JP2022127085A - Retroactive vaccine (preventive method that matches antibodies in the order of evolution of virus by repeating mucosal vaccine by going back virus by phylogenetic tree analysis) - Google Patents

Retroactive vaccine (preventive method that matches antibodies in the order of evolution of virus by repeating mucosal vaccine by going back virus by phylogenetic tree analysis) Download PDF

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JP2022127085A
JP2022127085A JP2021025022A JP2021025022A JP2022127085A JP 2022127085 A JP2022127085 A JP 2022127085A JP 2021025022 A JP2021025022 A JP 2021025022A JP 2021025022 A JP2021025022 A JP 2021025022A JP 2022127085 A JP2022127085 A JP 2022127085A
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良太郎 尾島
Ryotaro Oshima
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Abstract

To solve the problems that conventional injectable vaccines are painful and have side effects, mucous membranes such as the eyes, nose, and mouth cannot produce IgA antibodies, so they did not prevent infection, mucosal vaccines administered orally or nasally can induce immune responses centered on IgA in the mucosal system and IgG in the systemic system, but have a risk of a cytokine storm or aggravation in the case of the elderly, those with underlying diseases, and viruses with little history of infection, and additionally any of them have limitations in preventing mutants and are uniform methods.SOLUTION: Antibodies are matched in the order of the evolution of a virus by repeating a mucosal vaccine by going back the virus by phylogenetic tree analysis.SELECTED DRAWING: Figure 3

Description

本発明は、ウィルスの予防方法に関するものである。 The present invention relates to a virus prevention method.

１８９０年（明治２３年）、ローベルト・コッホの下で細菌学を研究していた北里柴三郎博士が抗体（抗毒素）を発見して以来（非特許文献１）、抗体に関して様々な研究がなされてきた。利根川進博士の「多様な抗体を生成する遺伝的原理の解明」では、初めから限りなく多様な抗体が用意されていて、新型ウィルス等の抗原に対して近い抗体で対応する。その間に抗体遺伝子が高頻度に突然変異を起こし抗原に合う抗体を作り出せることがわかった。その際に抗体を作り出すというよりは、抗原が抗体を選択するという解釈をしている（非特許文献２）。 In 1890 (Meiji 23), Dr. Shibasaburo Kitasato, who was studying bacteriology under Robert Koch, discovered an antibody (antitoxin) (Non-Patent Document 1), and since then, various studies have been conducted on antibodies. rice field. In Dr. Susumu Tonegawa's ``Elucidation of the genetic principle that generates various antibodies,'' an infinite variety of antibodies are prepared from the beginning, and antibodies that are similar to antigens such as new viruses are used. During that time, it was found that antibody genes mutated at high frequency and produced antibodies that matched antigens. At that time, it is interpreted that the antigen selects the antibody rather than producing the antibody (Non-Patent Document 2).

しかしウィルスは大陸の地域ごとに生息し、その塩基配列を変えることでそれぞれ変異していくので常に地域差が生じる。人類は膨大な種類の抗体を作れるが、遠い地域で進化したウィルスに感染した場合近い抗体を持っていないので、すぐには大量に抗体を作ることができずウィルスの方が早く増殖し重症化し感染拡大してしまう。したがってある地域で感染力と毒性を強めたウィルスが、他の地域で感染爆発することで今後もパンデミックが起きてしまう。 However, the virus inhabits each region of the continent and mutates by changing its base sequence, so there are always regional differences. Humans can create a huge variety of antibodies, but if they are infected with a virus that has evolved in a distant region, they will not have similar antibodies, so they will not be able to produce a large amount of antibodies immediately, and the virus will multiply faster and become more severe. spread the infection. Therefore, a virus that has strengthened its infectivity and toxicity in one region will explode in another region, causing a pandemic in the future.

