Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets

Wang, Lulan; Liu, Su Yang; Chen, Hsiang Wen; Xu, Juan; Chapon, Maxime; Zhang, Tao; Zhou, Fan; Wang, Yao E.; Quanquin, Natalie; Wang, Guiqin; Tian, Xiaoli; He, Zhanlong; Liu, Longding; Wu, Yu; Sanchez, David Jesse; Liang, Yuying; Jiang, Taijiao; Modlin, Robert L.; Bloom, Barry R.; Li, Qihan; Deng, Jane C.; Zhou, Paul; Qin, Frank Xiao Feng; Cheng, Genhong

doi:10.1016/j.chom.2017.02.007

Cited by 22 publications

(26 citation statements)

References 24 publications

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“…However, it was reported that non-specific immunity against non-influenza respiratory viruses in children vaccinated with a live-attenuated influenza vaccine (LAIV) was short-lived with the duration of as long as 1−2 weeks ( 62 ). Furthermore, many animal studies on cross-protection by LAIVs have presented protection data by performing in vivo challenge at 2−4 weeks after the vaccination ( 11 , 17 , 33 , 63 , 64 ). Considering these observations, our experimental design of the challenge at 5 weeks days after the boosting vaccination cannot be explained by non-specific mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, CAIVs have many immunological advantages in terms of cross-protection over the other vaccine platforms, including the delivery of a whole set of antigens, the induction of mucosal IgA antibodies, and T-cell responses, as well as the stimulation of innate immunity ( 12 – 15 ). Perhaps most importantly, it has been widely acknowledged that T-cell immunity, which targets viral proteins that are relatively conserved between different influenza strains, is the key to the cross-protection by natural infection or vaccination ( 16 , 17 ). Therefore, if all of these factors are combined properly and reinforced by a rational vaccination strategy, a CAIV is expected to serve as a powerful platform for a universal influenza vaccine.…”

Section: Introductionmentioning

confidence: 99%

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Pan-Influenza A Protection by Prime–Boost Vaccination with Cold-Adapted Live-Attenuated Influenza Vaccine in a Mouse Model

et al. 2018

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Influenza virus infections continually pose a major public health threat with seasonal epidemics and sporadic pandemics worldwide. While currently licensed influenza vaccines provide only strain-specific protection, antigenic drift and shift occasionally render the viruses resistant to the host immune responses, which highlight the need for a vaccine that provides broad protection against multiple subtypes. In this study, we suggest a vaccination strategy using cold-adapted, live attenuated influenza vaccines (CAIVs) to provide a broad, potent, and safe cross-protection covering antigenically distinct hemagglutinin (HA) groups 1 and 2 influenza viruses. Using a mouse model, we tested different prime–boost combinations of CAIVs for their ability to induce humoral and T-cell responses, and protective efficacy against H1 and H5 (HA group 1) as well as H3 and H7 (HA group 2) influenza viruses. Notably, even in the absence of antibody-mediated neutralizing activity or HA inhibitory activity in vitro, CAIVs provided a potent protection against heterologous and heterosubtypic lethal challenges in vivo. Heterologous combination of prime (H1)–boost (H5) vaccine strains showed the most potent cross-protection efficacy. In vivo depletion experiments demonstrated not only that T cells and natural killer cells contributed to the cross-protection, but also the involvement of antibody-dependent mechanisms for the cross-protection. Vaccination-induced antibodies did not enhance the infectivity of heterologous viruses, and prime vaccination did not interfere with neutralizing antibody generation by the boost vaccination, allaying vaccine safety concerns associated with heterogeneity between the vaccines and challenge strains. Our data show that CAIV-based strategy can serve as a simple but powerful option for developing a “truly” universal influenza vaccine providing pan-influenza A protection, which has not been achieved yet by other vaccine strategies. The promising results of potency, breadth, and safety demonstrated in the mouse model support further studies in higher animal models for clinical relevance.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pan-Influenza A Protection by Prime–Boost Vaccination with Cold-Adapted Live-Attenuated Influenza Vaccine in a Mouse Model

et al. 2018

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“…While highly successful, this method can present disadvantages, such as labor intensiveness, the difficulty in assessing multifunctional proteins, and a lack of insight into intergenic regions. We therefore chose to use a method that has proven successful in the study of other viral (17)(18)(19) and bacterial (20,21) genomes. We created an HSV-1 mutant library by random insertion of a disruptive 1.2-kbp transposon across the viral genome.…”

Section: Importancementioning

confidence: 99%

Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

Chapon

Parvatiyar

Aliyari

et al. 2019

J Virol

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In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I). HSV-1 evades the host immune system by encoding viral proteins that inhibit the type I interferon response. Applying differential selective pressure, we identified the three strongest viral IFN-I regulators in HSV-1. We report that the viral polymerase processivity factor UL42 interacts with the host transcription factor IFN regulatory factor 3 (IRF-3), inhibiting its phosphorylation and downstream beta interferon (IFN-β) gene transcription. This study represents a proof of concept for the use of high-throughput screening of the HSV-1 genome in investigating viral biology and offers new targets both for antiviral therapy and for oncolytic vector design. IMPORTANCE This work is the first to report the use of a high-throughput mutagenesis method to study the genome of HSV-1. We report three novel viral proteins potentially involved in regulating the host type I interferon response. We describe a novel mechanism by which the viral protein UL42 is able to suppress the production of beta interferon. The tool we introduce in this study can be used to study the HSV-1 genome in great detail to better understand viral gene functions.

