A Phase 2, single center, randomized, double blind study evaluating the safety, efficacy, and immunogenicity of MVA NP+M1 in the H3N2 human influenza challenge model; on healthy adult volunteers.

开始日期2019-06-03

申办/合作机构

Vaccitech (UK) Ltd.

NCT03880474 / Terminated临床2期

A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults Aged 18 Years and Over

A Phase 2b Study to Determine the Efficacy of Candidate Influenza Vaccine MVA-NP+M1 in Adults aged 18 years and over. To assess the effect of MVA-NP+M1 on the reduction of laboratory confirmed influenza when given as an adjunct to licensed quadrivalent influenza vaccine (QIV) in adults

开始日期2019-03-18

申办/合作机构

Vaccitech (UK) Ltd.

[+1]

NCT03300362 / Terminated临床2期

A Phase IIb Study to Determine the Safety and Efficacy of Candidate INfluenza Vaccine MVA-NP+M1 in Combination With Licensed InaCTivated inflUenza Vaccine in adultS Aged 65 Years and Above

A Phase IIb randomised, participant-blinded, placebo-controlled, multi-centre phase IIb efficacy study in 2030 volunteers aged 65 and over. The study will assess the safety and efficacy of the co-administration of a viral vectored vaccine, MVA- NP+M1, and the annual recommended licensed inactivated influenza vaccine (IIV). Within the main cohort 100 participants will be recruited to an immunology sub-cohort.

开始日期2017-10-13

申办/合作机构

Vaccitech (UK) Ltd.

[+1]

100 项与 VTP-100 相关的临床结果

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100 项与 VTP-100 相关的转化医学

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100 项与 VTP-100 相关的专利（医药）

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项与 VTP-100 相关的文献（医药）

2024-07-01·Lancet Microbe

Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study

Article

作者: Van Leuven, Katrin ; Kowalik Dobczyk, Monika ; Castellino, Flora ; Asher, Jason ; Rutkowski, Kathryn ; Walley, Ana Marie ; Thacker, Juilee ; Laurent, Cyril ; Klein, Jelle ; van Baalen, Carel ; Tucker, Gwen ; Filkov, Ella ; Eagling-Vose, Elizabeth ; Donabedian, Armen ; Ellis, Chris ; Treanor, John ; Evans, Thomas G

BACKGROUND:

Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients.

METHODS:

In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 10⁸ plaque forming units (4·3 × 10⁸ 50% tissue culture infectious dose [TCID₅₀]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 10⁶ TCID₅₀/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113.

FINDINGS:

Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported.

INTERPRETATION:

The use of an MVA vaccine to expand CD4⁺ or CD8⁺ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults.

FUNDING:

Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.

2022-06-01·The Lancet. Infectious diseases1区 · 医学

Efficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trial

1区 · 医学

Article

作者: Eagling-Vose, Elizabeth ; Rutkowski, Kathryn ; Argent, Chris ; Gilbert, Sarah ; Griffin, Paul ; Gillies, John ; Doughty, Julia ; Druce, Julian ; Kim, Joshua ; Thackwray, Susan ; Pryor, Melinda ; Wu, Jian ; Ellis, Chris ; Bussey, Louise ; Shakib, Sepehr ; Evans, Thomas G

BACKGROUND:

In animal, epidemiological, and human challenge studies, a pre-existing T-cell response to internal proteins of influenza A has been associated with improved virological and disease outcomes. The aim of this study was to assess whether inducing additional responses to conserved CD4 and CD8 T-cell antigens provides added benefit to standard influenza vaccination.

METHODS:

We designed a phase 2b, randomised, placebo-controlled, double-blind trial of a recombinant viral-vectored vaccine (modified vaccinia Ankara expressing virus nucleoprotein and matrix protein 1; MVA-NP+M1), which has been shown to induce both CD4 and CD8 T cells, at eight outpatient clinical trial sites in Australia over two consecutive influenza seasons. We recruited non-immunosuppressed adults (≥18 years) who had received the 2019 quadrivalent influenza vaccine (QIV) vaccine within 28 days before study enrolment and randomisation (day 0). Participants were randomly assigned (1:1) according to a computer-generated random sequence to receive one dose of 1·5 × 10⁸ plaque-forming units of MVA-NP+M1 or saline (placebo) intramuscularly. Randomisation was stratified by age (<65 years or ≥65 years). The patients and trial assessors were masked to treatment assignment. During the subsequent influenza seasons, participants with symptoms related to respiratory illness or influenza-like illness were to attend the clinic within 72 h of symptom onset for two nasal swabs for influenza testing by quantitative RT-PCR. The primary endpoint was the incidence rate of laboratory-confirmed influenza in the intention-to-treat (ITT) population. Safety (solicited adverse events within 7 days and unsolicited adverse events within 28 days after study vaccination, and serious adverse events for the study duration) was assessed in all randomly assigned participants who received at least one vaccination (according to the treatment received). The trial is registered with ClinicalTrials.gov, NCT03880474.

FINDINGS:

Between April 2 and June 14, 2019, 2152 adults were randomly allocated and received MVA-NP+M1 (n=1077) or placebo (n=1075), comprising the efficacy (ITT) analysis set. Participants were followed up throughout the 2019 Australia influenza season (May 1 to Oct 15, 2019). 419 (19·5%) of 2152 participants were aged 65 years or older. The incidence of laboratory-confirmed influenza did not differ between the MVA-NP+M1 group (35 of 1077 participants; 3·25% [95% CI 2·31-4·44]) and the placebo group (23 of 1075; 2·14% [1·39-3·14]; Fisher's exact p=0·14). 23 severe solicited local injection site reactions were reported in 13 (0·6%) of 2152 participants, 22 of which were reported in the MVA-NP + M1 group (in 12 [1·1%] participants). 100 severe systemic events were reported in 45 (4·2%) MVA-NP + M1 recipients, and 20 were reported in 14 (1·3%) placebo recipients. Three unsolicited grade 3 events in three participants (two headache and one nausea, all in the MVA-NP+M1 group) were deemed vaccine related. 21 serious adverse events were reported in 18 (1·7%) of 1077 participants in the MVA-NP+M1 group and 25 serious adverse events were reported in 22 (2·0%) of 1075 participants in the placebo group; none were considered vaccine related. The trial was stopped after one season for futility on the recommendation of the data monitoring committee.

