be permanent.
918 - 925. Delta Plus, Lambda (the VOI formerly known as C.37), and B.1.621
As noted in previous briefings, Delta has shown a pattern of spreading very fast, peaking, and then declining sharply irrespective of vaccination rates. Time to the peak seems to be about 2 months. That puts us just about a month away from the peak here in the US. What comes next? Likely another brief lull. And then? Infections due to Delta dropped suddenly after the peak in India and the UK but never went away. Now we are seeing Delta rising again in the UK, where they have stopped masking and staying flat at a fairly high rate in India. My crystal ball says we should probably expect the peak in September, followed by a drop in cases but not to pre-Delta levels, followed by a resurgence if we do not reinstitute universal masking and get significantly more people vaccinated (including boosters for those of us who were vaccinated early).
Another possibility is that we could see Delta quickly replaced by another new VOC. Delta Plus is a contender, as it is genotypically the same virus as Delta with one additional mutation in the RBD that is thought to enhance its ability to bind even more tightly to ACE2. India has declared Delta Plus as its own VOC but the WHO and CDC have not yet done so. It is not know how prevalent Delta Plus is in the US but it has been estimated to be higher here than anywhere else. However, such estimates are specious since neither the US nor India are doing widespread genomic sequencing.
Another candidate is Lambda. A new study from Japan indicates that a unique 7-amino-acid deletion mutation in the N-terminal domain of Lambda's spike is responsible for evasion from neutralizing antibodies and may make this VOI significantly more resistant to vaccine-induced immunity and natural immunity from prior infections. These findings mirror those of a study released a few weeks ago from Chile. According to the GISAID Initiative, there have been 1037 documented cases of Lambda so far in the US.
According to the WHO, Lambda (formerly designated as C.37) has been identified in over 80% of infections in Peru since April. The variant was first identified in Peru in August 2020. The WHO declared the Lambda a VOI (not a VOC) on June 14 because it became a dominant variant in large areas of South America but it has not been established yet whether or not it spread more quickly than the D614G 'wild type' strain, is more virulent, or has significantly better immune evasion. In January, it made up 1% of the genomically sequenced cases in Lima; by March, it was 50%, and by April, it was 80%. But its numbers appear to be waning now. Higher viral titers and better ACE-2 binding capacity are likely factors driving increased transmissibility and this is one way a VOC can outcompete other strains. But as we move closer to herd immunity, competition might shift toward selecting variants that have more immune escape. This, of course, is the dreaded outcome. If Lambda's immune evasion ability is significantly better than that of Delta, we could need an entirely new vaccine and have to start the herculean task of worldwide vaccination all over again.
A third candidate for the next wave is B.1.621 –a variant first identified in Colombia early this year that has become dominant there but has not yet earned its own Greek letter designation. The European CDC has listed it as a VOI. It carries several key mutations, including E484K, N501Y and D614G, that have been linked with increased transmissibility and immune evasion. Early reports have shown B.1.621 to have seeded in Florida. Again, because of low levels of genomic sequencing, it is hard to know how prevalent it is there (or elsewhere in the US).
926. The concept of leaky vaccines has been around for a while. Essentially, the idea is that if a vaccine helps the host to not get very sick but does not prevent the host from passing the virus to others, intelligent mutation can occur as a result of the virus being exposed to immune cells and antibodies. The term 'leaky vaccine' can also be replaced with 'imperfect vaccine' as it is meant to distinguish it from a 'perfect vaccine.' Perfect vaccines are so-named because they mimic the perfect immunity that humans naturally develop after having certain childhood disease. When a vaccine works perfectly, as do the childhood vaccines for smallpox, polio, mumps, rubella and measles, it prevents vaccinated individuals from not just from getting sick but also from transmitting the virus to others. Delta, which emerged because of too low vaccination rates, can now bypass imperfect vaccine-induced immunity at a fairly high rate and vaccinated people (and those with prior infections) can now catch C19, get sick, and pass it on, improving the virus' ability to mutate intelligently to become (evolutionarily) fitter. This is the first controlled study to validate the leaky vaccine theory, demonstrating how the virus can become more virulent through this process. But it would probably be more advantageous to Scov2 to improve its fitness by mutating toward better immune evasion and/or transmission. That's exactly what we're seeing.