Don't Panic Over Waning Antibodies. Here's Why.
A health care worker places a bandaid on the arm of a man who has just been vaccinated.
Since the Delta variant became predominant in the United States on July 7, both scientists and the media alike have been full of mixed messages ("breakthrough infections rare"; "breakthrough infections common"; "vaccines still work"; "vaccines losing their effectiveness") but – if we remember our infectious diseases history- one thing remains clear: immunity is the only way to get through a pandemic.
What Happened in the Past
The 1918 influenza pandemic was far the deadliest respiratory virus pandemic recorded in recent human history with over 50 million deaths (maybe even 100 million deaths, or 3% of the world's population) worldwide. Although they used some of the same measures we are using now (masks, distancing, event closures, as neither testing nor a vaccine existed back then), the deaths slowed only after enough of the population had either acquired immunity through natural infection or died. Indeed, the first influenza vaccine was not developed until 1942, more than 20 years later. As judged by the amount of suffering and death from 1918 influenza (and the deadly Delta surge in India in spring 2021), natural immunity is obviously a terrible way to get through a pandemic.
Similarly, measles was a highly transmissible respiratory virus that led to high levels of immunity among adults who were invariably exposed as children. However, measles led to deaths each year among the nonimmune until a vaccine was developed in 1963, largely restricting current measles outbreaks in the U.S. now to populations who decline to vaccinate. Smallpox also led to high levels of immunity through natural infection, which was often fatal. That's why unleashing smallpox on a largely nonimmune population in the New World was so deadly. Only an effective vaccine – and its administration worldwide, including among populations who declined smallpox vaccine at first via mandates – could control and then eventually eradicate smallpox from Earth.
Fully vaccinated people are already now able to generate some antibodies against all the variants we know of to date, thanks to their bank of memory B cells.
The Delta variant is extremely transmissible, making it unlikely we will ever eliminate or eradicate SARS-CoV-2. Even Australia, which had tried to maintain a COVID-zero nation with masks, distancing, lockdowns, testing and contact tracing before and during the vaccines, ended a strategy aimed at eliminating COVID-19 this week. But, luckily, since highly effective and safe vaccines were developed for COVID-19 less than a year after its advent on a nonimmune population and since vaccines are retaining their effectiveness against severe disease, we have a safe way out of the misery of this pandemic: more and more immunity. "Defanging" SARS-CoV-2 and stripping it of its ability to cause severe disease through immunity will relegate it to the fate of the other four circulating cold-causing coronaviruses, an inconvenience but not a world-stopper.
Immunity Is More Than Antibodies
When we say immunity, we have to be clear that we are talking about cellular immunity and immune memory, not only antibodies. This is a key point. Neutralizing antibodies, which prevent the virus from entering our cells, are generated by the vaccines. But those antibodies will necessarily wane over time since we cannot keep antibodies from every infection and vaccine we have ever seen in the bloodstream (or our blood would be thick as paste!). Vaccines with shorter intervals between doses (like Pfizer vaccines given 3 weeks apart) are likely to have their antibodies wane sooner than vaccines with longer intervals between doses (like Moderna), making mild symptomatic breakthroughs less likely with the Moderna vaccine than the Pfizer during our Delta surge, as a recent Mayo Clinic study showed.
Luckily, the vaccines generate B cells that get relegated to our memory banks and these memory B cells are able to produce high levels of antibodies to fight the virus if they see it again. Amazingly, these memory B cells will actually produce antibodies adapted against the COVID variants if they see a variant in the future, rather than the original antibodies directed against the ancestral strain. This is because memory B cells serve as a blueprint to make antibodies, like the blueprint of a house. If a house needs an extra column (or antibodies need to evolve to work against variants), the blueprint will oblige just as memory B cells will!
One problem with giving a 3rd dose of our current vaccines is that those antibodies won't be adapted towards the variants. Fully vaccinated people are already now able to generate some antibodies against all the variants we know of to date, thanks to their bank of memory B cells. In other words, no variant has evolved to date that completely evades our vaccines. Memory B cells, once generated by either natural infection or vaccination, should be long-lasting.
If memory B cells are formed by a vaccine, they should be as long-lasting as those from natural infection per various human studies. A 2008 Nature study found that survivors of the 1918 influenza pandemic were able to produce antibodies from memory B cells when exposed to the same influenza strain nine decades later. Of note, mild infections (such as the common cold from the cold-causing coronaviruses called 229E, NL63, OC43, and HKU1) may not reliably produce memory B cell immunity like more severe infections caused by SARS-CoV-2.