INTERPRETATION:

MVA-NP+M1 was well tolerated with no vaccine-associated serious adverse events. A vaccine designed to induce moderate T-cell responses to the cross-reactive internal proteins of influenza A did not lead to improved incidence when given within 28 days after standard QIV immunisation. A greater magnitude of T-cell response with a different vaccine or regimen, or localisation in the lungs via alternative delivery, such as intranasal or aerosol, might be successful and require further investigation.

FUNDING:

Vaccitech.

2020-08-04·The Journal of infectious diseases2区 · 医学

Modified Vaccinia Ankara–Vectored Vaccine Expressing Nucleoprotein and Matrix Protein 1 (M1) Activates Mucosal M1-Specific T-Cell Immunity and Tissue-Resident Memory T Cells in Human Nasopharynx-Associated Lymphoid Tissue

2区 · 医学

Article

作者: McNamara, Paul S ; Zhang, Qibo ; Leong, Sam ; Sharma, Ravi ; Krishnan, Madhan ; Ahmed, Muhammad S ; Puksuriwong, Suttida ; Gilbert, Sarah C ; Lambe, Teresa

Abstract:

Background:

Increasing evidence supports a critical role of CD8+ T-cell immunity against influenza. Activation of mucosal CD8+ T cells, particularly tissue-resident memory T (TRM) cells recognizing conserved epitopes would mediate rapid and broad protection. Matrix protein 1 (M1) is a well-conserved internal protein.

Methods:

We studied the capacity of modified vaccinia Ankara (MVA)–vectored vaccine expressing nucleoprotein (NP) and M1 (MVA-NP+M1) to activate M1-specific CD8+ T-cell response, including TRM cells, in nasopharynx-associated lymphoid tissue from children and adults.

Results:

After MVA-NP+M1 stimulation, M1 was abundantly expressed in adenotonsillar epithelial cells and B cells. MVA-NP+M1 activated a marked interferon γ–secreting T-cell response to M1 peptides. Using tetramer staining, we showed the vaccine activated a marked increase in M158–66 peptide-specific CD8+ T cells in tonsillar mononuclear cells of HLA-matched individuals. We also demonstrated MVA-NP+M1 activated a substantial increase in TRM cells exhibiting effector memory T-cell phenotype. On recall antigen recognition, M1-specific T cells rapidly undergo cytotoxic degranulation, release granzyme B and proinflammatory cytokines, leading to target cell killing.

Conclusions:

MVA-NP+M1 elicits a substantial M1-specific T-cell response, including TRM cells, in nasopharynx-associated lymphoid tissue, demonstrating its strong capacity to expand memory T-cell pool exhibiting effector memory T-cell phenotype, therefore offering great potential for rapid and broad protection against influenza reinfection.

项与 VTP-100 相关的新闻（医药）

2024-02-27

·Business Wire

Global H3N2 infection Drug Pipeline Landscape Report 2024: Insights on 15+ Companies and 20+ Pipeline Drugs - ResearchAndMarkets.com

DUBLIN--( BUSINESS WIRE )--The "H3N2 infection - Pipeline Insight, 2024" drug pipelines has been added to ResearchAndMarkets.com's offering. This report provides comprehensive insights about 15+ companies and 20+ pipeline drugs in H3N2 infection pipeline landscape. It covers the pipeline drug profiles, including clinical and nonclinical stage products. It also covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space. The report outlays comprehensive insights of present scenario and growth prospects across the indication. A detailed picture of the H3N2 infection pipeline landscape is provided which includes the disease overview and H3N2 infection treatment guidelines. The assessment part of the report embraces, in depth H3N2 infection commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, H3N2 infection collaborations, licensing, mergers and acquisition, funding, designations and other product related details. Report Highlights The companies and academics are working to assess challenges and seek opportunities that could influence H3N2 infection R&D. The therapies under development are focused on novel approaches to treat/improve H3N2 infection. H3N2 infection Emerging Drugs Chapters This segment of the H3N2 infection report encloses its detailed analysis of various drugs in different stages of clinical development, including phase III, II, II/III I, preclinical and Discovery. It also helps to understand clinical trial details, expressive pharmacological action, agreements and collaborations, and the latest news and press releases. H3N2 infection Emerging Drugs mRNA-1083: Moderna Therapeutics mRNA-1083 is under development for the prevention of influenza virus infection caused by influenza A/H1N1, A/H3N2, and influenza B/Yamagata and B/Victoria strains and coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in 18 to 79 years of age group. It is a combination vaccine of mRNA-1283, which encodes Receptor Binding Doman (RBD) and N-Terminal Domain (NTD) of the spike protein and mRNA-1010, which encodes hemagglutinin (HA) glycoproteins of influenza A/H1N1, A/H3N2, and influenza B/Yamagata and B/Victoria-lineages. It is administered through intramuscular route in the form of sterile liquid for injection. Currently, the drug is in Phase III stage of its clinical trial for the treatment H3N2 infection. CD-388: Cidara therapeutics CD-388 is under development of the treatment and prevention of influenza virus A, seasonal influenza, pandemic influenza and influenza virus B infections. The drug candidate is a second generation, anti-viral Fc conjugate (AVC). It comprises of two moieties attached through a chemical linker. One is a targeting moiety (TM) that recognizes cell surface target and another is an effector moiety (EM) that is recognized by the immune system. It is administered through intramuscular and subcutaneous route. Currently, the drug is in Phase II stage of its clinical trial for the treatment of H3N2 infection. PF-07845104: Pfizer PF-07845104 is a prophylactic saRNA Vaccine developed by Pfizer. Its therapeutics area include infectious respiratory diseases. Currently, the drug is in phase I stage of its clinical trial for the treatment of H3N2 infection. H3N2 infection: Therapeutic Assessment Major Players in H3N2 infection There are approx. 15+ key companies which are developing the therapies for H3N2 infection. The companies which have their H3N2 infection drug candidates in the most advanced stage, i.e. Phase III include, Moderna Therapeutics. Phases Late stage products (Phase III) Mid-stage products (Phase II) Early-stage product (Phase I) along with the details of Pre-clinical and Discovery stage candidates Discontinued & Inactive candidates Route of Administration Products have been categorized under various ROAs such as Intravenous Subcutaneous Oral Intramuscular Molecule Type Products have been categorized under various Molecule types such as Monoclonal antibody Small molecule Peptide Product Type H3N2 infection Report Insights H3N2 infection Pipeline Analysis Therapeutic Assessment Unmet Needs Impact of Drugs H3N2 infection Report Assessment Pipeline Product Profiles Therapeutic Assessment Pipeline Assessment Inactive drugs assessment Unmet Needs Key Players Novartis Vaccines PDS Biotechnology Corporation Sanofi Moderna Therapeutics Pfizer Cidara therapeutics GRDG SCIENECES FluGen Inc. Barinthus Biotherapeutics Key Products NanoFlu PDS0202 MRT-5400 mRNA 1083 PF-07845104 CD 388 Equivir H3N2 M2SR influenza vaccine MVA-NP+M1 For more information about this drug pipelines report visit https://www.researchandmarkets.com/r/kiulgc About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends.

