Posted on by Dr. Francis Collins
Many people, including me, have experienced a sense of gratitude and relief after receiving the new COVID-19 mRNA vaccines. But all of us are also wondering how long the vaccines will remain protective against SARS-CoV-2, the coronavirus responsible for COVID-19.
Earlier this year, clinical trials of the Moderna and Pfizer-BioNTech vaccines indicated that both immunizations appeared to protect for at least six months. Now, a study in the journal Nature provides some hopeful news that these mRNA vaccines may be protective even longer .
In the new study, researchers monitored key immune cells in the lymph nodes of a group of people who received both doses of the Pfizer-BioNTech mRNA vaccine. The work consistently found hallmarks of a strong, persistent immune response against SARS-CoV-2 that could be protective for years to come.
Though more research is needed, the findings add evidence that people who received mRNA COVID-19 vaccines may not need an additional “booster” shot for quite some time, unless SARS-CoV-2 evolves into new forms, or variants, that can evade this vaccine-induced immunity. That’s why it remains so critical that more Americans get vaccinated not only to protect themselves and their loved ones, but to help stop the virus’s spread in their communities and thereby reduce its ability to mutate.
The new study was conducted by an NIH-supported research team led by Jackson Turner, Jane O’Halloran, Rachel Presti, and Ali Ellebedy at Washington University School of Medicine, St. Louis. That work builds upon the group’s previous findings that people who survived COVID-19 had immune cells residing in their bone marrow for at least eight months after the infection that could recognize SARS-CoV-2 . The researchers wanted to see if similar, persistent immunity existed in people who hadn’t come down with COVID-19 but who were immunized with an mRNA vaccine.
To find out, Ellebedy and team recruited 14 healthy adults who were scheduled to receive both doses of the Pfizer-BioNTech vaccine. Three weeks after their first dose of vaccine, the volunteers underwent a lymph node biopsy, primarily from nodes in the armpit. Similar biopsies were repeated at four, five, seven, and 15 weeks after the first vaccine dose.
The lymph nodes are where the human immune system establishes so-called germinal centers, which function as “training camps” that teach immature immune cells to recognize new disease threats and attack them with acquired efficiency. In this case, the “threat” is the spike protein of SARS-COV-2 encoded by the vaccine.
By the 15-week mark, all of the participants sampled continued to have active germinal centers in their lymph nodes. These centers produced an army of cells trained to remember the spike protein, along with other types of cells, including antibody-producing plasmablasts, that were locked and loaded to neutralize this key protein. In fact, Ellebedy noted that even after the study ended at 15 weeks, he and his team continued to find no signs of germinal center activity slowing down in the lymph nodes of the vaccinated volunteers.
Ellebedy said the immune response observed in his team’s study appears so robust and persistent that he thinks that it could last for years. The researcher based his assessment on the fact that germinal center reactions that persist for several months or longer usually indicate an extremely vigorous immune response that culminates in the production of large numbers of long-lasting immune cells, called memory B cells. Some memory B cells can survive for years or even decades, which gives them the capacity to respond multiple times to the same infectious agent.
This study raises some really important issues for which we still don’t have complete answers: What is the most reliable correlate of immunity from COVID-19 vaccines? Are circulating spike protein antibodies (the easiest to measure) the best indicator? Do we need to know what’s happening in the lymph nodes? What about the T cells that are responsible for cell-mediated immunity?
If you follow the news, you may have seen a bit of a dust-up in the last week on this topic. Pfizer announced the need for a booster shot has become more apparent, based on serum antibodies. Meanwhile, the Food and Drug Administration and Centers for Disease Control and Prevention said such a conclusion would be premature, since vaccine protection looks really good right now, including for the delta variant that has all of us concerned.
We’ve still got a lot more to learn about the immunity generated by the mRNA vaccines. But this study—one of the first in humans to provide direct evidence of germinal center activity after mRNA vaccination—is a good place to continue the discussion.
