武漢株ベースの抗原原罪はオミクロン株複数回感染により緩和されるがmRNAワクチンによる抗原原罪は不活性化ワクチンによるものより緩和されにくいとの中国の論文

• Published: 22 November 2023

Repeated Omicron exposures override ancestral SARS-CoV-2 immune imprinting

Abstract

The continuing emergence of SARS-CoV-2 variants highlights the need to update COVID-19 vaccine compositions. However, immune imprinting induced by vaccination based on the ancestral (hereafter referred to as WT) strain would compromise the antibody response to Omicron-based boosters1,2,3,4,5. Vaccination strategies to counter immune imprinting are critically needed. Here we investigated the degree and dynamics of immune imprinting in mouse models and human cohorts, especially focusing on the role of repeated Omicron stimulation. In mice, the efficacy of single Omicron boosting is heavily limited when using variants that are antigenically distinct from WT—such as the XBB variant—and this concerning situation could be mitigated by a second Omicron booster. Similarly, in humans, repeated Omicron infections could alleviate WT vaccination-induced immune imprinting and generate broad neutralization responses in both plasma and nasal mucosa. Notably, deep mutational scanning-based epitope characterization of 781 receptor-binding domain (RBD)-targeting monoclonal antibodies isolated from repeated Omicron infection revealed that double Omicron exposure could induce a large proportion of matured Omicron-specific antibodies that have distinct RBD epitopes to WT-induced antibodies. Consequently, immune imprinting was largely mitigated, and the bias towards non-neutralizing epitopes observed in single Omicron exposures was restored. On the basis of the deep mutational scanning profiles, we identified evolution hotspots of XBB.1.5 RBD and demonstrated that these mutations could further boost the immune-evasion capability of XBB.1.5 while maintaining high ACE2-binding affinity. Our findings suggest that the WT component should be abandoned when updating COVID-19 vaccines, and individuals without prior Omicron exposure should receive two updated vaccine boosters.

 https://www.nature.com/articles/s41586-023-06753-7

Discussion

In summary, our findings suggest that secondary Omicron exposure is necessary to mitigate the immune imprinting conferred by previous ancestral virus exposure and to elicit higher levels of Omicron-specific antibodies. Accordingly, our recommendation is to administer two booster doses of Omicron-based vaccines to individuals who have not received prior Omicron-based vaccinations or have not been previously infected with the Omicron variant. Moreover, administering the second booster shot after a prolonged interval can provoke a wider and more efficient immune response, whereas incorporating WT virus into subsequent vaccine designs may worsen outcomes26.

Recently, several fast-growing XBB lineages, such as the variant of interest XBB.1.16, have acquired RBD mutations on K478. However, the K478 mutation did not emerge in our prediction of evolutionary trends for XBB.1.5 RBD. This contradiction may be attributed to the fact that our mutational prediction model relies primarily on the cohorts that we recruited, and we did not capture the immune background that introduced K478 mutation. One possible background that may give rise to K478 is repeated BA.5/BQ.1.1/XBB exposure, as F486 could mask the immunogenicity of K478. Another potential source of K478 is Delta-imprinted convalescent individuals who experienced BA.5/BQ.1.1/XBB infections, which could result in the generation of abundant K478X-sensitive monoclonal antibodies, given that Delta carries T478K. This may explain why K478X is observed mostly in India8,46.

The degree of immune imprinting might be different between mRNA and inactivated virus vaccinations. Recent studies have shown that subsequent exposure to Omicron twice after two doses of WT-based mRNA vaccines still produce significantly low levels of Omicron-specific antibodies, despite the enhanced neutralization breadth against BQ.1.1 and XBB variants47,48. Additionally, individuals who have received two doses of mRNA vaccines and experienced two rounds of Omicron infection also have low levels of Omicron-specific antibodies47. This indicates that mRNA vaccines may generate a stronger immune imprinting effect compared with inactivated vaccines, potentially owing to its stronger humoral immune response4,49. However, a direct comparison is needed for validation.

実質的に武漢株ベースの抗原原罪をオミクロンベースの抗原原罪に強引に書き換えるわけですな。

とりあえずオミクロンブースターを複数回接種しろってことですな。

mRNAワクチンの場合は２回じゃ足りんと…
まあ当然、中国共産党への忖度もあるでしょうが…
で、このオミクロンブースター乱れ打ちにより発生したオミクロンベースの抗原原罪。

オミクロンが更に変異したらまた新しい変異種のブースターを複数回接種して書き換えると…

死ぬまでエンドレスブースター接種のイタチごっこですな。

それにその間、ｍRNAワクチンだと様々な想定外のフレームシフトタンパク質に対する想定外の免疫反応の体験が蓄積していくわけで免疫システムがヤバいのでは？

で、大手メデイアが新型コロナワクチンにダメ出し、抗原原罪に関する記載も…

Opinion
F.D. Flam, Columnist
Wanted: A Covid Booster That Actually Works

Pfizer is struggling because not enough people are getting annual Covid shots. The problem is that the boosters aren’t very effective.
December 19, 2023 at 1:00 AM HST

By F.D. Flam
F.D. Flam is a Bloomberg Opinion columnist covering science. She is host of the “Follow the Science” podcast.

