知ってる人は知っている・・・
BA.5による第7波が広がる中、先に流行拡大した欧米諸国からの報告が増えてきました。「BA.5の入院・重症化リスクはBA.2よりも高い可能性がある」というものですが、僕たちはこの可能性を示唆する研究結果を、ふた月前(5月末)に公表していました。1/3 https://t.co/Mj4vI9cGby
— The Sato Lab (Kei Sato) (@SystemsVirology) July 27, 2022
ご参考まで、↓がその研究結果に関する連続ツイートです。流行が下火になりつつあったこともあり、当時はほとんど注目もされませんでした。2/3https://t.co/pDK2omhmYa
— The Sato Lab (Kei Sato) (@SystemsVirology) July 27, 2022
ちなみに当時の時系列↓
5/24: 都内で初めてBA.5の市中感染を確認
5/26: 僕たち(G2P-Japan)の研究成果を査読前論文として公表
5/27: ↑の内容を連続ツイートちなみにそんな中、当時これをニュースにした日本メディアは、5/30の産経ニュース @Sankei_news だけでした。3/3https://t.co/JyLTHZKRMP
— The Sato Lab (Kei Sato) (@SystemsVirology) July 27, 2022
#拡散希望 🔔速報🔔 新型コロナ研究コンソーシアムG2P-Japan🇯🇵のプレプリント第10弾を、bioRxiv @biorxivpreprint に発表しました。本研究では、#新しいオミクロン亜株(BA.4, BA.5, BA.2.12.1など)のウイルス学的性質(伝播力、免疫抵抗性、病原性)を解明しました。1/7https://t.co/UjNFtAAADW
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
1️⃣最近、スパイクタンパク質に新たな変異を獲得した #オミクロン 系統の亜株が、世界各地で出現し、流行拡大しています。具体的には、アメリカ🇺🇸のBA.2.12.1系統(+S:L452Q/S704L)、南アフリカ🇿🇦のBA.4, BA.5系統(+S:HV69-70del/L452R/F486V/R493Q)などです。2/7 pic.twitter.com/bfZTHrMgJg
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
2️⃣ウイルス配列の数理統計解析によって、これらの #新しいオミクロン亜株 の #伝播力 は、BA.2よりも約1.2倍高いことを明らかにしました。実際、南アフリカやアメリカなどの国では、すでに新しいオミクロン亜株への置き換わりが進んでいます。3/7 pic.twitter.com/1FizRsUngl
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
3️⃣中和試験の結果、BA.4/5は、BA.1あるいはBA.2に感染したワクチン接種者(つまり、オミクロンのブレイクスルー感染者)の血清に対し、BA.2の約2倍の抵抗性を示しました(図右)。なお、ワクチン未接種でBA.1あるいはBA.2に感染したひとの血清は、ほぼまったく中和活性を示しませんでした(図左)。4/7 pic.twitter.com/ACc174BUrS
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
4️⃣これらの #新しいオミクロン亜株 の臨床分離株が未取得であったため、BA.2.12.1あるいはBA.4/5のスパイクタンパク質を持った新型コロナウイルス(ベースはBA.2)を人工合成し、ハムスターを用いた感染実験を実施しました。その結果、BA.4/5の病原性は、BA.2よりも高いことを明らかにしました。5/7 pic.twitter.com/pvau0fNIM1
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
注:スパイクタンパク質以外の領域には、BA.4とBA.2の間には6個、BA.5とBA.2の間には2個の変異しかありません。そのため、今回実験に用いた組換えウイルスは、臨床分離株の性質を強く反映したものであろうと考えています。6/7
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
まとめ▶️ #新しいオミクロン亜株 、特にBA.4, BA.5系統のオミクロン株は、伝播力、免疫抵抗性、病原性のいずれの点においても、BA.2系統(現在主流のオミクロン株)よりリスクの高い変異株です。流行の動向は今後の対策次第ですが、リスクの高い変異株が出現していることに警戒すべきと考えます。7/7
— The Sato Lab (Kei Sato) (@SystemsVirology) May 26, 2022
◆Virological characteristics of the novel SARS-CoV-2 Omicron variants including BA.2.12.1, BA.4 and BA.5【bioRxiv 2022年5月26日】
Abstract
After the global spread of SARS-CoV-2 Omicron BA.2 lineage, some BA.2-related variants that acquire mutations in the L452 residue of spike protein, such as BA.2.9.1 and BA.2.13 (L452M), BA.2.12.1 (L452Q), and BA.2.11, BA.4 and BA.5 (L452R), emerged in multiple countries. Our statistical analysis showed that the effective reproduction numbers of these L452R/M/Q-bearing BA.2-related Omicron variants are greater than that of the original BA.2. Neutralization experiments revealed that the immunity induced by BA.1 and BA.2 infections is less effective against BA.4/5. Cell culture experiments showed that BA.2.12.1 and BA.4/5 replicate more efficiently in human alveolar epithelial cells than BA.2, and particularly, BA.4/5 is more fusogenic than BA.2. Furthermore, infection experiments using hamsters indicated that BA.4/5 is more pathogenic than BA.2. Altogether, our multiscale investigations suggest that the risk of L452R/M/Q-bearing BA.2-related Omicron variants, particularly BA.4 and BA.5, to global health is potentially greater than that of original BA.2.