Right about now, you may be worrying about a super-variant that might yet emerge to evade all our hard-won immune responses. But most immunologists do not think this is very realistic because of T cells. How are T cells different from B Cells? While B cells are like the memory banks to produce antibodies when needed (helped by T cells), T cells will specifically amplify in response to a piece of the virus and help recruit cells to attack the pathogen directly. We likely have T cells to thank for the vaccine's incredible durability in protecting us against severe disease. Data from La Jolla Immunology Institute and UCSF show that the T cell response from the Pfizer vaccine is strong across all the variants.
Think of your spike protein as being comprised of 100 houses with a T cell there to cover each house (to protect you against severe disease). The variants have around 13 mutations along the spike protein so 13 of those T cells won't work, but there are over 80 T cells remaining to protect your "houses" or your body against severe disease.
Although these are theoretical numbers and we don't know exactly the number of T cell antigens (or "epitopes") across the spike protein, one review showed 1400 across the whole virus, with many of those in the spike protein. Another study showed that there were 87 epitopes across the spike protein to which T cells respond, and mutations in one of the variants (beta) took those down to 75. The virus cannot mutate indefinitely in its spike protein and still retain function. This is why it is unlikely we will get a variant that will evade the in-breadth, robust response of our T cells.
Where We Go From Here
So, what does this mean for getting through this pandemic? Immunity and more immunity. For those of us who are vaccinated, if we get exposed to the Delta variant, it will boost our immune response although the memory B cells might take 3-5 days to make new antibodies, which can leave us susceptible to a mild breakthrough infection. That's part of the reason the CDC put back masks for the vaccinated in late July. For those who are unvaccinated, immunity will be gained from Delta but often through terrible ways like severe disease.
The way for the U.S. to determine the need for 3rd shots among those who are not obviously immunocompromised, given the amazing immune memory generated by the vaccines among immunocompetent individuals, is to analyze the cases of the ~6000 individuals who have had severe breakthrough infections among the 171 million Americans fully vaccinated. Define their co-morbidities and age ranges, and boost those susceptible to severe infections (examples could include older people, those with co-morbidities, health care workers, and residents of long-term care facilities). This is an approach likely to be taken by the CDC's Advisory Committee on Immunization Practices.
If immunity is the only way to get through the pandemic and if variants are caused mostly by large populations being unvaccinated, there is not only a moral and ethical imperative but a practical imperative to vaccinate the world in order to keep us all safe. Immunocompetent Americans can boost their antibodies, which may enhance their ability to avoid mild breakthrough infections, but the initial shots still work well against the most important outcomes: hospitalizations and deaths.
There has been no randomized, controlled trial to assess whether three shots vs. two shots meaningfully improve those outcomes. While we ought to trust immune memory to get the immunocompetent in the United States through, we can hasten the end of this pandemic by providing surplus vaccines to poor countries to combat severe disease. Doing so would not only revitalize the role of the U.S. as a global health leader – it would save countless lives.
Chicken that is grown entirely in a laboratory, without harming a single bird, could be sold in supermarkets in the coming months. But critics say the doubts about lab-grown meat have not been appropriately explored.
Last November, when the U.S. Food and Drug Administration disclosed that chicken from a California firm called UPSIDE Foods did not raise safety concerns, it drily upended how humans have obtained animal protein for thousands of generations.
“The FDA is ready to work with additional firms developing cultured animal cell food and production processes to ensure their food is safe and lawful,” the agency said in a statement at the time.
Assuming UPSIDE obtains clearances from the U.S. Department of Agriculture, its chicken – grown entirely in a laboratory without harming a single bird – could be sold in supermarkets in the coming months.
“Ultimately, we want our products to be available everywhere meat is sold, including retail and food service channels,” a company spokesperson said. The upscale French restaurant Atelier Crenn in San Francisco will have UPSIDE chicken on its menu once it is approved, she added.
Known as lab-grown or cultured meat, a product such as UPSIDE’s is created using stem cells and other tissue obtained from a chicken, cow or other livestock. Those cells are then multiplied in a nutrient-dense environment, usually in conjunction with a “scaffold” of plant-based materials or gelatin to give them a familiar form, such as a chicken breast or a ribeye steak. A Dutch company called Mosa Meat claims it can produce 80,000 hamburgers derived from a cluster of tissue the size of a sesame seed.
