ウイルスの変異の速さと多様性化にワクチン開発が追いついていない現状で、ワクチン接種を勧めるのはとても賛同できないのだけど(不活化ワクチンならまだしもmRNAワクチンとかマジ勘弁)、自然感染で免疫を獲得しようという愚かすぎる考えも絶対にダメ。
自分の身1人分だけを守るなら、マスク着用や鼻うがい・洗眼、換気のグレードを上げる(雑踏な環境を極力避ける)とか、非薬理的手法を徹底することで感染の大波をやり過ごすこともできなくはないの…PCR検査の無料化と普及拡大が実現できてればよかったのに…とは実感する。
スペイン風邪に子ども時代に感染した人のその後の研究とか、見ていないのかな。数10年単位で影響が残っている。感染しないのがベストだけれど、ワクチンをうって感染するのがベター。ノーワクチンで自然感染を繰り返すのは避けたほうがいい。https://t.co/DJD7o37hQm
— Offside🌻 (@yfuruse) August 1, 2023
抗体は役に立たない、自然免疫と細胞性免疫で制御すべしと唱える人々がおられますが、もしも人が抗体を作れなかったら、どうなるか? ケースレポートしました。https://t.co/EnXljOR3SV
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
通常の人の免疫が働いている場合のウイルスの増殖のイメージ(左から右に) pic.twitter.com/5siWYNwSqf
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
抗体が無い場合。細胞性免疫は感染細胞を殺すことにより、ウイルスの産生工場を爆破しますが、すでに生産されていたウイルスは飛び散り、新しく別の細胞への進入を防ぐことができません。 pic.twitter.com/rBAeYa3gTn
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
この論文の症例では、通常の人で細胞性免疫を担うはずのCD8陽性T細胞ではなく、CD4-CTLと呼ばれる珍しい細胞が頑張ってウイルスの増殖を抑えようとしていましたが、200日を超えてウイルスの変異に負けてしまいました。ADE of infectionを恐れるあまりに、抗S抗体を避けようとする一派がいますが
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
あまりにナンセンスな考えと言えましょう。
私は、抗S抗体によるADE of infectionはSARS-CoV-2では生じず、むしろ感染によって作られるNタンパクに対する抗N抗体による、ADE of cytokine productionを警戒しています。 pic.twitter.com/PThZPU2UFf— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
Nタンパク質は、レクチン経路を介して補体を活性化し、マクロファージからIL-6,8,TNF-aを産生し、サイトカインストームと血管炎の原因となっている。そこに抗N抗体が有るとFcRを介してマクロファージへのNの取り込みがenhanceされる。私が2度目の感染を避けてほしいと説く理由です。 pic.twitter.com/u2Fq6ZZCAN
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
先ほどの抗体がない場合の図、こちらの方がわかりやすいかもしれません。 pic.twitter.com/2rusksIHhp
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
ワクチン未接種での自然感染の方が、ワクチンよりも優れた免疫になるとは、私は思っていません。ハイブリッド免疫が最強になるのは、vaccine-prime の場合です。 pic.twitter.com/lbKsKM5eLQ
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 27, 2023
SRAS-CoV-2の自然感染では、3つの弱点があります。
1、抗体を作るB細胞の教育の場であるgerminal center(胚中心)の形成不全。
これは自己抗体産生細胞のnegative selectionにも悪影響を及ぼす危険があります。https://t.co/ezzpNdiSsp— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 28, 2023
2. 細胞傷害性T細胞の誘導が実は弱い。https://t.co/FlsZCzTRER
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 28, 2023
3. 自然免疫を担当する形質細胞様樹状細胞がインターフェロンを出さなくなる影響は半年も続くらしい。https://t.co/AZlXe0nDOE
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 28, 2023
Long-COVIDもワクチンで予防できると明らかになりつつあります。若い人は死なないけども、働けない、学校に行けなくなるなどの倦怠感から来るQOLの低下は無視できないと思います。https://t.co/yoOylgw0NT
— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 28, 2023
もしかすると腸管に持続感染してしまうかもしれないのもワクチン未接種ノーガード自然感染の弱点です。
「ウイルスとの共生」ウィズコロナが持続感染を意味するなら、私はNo thank youです。避けられるものなら避けたいです。(で、最初のツイートに戻る)https://t.co/n8LiAy99S1— Emi E. Nakayama MD, PhD (@EmiNakayama7) May 28, 2023
4つ目(子供さんの感染による免疫獲得のデメリット)
↑
New!https://t.co/GjXWd20sC7— Emi E. Nakayama MD, PhD (@EmiNakayama7) June 11, 2023
新型コロナ感染小児に稀に起こるMIS-Cで注目結果(preprint)
MIS-Cの子を調べ次の可能性浮上
感染→コロナのN(ヌクレオカプシド)領域に対し異常な免疫反応→同免疫が自己の蛋白と反応→発症
接種の反応はS(スパイク)対象で無関係な上MIS-Cが減ったのも接種等で免疫が抗S等にシフトしたからの可能性
— 大津秀一🍀医師🍀緩和ケア内科🍀早期からの緩和ケア外来🍀院長🍀「どこでも緩和®」で全国対応可 (@shuichiotsu) June 9, 2023
・出典、MIS-C(小児多系統炎症性症候群)に関してhttps://t.co/5AS9QNE6b6
抗N(ヌクレオカプシド)の免疫が悪さをする可能性は以前から中山先生 @EmiNakayama7 が指摘されていたが本研究もMIS-Cの原因でそれが浮上
