Immune-engineered H7N9 influenza hemagglutinin improves protection against viral influenza virus challenge

AbstractWhile vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

Download Full-text

Thapsigargin Is a Broad-Spectrum Inhibitor of Major Human Respiratory Viruses: Coronavirus, Respiratory Syncytial Virus and Influenza A Virus

Viruses ◽

10.3390/v13020234 ◽

2021 ◽

Vol 13 (2) ◽

pp. 234

Author(s):

Sarah Al-Beltagi ◽

Cristian Alexandru Preda ◽

Leah V. Goulding ◽

Joe James ◽

Juan Pu ◽

...

Keyword(s):

Influenza Virus ◽

Respiratory Syncytial Virus ◽

Influenza A Virus ◽

Broad Spectrum ◽

Influenza A ◽

Respiratory Viruses ◽

Influenza Viruses ◽

Virus Challenge ◽

2009 H1n1 ◽

Syncytial Virus

The long-term control strategy of SARS-CoV-2 and other major respiratory viruses needs to include antivirals to treat acute infections, in addition to the judicious use of effective vaccines. Whilst COVID-19 vaccines are being rolled out for mass vaccination, the modest number of antivirals in use or development for any disease bears testament to the challenges of antiviral development. We recently showed that non-cytotoxic levels of thapsigargin (TG), an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca2+ ATPase pump, induces a potent host innate immune antiviral response that blocks influenza A virus replication. Here we show that TG is also highly effective in blocking the replication of respiratory syncytial virus (RSV), common cold coronavirus OC43, SARS-CoV-2 and influenza A virus in immortalized or primary human cells. TG’s antiviral performance was significantly better than remdesivir and ribavirin in their respective inhibition of OC43 and RSV. Notably, TG was just as inhibitory to coronaviruses (OC43 and SARS-CoV-2) and influenza viruses (USSR H1N1 and pdm 2009 H1N1) in separate infections as in co-infections. Post-infection oral gavage of acid-stable TG protected mice against a lethal influenza virus challenge. Together with its ability to inhibit the different viruses before or during active infection, and with an antiviral duration of at least 48 h post-TG exposure, we propose that TG (or its derivatives) is a promising broad-spectrum inhibitor against SARS-CoV-2, OC43, RSV and influenza virus.

Download Full-text

A Live-Attenuated Prime, Inactivated Boost Vaccination Strategy with Chimeric Hemagglutinin-Based Universal Influenza Virus Vaccines Provides Protection in Ferrets: A Confirmatory Study

Vaccines ◽

10.3390/vaccines6030047 ◽

2018 ◽

Vol 6 (3) ◽

pp. 47 ◽

Cited By ~ 15

Author(s):

Raffael Nachbagauer ◽

Florian Krammer ◽

Randy Albrecht

Keyword(s):

Influenza Virus ◽

Respiratory Tract ◽

Virus Vaccine ◽

Influenza Viruses ◽

Inactivated Vaccine ◽

Upper Respiratory Tract ◽

Live Attenuated Vaccine ◽

Virus Surface ◽

Virus Challenge ◽

Attenuated Vaccine

Influenza viruses cause severe diseases and mortality in humans on an annual basis. The current influenza virus vaccines can confer protection when they are well-matched with the circulating strains. However, due to constant changes of the virus surface glycoproteins, the vaccine efficacy can drop substantially in some seasons. In addition, the current seasonal influenza virus vaccines do not protect from avian influenza viruses of human pandemic potential. Novel influenza virus vaccines that aim to elicit antibodies against conserved epitopes like the hemagglutinin stalk could not only reduce the burden of drifted seasonal viruses but potentially also protect humans from infection with zoonotic and emerging pandemic influenza viruses. In this paper, we generated influenza virus vaccine constructs that express chimeric hemagglutinins consisting of exotic, avian head domains and a consistent stalk domain of a seasonal virus. Using such viruses in a sequential immunization regimen can redirect the immune response towards conserved epitopes. In this study, male ferrets received a live-attenuated vaccine virus based on the A/Ann Arbor/6/60 strain expressing a chimeric H8/1 (cH8/1) hemagglutinin, which was followed by a heterologous booster vaccination with a cH5/1N1 formalin inactivated non-adjuvanted whole virus. This group was compared to a second group that received a cH8/1N1 inactivated vaccine followed by a cH5/1N1 inactivated vaccine. Both groups showed a reduction in viral titers in the upper respiratory tract after the A(H1N1)pdm09 virus challenge. Animals that received the live-attenuated vaccine had low or undetectable titers in the lower respiratory tract. The results support the further development of chimeric hemagglutinin-based vaccination strategies. The outcome of this study confirms and corroborates findings from female ferrets primed with a A/Leningrad/134/17/57-based live attenuated cH8/1N1 vaccine followed by vaccination with an AS03-adjuvanted cH5/1N1 split virus vaccine 10.