Critics say the doubts about lab-grown meat and the possibility it could merge “Brave New World” with “The Jungle” and “Soylent Green” have not been appropriately explored.
That’s a far cry from when it took months of work to create the first lab-grown hamburger a decade ago. That minuscule patty – which did not contain any fat and was literally plucked from a Petri dish to go into a frying pan – cost about $325,000 to produce.
Just a decade later, an Israeli company called Future Meat said it can produce lab-grown meat for about $1.70 per pound. It plans to open a production facility in the U.S. sometime in 2023 and distribute its products under the brand name “Believer.”
Costs for production have sunk so low that researchers at Carnegie Mellon University in Pittsburgh expect sometime in early 2024 to produce lab-grown Wagyu steak to showcase the viability of growing high-end cuts of beef cheaply. The Carnegie Mellon team is producing its Wagyu using a consumer 3-D printer bought secondhand on eBay and modified to print the highly marbled flesh using a method developed by the university. The device costs $200 – about the same as a pound of Wagyu in the U.S. The initiative’s modest five-figure budget was successfully crowdfunded last year.
“The big cost is going to be the cells (which are being extracted by a cow somewhere in Pennsylvania), but otherwise printing doesn’t add much to the process,” said Rosalyn Abbott, a Carnegie Mellon assistant professor of bioengineering who is co-leader on the project. “But it adds value, unlike doing this with ground meat.”
Lab-Grown Meat’s Promise
Proponents of lab-grown meat say it will cut down on traditional agriculture, which has been a leading contributor to deforestation, water shortages and contaminated waterways from animal waste, as well as climate change.
An Oxford University study from 2011 concludes lab-grown meat could have greenhouse emissions 96 percent lower compared to traditionally raised livestock. Moreover, proponents of lab-grown meat claim that the suffering of animals would decline dramatically, as they would no longer need to be warehoused and slaughtered. A recently opened 26-story high-rise in China dedicated to the raising and slaughtering of pigs illustrates the current plight of livestock in stark terms.
Scientists may even learn how to tweak lab-grown meat to make it more nutritious. Natural red meat is high in saturated fat and, if it’s eaten too often, can lead to chronic diseases. In lab versions, the saturated fat could be swapped for healthier, omega-3 fatty acids.
But critics say the doubts about lab-grown meat and the possibility it could merge “Brave New World” with “The Jungle” and “Soylent Green” have not been appropriately explored.
A Slippery Slope?
Some academics who have studied the moral and ethical issues surrounding lab-grown meat believe it will have a tough path ahead gaining acceptance by consumers. Should it actually succeed in gaining acceptance, many ethical questions must be answered.
“People might be interested” in lab-grown meat, perhaps as a curiosity, said Carlos Alvaro, an associate professor of philosophy at the New York City College of Technology, part of the City University of New York. But the allure of traditionally sourced meat has been baked – or perhaps grilled – into people’s minds for so long that they may not want to make the switch. Plant-based meat provides a recent example of the uphill battle involved in changing old food habits, with Beyond Meat’s stock prices dipping nearly 80 percent in 2022.
"There are many studies showing that people don’t really care about the environment (to that extent)," Alvaro said. "So I don’t know how you would convince people to do this because of the environment.”
“From my research, I understand that the taste (of lab-grown meat) is not quite there,” Alvaro said, noting that the amino acids, sugars and other nutrients required to grow cultivated meat do not mimic what livestock are fed. He also observed that the multiplication of cells as part of the process “really mimic cancer cells” in the way they grow, another off-putting thought for would-be consumers of the product.
Alvaro is also convinced the public will not buy into any argument that lab-grown meat is more environmentally friendly.
“If people care about the environment, they either try and consume considerably less meat and other animal products, or they go vegan or vegetarian,” he said. “But there are many studies showing that people don’t really care about the environment (to that extent). So I don’t know how you would convince people to do this because of the environment.”
Ben Bramble, a professor at Australian National University who previously held posts at Princeton and Trinity College in Ireland, takes a slightly different tack. He noted that “if lab-grown meat becomes cheaper, healthier, or tastier than regular meat, there will be a large market for it. If it becomes all of these things, it will dominate the market.”
However, Bramble has misgivings about that occurring. He believes a smooth transition from traditionally sourced meat to a lab-grown version would allow humans to elide over the decades of animal cruelty perpetrated by large-scale agriculture, without fully reckoning with and learning from this injustice.