Introduction
Since the end of November 2021, the SARS-CoV-2 Omicron variant (B.1.1.529 and BA lineages) has spread worldwide and has outcompeted prior SARS-CoV-2 variants of concern (VOCs) such as Delta. After the surge of Omicron BA.1 variant, another Omicron variant, BA.2, outcompeted BA.1 and has become the most dominant variant in the world (Ito et al., 2022; UKHSA, 2022; Yamasoba et al., 2022a). Thereafter, as of May 2022, the Omicron subvariants that harbor the substitution at the L452 residue of spike (S) protein, such as BA.4 and BA.5, were frequently detected (Tegally et al., 2022; WHO, 2022). These observations suggest that these novel Omicron subvariants bearing mutations at the S L452 residue are more transmissible than Omicron BA.2. These recent developments have led the WHO to these Omicron subvariants bearing mutations at the S L452 residue, BA.4, BA.5, BA.2.12.1, BA.2.9.1 and BA.2.11, as VOC lineages under monitoring (VOC-LUM) on May 18, 2022 (WHO, 2022).
Resistance to antiviral humoral immunity can be mainly determined by the mutations in the S protein. For instance, Omicron BA.1 exhibits profound resistance to neutralizing antibodies induced by vaccination and natural SARS-CoV-2 infection as well as therapeutic monoclonal antibodies (Cao et al., 2021; Cele et al., 2021; Dejnirattisai et al., 2022; Garcia-Beltran et al., 2021; Liu et al., 2021; Meng et al., 2022; Planas et al., 2021; Takashita et al., 2022a; VanBlargan et al., 2022) and BA.2 (Bruel et al., 2022; Takashita et al., 2022b; Yamasoba et al., 2022a; Yamasoba et al., 2022b). In addition to immune evasion, the mutations in the S protein potentially modulate viral pathogenicity. Particularly, the fusogenicity of S protein in in vitro cell cultures is closely associated with viral pathogenicity in an experimental hamster model. For example, the Delta S is highly fusogenic in cell cultures and highly pathogenic in hamsters when compared to ancestral D614G-bearing B.1.1 S (Saito et al., 2022). In contrast, the Omicron BA.1 S is less fusogenic and pathogenic than B.1.1 S (Meng et al., 2022; Suzuki et al., 2022). Furthermore, we have recently demonstrated that the Omicron BA.2 S is more fusogenic and potentially confers the virus higher pathogenicity than Omicron BA.1 S (Yamasoba et al., 2022a).
Newly emerging SARS-CoV-2 variants need to be carefully and rapidly assessed for a potential increase in growth efficacy in the human population, pathogenicity and/or evasion from antiviral immunity. The substitution at the L452 residue of SARS-CoV-2 S protein was detected in Delta (L452R) and Lambda (L452Q) variants, which were previously classified as a VOC and a variant of interest (VOI), respectively (WHO, 2022). Importantly, we previously demonstrated that the L452R (Motozono et al., 2021) and L452Q (Kimura et al., 2022a) mutations increase viral infectivity by promoting the binding of S receptor binding domain (RBD) to human ACE2. We have recently characterized the virological features of SARS-CoV-2 Omicron BA.1 (Meng et al., 2022; Suzuki et al., 2022) and BA.2 (Yamasoba et al., 2022a). However, the impact of the substitution of S L452 residue on the virological characteristics of Omicron BA.2 remains unclear. Together with these findings, it is reasonable to assume that the novel BA.2-related Omicron variants bearing mutations at S L452 residue can be a potential risk for global health, and we herein elucidate the virological characteristics of these novel Omicron variants.