Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates.
Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates.
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DOI：
10.1126/science.abj0299
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发表时间：
2021-09-17
期刊：
影响因子：
--
通讯作者：
Seder RA
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作者：
Corbett KS;Nason MC;Flach B;Gagne M;O'Connell S;Johnston TS;Shah SN;Edara VV;Floyd K;Lai L;McDanal C;Francica JR;Flynn B;Wu K;Choi A;Koch M;Abiona OM;Werner AP;Moliva JI;Andrew SF;Donaldson MM;Fintzi J;Flebbe DR;Lamb E;Noe AT;Nurmukhambetova ST;Provost SJ;Cook A;Dodson A;Faudree A;Greenhouse J;Kar S;Pessaint L;Porto M;Steingrebe K;Valentin D;Zouantcha S;Bock KW;Minai M;Nagata BM;van de Wetering R;Boyoglu-Barnum S;Leung K;Shi W;Yang ES;Zhang Y;Todd JM;Wang L;Alvarado GS;Andersen H;Foulds KE;Edwards DK;Mascola JR;Moore IN;Lewis MG;Carfi A;Montefiori D;Suthar MS;McDermott A;Roederer M;Sullivan NJ;Douek DC;Graham BS;Seder RA
保护的免疫相关点是用来衡量疫苗诱导的免疫原性和保护的临床终点。Corbett等人研究了非人灵长类动物（NHP）对不同剂量mRNA-1273 （Moderna）疫苗的免疫反应，以提供一系列免疫反应和保护结果。他们确定循环刺突蛋白特异性抗体与防止呼吸道中严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）复制相关。被动转移的NHP抗体足以介导仓鼠对SARS-CoV-2攻击的保护，强调抗体是机制相关的。下呼吸道的保护需要较低的血清抗体浓度，这可能解释了为什么目前大多数疫苗对严重的下呼吸道疾病非常有效。降低上呼吸道感染所需的较高抗体阈值对促进限制传播具有潜在意义。-STS mRNA-1273疫苗诱导的抗体反应是非人灵长类动物抗SARS-CoV-2感染的机制相关。大规模接种严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）疫苗是控制COVID-19大流行最有效的公共卫生干预措施。Moderna的mRNA-1273和辉瑞/BioNTech的BNT162b2这两种基于mrna的疫苗都编码预灌注稳定的刺突糖蛋白S-2P，在中期3期分析中显示，对症状性COVID-19的疗效为50%至94%，目前正在全球范围内使用。在3期试验中，其他几种疫苗对症状性COVID-19的疗效已显示出60%至80%，一些候选疫苗处于临床开发的早期阶段。保护的免疫相关性可用于为潜在的剂量减少提供信息，提前批准其他候选疫苗以代替3期疗效数据，将适应症扩展到其他年龄组，并提供对保护的免疫机制的见解。在评估疫苗对SARS-CoV-2的免疫原性和保护作用时，非人灵长类动物（NHPs）已成为临床转化的有用模型。与啮齿类动物相比，NHP的先天免疫反应以及B和T细胞库显示出与人类更大的相似性，从而允许使用临床适用的疫苗剂量和方案来评估免疫反应。感染SARS-CoV-2后，NHPs在上呼吸道和下呼吸道有短暂的病毒复制，肺部有轻度炎症，重现了人类轻度感染的特征。在这里，我们使用了先前NHP mRNA-1273疫苗研究的免疫原性和保护评估，并结合了剂量递减研究的新数据。我们评估了体液和细胞免疫的多重测量与攻击后上呼吸道和下呼吸道病毒复制减少的相关性。对接种后支气管肺泡灌洗液（BAL）和鼻拭子（NS）中的抗体进行分析，以评估部位特异性免疫相关因素。最后，将mrna免疫NHPs的免疫球蛋白G （IgG）被动转移到高致病性叙利亚仓鼠SARS-CoV-2攻毒模型中，以确定这些抗体是否足以提供保护。在第0周和第4周，NHPs要么不接种疫苗，要么接种0.3 ~ 100 μg mRNA-1273（编码S-2P的mRNA疫苗）。mRNA-1273疫苗以剂量依赖的方式引起循环和粘膜抗体反应。使用世界卫生组织测量s特异性IgG的标准，s结合滴度增加10倍与攻毒后BAL和NS中的病毒复制减少10倍相关。s特异性IgG >336 IU/ml的动物没有出现BAL亚基因组RNA (sgRNA) >1万拷贝/ml， s特异性IgG >645 IU/ml的动物没有出现NS sgRNA >10万拷贝/拭子，因此选择这些作为保护阈值。BAL中病毒复制的减少与肺组织中有限的炎症和病毒抗原检测有关。最后，疫苗诱导的IgG从NHPs被动转移到naïve仓鼠，足以介导保护。mRNA-1273疫苗诱导的抗体反应是NHPs抗SARS-CoV-2感染的机制相关。血清抗体浓度低于上呼吸道时，下呼吸道的保护作用得以实现。这些数据部分解释了疫苗对严重下呼吸道疾病的疗效大于对轻度上呼吸道疾病的疗效这一一致发现。这些发现对于如何通过增强上呼吸道所需的免疫力来维持对下呼吸道严重疾病的保护并限制轻度感染和传播具有潜在的意义。接种mrna -1273疫苗的NHPs血清和粘膜峰值特异性IgG水平与SARS-CoV-2攻击后上呼吸道和下呼吸道病毒复制的减少呈负相关。保护的免疫相关因素可用作疫苗效力的替代终点。在这里，非人灵长类动物（NHPs）要么没有接种疫苗，要么接种0.3至100 μg的mRNA-1273严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）疫苗。mRNA-1273疫苗以剂量依赖的方式引起循环和粘膜抗体反应。在接种过SARS-CoV-2疫苗的动物中，病毒复制在支气管肺泡灌洗液和鼻拭子中显著减少，并且与抗s抗体水平和中和活性最密切相关。较低的抗体水平需要减少病毒复制在下气道比在上呼吸道。mrna -1273诱导的免疫球蛋白G被动转移到naïve仓鼠，足以介导保护。因此，mRNA-1273疫苗诱导的体液免疫反应是NHPs对SARS-CoV-2保护的机制相关。
Immune correlates of protection are clinical end points used to gauge vaccine-induced immunogenicity and protection. Corbett et al. studied nonhuman primate (NHP) immune responses to various doses of the mRNA-1273 (Moderna) vaccine to provide a range of immune responses and protective outcomes. They determined that circulating spike protein–specific antibodies correlated with protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the airways. Passively transferred NHP antibodies were sufficient to mediate protection against SARS-CoV-2 challenge in hamsters, emphasizing that antibodies are mechanistic correlates. Protection of the lower respiratory tract required lower serum antibody concentrations, possibly explaining why most current vaccines are highly effective against severe lower airway disease. The higher antibody threshold required for reducing upper airway infection has potential implications for boosting to limit transmission. —STS mRNA-1273 vaccine–induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 infection in nonhuman primates. Mass vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) offers the most efficient