オミクロン感染しても武漢株免疫が邪魔をして、武漢株免疫の方が出るためにオミクロン免疫が弱くなってしまう・・・抗原原罪？！

投稿日投稿者しとらす

一昨年のデルタ株流行の時は抗原原罪なんて知らなかったし、SARS-CoV-2ウイルスの一般的な侵入経路とか鼻うがいの効用とかも知らなくて、今みたいに地域限定とはいえ無料でPCR検査が受診できる環境もなかったので、仕方無しに「何も（副作用）起こらないでくれよ」と祈りながらワクチン2回接種したのですが、わずか半年後に「後悔先に立たず」になるとは・・・orz

更に1年経って、いろんな知識を得ることができました。Twitterで日本語情報を提供してくださってる方々には感謝の念しかありません。

・・・ところで・・・

私の信頼するついったらーさんたちが会話の中で免疫学のテキストとして『JANEWAY’S 免疫生物学』を持っていらっしゃったので、この分野は門外漢の自分が1年以上前にアレコレ迷って購入した免疫学の本はこれで合ってたんだな〜と安心しました（ほとんど積読なのは内緒）。
ってなわけで、ちゃんとした医学部で免疫学の講義に広く使われているのが『JANEWAY’S 免疫生物学』。もう1つの『エッセンシャル免疫学』はやや入門編よりな位置づけで、序文でもエッセンシャルで一通り概要を把握したら次は『免疫生物学』でしっかり勉強してね、みたいなことがサラッと書かれてます。無謀にも独学する気でいる私は両方買いました。

 

◆Effectiveness of the Coronavirus Disease 2019 (COVID-19) Bivalent Vaccine【medRxiv　2022年12月17日】

ABSTRACT

Background The purpose of this study was to evaluate whether a bivalent COVID-19 vaccine protects against COVID-19.

Methods Employees of Cleveland Clinic in employment on the day the bivalent COVID-19 vaccine first became available to employees, were included. The cumulative incidence of COVID-19 was examined over the following weeks. Protection provided by vaccination (analyzed as a time-dependent covariate) was evaluated using Cox proportional hazards regression. The analysis was adjusted for the pandemic phase when the last prior COVID-19 episode occurred, and the number of prior vaccine doses received.

Results Among 51011 employees, 20689 (41%) had had a previous documented episode of COVID-19, and 42064 (83%) had received at least two doses of a COVID-19 vaccine. COVID-19 occurred in 2452 (5%) during the study. Risk of COVID-19 increased with time since the most recent prior COVID-19 episode and with the number of vaccine doses previously received. In multivariable analysis, the bivalent vaccinated state was independently associated with lower risk of COVID-19 (HR, .70; 95% C.I., .61-.80), leading to an estimated vaccine effectiveness (VE) of 30% (95% CI, 20-39%). Compared to last exposure to SARS-CoV-2 within 90 days, last exposure 6-9 months previously was associated with twice the risk of COVID-19, and last exposure 9-12 months previously with 3.5 times the risk.

Conclusions The bivalent COVID-19 vaccine given to working-aged adults afforded modest protection overall against COVID-19, while the virus strains dominant in the community were those represented in the vaccine.

Summary Among 51011 working-aged Cleveland Clinic employees, the bivalent COVID-19 vaccine booster was 30% effective in preventing infection, during the time when the virus strains dominant in the community were represented in the vaccine.

INTRODUCTION

When the original Coronavirus Disease 2019 (COVID-19) vaccines first became available in 2020, there was ample evidence of efficacy from randomized clinical trials [1,2].Vaccine effectiveness was subsequently confirmed by clinical effectiveness data in the real world outside of clinical trials [3,4], including an effectiveness estimate of 97% among employees within our own healthcare system [5]. This was when the human population had just encountered the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus, and the pathogen had exacted a high burden of morbidity and mortality across the world. The vaccines were amazingly effective in preventing COVID-19, saved a large number of lives, and changed the impact of the pandemic.

