Insights into human immunity from Omicron "Nature" long article

Author of the original text: Cassandra Willyard immunologists have conducted in-depth research on how the human body defends against multiple new coronavirus variants, and obtained a lot of new knowledge and some surprises
.

No one could have predicted that Omicron could spread around the world so quickly
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While the wave of infections has begun to ebb in many countries, the number of confirmed cases globally is still climbing
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There were 23 million new cases in the last week of late January, and before that peaked at 5 million a week
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Unaware public health officials are still doing their best to contain the spread of Omicron and prevent those infected from causing a run on medical resources
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Omicron presents immunologists with new puzzles that need to be solved
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Preliminary data show that the current vaccine designed against the original strain of the new coronavirus is not effective in preventing Omicron infection, but appears to reduce hospitalization or mortality
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The protection provided by two doses of mRNA vaccine dropped to less than 40% a few months after the second shot [1,2], but the third "booster shot" seems to be able to pull back one
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One report found that the protection against infection two weeks after the third shot was 60%-70%[1], and the protective effect on severe cases seemed to be strong[2]
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"This result is exciting
,
" says immunologist Mark Slifka of Oregon Health and Science University
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But this result is also surprising
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Why would a third injection of a vaccine targeting the original viral spike protein (the protein the virus uses to enter cells) work against Omicron, which has more than 30 mutations in the spike protein? A medical worker in the Philippines prepares a dose of a Covid-19 vaccine during the Omicron outbreak in January
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Source: Basilio Sepe/ZUMA Wire/Shutterstock The human immune system has a characteristic - it remembers previous infections, but it doesn't necessarily make a lasting response
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Some infections and immunizations induce life-long protection, but otherwise the immune response is weak, requiring regular reminders of a booster shot or a newly designed vaccine
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The Covid-19 pandemic has given the world the opportunity to recognize this super-complex but vitally important biological phenomenon
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"This is really an incredible natural experiment," said Donna Farber, an immunologist at Columbia University in New York.
"Who would believe that we have the opportunity to monitor human immune responses in real time
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" About 10 billion doses of the new crown vaccine have been injected around the world, and there are many varieties.
More than a dozen; five worrying variants are still circulating, and scientists can't wait to answer a few key questions: How long will the vaccine's protection be sustained? In what form does this protection exist? Are vaccines designed against the original coronavirus effective against other variants, such as Omicron? "This discovery is just the beginning, " says John Wherry, an immunologist at the Perelman School of Medicine at the University of Pennsylvania
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The findings that follow are not only relevant to how to fight Covid-19, but are also crucial to our understanding of some of the fundamental features of immune memory .
Making memories last longer As soon as a pathogen enters the body, the immune system kicks in .
But it will be days before specific cells that can target viruses and bacteria join the fight







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These B and T cells clear infection and remember the invader when the fight is over
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B cells are "the first line of defense," says Ali Ellebedy, an immunologist at the University of Washington School of Medicine
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When first exposed to a pathogen, activated B cells rapidly divide and differentiate into plasma cells that produce antibodies (a protein)
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Antibodies can find suspected invaders and catch them all, and some antibodies may also bind to parts of the pathogen, directly cutting off the possibility of the pathogen infecting cells
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These antibodies are what we call "neutralizing" antibodies
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"Only neutralizing antibodies give you sterilizing immunity,
"
says Shane Crotty, an immunologist at the La Jolla Institute of Allergy and Immunology
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That's why researchers often use neutralizing antibody levels as a measure of immune protection
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In September 2020, several studies[3,4] reported a decrease in neutralizing antibody levels in patients who recovered from COVID-19
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As a result, some experts have warned that immunity to the new coronavirus may be waning
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But immunologists are not at all surprised
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Antibodies are naturally diminished after infection
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Short-lived B cells that produce antibodies quickly die off
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"We've known this for a long time ," said Rafi Ahmed, an immunologist and director of the Emory Vaccine Center at Emory University
.