临床2期疫苗临床3期临床1期

2023-12-03

·生物制品圈

人用疫苗生产用细胞基质使用现状及研究进展

中文摘要疫苗是预防控制传染性疾病的最有效手段，传染性疾病中约80%是由病毒引起的。传统病毒类疫苗的制备需经过病毒培养、抗原收获、抗原浓缩、纯化过滤等过程。由于病毒的生长和繁殖必须在细胞内进行，因此细胞基质的优劣直接影响疫苗的质量。此文对各类细胞基质使用情况及优缺点进行综述，旨在为选择合适的人用疫苗生产用细胞基质提供参考。正文疫苗的研发和使用为人类健康构筑了一道免疫屏障，疫苗的制备首先需要病原微生物的增殖。病毒的生长和繁殖离不开细胞，为病毒增殖提供营养的细胞称为细胞基质，包括原代细胞、传代细胞及二倍体细胞。早期曾使用受感染的人或动物组织以及被感染的血清等生产疫苗，使用细胞基质生产疫苗是当今疫苗生产企业的主流。细胞基质疫苗生产工艺经历了3次重要的变革：第1次变革是使用原代细胞培养技术成功研制脊髓灰质炎疫苗；第2次变革是从原代细胞中获得传代细胞和二倍体细胞；第3次变革是结合基因工程、克隆等分子技术建立专利细胞系。细胞基质的优劣直接影响疫苗产品的产量和质量，选择合适的细胞基质进行疫苗生产对于疫苗企业而言意义重大。本文对各类细胞基质使用情况及优缺点进行综述，旨在为选择合适的人用疫苗生产用细胞基质提供参考。1原代细胞原代细胞是指将来自健康动物的组织或胚胎以适当的方式消化分散后进行培养的细胞。我国已上市的疫苗中，乙型脑炎疫苗、肾综合征出血热疫苗、狂犬病疫苗均使用了地鼠肾细胞，麻疹、腮腺炎疫苗使用了鸡胚细胞，风疹疫苗、轮状病毒疫苗分别使用了兔肾细胞和牛肾细胞。原代细胞无致瘤性，对多种病毒敏感，易于培养，适合规模化生产；缺点是外源因子污染风险大，受动物个体差异影响较大，无法充分鉴定和标准化。1.1鸡胚细胞鸡胚细胞基质灭活流感疫苗上市已有80多年，具有良好的安全性和免疫原性，已在全球范围内大规模接种。德国的人用狂犬病疫苗Rabipur®是采用Flury LEP株狂犬病病毒适应鸡胚细胞培养而成，疫苗有效且耐受性良好，至今仍被广泛使用。鸡胚细胞的优点是对各类病毒广泛敏感且接种病毒不会产生针对性抗体，培养简便易操作；缺点是存在供应不足的风险，产量不一致，耗时，制造成本高以及鸡蛋成分可能引发过敏反应等。1.2地鼠肾细胞我国于1965年使用原代地鼠肾（primary hamster kidney，PHK）细胞成功研制狂犬病灭活疫苗，目前仍在市场上使用。1968年，使用狂犬病病毒SAD株适应PHK细胞制备的狂犬病灭活疫苗在加拿大批准上市。俄罗斯至今仍在使用PHK细胞培养的Vnukovo-32狂犬病灭活疫苗。我国使用乙型脑炎病毒JEVSA14-14-2减毒株接种PHK细胞生产的灭活疫苗和减毒活疫苗，相对于鼠脑灭活疫苗免疫效果良好、成本低、不良反应少。李佳林等建立了PHK细胞工厂传代培养狂犬病病毒工艺，为狂犬病疫苗的规模化生产提供了参考。由于PHK细胞需要贴壁生长，而传统的生物反应器通常用于悬浮细胞的培养，难以提供足够的表面积来支持大量贴壁细胞的生长，因此PHK细胞在生物反应器中进行大规模培养存在一定的困难，制约了其在疫苗研发方面的应用。2传代细胞传代细胞是初始细胞（原代细胞或已建立的细胞系）经过细胞分裂进行连续传代而得到的细胞群。由于肿瘤组织具有致瘤性，出于安全考虑，用于疫苗生产的传代细胞大都来源于正常组织。疫苗生产常用的传代细胞有Vero细胞、Madin-Darby犬肾（Madin-Darby canine kidney，MDCK）细胞、中国仓鼠卵巢（Chinese hamster ovary，CHO）细胞等。Vero细胞适合流感病毒、麻疹病毒、腮腺炎病毒、天花病毒、脊髓灰质炎病毒、虫媒病毒的培养。MDCK细胞适合甲型和乙型流感病毒、脊髓灰质炎病毒等病毒的培养。CHO细胞适合乙型肝炎（乙肝）疫苗、新型冠状病毒重组亚单位疫苗等蛋白类疫苗的生产。2.1Vero细胞Vero细胞对多种病毒易感，感染后不产生干扰素，增殖力强，生产的病毒抗原具有良好的稳定性，可实现大规模培养，被WHO推荐为病毒性疫苗生产的首选细胞系。根据WHO的评估，Vero细胞在150代以内仍能保持其稳定的遗传特性和生长特性，没有观察到明显的细胞异常或致瘤性，上述代次范围内的Vero细胞被认为是适合病毒性疫苗生产的可靠和安全的细胞基质。目前国内使用Vero细胞生产的疫苗有人用狂犬病纯化疫苗、脊髓灰质炎灭活疫苗、新型冠状病毒灭活疫苗等。国外使用Vero细胞生产的疫苗有流感疫苗（Vepacel®和Preflucel®）、脊髓灰质炎疫苗（IMOVAX Polio®和OPV® ）、狂犬病疫苗（VERORAB® ）等。张炎华等报道，新型冠状病毒感染Vero-E6细胞48 h内迅速增殖，平均复制周期约为3.29 h，48 h后病毒感染滴度逐渐下降。刘鹏等使用自主研制的Vero细胞悬浮培养基（VSM-1）在搅拌瓶中驯化贴壁Vero细胞适应悬浮培养，接种H5N1和H7N9流感病毒后，悬浮Vero细胞平均血凝滴度均高于贴壁对照组。Vero细胞的缺点如下：悬浮驯化较难，大多使用微载体培养法，生产成本较高，效率低；可用的无血清培养基较少，疫苗质量和生产效率差异较大。目前研发改进主要从以下两方面进行：开发安全、稳定、可控的无血清培养基，或者通过基因工程手段改造Vero细胞，降低Vero细胞对血清的依赖性；通过Vero细胞的悬浮驯化实现Vero细胞的高密度培养，提高疫苗质量和产量。2.2MDCK细胞MDCK细胞因具有致瘤性而不如Vero细胞使用广泛，主要用于流感疫苗的生产。目前国外已有MDCK细胞基质流感疫苗上市，尚未出现不良反应报道。国内首个MDCK细胞流感疫苗于2022年10月启动临床研究。MDCK细胞对不同型和亚型流感病毒株都具有广泛的敏感性，且可以实现病毒的有效扩增，被广泛应用于流感病毒的分离、培养和感染性滴度检测。张哲罡报道，MDCK细胞基质流感疫苗诱导小鼠的细胞免疫及天然免疫的能力优于鸡胚细胞基质流感疫苗。马萍等报道，使用MDCK细胞进行流感疫苗的生产可以显著提高疫苗的效力。相比于Vero细胞，MDCK细胞对流感病毒更敏感，并且能够获得更高的病毒滴度。赵彩红等建立了无血清悬浮培养MDCK细胞系，实现了从5 L到75 L生物反应器的高密度线性放大培养。随着对细胞系安全性和稳定性的不断关注，无致瘤性MDCK细胞系成为研究和应用的前沿。这种细胞系具有与传统MDCK细胞相似的生长特性和对流感病毒的敏感性，但不会导致肿瘤的发生。目前，美国Medlmmune公司已经成功开发了这种细胞系，裸鼠注射剂量达107细胞后未出现致瘤性，该细胞系还可以在无血清培养基中生长。2.3CHO细胞CHO细胞能对蛋白质进行准确加工和修饰，表达的蛋白质纯度高、杂质少、与天然蛋白质接近，是生产重组蛋白疫苗的首选。20世纪90年代初，中国预防医学科学院病毒学研究所和长春生物制品研究所等机构共同研制了CHO细胞表达的基因工程乙肝疫苗。随后，兰州生物制品研究所、成都生物制品研究所、石家庄华北制药集团等研发的CHO细胞重组乙肝疫苗也获批上市。