public health intervention to control the COVID-19 pandemic. Two mRNA-based vaccines, Moderna’s mRNA-1273 and Pfizer/BioNTech’s BNT162b2, both of which encode the prefusion-stabilized spike glycoprotein S-2P, showed >94% efficacy against symptomatic COVID-19 in interim phase 3 analyses and are currently being administered globally. Several other vaccines have shown 60 to 80% efficacy against symptomatic COVID-19 in phase 3 trials, and a number of candidate vaccines are in earlier stages of clinical development. An immune correlate of protection can be used to inform potential dose reduction, advance approval of other vaccine candidates in lieu of phase 3 efficacy data, extend indications for use to other age groups, and provide insights into the immune mechanisms of protection. In assessing immunogenicity and protection of vaccines against SARS-CoV-2, nonhuman primates (NHPs) have been a useful model for clinical translation. NHP innate immune responses and B and T cell repertoires show much greater similarity to humans than do those of rodents, allowing immune responses to be assessed using clinically applicable vaccine doses and regimens. After SARS-CoV-2 infection, NHPs have transient viral replication in the upper and lower airways and mild inflammation in the lung that recapitulates the features of mild infection in humans. Here, we used immunogenicity and protection assessments from a previous NHP mRNA-1273 vaccine study combined with new data from a dose de-escalation study. We evaluated how multiple measurements of humoral and cellular immunity correlate with the reduction of viral replication in the upper and lower airway after challenge. Antibodies in bronchoalveolar lavage (BAL) and nasal swabs (NS) after vaccination were analyzed to assess site-specific immune correlates. Finally, immunoglobulin G (IgG) from mRNA-immunized NHPs was passively transferred in a highly pathogenic Syrian hamster SARS-CoV-2 challenge model to determine whether these antibodies were sufficient for protection. NHPs received either no vaccine or doses ranging from 0.3 to 100 μg of mRNA-1273, an mRNA vaccine encoding S-2P, at weeks 0 and 4. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Using the World Health Organization standard for measuring S-specific IgG, a 10-fold increase in S-binding titers was associated with ~10-fold reductions in viral replication in BAL and NS after challenge. No animal with S-specific IgG >336 IU/ml had BAL subgenomic RNA (sgRNA) >10,000 copies/ml, and no animal with S-specific IgG >645 IU/ml had NS sgRNA >100,000 copies/swab, so these were chosen as the thresholds for protection. These reductions in viral replication in BAL were associated with limited inflammation and viral antigen detection in lung tissue. Finally, passive transfer of vaccine-induced IgG from NHPs to naïve hamsters was sufficient to mediate protection. mRNA-1273 vaccine–induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHPs. Protection in the lower respiratory tract was achieved at lower serum antibody concentrations than in the upper respiratory tract. These data explain in part the consistent finding that vaccine efficacy against severe lower tract disease is greater than that against mild upper tract disease. These findings have potential implications for how additional boosting may sustain protection against severe disease in the lower respiratory tract and limit mild infection and transmission by enhancing the immunity required in the upper respiratory tract. Levels of serum and mucosal spike-specific IgG in mRNA-1273–vaccinated NHPs were inversely correlated with the reduction of viral replication in the upper airway and lower airway after SARS-CoV-2 challenge. Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti–S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273–induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine–induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.
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DOI：
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发表时间：
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