scholarly journals Intradermal vaccination of live attenuated influenza vaccine protects mice against homologous and heterologous influenza challenges

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Andrew Chak-Yiu Lee ◽  
Anna Jinxia Zhang ◽  
Can Li ◽  
Yanxia Chen ◽  
Feifei Liu ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Protective Efficacy ◽  
Intradermal Injection ◽  
Temperature Sensitive ◽  
Airway Epithelial ◽  
Intradermal Vaccination ◽  
Protection Mechanism ◽  
Virus Challenge ◽  
Live Attenuated Influenza Vaccine

AbstractWe previously developed a temperature-sensitive, and NS1 gene deleted live attenuated influenza vaccine (DelNS1-LAIV) and demonstrated its potent protective efficacy in intranasally vaccinated mice. Here we investigated whether intradermal (i.d.) vaccination induces protective immunity. Our results showed that DelNS1-LAIV intradermal vaccination conferred effective and long-lasting protection against lethal virus challenge in mice. A single intradermal injection of DelNS1-LAIV conferred 100% survival with no weight loss in mice after A(H1N1)09 influenza virus (H1N1/415742Md) challenge. DelNS1-LAIV injection resulted in a significant reduction of lung viral load and reduced airway epithelial cell death and lung inflammatory cytokine responses at day 2 and 4 post challenge. Full protections of mice lasted for 6 months after immunization. In vitro infection of DelNS1-LAIV in monocyte-derived dendritic cells (MoDCs) demonstrated activation of antigen-presenting cells at 33 °C, together with the results of abortive replication of DelNS1-LAIV in skin tissue and strong upregulation of inflammatory cytokines/chemokines expression, our results suggested the strong immunogenicity of this vaccine. Further, we demonstrate that the underlying protection mechanism induced by intradermal DelNS1-LAIV is mainly attributed to antibody responses. Together, this study opens up an alternative route for the administration of LAIV, which may benefit individuals not suitable for intranasal LAIV immunization.

scholarly journals A Live Attenuated Influenza Vaccine Elicits Enhanced Heterologous Protection When the Internal Genes of the Vaccine Are Matched to Those of the Challenge Virus

2019 ◽  
Vol 94 (4) ◽  
Author(s):  
Andrew Smith ◽  
Laura Rodriguez ◽  
Maya El Ghouayel ◽  
Aitor Nogales ◽  
Jeffrey M. Chamberlain ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Influenza A ◽  
H1n1 Virus ◽  
Influenza Infection ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Temperature Sensitive ◽  
Live Attenuated Influenza Vaccine ◽  
Cell Immunity

ABSTRACT Influenza A virus (IAV) causes significant morbidity and mortality, despite the availability of viral vaccines. The efficacy of live attenuated influenza vaccines (LAIVs) has been especially poor in recent years. One potential reason is that the master donor virus (MDV), on which all LAIVs are based, contains either the internal genes of the 1960 A/Ann Arbor/6/60 or the 1957 A/Leningrad/17/57 H2N2 viruses (i.e., they diverge considerably from currently circulating strains). We previously showed that introduction of the temperature-sensitive (ts) residue signature of the AA/60 MDV into a 2009 pandemic A/California/04/09 H1N1 virus (Cal/09) results in only 10-fold in vivo attenuation in mice. We have previously shown that the ts residue signature of the Russian A/Leningrad/17/57 H2N2 LAIV (Len LAIV) more robustly attenuates the prototypical A/Puerto Rico/8/1934 (PR8) H1N1 virus. In this work, we therefore introduced the ts signature from Len LAIV into Cal/09. This new Cal/09 LAIV is ts in vitro, highly attenuated (att) in mice, and protects from a lethal homologous challenge. In addition, when our Cal/09 LAIV with PR8 hemagglutinin and neuraminidase was used to vaccinate mice, it provided enhanced protection against a wild-type Cal/09 challenge relative to a PR8 LAIV with the same attenuating mutations. These findings suggest it may be possible to improve the efficacy of LAIVs by better matching the sequence of the MDV to currently circulating strains. IMPORTANCE Seasonal influenza infection remains a major cause of disease and death, underscoring the need for improved vaccines. Among current influenza vaccines, the live attenuated influenza vaccine (LAIV) is unique in its ability to elicit T-cell immunity to the conserved internal proteins of the virus. Despite this, LAIV has shown limited efficacy in recent years. One possible reason is that the conserved, internal genes of all current LAIVs derive from virus strains that were isolated between 1957 and 1960 and that, as a result, do not resemble currently circulating influenza viruses. We have therefore developed and tested a new LAIV, based on a currently circulating pandemic strain of influenza. Our results show that this new LAIV elicits improved protective immunity compared to a more conventional LAIV.