英国葛兰素史克公司研发的CHO细胞带状疱疹疫苗Shingrix（欣安立适）于2017年10月获FDA批准上市。2021年，中国科学院微生物研究所与安徽智飞龙科马生物制药有限公司共同研发了重组亚单位COVID-19疫苗，该疫苗具有良好的安全性和免疫原性；III期临床试验结果显示，3剂次疫苗接种6个月后，预防新型冠状病毒Alpha、Delta和Kappa等突变株引起的有症状感染的保护力为75.7%；预防重症、危重症感染的保护力为87.6%。CHO细胞在表达蛋白质时存在一定程度的异质性，包括糖基化模式和蛋白质折叠状态的差异，可能需要进一步后处理和纯化步骤来获得所需的产物。CHO细胞在培养过程中对氧气和营养物质的需求较高，特别是对血清和氨基酸的依赖性较大，培养成本相对较高。今后的研究可以从培养基的优化、高产重组CHO细胞株的构建、大规模培养3个方面展开，进一步提高重组蛋白在CHO细胞表达系统中的产量。3人二倍体细胞二倍体细胞通常来源于正常胎儿组织，可在一定代次内进行体外传代培养。目前用于疫苗生产的人二倍体细胞主要包括由英国汉普斯特德实验室制备的MRC-5细胞和我国自主研发的2BS细胞、KMB-17细胞。二倍体细胞作为人源细胞，与原代细胞相比外源因子污染风险低，与传代细胞相比无致瘤性，安全性好。刘欣玉等对疫苗生产用人二倍体细胞2BS和MRC-5中猪圆环病毒进行检测，结果为阴性。人二倍体细胞与人的抗原性一致，避免了疫苗的宿主细胞蛋白和外源DNA残留的问题，可以显著降低疫苗接种不良反应率。范斌等报道，使用Vero细胞生产的纯化狂犬病疫苗可能引发一些不良反应，如注射部位疼痛、发红、肿胀等，而人二倍体细胞狂犬病疫苗的注射往往耐受性更好，不良反应较少。尽管人二倍体细胞在疫苗生产中具有明显的优势，但其大规模培养仍面临挑战。人二倍体细胞的培养需要严格的环境控制、特定的培养基配方和复杂的培养技术，增加了生产过程的复杂性和成本。此外，人二倍体细胞的生长特性和代谢特点对培养条件的要求更为苛刻，大规模生产中的稳定性和一致性也是一个挑战。4新型细胞基质为了更好地适应特定生产工艺，生产商正在研发新型细胞基质，已经报道的专利细胞系有PER.C6®、AGE1.CR.pIX、EB66®、PBS-12SF、DuckCelt®-T17和MFF-8C1等。这些细胞系大都可以进行无血清悬浮培养。由荷兰Crucell公司研发的PER.C6®来源于人胚视网膜细胞，对腺病毒、流感病毒、脊髓灰质炎病毒、埃博拉病毒敏感。在比利时进行的首次临床研究评估了基于高产PER.C6®细胞系生产的Sabin株脊髓灰质炎病毒灭活疫苗（Sabin inactivated poliovirus vaccine，sIPV），结果表明基于PER.C6®细胞的sIPV在已有抗脊髓灰质炎病毒抗体的成人中具有良好的耐受性和高度的免疫原性。随后在婴儿中进行的评估也显示，基于PER.C6®细胞的sIPV对3个型别Sabin株病毒均诱导了较高的血清转化率和中和抗体几何平均滴度，安全性和免疫原性可接受。AGE1.CR.pIX由德国ProBioGen公司研发，来源于鸭视网膜细胞，对天花病毒、鸡痘病毒、流感病毒敏感。目前英国Vaccitech公司利用AGE1.CR.pIX研发了通用型甲型流感疫苗MVA-NP+M1。Trabelsi 等的研究表明，在 AGE1.CR.pIX 悬浮细胞系中，用化学限定的培养基能以可扩展工艺有效生产兽用狂犬病疫苗。EB66®由法国Valneva公司研发，来源于鸭胚细胞，对流感病毒、麻疹病毒、流行性腮腺炎病毒、痘病毒等病毒敏感。2014年，基于EB66®细胞的H5N1大流行流感储备疫苗在日本获得上市许可。Endo等开发了使用EB66®细胞培养平台（KD-295）生产的AS03佐剂H5N1流感疫苗，具有良好的耐受性和高免疫原性。Nikolay等报道，EB66®灌注培养可以有效提高黄病毒和寨卡病毒的产量。Coussens等建立了一种永生化的鸡胚细胞系，称为PBS-12SF，该细胞系适合在无血清条件下生长，能够将人和重组H5N1流感毒株扩增至高滴度。在许多情况下，PBS-12SF细胞培养的流感病毒滴度高于原代鸡胚肾细胞、MDCK细胞和Vero细胞。此外，在PBS-12SF细胞培养中，流感病毒被释放到培养液，不需要外源蛋白酶，这可以简化疫苗生产的下游处理。DuckCelt®-T17细胞系是由鸭端粒酶逆转录酶组成性表达的原代鸭胚胎细胞培养而成，在批量悬浮培养和无血清条件下生长的最高密度可达6.5X106 ml-1，培养体积可以从10 ml放大到3 L生物反应器。通过优化感染条件，使用DuckCelt®-T17细胞系培养各种人、禽和猪流感病毒，大部分可以获得高感染滴度（>5.8 lgTCID50/ml）。Dong等通过单细胞克隆从蹶鱼鱼苗的早期原代培养物中建立了新的成纤维细胞样细胞系，命名为MFF-8C1。MFF-8C1细胞在含10%胎牛血清的Dulbecco改良Eagle培养基中生长良好，培养的巨细胞病毒悬浮液对感染的蹶鱼具有高度毒性，是用于巨细胞病毒疫苗生产的有前途的候选细胞基质。5总结与展望引入和建立用于病毒性疫苗生产的新细胞基质是一个繁琐、耗时且成本高昂的过程，目前仍然只有少量的细胞基质可用。用于疫苗生产的理想细胞基质应当显示出“工业友好”的特性：能快速、高密度增殖，具有广泛的病毒敏感性及较高的感染滴度，保持其安全性及传代过程中的稳定性，可以满足大规模生产的需求。此外，细胞基质作为疫苗制剂的组成部分，必须满足安全和监管法规的要求，主要考虑外源因子污染、逆转录酶活性、细胞致瘤性、细胞DNA残留和蛋白残留、抗生素残留等。原代细胞虽然培养简单，可以大规模生产，但是不同个体动物的细胞在质量和病毒敏感性方面存在较大差异，培养过程中容易受外源因子污染。与之相比，传代细胞使用细胞种子库生产，经过充分鉴定和标准化，外源因子污染风险较小，有利于进行质量控制，但是存在致瘤的潜在风险。二倍体细胞无致瘤性，安全性好，但是培养难度大，难于大规模生产。新型细胞基质的研发产生了专利细胞系，可以进行无血清悬浮培养。无血清培养可以降低培养基成本，以及避免血清差异带来的批间差异，而悬浮培养可以加大细胞培养密度从而提高产量。专利细胞系适合大规模生产，但是其安全性和有效性还有待评估和验证。目前尚无细胞基质能满足所有的标准，每种新候选疫苗都需要考虑和评估不同的细胞基质，以选择最佳的细胞基质平台。作者程尧程小玲申瑷琳综述施金荣审校武汉生物制品研究所有限责任公司质量控制室，武汉 430207通信作者：施金荣，Email：jrshi2002@sohu.com引用本文：程尧, 程小玲, 申瑷琳, 等. 人用疫苗生产用细胞基质使用现状及研究进展 [J]. 国际生物制品学杂志, 2023, 46(5): 295-299. DOI: 10.3760/cma.j.cn311962-20221108-00078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。

