BCGはCoVID-19予防に有効かも知れない
BCGはCoVID-19予防に有効かも知れない
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2020/03/27にインターネットで、「BCGはCoVID-19を予防する」という情報が出回っていました。
細菌とウイルスが相互作用する(ように見える)ことは幾つかの論文で知られていましたが、一般的なことでは無いので、にわかに信じ難く、ここに書いていませんでした。
しかしメカニズムに関する基礎的な文献があったので、ここに書き留めておくことにしました。
BCG接種は、MacrophageのNOD2遺伝子やIL1-βの転写遺伝子のEpigeneticを通じて、抗ウイルス作用を発揮して、少なくとも黄熱病の発症を抑制したり、乳幼児死亡率を下げたりしているようです。
現在、オランダとオーストラリアで前方視的治験が始まったようで、決着が付いたら、またここに追記しようと思います。
（※ 2020/03/31記載、管理者文責）
https://www.mnhrl.com/mortality(covid19)-bcgvaccinationpolicies-2020-4-1/?fbclid=IwAR2Ngeoi1tvSyvhabyDAkLRmqDbT8AdVVPGHlBDIJng_pG9qPQkk8FBwX3g
■WHO Coronavirus disease (COVID-2019) situation reports
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
■THE BCG WORLD ATLAS 2nd Edition
http://www.bcgatlas.org/index.php
BCGが効果を示す理論的な根拠として、上記の論文には以下のように書かれています。
「BCGワクチン接種などのワクチンは、非特異的免疫効果を生み出し、他の病原体に対する反応を改善することが示されている。たとえば、BCGワクチン接種マウスではCD4 +細胞からのIFN-Y産生の増加によって免疫が強化されているという報告もある。この現象は「trained immunity」と呼ばれ、炎症促進性サイトカイン、具体的には抗ウイルス免疫で重要な役割を果たすことが示されている。ギニアでの研究では、BCGでワクチンを接種した子供は、全体的な死亡率が50％減少することが観察されている。」
The above paper "Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study" described that "Several vaccines including the BCG vaccination have been shown to produce non-specific immune effects leading to improved response against other non- mycobacterial pathogens. For instance, BCG vaccinated mice infected with the vaccinia virus were protected by increased IFN-Y production from CD4+ cells . This phenomenon was named‘trained immunity’ and is proposed to be caused by metabolic and epigenetic changes leading to promotion of genetic regions encoding for pro-inflammatory cytokines . BCG vaccination significantly increases the secretion of pro-inflammatory cytokines, specifically IL-1B, which has been shown to play a vital role in antiviral immunity . Additionally, a study in Guinea-Bissau found that children vaccinated with BCG were observed to have a 50% reduction in overall mortality, which was attributed to the vaccine’s effect on reducing respiratory infections and sepsis. "
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以下は本来のBCGの効果です。
★乳幼児期にBCGワクチンを接種することで、結核の発症を70％程度現象させる。
（J R Soc Med. 2017;110(11):428.）
★BCGワクチンが乳幼児期の結核性髄膜炎や粟粒結核を80％程度予防する。
（Int J Epidemiol. 1993;22(6):1154.）
★BCGワクチンが小児期の呼吸器感染症や敗血症を40-50%減らす。
（Clin Infect Dis. 2015;60(11):1611.）
★BCGワクチンが低出生体重児の死亡率を減らす。
（Clin Infect Dis. 2017;65(7):1183.）
★BCGワクチンが白血球の成分の一つである単球に働きかけて自然免疫を強化するゲノム変化を起こす。
(Cell Rep. 2016 Dec 6;17(10):2562-2571.)
★BCGワクチンが炎症促進性サイトカイン、特にIL-1Bの分泌を増加させる。
(Science. 2016 Apr 22;352(6284):aaf1098.)
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TNFαおよびIL-6産生におけるワクチン接種後の増加は、ウイルス血症と相関していませんでした（図4AおよびS4A）。
対照的に、BCGワクチン接種後のIL-1β産生能力の増加は、その後の黄熱感染後のウイルス血症の低下を強く予測した（図4Aおよび4B）。
他のサイトカインの中で、カンジダアルビカンスによる刺激によるIL-10の誘導もウイルス血症と負の相関を示しました（図4A、4B、およびS4A）。
興味深いことに、ウイルス血症は、PBMCによるIFNγ産生によって測定されるように、BCGによるYFVに対する特定の細胞応答の誘導と相関していませんでした（図4CおよびS4B）。
さらにウイルス血症とTh17サイトカインIL-17およびIL-22の濃度との間に相関関係は見られませんでした（図S4A）。
BCGワクチン接種後のCD8 +および多機能CD4 +応答の誘導を発見したため、これは注目に値します。
（図S2）(Boer et al、2015、Kleinnijenhuis et al、2012）
黄熱中和抗体価の濃度も、サイトカインの誘導とは相関していませんでした。（獲得的でも適応的でもありません）
サイトカイン誘導との相関関係とは別に、BCGと黄熱ウイルス血症によって引き起こされるエピジェネティックな変化の相関関係も測定されました。
そのために、図1に示すボランティアは、BCGワクチン接種に対する応答者（R、最大黄熱ウイルス血症CT> 36）と非応答者（NR、CT <36）のグループに分けられました。
遺伝子領域レベルでの既存のH3K27Acエピジェネティックな差異（ベースライン、BCGワクチン接種前）は、RとNRの間で決定され、これら2つのボランティアグループ間の重要な差異が特定され、ワクチン接種後の応答に重要な経路が示唆されました。
興味深いことに、この分析で上位にランク付けされたゲノム領域は、NOD2をコードする遺伝子の7.6 kb上流（FC = 6.3、調整後のp値= 2.42×10-8）であり、ムラミルジペプチドを認識する自然免疫受容体です：
以前の研究では、受容体の欠陥につながるNOD2変異を持つ個人から分離された単球は、BCGを使用してin vitroでトレーニングすることはできませんでした。
（Arts et al、2015、Kleinnijenhuis et al、2012）（図5Aおよび5B）
さらに、RとNRの間のH3K27acプロファイルの経路分析は、いくつかの興味深い結果を明らかにします。
もう一度、RNA-seq分析では、細胞が分析前に再刺激されなかったため、予想どおり明確なパターンが示されませんでした（図5C）。
エピジェネティック（RNAではない）レベルで主に示差的に制御される経路には、BCGワクチン接種と一致する「TB潜伏感染」、および「免疫応答」や「サイトカイン刺激への応答」などの一般的な免疫経路がありました。 （図S5A）
黄熱ウイルス血症に対する保護のエピジェネティックな相関関係を示しています。
IL-1β経路の遺伝子の遺伝的多型は、訓練された免疫応答を調節します。
黄熱ウイルス血症に対する防御の訓練された免疫相関としてのIL-1βの役割は、追加の遺伝学的および免疫学的検証研究によって裏付けられました。
まず、健康なボランティアの200FGコホートにおいて、BCG誘発訓練免疫サイトカイン応答に対するIL1Bの遺伝的変異の影響を調べました。（Li et al、2016）
驚くべきことに、BCGによって誘発された訓練された免疫を示すサイトカイン応答は、IL-1β（IL1B; rs16944）をコードする遺伝子のプロモーター領域にある既知の多型によって変調されました（図6A）。
rs16944のA対立遺伝子の2つのコピーの存在は、訓練された免疫応答に関連するサイトカイン産生の有意な障害と関連していました。
興味深いことに、in vitroの研究では、IL1B rs16944 A対立遺伝子がIL-1β産生の低下に関連していることが示されています。（Wen et al、2006、Wójtowiczet al、2015）
これらの調査結果に沿って、GG遺伝子型を受け継いだ個人と比較して、AA遺伝子型を持つ個人ではIL-1βのmRNA発現の低下を示しました（図S5B）。
BCG誘発訓練免疫におけるIL-1βの役割をさらにサポートするため、IL-1およびIL-18受容体とインフラマソームコンポーネントPYCARD / ASCをコードするいくつかの追加のIL-1ファミリー遺伝子の多型は、強い影響を示した訓練された免疫に関連するサイトカインの誘導について（図6B）。