mRNAワクチンはSへの免疫反応が起こる一方で、感染はNへも起こる
注目される知見 pic.twitter.com/pPSFoRhljM
— 大津秀一🍀医師🍀緩和ケア内科🍀早期からの緩和ケア外来🍀院長🍀「どこでも緩和®」で全国対応可 (@shuichiotsu) June 9, 2023
感染が前駆するとNへ免疫反応が起き稀に通常と異なる反応から自己の蛋白とも反応MIS-Cに進展
一方接種での免疫はSへのものでこれは起きずむしろ感染時も上述の反応回避される可能性
感染すればOK等の発信がこの様な事がわかる前から継続的に為されてきたが改めて感染と接種は異なると認識させる結果
— 大津秀一🍀医師🍀緩和ケア内科🍀早期からの緩和ケア外来🍀院長🍀「どこでも緩和®」で全国対応可 (@shuichiotsu) June 9, 2023
◆COVID-19 relapse associated with SARS-CoV-2 evasion from CD4+ T-cell recognition in an agammaglobulinemia patient【Cell iScience 2023年5月19日】
Summary
A 25-year-old patient with a primary immunodeficiency lacking immunoglobulin production experienced a relapse after a 239-day period of persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Viral genetic sequencing demonstrated that SARS-CoV-2 had evolved during the infection period, with at least five mutations associated with host cellular immune recognition. Among them, the T32I mutation in ORF3a was found to evade recognition by CD4+ T cells. The virus found after relapse showed an increased proliferative capacity in vitro. SARS-CoV-2 may have evolved to evade recognition by CD4+ T cells and increased in its proliferative capacity during the persistent infection, likely leading to relapse. These mutations may further affect viral clearance in hosts with similar types of human leukocyte antigens. The early elimination of SARS-CoV-2 in immunocompromised patients is therefore important not only to improve the condition of patients but also to prevent the emergence of mutants that threaten public health.
Introduction
X-linked agammaglobulinemia (XLA) is a rare primary humoral immunodeficiency that was first reported by Bruton in 1952. In XLA, abnormalities in Bruton’s tyrosine kinase prevent normal B-cell maturation, resulting in agammaglobulinemia. The prognosis is generally good if globulin preparations are administered regularly.
Coronavirus disease 2019 (COVID-19) can become chronic and relapse in patients with primary and secondary antibody deficiencies. Previous reports have shown that convalescent plasma,7,8 remdesivir plus convalescent plasma, and remdesivir plus a monoclonal antibody cocktail have therapeutic effects in COVID-19 cases with XLA. Polyfunctional CD8+ T-cell responses have also been observed during the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with XLA. A recent analysis of SARS-CoV-2 infection in an immunocompromised patient demonstrated viral evolution and reduced sensitivity to neutralizing antibodies, which was either dependent on or independent of convalescent plasma therapy.
Here, we present an XLA case in which SARS-CoV-2 infection persisted for more than 239 days without specific humoral immunity to SARS-CoV-2. The patient experienced a relapse as SARS-CoV-2 evolved during the infection period. The clinical course of the patient, intra-host evolution of SARS-CoV-2 during persistent and relapsing infection for more than 239 days, and SARS-CoV-2-specific T-cell responses in the absence of humoral immunity have been described.
