mRNA-1273 SARS-CoV-2疫苗的效力和安全性
Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
背景
我們需要疫苗來預防COVID-19，並且保護併發症發生風險高的人群。mRNA-1273疫苗是脂質納米顆粒包裹的mRNA疫苗，可編碼COVID-19致病病毒SARS-CoV-2的融合前穩定的全長刺突蛋白。Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.方法
此項3期、隨機、觀察者設盲的安慰劑對照試驗是在美國99個醫療中心開展。我們以1:1的比例將SARS-CoV-2感染風險高或併發症發生風險高的人員隨機分組，兩組分別間隔28天接受兩次mRNA-1273（100 μg）或安慰劑肌肉注射。主要終點是在未感染過SARS-CoV-2的參與者中預防了接種第二劑至少14天之後發病的COVID-19。This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2.結果
本試驗納入了30,420名志願者，並以1:1的比例隨機分配其接種疫苗或安慰劑（每組15,210名參與者）。超過96%的參與者接受了兩次注射，基線時2.2%有SARS-CoV-2感染證據（血清學、病毒學或兩者均有）。安慰劑組185例參與者（每1000人-年56.5例；95%置信區間[CI]，48.7~65.3）和mRNA-1273組11例參與者（每1000人-年3.3例；95% CI，1.7~6.0）被確診為症狀的COVID-19；疫苗有效率為94.1%（95% CI，89.3%~96.8%；P<0.001）。各項關鍵次要分析中的效力相似，這些次要分析包括接種第一劑後14天進行的評估，將基線有SARS-CoV-2感染證據的參與者納入其中的分析以及在≥65歲參與者中進行的分析。30例參與者患重症COVID-19，其中1例死亡；全部30例均屬於安慰組。在mRNA-1273組中，接種疫苗後的中度一過性反應原性較常見。兩組的嚴重不良事件均很少，且發生率相似。
Result
The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups.
結論
mRNA-1273預防COVID-19（包括重症疾病）的有效率為94.1%。除一過性局部和全身性反應之外，未發現其他安全性問題。（由美國生物醫學高級研究與開發管理局[Biomedical and Advanced Research and Development Authority]和美國國立過敏和傳染病研究所[National Institute of Allergy and Infectious Diseases]資助；在ClinicalTrials.gov註冊號為NCT04470427。）
Conclusions
The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
Lindsey R. Baden, Hana M. El Sahly, Brandon Essink, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. DOI: 10.1056/NEJMoa2035389應用羥氯喹預防COVID-19的整群隨機試驗
A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19
背景
目前對SARS-CoV-2感染採取的預防策略僅限於非藥物幹預措施。有人提議將羥氯喹用於旨在預防COVID-19的暴露後治療，但仍缺乏明確證據。
Current strategies for preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited to nonpharmacologic interventions. Hydroxychloroquine has been proposed as a postexposure therapy to prevent coronavirus disease 2019 (Covid-19), but definitive evidence is lacking.方法
我們在西班牙加泰隆尼亞PCR（聚合酶鏈反應）確診COVID-19患者的無症狀接觸者中開展了一項開放標籤的整群隨機試驗。我們將接觸者整群隨機分配至羥氯喹組（以800 mg劑量用藥一次，之後6日每日用藥400 mg）或常規治療組（未接受特定治療）。主要結局是14天內PCR確診的有症狀COVID-19。次要結局是SARS-CoV-2感染（定義為有與COVID-19相吻合的症狀或PCR檢測結果呈陽性[不論是否有症狀]）。我們對不良事件進行了長達28天的評估。
We conducted an open-label, cluster-randomized trial involving asymptomatic contacts of patients with polymerase-chain-reaction (PCR)–confirmed Covid-19 in Catalonia, Spain. We randomly assigned clusters of contacts to the hydroxychloroquine group (which received the drug at a dose of 800 mg once, followed by 400 mg daily for 6 days) or to the usual-care group (which received no specific therapy). The primary outcome was PCR-confirmed, symptomatic Covid-19 within 14 days. The secondary outcome was SARS-CoV-2 infection, defined by symptoms compatible with Covid-19 or a positive PCR test regardless of symptoms. Adverse events were assessed for up to 28 days.