The public’s waning concern over Covid is the main reason cited for plunging stock prices and impending layoffs at Pfizer. The company bet big that people would sign up for annual Covid-19 mRNA boosters the way they do for flu shots. But people aren’t: On Friday, Dec. 15, the Centers for Disease Control and Prevention reported that only 18% of adults had gotten the latest Covid shot, compared with 42% who’d gotten a flu shot.

One challenge facing the fall booster campaign is the lack of a seasonal pattern for Covid. With the flu, there’s a predictable seasonal pattern and getting a shot in the fall can protect the vulnerable through the worst of the winter wave. By contrast, Covid continues to show surges of activity all year.

But the bigger problem is the quality of the new Covid boosters. Past boosters have offered weak, fast-waning protection against infection. And there’s little evidence that they prevent transmission. The CDC is still arguing that they prevent spread of the virus, but some respected infectious disease experts call this incorrect. Some experts also argue there’s no evidence that giving young people multiple boosters does anything to lower their odds of infecting grandma or grandpa.

There is a consensus that booster shots offer temporary increases in protection against severe disease and death, making them important for the elderly and people with certain health conditions. But there’s room to do better — maybe with a new kind of shot, or maybe with a smarter use of the many kinds of vaccines available today.


At this point, it’s clear from all the infections that the vaccine isn’t living up to early hopes. “The initial impression that these vaccines were 95% effective against symptomatic infection and 100% effective against severe disease are no longer accurate,” said Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School. That’s because our antibodies wane over time and the virus mutated much faster and more radically than scientists had expected.

The good news is that those initial vaccines do continue to protect people to some extent from severe disease and death in part through what’s called cellular immunity. Immune cells — B and T cells — retain a memory of the vaccine and can start to attack the virus or make new antibodies that do so after 3-7 days.

A booster might temporarily increase antibodies, but most of the protection conferred by those wanes within about four months, according to data from the North Carolina Department of Public Health.

Barouch thinks a better booster is possible. In a study published last week in Nature, he and colleagues showed that in monkeys, an inhaled vaccine had strong protection against infection, a nasal vaccine intermediate protection, and an injection very little or no protection.

The invention of a vaccine that would directly protect the respiratory tract is “not far-fetched,” he says. There’s already an inhaled vaccine made by CanSino Bio on the market in China.


There’s another problem facing Covid booster campaigns: the fast evolution of the virus and the stubborn tendency of our immune systems to insist on fighting the original variant, since that’s what we were first vaccinated against.

This stubborn tendency is called imprinting, and may explain why so many fully vaccinated, multiple-boosted people have gotten omicron not just once but sometimes two or three times. It also explains data showing that the bivalent booster offered in 2022, with components of the initial strain and omicron, didn’t produce any more omicron-neutralizing antibodies than the original booster.

The 2023 boosters don’t have the original strain — they are monovalent and aimed at the omicron sub-variant XBB.1.5, which was dominant earlier in the year. Many scientists say this is a big improvement. A study published last month in Nature showed that repeat exposures to omicron through infection or omicron-only booster shots can start to override the immune imprinting that has our immune systems stuck on the extinct original version of this virus.

Peking University researcher Yunlong (Richard) Cao, who headed the study, said exposure to omicron generates what are called naïve B cells, and over time these become tuned to fight omicron. After two exposures, the body is better able to fight off future exposures to omicron.

As a caveat, he said, this study involved subjects in China who were very rarely exposed to the virus before omicron, and who got a different kind of vaccine called an inactivated virus. Similar studies that followed people who got mRNA shots saw no overriding of the imprinting.

Cao said the mRNA vaccines are more immunogenic than the ones used in China, which can make them more powerful but might render the imprinting effect stronger too. It might take people in the US and elsewhere more exposures to omicron-only boosters or infections to retune their immune systems toward the new version of the virus — though the virus will continue to evolve as well.

The take-home message, he said, is that booster shots can have long-term impacts — and that we need to start thinking about how to battle this disease in the long term. We have multiple approved vaccines to explore and new ideas are coming from research labs all the time. We’re not ready to settle into a yearly boosting schedule with mRNA shots.

If people are sick and tired of anything, it’s getting Covid. If we had a new shot that kept us Covid-free for at least a year, more people would be willing to get it.

https://www.bloomberg.com/opinion/articles/2023-12-19/pfizer-covid-boosters-aren-t-strong-enough-against-omicron

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