◆Spheromers reveal robust T cell responses to the Pfizer/BioNTech vaccine and attenuated peripheral CD8+ T cell responses post SARS-CoV-2 infection【Cell Immunity 2023年4月11日】
Summary
T cells are a critical component of the response to SARS-CoV-2, but their kinetics after infection and vaccination are insufficiently understood. Using “spheromer” peptide-MHC multimer reagents, we analyzed healthy subjects receiving two doses of the Pfizer/BioNTech BNT162b2 vaccine. Vaccination resulted in robust spike-specific T cell responses for the dominant CD4+ (HLA-DRB1∗15:01/S191) and CD8+ (HLA-A∗02/S691) T cell epitopes. Antigen-specific CD4+ and CD8+ T cell responses were asynchronous, with the peak CD4+ T cell responses occurring 1 week post the second vaccination (boost), whereas CD8+ T cells peaked 2 weeks later. These peripheral T cell responses were elevated compared with COVID-19 patients. We also found that previous SARS-CoV-2 infection resulted in decreased CD8+ T cell activation and expansion, suggesting that previous infection can influence the T cell response to vaccination.
Introduction
The COVID-19 pandemic has resulted in the rapid development of several novel vaccine platforms, including the mRNA-based Pfizer/BioNTech BNT162b2 vaccine. The mRNA vaccine formulations show high levels of protection and stimulate robust innate and adaptive immune responses. They induce neutralizing antibodies, although circulating titers decrease after just months.5,7 By contrast, analyses of the magnitude and durability of SARS-CoV-2-specific T cell responses are limited, with most studies relying on bulk measurements after in vitro peptide stimulation.4,8 Although rapid and useful, these studies underestimate the frequency of epitope-specific T cells6 and may not be able to identify specific immunodominant epitopes efficiently. Peptide-major histocompatibility complex (pMHC) multimers address these limitations and provide a more quantitative and epitope-specific picture of the T cell response.
T cell responses play a critical role in controlling disease after SARS-CoV-2 infection. Breakthrough virus in the nasal swabs is seen in all convalescent rhesus macaques with waning or suboptimal neutralizing antibody titers on rechallenge with SARS-CoV-2 after CD8+ T cell depletion. Recovery from COVID-19 in patients undergoing B cell depleting therapies further highlights the importance of T cells in SARS-CoV-2 viral clearance. CD8+ T cell responses to conserved coronavirus epitopes correlate with mild COVID-19 disease symptoms. Rapid expansion of cross-reactive T cells is also seen in individuals with abortive SARS-CoV-2 infection, suggesting their protective role. Thus, it is important to understand the kinetics of T cell priming and how these events compare across SARS-CoV-2 naive vaccinees versus COVID-19 patients.
In this study, we used the spheromer technology to identify dominant T cell epitopes after BNT162b2 vaccination. This platform is based on an engineered form of maxiferritin, where 12 pMHCs carried by each nanoparticle are able to detect ∼3- to 5-fold more antigen-specific T cells compared with other multimers. Here, we designed a panel of forty-nine predicted epitopes, spanning both spike and non-spike proteins from the original Wuhan-Hu-1 SARS-CoV-2 strain. We probed a total of 351 blood samples collected from vaccinated volunteers with time points ranging from pre-vaccination up to 4 months after the first dose. Overall, BNT162b2 vaccination resulted in polyfunctional CD8+ and CD4+ T cell responses across all volunteers, likely contributing to its remarkable efficacy. We observed distinct CD8+ and CD4+ T cell kinetics after mRNA vaccination. This disparity between the two major T cell responses is unusual, since in other vaccination studies both CD4+ and CD8+ peak in circulation approximately 1 week after stimulating a recall response. This coordination of T cell subsets was also seen in a Celiac challenge study. We speculate that this may be a unique feature of mRNA vaccines. To assess the differences in T cell responses elicited by vaccination versus natural infection, we determined the response in two independent local patient cohorts. We observed lower frequencies of spike-specific T cells in circulation after infection compared with mRNA vaccination, especially in the CD8+ T cell compartment with a skewing of the response hierarchy among the tested epitopes. We also noticed qualitative differences in the virus-specific T cells. Vaccination led to the rapid induction of effector T cells that contracted by day 90, concomitant with an increase in the frequency of memory T cells. By contrast, only low levels of virus-specific memory CD8+ T cells could be detected in COVID-19 patients, even at 5 months post-symptom onset.