scholarly journals A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 296
Author(s):  
Irina Kiseleva ◽  
Irina Isakova-Sivak ◽  
Marina Stukova ◽  
Marianna Erofeeva ◽  
Svetlana Donina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Influenza Vaccine ◽  
Phase 1 ◽  
Healthy Adults ◽  
Controlled Study ◽  
Temperature Sensitive ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Human Influenza Virus ◽  
Live Attenuated Influenza Vaccine

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

scholarly journals Experimental Infection Using Mouse-Adapted Influenza B Virus in a Mouse Model

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 470 ◽  
Author(s):  
Elena Prokopyeva ◽  
Olga Kurskaya ◽  
Ivan Sobolev ◽  
Mariia Solomatina ◽  
Tatyana Murashkina ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Drug Testing ◽  
Protective Efficacy ◽  
Influenza B Virus ◽  
Infection Model ◽  
Influenza B ◽  
Post Inoculation ◽  
B Virus

Every year, influenza B viruses (IBVs) contribute to annual illness, and infection can lead to serious respiratory disease among humans. More attention is needed in several areas, such as increasing virulence or pathogenicity of circulating B viruses and developing vaccines against current influenza. Since preclinical trials of anti-influenza drugs are mainly conducted in mice, we developed an appropriate infection model, using an antigenically-relevant IBV strain, for furtherance of anti-influenza drug testing and influenza vaccine protective efficacy analysis. A Victoria lineage (clade 1A) IBV was serially passaged 17 times in BALB/c mice, and adaptive amino acid substitutions were found in hemagglutinin (HA) (T214I) and neuraminidase (NA) (D432N). By electron microscopy, spherical and elliptical IBV forms were noted. Light microscopy showed that mouse-adapted IBVs caused influenza pneumonia on day 6 post inoculation. We evaluated the illness pathogenicity, viral load, and histopathological features of mouse-adapted IBVs and estimated anti-influenza drugs and vaccine efficiency in vitro and in vivo. Assessment of an investigational anti-influenza drug (oseltamivir ethoxysuccinate) and an influenza vaccine (Ultrix®, SPBNIIVS, Saint Petersburg, Russia) showed effectiveness against the mouse-adapted influenza B virus.

scholarly journals Universal Live-Attenuated Influenza Vaccine Candidates Expressing Multiple M2e Epitopes Protect Ferrets against a High-Dose Heterologous Virus Challenge

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1280
Author(s):  
Daria Mezhenskaya ◽  
Irina Isakova-Sivak ◽  
Victoria Matyushenko ◽  
Svetlana Donina ◽  
Andrey Rekstin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza Vaccine ◽  
Swine Influenza ◽  
Influenza Viruses ◽  
High Dose ◽  
Virus Challenge ◽  
Consensus Sequences ◽  
Degree Of Protection ◽  
Live Attenuated Influenza Vaccine ◽  
Universal Influenza Vaccine

The development of an influenza vaccine with broad protection and durability remains an attractive idea due to the high mutation rate of the influenza virus. An extracellular domain of Matrix 2 protein (M2e) is among the most attractive target for the universal influenza vaccine owing to its high conservancy rate. Here, we generated two recombinant live attenuated influenza vaccine (LAIV) candidates encoding four M2e epitopes representing consensus sequences of human, avian and swine influenza viruses, and studied them in a preclinical ferret model. Both LAIV+4M2e viruses induced higher levels of M2e-specific antibodies compared to the control LAIV strain, with the LAIV/HA+4M2e candidate being significantly more immunogenic than the LAIV/NS+4M2e counterpart. A high-dose heterosubtypic influenza virus challenge revealed the highest degree of protection after immunization with LAIV/HA+4M2e strain, followed by the NS-modified LAIV and the classical LAIV virus. Furthermore, only the immune sera from the LAIV/HA+4M2e-immunized ferrets protected mice from a panel of lethal influenza viruses encoding M genes of various origins. These data suggest that the improved cross-protection of the LAIV/HA+4M2e universal influenza vaccine candidate was mediated by the M2e-targeted antibodies. Taking into account the safety profile and improved cross-protective potential, the LAIV/HA+4M2e vaccine warrants its further evaluation in a phase I clinical trial.

scholarly journals A Single Mutation at PB1 Residue 319 Dramatically Increases the Safety of PR8 Live Attenuated Influenza Vaccine in a Murine Model without Compromising Vaccine Efficacy

