Subsequent vaccinations have been shown to give stronger immunity to those who have recovered from COVID-19 than those who have never been infected.This is one of the big mysteries surrounding the pandemic.

Theodora Hatziioannou and Paul Bieniasz, virologists at Rockefeller University (New York, USA), said that the new coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2020; SARS-CoV-2) will infect human cells from around the fall of 2. We have been aiming to modify the "spike protein" used in the process to create a mutant virus that can avoid any antibody that blocks infection.At that time, mutant strains such as the Delta strain had not yet appeared.

The purpose of the study was to identify key sites of neutralizing antibodies in peplomer proteins. Hatziioannou et al. Introduced potentially problematic mutations identified in experimental and epidemic mutants into "pseudotype" viruses [harmless viruses that cannot cause the new coronavirus infection (COVID-19)]. By doing so, the effect of the mutation added to the spike protein was tested.Nature 2021 year 9 month 20 day issueResearch report published in1According to the report, the mutant virus with 20 mutated peplomers showed complete resistance to neutralizing antibodies produced by infection or vaccination.However, there were exceptions.

This mutant virus is much more resistant to attack from the immune system than known natural mutants, but those who were vaccinated months after recovering from COVID-19 did. I had an antibody that could incapacitate.The antibodies possessed by these people even blocked coronaviruses of a different type than SARS-CoV-2. "I think it's likely to be effective against all future variants of SARS-CoV-2," says Hatziioannou.

With new variants of coronavirus being watched around the world, the mechanism by which such "superimmunity" occurs is one of the major mysteries surrounding pandemics.Researchers hope that by scrutinizing the difference between infectious and vaccinated immune defenses, we may find ways to safely achieve higher levels of infectious protection.

"Superimmunity is also associated with booster inoculation and the strength of the immune response to emerging variants," said Mehul Suthar, a virologist at Emory University in Atlanta, Georgia. "We are trying to figure out this problem."

Hybrid immunity

Researchers began to realize that people who recovered from COVID-19 had unique characteristics in their response to vaccines shortly after vaccination began in each country.Rishi Goel, an immunological scientist at the University of Pennsylvania (Philadelphia, USA) who is studying superimmunity, the "hybrid immunity" that can be obtained by vaccination after infection, said, "It is extraordinarily high, which cannot be obtained by two vaccinations alone. It turns out that a level of antibody is produced. "

The sera of people with hybrid immunity (blood fractions containing antibodies) are the first beta variants and other coronaviruses detected in South Africa compared to the sera of people vaccinated without experience of infection. Early studies have shown that the ability to neutralize strains that escape immunity, such as2..However, it was not clear whether it was simply due to high antibody levels or for some other reason.

Recent studies suggest that at least some of the hybrid immunity comes from immune cells called memory B cells.Most of the antibodies produced after infection and vaccination are produced by activated B cells called plasma cells, which are short-lived and their antibody levels drop when they die.The main source of antibody after plasma cell death is memory B cells, which are induced by infection or vaccination, but the number is much lower than that of plasma cells.

According to Rockefeller University immunologist Michel Nussenzweig, some long-lived memory B cells produce more potent antibodies than plasma cells.This is because as they mature in the lymph nodes, they acquire mutations that enhance the ability of the antibody to bind to the spike protein. When a person recovering from COVID-19 is again exposed to the SARS-CoV-2 peplomer, these cells proliferate and produce large amounts of potent antibodies.

"These cells start working together when they encounter the antigen, in which case the mRNA vaccine acts as the antigen," Goel says.In other words, in theory, there is the same effect when a person who has been infected receives the first vaccination and when a person who has not been infected receives the second vaccination.

The background of the strong response of hybrid immunity may be related to the difference between infection-induced memory B cells and vaccination-induced memory B cells, as well as the differences in the antibodies they produce.Infection and vaccination differ greatly in the way spike proteins are presented to the immune system, says Nussenzweig.

Nussenzweig's research team compared antibody responses between infected and vaccinated individuals in a series of studies (Hatziioannou and Bieniasz also participated in this study).3 – 5 Feet..The results suggest that both infection and vaccination induce memory B cells that produce potent antibodies, but the effect is stronger after infection.

The team at Nussenzweig et al. Isolated hundreds of memory B cells, each producing a unique antibody, from people who had been infected or vaccinated for different periods of time.For antibodies produced by natural infection, antibody levels and the variety of mutant strains that could be blocked continued to increase over the first year after infection.On the other hand, many of the antibodies produced by vaccination appeared to have stopped changing within a few weeks of the second vaccination.In addition, infection-induced memory B cells were more likely to produce antibodies that could block immune-flight mutants such as beta and delta strains.