We also evaluated the impact of BNT162b2 vaccination on T cell responses after SARS-CoV-2 infection. Although previous infection had almost no effect on the CD4+ T cell response induced on vaccination, we observed a decrease (3.6- to 54.1-fold at peak) in the frequency of circulating spike-specific CD8+ T cells, and these had attenuated functionality compared with naive vaccinees. This suggests that SARS-CoV-2 virus infection may cause long-term damage to the patients’ immune system well after viral clearance.
◆A distinct cross-reactive autoimmune response in multisystem inflammatory syndrome in children (MIS-C)【medRxiv 2023年5月30日】
Abstract
Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of MIS-C patient samples (n=199) to identify a distinct set of host proteins that are differentially targeted by patient autoantibodies relative to matched controls. We identified an autoreactive epitope within SNX8, a protein expressed primarily in immune cells which regulates an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed the SARS-CoV-2 proteome-wide MIS-C patient antibody response and found it to be differentially reactive to a distinct domain of the SARS-CoV-2 nucleocapsid (N) protein relative to controls. This viral N region and the mapped SNX8 epitope bear remarkable biochemical similarity. Furthermore, we find that many children with anti-SNX8 autoantibodies also have T-cells cross-reactive to both SNX8 and this distinct domain of the SARS-CoV-2 N protein. Together, these findings suggest that MIS-C patients develop a distinct immune response against the SARS-CoV-2 N protein that is associated with cross reactivity to the self-protein SNX8, demonstrating a link from the infection to the inflammatory syndrome.
Introduction
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to a broad spectrum of disease. The course of disease in children is often mild but can become severe due to a variety of known and yet-to-be discovered factors. In rare cases children develop multisystem inflammatory syndrome in children (MIS-C), a post-infectious complication which often results in critical illness. The disease was hypothesized to be related to Kawasaki Disease, which presents similarly with prolonged fever, systemic inflammation, rash, conjunctivitis, and can be complicated by myocarditis and coronary artery aneurysms. In contrast to Kawasaki Disease, however, MIS-C is temporally associated after a SARS-CoV-2 infection, and more commonly includes shock, cardiac dysfunction, and multi-organ system involvement including gastrointestinal symptoms and hematologic findings, such as thrombocytopenia and lymphopenia. Through extensive characterization, MIS-C has been shown to have a distinctive inflammatory and cytokine signature, with evidence of altered innate and adaptive immunity as well as autoimmunity.
While the pathophysiological link between SARS-CoV-2 and MIS-C remains enigmatic, other autoimmune diseases are the consequence of exposure to novel antigens in the form of a virus or oncoprotein. For example, multiple sclerosis is associated with Epstein-Barr-Virus infection, and recent data suggests that B-cells and T-cells which are cross-reactive between a viral protein (EBNA1) and several host proteins may contribute to disease development. In addition, decades of paraneoplastic autoimmune encephalitis research, including anti-Hu, anti-Yo, anti-kelch-like protein 11, and many others, highlight the importance of autoreactive B-cells and T-cells working in concert to cause disease by targeting a shared intracellular antigen, and in certain cases a shared epitope.
Though cross-reactivity has not yet been identified in MIS-C, multiple autoantibodies have been reported, including those targeting interlueukin-1 receptor antagonist (IL-1Ra). Distinctive T-cell signatures have also been reported in MIS-C, including an expansion of TRVB11-2 T-cells accompanied by autoimmune-associated B-cell expansions. Because the T-cell expansion is not monoclonal, many have speculated that a yet-to-be-identified superantigen is responsible. However, recent experiments suggest the expansion may instead by the result of activated tissue-resident T-cells, though the antigenic target of these T-cells remains unknown. Altered innate immune function has also been implicated in a subset of MIS-C cases, including inborn errors of immunity involving regulation of the mitochondrial antiviral-signaling (MAVS) protein pathway.
Here, children previously infected with SARS-CoV-2-with (n=199) and without (n=45) MIS-C were enrolled and comprehensively profiled for autoreactive antibodies as well as those targeting SARS-CoV-2. Differential autoreactivity highlighted an epitope motif which is shared by the viral N protein and the human SNX8 protein. SNX8 is expressed by immune cells across multiple tissues and modulates MAVS activity. This cross-reactive epitope motif is targeted by both B-cells and T-cells, suggesting that a subset of MIS-C may be triggered by molecular mimicry.