“My fear is that if we all switch over to lab-grown meat because it has become cheaper, healthier, or tastier than regular meat, we might never come to realize what we have done, and the terrible things we are capable of,” he said. “This would be a catastrophe.”
Bramble’s writings about cultured meat also raise some serious moral conundrums. If, for example, animal meat may be cultivated without killing animals, why not create products from human protein?
Actually, that’s already happened.
It occurred in 2019, when Orkan Telhan, a professor of fine arts at the University of Pennsylvania, collaborated with two scientists to create an art exhibit at the Philadelphia Museum of Art on the future of foodstuffs.
Although the exhibit included bioengineered bread and genetically modified salmon, it was an installation called “Ouroboros Steak” that drew the most attention. That was comprised of pieces of human flesh grown in a lab from cultivated cells and expired blood products obtained from online sources.
The exhibit was presented as four tiny morsels of red meat – shaped in patterns suggesting an ouroboros, a dragon eating its own tail. They were placed in tiny individual saucers atop a larger plate and placemat with a calico pattern, suggesting an item to order in a diner. The artwork drew international headlines – as well as condemnation for Telhan’s vision.
Telhan’s artwork is intended to critique the overarching assumption that lab-grown meat will eventually replace more traditional production methods, as well as the lack of transparency surrounding many processed foodstuffs. “They think that this problem (from industrial-scale agriculture) is going be solved by this new technology,” Telhan said. “I am critical (of) that perspective.”
Unlike Bramble, Telhan is not against lab-grown meat, so long as its producers are transparent about the sourcing of materials and its cultivation. But he believes that large-scale agricultural meat production – which dates back centuries – is not going to be replaced so quickly.
“We see this again and again with different industries, like algae-based fuels. A lot of companies were excited about this, and promoted it,” Telhan said. “And years later, we know these fuels work. But to be able to displace the oil industry means building the infrastructure to scale takes billions of dollars, and nobody has the patience or money to do it.”
Alvaro concurred on this point, which he believes is already weakened because a large swath of consumers aren’t concerned about environmental degradation.
“They’re going to have to sell this big, but in order to convince people to do so, they have to convince them to eat this product instead of regular meat,” Alvaro said.
Hidden Tweaks?
Moreover, if lab-based meat does obtain a significant market share, Telhan suggested companies may do things to the product – such as to genetically modify it to become more profitable – and never notify consumers. That is a particular concern in the U.S., where regulations regarding such modifications are vastly more relaxed than in the European Union.
“I think that they have really good objectives, and they aspire to good objectives,” Telhan said. “But the system itself doesn't really allow for that much transparency.”
No matter what the future holds, sometime next year Carnegie Mellon is expected to hold a press conference announcing it has produced a cut of the world’s most expensive beef with the help of a modified piece of consumer electronics. It will likely take place at around the same time UPSIDE chicken will be available for purchase in supermarkets and restaurants, pending the USDA’s approvals.
Abbott, the Carnegie Mellon professor, suggested the future event will be both informative and celebratory.
“I think Carnegie Mellon would have someone potentially cook it for us,” she said. “Like have a really good chef in New York City do it.”
In this week's Friday Five, breathing this way may cut down on anxiety, a fasting regimen that could make you sick, this type of job makes men more virile, 3D printed hearts could save your life, and the role of metformin in preventing dementia.
The Friday Five covers five stories in research that you may have missed this week. There are plenty of controversies and troubling ethical issues in science – and we get into many of them in our online magazine – but this news roundup focuses on scientific creativity and progress to give you a therapeutic dose of inspiration headed into the weekend.
Here are the promising studies covered in this week's Friday Five, featuring interviews with Dr. David Spiegel, associate chair of psychiatry and behavioral sciences at Stanford, and Dr. Filip Swirski, professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai.
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Here are the promising studies covered in this week's Friday Five, featuring interviews with Dr. David Spiegel, associate chair of psychiatry and behavioral sciences at Stanford, and Dr. Filip Swirski, professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai.
- Breathing this way cuts down on anxiety*
- Could your fasting regimen make you sick?
- This type of job makes men more virile
- 3D printed hearts could save your life
- Yet another potential benefit of metformin
* This video with Dr. Andrew Huberman of Stanford shows exactly how to do the breathing practice.