対照的に、TNFαをコードする遺伝子の多型は、in vitroで訓練された免疫応答を調整せず、IL6の1つの多型のみが訓練に弱く影響することがわかりました。（データは示していません）
訓練された免疫応答の媒介におけるIL-1βの役割に関するさらなる洞察を得るために、次に、IL-1β自体が試験管内で訓練された免疫を誘導できるかどうかを評価しました。
以前に説明したトレーニング済み免疫のin vitroモデル（Bekkering et al、2016、Kleinnijenhuis et al、2012）を使用して、単球をIL-1β（1–10 ng / mL）でプライミングして24時間（図6C）生産を増強6日目のLPS再刺激時の炎症性サイトカインIL-6およびTNFαの変化をみました。（図6D）
またIL-1βまたはBCGでトレーニングされ、YFVで再刺激された単球によるIL-8産生の増強も観察しました。
IL-8のmRNA発現分析により、BCGとIL-1βの両方でトレーニングされた単球において、コントロールと比較してIL-8のアップレギュレーションが増強されていることが示されました。（図6E）
6日目にYFVで再刺激しても、IL-6やTNFαの産生には至りませんでした。（データ未掲載）
ヒストンメチルトランスフェラーゼ阻害剤MTA（5'-デオキシ-5'-メチルチオ-アデノシン）による前処理は、IL-1β誘発トレーニング免疫応答を無効にし、IL-1βのin vitroトレーニング効果がエピジェネティックなリプログラミングによって媒介されることを示唆しています単球（図6F）。
これは、TNFA、IL6、およびIL1βのプロモーター領域におけるIL-1β処理6日後のIL-1βを介したエピジェネティックな変化の誘導によって確認され、ヒストン3でのリジン4のトリメチル化が増加させた。（H3K4me3、図6G）遺伝子転写を増加させ、リプレッサーマークであるヒストン3（H3K9me3;図6H）でのリジン9のトリメチル化を減少させた。
IL-1βによって誘発されたH3K4me3の増加とH3K9me3の減少は、IL1Bのプロモーターで最も顕著でした。
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BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity
Rob J.W. Arts, Simone J.C.F.M. Moorlag, Boris Novakovic, Hendrik G. Stunnenberg, Reinout van Crevel, Mihai G. Netea, Show all authors, Show footnotes
DOI:https://doi.org/10.1016/j.chom.2017.12.010
https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(17)30546-2?fbclid=IwAR3SH9hPwGs_l3bt4VGkGpgCwmQX-2bXdLeaOTmNz4W_KqowPFqkije58ek
Highlights
Highlights
BCG vaccination of humans induces genome-wide epigenetic reprogramming in monocytes
BCG-induced changes correlate with protection against experimental virus infection
Viremia reduction correlates with IL-1β upregulation, indicative of trained immunity
SNPs in IL1B affect the induction of trained immunity by BCG
Summary
The tuberculosis vaccine bacillus Calmette-Guérin (BCG) has heterologous beneficial effects against non-related infections.
The basis of these effects has been poorly explored in humans. In a randomized placebo-controlled human challenge study, we found that BCG vaccination induced genome-wide epigenetic reprograming of monocytes and protected against experimental infection with an attenuated yellow fever virus vaccine strain.
Epigenetic reprogramming was accompanied by functional changes indicative of trained immunity.
Reduction of viremia was highly correlated with the upregulation of IL-1β, a heterologous cytokine associated with the induction of trained immunity, but not with the specific IFNγ response.
The importance of IL-1β for the induction of trained immunity was validated through genetic, epigenetic, and immunological studies. In conclusion, BCG induces epigenetic reprogramming in human monocytes in vivo, followed by functional reprogramming and protection against non-related viral infections, with a key role for IL-1β as a mediator of trained immunity responses.
Introduction
Bacillus Calmette-Guérin (BCG) is a live-attenuated vaccine strain of Mycobacterium bovis that protects against mycobacterial infections such as tuberculosis and leprosy and has now been used for almost a century (Colditz et al., 1994, Zumla et al., 2013). Interestingly, the BCG vaccine also has heterologous protective effects against non-related infections: several epidemiological studies have shown that vaccination at birth results in reduced child mortality (Hirve et al., 2012, Kristensen et al., 2000, Moulton et al., 2005, Roth et al., 2005).
These beneficial effects of BCG have been validated in randomized controlled trials, and the reduced mortality appeared to be mainly due to protection against neonatal sepsis and respiratory infections (Aaby et al., 2011, Biering-Sørensen et al., 2012, Roth et al., 2004).
BCG vaccination has been also shown to protect against mortality in murine experimental models of non-mycobacterial infections (summarized in Blok et al., 2015). Lastly, BCG is used as non-specific immunotherapy in cancer, with BCG installations in bladder cancer inducing immune-stimulating effects that slow tumor progression (Han and Pan, 2006).
Two types of immunological mechanisms have been suggested to mediate these effects.
First, CD4 and CD8 memory cells can be activated in an antigen-independent manner (e.g., by cytokines stimulated by a secondary infection), a process called heterologous immunity (Berg et al., 2002, Berg et al., 2003, Lertmemongkolchai et al., 2001, Mathurin et al., 2009).
Second, BCG vaccination induces histone modifications and epigenetic reprogramming of human monocytes at the promoter sites of genes encoding for inflammatory cytokines such as TNFA and IL6, resulting in a more active innate immune response upon restimulation, a process called trained immunity (Kleinnijenhuis et al., 2012, Netea et al., 2016).