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The key is whether the body produces long-lived B cells that can target the pathogen when it reappears
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These cells usually form within structures called germinal centres
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During infection, germinal centers appear in lymph nodes, acting as a sort of training camp for B cells, allowing cells to proliferate and mutate
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Only those cells that produce high-quality antibodies that bind tightly to the surface of the virus survive
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"It's like a knockout game," Ellebedy said
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Within a month or so, the cells that produce these superconjugates become memory B cells circulating in the blood (see "B-cell memory")
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They don't make antibodies, but if they encounter a virus or viral protein, they can divide rapidly and become antibody-producing plasma cells
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What remains are long-lived plasma cells that primarily reside in the bone marrow and produce small but steady high-quality antibodies
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"Those cells are basically with us for life
,
" Ellebedy said
.

Source: Nik Spencer/Nature It is normal for antibody levels to drop after infection
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What immunologists want to know most is when, or if this decline will stop
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In April 2020, Ahmed and his team began studying patients who have recovered from Covid-19
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They found that these people's antibody levels dropped rapidly within 2 to 3 months of infection
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But after almost 4 months, the downward curve started to flatten
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They published the results for the first 8 months [5], but have now accumulated 450 days of data, and Ahmed is encouraged by the results they have seen
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So far, "the shape of the curve looks great," he said.
"The curve is very flat
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" The immune response after a vaccine more or less mimics what it would be like after infection, but in one very different way
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When infected with the new coronavirus, the immune system can see what the entire virus looks like; and even the most effective vaccines use only one viral protein to induce an immune response—the spike protein
.

Whether antibody levels also plateau after vaccination is unclear
.

Wherry and his colleagues analyzed the immune responses of 61 people six months after the first dose and found that antibody levels peaked a week after the second dose and declined rapidly in the following months
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After that, the rate of descent is much slower [6]
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Decreased levels of antibodies are bound to lead to less protection
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Some countries have made these vaccines widely available since December 2020, and the initial effectiveness was really good
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But by July 2021, breakthrough infections began to appear
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Pfizer-BioNTech's mRNA vaccine was widely vaccinated in Israel, and local data showed that the vaccine's protection against infection fell from 95% to 39% in 5 months (see go.
nature.
com/3hjdxtn; provided in Hebrew language and English)
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These data seem to reflect a weakening of vaccine efficacy
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The researchers also found that over time, the vaccine lost its ability to prevent infection, but not severe disease
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The ability to prevent infection may be diminished, but the ability to prevent hospitalization seems to be always on the line
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"This protective immunity may persist for several years
,
" Crotty said
.

The rescue of cells' immune memory depends on more than just antibodies
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Even when antibody levels drop, memory B cells recognize the re-emerging invader, divide and rapidly produce antibodies to attack
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The memory B-cell response also increased over time—at least in the short term
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In Wherry's study [6], 6 months after the subjects were vaccinated, the number of memory B cells increased, and these memory B cells not only responded to the original new coronavirus strain, but also to the other three variants of concern produce a response
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Then there are T cells, the third pillar of immune memory
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When confronted with an antigen, these T cells proliferate to form a pool of effector cells that clear the infection
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Killer T cells divide rapidly, killing infected cells; various helper T cells release chemical signals that activate other parts of the immune system, including B cells
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When the threat recedes, some of these cells persist as memory T cells (see "T cell memory")
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Source: Nik Spencer/Nature In some people, T cells left behind from previous infections with coronaviruses, such as those that cause the common cold, can also recognize the new coronavirus
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These cells may be able to fight the new crown infection, or even completely block the infection
.

One study [7] showed that health care workers who had been exposed to the new coronavirus but never tested positive could find weak signs of a response to infection in their bodies
.

The team speculates that cross-reactive T cells can block infection before it occurs
.
"These people do have an infection in
the broadest sense, " said Mala Maini, an immunologist at University College London who led the study, but "the viral load may not be high because these viruses are killed off very quickly .
" This view is still controversial, and the probability of occurrence is likely to be extremely low .
Memory cells generally don't use neutralizing antibodies to block infection, but they don't actually need to .
In the case of COVID-19, infection occurs quickly, but it will take some time to become severe .
This gives the memory T cells time to function .
When re-exposed to the virus or booster needles, these cells go into overdrive, "proliferating like crazy," Crotty said, "and in 24 hours, you have a 10-fold increase in the number of memory T cells .
" It may not be fast enough for the United States, Crotty said, but it is enough to prevent hospitalizations .
Moreover, viruses are easily helpless in the face of T-cell responses .
Because each person's T cells recognize different parts of the virus .
So the virus can mutate to escape one person's T cell response, but it cannot escape another person's T cell response .
"The concept of escape is meaningless at the crowd level






