Although the vaccines were very effective, the majority of the population in resource-poor countries could not get vaccinated in time, and waves of infection occurred around the world. Continued acquisition of mutations in the virus, from natural evolution in response to interaction with the immune response among the human population, led to the emergence and spread of SARS-CoV-2 variants. Despite this, those previously infected or vaccinated continued to have substantial protection against reinfection by virtual of natural or vaccine-induced immunity [6]. The arrival of the Omicron variant in December 2021, brought a significant change to the immune protection landscape. Previously infected or vaccinated individuals were no longer protected from COVID-19 [6]. Vaccine boosting provided some protection against the Omicron variant [7,8], but the degree of protection was not near that of the original vaccine against the pre-Omicron variants of SARS-CoV-2 [8]. After the emergence of the Omicron variant, prior infection with an earlier lineage of the Omicron variant protected against subsequent infection with a subsequent lineage [9], but such protection appeared to wear off within a few months [10]. During the Omicron phase of the pandemic, protection from vaccine-induced immunity decreased within a few months after vaccine boosting [8].

Recognition that the original COVID-19 vaccines provided much less protection after the emergence of the Omicron variant, spurred efforts to produce newer vaccines that were more effective. These efforts culminated in the approval by the US Food and Drug Administration, on 31 August 2022, of bivalent COVID-19 mRNA vaccines, which contained antigens represented in the original vaccine as well as antigens representing the BA.4/BA.5 lineages of the Omicron variant. Given the demonstrated safety of the earlier mRNA vaccines and the perceived urgency of need of a more effective preventive tool, these vaccines were approved without demonstration of effectiveness in clinical studies.

The purpose of this study was to evaluate whether the bivalent COVID-19 vaccine protects against COVID-19.

 

◆Bivalent Covid-19 Vaccines — A Cautionary Tale
【The New England Journal of Medicine：Paul A. Offit, M.D.　2022年12月14日】

In November 2019, a bat coronavirus made its debut in humans in Wuhan, China. Two months later, the original strain of SARS-CoV-2, called the Wuhan-1 or ancestral strain, was isolated and sequenced. It was now possible to make a vaccine. All the vaccines, including the mRNA vaccines made by Pfizer–BioNTech and Moderna, the viral vector vaccines made by Johnson & Johnson–Janssen and AstraZeneca, and the purified protein vaccine made by Novavax, were designed to prevent disease caused by the ancestral strain.

As the virus evolved, the ancestral strain was soon replaced by a series of variants. In the United States in 2020 and 2021, such variants included D614G, alpha, and delta, each of which was more contagious than the previous variant. In a U.S. study involving 8100 immunocompetent adults conducted between March and December 2021, two doses of mRNA vaccines — which were authorized by the Food and Drug Administration (FDA) and recommended by the Centers for Disease Control and Prevention (CDC) in December 2020 — continued to protect against hospitalization caused by these three virus variants.1 For vaccines against SARS-CoV-2, a mucosal infection with a short incubation period, protection from severe disease is the only reasonable and attainable goal.

In November 2021, a new variant, called omicron (subvariant BA.1), was detected in southern Africa. The omicron variant contained an alarming number of mutations (more than 30) in the spike protein, including at least 15 mutations in the receptor-binding domain, the primary target of neutralizing antibodies. Researchers found that serum samples obtained from people who were vaccinated against or previously infected with SARS-CoV-2 exhibited substantially lower neutralizing activity against BA.1 than against the ancestral strain and other strains. Furthermore, many commercially available monoclonal-antibody preparations were ineffective against this variant. Although it was reassuring that early data from southern Africa showed that previous infection or vaccination protected against severe disease caused by omicron,2 public health officials worried that the BA.1 strain posed a serious threat to the effectiveness of existing Covid-19 vaccines and therapies.

Given the ability to use mRNA technology to respond quickly to variant strains, bivalent vaccines were created to counter this new threat. In January and February 2022, Pfizer–BioNTech produced a bivalent vaccine containing 15 μg of mRNA directed against the ancestral strain of SARS-CoV-2 and 15 μg directed against BA.1. Moderna used 25 μg of mRNA directed against each of the same two strains. The combined quantities mirrored the amount of mRNA in each company’s monovalent booster dose for adults (30 μg for Pfizer–BioNTech and 50 μg for Moderna).

On June 28, 2022, researchers from Pfizer–BioNTech and Moderna presented data on their bivalent vaccines to the FDA’s Vaccines and Related Biological Products Advisory Committee (of which I am a member). The results were underwhelming. Bivalent boosters resulted in levels of neutralizing antibodies against BA.1 that were only 1.5 to 1.75 times as high as those achieved with monovalent boosters. Previous experience with the companies’ vaccines suggested that this difference was unlikely to be clinically significant. Safety data were reassuring. At the time of the FDA presentation, BA.1 was no longer circulating in the United States, having been replaced by more immune-evasive and contagious omicron subvariants. But winter was around the corner. The FDA advisory committee, sensing the urgency of responding to these immune-evasive strains, voted to authorize bivalent vaccines with an understanding that they would target omicron subvariants BA.4 and BA.5, which at the time had accounted for more than 95% of circulating strains.