A research team led by Duane Wesemann, an immunological scholar at the Harvard University School of Medicine (Boston, Massachusetts, USA), is more versatile because more areas of spike proteins are targeted by the immune system in natural infections than in mRNA vaccination. An unexamined paper submitted to a preprint server reports the formation of an antibody pool that can recognize various mutant strains.6..People with hybrid immunity also maintained high antibody levels consistently for 7 months, with more stable antibody levels.

"Not surprising"

Many studies of hybrid immunity have not followed up vaccinated people without experience of infection for as long as those who recovered from COVID-19.As a result, researchers point out that B cells in people who have never been infected may also produce more antibodies over time, boosted vaccines, or both.A stable pool of memory B cells is formed and can take several months to mature.

Ali Ellebedy, an immunologist studying B cells at Washington University in St. Louis, Missouri, said, "It's not surprising that people who have been infected and vaccinated respond well. Hey. " "It's like competing a player who started three or four months ago in a race with a player who just started."

Studies have shown that the immunity of people who have never been infected and have been vaccinated twice is catching up. Ellebedy's research team collected lymph node specimens from people vaccinated with the mRNA vaccine, and some of the vaccinated memory B cells caused the cold by 2 weeks after the second vaccination. We have found signs of acquiring mutations that will produce antibodies that can recognize a variety of coronaviruses, including viruses.7.

Matthieu Mahévas, an immunologist at Necker Children's Hospital in Paris, France, says that even people who have never been infected may be able to obtain hybrid immunity with a third vaccination. Mahévas' research team found that some memory B cells began to produce antibodies that could recognize beta and delta strains two months after vaccination, even in people who had never been infected.8.. "It is clear that increasing the number of these Memory B cells will result in strong neutralizing antibodies," says Mahévas.By extending the vaccination interval, one aspect of hybrid immunity could be mimicked.

Mechanism and effect

Understanding how hybrid immunity works will be the key to mimic it, scientists say.Although recent studies have focused on antibody responses by B cells, it has also been found that T cell responses may also differ between infection and vaccination.Spontaneous infections also elicit responses to viral proteins other than spike proteins.Nussenzweig suspects that some factor specific to natural infections may be important.During infection, millions of viral particles settle in the respiratory tract.Immune cells that visit nearby lymph nodes (the organ where Memory B cells mature) encounter vast amounts of viral particles.This persistence may also help sharpen the response of B cells to SARS-CoV-2, as viral proteins are still detected in the intestine months after recovery from infection. There is sex.

It is also important to assess the actual effects of hybrid immunity, researchers say.A pre-reviewed paper submitted by a Qatar research team reports that Pfizer / Biontech mRNA vaccinated people are less likely to get COVID-19 than those who have never been infected. (Editor's note: There was almost no difference with the Moderna vaccine)9.

Researchers of hybrid immunity have emphasized that given the risk of SARS-CoV-2 infection, even if there are potential benefits, it should be avoided to dare to infect and acquire hybrid immunity. ing.Andrés Finzi, a virologist at the University of Montreal (Canada), says, "I have no intention of recommending that you get infected and then vaccinated to get a good immune response." "There is no guarantee that it will not get infected and become serious."

(Translation: Yoichi Fujiyama)

References

1. Schmidt, F. et al. Nature https://doi.org/10.1038/s41586-021-04005-0 (2021)
2. Stamatatos, L. et al. Science 372, 1413-1418 (2021).
3. Gaebler, C. et al. Nature 591, 639-644 (2021).
4. Wang, Z. et al. Nature 595, 426-431 (2021).
5. Cho, A. et al. Nature https://doi.org/10.1038/s41586-021-04060-7 (2021)
6. Chen, Y. et al. Preprint at bioRxiv https://doi.org/10.1101/2021.09.09.459504 (2021)
7. Turner, JS et al. Nature 596, 109-113 (2021).
8. Sokal, A. et al. Immunity https://doi.org/10.1016/j.immuni.2021.09.011 (2021)
9. Abu-Raddad, LJ et al. Preprint at medRxiv https://doi.org/10.1101/2021.07.25.21261093 (2021)

 
* This article is reprinted from "Nature Digest".
Reprinted from: Nature Digest 2021 No. 12
"The mystery of "super immunity" brought about by vaccination after COVID recovery'
Nature Digest Vol. 18 No. 12 | doi: 10.1038 / ndigest.2021.211213