Flu Universal Vaccines: New Tricks on an Old Virus

Conventional influenza vaccines are based on predicting the circulating viruses year by year, conferring limited effectiveness since the antigenicity of vaccine strains does not always match the circulating viruses. This necessitates development of universal influenza vaccines that provide broader and lasting protection against pan-influenza viruses. The discovery of the highly conserved immunogens(epitopes) of influenza viruses provides attractive targets for universal vaccine design. Here we review the current understanding with broadly protective immunogens(epitopes) and discuss several important considerations to achieve the goal of universal influenza vaccines.     

PML Suppresses Influenza Virus Replication by Promoting FBXW7 Expression

Virologica Sinica - Influenza A viruses (IAV) are responsible for seasonal flu epidemics, which can lead to high morbidity and mortality each year. Like other viruses, influenza virus can hijack...     

Epidemiological Characteristics of Influenza A and B in Macau, 2010–2018

Virologica Sinica - Influenza is one of the major respiratory diseases in humans. Macau is a tourist city with high density of population and special population mobility. The study on the...     

帕拉米韦氯化钠注射液对流感病毒A型肺炎患儿的成本-效益分析

目的:探讨帕拉米韦氯化钠注射液对流感病毒A型肺炎患儿的成本-效益。方法:选择我院2015年1月至2018年12月收治的96例流感病毒A型肺炎患儿,根据随机数字表法,将96例患儿分为A组及B组,每组48例,A组患儿给予磷酸奥司他韦颗粒,B组患儿给予帕拉米韦氯化钠注射液,对比两组患儿的治疗效果、临床症状消失时间、住院时间、用药成本、成本-效益,对比两组患儿治疗前及治疗后的血常规及肝肾功能,对比两组患儿的不良反应发生率。结果:B组患儿的治疗有效率明显较A组高(P<0.05)。观察组患儿的临床症状消失时间及住院时间明显较对照组低(P<0.05)。A组患儿的平均用药成本明显低于B组(P<0.05),A组的成本-效益较B组低。与治疗前相比,治疗后两组患儿的中性粒细胞总数明显升高,白细胞总数、淋巴细胞总数明显降低(P<0.05);而治疗前后,两组患儿的血常规指标对比无统计学意义(P>0.05)。治疗前后,两组患儿的肝肾功能对比均无统计学意义(P>0.05)。B组患儿的不良反应发生率较A组高,但组间对比无统计学意义(P>0.05)。结论:与磷酸奥司他韦相比,帕拉米韦氯化钠注射液对流感病毒A型肺炎患儿的疗效更佳,但其成本-效益较低,临床上可根据患儿实际情况选择用药。     

Correlation of adhesion molecules and non-typeable haemophilus influenzae growth in a mice coinfected model of acute inflammation

Primary influenza virus (IV) infection can predispose hosts to secondary infection with Haemophilus influenzae (H. influenzae), which further increases the severity and mortality of the disease. While adhesion molecules play a key role in the host inflammatory response and H. influenzae colonization, it remains to be clarified which types of adhesion molecules are associated with H. influenzae colonization and invasion following IV infection. In this study, we established a mouse model of co-infection with influenza A virus (A/Puerto Rico/8/34, H1N1) (PR8) and non-typeable H. influenzae (NTHi) and found that sequential infection with PR8 and NTHi induced a lethal synergy in mice. This outcome may be possibly due to increased NTHi loads, greater lung damage and higher levels of cytokines. Furthermore, the protein levels of intracellular adhesion molecules-1 (ICAM-1) and Fibronectin (Fn) were significantly increased in the lungs of coinfected mice, but the levels of carcinoembryonic adhesion molecule (CEACAM)-1, CEACAM-5 and platelet-activating factor receptor (PAFr) were unaffected. Both the protein levels of ICAM-1 and Fn were positively correlated with NTHi growth. These results indicate the correlation between adhesion molecules, including ICAM-1 and Fn, and NTHi growth in secondary NTHi pneumonia following primary IV infection.     

Predictive markers of safety and immunogenicity of adjuvanted vaccines

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.     