Download Full-text

Exacerbation of Influenza Virus Infections in Mice by Intranasal Treatments and Implications for Evaluation of Antiviral Drugs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01664-12 ◽

2012 ◽

Vol 56 (12) ◽

pp. 6328-6333 ◽

Cited By ~ 15

Author(s):

Donald F. Smee ◽

Mark von Itzstein ◽

Beenu Bhatt ◽

E. Bart Tarbet

Keyword(s):

Influenza Virus ◽

Influenza A ◽

H1n1 Virus ◽

Antiviral Agent ◽

Virus Production ◽

Lung Pathology ◽

Virus Infections ◽

Challenge Dose ◽

Virus Challenge ◽

Time To Death

ABSTRACTCompounds lacking oral activity may be delivered intranasally to treat influenza virus infections in mice. However, intranasal treatments greatly enhance the virulence of such virus infections. This can be partially compensated for by giving reduced virus challenge doses. These can be 100- to 1,000-fold lower than infections without such treatment and still cause equivalent mortality. We found that intranasal liquid treatments facilitate virus production (probably through enhanced virus spread) and that lung pneumonia was delayed by only 2 days relative to a 1,000-fold higher virus challenge dose not accompanied by intranasal treatments. In one study, zanamivir was 90 to 100% effective at 10 mg/kg/day by oral, intraperitoneal, and intramuscular routes against influenza A/California/04/2009 (H1N1) virus in mice. However, the same compound administered intranasally at 20 mg/kg/day for 5 days gave no protection from death although the time to death was significantly delayed. A related compound, Neu5Ac2en (N-acetyl-2,3-dehydro-2-deoxyneuraminic acid), was ineffective at 100 mg/kg/day. Intranasal zanamivir and Neu5Ac2en were 70 to 100% protective against influenza A/NWS/33 (H1N1) virus infections at 0.1 to 10 and 30 to 100 mg/kg/day, respectively. Somewhat more difficult to treat was A/Victoria/3/75 virus that required 10 mg/kg/day of zanamivir to achieve full protection. These results illustrate that treatment of influenza virus infections by the intranasal route requires consideration of both virus challenge dose and virus strain in order to avoid compromising the effectiveness of a potentially useful antiviral agent. In addition, the intranasal treatments were shown to facilitate virus replication and promote lung pathology.

Download Full-text

Broadly-neutralizing antibodies that bind to the influenza hemagglutinin stalk domain enhance the effectiveness of neuraminidase inhibitors via Fc-mediated effector functions

10.1101/2021.11.17.468248 ◽

2021 ◽

Author(s):

Ali Zhang ◽

Hanu Chaudhari ◽

Yonathan Agung ◽

Michael D'Agostino ◽

Jann Ang ◽

...

Keyword(s):

Influenza Virus ◽

Neutralizing Antibodies ◽

Influenza Virus Infection ◽

Dependent Manner ◽

Neuraminidase Inhibitors ◽

Immune Effector ◽

Effector Cells ◽

Individual Level ◽

Influenza Hemagglutinin ◽

Stalk Domain

The conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next generation universal influenza vaccines. Protection provided by hemagglutinin stalk binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level, and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual's titers of stalk-binding antibodies, and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.

Download Full-text

The limited role of the human interferon system response to respiratory syncytial virus challenge: analysis and comparison to influenza virus challenge

Microbial Pathogenesis ◽

10.1016/0882-4010(92)90003-7 ◽

1992 ◽

Vol 12 (6) ◽

pp. 409-414 ◽

Cited By ~ 22

Author(s):

Norbert J. Roberts ◽

John Hiscott ◽

Denise J. Signs

Keyword(s):

Influenza Virus ◽

Respiratory Syncytial Virus ◽

Human Interferon ◽

System Response ◽

Virus Challenge ◽

Limited Role ◽

Interferon System ◽

Syncytial Virus

Download Full-text

Rapid isolation of a potent human antibody against H7N9 influenza virus from an infected patient

Antiviral Research ◽

10.1016/j.antiviral.2019.104564 ◽

2019 ◽

Vol 170 ◽

pp. 104564

Author(s):

Junxin Li ◽

Yang Yang ◽

Min Wang ◽

Xiaohu Ren ◽

Zheng Yang ◽

...

Keyword(s):

Influenza Virus ◽

Infected Patient ◽

Human Antibody ◽

Rapid Isolation ◽

H7n9 Influenza Virus ◽

H7n9 Influenza

Download Full-text

Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin

eLife ◽

10.7554/elife.49324 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 26

Author(s):

Juhye M Lee ◽

Rachel Eguia ◽

Seth J Zost ◽

Saket Choudhary ◽

Patrick C Wilson ◽

...

Keyword(s):

Influenza Virus ◽

Viral Evolution ◽

Surface Protein ◽

Viral Escape ◽

Viral Neutralization ◽

Influenza Hemagglutinin ◽

Human Sera ◽

Order Of Magnitude ◽

Amino Acid Mutations ◽

Major Surface

A longstanding question is how influenza virus evolves to escape human immunity, which is polyclonal and can target many distinct epitopes. Here, we map how all amino-acid mutations to influenza’s major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is not present among ferrets that have been infected just once with a defined viral strain. Our results show how different single mutations help influenza virus escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.

Download Full-text