 SARS-CoV-2 mRNA vaccines induce persistent human germinal centre responses. Turner JS, O’Halloran JA, Kalaidina E, Kim W, Schmitz AJ, Zhou JQ, Lei T, Thapa M, Chen RE, Case JB, Amanat F, Rauseo AM, Haile A, Xie X, Klebert MK, Suessen T, Middleton WD, Shi PY, Krammer F, Teefey SA, Diamond MS, Presti RM, Ellebedy AH. Nature. 2021 Jun 28. [Online ahead of print]
 SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Turner JS, Kim W, Kalaidina E, Goss CW, Rauseo AM, Schmitz AJ, Hansen L, Haile A, Klebert MK, Pusic I, O’Halloran JA, Presti RM, Ellebedy AH. Nature. 2021 May 24. [Online ahead of print]
COVID-19 Research (NIH)
Ellebedy Lab (Washington University, St. Louis)
NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
There are now several monoclonal antibodies, identical copies of a therapeutic antibody produced in large numbers, that are authorized for the treatment of COVID-19. But in the ongoing effort to beat this terrible pandemic, there’s plenty of room for continued improvements in treating infections with SARS-CoV-2, the virus that causes COVID-19.
With this in mind, I’m pleased to share progress in the development of a specially engineered therapeutic antibody that could be delivered through a nasal spray. Preclinical studies also suggest it may work even better than existing antibody treatments to fight COVID-19, especially now that new SARS-CoV-2 “variants of concern” have become increasingly prevalent.
These findings come from Zhiqiang An, The University of Texas Health Science Center at Houston, and Pei-Yong Shi, The University of Texas Medical Branch at Galveston, and their colleagues. The NIH-supported team recognized that the monoclonal antibodies currently in use all require time-consuming, intravenous infusion at high doses, which has limited their use. Furthermore, because they are delivered through the bloodstream, they aren’t able to reach directly the primary sites of viral infection in the nasal passages and lungs. With the emergence of new SARS-CoV-2 variants, there’s also growing evidence that some of those therapeutic antibodies are becoming less effective in targeting the virus.
Antibodies come in different types. Immunoglobulin G (IgG) antibodies, for example, are most prevalent in the blood and have the potential to confer sustained immunity. Immunoglobulin A (IgA) antibodies are found in tears, mucus, and other bodily secretions where they protect the body’s moist, inner linings, or mucosal surfaces, of the respiratory and gastrointestinal tracts. Immunoglobulin M (IgM) antibodies are also important for protecting mucosal surfaces and are produced first when fighting an infection.
Though IgA and IgM antibodies differ structurally, both can be administered in an inhaled mist. However, monoclonal antibodies now used to treat COVID-19 are of the IgG type, which must be IV infused.
In the new study, the researchers stitched IgG fragments known for their ability to target SARS-CoV-2 together with those rapidly responding IgM antibodies. They found that this engineered IgM antibody, which they call IgM-14, is more than 230 times better than the IgG antibody that they started with in neutralizing SARS-CoV-2.
Importantly, IgM-14 also does a good job of neutralizing SARS-CoV-2 variants of concern. These include the B.1.1.7 “U.K.” variant (now also called Alpha), the P.1 “Brazilian” variant (called Gamma), and the B.1.351 “South African” variant (called Beta). It also works against 21 other variants carrying alterations in the receptor binding domain (RBD) of the virus’ all-important spike protein. This protein, which allows SARS-CoV-2 to infect human cells, is a prime target for antibodies. Many of these alterations are expected to make the virus more resistant to monoclonal IgG antibodies that are now authorized by the FDA for emergency use.
But would it work to protect against coronavirus infection in a living animal? To find out, the researchers tried it in mice. They squirted a single dose of the IgM-14 antibody into the noses of mice either six hours before exposure to SARS-CoV-2 or six hours after infection with either the P.1 or B.1.351 variants.
