Valera LLC

导读：目前寨卡病毒(ZIKV，Zika Virus)已成为美洲、非洲和亚洲的全球性疾病，而寨卡病毒感染的出现促使了全球各国共同努力研发安全有效的疫苗。 2017年3月9日，华盛顿大学联合Moderna旗下Valera公司的研究人员在Cell上发表题目为《Modified mRNA vaccines protect against Zika virus infection》的文章，利用脂质纳米颗粒（LNP，Lipid Nanoparticles）包裹了一段编码寨卡病毒结构蛋白的mRNA，并在小鼠中测试了其免疫原性和保护效果。研究表明，该mRNA-LNP候选疫苗足以在小鼠体内产生高浓度的中和性抗体来抵抗寨卡病毒感染。而经过改良后，这一抗体还能防止小鼠体内出现和登革热病毒（DENV，Dengue Virus）相关的副作用，这一结果有望在临床上得到应用。 经过修饰的mRNA疫苗对寨卡病毒的免疫反应 01 寨卡病毒（ZIKV）疫苗研发概况 ZIKV于1947年在乌干达的寨卡森林的一只恒河猴体内被发现，一直以来ZIKV在伊蚊属蚊子和非人类灵长类动物之间循环，并在非洲和亚洲的部分地区间歇性地传播到人类群体中。在西半球的传播背景下，近期观察到了更严重的临床后果，包括可导致胎儿发育异常、成人患吉兰 - 巴雷综合征等，目前尚无有效的治疗方法，疫苗研发迫在眉睫。ZIKV高效抑制性单克隆抗体（mAbs，Monoclonal Antibodies ）可通过接种编码M-E蛋白或prM-E的DNA质粒产生中和ZIKV的抗体，从而产生分泌型病毒样亚病毒颗粒（SVPs，Subviral Particles）。 由于ZIKV与登革热病毒（DENV）之间的序列相似性，人类抗寨卡病毒抗体反应的交叉反应性给疫苗研发带来了问题。而初次感染DENV会产生保护同源血清型的抗体反应，二次感染不同血清型的DENV可能会导致致命的休克并发症，综上ZIKV 与 DENV 关系密切，疫苗研发需考虑交叉反应性抗体的问题，以避免增强 DENV 感染的风险。 02 Moderna寨卡病毒mRNA疫苗设计  脂质纳米颗粒（LNP）用于肌肉注射以诱导体内高水平的蛋白质表达（图1A）。作者设计了一种经过修饰的mRNA，它与来自美洲的菌株的氨基酸序列相似性大于99%（图1B）。采用化学合成的方法将其包裹到LNP中。 将含有IgE-signal-prM-E mRNA（IgEsig-prM-E）的LNP与293T或HeLa细胞共孵育，通过电子显微镜（图1C）、蛋白免疫印迹（图1D）和质谱分析结果显示，细胞上清液中存在约30nm大小的SVPs，实现了高效的表达和分泌。 03 在AG129小鼠中的免疫原性和效力 评估IgEsig-prM-E LNP对免疫功能低下小鼠（缺乏I型和II型干扰素（IFN，interferon ）信号响应）的免疫原性和保护活性。将8周AG129雄性和雌性小鼠被分为五组，每组小鼠通过肌肉注射2μg或10μg IgEsig-prM-E LNP或10μg非翻译RNA LNP。第1、3、5组在接种后21天接受相同剂量的加强注射，而第2、4组未进行加强注射（如图1E所示）。在接种后第42天，小鼠进行采血以进行血清中和抗体分析（如图1F-H）。 结果显示，接受加强注射的IgEsig-prM-E LNP的小鼠对寨卡病毒的血清中和反应最强，保护小鼠免受ZIKV的感染。 图1 ZIKV mRNA LNP疫苗在AG129小鼠中的试验 04 在C57BL/6小鼠中的免疫原性和效力 为了测试免疫原性IgEsig-prM-E LNP疫苗在免疫功能正常的小鼠中的有效性，作者通过向8周雄性C57BL/6野生型小鼠注射10μg的IgEsig-prM-E LNP。在第28天和第56天之前进行了一次采血。结果显示，在加强注射前，血清中和滴度相对较低；然而，在加强注射4周后（EC50为1/10,000），18周滴度达到峰值并保持在较高水平（图2A-C）。在感染前一天将2毫克的阻断性抗-Ifnar1抗体传递给小鼠，所有接种IgEsig-prM-E LNP的小鼠都对致命的寨卡病毒感染具有免疫力，而对照组的存活率为30%（图2D）。接种IgEsig-prM-E mRNA LNP的小鼠无体重下降和病毒血症（图2E、2F）。 图2 寨卡病毒mRNA脂质纳米粒疫苗对C57BL/6小鼠的保护作用 05 缺乏免疫原性E-DII-FL表位的修饰疫苗的保护作用 通过工程技术在E-DII-FL（prM-E-FL）上引入四个突变（T76R、Q77E、W101R和L107R）以消除FL特异性的抗体活性。另外将IgE序列替换为日本脑炎病毒（JEVsig）的序列进一步优化了密码子使用（图3A）。通过确认一种针对E蛋白的单克隆抗体（WNV E60）无法与prM-E-FL mRNA结合，证实了FL反应性的丧失（图3B）。 8周龄雌性BALB/c小鼠在免疫前接受2μg或10μg的IgEsig-prM-E或JEVsig-prM-E（WT或FL突变体）LNP免疫，4周后接受相同剂量的LNP加强免疫，在首次免疫后的第8周分析血清中的中和活性（图3），结果显示出相似的中和滴度（图3C），EC50值约为1/5,000（图3E）。其中WT JEVsig-prM-E LNP诱导了更强的抑制反应，EC50值约为1/100,000（图3D-E）和EC90值约为1/10,000（图3F）。 图3 含有WT或突变FL序列的ZIKV mRNA LNP疫苗对BALB/c小鼠A的保护作用 06 DII突变使细胞和小鼠中的ADE效应降低 为了评估mRNA疫苗是否降低了DENV诱导交叉反应增强抗体的产生，将接种登革病毒血清型1（DENV-1）重组病毒样颗粒（RVPs）后8周获得的血清稀释液与表达激活人Fc-γ受体IIA（CD32A）的K562细胞共培养，接种IgEsig-prM-E-FL或JEVsig-prM-E-FL LNP的小鼠血清中抗体产生的效率大大降低（图4A-C）。在接种融合环突变形式的小鼠中，峰值血清增强滴度（PET，Peak Serum Enhancement Titer ）降低了约100倍（图4D）。在细胞培养中观察到类似的增强能力降低（图4A、B和E）。通过细胞培养试验判断，引入突变降低了产生增强DENA抗体的能力。使用已建立的AG129小鼠登革病毒2型被动转移模型，将来自IgEsig-prM-E、IgEsig-prM-E-FL、JEVsig-prM-E、JEVsig-prM-E-FL接种小鼠的血清注入AG129小鼠体内。结果显示接种了IgEsig-prM-E或JEVsig-prM-E小鼠的血清在体外能抑制DENV-2感染（图4F）。 图4 含有突变FL序列的ZIKV mRNA LNP疫苗在细胞培养和AG129小鼠体内效应 07 总结 本文选择LNP作为递送修饰mRNA疫苗的载体，该 mRNA 疫苗平台能诱导产生高滴度的中和抗体，保护小鼠免受 ZIKV 感染，且具有持久性。