Evaluation of a Liposome-Supplemented Intranasal Influenza Subunit Vaccine in a Murine Model System: Induction of Systemic and Local Mucosal Immunity

Abstract

This study reports on the mucosal immunoadjuvant activity of liposomes in an experimental influenza subunit vaccine administered intranasally (i.n.) to mice. Antibody responses induced by the i.n. liposomal vaccine were compared to those induced by an influenza infection or by subcutaneous (s.c.) injection of subunit antigen alone, the conventional route of human flu vaccination. Negatively charged liposomes, but not positively charged or zwitter-ionic liposomes, coadministered i.n. with influenza subunit antigen, significantly stimulated systemic IgG levels and local antibody responses in pulmonary secretions, relative to the responses upon i.n. administration of subunit antigen alone. I.n. immunization with liposome-supplemented subunit antigen as well as s.c. immunization with subunit antigen alone or infection induced high levels of IgG antibodies in serum and pulmonary secretions, with a preferential induction of IgGl upon immunization and IgG2a upon infection. Both i.n. immunization with liposome-supplemented antigen and infection, but not s.c. immunization with subunit antigen alone, induced local secretion of S-IgA. At the same time, both IgA-and IgG-secreting cells appeared in (he lungs and lung-associated lymph nodes, suggestive of local antibody production. In conclusion, the liposomal adjuvant system, combined with a mucosal administration protocol, provides a promising strategy for induction of both systemic and local antibody responses against influenza virus.     

Induction of Anti-influenza Immunity by Modified Green Fluorescent Protein (GFP) Carrying Hemagglutinin-derived Epitope Structure

The development of vaccination methods that can overcome the emergence of new types of influenza strains caused by escape mutations is desirable to avoid future pandemics. Here, a novel type of immunogen was designed that targeted the conformation of a highly conserved region of influenza A virus hemagglutinin (HA) composed of two separate sequences that associate to form an anti-parallel β-sheet structure. Our previous study identified this β-sheet region as the structural core in the epitope of a characteristic antibody (B-1) that strongly neutralizes a wide variety of strains within the H3N2 serotype, and therefore this β-sheet region was considered a good target to induce broadly reactive immunity against the influenza A virus. To design the immunogen, residues derived from the B-1 epitope were introduced directly onto a part of enhanced green fluorescent protein (EGFP), whose surface is mostly composed of β-sheets. Through site-directed mutagenesis, several modified EGFPs with an epitope-mimicking structure embedded in their surface were prepared. Two EGFP variants, differing from wild-type (parental) EGFP by only five and nine residues, induced mice to produce antibodies that specifically bind to H3-type HA and neutralize H3N2 virus. Moreover, three of five mice immunized with each of these EGFP variants followed by a booster with equivalent mCherry variants acquired anti-viral immunity against challenge with H3N2 virus at a lethal dosage. In contrast to conventional methods, such as split HA vaccine, preparation of this type of immunogen requires less time and is therefore expected to be quickly responsive to newly emerged influenza viral strains.     

Sialylneolacto-N-tetraose c (LSTc)-bearing Liposomal Decoys Capture Influenza A Virus

Influenza is a severe disease in humans and animals with few effective therapies available. All strains of influenza virus are prone to developing drug resistance due to the high mutation rate in the viral genome. A therapeutic agent that targets a highly conserved region of the virus could bypass resistance and also be effective against multiple strains of influenza. Influenza uses many individually weak ligand binding interactions for a high avidity multivalent attachment to sialic acid-bearing cells. Polymerized sialic acid analogs can form multivalent interactions with influenza but are not ideal therapeutics due to solubility and toxicity issues. We used liposomes as a novel means for delivery of the glycan sialylneolacto-N-tetraose c (LSTc). LSTc-bearing decoy liposomes form multivalent, polymer-like interactions with influenza virus. Decoy liposomes competitively bind influenza virus in hemagglutination inhibition assays and inhibit infection of target cells in a dose-dependent manner. Inhibition is specific for influenza virus, as inhibition of Sendai virus and respiratory syncytial virus is not observed. In contrast, monovalent LSTc does not bind influenza virus or inhibit infectivity. LSTc decoy liposomes prevent the spread of influenza virus during multiple rounds of replication in vitro and extend survival of mice challenged with a lethal dose of virus. LSTc decoy liposomes co-localize with fluorescently tagged influenza virus, whereas control liposomes do not. Considering the conservation of the hemagglutinin binding pocket and the ability of decoy liposomes to form high avidity interactions with influenza hemagglutinin, our decoy liposomes have potential as a new therapeutic agent against emerging influenza strains.