scholarly journals A Novel Recombinant Influenza Virus Neuraminidase Vaccine Candidate Stabilized by a Measles Virus Phosphoprotein Tetramerization Domain Provides Robust Protection from Virus Challenge in the Mouse Model

mBio ◽  
2021 ◽  
Author(s):  
Shirin Strohmeier ◽  
Fatima Amanat ◽  
Xueyong Zhu ◽  
Meagan McMahon ◽  
Meagan E. Deming ◽  
...  
Keyword(s):  
Health Care ◽  
Influenza Virus ◽  
High Risk ◽  
Measles Virus ◽  
Vaccine Candidate ◽  
Influenza Virus Vaccine ◽  
Virus Infections ◽  
Virus Challenge ◽  
Tetramerization Domain ◽  
Influenza Virus Neuraminidase

Influenza virus infections remain a high risk to human health, causing up to 650,000 deaths worldwide every year, with an enormous burden on the health care system. Since currently available seasonal vaccines are only partially effective and often mismatched to the circulating strains, a broader protective influenza virus vaccine is needed.

scholarly journals Enhancing Neuraminidase Immunogenicity of Influenza A Viruses by Rewiring RNA Packaging Signals

2020 ◽  
Vol 94 (16) ◽  
Author(s):  
Allen Zheng ◽  
Weina Sun ◽  
Xiaoli Xiong ◽  
Alec W. Freyn ◽  
Julia Peukes ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
Virus Surface ◽  
Virus Challenge ◽  
Packaging Signals

ABSTRACT Humoral immune protection against influenza virus infection is mediated largely by antibodies against hemagglutinin (HA) and neuraminidase (NA), the two major glycoproteins on the virus surface. While influenza virus vaccination efforts have focused mainly on HA, NA-based immunity has been shown to reduce disease severity and provide heterologous protection. Current seasonal vaccines do not elicit strong anti-NA responses—in part due to the immunodominance of the HA protein. Here, we demonstrate that by swapping the 5′ and 3′ terminal packaging signals of the HA and NA genomic segments, which contain the RNA promoters, we are able to rescue influenza viruses that express more NA and less HA. Vaccination with formalin-inactivated “rewired” viruses significantly enhances the anti-NA antibody response compared to vaccination with unmodified viruses. Passive transfer of sera from mice immunized with rewired virus vaccines shows better protection against influenza virus challenge. Our results provide evidence that the immunodominance of HA stems in part from its abundance on the viral surface, and that rewiring viral packaging signals—thereby increasing the NA content on viral particles—is a viable strategy for improving the immunogenicity of NA in an influenza virus vaccine. IMPORTANCE Influenza virus infections are a major source of morbidity and mortality worldwide. Increasing evidence highlights neuraminidase as a potential vaccination target. This report demonstrates the efficacy of rewiring influenza virus packaging signals for creating vaccines with more neuraminidase content which provide better neuraminidase (NA)-based protection.

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

2012 ◽  
Vol 56 (12) ◽  
pp. 6328-6333 ◽  
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.

scholarly journals Evaluation of Replication and Cross-Reactive Antibody Responses of H2 Subtype Influenza Viruses in Mice and Ferrets

2010 ◽  
Vol 84 (15) ◽  
pp. 7695-7702 ◽  
Author(s):  
Grace L. Chen ◽  
Elaine W. Lamirande ◽  
Chin-Fen Yang ◽  
Hong Jin ◽  
George Kemble ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Pandemic Influenza ◽  
Vaccine Candidate ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Antibody Responses ◽  
Wild Type ◽  
Preparedness Planning ◽  
Kinetics Of ◽  
Reactive Antibody

ABSTRACT H2 influenza viruses have not circulated in humans since 1968, and therefore a large segment of the population would likely be susceptible to infection should H2 influenza viruses reemerge. The development of an H2 pandemic influenza virus vaccine candidate should therefore be considered a priority in pandemic influenza preparedness planning. We selected a group of geographically and temporally diverse wild-type H2 influenza viruses and evaluated the kinetics of replication and compared the ability of these viruses to induce a broadly cross-reactive antibody response in mice and ferrets. In both mice and ferrets, A/Japan/305/1957 (H2N2), A/mallard/NY/1978 (H2N2), and A/swine/MO/2006 (H2N3) elicited the broadest cross-reactive antibody responses against heterologous H2 influenza viruses as measured by hemagglutination inhibition and microneutralization assays. These data suggested that these three viruses may be suitable candidates for development as live attenuated H2 pandemic influenza virus vaccines.

scholarly journals A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin

2021 ◽  
Author(s):  
Jenna J. Guthmiller ◽  
Julianna Han ◽  
Henry A. Utset ◽  
Lei Li ◽  
Linda Yu-Ling Lan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Memory ◽  
Influenza Virus Vaccine ◽  
Virus Infections ◽  
Broadly Neutralizing Antibodies ◽  
Cell Repertoire ◽  
Influenza Virus Hemagglutinin

SummaryBroadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is “anchored” to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an underappreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.

Intranasal inoculate of influenza virus vaccine against lethal virus challenge

Vaccine ◽  
2018 ◽  
Vol 36 (29) ◽  
pp. 4354-4361 ◽  
Author(s):  
Xueting Fan ◽  
Qiudong Su ◽  
Feng Qiu ◽  
Yao Yi ◽  
Liping Shen ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza Virus Vaccine ◽  
Virus Challenge

scholarly journals Identification of GS 4104 as an Orally Bioavailable Prodrug of the Influenza Virus Neuraminidase Inhibitor GS 4071

1998 ◽  
Vol 42 (3) ◽  
pp. 647-653 ◽  
Author(s):  
Weixing Li ◽  
Paul A. Escarpe ◽  
Eugene J. Eisenberg ◽  
Kenneth C. Cundy ◽  
Clive Sweet ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Ethyl Ester ◽  
Oral Bioavailability ◽  
Influenza A ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Neuraminidase Activity ◽  
Orally Bioavailable ◽  
Influenza Virus Neuraminidase

ABSTRACT GS 4071 is a potent carbocyclic transition-state analog inhibitor of influenza virus neuraminidase with activity against both influenza A and B viruses in vitro. GS 4116, the guanidino analog of GS 4071, is a 10-fold more potent inhibitor of influenza virus replication in tissue culture than GS 4071. In this study we determined the oral bioavailabilities of GS 4071, GS 4116, and their respective ethyl ester prodrugs in rats. Both parent compounds and the prodrug of the guanidino analog exhibited poor oral bioavailability (2 to 4%) and low peak concentrations in plasma (C maxs; C max<0.06 μg/ml). In contrast, GS 4104, the ethyl ester prodrug of GS 4071, exhibited good oral bioavailability (35%) as GS 4071 and high C maxs of GS 4071 (Cmax = 0.47 μg/ml) which are 150 times the concentration necessary to inhibit influenza virus neuraminidase activity by 90%. The bioavailability of GS 4104 as GS 4071 was also determined in mice (30%), ferrets (11%), and dogs (73%). The plasma of all four species exhibited high, sustained concentrations of GS 4071 such that at 12 h postdosing the concentrations of GS 4071 in plasma exceeded those necessary to inhibit influenza virus neuraminidase activity by 90%. These results demonstrate that GS 4104 is an orally bioavailable prodrug of GS 4071 in animals and that it has the potential to be an oral agent for the prevention and treatment of influenza A and B virus infections in humans.

Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles

2019 ◽  
Vol 4 (41) ◽  
pp. eaay6125 ◽  
Author(s):  
Velislava N. Petrova ◽  
Bevan Sawatsky ◽  
Alvin X. Han ◽  
Brigitta M. Laksono ◽  
Lisa Walz ◽  
...  
Keyword(s):  
Influenza Virus ◽  
B Cell ◽  
Measles Virus ◽  
B Lymphocyte ◽  
Human Peripheral Blood ◽  
Herd Immunity ◽  
Peripheral Blood Lymphocytes ◽  
Immune Memory ◽  
Virus Challenge

Measles is a disease caused by the highly infectious measles virus (MeV) that results in both viremia and lymphopenia. Lymphocyte counts recover shortly after the disappearance of measles-associated rash, but immunosuppression can persist for months to years after infection, resulting in increased incidence of secondary infections. Animal models and in vitro studies have proposed various immunological factors underlying this prolonged immune impairment, but the precise mechanisms operating in humans are unknown. Using B cell receptor (BCR) sequencing of human peripheral blood lymphocytes before and after MeV infection, we identified two immunological consequences from measles underlying immunosuppression: (i) incomplete reconstitution of the naïve B cell pool leading to immunological immaturity and (ii) compromised immune memory to previously encountered pathogens due to depletion of previously expanded B memory clones. Using a surrogate model of measles in ferrets, we investigated the clinical consequences of morbillivirus infection and demonstrated a depletion of vaccine-acquired immunity to influenza virus, leading to a compromised immune recall response and increased disease severity after secondary influenza virus challenge. Our results show that MeV infection causes changes in naïve and memory B lymphocyte diversity that persist after the resolution of clinical disease and thus contribute to compromised immunity to previous infections or vaccinations. This work highlights the importance of MeV vaccination not only for the control of measles but also for the maintenance of herd immunity to other pathogens, which can be compromised after MeV infection.

scholarly journals Potent and Long-Acting Dimeric Inhibitors of Influenza Virus Neuraminidase Are Effective at a Once-Weekly Dosing Regimen

2004 ◽  
Vol 48 (12) ◽  
pp. 4542-4549 ◽  
Author(s):  
Simon J. F. Macdonald ◽  
Keith G. Watson ◽  
Rachel Cameron ◽  
David K. Chalmers ◽  
Derek A. Demaine ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Low Dose ◽  
Neuraminidase Inhibitor ◽  
Virus Infections ◽  
Dosing Regimen ◽  
Influenza Virus Replication ◽  
Long Acting ◽  
Influenza Virus Neuraminidase

ABSTRACT Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 Å, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.

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