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In addition, T cells can find parts of the virus (or spike protein) that antibodies cannot, including those that are less prone to mutation
.
Multiple studies have found that although Omicron is mutated, people who have been vaccinated or infected with Covid-19 Humans with the virus have the same T-cell response to Omicron as to Delta [8,9] .
Observations of Omicron transmission have also found this to be the case .
T-cell responses may also trigger a "decoupling" phenomenon .
In areas where higher levels of immunity have been achieved due to previous infections or vaccines, Omicron's confirmed cases are increasing rapidly, but hospitalizations and deaths are increasing relatively slowly .
Immunity evolved The perfect vaccine would not only mobilize a long-lasting immune response, but also In the face of the mutation and evolution of the virus, there is also a wide range of protection .
In the face of the raging Omicron, the vaccine seems to be losing its power .
But the immune system still has a few hands to deal with the cunning virus .
Some of them are hidden in the germinal center .
In Here, B-cell training not only increases the ability of the antibodies to bind to the original target, but also increases the number of binding sites they recognize, increasing their probability of finding variants .
"Indirectly, does vaccine immunization as a whole do not Success depends on how powerful the germinal center is .
"Without the germinal center," Dogma argues, "we would have no memory .
"But that may not be entirely true .



























The immune system also has "a large set of other pathways" that are less visible and less studied, says Stephanie Eisenbarth, director of the Center for Human Immunobiology at Northwestern University Feinberg School of Medicine
.

Eisenbarth and her colleagues have shown that even mice without the ability to form germinal centers can produce long-lived plasma cells [10]
.

While where these cells come from is unclear, like the plasma cells produced in the germinal center, these cells appear to bind tightly to their targets
.

New data show that Omicron is still largely able to escape past infection or vaccine-induced antibodies (see: What shall I do with you: Omicron makes epidemic prevention policies harder)
.

According to Pfizer, people who received two doses of the vaccine had a 25-fold reduction in Omicron's ability to neutralize (compared to the original new coronavirus)
.

Whether the third shot will restore protection remains unclear
.

A third shot might boost the levels of all antibodies equally, including a small number of antibodies that recognize unmutated sites on the Omicron spike protein
.

"We know from some of the data that these companies have published that the boosting effect of the third-targeted antibody is very, very good," Wherry said
.

But it looks as if the third-targeted booster increases the breadth of the immune response
.

Israeli officials approved the fourth dose of the new crown vaccine in January, hoping to enhance the immune memory of the population
.

Source: Amir Levy/Getty In one study [11], researchers assessed the ability of their antibodies to neutralize viruses containing the SARS-CoV-2 spike protein in people who received Moderna, Pfizer-BioNTech, or Johnson & Johnson vaccines
.

The blood of people who had received one or two shots of the vaccine had little ability to neutralize Omicron; the blood of people who had received a booster shot of the mRNA vaccine was effective against Omicron
.

Their ability to neutralize Omicron was only 4 to 6 times lower than that of the original strain
.

People who have received two shots have memory B cells that can bind to Omicron [12]
.

A third shot might drive these memory cells into antibody-producing cells
.

"An important job of memory B cells is to keep track of the immune system's various guesses about what a mutant strain might look like," Crotty said
.

Wherry also suggested another possibility
.

The booster needles might help form germinal centers, kicking off B cells to start another round of mutation
.

"That's an issue we're going to keep a close eye on," he said
.

Slifka speculates that the antibodies produced by the first shot of the vaccine would bind tightly to the easily found signature of the spike protein
.

In the next few shots, existing antibodies quickly bind to these signatures, leaving less-obvious targets for B cells
.

However, there is another side to the good news about the booster needle
.

It is still unclear how long the protective effects of the booster needles will last
.

Data from the United Kingdom show that this protection declines rapidly [13]
.

The three-dose Pfizer-BioNTech vaccine initially provided 70 percent protection
.

But by week 10, protection against infection drops to 45%
.

The latest report from Israel also shows that the fourth needle does not seem to be effective in improving protection
.

This suggests that the next most important step may be to develop Omicron-specific booster needles
.