In all cases, the antibody delivered in this way worked two days later to reduce dramatically the amount of SARS-CoV-2 in the lungs. That’s important because the amount of virus in the respiratory tracts of infected people is closely linked to severe illness and death due to COVID-19. If the new therapeutic antibody is proven safe and effective in people, it suggests it could become an important tool for reducing the severity of COVID-19, or perhaps even preventing infection altogether.
The researchers already have licensed this new antibody to a biotechnology partner called IGM Biosciences, Mountain View, CA, for further development and future testing in a clinical trial. If all goes well, the hope is that we’ll have a safe and effective nasal spray to serve as an extra line of defense in the fight against COVID-19.
 Nasal delivery of an IgM offers broad protection from SARS-CoV-2 variants. Ku Z, Xie X, Hinton PR, Liu X, Ye X, Muruato AE, Ng DC, Biswas S, Zou J, Liu Y, Pandya D, Menachery VD, Rahman S, Cao YA, Deng H, Xiong W, Carlin KB, Liu J, Su H, Haanes EJ, Keyt BA, Zhang N, Carroll SF, Shi PY, An Z. Nature. 2021 Jun 3.
COVID-19 Research (NIH)
Zhiqiang An (The University of Texas Health Science Center at Houston)
Pei-Yong Shi (The University of Texas Medical Branch at Galveston)
IGM Biosciences (Mountain View, CA)
NIH Support: National Institute of Allergy and Infectious Diseases; National Center for Advancing Translational Sciences; National Cancer Institute
Posted on by Dr. Francis Collins
For many people who’ve had COVID-19, the infections were thankfully mild and relatively brief. But these individuals’ immune systems still hold onto enduring clues about how best to neutralize SARS-CoV-2, the coronavirus that causes COVID-19. Discovering these clues could point the way for researchers to design highly targeted treatments that could help to save the lives of folks with more severe infections.
An NIH-funded study, published recently in the journal Science, offers the most-detailed picture yet of the array of antibodies against SARS-CoV-2 found in people who’ve fully recovered from mild cases of COVID-19. This picture suggests that an effective neutralizing immune response targets a wider swath of the virus’ now-infamous spike protein than previously recognized.
To date, most studies of natural antibodies that block SARS-CoV-2 have zeroed in on those that target a specific portion of the spike protein known as the receptor-binding domain (RBD)—and with good reason. The RBD is the portion of the spike that attaches directly to human cells. As a result, antibodies specifically targeting the RBD were an excellent place to begin the search for antibodies capable of fending off SARS-CoV-2.
The new study, led by Gregory Ippolito and Jason Lavinder, The University of Texas at Austin, took a different approach. Rather than narrowing the search, Ippolito, Lavinder, and colleagues analyzed the complete repertoire of antibodies against the spike protein from four people soon after their recoveries from mild COVID-19.
What the researchers found was a bit of a surprise: the vast majority of antibodies—about 84 percent—targeted other portions of the spike protein than the RBD. This suggests a successful immune response doesn’t concentrate on the RBD. It involves production of antibodies capable of covering areas across the entire spike.
The researchers liken the spike protein to an umbrella, with the RBD at the tip of the “canopy.” While some antibodies do bind RBD at the tip, many others apparently target the protein’s canopy, known as the N-terminal domain (NTD).
Further study in cell culture showed that NTD-directed antibodies do indeed neutralize the virus. They also prevented a lethal mouse-adapted version of the coronavirus from infecting mice.
One reason these findings are particularly noteworthy is that the NTD is one part of the viral spike protein that has mutated frequently, especially in several emerging variants of concern, including the B.1.1.7 “U.K. variant” and the B.1.351 “South African variant.” It suggests that one reason these variants are so effective at evading our immune systems to cause breakthrough infections, or re-infections, is that they’ve mutated their way around some of the human antibodies that had been most successful in combating the original coronavirus variant.