另外FL 突变的 mRNA 疫苗能减少交叉反应性抗体的产生，降低 DENV 感染的增强作用，但中和滴度有所降低。JEVsig-prM-E mRNA LNP诱导了显著的中和滴度，在大多数动物中提供了灭活免疫。 该平台为 ZIKV 疫苗的研发提供了一种有潜力的方法，未来可进一步研究其在怀孕小鼠、非人灵长类动物和人类中的免疫原性和保护效力。 参考文献  [1] Richner JM, Himansu S, Dowd KA, Butler SL, Salazar V, Fox JM, Julander JG, Tang WW, Shresta S, Pierson TC, Ciaramella G, Diamond MS. Modified mRNA Vaccines Protect against Zika Virus Infection. Cell. 2017 Mar 9;168(6):1114-1125.e10. doi: 10.1016/j.cell.2017.02.017. 识别微信二维码，添加生物制品圈小编，符合条件者即可加入 生物制品微信群！ 请注明：姓名+研究方向！ 版 权 声 明 本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

Virtual mental health platform Valera Health announced it is now an in-network provider for Humana Medicare Advantage members in 10 states in the U.S., with nationwide expansion expected in September. Valera offers a virtual platform for high-acuity patients aged six and above with serious mental illness and severe depression. The company matches patients to a health coach, who helps them find a therapist or doctor who meets their needs. The New York-based company works via a team-based model that includes nurse practitioners, licensed therapists, case managers and psychiatrists. Clients reach providers through the Valera app. The company also offers a library of mental health resources. "We are looking forward to partnering with Valera Health to support the behavioral health needs in our Medicare Advantage population across our mutual footprint," Cassie Gochenaur, Humana's associate vice president of Behavioral Health, said in a statement. "With a growing demand for all levels of behavioral health support, strong provider partnerships for both in-person and virtual care are a key aspect of ensuring quality and timely care for our membership." THE LARGER TREND In 2021, Valera raised $15 million in funding and last year, the company announced it scored $44.5 million in growth equity financing. Mental healthcare continues to make up a significant portion of telehealth utilization. According to FAIR Health's Monthly Telehealth Regional Tracker, mental health diagnoses rose from 67.4% of telehealth claim lines in March to 68.4% in April, the fourth month of national increases. Other virtual platforms offering high-acuity mental healthcare include virtual psychiatry company Iris Telehealth, teletherapy provider Sensible Care and mental health startup UpLift.

NEW YORK, July 6, 2023 /PRNewswire/ -- Valera Health, a telemental healthcare provider known for its high-quality and accessible care, announced today its comprehensive mental health services are now in-network for some Humana Medicare Advantage members. Valera's services are now available to Humana Medicare Advantage members in 10 states with nationwide expansion coming in September. Valera provides measurement-based virtual services across the continuum of care from mild to serious mental illness. Valera's multidisciplinary service model provides therapy, medication management and case management services