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“…There are global efforts to increase the breadth of protection of influenza vaccines, with an eventual goal of universal protection (reviewed in), and most strategies have been evaluated in ferret models. A non‐exhaustive list of strategies to induce heterosubtypic immunity against influenza evaluated in ferrets include: HA stem vaccination; prime‐boost with chimeric HA‐based vaccines; use of conserved influenza proteins such as nucleoprotein (NP), matrix‐1 (M1), matrix‐2 (M2) and RNA polymerase subunit B1 (PB1); replication‐deficient viruses; live attenuated formulations; the use of potent adjuvants such as Protollin, glucopyranosyl lipid adjuvant—aqueous formulation (GLA‐AF), CoVaccine HT, cationic adjuvant formulation and poly‐g‐glutamic/chitosan nanogel; Escherichia coli ‐derived vaccines; DNA, mRNA and viral vector vaccines; and the use of virus‐like particles (VLP) . Additional examples of important ferret studies include (but are not limited to) evaluating the influence of changing the route of influenza inoculation on subsequent immunity and the use of neuraminidase (NA) inhibitors as prophylaxis …”

Section: Ferrets For Influenza Surveillance and Vaccine Developmentmentioning

confidence: 99%

Improving immunological insights into the ferret model of human viral infectious disease

Wong

Layton

Wheatley

et al. 2019

Influenza Resp Viruses

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Influenza Other Respi Viruses. 2019;13:535-546. | 535 wileyonlinelibrary.com/journal/irv 1 | INTRODUC TI ON Animal models have proved critical in developing concepts of immunity to infection. Non-human primates (NHP) are a highly humanrelevant disease model for infectious agents due to high genetic conservation between humans and NHP. 1-3 However, significant cost and ethical issues often necessitate the use of smaller animal models for both basic and translational research. Mice (Mus musculus) are a favoured small animal model due to widespread availability, incisive transgenic models, comprehensive genomic information 4 and readily available reagents. However, for many viruses, alternative animal models better recapitulate human physiology and disease. Ferrets (Mustela putorius furo) have been employed to study the pathogenesis of a variety of human pathogens, including human and avian influenzas, coronaviruses including severe acute respiratory syndrome (SARS-CoV), 5-14 human respiratory syncytial virus (HRSV), 15-20 human metapneumovirus (HMPV), 21 Ebola virus 22-28 and henipavirus (Nipah virus and Hendra virus). 29-34 While ferretscan be productively infected with many of these viruses, a lack of some tools to interrogate ferret immunological responses to infection limits insights that might impact the development of vaccines and/or therapeutics. Here, we review recent insights gained from ferret models of human respiratory diseases, with a major focus on influenza, and highlight several knowledge gaps whose closure will greatly enhance the informational gain from ferret models to advance development of human vaccines and therapeutics. AbstractFerrets are a well-established model for studying both the pathogenesis and transmission of human respiratory viruses and evaluation of antiviral vaccines. Advanced immunological studies would add substantial value to the ferret models of disease but are hindered by the low number of ferret-reactive reagents available for flow cytometry and immunohistochemistry. Nevertheless, progress has been made to understand immune responses in the ferret model with a limited set of ferret-specific reagents and assays. This review examines current immunological insights gained from the ferret model across relevant human respiratory diseases, with a focus on influenza viruses. We highlight key knowledge gaps that need to be bridged to advance the utility of ferrets for immunological studies. K E Y W O R D S ferret, immunology, influenza How to cite this article: Wong J, Layton D, Wheatley AK, Kent SJ. Improving immunological insights into the ferret model of human viral infectious disease. Influenza Other Respi Viruses. 2019;13:535-546. https ://doi.

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Generation of a Live Attenuated Influenza Vaccine that Elicits Broad Protection in Mice and Ferrets

Cited by 22 publications

References 24 publications

Pan-Influenza A Protection by Prime–Boost Vaccination with Cold-Adapted Live-Attenuated Influenza Vaccine in a Mouse Model

Pan-Influenza A Protection by Prime–Boost Vaccination with Cold-Adapted Live-Attenuated Influenza Vaccine in a Mouse Model

Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

Improving immunological insights into the ferret model of human viral infectious disease

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