Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses.
Unadjuvanted intranasal spike vaccine elicits protective mucosal immunity against sarbecoviruses.
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DOI：
10.1126/science.abo2523
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发表时间：
2022-11-25
期刊：
影响因子：
56.9
通讯作者：
Iwasaki, Akiko
中科院分区：
文献类型：
--
作者：
Mao, Tianyang;Israelow, Benjamin;Pena-Hernandez, Mario A.;Suberi, Alexandra;Zhou, Liqun;Luyten, Sophia;Reschke, Melanie;Dong, Huiping;Homer, Robert J.;Saltzman, W. Mark;Iwasaki, Akiko
严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）大流行突出表明，不仅需要预防疾病，还需要预防传播的疫苗。注射疫苗可诱导强大的全身免疫，但呼吸道黏膜免疫能力较差。我们开发了一种我们称之为“初始和峰值”的疫苗策略，它利用初级疫苗（prime）产生的现有免疫力，通过使用无佐剂的鼻内峰值增强剂（spike）在呼吸道内引发粘膜免疫记忆。我们发现，prime和spike诱导了强大的常驻记忆B和T细胞反应，诱导了呼吸道粘膜的免疫球蛋白A，增强了全身免疫，并完全保护了具有部分免疫的小鼠免受致命的SARS-CoV-2感染。利用不同的刺突蛋白，引物和刺突能够诱导针对sarbecovirus的交叉反应性免疫。在COVID-19疫苗广泛使用近两年后，疫苗诱导的免疫力下降和病毒突变有增无减，导致疫苗有效性下降。Mao等人在COVID-19动物模型中开发了一种替代疫苗增强策略，他们称之为“初始和峰值”。在首次接种信使RNA疫苗（“原疫苗”）后，动物接受了鼻内剂量的无佐剂严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）刺突蛋白（“刺突”）。这种方法在粘膜中产生了强大的细胞和基于抗体的免疫，像注射外注射一样有效和持久地保护动物，同时也更好地阻止病毒传播。Spike可以以多种配方使用，如果是从SARS-CoV-1衍生出来的，可以对两种病毒提供强有力的交叉保护。鼻内刺突蛋白增强可在动物中产生广泛的保护性抗sarbecvirus粘膜免疫。在严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）大流行的第一年，利用脂质纳米颗粒封装的修饰mRNA和复制缺陷腺病毒载体等新技术，开发了多种高效疫苗。初步试验表明，疫苗对有症状疾病的有效性为90%。其他研究表明，接种疫苗个人的家庭接触者的感染率下降，表明传播率下降。不幸的是，对疫苗的免疫力下降，以及病毒不断进化，具有越来越多的传染性和免疫逃避性变异，导致疫苗有效性下降。疫苗在预防传播方面也变得不那么有效，部分原因可能是呼吸道粘膜免疫诱导能力差。尽管疫苗接种的目标是预防个体发病率和死亡率，但SARS-CoV-2在整个大流行期间的演变突出表明，需要更好地预防传播的疫苗。注射疫苗可诱导强大的全身免疫，对疾病有保护作用。然而，它们在上呼吸道黏膜内引起免疫力低下，从而发生病毒传播。SARS-CoV-2和流感病毒的临床前研究表明，与注射疫苗相比，鼻内疫苗可减少病毒的脱落和传播。尽管有这些研究，目前只有一种呼吸道粘膜疫苗，fluumist，这是一种活的适应感冒的流感病毒。目前大多数粘膜给药SARS-CoV-2疫苗的临床试验依赖于复制缺陷型或减毒型病毒载体，其安全性和有效性尚未确定。随着抗媒介免疫的发展，所有这些策略都变得不那么有效。在这里，我们利用预先存在的免疫力，通过鼻内给予无佐剂的刺突蛋白或mRNA来增强粘膜免疫力。这就避免了在呼吸道中使用病毒载体或佐剂。我们描述了一种替代疫苗策略的临床前开发，我们称之为“初始和峰值”（P&S），它利用一次疫苗（初始）产生的现有免疫力，通过使用无佐剂的鼻内峰值增强剂，在呼吸道内引发粘膜免疫记忆。P&S引发了强大的粘膜细胞和体液记忆反应，包括组织驻留记忆CD8+ T细胞、CD4+ T细胞和B细胞的建立。此外，我们发现粘膜免疫球蛋白A （IgA）和IgG有很强的诱导作用。鼻内增强剂可以通过不同的疫苗配方进行递送，从无佐剂的三聚体重组刺突蛋白到由免疫沉默聚胺-共酯（PACE）聚合物封装的刺突编码mRNA。我们发现鼻内无佐剂刺突增强剂可以在初次免疫几个月后使用，并提供与mrna -脂质纳米颗粒（LNP）增强剂相当的全身中和抗体反应。P&S具有耐久性，可在接种疫苗后长达118天免受致命的SCV2攻击。P&S对仓鼠具有保护作用，在阻断传播方面优于mRNA-LNP prime-boost。最后，通过使用来自SARS-CoV-1的发散刺突抗原，我们证明了P&S可以产生针对SCV1的粘膜免疫，同时还可以增强针对SARS-CoV-2的全身和粘膜中和抗体。SARS-CoV-2将继续进化，变得更具免疫规避性和传染性。在可预见的未来，我们将需要增加人口。呼吸道黏膜提供了一个强大的屏障，对病毒性病原体后给予P&S。因此，通过接种疫苗加强粘膜免疫对增强保护和减轻传播具有重大希望。随着新变种的出现，它将成为对抗其他呼吸道病原体和下一次大流行的重要工具。P&S将初次接种产生的全身免疫转化为呼吸道粘膜的局部免疫。P&S可防止SARS-CoV-2 （SCV2）感染后的疾病发展、呼吸道病毒复制和接触传播。使用来自SARS-CoV-1 （SCV1）的不同刺突蛋白进行鼻内增强可诱导针对多种sarbecovirus分支的粘膜免疫。
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has highlighted the need for vaccines that not only prevent disease but also prevent transmission. Parenteral vaccines induce robust systemic immunity but poor immunity at the respiratory mucosa. We developed a vaccine strategy that we call “prime and spike,” which leverages existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike boosters (spike). We show that prime and spike induces robust resident memory B and T cell responses, induces immunoglobulin A at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, prime and spike enables the induction of cross-reactive immunity against sarbecoviruses. Nearly 2 years after COVID-19 vaccines became widely available, a combination of waning vaccine-induced immunity and unabated viral mutations have resulted in reduced vaccine effectiveness. Mao et al. developed an alternative vaccine-boosting strategy they call “prime and spike” in animal models of COVID-19. After primary vaccination with a messenger RNA vaccine (“prime”), animals received an intranasal dose of unadjuvanted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (“spike”). This approach resulted in robust cellular and antibody-based immunity in the mucosa that protected animals as strongly and durably as a parenteral boost while also blocking viral transmission better. Spike could be administered in a variety of formulations and, if derived from SARS-CoV-1, could offer strong cross-protection against both viruses. —STS An intranasal spike protein boost generates broadly protective anti-sarbecovirus mucosal immunity in animals. During the first year of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, multiple highly effective vaccines have been developed, using new technologies such as modified mRNA encapsulated in lipid nanoparticles and replication-deficient adenoviral vectors. Initial trials showed vaccine effectiveness >90% against symptomatic disease. Additional studies showed decreased infection rates of household contacts of vaccinated individuals, suggesting