COVID-19 Vaccine (recombinant, adjuvanted) (Sanofi)

“ 补体系统在病原体免疫监测和组织内稳态中起着关键作用。然而，破坏其严格的调控机制，会助长炎症损伤的恶性循环，使病情恶化。针对罕见的临床疾病，如阵发性睡眠性血红蛋白尿症和不典型溶血性尿毒症，建立了靶向补体系统药物开发。” 补体系统激活是一种高度保守的机制，通过这种机制，天然免疫感官触发危险信号，破坏组织稳态。它通过可溶性模式识别受体，识别免疫复合物、受损细胞或微生物病原体上的分子特征(例如，不同的碳水化合物)，这些受体再由三个典型途径(分别称为经典途径CP、凝集素LP和替代途径AP）组成的蛋白水解级联中形成触发复合物。这些高度有序的相互作用形成了系统中心“工作马”：C3和C5的转化酶。这些转化酶是多蛋白的集合，具有短暂的酶活性，并通过产生关键蛋白C3和C5的生物活性片段进一步放大补体反应，这些片段修饰靶表面(调理机制)，促进吞噬、炎症和免疫调节过程。通过直接膜攻击复合物(MAC)介导裂解，进一步激活终末(Lytic)通路导致补体调理细胞被清除。 补体激活不仅提供快速保护，免受感染挑战，但也可滑向“黑暗面”，成为大量炎症或自身免疫性疾病的驱动者或病理恶化推动者。当流体相和表面导向的补体调节不受影响时，补体蛋白通过保护健康细胞来维持其免疫监视功能。然而，当细胞受损，或者它的表面不在适合补体保护时，这些因素驱动C3b进入分解周期，阻止AP扩增和进一步发生C3片段沉积。在这种情况下，表面结合C3和C5转换酶的组合体促进效应物的产生和炎症组织的损伤。事实上，过度或放松管制的补体激活与多种疾病的发病有关，包括急性炎症状态(如脓毒症、缺血性中风和抗体介导的移植物排斥反应)、眼病和牙周疾病，包括癌症、自身免疫和年龄相关的神经退行性疾病、肾脏疾病和具有血栓炎症特征的慢性溶血性疾病。 由于补体显著的致病作用，近年来各种补体效应物作为治疗可控性靶点和药物研制的靶点受到了广泛的关注。简单列举6款上市药物。 1. C5 单克隆抗体：eculizumab(Soliris，Alexion)2007年FDA批准了第一款补体特异性药物 eculizumab(Soliris，Alexion)用于治疗突发性睡眠性血红蛋白尿症(PNH)，标志着补体药物发现方面的一个重要里程碑。 2. C1抑制剂Cinryze（C1酯酶抑制剂）C1-INH是一种血浆丝氨酸蛋白酶抑制剂，对CP和LP以及凝血、激酶和纤溶级联具有广泛的特异性。2008年，C1-INH(Cinryze)获得美国食品和药物管理局(FDA)批准用于遗传性血管水肿患者。 3. C3抑制剂EMPAVELI™(pegcetacoplan，Apellis)pegcetacoplan是一种合成的环肽，特异性地与C3和C3b结合。目前pegcetacoplan正被用于治疗多种疾病，包括PNH、地图样萎缩(GA)和C3肾小球病。 4.C5 单克隆抗体长效款raculizumab（Ultomiris，Alexion)2022年4月28日，阿斯利康公司宣布旗下药品雷夫利珠单抗（Ravulizumab）获得美国FDA批准，用于治疗抗乙酰胆碱受体（AChR）抗体阳性的全身型重症肌无力成人患者，这也是FDA批准的首个用于治疗该病的长效C5补体抑制剂。只需要每8周而不是每两周服用一次，这是改进病人管理的重要一步。 5. C1s抑制剂：sutimlimab（Enjaymo™，Sanofi）2022年2月4日，赛诺菲(Sanofi)宣布美国食品药品监督管理局(FDA)已批准Enjaymo™(sutimlimab-jome)，用于减少患有冷凝集素病(CAD)的成年人因溶血引起的红细胞输注需求。Enjaymo是第一个也是唯一一个获准用于冷凝集素病患者的治疗方法，通过抑制红细胞的破坏（溶血）起作用。 6. C5抑制剂Avacincaptad pegol (IZERVAY™; formerly Zimura®)2023年8月7日，VERIC bio公司宣布，其补体因子C5抑制剂Zimura治疗年龄相关性黄斑变性(AMD)相关的继发性地图样萎缩(GA)获得FDA批准上市，成为首款用于GA的补体C5抑制剂，商品名为Izervay。 参考文献： Ricklin, D., Nat. Rev.Nephrol. 12, 383–401 (2016). Rankin, L. C. Cell 173,554–567 (2018). Ricklin, D., . Nat. Immunol. 11, 785–797 (2010). Hajishengallis, Nat. Immunol. 18，1288–1298 (2017). Ricklin, D.Immunol. Rev. 274, 5–8 (2016). Merle, N. SFront. Immunol. 6, 262 (2015). Ricklin, D.J. Immunol. 190, 3839–3847 (2013). Schmidt, C. Q., L. Immunol. Rev.274, 152–171 (2016). Dimitrios， Nature Reviews Drug Discovery，2019 内容来源于网络，如有侵权，请联系删除。

The UK Medicines and Healthcare products Regulatory Agency (MHRA) has approved nine vaccines to treat the virus, with a range of antivirals available to patients to reduce the severity of symptoms and help manage the disease. Credit: Shutterstock/ZorroGabriel. Covid-19 cases in the UK have been picking up since November, with a 39% increase in positive tests in the last seven days alone. Research shows that the UK is currently in a seasonal spike of Covid-19 infections, with November to April estimated to exhibit high disease activity. Yet another vaccine was recently added to the UK’s fully approved line-up. In October 2023, Novavax ’s prototype, Nuvaxovid, gained full marketing authorisation from the MHRA for use in individuals aged 12 and older. An updated vaccine was approved on 24 January. Nuvaxovid was originally greenlit under an emergency use authorisation in 2022. Novavax CEO John Jacobs said in a 24 January statement announcing full approval of the updated vaccine: “Today’s MHRA authorisation is recognition of the role our vaccine can have in protecting the British public against Covid-19 this year.” Nuvaxovid’s inclusion marked the entry of another protein sub-unit-based vaccine to those available in the UK. It joins long-standing vaccines present from near the beginning of the pandemic, including Pfizer/BioNTech’s Comirnaty and Moderna ’s Spikevax, both RNA vaccines, and Oxford/AstraZeneca’s viral vector-based Vaxzevria. Janssen and Valneva also have MHRA-approved vaccines. GSK/Sanofi’s VidPrevtyn Beta, another protein-based variant Covid-19 vaccine, was approved for use as a booster in December 2022. HIPRA Human Health’s Bimervax was approved in August 2023, becoming the ninth Covid-19 vaccine authorised by the MHRA. Amid signs that Covid-19 will become a seasonally spiking virus, the UK’s autumn booster programme aims to reduce hospitalisations in those most at risk from sivere disease. In the current programme, those aged 65 years and over are eligible, along with those who meet certain criteria. Omicron BA.2.86 has emerged as the dominant variant throughout winter. While early indications show that it is no more dangerous than other variants, data is limited and the UK Health Security Agency (UKHSA) continues to monitor its circulation. The UKHSA’s chief medical advisor, Professor Susan Hopkins, said in September 2023: “The autumn vaccination programme started this month, and this new [variant] data shows once again how important it is that the most vulnerable among us are fully vaccinated in order to receive the greatest possible protection.” The UKHSA reported that last autumn’s booster programme resulted in patients being 53% less likely to be admitted to hospital with the disease in the 2–4 weeks following vaccination. Away from prevention and looking at the treatment outlook, more than a million patients will soon gain access to Pfizer’s antiviral pill Paxlovid (nirmatrelvir/ritonavir). The drug is already recommended to an estimated 3.9 million people who meet certain criteria and, following recommendation by the National Institute of Care and Excellence, a further 1.4 million patients will be eligible. Alongside Paxlovid, the NHS offers Veklury (remdesivir) from Gilead Sciences and MSD’s Lagevrio (molnupiravir). GSK/Vir Biotech’s Xevudy (sotrovimab) is a monoclonal antibody given to Covid-19 patients on the NHS who are unsuitable for antivirals. Approved by the MHRA in December 2021, Paxlovid has been a source of high revenue for Pfizer. The antiviral saw peak global sales in 2022, totalling $18.9bn. Annual sales of the drug have since declined as the number of Covid-19 infections has fallen. Paxlovid is currently transitioning to the US commercial market . The US commercial price for Paxlovid has been set at nearly $1,400 per five-day course – nearly triple what the US Government paid.