Also noteworthy, about 40 percent of the circulating antibodies target yet another portion of the spike called the S2 subunit. This finding is especially encouraging because this portion of SARS-CoV-2 does not seem as mutable as the NTD segment, suggesting that S2-directed antibodies might offer a layer of protection against a wider array of variants. What’s more, the S2 subunit may make an ideal target for a possible pan-coronavirus vaccine since this portion of the spike is widely conserved in SARS-CoV-2 and related coronaviruses.
Taken together, these findings will prove useful for designing COVID-19 vaccine booster shots or future vaccines tailored to combat SARS-COV-2 variants of concern. The findings also drive home the conclusion that the more we learn about SARS-CoV-2 and the immune system’s response to neutralize it, the better position we all will be in to thwart this novel coronavirus and any others that might emerge in the future.
 Prevalent, protective, and convergent IgG recognition of SARS-CoV-2 non-RBD spike epitopes. Voss WN, Hou YJ, Johnson NV, Delidakis G, Kim JE, Javanmardi K, Horton AP, Bartzoka F, Paresi CJ, Tanno Y, Chou CW, Abbasi SA, Pickens W, George K, Boutz DR, Towers DM, McDaniel JR, Billick D, Goike J, Rowe L, Batra D, Pohl J, Lee J, Gangappa S, Sambhara S, Gadush M, Wang N, Person MD, Iverson BL, Gollihar JD, Dye J, Herbert A, Finkelstein IJ, Baric RS, McLellan JS, Georgiou G, Lavinder JJ, Ippolito GC. Science. 2021 May 4:eabg5268.
COVID-19 Research (NIH)
Gregory Ippolito (University of Texas at Austin)
NIH Support: National Institute of Allergy and Infectious Diseases; National Cancer Institute; National Institute of General Medical Sciences; National Center for Advancing Translational Sciences
Posted on by Dr. Francis Collins
This striking portrait features the spike protein that crowns SARS-CoV-2, the coronavirus that causes COVID-19. This highly flexible protein has settled here into one of its many possible conformations during the process of docking onto a human cell before infecting it.
This portrait, however, isn’t painted on canvas. It was created on a computer screen from sophisticated 3D simulations of the spike protein in action. The aim was to map its many shape-shifting maneuvers accurately at the atomic level in hopes of detecting exploitable structural vulnerabilities to thwart the virus.
For example, notice the many chain-like structures (green) that adorn the protein’s surface (white). They are sugar molecules called glycans that are thought to shield the spike protein by sweeping away antibodies. Also notice areas (purple) that the simulation identified as the most-attractive targets for antibodies, based on their apparent lack of protection by those glycans.
This work, published recently in the journal PLoS Computational Biology , was performed by a German research team that included Mateusz Sikora, Max Planck Institute of Biophysics, Frankfurt. The researchers used a computer application called molecular dynamics (MD) simulation to power up and model the conformational changes in the spike protein on a time scale of a few microseconds. (A microsecond is 0.000001 second.)
The new simulations suggest that glycans act as a dynamic shield on the spike protein. They liken them to windshield wipers on a car. Rather than being fixed in space, those glycans sweep back and forth to protect more of the protein surface than initially meets the eye.
But just as wipers miss spots on a windshield that lie beyond their tips, glycans also miss spots of the protein just beyond their reach. It’s those spots that the researchers suggest might be prime targets on the spike protein that are especially promising for the design of future vaccines and therapeutic antibodies.
This same approach can now be applied to identifying weak spots in the coronavirus’s armor. It also may help researchers understand more fully the implications of newly emerging SARS-CoV-2 variants. The hope is that by capturing this devastating virus and its most critical proteins in action, we can continue to develop and improve upon vaccines and therapeutics.
 Computational epitope map of SARS-CoV-2 spike protein. Sikora M, von Bülow S, Blanc FEC, Gecht M, Covino R, Hummer G. PLoS Comput Biol. 2021 Apr 1;17(4):e1008790.
COVID-19 Research (NIH)
Mateusz Sikora (Max Planck Institute of Biophysics, Frankfurt, Germany)
The surprising properties of the coronavirus envelope (Interview with Mateusz Sikora), Scilog, November 16, 2020.