decreased rates of transmission. Unfortunately, waning immunity to vaccines and continued viral evolution with increasingly transmissible and immune-evasive variants have led to decreased vaccine effectiveness. Vaccines have also become much less effective at preventing transmission, which may be in part because of the poor induction of mucosal immunity within the respiratory tract. Although the goal of vaccination has been to prevent individual morbidity and mortality, the evolution of SARS-CoV-2 throughout the pandemic has highlighted the need for vaccines that better prevent transmission. Parenteral vaccines induce robust systemic immunity that is protective against disease. However, they induce poor immunity within the upper respiratory mucosa, where viral transmission occurs. Preclinical studies of both SARS-CoV-2 and influenza virus have demonstrated that intranasal vaccination decreases viral shedding and transmission relative to parenteral vaccines. Despite these studies, there is only one currently approved respiratory mucosal vaccine, FluMist, which is a live cold-adapted influenza virus. Most current clinical trials of mucosally administered SARS-CoV-2 vaccines rely on either replication-deficient or attenuated viral vectors, the safety and efficacy of which have yet to be established. All of these strategies become less effective with the development of antivector immunity. Here, we instead leverage preexisting immunity to boost mucosal immunity by intranasally administering unadjuvanted spike protein or mRNA. This consequently avoids the use of viral vectors or adjuvants in the respiratory tract. We describe the preclinical development of an alternative vaccine strategy that we term “prime and spike” (P&S), which uses existing immunity generated by primary vaccination (prime) to elicit mucosal immune memory within the respiratory tract by using unadjuvanted intranasal spike booster. P&S elicits robust mucosal cellular and humoral memory responses, including the establishment of tissue-resident memory CD8+ T cells, CD4+ T cells, and B cells. Additionally, we found robust induction of mucosal immunoglobulin A (IgA) and IgG. Intranasal boosters can be delivered through distinct vaccine formulations, ranging from unadjuvanted trimeric recombinant spike proteins to spike-encoding mRNA encapsulated by immunosilent poly(amine-co-ester) (PACE) polymers. We found that an intranasal unadjuvanted spike booster can be administered months out from primary immunization and offers systemic neutralizing antibody responses comparable with that of mRNA–lipid nanoparticle (LNP) boost. P&S shows durability, leading to protection from lethal SCV2 challenge for as long as 118 days from vaccination. P&S is protective in hamsters and is superior to mRNA-LNP prime-boost at blocking transmission. Last, by using a divergent spike antigen from SARS-CoV-1, we demonstrate that P&S can generate mucosal immunity to SCV1 while also boosting systemic and mucosal neutralizing antibodies to SARS-CoV-2. SARS-CoV-2 will continue to evolve and become more immune evasive and transmissible. We will require boosting in human populations for the foreseeable future. The respiratory mucosa provides a formidable barrier against viral pathogens after P&S administration. Therefore, strengthening mucosal immunity through vaccination holds substantial promise for enhancing protection and mitigating transmission. As new variants emerge, it will be a vital tool in combating other respiratory pathogens and the next pandemic. P&S converts systemic immunity generated by primary vaccination into local immunity in the respiratory mucosa. P&S affords protection against disease development, respiratory viral replication, and contact transmission after SARS-CoV-2 (SCV2) infection. Intranasal boosting by using a divergent spike protein from SARS-CoV-1 (SCV1) induces mucosal immunity against diverse sarbecovirus clades.
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DOI：
10.1126/science.abm0620
发表时间：
2022-01-21
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
通讯作者：
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影响因子：
6.2
作者：
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通讯作者：
Saltzman WM
DOI：
10.1016/j.xcrm.2021.100230
发表时间：
2021-04-20
期刊：
Cell reports. Medicine
影响因子：
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作者：
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通讯作者：
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影响因子：
56.9
作者：
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通讯作者：
McLellan, Jason S.
影响因子：
82.9
作者：
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