A series of rapid-fire policy decisions followed. On June 29, 2022, the day after the advisory committee meeting, the Biden administration agreed to purchase 105 million doses of Pfizer–BioNTech’s bivalent vaccine containing BA.4 and BA.5 mRNA. One month later, on July 29, 2022, the administration agreed to purchase 66 million doses of Moderna’s bivalent vaccine, intending to offer both vaccines in the fall and winter. On September 1, 2022, the FDA withdrew its emergency use authorization for monovalent vaccine boosters and the CDC recommended bivalent vaccine boosters for everyone 12 years of age or older. On October 12, 2022, the CDC extended this recommendation to include everyone 5 years of age or older. At that point, no data from humans, including immunogenicity data, were available for comparing the relative capacities of the monovalent and bivalent vaccines to protect against BA.4 and BA.5.

On October 24, 2022, David Ho and colleagues released the results of a study examining levels of neutralizing antibodies against BA.4 and BA.5 after receipt of a monovalent or bivalent booster dose. They found “no significant difference in neutralization of any SARS-CoV-2 variant,” including BA.4 and BA.5, between the two groups.3 One day later, Dan Barouch and colleagues released the results of a similar study, finding that “BA.5 [neutralizing-antibody] titers were comparable following monovalent and bivalent mRNA boosters.” Barouch and colleagues also noted no appreciable differences in CD4+ or CD8+ T-cell responses between participants in the monovalent-booster group and those in the bivalent-booster group.4 Neither research group found the bivalent boosters to elicit superior immune responses. The results are now published in the Journal.

Why did the strategy for significantly increasing BA.4 and BA.5 neutralizing antibodies using a bivalent vaccine fail? The most likely explanation is imprinting. The immune systems of people immunized with the bivalent vaccine, all of whom had previously been vaccinated, were primed to respond to the ancestral strain of SARS-CoV-2. They therefore probably responded to epitopes shared by BA.4 and BA.5 and the ancestral strain, rather than to new epitopes on BA.4 and BA.5. This effect could possibly be moderated by immunizing people either with BA.4 and BA.5 mRNA alone or with a greater quantity of BA.4 and BA.5 mRNA. Evidence in support of these strategies can be found in Pfizer–BioNTech’s data regarding its BA.1-containing bivalent vaccine, which showed that BA.1-specific neutralizing-antibody responses were greater in persons who were injected with a monovalent vaccine containing 30 μg or 60 μg of BA.1 mRNA or a bivalent vaccine containing 30 μg of BA.1 mRNA and 30 μg of ancestral-strain mRNA than in those who received a bivalent vaccine containing 15 μg of each type of mRNA.

On November 22, 2022, the CDC published data on the effectiveness of the BA.4 and BA.5 mRNA vaccines for preventing symptomatic infection within 2 months after receipt of the booster dose. For people who had received a monovalent vaccine 2 to 3 months earlier, the extra protection associated with the bivalent booster dose ranged from 28 to 31%. For those who had received a monovalent vaccine more than 8 months earlier, the extra protection ranged from 43 to 56%.5 Given the results of previous studies, it’s likely that this moderate increase in protection against probably generally mild disease will be short lived. As of November 15, 2022, only about 10% of the population for whom the bivalent vaccine had been recommended had received it.5 By December 2022, the BA.4 strain was no longer circulating, and BA.5 accounted for less than 25% of circulating SARS-CoV-2 strains, having been partially replaced by more immune-evasive strains, such as BQ.1, BQ.1.1, BF.7, XBB, and XBB.1.

What lessons can be learned from our experience with bivalent vaccines?

Fortunately, SARS-CoV-2 variants haven’t evolved to resist the protection against severe disease offered by vaccination or previous infection. If that happens, we will need to create a variant-specific vaccine. Although boosting with a bivalent vaccine is likely to have a similar effect as boosting with a monovalent vaccine, booster dosing is probably best reserved for the people most likely to need protection against severe disease — specifically, older adults, people with multiple coexisting conditions that put them at high risk for serious illness, and those who are immunocompromised. In the meantime, I believe we should stop trying to prevent all symptomatic infections in healthy, young people by boosting them with vaccines containing mRNA from strains that might disappear a few months later.