疫苗上市批准

2022-07-04

·生物制品圈

流感减毒活疫苗可以预防新型冠状病毒吗？

摘要：不论是流感病毒还是新型冠状病毒（SARS-CoV-2），这些呼吸道病毒因其容易大规模传播、防控困难、造成危害大而受到广泛关注。最近研究表明，如果共同感染流感病毒和SARS-CoV-2会出现更加严重的临床症状，但是，若在感染SARS-CoV-2前接种流感疫苗能够显著降低SARS-CoV-2感染风险以及减轻COVID-19疾病严重程度，这些发现支持了呼吸道病毒的交叉保护作用。那么流感减毒活疫苗能否预防SARS-CoV-2感染或减轻疾病症状？本文将从流感疫苗研究进展、流感减毒活疫苗（LAIV）研究进展以及其对SARS-CoV-2保护作用研究进展进行综述。一、流感疫苗研究进展流感严重破坏公共卫生系统的建设，每年全球约有10亿感染病例并造成29万~65万与流感相关的呼吸道死亡病例[1]。当流感大流行发生时，这一数字还会急剧增加。接种流感疫苗是预防控制流感疾病的有效措施。目前上市的流感疫苗包括流感灭活疫苗（inactivated influenza vaccines，IIV）、流感减毒活疫苗（live-attenuated influenza vaccines，LAIV）和重组蛋白疫苗（recombinant influenza vaccines，RIV）3种类型[2]，中国和美国目前获批上市的季节性流感疫苗汇总见表1。表1. 中美获得许可的季节性流感疫苗由于安全性高和生产技术成熟，目前IIV是最常用的流感疫苗。然而，传统IIV的生产基质是鸡胚。基于鸡胚生产的流感疫苗最大的缺陷是生产周期长，尤其是在流感大流行期间，鸡胚供应问题可能影响疫苗的产量。值得注意的是，流感病毒在鸡胚传代过程中存在产生突变的可能，因此会影响疫苗效力[3]。此外，还有部分人群对鸡胚成分过敏也限制了鸡胚流感疫苗的使用。与IIV和RIV相比，LAIV单胚产量高于IIV，此外，LAIV通过模拟自然感染诱导更为广泛的免疫反应[4]。当前对流感疫苗的研究主要集中在缩短生产周期和提高毒株特异性免疫反应以及存在交叉免疫的广谱疫苗株研发（通用流感疫苗）。新一代流感疫苗包括病毒样颗粒（virus-like particles, VLP）、多肽疫苗、病毒载体疫苗和核酸疫苗。VLP是一种有效的疫苗成分，多种免疫原已在VLP上进行了试验，包括HA、基质蛋白2（matrix protein 2, M2）和神经氨酸酶（neuraminidase , NA）。与VLP相比，多肽疫苗则侧重于流感病毒的最小表位，如诱导T细胞免疫的核蛋白（nucleoprotein, NP）和基质蛋白（matrix protein 1, M1）。然而，与VLP疫苗一样需要递送载体辅助抗原运送到指定位置，同时为了具有足够的免疫原性，多肽疫苗通常需要添加佐剂。核酸疫苗避免了载体疫苗的抗载体免疫反应，避免了预存免疫的限制。Petsch等[5]将mRNA疫苗应用于流感疫苗，这种疫苗可快速制备，且在几种动物模型的研究中均证实了对流感的保护作用。然而，不管是灭活疫苗、减毒活疫苗、重组亚单位疫苗还是新一代疫苗均是以诱导先天性免疫和适应性免疫（体液免疫和细胞免疫）反应为目的。图1.不同类型流感疫苗的免疫应答二、流感减毒活疫苗研究进展早在1930年，由俄罗斯的阿纳托利教授团队观察发现，流感病毒经过小鼠肺部连续传代后其毒力减弱，该发现促进了关于宿主范围突变株的研究。20世纪60年代，自俄罗斯通过温度梯度降低法首次获得具有冷适应性的流感病毒以来，LAIV的研发备受关注。经低温条件筛选的流感病毒具有冷适应性、温度敏感性和减毒性，在上呼吸道（25 ℃）的复制能力较野毒株更好，因此可以刺激强的免疫应答；而在温度较高的下呼吸道（38 ℃）的复制能力比野生型的流感病毒低得多，因此该毒株不会引起肺部炎症；该病毒株毒力大幅削减，因此不会导致受种者感染流感，保证安全。反向遗传学技术的出现大大推动了LAIV的发展。近年来，借助反向遗传学技术，以冷适应减毒株为主供体株或以病毒基因定向改造为策略，研发新一代的LAIV成为当今流感疫苗研究热点，见图2。目前，应用LAIV的国家主要包括美国、俄罗斯、中国等多个国家。其中俄罗斯已成功应用LAIV多年，研究表明，该疫苗安全有效，在3岁以上儿童、成人及老人免疫1次即可产生良好的免疫保护。图2.新型LAIV制备流程2009年，由MedImune制造的一种鼻内免疫的LAIV（FluMist）在美国获得批准，利用反向遗传学技术来生产的冷适应性LAIV可安全用于2~49岁的儿童和成人，是一种四价流感疫苗[11]。FluMist是美国市场上销售的第一个通过鼻腔给药的疫苗；2011年，该疫苗被欧洲药品管理局批注使用。而在我国，长春百克生物科技股份公司（百克生物）与WHO合作的冻干鼻喷流感减毒活疫苗—感雾®获批签发合格证明，正式上市销售，这标志着我国流感疫苗全面进入鼻喷时代。与IIV和RIV主要诱导体液反应相比，LAIV不仅可同时刺激体液免疫和细胞免疫，还能诱导先天性免疫（黏膜免疫）反应，免疫效应持续时间更长，在这方面优于IIV和RIV[6-8]。该疫苗使用SPF鸡胚生产，不含灭活剂、裂解剂和防腐剂，除能有效抵御疫苗株病毒外，还可以对其它亚型流感病毒产生交叉免疫。三、流感减毒活疫苗对新型冠状病毒保护性研究进展新型冠状病毒（SARS-CoV-2）与其他呼吸道病毒，例如与流感病毒合并流行可能对全球卫生系统造成不可预测的风险。研究表明，共同感染两种病毒的患者疾病症状可能更为严重。研究人员发现，某些疫苗具有增强先天性免疫应答，提供非特异性保护的作用，换句话讲，接种此类疫苗可以训练免疫系统的应答反应。根据最新的流行病学研究表明，流感疫苗和COVID-19之间存在交叉免疫保护机制[12]。一项在巴西进行的IIV3接种与COVID-19死亡率以及严重临床结局的相关性研究中，近期接种过流感疫苗的患者需要重症监护治疗的几率平均降低7%（95%CI：0.87~0.98），需要有创呼吸支持的几率降低17%（95%CI：0.77~0.88），死亡几率降低16%（95%CI：0.78~0.90），接种IIV的COVID-19患者的健康状况明显优于未接种疫苗的患者[13]。在SARS-CoV-2大流行的最初几个月，虽然COVID-19疫苗仍在研制中，但研究人员对现有疫苗可能提供一些SARS-CoV-2防护的可能性非常感兴趣[14]。由卡塔尔威尔康奈尔医学公司（Weill Cornell Medicine）传染病流行病学家Abu Raddad领导的一个团队分析了该国30774名医务人员的健康记录。医务人员在健康相关行为方面的差异较小，可以减小“健康用户效应”带来的研究分析偏差。研究人员跟踪了518名SARS-CoV-2检测呈阳性的医务工作者，并将他们与2000多名病毒检测呈阴性的参与者进行对比。与未接种过流感疫苗者相比，接种流感疫苗者预防SARS-CoV-2感染＞14天的有效性为29.7% （95% CI: 0.55~0.48），感染风险降低30%（95% CI：0.52~0.95）；预防COVID-19严重、危重疾病或死亡的有效性则为88.9%（95% CI: 0.04~0.99），风险降低89%（95%CI：0.01~0.96）。