結果
分析納入了2020年3月17日至4月28日期間發現的672例COVID-19指示病例的2314名健康接觸者。共計1116名接觸者被隨機分配接受羥氯喹，1198名被分配接受常規治療。在羥氯喹組和常規治療組中，PCR確診的有症狀COVID-19發病率（分別為5.7%和6.2%；風險比，0.86[95%置信區間，0.52~1.42]）相似。此外，羥氯喹組的SARS-CoV-2傳播發生率並未低於常規治療組（分別為18.7%和17.8%）。羥氯喹組的不良事件發生率高於常規治療組（56.1% vs. 5.9%），但並無與治療相關的嚴重不良事件報告。
Result
The analysis included 2314 healthy contacts of 672 index case patients with Covid-19 who were identified between March 17 and April 28, 2020. A total of 1116 contacts were randomly assigned to receive hydroxychloroquine and 1198 to receive usual care. Results were similar in the hydroxychloroquine and usual-care groups with respect to the incidence of PCR-confirmed, symptomatic Covid-19 (5.7% and 6.2%, respectively; risk ratio, 0.86 [95% confidence interval, 0.52 to 1.42]). In addition, hydroxychloroquine was not associated with a lower incidence of SARS-CoV-2 transmission than usual care (18.7% and 17.8%, respectively). The incidence of adverse events was higher in the hydroxychloroquine group than in the usual-care group (56.1% vs. 5.9%), but no treatment-related serious adverse events were reported.結論
接觸過PCR檢測結果陽性患者的健康人應用羥氯喹進行暴露後治療未能預防SARS-CoV-2感染，也未能預防有症狀的COVID-19。（由YoMeCorono籌款活動[crowdfunding campaign YoMeCorono]等資助；BCN-PEP-CoV2在ClinicalTrials.gov註冊號為NCT04304053。）
Conclusions
Postexposure therapy with hydroxychloroquine did not prevent SARS-CoV-2 infection or symptomatic Covid-19 in healthy persons exposed to a PCR-positive case patient. (Funded by the crowdfunding campaign YoMeCorono and others; BCN-PEP-CoV2 ClinicalTrials.gov number, NCT04304053.)Oriol Mitjà, Marc Corbacho-Monné, Maria Ubals, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. DOI: 10.1056/NEJMoa2021801
在113,000多名女性中進行的乳腺癌風險基因關聯分析
Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women
背景
乳腺癌易感性的基因檢測已被廣泛應用，但其中許多基因與乳腺癌之間的關聯證據薄弱，基礎風險估計值不精確，而且缺乏可靠的亞型特異的風險估計值。
Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.方法
我們應用由34個推測的易感基因構成的基因面板，對60,466例乳腺癌女性患者和53,461例對照女性的樣本進行了測序。在對這些基因的蛋白質截短變異體和罕見錯義變異體分別進行的分析中，我們估算了對於總體乳腺癌和乳腺癌亞型的比值比。我們根據結構域和致病性分類結果評估了錯義變異體相關性。。
We used a panel of 34 putative susceptibility genes to perform sequencing on samples from 60,466 women with breast cancer and 53,461 controls. In separate analyses for protein-truncating variants and rare missense variants in these genes, we estimated odds ratios for breast cancer overall and tumor subtypes. We evaluated missense-variant associations according to domain and classification of pathogenicity.結果
5個基因（ATM、BRCA1、BRCA2、CHEK2和PALB2）的蛋白質截短變異體與總體乳腺癌風險相關且P值小於0.0001。另外4個基因（BARD1、RAD51C、RAD51D和TP53）的蛋白質截短變異體與總體乳腺癌風險相關且P值小於0.05，貝葉斯錯誤發現概率小於0.05。在其餘25個基因中，對於19個的蛋白質截短變異體，總體乳腺癌的比值比的95%置信區間的上限小於2.0。對於ATM和CHEK2的蛋白質截短變異體，雌激素受體（ER）陽性乳腺癌的比值比大於ER陰性乳腺癌；對於BARD1、BRCA1、BRCA2、PALB2、RAD51C和RAD51D的蛋白質截短變異體，ER陰性乳腺癌的比值比大於ER陽性乳腺癌。ATM、CHEK2和TP53的罕見錯義變異體（匯總結果）與總體乳腺癌風險相關且P值小於0.001。對於BRCA1、BRCA2和TP53，根據標準歸類為致病性的錯義變異體（匯總結果）與總體乳腺癌風險相關，且風險與蛋白質截短變異體相似。
Result
Protein-truncating variants in 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) were associated with a risk of breast cancer overall with a P value of less than 0.0001. Protein-truncating variants in 4 other genes (BARD1, RAD51C, RAD51D, and TP53) were associated with a risk of breast cancer overall with a P value of less than 0.05 and a Bayesian false-discovery probability of less than 0.05. For protein-truncating variants in 19 of the remaining 25 genes, the upper limit of the 95% confidence interval of the odds ratio for breast cancer overall was less than 2.0. For protein-truncating variants in ATM and CHEK2, odds ratios were higher for estrogen receptor (ER)–positive disease than for ER-negative disease; for protein-truncating variants in BARD1, BRCA1, BRCA2, PALB2, RAD51C, and RAD51D, odds ratios were higher for ER-negative disease than for ER-positive disease. Rare missense variants (in aggregate) in ATM, CHEK2, and TP53 were associated with a risk of breast cancer overall with a P value of less than 0.001. For BRCA1, BRCA2, and TP53, missense variants (in aggregate) that would be classified as pathogenic according to standard criteria were associated with a risk of breast cancer overall, with the risk being similar to that of protein-truncating variants.