2015 ◽  
Vol 90 (5) ◽  
pp. 2702-2705 ◽  
Author(s):  
Andrew Cox ◽  
Stephen Dewhurst
Keyword(s):  
At Risk ◽  
Amino Acid ◽  
Influenza Vaccine ◽  
Murine Model ◽  
Vaccine Efficacy ◽  
Protective Efficacy ◽  
Fold Increase ◽  
Single Mutation ◽  
Live Attenuated Influenza Vaccine ◽  
Amino Acid Mutations

The live attenuated influenza vaccine (LAIV) is preferentially recommended for use in most children yet remains unsafe for the groups most at risk. Here we have improved the safety of a mouse-adapted live attenuated influenza vaccine containing the same attenuating amino acid mutations as in human LAIV by adding an additional mutation at PB1 residue 319. This results in a vaccine with a 20-fold decrease in protective efficacy and a 10,000-fold increase in safety.

scholarly journals Increasing the Safety Profile of the Master Donor Live Attenuated Influenza Vaccine

Pathogens ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 86 ◽  
Author(s):  
Thomas A. Hilimire ◽  
Aitor Nogales ◽  
Kevin Chiem ◽  
Javier Ortego ◽  
Luis Martinez-Sobrido
Keyword(s):  
Influenza Vaccine ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Infection ◽  
Vaccination Campaign ◽  
The Elderly ◽  
Antiviral Responses ◽  
Live Attenuated Influenza Vaccine ◽  
Ann Arbor ◽  
Health Burdens

Seasonal influenza epidemics remain one of the largest public health burdens nowadays. The best and most effective strategy to date in preventing influenza infection is a worldwide vaccination campaign. Currently, two vaccines are available to the public for the treatment of influenza infection, the chemically Inactivated Influenza Vaccine (IIV) and the Live Attenuated Influenza Vaccine (LAIV). However, the LAIV is not recommended for parts of the population, such as children under the age of two, immunocompromised individuals, the elderly, and pregnant adults. In order to improve the safety of the LAIV and make it available to more of the population, we sought to further attenuate the LAIV. In this study, we demonstrate that the influenza A virus (IAV) master donor virus (MDV) A/Ann Arbor/6/60 H2N2 LAIV can inhibit host gene expression using both the PA-X and NS1 proteins. Furthermore, we show that by removing PA-X, we can limit the replication of the MDV LAIV in a mouse model, while maintaining full protective efficacy. This work demonstrates a broadly applicable strategy of tuning the amount of host antiviral responses induced by the IAV MDV for the development of newer and safer LAIVs. Moreover, our results also demonstrate, for the first time, the feasibility of genetically manipulating the backbone of the IAV MDV to improve the efficacy of the current IAV LAIV.

scholarly journals Oral Hsp90 inhibitor, SNX-5422, attenuates SARS-CoV-2 replication and dampens inflammation in airway cells

2021 ◽  
Author(s):  
Ria Goswami ◽  
Veronica S. Russell ◽  
Joshua J. Tu ◽  
Philip Hughes ◽  
Francine Kelly ◽  
...  
Keyword(s):  
Protective Efficacy ◽  
Hsp90 Inhibitor ◽  
Airway Epithelial Cells ◽  
Vaccine Hesitancy ◽  
Airway Epithelial ◽  
Early Therapy ◽  
Disease Outcomes ◽  
Anti Cancer ◽  
Orally Bioavailable

SUMMARYCurrently available SARS-CoV-2 therapeutics are targeted towards moderately to severely ill patients and require intravenous infusions, with limited options for exposed or infected patients with no or mild symptoms. While vaccines have demonstrated protective efficacy, vaccine hesitancy and logistical distribution challenges will delay their ability to end the pandemic. Hence, there is a need for rapidly translatable, easy-to-administer-therapeutics, that can prevent SARS-CoV-2 disease progression, when administered in the early stages of infection. We demonstrate that an orally bioavailable Hsp90 inhibitor, SNX-5422, currently in clinical trials as an anti-cancer therapeutic, inhibits SARS-CoV-2 replication in vitro at a high selectivity index. SNX-5422 treatment of human primary airway epithelial cells dampened expression of inflammatory pathways associated with poor SARS-CoV-2 disease outcomes. Additionally, SNX-5422 interrupted expression of host factors that are crucial for SARS-CoV-2 replication machinery. Development of SNX-5422 as SARS-CoV-2-early-therapy will dampen disease severity, resulting in better clinical outcomes and reduced hospitalizations.

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