这项研究证实了使用流感疫苗可以增强先天性免疫应答帮助人体抵御SARS-CoV-2，同时接种流感疫苗还可显著降低SARS-CoV-2感染风险和COVID-19疾病的严重程度[15]。瑞士巴塞尔大学的流行病学家Günther Fink表示，卡塔尔的研究进一步支持了这一说法，并且他本人的研究小组研究结果也与之相似，但是目前尚不清楚这种保护能维持多久[14]。那么LAIV能否同IIV一样，可以预防SARS-CoV-2感染或减轻COVID-19临床症状？最近，Ryan等[16]在雪貂模型中证实，在SARS-CoV-2感染前/后3天，为雪貂接种四价LAIV，并未加重SARS-CoV-2病程或肺部病变，见图3、4。这一结果表明，SARS-CoV-2感染者接种LAIV并不会加重疾病严重程度。图3.评估LAIV对雪貂SARS-CoV-2感染影响的研究设计图4.肺和鼻腔组织的组织病理学检查此研究同时表明，在SARS-CoV-2感染前接种LAIV可显著抑制SARS-CoV-2在上呼吸道的复制与病毒释放，进而达到预防SARS-CoV-2感染或者减轻COVID-19症状[16]，见图5。最新研究报道，LAIV确实可显著降低SARS-CoV-2感染风险和COVID-19疾病严重程度。这种保护机制目前尚无法完全阐述清楚，可能是由于免疫反应性的普遍提高，增强了非特异性免疫应答或驯化了特异性免疫。前者持续的时间通常不会超过几周，而且即使是特异性COVID-19疫苗，其有效性也会随时间而降低，可能不会发挥长期的保护作用。图5. 流感疫苗预防SARS-CoV感染的有效性一些证据表明，流感疫苗可能刺激非特异性免疫反应，从而降低SARS-CoV-2感染的风险或感染后COVID-19的严重程度[17]。免疫记忆是获得性免疫系统的一个特征，但先天免疫系统的激活也会增强对后续触发因素的反应，这一过程被称为驯化免疫（Trained immunity）。过去十年的研究指出，训练有素的免疫系统对宿主防御有广泛的益处[19]。Huang[17]对2019年7月1日至2020年6月30日的数据进行了回顾性横断面研究，研究人群为年龄在65岁或以上的成年人，他们在2019年9月1日至12月31日期间接种了流感疫苗，主要结果和衡量指标是2020年1月15日后新冠病毒感染和严重新冠病毒疾病的几率。该研究发现，流感疫苗接种组和未接种流感疫苗组之间新冠病毒感染风险的调整后优势比（aOR）为0.76（95% CI，0.75–0.77）。在新冠肺炎患者中，流感疫苗接种组和未接种流感疫苗组之间发生严重新冠肺炎疾病的aOR为0.72（95%CI，0.68–0.76）。当比较流感疫苗接种组和其他疫苗接种组时，新冠病毒感染的aOR为0.95（95%CI，0.93–0.97），而发展为严重新冠病毒疾病的aOR为0.95（95%CI，0.80–1.13），见6。图6.流感疫苗预防COVID-19感染或者COVID-19疾病效力最近的流行病学研究表明，除了疾病特异性作用外，针对传染病的疫苗对免疫系统处理其他病原体的能力也有非特异性作用。例如，在随机试验中，结核病和麻疹疫苗与儿童总体死亡率的大幅降低有关，这已经远远超出预防目标疾病的范围。新的研究表明，疫苗的非特异性作用与适应性免疫系统与无关病原体的交叉反应有关，并与通过表观遗传重编程训练先天免疫系统有关[18]。另一个可能的机制是由于“旁观者免疫”（bystander immunity），这是由于长期存在的感染和炎症刺激，使自身抗原暴露于宿主免疫系统[20]。实际上，抗体记忆需要分子识别、基因表达程序和克隆动力学的协调。Horns等[20]使用单细胞和全套测序研究人类抗体记忆反应，揭示了记忆B细胞激活的转录程序、广泛结合的抗流感抗体以及流感疫苗接种后非疫苗结合抗体的广泛旁观者激活，见图7。图7.“旁观者免疫”激活非疫苗特异性抗体考虑到流感疫苗在成人中的安全性，建议接种流感疫苗，至少部分作为“旁观者佐剂”（bystander adjuvant），可以尽量减少COVID-19的严重程度[21]。除了流感疫苗以外，也有研究显示麻腮风三联疫苗有助于预防新冠感染和降低重症、死亡风险[16]。Zeng等[22]提出的假设是，对先前流感感染产生的免疫力将至少部分促进抗SARS-CoV-2免疫力。为了更好的预防SARS-CoV-2，尤其是在COVID-19疾病的高风险人群中推广流感疫苗的普种计划是非常有必要的！参考文献[1]Iuliano AD, Roguski KM, Chang HH, et al. Estimates of global seasonal influenza-associated respiratory mortality: a modelling study [J]. Lancet, 2018, 391(10127): 1285-1300. DOI: 10.1016/S0140-6736(17)33293-2.[2]Nuwarda RF, Alharbi AA, Kayser V. An Overview of Influenza Viruses and Vaccines. Vaccines (Basel). 2021;9(9):1032. doi:10.3390/vaccines9091032.[3]Paules CI, Sullivan SG, Subbarao K, et al. Chasing seasonal influenza - the need for a universal influenza vaccine [J]. N Engl J Med, 2018, 378(1): 7-9. DOI: 10.1056/NEJMp1714916.[4]Mohn KG, Smith I, Sjursen H, et al. Immune responses after live attenuated influenza vaccination [J]. Hum Vaccin Immunother, 2018, 14(3): 571-578. DOI: 10.1080/21645515.2017.1377376.[5]Petsch B, Schnee M, Vogel AB, et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection [J]. Nat Biotechnol, 2012, 30(12):1210-1216. DOI: 10.1038/nbt.2436.[6]Keshavarz M, Mirzaei H, Salemi M, et al. Influenza vaccine: Where are we and where do we go [J]. Rev Med Virol, 2019, 29(1): e2014. DOI:10.1002/rmv.2014.[7]Clements ML, Murphy BR. Development and persistence of local and systemic antibody responses in adults given live attenuated or inactivated influenza A virus vaccine [J]. J Clin Microbiol, 1986, 23(1): 66-72. DOI:10.1128/jcm.23.1.66-72.1986.[8]Piedra PA, Yan L, Kotloff K, et al. Safety of the trivalent, cold-adapted influenza vaccine in preschool-aged children [J]. Pediatrics, 2002, 110(4): 662-672. DOI:10.1542/peds.110.4.662.[9]Diebold SS. Recognition of viral single-stranded RNA by Toll-like receptors [J]. Adv Drug Deliv Rev, 2008, 60(7): 813-823. DOI:10.1016/j.addr.2007.11.004.[10]Toback SL, Ambrose CS, Eaton A, et al. A postlicensure evaluation of the safety of Ann Arbor strain live attenuated influenza vaccine in children 24-59 months of age [J]. Vaccine, 2013, 31(14): 1812-1818. DOI:10.1016/j.vaccine.2013.01.055.[11]Nuwarda RF, Alharbi AA, Kayser V. An Overview of Influenza Viruses and Vaccines [J]. Vaccines (Basel), 2021, 9(9):1032. DOI:10.3390/vaccines9091032.[12]Debisarun PA, Gössling KL, Bulut O, et al. Induction of trained immunity by influenza vaccination - impact on COVID-19 [J]. PLoS Pathog, 2021,17(10):e1009928. DOI:10.1371/journal.ppat.1009928.[13]Fink G, Orlova-Fink N, Schindler T, et al. Inactivated trivalent influenza vaccination is associated with lower mortality among patients with COVID-19 in Brazil [J]. BMJ Evid Based Med. 2020, bmjebm-2020-111549. DOI:10.1136/bmjebm-2020-111549.[14]Callaway E. Flu vaccine could cut COVID risk [J]. Nature, 2022. DOI:10.1038/d41586-022-01315-9.[15]Elias T, Sami A, Muna A A, et al. Effectiveness of influenza vaccination against SARS-CoV-2 infection among healthcare workers in Qatar [J]. medRxiv 2022. 05. 09. DOI:10.1101/2022.05.09.22274802.[16]Ryan KA, Schewe KE, Crowe J, et al. Sequential Delivery of Live Attenuated Influenza Vaccine and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in the Ferret Model Can Reduce SARS-CoV-2 Shedding and Does Not Result in Enhanced Lung Pathology [J]. J Infect Dis, 2022, 225(3): 404-412. DOI:10.1093/infdis/jiab594.[17]Huang K, Lin SW, Sheng WH, Wang CC. Influenza vaccination and the risk of COVID-19 infection and severe illness in older adults in the United States. Sci Rep. 2021;11(1):11025. doi:10.1038/s41598-021-90068-y.[18]Benn CS, Netea MG, Selin LK, Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 2013;34(9):431-439. doi:10.1016/j.it.2013.04.004[19]Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20(6):375-388. doi:10.1038/s41577-020-0285-6.[20]Horns F, Dekker CL, Quake SR. Memory B Cell Activation, Broad Anti-influenza Antibodies, and Bystander Activation Revealed by Single-Cell Transcriptomics. Cell Rep. 2020;30(3):905-913.e6. doi:10.1016/j.celrep.2019.12.063.[21]Salem ML, El-Hennawy D. The possible beneficial adjuvant effect of influenza vaccine to minimize the severity of COVID-19 [published online ahead of print, 2020 Apr 22]. Med Hypotheses. 2020;140:109752. doi:10.1016/j.mehy.2020.109752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。