in one place. "We are looking forward to partnering with Valera Health to support the behavioral health needs in our Medicare Advantage population across our mutual footprint," said Cassie Gochenaur, Humana's Associate Vice President of Behavioral Health. "With a growing demand for all levels of behavioral health support, strong provider partnerships for both in-person and virtual care are a key aspect of ensuring quality and timely care for our membership." Valera's team-based care model and proprietary technology allows providers to treat patients in Healthcare Provider Shortage Areas (HPSAs) or those who may not be able to access care in person. Expanding teleheath care options makes it easier for Humana's members to access the care they need through a large network of qualified clinicians. Research shows that 25% of Medicare beneficiaries have a mental illness. Through this collaboration between Humana and Valera, these expanded care options will offer support to beneficiaries seeking mental health care, including those with serious mental illness. "We're thrilled to be able to serve Humana's Medicare beneficiaries across the country with high-quality mental health care," said Dr. Tom Tsang, Co-Founder and Chief Strategy Officer at Valera Health. "Humana's continuous dedication to whole-person care and well-being makes them a great partner in making these critical services accessible and affordable to all who need it." Valera's services are available to more than 60 million lives across 10 states. Valera works with large health systems, primary care, and specialty providers to ensure patient's mental health care is integrated in a whole-person view. About Valera Health: Founded by a team of highly experienced physicians and clinicians, at the heart of Valera Health is the belief that high-quality mental healthcare should be affordable and accessible for all. We also believe that mental healthcare shouldn't be "one size fits all, which is why Valera Health tailors its services to fulfill the individual needs of each patient using a complete care model. Our diverse team is transforming telemental healthcare one patient at a time. About Humana: Humana Inc. is committed to putting health first – for our teammates, our customers, and our company. Through our Humana insurance services, and our CenterWell health care services, we make it easier for the millions of people we serve to achieve their best health – delivering the care and service they need, when they need it. These efforts are leading to a better quality of life for people with Medicare, Medicaid, families, individuals, military service personnel, and communities at large. Learn more about what we offer at Humana.com and at CenterWell.com. Other providers are available in the Humana network. For more information about Valera Health services visit . Press inquiries can be sent: Tucker Stevenson [email protected] SOURCE Valera Health