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.
Dec. 17th Event: The Latest on Omicron, Boosters, and Immunity
The Omicron variant poses new uncertainty for the vaccines, which four leading experts will address during our virtual event on December 17th, 2021.
This virtual event will convene leading scientific and medical experts to discuss the most pressing questions around the new Omicron variant, including what we know so far about its ability to evade COVID-19 vaccines, the role of boosters in eliciting heightened immunity, and the science behind variants and vaccines. A public Q&A will follow the expert discussion.
EVENT INFORMATION:
Date: Friday Dec 17, 2021
2:00pm - 3:30pm EST
Dr. Céline Gounder, MD, ScM, is the CEO/President/Founder of Just Human Productions, a non-profit multimedia organization. She is also the host and producer of American Diagnosis, a podcast on health and social justice, and Epidemic, a podcast about infectious disease epidemics and pandemics. She served on the Biden-Harris Transition COVID-19 Advisory Board.
Dr. Theodora Hatziioannou, Ph.D., is a Research Associate Professor in the Laboratory of Retrovirology at The Rockefeller University. Her research includes identifying plasma samples from recovered COVID-19 patients that contain antibodies capable of neutralizing the SARS-CoV-2 coronavirus.
Dr. Onyema Ogbuagu, MBBCh, is an Associate Professor at Yale School of Medicine and an infectious disease specialist who treats COVID-19 patients and leads Yale’s clinical studies around COVID-19. He ran Yale’s trial of the Pfizer/BioNTech vaccine.
Dr. Eric Topol, M.D., is a cardiologist, scientist, professor of molecular medicine, and the director and founder of Scripps Research Translational Institute. He has led clinical trials in over 40 countries with over 200,000 patients and pioneered the development of many routinely used medications.
This event is the fourth of a four-part series co-hosted by Leaps.org, the Aspen Institute Science & Society Program, and the Sabin–Aspen Vaccine Science & Policy Group, with generous support from the Gordon and Betty Moore Foundation and the Howard Hughes Medical Institute.
Kira Peikoff is the editor-in-chief of Leaps.org. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.
7 Things to Know about the U.S.’s Capability to Detect Omicron
A visualization of the original coronavirus causing COVID-19, which has now been detected across the globe in a highly mutated form called Omicron.
If the new variant Omicron isn’t here already – which many experts suspect that it is – it will be soon. While we wait for scientists to conduct the necessary research to characterize its transmissibility, potential fitness at immune evasion, and disease severity, we wanted to give Leaps.org readers a window into how the U.S. is positioned to detect the variant. So we spoke to Kelly Wroblewski, director of infectious diseases at the Association of Public Health Laboratories, a membership organization that represents state and local government health labs in the United States. Here are seven insights she shared.
1) If you test positive for COVID-19 with a standard PCR test, the diagnostic report will not tell you which variant you have. There are no diagnostic tests available for your doctor to order to identify variants. To find out the variant, the specimen must be sent to a commercial, clinical, academic, or public health laboratory for genetic sequencing.
2) Today, the U.S. sequences about 5 to 10 percent of all diagnostic specimens that test positive for SARS-CoV-2 in order to determine which variants are circulating and where. Last week nationally, for example, labs sequenced about 80,000 samples. This represents a massive increase from last year at this time, when labs were only sequencing about 8,000 specimens per week. Currently, 99.5 percent of circulating SARS-CoV-2 virus in the U.S. is the Delta variant.
3) The U.S. is “very well prepared” to detect Omicron, Wroblewski says, “particularly compared to where we were when the Alpha variant, or B117 first emerged.” Of the hunt for Omicron, she adds, “it’s very reminiscent of that time, except we are doing so much more sequencing and we have so much better coverage with our sequencing geographically, and we're doing it in a much more timely way. We have the ability to find emerging variants that are circulating in 0.01 percent of the population.”
4) Deciding which specimens to sample is not totally random. Samples that have more virus are likely to lead to better sequencing results. Labs also look to have a diverse set of representative samples, meaning across geographic regions and across gender, race, ethnicity, and age groups. Clinical diversity is also important, such as including pregnant women, severe in-patient cases, mild cases, etc.
5) Sequencing more is not necessarily better to find Omicron faster. “We will increase the number of sequences to a certain extent,” Wroblewski says. “Where we exhibit some caution is doing that indiscriminately isn’t the most effective use of time and resources. The important thing is to try to find Omicron, and if you increase your testing capacity too much, right now, it's still predominantly Delta in the U.S. by a long shot. So you’re mostly going to sequence Delta and you run the risk of delaying your discovery of Omicron, if you focus solely on increasing sequencing.”
So besides just ramping up the sheer numbers of sequencing, diagnostic labs across the country are now advised to preferentially use a certain PCR test made by Thermo Fisher that can help hasten the detection of Omicron. It turns out that Omicron’s specific mutations in the Spike protein mean that the Spike is not picked up on this PCR test, which yields a type of result called an S-gene target failure. Yet the test will still accurately pick up a COVID-19 diagnosis, because it detects two other gene targets on Omicron that are not mutated. “That S-gene target failure gives you a good indication that you may have Omicron. It’s a good early screen.”
Labs will then still need to sequence the whole genome to confirm it matches the Omicron sequence. “So right now, the new recommendation is to use [the Thermo Fisher test] as much as possible to give us a better chance of detecting Omicron more quickly.”
6) This Thermo Fisher test is “fairly widely used” in the U.S. already, so many labs are already well positioned to make the shift. “In early to mid 2020,” Wroblewski explains, “when the supply chain issue for testing was acute, many public health labs implemented five, six, seven, eight different tests, just so they could get enough supplies to do all the testing. Now that we're in a much better place supply-chain wise, it's very difficult and time consuming and cumbersome to maintain all those different test methods all the time, and many, many labs scaled back to only one or two. And so this [new recommendation] would just be shifting to two for some labs that will be shifting to them.”
7) Once Omicron is found here, labs will be focused on finding as many cases as possible, and the CDC will be conducting a variety of studies to determine the impact of the variant on diagnostics, therapeutics, and vaccines. Epidemiologists at the local, state, and federal level will analyze which populations it is spreading in, as well as the severity of the disease it causes. They will work to sort out different impacts on vaccinated vs. unvaccinated populations. The ultimate goal, Wroblewski concludes, is to “use all of that information to make better public health decisions and inform the public about what’s going on.”
Kira Peikoff is the editor-in-chief of Leaps.org. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.