Pfizer and Moderna are already working on this type of mRNA vaccine
.

In January, Pfizer CEO Albert Bourla said an Omicron-specific vaccine would be available in March
.

But by then, many people had been infected with Omicron and thus had some immunity
.

Pfizer is still designing a vaccine that contains both the original spike protein and the Omicron spike protein
.

The ultimate goal is certainly to develop a vaccine that produces long-lasting immunity without multiple boosters
.

The miracle formula Covid-19 may also teach us how to improve vaccinations
.

In 2019, Slifka and his colleague Ian Amanna published a review analyzing different types of vaccines [14] and summarizing what patterns predict which vaccines induce sustained immunity and which vaccines do not
.

Of the types of vaccines they analyzed, the ones with the longest protection appeared to be live virus vaccines
.

These vaccines contain pathogens that have been altered to not cause disease
.

Since these vaccines closely mimic actual infection conditions, they are more likely to induce long-lasting responses
.

But vaccines containing whole inactivated virus or partial virus proteins can also induce good immune memory
.

The key here, Slifka says, is how long the antigen can persist
.

"You don't need to be chronically infected," he said, "but the stimulation of the immune system has to be maintained for a while
.

" Slifka and Amanna's review did not include mRNA vaccines—the technology isn't widely available, but Seems to be the trend of the future
.

For mRNA vaccines, the antigen is produced by cells in the body (derived from an mRNA template)
.

Antigens only exist for a few weeks
.

Evidence so far suggests that immunity may also be short-lived
.

However, RNA vaccines that can replicate in the body may lead to longer-lasting immunity (see: How RNA vaccines can overtake the new crown epidemic?)
.

The new coronavirus gives scientists the opportunity to observe and compare the effects of different vaccines, including vaccines using full-length inactivated virus, protein vaccines, mRNA vaccines, adenovirus vector vaccines (such as Oxford-AstraZeneca or Johnson & Johnson vaccine)
.

Some of the results even caught the researchers by surprise
.
For example, the response to a J&J vaccine was initially weaker than that of the mRNA vaccine, but then gradually increased, says
Deepta Bhattacharya, an immunologist at the University of Arizona in the United States
.

Know what happens when you mix and match different vaccines
.

The Com-CoV research project in the UK has been working on this since the early days of the outbreak
.

Its latest data [15] show that people who received the first dose of the Oxford-AstraZeneca or Pfizer-BioNTech vaccine, followed by the Moderna vaccine, had higher rates than those who received both doses of the same vaccine.
immune response
.

"You can think of it as cross-training
,
" Wherry said
.

Mixing and matching different types of vaccines can form a more flexible immune memory
.

Adding more targets might also induce better protection
.

The most effective vaccines currently target the spike protein, but T cells can see the entire virus, says Stanford University immunologist Bali Pulendran
.

He likens immune memory to a giant crystal lamp hanging from three strands: one strand is the antibody response, one strand is the memory B cell, and one strand is the memory T cell
.

Each strand is important and needs to be considered in vaccine design
.

If one or two strands were cut, Pulendran asked, “Dare we still stand below?” Developing a vaccine with broad, sustained neutralization of the coronavirus will always be a hurdle
.

The difficulty lies in the nature of the virus itself
.

"If you look at the history of respiratory infections, they've been very difficult to prevent
,
" Ahmed said
.

Influenza viruses and respiratory syncytial virus fall into this category, as does the common cold
.

For systemic infections, such as measles, it takes time for the virus to spread and cause disease in the body
.

Respiratory infections occur the moment the virus enters
.

For these pathogens, preventing severe illness may be the best outcome one can hope for
.

However, many are still very optimistic
.

"Right now, everyone and their mothers are working on the new coronavirus
,
" said Scott Hensley, an immunologist at the Perelman School of Medicine
.

This level of attention has greatly improved the ability of immunologists to dissect the body's immune response
.

The resulting findings may help them design a vaccine that provides long-lasting, broad protection
.

"Where's the magic formula?" Pulendran asked, "There is an unfathomable fundamental problem behind this, and if it can be solved, it will turn the whole vaccinology upside down
.

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Original article titled What the Omicron wave is revealing about human immunity Published as the title on the news feature section of "Nature" on February 2, 2022 © naturedoi: 10.
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