結論
本研究的結果確定了在臨床上可納入基因面板，用於預測乳腺癌風險的最有用基因，並提供了與蛋白質截短變異體相關的風險估計值，這些結果可以指導遺傳諮詢。（由歐盟地平線2020[European Union Horizon 2020]計劃等資助。）
Conclusions
The results of this study define the genes that are most clinically useful for inclusion on panels for the prediction of breast cancer risk, as well as provide estimates of the risks associated with protein-truncating variants, to guide genetic counseling. (Funded by European Union Horizon 2020 programs and others.)Breast Cancer Association Consortium. Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women. DOI: 10.1056/NEJMoa1913948本周五 中午十二點 app和官網發布全文中譯
對之前發現的乳腺癌相關基因進行的人群研究
A Population-Based Study of Genes Previously Implicated in Breast Cancer
背景
為了對攜帶遺傳性致病變異體的女性進行風險評估和管理，我們亟需與癌症易感基因的生殖細胞系致病變異體相關乳腺癌風險的人群估計值。
Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.方法
在一項基於人群的病例對照研究中，我們在參與CARRIERS（與易感性相關的癌症風險估計，Cancer Risk Estimates Related to Susceptibility）聯盟人群研究的32,247例乳腺癌女性患者（病例）和32,544例未患病女性（對照）中，利用基於多基因擴增子的定製基因面板進行了測序，目的是在28個癌症易感基因中識別生殖細胞系致病變異體。我們評估了各基因的致病變異體與乳腺癌風險的關聯。
In a population-based case–control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.結果
在12個已知的乳腺癌易感基因中，我們檢測出5.03%的病例和1.63%的對照有上述基因的致病變異體。BRCA1和BRCA2的致病變異體與乳腺癌的高風險相關，比值比分別為7.62（95%置信區間[CI]，5.33~11.27）和5.23（95% CI，4.09~6.77）。PALB2的致病變異體與中等風險相關（比值比，3.83；95% CI，2.68~5.63）。BARD1、RAD51C和RAD51D的致病變異體與雌激素受體陰性乳腺癌和三陰性乳腺癌的風險增加相關，而ATM、CDH1和CHEK2的致病變異體與雌激素受體陽性乳腺癌的風險增加相關。16個候選乳腺癌易感基因的致病變異體（包括NBN的c.657_661del5始祖致病變異體）與乳腺癌風險增加無關。
Result
Pathogenic variants in 12 established breast cancer–predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor–negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor–positive breast cancer. Pathogenic variants in 16 candidate breast cancer–predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.
結論
本研究提供了在美國人群中與已知乳腺癌易感基因的致病變異體相關的乳腺癌患病率和風險估計值。這些估計值可指導乳腺癌的檢查和篩查，並改善一般人群中攜帶這些基因的遺傳性致病變異體的女性的臨床管理策略。（由美國國立衛生研究院和乳腺癌研究基金會[Breast Cancer Research Foundation]資助。）
Conclusions
This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer–predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.)本周五 中午十二點 app和官網發布全文中譯
關注《NEJM醫學前沿》
本文由嘉會醫學研究和教育集團（JMRE）與《新英格蘭醫學雜誌》（NEJM）聯手打造的《NEJM醫學前沿》翻譯、編寫或約稿。中譯全文及所含圖表等由NEJM集團獨家授權。如需轉載，請留言或聯繫nejmqianyan@nejmqianyan.cn。未經授權的翻譯是侵權行為，版權方保留追究法律責任的權利。點擊「閱讀原文」 第一時間獲得NEJM最新論著摘要