信使RNA合作抗体疫苗

100 项与 VTP-100 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
流感病毒感染	临床2期	英国	Vaccitech (UK) Ltd.	2017-10-13

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03880474 (FLU009, Pubmed \| Lancet Infect Dis) 人工标引	临床2期	甲型流感病毒感染	2,152	MVA-NP+M1	憲鏇願襯繭糧築願選鑰(顧鑰鏇鑰憲襯積窪獵範) = 蓋鹹夢窪窪衊選築願夢醖積壓積鏇築夢襯夢遞 (艱觸願願繭築鏇願糧鏇 ) 更多	积极	2022-03-16
				Placebo	憲鏇願襯繭糧築願選鑰(顧鑰鏇鑰憲襯積窪獵範) = 壓鹽顧顧衊淵鹽蓋壓窪醖積壓積鏇築夢襯夢遞 (艱觸願願繭築鏇願糧鏇 ) 更多
NCT03880474 (FLU009, CTgov)	临床2期	流感病毒感染	2,364	MVA-NP (MVA-NP+M1 Group)	獵齋襯膚鹹壓範鬱遞顧(積壓願憲壓齋積糧襯積): Relative Risk = 1.52 (95% CI, 0.90 ~ 2.55), P-Value = 0.1146; Relative Risk = 1.52 (95% CI, 0.90 ~ 2.55), P-Value = 0.1146 更多	-	2021-04-26
				Placebo (Saline Placebo Group)