COVID-19 immune response
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
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
A crucial question for COVID-19 researchers is what causes progression of the initial infection, leading to life-threatening respiratory illness. A good place to look for clues is in the lungs of those COVID-19 patients who’ve tragically lost their lives to acute respiratory distress syndrome (ARDS), in which fluid and cellular infiltrates build up in the lung’s air sacs, called alveoli, keeping them from exchanging oxygen with the bloodstream.
As shown above, a team of NIH-funded researchers has done just that, capturing changes in the lungs over the course of a COVID-19 infection at unprecedented, single-cell resolution. These imaging data add evidence that SARS-CoV-2, the coronavirus that causes COVID-19, primarily infects cells at the surface of the air sacs. Their findings also offer valuable clues for treating the most severe consequences of COVID-19, suggesting that a certain type of scavenging immune cell might be driving the widespread lung inflammation that leads to ARDS.
The findings, published in Nature , come from Olivier Elemento and Robert E. Schwartz, Weill Cornell Medicine, New York. They already knew from earlier COVID-19 studies about the body’s own immune response causing the lung inflammation that leads to ARDS. What was missing was an understanding of the precise interplay between immune cells and lung tissue infected with SARS-CoV-2. It also wasn’t clear how the ARDS seen with COVID-19 compared to the ARDS seen in other serious respiratory diseases, including influenza and bacterial pneumonia.
Traditional tissue analysis uses chemical stains or tagged antibodies to label certain proteins and visualize important features in autopsied human tissues. But using these older techniques, it isn’t possible to capture more than a few such proteins at once. To get a more finely detailed view, the researchers used a more advanced technology called imaging mass cytometry .
This approach uses a collection of lanthanide metal-tagged antibodies to label simultaneously dozens of molecular markers on cells within tissues. Next, a special laser scans the labeled tissue sections, which vaporizes the heavy metal tags. As the metals are vaporized, their distinct signatures are detected in a mass spectrometer along with their spatial position relative to the laser. The technique makes it possible to map precisely where a diversity of distinct cell types is located in a tissue sample with respect to one another.
In the new study, the researchers applied the method to 19 lung tissue samples from patients who had died of severe COVID-19, acute bacterial pneumonia, or bacterial or influenza-related ARDS. They included 36 markers to differentiate various types of lung and immune cells as well as the SARS-CoV-2 spike protein and molecular signs of immune activation, inflammation, and cell death. For comparison, they also mapped four lung tissue samples from people who had died without lung disease.
Altogether, they captured more than 200 lung tissue maps, representing more than 660,000 cells across all the tissues sampled. Those images showed in all cases that respiratory infection led to a thickening of the walls surrounding alveoli as immune cells entered. They also showed an increase in cell death in infected compared to healthy lungs.
Their maps suggest that what happens in the lungs of COVID-19 patients who die with ARDS isn’t entirely unique. It’s similar to what happens in the lungs of those with other life-threatening respiratory infections who also die with ARDS.
They did, however, reveal a potentially prominent role in COVID-19 for white blood cells called macrophages. The results showed that macrophages are much more abundant in the lungs of severe COVID-19 patients compared to other lung infections.
In late COVID-19, macrophages also increase in the walls of alveoli, where they interact with lung cells known as fibroblasts. This suggests these interactions may play a role in the buildup of damaging fibrous tissue, or scarring, in the alveoli that tends to be seen in severe COVID-19 respiratory infections.
While the virus initiates this life-threatening damage, its progression may not depend on the persistence of the virus, but on an overreaction of the immune system. This may explain why immunomodulatory treatments like dexamethasone can provide benefit to the sickest patients with COVID-19. To learn even more, the researchers are making their data and maps available as a resource for scientists around the world who are busily working to understand this devastating illness and help put an end to the terrible toll caused by this pandemic.
 The spatial landscape of lung pathology during COVID-19 progression. Rendeiro AF, Ravichandran H, Bram Y, Chandar V, Kim J, Meydan C, Park J, Foox J, Hether T, Warren S, Kim Y, Reeves J, Salvatore S, Mason CE, Swanson EC, Borczuk AC, Elemento O, Schwartz RE. Nature. 2021 Mar 29.
 Mass cytometry imaging for the study of human diseases-applications and data analysis strategies. Baharlou H, Canete NP, Cunningham AL, Harman AN, Patrick E. Front Immunol. 2019 Nov 14;10:2657.
COVID-19 Research (NIH)
Elemento Lab (Weill Cornell Medicine, New York)
Schwartz Lab (Weill Cornell Medicine)
NIH Support: National Center for Advancing Translational Sciences; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute