流感（Influenza）是一种高度传染性的呼吸道疾病，由流感病毒引起。这种病毒易于变异，每年都可能产生新的病毒株，这使得流感成为一个全球性的公共卫生问题。

特别需要强调的是，流感的中文意思是流行性感冒。实际上，流感（Influenza, flu）和普通感冒（common cold）是完全不同的两个疾病；流感更不是严重的感冒。

美国每年有1.2万人-6.2万人死于流感，不管是个人、社会还是政府，对于流感的预防都极为重视。比如美国18岁以上民众中，每年有一半的人会接种流感疫苗；并且，大部分医疗机构强制性要求医务人员接种流感疫苗；去家庭医生那里做年度常规体检，医生一定会问是否接种了流感疫苗，大部分人体检时就接种了疫苗。

【未解决的临床问题】

• 疫苗匹配问题：由于流感病毒的高度变异性，每年疫苗的研发都需要预测最有可能流行的病毒株，但这种预测不总是准确的。疫苗效果的不确定性是流感预防中的一个重大挑战。

• 抗病毒药物的耐药性：现有的抗流感病毒药物（如奥司他韦）已经出现了耐药性的问题，限制了治疗选项。

• 全球监控和应对：流感的全球监控网络需要实时更新和共享病毒株信息，以便迅速应对疫情爆发。然而，数据共享和国际合作仍有待加强。

• 高风险群体的保护：尽管已经明确了流感的高风险人群，但如何更有效地保护这些群体，减少严重并发症和死亡仍是公共卫生领域的关键问题。

总体而言，流感的管理需要全球卫生组织、各国政府和科研机构的共同努力，不断改进疫苗、加强监控和提高公众的疾病认知，以有效控制流感的传播和减轻其对公共健康的影响。

我们仅对美国国立卫生研究院（NIH）资助的在研流感相关项目进行梳理，希望给同仁们的选题思路提供一点启发。

2024年，以“Influenza”为检索词、在题目中进行检索，美国NIH针对流感的在研有335项。

一，谁获得了这些研究？

1，在研流感基金最多的PI

• ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI 的 KRAMMER, FLORIAN

• NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES 的 GALL, JASON

• ST. JUDE CHILDREN'S RESEARCH HOSPITAL 的 WEBBY, RICHARD

• DUKE UNIVERSITY 的 JOHNSON, MATTHEW

• DUKE UNIVERSITY 的 MOODY, TONY

2，流感基金最多的研究机构

• 杜克大学

• 西奈山伊坎医学院

• 美国国家过敏和传染病研究所

• 圣犹大儿童研究医院

• 埃默里大学等

二，流感研究热点是什么？

流感研究领域总览（根据关键词）

A，关于通用流感疫苗（Universal Influenza Vaccine）的研究项目最多

有 72 项在研基金涉及到了通用流感疫苗，关注最多的方面包括交叉保护（Cross Protection）、具体目标（Specific Aims）、流感血凝素 HA（Influenza Hemagglutinin HA）、诱发（Eliciting）、动物模型（Animal Models）、发病率和死亡率（Morbidity and Mortality）等研究。

B，关于T细胞（T Cell）的研究项目

有 66 项在研基金涉及到了T细胞，关注最多的方面包括CD8 T细胞、CD4 T细胞、免疫系统（Immune System）、IAV、适应性免疫（Adaptive Immunity）、佐剂（Adjuvants）等研究。

C，关于B细胞（B Cell）的研究项目

有 55 项在研基金涉及到了B细胞，关注最多的方面包括IAV、适应性免疫（Adaptive Immunity）、暴露（Exposure）、CD4 T细胞、血凝素和神经氨酸酶（HA and NA）、既有免疫力（Preexisting Immunity）等研究。

其他狼疮研究大的方向也包括禽流感病毒感染（IAV Infection）、传播（Transmission）、公共卫生（Public Health）等。

三，借鉴与突破

我们也分享在流感领域的几项课题摘要，希望对同仁们有所启发。

A，Development/production of universal influenza vaccines

Influenza vaccines conferring immunity against multiple strains of virus will be developed at the VPP and manufactured through the VCMP for human clinical trials in compliance with current Good Manufacturing Practices (cGMP) and released for use in human clinical trials in healthy human volunteers. These vaccines may confer broad immunity, a "universal influenza vaccine," over a period of several years against multiple strains in contrast to seasonal products that are only useful for a single season. If these trials demonstrate safety and immunogenicity of these vaccines in human trials, further evaluation may take place in larger (Phase 2) trials which will necessitate production of the clinical trial materials (CTM) at larger scale. Such vaccines would be effective over multiple seasons and would require lengthy clinical study and monitoring for effectiveness across strains that vary from season to season. Vaccines under development include nanoparticle-based vaccines specific to certain influenza strains as well as more broadly applicable or universal influenza vaccines. Future vaccines will include multivalent nanoparticle approaches.

B, A deep longitudinal analysis of next generation influenza vaccines in older adults

The central goal of this proposal is to understand the mechanisms that lead to a loss of response to influenza vaccine in older adults through establishment of the 3FluAging cohort of healthy older adults who will be vaccinated with three different influenza vaccines three years in a row. We hypothesize that aging impacts specific regulatory mechanisms of humoral immunity to reduce vaccine effectiveness.

In Aim 1, we will establish a cohort of 60 healthy older adults (≥65yrs) who will sequentially receive three different annual influenza vaccines, with serial blood and microbiome sample collection during three years of follow-up. Participants will undergo regular clinical assessments.

In Aim 2, we will decipher the magnitude and immunodominance pattern of the humoral response to influenza virus in healthy older individuals upon vaccination. For each vaccine, we will characterize antibody titer and quality and will define responders and non-responders.

In Aim 3, we will characterize the epigenome, transcriptome, cytokine production, and cell proportions of blood leukocytes in vaccinated healthy older participants. We will identify specific (epi)genomic and functional signatures, and their longevity, associated with vaccine response. We will also sequence all participants to uncover the role of genetic variation on influenza vaccine responses.

In Aim 4, we will assess the function of T helper cells and antigen presenting cells, specifically dendritic cells, in influenza vaccine responders and non-responders.

By identifying responders and non-responders for each vaccine and integrating these data with baseline immune status multi-omic signatures, we will determine which immune features can predict vaccine responsiveness. We expect to identify humoral immunity pathways that are altered in aging that can be used as the basis for designing novel approaches to boost efficacy of the most commonly used, as well as emerging, influenza vaccines..