その予防のための従来の注射ワクチンでは、痛みを伴い副作用があった。また粘膜である目、鼻、口などにはIgA抗体を作れないので、感染予防にはならなかった（特許文献１）。また経口・経鼻投与による粘膜ワクチンでは、粘膜系にはIgA、全身系ではIgGを中心とする免疫応答を誘導できる（特許文献２，非特許文献３）が、高齢者や基礎疾患者、過去に罹患歴の少ないウィルスの場合、サイトカインストームや重症化のリスクがあった。またいずれも変異種への予防に限界があり、画一的な方法であった。 Conventional injection vaccines for its prevention are painful and have side effects. In addition, since IgA antibodies cannot be produced in mucous membranes such as the eyes, nose, and mouth, it was not possible to prevent infection (Patent Document 1). In addition, mucosal vaccines administered orally and nasally can induce immune responses centered on IgA in the mucosal system and IgG in the systemic system (Patent Document 2, Non-Patent Document 3), but the elderly, those with underlying diseases, and the past There was a risk of cytokine storm and severe disease in the case of a virus with a low history of disease. In addition, all methods have limitations in preventing mutants and are uniform methods.

この改善策として本発明は、系統樹解析によりウィルスを遡り粘膜ワクチンを繰り返すことで、ウィルスの進化順に抗体を合わせていく。抗原のエピトープと抗体のパラトープには引力が働き、安定して結合する。自然感染に近いので副作用や重症化リスクが減り、全身に最も強い免疫ができる（非特許文献４）。またＴ細胞も活性化できるので強い免疫力を長期間維持でき、抗原の進化の流れに沿って抗体を作るので変異種も予防できる。また個人にカスタマイズできるので体質に合った予防が可能である。 As a remedy for this, the present invention traces back the virus by phylogenetic tree analysis and repeats the mucosal vaccine, thereby matching antibodies in the order of evolution of the virus. The epitope of the antigen and the paratope of the antibody are attracted to each other and stably bind to each other. Since it is close to natural infection, the risk of side effects and aggravation is reduced, and the strongest immunity can be provided to the whole body (Non-Patent Document 4). In addition, since T cells can also be activated, strong immunity can be maintained for a long period of time. In addition, since it can be customized for each individual, it is possible to prevent it according to one's physical constitution.

特開昭６３－２６４５３２JP-A-63-264532 特表２００１－５０３９８１Special table 2001-503981

山崎光夫著「北里柴三郎（上）雷と呼ばれた男～新装版～」、p230-p231、中公文庫、2019年Mitsuo Yamazaki, Shibasaburo Kitasato (Part 1) The Man Called Thunder, p230-p231, Chuko Bunko, 2019 立花隆、利根川進著「精神と物質」p317-p322、文春文庫、1993年Takashi Tachibana, Susumu Tonegawa, Spirit and Matter, p317-p322, Bunshun Bunko, 1993 谷口克、宮坂昌之編集、清野宏著「標準免疫学～第二版～8B粘膜免疫と経口免疫寛容」p316-p326、医学書院、2002年Edited by Masaru Taniguchi and Masayuki Miyasaka, Hiroshi Seino, "Standard Immunology-Second Edition-8B Mucosal Immunity and Oral Tolerance" p316-p326, Igaku Shoin, 2002 母里啓子著「インフルエンザ・ワクチンは打たないで！」、p182-p184、双葉社、2007年Keiko Mozato, "Don't Get Influenza Vaccine!", p182-p184, Futabasha, 2007

解決しようとする問題点は、従来の注射ワクチンでは痛みを伴い副作用があった。また粘膜である目、鼻、口などにはIgA抗体を作れないので、感染予防にはならなかった。また経口・経鼻投与による粘膜ワクチンでは、粘膜系にはIgA、全身系ではIgGを中心とする免疫応答を誘導できるが、高齢者や基礎疾患者、過去に罹患歴の少ないウィルスの場合、サイトカインストームや重症化のリスクがあった。またいずれも変異種への予防に限界があり、画一的な方法であった。 The problem to be solved is that conventional injection vaccines are painful and have side effects. In addition, mucous membranes such as the eyes, nose, and mouth cannot produce IgA antibodies, so they did not prevent infection. In addition, mucosal vaccines administered orally and nasally can induce immune responses centered on IgA in the mucosal system and IgG in the systemic system. There was a risk of a storm or aggravation. In addition, all methods have limitations in preventing mutants and are uniform methods.

本発明は、系統樹解析によりウィルスを遡り粘膜ワクチンを繰り返すことで、ウィルスの進化順に抗体を合わせていくことを最も主要な特徴とする。 The most important feature of the present invention is matching antibodies in the order of evolution of viruses by repeating mucosal vaccines by going back to viruses by phylogenetic tree analysis.

本発明の予防方法は自然感染に近いので副作用や重症化リスクが減り、全身に最も強い免疫ができる。またＴ細胞も活性化できるので強い免疫力を長期間維持でき、抗原の進化の流れに沿って抗体を作るので変異種も予防できる。また個人にカスタマイズできるので体質に合った予防が可能である。 Since the preventive method of the present invention is close to natural infection, the risk of side effects and aggravation is reduced, and the strongest immunity can be provided to the whole body. In addition, since T cells can also be activated, strong immunity can be maintained for a long period of time. In addition, since it can be customized for each individual, it is possible to prevent it according to one's physical constitution.

図１はウィルスの系統樹を示す説明図である。FIG. 1 is an explanatory diagram showing the phylogenetic tree of viruses. 図２はウィルスを遡り粘膜ワクチンを繰り返すフローチャートである。FIG. 2 is a flow chart for tracing the virus and repeating the mucosal vaccine. 図３は生ワクチンを投与する体の部位を示す説明図である。FIG. 3 is an explanatory diagram showing the parts of the body where the live vaccine is administered.

副作用や重症化のリスクを減らす感染予防をするという目的を、系統樹解析によりウィルスを遡り粘膜ワクチンを繰り返すという自然感染に近い方法で実現した。 The purpose of preventing infection by reducing the risk of side effects and aggravation was achieved by a method similar to natural infection, in which phylogenetic tree analysis traces back the virus and repeats mucosal vaccines.

図１は、ウィルスの系統樹を示す説明図であって、スタートとなるウィルス１を１、次のウィルス２を２、感染予防したい最新の新型ウィルス３を３とする。各ノードが最も近い共通祖先ウィルスである。 FIG. 1 is an explanatory diagram showing a phylogenetic tree of viruses, where 1 is the starting virus 1, 2 is the next virus 2, and 3 is the latest new virus 3 to be prevented from infection. Each node is the closest common ancestor virus.

図２は、ウィルスを遡り粘膜ワクチンを繰り返すフローチャートである。以下に実施例を示す。 FIG. 2 is a flow chart of tracing back the virus and repeating the mucosal vaccine. Examples are shown below.

スタートとなるウィルス１は地域や人によって異なり、ウィルスの分類である種、属、科、目を適宜遡る。ウィルス１を決定するのに抗体検査がある。また体温変化（許容差±0.3℃）や血中酸素濃度の変化（許容差－3％）、風邪の症状で判断する（抗体検査と合わせて以下「検査A」とする）。許容差は任意の基準とする。系統樹解析によってウィルスを遡り、検査Aにより異常がなければそれをウィルス１とする。 The starting virus 1 differs depending on the region and the person, and the virus is classified by species, genus, family, and order as appropriate. There is an antibody test to determine Virus 1. In addition, it is judged by changes in body temperature (tolerance ±0.3°C), changes in blood oxygen concentration (tolerance -3%), and cold symptoms (hereinafter referred to as “test A” together with antibody test). Tolerances are arbitrary criteria. The virus is traced back by phylogenetic tree analysis, and if there is no abnormality in test A, it is designated as virus 1.

スタートとなるウィルス１に粘膜から感染する（ステップ１）。検査Aにより異常が出た場合は中止、許容差を超えた場合は数日おいてステップ１をやり直し、変化が許容差内ならばウィルス２に進む（ステップ２）。 Mucous membranes are infected with the starting virus 1 (Step 1). If an abnormality is found in inspection A, the test is stopped. If the tolerance is exceeded, step 1 is repeated after a few days. If the change is within the tolerance, proceed to virus 2 (step 2).

ウィルス２に粘膜から感染する（ステップ３）。同様に、検査Aにより異常が出た場合は中止、許容差を超えた場合は数日おいてステップ３をやり直し、変化が許容差内ならばウィルス３に進む（ステップ４）。 Virus 2 infects mucous membranes (step 3). Similarly, if an abnormality is found in the inspection A, it is stopped, if the tolerance is exceeded, step 3 is repeated after a few days, and if the change is within the tolerance, proceed to virus 3 (step 4).

ウィルス３に粘膜から感染する（ステップ５）。同様に、検査Aにより異常が出た場合は中止、許容差を超えた場合は数日おいてステップ５をやり直し、変化が許容差内ならば終了である（ステップ６）。 Virus 3 infects mucous membranes (step 5). Similarly, if an abnormality is found in inspection A, the process is stopped. If the tolerance is exceeded, step 5 is repeated after a few days. If the change is within the tolerance, the process ends (step 6).

図３は、感染する粘膜部位を示す説明図である。生ワクチンを眼瞼に滴下、経口・経鼻からの吸引を繰り返し全身に免疫をつくる。 FIG. 3 is an explanatory diagram showing a mucous membrane site to be infected. The live vaccine is dripped onto the eyelids and repeatedly sucked orally and through the nose to build immunity throughout the body.

あらゆる風邪ウィルスに適用できるが、再感染するコロナウィルスやライノウィルスの場合、局所での分泌型抗体による感染防御は特に有効である。その他の感染症にも応用できる。こうして新型ウィルスを遡って経口・経鼻投与する粘膜ワクチンにより全身に抗体を作り出す。新型ウィルスがさらに変異してもこの予防法で獲得した抗体でまずは対応し、変異ウィルスに適合する新たな抗体をスムーズに作り出せる。エピトープとパラトープの結合力であるアフィリティを最大とすることができ、安定して抗原が中和され重症化リスクが大幅に減少する。自然感染に近いので最も強い免疫が維持できる。本発明の遡及ワクチンは日本国産ワクチンであるが、集団免疫である各国の人口の６割～７割が免疫を持つまで繰り返せばパンデミックも収束する。 Although it can be applied to any cold virus, local secretory antibody protection is particularly effective in the case of reinfected coronaviruses and rhinoviruses. It can also be applied to other infectious diseases. In this way, antibodies are produced throughout the body by mucosal vaccines that are administered orally and nasally by tracing back to the new virus. Even if the new virus mutates further, the antibodies acquired by this preventive method can be used to deal with it, and new antibodies that are compatible with the mutated virus can be smoothly produced. The affinity, which is the binding force between the epitope and the paratope, can be maximized, the antigen is stably neutralized, and the risk of aggravation is greatly reduced. Since it is close to natural infection, the strongest immunity can be maintained. The retroactive vaccine of the present invention is a vaccine made in Japan, but if it is repeated until 60% to 70% of the population of each country with herd immunity becomes immune, the pandemic will converge.

１ 系統樹解析により遡ったスタートとなるウィルス１
２ 次のウィルス２
３ 感染予防したい最新の新型ウィルス３ 1 Virus 1 as a starting point retroactively by phylogenetic tree analysis
2 next virus 2
3 The latest new virus that you want to prevent infection 3

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遡及ワクチン（系統樹解析によりウィルスを遡り粘膜ワクチンを繰り返すことで、ウィルスの進化順に抗体を合わせていく予防方法） Retroactive vaccine (Preventive method that matches antibodies in the order of evolution of the virus by repeating mucosal vaccine by going back to the virus by phylogenetic tree analysis)
JP2021025022A 2021-02-19 2021-02-19 Retroactive vaccine (preventive method that matches antibodies in the order of evolution of virus by repeating mucosal vaccine by going back virus by phylogenetic tree analysis) Pending JP2022127085A (en)

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