However, the extent of the effects of BCG on histone modifications at a genome-wide level remains unknown.
Moreover, while the described epidemiological studies clearly suggest protective heterologous effects of BCG, controlled experimental studies in humans to establish the immunological basis for these observations remain outstanding, and the potential role of trained immunity in mediating these effects has not been assessed.
In this study, we examined the effects of BCG vaccination on genome-wide histone modifications induced in circulating monocytes by BCG vaccination.
Subsequently, we examined the functional changes induced by BCG in monocytes and examined how BCG vaccination impacts viral, serological, and immunological parameters after yellow fever vaccine (YFV) administration.
YFV is an attenuated viral strain that can be detected in the circulation after vaccination, thereby being an ideal model of experimental viral infection in humans.
We show that BCG vaccination reduces the level of YFV viremia after vaccination and that this effect correlates with induction of cytokine responses indicative of trained immunity, with a crucial role for IL-1β production and release.
Results
BCG Vaccination Induces Genome-wide Epigenetic Reprogramming of Human Monocytes In Vivo
BCG Vaccination Induces Genome-wide Epigenetic Reprogramming of Human Monocytes In Vivo
In vitro experiments have previously shown that the increased cytokine responses after monocyte training with BCG are the result of epigenetic changes (Arts et al., 2015).
In order to examine the genome-wide rewiring of the epigenetic program by BCG, monocytes from seven donors were analyzed by chromatin immunoprecipitation sequencing (ChIP-seq) to determine genome-wide changes in the distribution of histone H3 acetylation at lysine 27 (H3K27ac), a marker of active promoters and enhancers, at “baseline” (before BCG vaccination, day −28) and “BCG 1 month” (1 month after BCG vaccination, day 0).
Correlation plots of whole-genome H3K27ac sequencing reads showed a clear separation of the baseline and BCG samples, especially when analysis was limited to peaks that were highly induced (> 3 SD) in at least one donor or with a statistical significant fold change of at least 1.5 (Figures 1A and S1A).
The heatmap clearly shows the separation of baseline and post-BCG samples according to 646 differential H3K27ac peaks (Figure 1B).
A similar effect was seen when analysis was restricted to peaks related to promoters (Figures S1B and S1C).
Finally, pathway analysis including genes near the 646 differential peaks showed differential regulation of several important signaling- and inflammatory-related pathways (Figure 1C; Tables S2 and S3).
Figure 1BCG Vaccination Induced Genome-wide H3K27ac Changes in Monocytes
(A–D) Monocytes from seven donors were analyzed by ChIP-seq to determine the distribution of H3K27ac at “baseline” (before BCG vaccination, −28d) and “BCG 1 month” (1 month after BCG vaccination, 0d).
(A) Spearman’s correlation plot showing the relationship between the different donors and exposures, based on sequencing reads at (1) all H3K27ac peaks, (2) peaks dynamic in at least one donor after BCG exposure, and (3) peaks dynamic between the baseline and BCG 1 month groups (p < 0.05, FC > 1.5). Based on all H3K27ac peaks, we observe mixing of the baseline and BCG samples, which suggests little global change in H3K27ac in response to BCG. However, based on significantly different peaks (2, 3), clear separation between baseline and BCG-exposed monocytes can be observed.
(B) Heatmap of 646 peaks showing differences between baseline and BCG-exposed groups; most of these changes are increased H3K27ac signal in BCG-exposed monocytes.
(C) Top pathways associated with genes near the 646 differential peaks and names of genes associated with inflammation and cytokine signaling.
(D) Genes involved in the FcɛRI signaling pathway. The heatmap shows the H3K27ac relative signal before and 1 month after BCG vaccination. The genomic locations are named by their closest gene and the distance in base pairs (bp). The spiderweb plot shows the same genes with the corresponding reads per peak (n = 7).
Most changes induced by BCG vaccination in promoter regions involve G protein-coupled receptors and protein kinases, indicating the extensive effect of BCG on remodeling signal transduction molecules (Table S3).
Accordingly, BCG induces increased H3K27ac in several important signaling pathways, including the PI3K/AKT (phosphatidylinositol 3-kinase) pathway, epidermal growth factor receptor (EGFR), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) signaling pathways (Table S3) (upregulated genes involved in these pathways can be found in Table S4).
Interestingly, genes such as AKT1, MAPKs, and PI3K-related genes that have been shown to be major regulators in β-glucan-induced trained immunity appear to be also important in BCG-induced trained immunity (Cheng et al., 2014, Saeed et al., 2014) (Figure 1D; Table S4).
Genes directly involved in the inflammatory response and cytokine production also showed increased H3K27ac upon BCG vaccination.
Intriguingly, the receptor of oxidized low-density lipoprotein (oxLDL), OLR1, a marker of atherosclerosis, previously shown to induce a long-term pro-inflammatory phenotype in monocytes (Bekkering et al., 2014), was also differentially regulated upon BCG vaccination (Table S3).
RNA sequencing has also been performed on the same samples, but as expected and as shown before (Novakovic et al., 2016, Saeed et al., 2014), no major differences were found. This shows that trained monocytes are epigenetically primed to respond (transcriptionally) differently to a secondary stimulus (e.g., ex vivo stimulation), but that in resting state they do not display a changed transcriptional program.
Epigenetic Reprogramming Is Accompanied by Functional Changes
Epigenetic Reprogramming Is Accompanied by Functional Changes
In line with our previous finding of BCG-induced functional changes in monocytes (Arts et al., 2016, Cheng et al., 2016), we demonstrate that genes involved in the PI3K/AKT/mTOR pathway are already marked at epigenetic level.
This pathway has a crucial role for the increased cytokine production capacity during induction of trained immunity (Arts et al., 2016, Cheng et al., 2016), and these epigenetic changes upon BCG vaccination were indeed accompanied by enhanced ex vivo cytokine responses to unrelated pathogens, as shown by increased cytokine production capacity 1 month after BCG vaccination (Figures 2A, 2B , and S2), which was not the result of differences in monocyte subpopulations or total monocyte number (Figure S3A).
Heterologous T cell responses were moderately increased after BCG vaccination (Figure S2). Induction of monocyte-derived cytokine production (used here as a readout of trained immunity) varied between individuals, with unsupervised cluster analysis of increased cytokine production 1 month after BCG vaccination clearly showing a cluster of innate cytokines and a second cluster of T helper 1/Th17 lymphocyte cytokines. Within the innate cytokine cluster, the induction of IL-1β and IL-6 production was highly correlated (Figure 2C).
Figure 2BCG Induces Trained Immunity In Vivo
(A) Healthy volunteers randomly received BCG or placebo vaccination. Before vaccination and 1 month later, blood was drawn and PBMCs were isolated and restimulated ex vivo.
(B) Fold increases (compared to baseline) of IL-1β, TNFα, and IL-6 production to LPS, M. tuberculosis (MTB), and C. albicans are shown (mean ± SEM, n = 15 per group, ∗p < 0.05 BCG versus placebo, #p < 0.01 mean versus 1, ##p < 0.01 mean versus 1, fold increase baseline versus 1 month, Mann-Whitney U test).
(C) Unsupervised clustering analysis performed on Spearman’s correlations of fold induction of cytokines as presented in (B). IL-1β, TNFα, IL-6, and IL10 were determined after 24 hr and IL-17, IL-22, and IFNγ after 7 day ex vivoincubation with LPS, M. tuberculosis (MTB), S. aureus, or C. albicans.
BCG Vaccination Lowers Yellow Fever Viremia
BCG Vaccination Lowers Yellow Fever Viremia
To examine the clinical significance of the observed epigenetic and functional effects of BCG, we used the live-attenuated YFV as a model for a viral human infection.
YFV viremia, determined by RT-PCR, peaked on day 5 after vaccination, as previously reported by others (Edupuganti et al., 2013) (Figures 3A, 3B , and S3B).
Subjects who had been BCG vaccinated 1 month prior to yellow fever vaccination showed significantly lower viremia compared to subjects who had received placebo vaccination (Figure 3B, higher CT values, thus lower viremia, for BCG-vaccinated volunteers).
Lower circulating virus concentrations in BCG-vaccinated volunteers were also reflected by lower concentration of circulating cytokines (Figure 3C).
Circulating IL-1β concentrations before and after vaccination were below detection limit. Importantly, when yellow fever-neutralizing antibodies were measured at 3 months post-vaccination, no significant differences were found between the two groups (Figure 3D), suggesting that BCG vaccination has minor impact on humoral responses to yellow fever vaccination, despite the diminished viremia. In addition, BCG vaccination did not change the specific cellular response to YFV as measured by IFNγ production by PBMCs (Figure S3C).
Figure 3BCG Vaccination Lowers Yellow Fever Vaccine Viremia
(A) Post-vaccination viremia was determined by PCR 3, 5, and 7 days after YFV.
(B) Viremia at day 5 post-infection. CT values and corresponding calculated relative viremia (CT 40 is set as 1, by the formula Relative Viremia = 2 ˆ (40 − Ctvalue)) are shown (mean ± SEM, n = 15 per group, ∗p < 0.05, Mann-Whitney U test).
(C) Circulating cytokines were determined 5 days post-vaccination in plasma. IL-1β and IL-10 were below detection limit in almost all samples (mean ± SEM, n = 15 per group, ∗p < 0.05, ∗∗p < 0.01, Mann-Whitney U test).
(D) Yellow fever-neutralizing antibodies were determined 90 days after yellow fever vaccination.
Non-specific IL-1β Production Increase after BCG Vaccination Is a Correlate of Protection against Yellow Fever Viremia
Non-specific IL-1β Production Increase after BCG Vaccination Is a Correlate of Protection against Yellow Fever Viremia
We next determined whether the induction of ex vivo cytokine responses associated with trained immunity, as noted earlier, correlated with yellow fever viremia.
Post-vaccination increases in TNFα and IL-6 production did not correlate with viremia (Figures 4A and S4A).
In contrast, increased IL-1β production capacity after BCG vaccination strongly predicted lower viremia after subsequent yellow fever infection (Figures 4A and 4B).
Among the other cytokines, induction of IL-10 upon stimulation with Candida albicans also displayed a negative correlation with viremia (Figures 4A, 4B, and S4A).
Interestingly, viremia did not correlate with induction of specific cellular responses to YFV by BCG as measured by IFNγ production by PBMCs (Figures 4C and S4B).
In addition, no correlation was found between viremia and concentrations of the Th17 cytokines IL-17 and IL-22 (Figure S4A).
This is remarkable, as we and others have found an induction of CD8+ and polyfunctional CD4+ responses after BCG vaccination (Figure S2) (Boer et al., 2015, Kleinnijenhuis et al., 2012).
Concentrations of yellow fever-neutralizing antibody titers also did not correlate with induction of cytokines (neither innate nor adaptive) (Figure 4D).
Figure 4Induction of IL-1β Negatively Correlates with Yellow Fever Viremia
(A) Fold induction of cytokine production 1 month after BCG vaccination (as shown in Figure 2B) compared with yellow fever viremia at day 5 post-vaccination (as shown in Figure 3B). Spearman’s correlation coefficients and their p values are shown in two separate matrices. Induction of IL-1β shows high correlations with suppression of yellow fever viremia for all stimuli used.
(B) An example is shown of fold increase (a month after BCG vaccination) of IL-1β by C. albicans stimulation, which correlated with yellow fever viremia (CT values, high CT value corresponds with low levels of viremia).
(C) On the other hand, induction of IFNγ production did not correlate with yellow fever viremia suppression. Even IFNγ production to YFV stimulation did not correlate.
(D) Fold induction of cytokine production 1 month after BCG vaccination (as shown in Figure 1B) for IL-1β and IFNγ compared with yellow fever antibody titer 90 days post-vaccination (as shown in Figure 3D). Spearman’s correlation coefficients and their p values are shown (n = 15 per group).
All correlations with other cytokines can be found in Figure S4.
Epigenetic Differences Influence Yellow Fever Viremia
Epigenetic Differences Influence Yellow Fever Viremia
Apart from the correlation with cytokine induction, correlation of epigenetic changes induced by BCG and yellow fever viremia were also determined. In order to do so, volunteers presented in Figure 1 were divided into a group of responders to BCG vaccination (R, maximum yellow fever viremia CT > 36) and non-responders (NR, CT < 36).
Pre-existing H3K27Ac epigenetic differences (at baseline, before BCG vaccination) at the gene region level were determined between R and NR, and we identified important differences between these two groups of volunteers, suggestive of the pathways important for the post-vaccination response.
Interestingly, the top-ranked genomic region in this analysis was 7.6 kb upstream of the gene coding for NOD2 (FC = 6.3, adjusted p value = 2.42 × 10−8), the innate immune receptor recognizing muramyl dipeptide: an earlier study demonstrated that monocytes isolated from individuals with NOD2 mutations leading to a defective receptor cannot be trained in vitro with BCG (Arts et al., 2015, Kleinnijenhuis et al., 2012) (Figures 5A and 5B ).
Figure 5H3K27ac Whole-Genome Analysis of Monocytes between Responders and Non-Responders
(A–C) Monocytes from seven donors were analyzed by ChIP-seq to determine the distribution of H3K27ac at “baseline” (before BCG vaccination, −28d) and “BCG 1 month” (1 month after BCG vaccination, 0d). Based on yellow fever viremia, BCG responders (R) and BCG non-responders (NR) were defined, respectively, by yellow fever CT values above or below 36.
(A) Peaks dynamic between the BCG responders (R) and non-responders (p adjusted < 0.05, FC > 1.5) were defined and named after their closest gene (gene name, number of base pairs distance from gene).
(B) Track of the H3K27ac peaks near the NOD gene.
(C) RNA sequencing (right panel) and H3K27ac peak analysis (left panel, p < 0.05, FC > 1.5) are shown between responders and non-responders. GO term analysis is shown in the table. Pathway analysis of these genes can be found in Figure S5A.
Furthermore, pathway analysis of H3K27ac profiles between R and NR reveals several interesting results.
Once more, RNA-seq analysis did not show a clear pattern, as expected, as cells were not re-stimulated prior to analysis (Figure 5C).
Among the main differentially regulated pathways at the epigenetic (but not RNA) level was “TB latent infection,” which is in line with the BCG vaccination, as well as general immunological pathways such as “Immune Response” and “Response to Cytokine Stimulus” (Figure S5A), showing the epigenetic correlates of protection to yellow fever viremia.
Genetic Polymorphisms in Genes of IL-1β Pathway Modulate Trained Immunity Response
Genetic Polymorphisms in Genes of IL-1β Pathway Modulate Trained Immunity Response
The role of IL-1β as a trained immunity correlate of protection against yellow fever viremia was supported by additional genetic and immunological validation studies.
First, we examined the effect of genetic variations in IL1B on BCG-induced trained immunity cytokine responses in the 200FG cohort of healthy volunteers (Li et al., 2016).
Strikingly, the cytokine responses indicative of trained immunity that were induced by BCG were modulated by a known polymorphism located in the promoter region of the gene encoding IL-1β (IL1B; rs16944) (Figure 6A).
The presence of two copies of the A allele of rs16944 was associated with significantly impaired cytokine production associated with trained immunity responses.
Interestingly, in vitro studies have shown that the IL1B rs16944 A allele is associated with decreased IL-1β production (Wen et al., 2006, Wójtowicz et al., 2015).
In line with these findings, we demonstrated reduced mRNA expression of IL-1β in individuals having the AA genotype compared to individuals who inherited the GG genotype (Figure S5B).
As further support for the role for IL-1β in BCG-induced trained immunity, polymorphisms in several additional IL-1 family genes, encoding IL-1 and IL-18 receptors as well as the inflammasome component PYCARD/ASC, showed a strong impact on the induction of cytokines associated with trained immunity (Figure 6B).
In contrast, polymorphisms in the gene encoding TNFα did not modulate in vitro trained immunity responses, and only one polymorphism in IL6 was found to weakly affect training (data not shown).
Figure 6The Role of IL-1β for Trained Immunity
(A) Genetic variations in IL-1β were assessed in DNA samples from 98 healthy volunteers from the 200FG cohort by a genome-wide Illumina Infinium SNP array. Monocytes were isolated and stimulated in vitro with culture medium (negative control) or BCG (10 μg/mL) for 24 hr. On day 6, cells were restimulated with culture medium or LPS (10 ng/mL). After 24 hr, supernatants were taken and cytokine concentrations were assessed using ELISA. Medium-restimulated cells did not produce detectible cytokine production. A SNP in IL-1β (IL1B; rs16944) was found to affect the trained immunity response induced by BCG (mean ± SEM, ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001, Mann-Whitney U test).
(B) Additional genetic analysis in genes of the IL-1 pathway identify polymorphisms in the IL-1 and IL-18 receptors, as well as the inflammasome component PYCARD/ASC, that significantly modulate BCG-induced trained immunity.
(C) Schematic outline of the in vitro training experiments. Human monocytes were primed for 24 hr with culture medium or different concentrations of IL-1β. On day 6, cells were restimulated for 24 hr with LPS, and levels of IL-6 and TNFα were assessed (mean ± SEM, n = 7, ∗p < 0.05).
(D) Human monocytes were primed for 24 hr with culture medium or different concentrations of IL-1β. On day 6, cells were restimulated for 24 hr with LPS, and levels of IL-6 and TNFα were assessed (mean ± SEM, n = 7, ∗p < 0.05).
(E) Human monocytes were incubated with either culture medium, IL-1β (10 ng/mL), or BCG (5 μg/mL). At day 6, cells were restimulated with YFV (1,000 IU/mL). Concentrations of IL-8 in the supernatants were measured after 24 hr (mean ± SEM, n = 6), and mRNA expression of IL-8 was determined after 4 hr restimulation (mean ± SEM, n = 3 in duplo, ∗p < 0.05, Wilcoxon signed-rank test).
(F) Monocytes were stimulated for 24 hr with culture medium or IL-1β (100 ng/mL) in the presence or absence of MTA (1 mM). On day 6, after restimulation with LPS for 24 hr, IL-6 and TNFα were measured in the supernatants (mean ± SEM, n = 7, ∗p < 0.05, Wilcoxon signed-rank test).
(G and H) Human monocytes were stimulated for 24 hr with culture medium or IL-1β (100 ng/mL). Chromatin was fixated on day 6 and ChIP-qPCR was performed. H3K4me3 and H3K9me3 were determined at promoters of IL6, TNFA, and IL1B (mean ± SEM, n = 8, ∗p < 0.05, Wilcoxon signed-rank test).
Epigenetic Changes Mediate IL-1β-Induced Trained Immunity
Epigenetic Changes Mediate IL-1β-Induced Trained Immunity
To obtain further insight into the role of IL-1β in mediating trained immunity responses, we next assessed whether IL-1β itself can induce trained immunity in vitro.
Using the previously described in vitro model of trained immunity (Bekkering et al., 2016, Kleinnijenhuis et al., 2012), priming of monocytes with IL-1β (1–10 ng/mL) for 24 hr (Figure 6C) enhanced production of the pro-inflammatory cytokines IL-6 and TNFα upon LPS restimulation on day 6 (Figure 6D).
We also observed enhanced IL-8 production by monocytes that were trained with IL-1β or BCG and were restimulated with YFV.
mRNA expression analysis of IL-8 demonstrated an enhanced upregulation of IL-8 in both BCG and IL-1β trained monocytes compared to control (Figure 6E).
Restimulation with YFV on day 6 did not lead to IL-6 or TNFα production (data not shown).
Pre-treatment with the histone methyltransferase inhibitor MTA (5′- deoxy-5′-methylthio-adenosine) abrogated the IL-1β-induced trained immunity response, suggesting that the in vitro training effect of IL-1β is mediated via epigenetic reprogramming of monocytes (Figure 6F).
This was confirmed by IL-1β-mediated induction of epigenetic changes 6 days after IL-1β treatment in promoter regions of TNFA, IL6, and IL1B, with increased trimethylation of lysine 4 at histone 3 (H3K4me3; Figure 6G), a marker of increased gene transcription, and reduced trimethylation of lysine 9 at histone 3 (H3K9me3; Figure 6H), a repressor mark.
The increase of H3K4me3 and the decrease of H3K9me3 induced by IL-1β was most pronounced at the promoter of IL1B.
Discussion
Recent studies demonstrated that functional adaptation of innate immune cells after an infection or vaccination, which is induced through epigenetic reprogramming, is responsible for a de facto innate immune memory, also termed trained immunity (Netea et al., 2016).
BCG vaccination has long been known to be accompanied by lower mortality in vaccinated children, an effect that cannot be fully ascribed to protection against tuberculosis, but that is probably due to protection against neonatal sepsis and respiratory tract infections.
Although it has been reported that this heterologous protection is due at least in part to induction of trained immunity (Kleinnijenhuis et al., 2012), no comprehensive assessment of the epigenetic programs induced by BCG has been done until now.
Also, evidence for protective effects of BCG-induced trained immunity on unrelated infections in humans is outstanding.
In this study, we describe the epigenetic changes induced at a genome scale by BCG in human monocytes.
We chose to study the H3K27ac histone mark because it is associated with an “active” chromatin state at both gene promoters and enhancers.
Moreover, we previously showed a strong correlation between H3K27ac and H3K4me3 changes during trained immunity, with H3K27ac being the most dynamic mark (Saeed et al., 2014).
Among the genes displaying increased H3K27ac, we identified enrichment in genes encoding for proteins involved in cellular signaling as well as inflammation: cytokines and chemokines, the EGFR and VEGF pathways.
In addition, the PI3K/AKT pathway is also shown to be upregulated, and this is supported by the recent studies demonstrating its involvement in the induction of trained immunity by both BCG and β-glucan (Arts et al., 2016, Cheng et al., 2014).
The epigenetic profile induced by BCG shows close similarities to the trained immunity induced by β-glucan in vitro (Saeed et al., 2014), suggesting there is a core trained immunity response induced by different stimuli.
The epigenetic reprogramming of monocytes induced by BCG vaccination is accompanied by significantly altered responses of innate immune cells.
This process is clearly illustrated here by higher pro-inflammatory cytokine production (TNFα, IL-1β, IL-6) of PBMCs from BCG-vaccinated volunteers, compared to placebo-treated individuals.
We have in this case opted for PBMC stimulation (and not highly purified monocytes) to mimic as closely as possible the in vivo clinical situation.
In addition, while the epigenetic changes observed in highly purified monocytes are indicative of the induction of trained immunity programs by BCG vaccination, the functional consequences measured in PBMCs may be also influenced by the presence of lymphocytes.
Differences in cytokine production after BCG vaccination were seen in earlier studies both in children (Jensen et al., 2015) and in adults (Kleinnijenhuis et al., 2012).
The amplitude of the cytokine responses indicative of trained immunity induction in the current study is somewhat less strong compared to previous studies, probably due to BCG batch differences (Biering-Sørensen et al., 2015).
Unequivocally, demonstration of a correlation between the induction of trained immunity and protection against a controlled infection in humans has been outstanding.
Our proof-of-principle study showed that BCG vaccination protects against a subsequent, non-related viral infection in a human controlled model of YFV infection.
This model has the advantage of the use of a live virus, which has no deleterious effects on the host and which can be quantitatively monitored by PCR.
The demonstration of a significantly lower peak of viremia in BCG-vaccinated individuals compared to individuals injected with placebo clearly demonstrates the capacity of BCG to protect against non-related infections in humans.
The lower viremia was also accompanied by lower circulating inflammatory mediators in the BCG-vaccinated individuals.
This result is expected, as the high cytokine production capacity upon BCG vaccination will lead to a rapid local antimicrobial response and subsequent elimination of the pathogen, thereby preventing a systemic reaction and high levels of circulating cytokines (Netea et al., 2003, van der Poll et al., 2017).
Importantly, despite the lower virus load, BCG vaccination did not affect generation of protective anti-yellow fever antibodies and did not affect the specific effect of YFV.
This suggests that BCG might improve the antigen-presenting capacity and adaptive responses, in line with a study showing beneficial effects on the response to influenza vaccine (Leentjens et al., 2015).
The observed effects that are indicative of trained immunity induction are clinically very relevant, as epidemiological studies have shown that BCG vaccination results in lower all-cause mortality in the first month after birth (Aaby et al., 2011, Roth et al., 2004).
However, long-term studies with broader analysis of monocyte function are warranted in order to determine the duration of the BCG effect.
Importantly, significant differences in epigenetic markers were apparent on monocytes from BCG responders (with low yellow fever viremia) and BCG non-responders (with higher viremia).
H3K27ac at the level of the NOD2 receptor (which is essential for the induction of BCG-induced trained immunity [Kleinnijenhuis et al., 2012]) correlated best with response to BCG.
Additional immune pathways related to cytokine production and innate immune responses were shown to be of importance.
One of the most remarkable observations was made when the correlates of protection against viremia were investigated.
It was previously suggested that development of a scar after BCG vaccination could be used as a marker for non-specific effects and childhood survival (Garly et al., 2003, Roth et al., 2005).
However, all BCG-vaccinated volunteers developed a scar with a comparable size (0.5–0.7 cm), and we observed no correlation of this with protection.
In addition, the fold change of heterologous T cell responses (IFNγ, IL-17, and IL-22 production) upon BCG vaccination did not show any correlation with the YFV viremia.
In contrast, the post-BCG fold increase of IL-1β production strongly correlated with lower viremia after YFV administration, while production of other monocyte-derived cytokines showed less correlation.
This suggests that induction of IL-1β production stimulated by non-related pathogens, which is an indicator of trained immunity responses, rather than adaptive cellular responses as assessed by IFNγ production induced by specific stimuli, is responsible for the protection induced by BCG against the viral infection.
The fact that the increase in the capacity of innate immune cells to release IL-1β is the stronger correlate of protection suggests that this cytokine is a crucial component of trained immunity.
This finding is highly relevant due to the direct protective effect of higher IL-1β levels in viral infections (Azuma et al., 1992, Iida et al., 1989, Sergerie et al., 2007), although other mechanisms are possible as well.
The role of IL-1β is supported by complementary genetic and immunological studies.
By studying in vitro training of monocytes induced by BCG in cells isolated from healthy volunteers of the 200FG cohort (Li et al., 2016), we demonstrate that genetic polymorphisms in the gene encoding for IL-1β, but also other genes of the IL-1 pathway such as the inflammasome component ASC/PYCARD and genes encoding for the IL-1 and IL-18 receptors, are associated with the magnitude of the individual trained immunity response induced by BCG.
In follow-up experiments, we found that IL-1β itself can induce trained immunity, and that this effect is accompanied by epigenetic changes at the level of histone methylation (H3K4me3 and H3K9me3).
This may explain earlier studies that have shown that administration of one dose of IL-1β to mice before infection can protect against lethal bacterial and fungal sepsis (van der Meer et al., 1988).
In addition, IL-1β is well known to exert strong effects on myelopoiesis (Dinarello, 2002), and one may hypothesize that IL-1β represents the endogenous mediator between the peripheral stimulation of monocytes and macrophages by BCG and long-term functional reprogramming at the level of bone marrow progenitors.
Indeed, accompanying studies from the International Trained Immunity Consortium (INTRIM) in an upcoming issue of Cell demonstrate that effects at the level of myeloid cell progenitors are crucial for the induction of trained immunity by β-glucan (Mitroulis et al., 2018), BCG (Kaufmann et al., 2018), and Western-type diet (Christ et al., 2018) and identify IL-1β and the inflammasome pathway as key mediators of this process (Mitroulis et al., 2018, Christ et al., 2018).
Mitroulis et al. show that the adaptations in hematopoietic stem and progenitor cells (HSPCs) are associated with an increase in IL-1β (and not other cytokines) in the bone marrow fluid, while inhibition of IL-1β prevented the β-glucan-dependent expansion of HSPCs and the effects on myeloid cell progenitors. Similarly, Christ et al. demonstrate that a Western-type diet is able to induce trained immunity in mice, and IL-1 plays an important role in this effect.
Thus, Western-type diet did not induce trained immunity and myeloid progenitor reprogramming in NLRP3 knockout mice that have defects in IL-1β processing.
Similarly, genetic analysis revealed that polymorphisms in NLRP3 influenced oxLDL-induced trained immunity in human cells.
As dysregulated IL-1β production plays a pivotal role in the etiology of many autoinflammatory diseases, the capacity of IL-1β to induce trained immunity may represent a central event in the pathophysiology of these disorders.
This needs further investigation, as it may represent a therapeutic target for these diseases. Indeed, the accompanying study by Bekkering et al. of the INTRIM Consortium shows a dysregulated trained immunity phenotype in monocytes isolated from patients with hyper IgD syndrome (Bekkering et al., 2018), a well-known autoinflammatory syndrome.
In conclusion, in the present study we report the broad epigenetic program induced by BCG vaccination in humans, which results in increased activation of circulating monocytes. Furthermore, we show that BCG vaccination can protect against a non-related viral infection in an experimental model of human infection and report that IL-1β-mediated responses, which are indicative of the induction of trained immunity, are the most reliable correlate of this protection.
Additional genetic and immunological validation studies demonstrate that IL-1 pathway is crucial for an efficient induction of trained immunity in humans, and this may have important implications for both vaccination and the pathophysiology of autoinflammatory diseases.
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MaxPlanck研究所でも治験が行われるようです。
数ヶ月後には結果が分かるかも知れません。
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COVID-19は世界のほとんどの国に広がっています。
不可思議なことに、この病気の影響は国によって異なります。
これらの違いは、文化的規範、緩和努力、および健康インフラストラクチャの違いに起因しています。
ここでは、COVID-19の影響における国別の違いは、カルメットゲラン菌（BCG）の小児期のワクチン接種に関するさまざまな国の政策によって部分的に説明できると提案します。
BCGワクチン接種は、呼吸器感染症に対して幅広い保護を提供すると報告されています。
多くの国のBCGワクチン接種政策を、COVID-19の罹患率と死亡率と比較しました。
BCGワクチン接種の普遍的な政策がない国（イタリア、オランダ、米国）は、普遍的かつ長期にわたるBCG政策を持つ国と比較して、深刻な影響を受けていることがわかりました。
普遍的なBCG政策の開始が遅い国（イランは1984年開始）は死亡率が高く、BCGが予防接種を受けた高齢者を保護するという考えと一致しています。
また、BCGワクチン接種により、国で報告されたCOVID-19の症例数も減少したこともわかりました。
罹患率と死亡率の低下の組み合わせにより、BCGワクチン接種はCOVID-19との戦いにおける潜在的な新しいツールになります。
Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study
Aaron Miller, Mac Josh Reandelar, Kimberly Fasciglione, Violeta Roumenova, Yan Li, Gonzalo H Otazu
doi: https://doi.org/10.1101/2020.03.24.20042937
This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
COVID-19 has spread to most countries in the world. Puzzlingly, the impact of the disease is different in different countries.
These differences are attributed to differences in cultural norms, mitigation efforts, and health infrastructure.
Here we propose that national differences in COVID-19 impact could be partially explained by the different national policies respect to Bacillus Calmette-Guerin (BCG) childhood vaccination.
BCG vaccination has been reported to offer broad protection to respiratory infections.
We compared large number of countries BCG vaccination policies with the morbidity and mortality for COVID-19.
We found that countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies.
Countries that have a late start of universal BCG policy (Iran, 1984) had high mortality, consistent with the idea that BCG protects the vaccinated elderly population.
We also found that BCG vaccination also reduced the number of reported COVID-19 cases in a country.
The combination of reduced morbidity and mortality makes BCG vaccination a potential new tool in the fight against COVID-19.
Can a century-old TB vaccine steel the immune system against the new coronavirus?
Can a century-old TB vaccine steel the immune system against the new coronavirus?
By Jop de VriezeMar. 23, 2020 , 6:25 AM
Researchers in four countries will soon start a clinical trial of an unorthodox approach to the new coronavirus.
They will test whether a century-old vaccine against tuberculosis (TB), a bacterial disease, can rev up the human immune system in a broad way, allowing it to better fight the virus that causes coronavirus disease 2019 and, perhaps, prevent infection with it altogether.
The studies will be done in physicians and nurses, who are at higher risk of becoming infected with the respiratory disease than the general population, and in the elderly, who are at higher risk of serious illness if they become infected.
A team in the Netherlands will kick off the first of the trials this week.
They will recruit 1000 health care workers in eight Dutch hospitals who will either receive the vaccine, called bacillus Calmette-Guérin (BCG), or a placebo.
BCG contains a live, weakened strain of Mycobacterium bovis, a cousin of M. tuberculosis, the microbe that causes TB. (The vaccine is named after French microbiologists Albert Calmette and Camille Guérin, who developed it in the early 20th century.)
The vaccine is given to children in their first year of life in most countries of the world, and is safe and cheap—but far from perfect:
It prevents about 60% of TB cases in children on average, with large differences between countries.
Vaccines generally raise immune responses specific to a targeted pathogen, such as antibodies that bind and neutralize one type of virus but not others.
But BCG may also increase the ability of the immune system to fight off pathogens other than the TB bacterium, according to clinical and observational studies published over several decades by Danish researchers Peter Aaby and Christine Stabell Benn, who live and work in Guinea-Bissau.
They concluded the vaccine prevents about 30% of infections with any known pathogen, including viruses, in the first year after it’s given.
The studies published in this field have been criticized for their methodology, however; a 2014 review ordered by the World Health Organization concluded that BCG appeared to lower overall mortality in children, but rated confidence in the findings as “very low.”
A 2016 review was a bit more positive about BCG’s potential benefits but said randomized trials were needed.
Since then, the clinical evidence has strengthened and several groups have made important steps investigating how BCG may generally boost the immune system.
Mihai Netea, an infectious disease specialist at Radboud University Medical Center, discovered that the vaccine may defy textbook knowledge of how immunity works.
When a pathogen enters the body, white blood cells of the “innate” arm of the immune system attack it first; they may handle up to 99% of infections.
If these cells fail, they call in the “adaptive” immune system, and T cells and antibody-producing B cells start to divide to join the fight.
Key to this is that certain T cells or antibodies are specific to the pathogen; their presence is amplified the most.
Once the pathogen is eliminated, a small portion of these pathogen-specific cells transform into memory cells that speed up T cell and B cell production the next time the same pathogen attacks.
Vaccines are based on this mechanism of immunity.
The innate immune system, composed of white blood cells such as macrophages, natural killer cells, and neutrophils, was supposed to have no such memory.
But Netea’s team discovered that BCG, which can remain alive in the human skin for up to several months, triggers not only Mycobacterium-specific memory B and T cells, but also stimulates the innate blood cells for a prolonged period.
“Trained immunity,” Netea and colleagues call it. In a randomized placebo-controlled study published in 2018, the team showed that BCG vaccination protects against experimental infection with a weakened form of the yellow fever virus, which is used as a vaccine.
Together with Evangelos Giamarellos from the University of Athens, Netea has set up a study in Greece to see whether BCG can increase resistance to infections overall in elderly people.
He is planning to start a similar study in the Netherlands soon.
The trial was designed before the new coronavirus emerged, but the pandemic may reveal BCG’s broad effects more clearly, Netea says.
For the health care worker study, Neeta teamed up with epidemiologist and microbiologist Marc Bonten of UMC Utrecht. “There is a lot of enthusiasm to participate,” among the workers, Bonten says.
The team decided not to use actual infection with coronavirus as the study outcome, but “unplanned absenteeism.”
“We don’t have a large budget and it won’t be feasible to visit the sick professionals at home,” Bonten says.
Looking at absenteeism has the advantage that any beneficial effects of the BCG vaccine on influenza and other infections may be captured as well, he says.
Although the study is randomized, participants will likely know if they got the vaccine instead of a placebo.
BCG often causes a pustule at the injection site that may persist for months, usually resulting in a scar.
But the researchers will be blinded to which arm of the study—vaccine or placebo—a person is in.
A research group at the University of Melbourne is setting up a BCG study among health care workers using the exact same protocol. Another research group at the University of Exeter will do a similar study in the elderly.
And a team at the Max Planck Institute for Infection Biology last week announced that—inspired by Netea’s work—it will embark on a similar trial in elderly people and health workers with VPM1002, a genetically modified version of BCG that has not yet been approved for use against TB.
Eleanor Fish, an immunologist at the of the University of Toronto, says the vaccine probably won’t eliminate infections with the new coronavirus completely, but is likely to dampen its impact on individuals. Fish says she’d take the vaccine herself if she could get a hold of it, and even wonders whether it’s ethical to withhold its potential benefits from trial subjects in the placebo arm.
But Netea says the randomized design is critical:
“Otherwise we would never know if this is good for people.”
The team may have answers within a few months.
doi:10.1126/science.abb8297
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（※管理者注：BCGは感染を予防するが、死亡率にはそれほど影響しない。）
藤田保健衛生大学の宮川先生とイタリアのGiovanni先生の研究です。
BCGが関連のない感染症に対して非特異的な有益な効果をもたらすという証拠がいくつかあります。
ここでは、199の国/地域とBCG World Atlasで公開されているCOVID-19の公開データを使用して、COVID-19によるBCGワクチン接種と有病率および死亡率との関連性を検討しました。
線形回帰モデリングを使用することにより、人口100万人あたりの総症例数と死亡数は、BCGワクチン投与に関する国の方針に大きく関連していることがわかりました。
BCGワクチン接種方針によって説明される症例と死亡の差異の量は、12.5％から38％の範囲でした。
重要なことに、この効果は、国の平均余命と2020年2月と3月の平均気温を補正した後も有意であり、それらはそれぞれ症例数と死亡指数と有意に相関しています。
対照的に、死亡と症例の比率は弱く影響を受けました。
この後者の結果は、BCGワクチン接種が死亡率（すなわち、死亡/症例比）を低下させるのではなく、ウイルスの全体的な拡散または疾患の進行を妨げている可能性があることを示唆しています。
最後に、国をケースの高、中、または低の成長率を示す3つのカテゴリに大まかに分類することにより、BCGグループ間で勾配カテゴリ間に非常に有意な差が見られ、ウイルスの広がりが始まってからの時間が主要な交絡因子ではありませんでした。
この研究は、多くの未知の交絡因子に潜在的に苦しんでいるが、これらの団体は、BCGワクチン接種がSARS-CoV-2に対する保護を提供する可能性があるという考えを支持します。
Association of BCG vaccination policy with prevalence and mortality of COVID-19
Association of BCG vaccination policy with prevalence and mortality of COVID-19
Giovanni Sala, Tsuyoshi Miyakawa
doi: https://doi.org/10.1101/2020.03.30.20048165
This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.
Abstract
Abstract
There is some evidence that tuberculosis vaccine bacillus Calmette-Guérin (BCG) has non-specific beneficial effects against non-related infections. Here, we examined the possible association between BCG vaccination with prevalence and mortality by COVID-19 by using publicly available data of COVID-19 in 199 countries/regions and the BCG World Atlas. By using linear regression modeling, we found that the number of total cases and deaths per one million population were significantly associated with the country's policy concerning BCG vaccine administration. The amount of variance in cases and deaths explained by BCG vaccination policy ranged between 12.5% and 38%. Importantly, this effect remained significant after controlling for the country's life expectancy and the average temperature in February and March 2020, which themselves are significantly correlated with the cases and deaths indices, respectively. By contrast, the ratio between deaths and cases was weakly affected. This latter outcome suggested that BCG vaccination may have hindered the overall spread of the virus or progression of the disease rather than reducing mortality rates (i.e., deaths/cases ratio). Finally, by roughly dividing countries into three categories showing high, middle, or low growth rate of the cases, we found a highly significant difference between the slope categories among the BCG groups, suggesting that the time since the onset of the spread of the virus was not a major confounding factor. While this study potentially suffers from a number of unknown confounding factors, these associations support the idea that BCG vaccination may provide protection against SARS-CoV-2, which, together with its proven safety, encourages consideration of further detailed epidemiological studies, large-scale clinical trials on the efficacy of this vaccine on COVID-19, and/or re-introduction of BCG vaccination practice in the countries which are currently devoid of the practice.
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