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Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge This information is current as of September 28, 2021. Claire M. Tully, Senthil Chinnakannan, Caitlin E. Mullarkey, Marta Ulaszewska, Francesca Ferrara, Nigel Temperton, Sarah C. Gilbert and Teresa Lambe J Immunol 2017; 199:1333-1341; Prepublished online 19 July 2017; Downloaded from doi: 10.4049/jimmunol.1600939 http://www.jimmunol.org/content/199/4/1333 http://www.jimmunol.org/ References This article cites 42 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/199/4/1333.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Novel Bivalent Viral-Vectored Vaccines Induce Potent Humoral and Cellular Immune Responses Conferring Protection against Stringent Influenza A Virus Challenge Claire M. Tully,* Senthil Chinnakannan,† Caitlin E. Mullarkey,‡ Marta Ulaszewska,* Francesca Ferrara,x Nigel Temperton,x Sarah C. Gilbert,* and Teresa Lambe* Seasonal influenza viruses are a common cause of acute respiratory illness worldwide and generate a significant socioeconomic burden. Influenza viruses mutate rapidly, necessitating annual vaccine reformulation because traditional vaccines do not typically induce broad-spectrum immunity. In addition to seasonal infections, emerging pandemic influenza viruses present a continued threat to global public health. Pandemic influenza viruses have consistently higher attack rates and are typically associated with greater mortality compared with seasonal strains. Ongoing strategies to improve vaccine efficacy typically focus on providing Downloaded from broad-spectrum immunity; although B and T cells can mediate heterosubtypic responses, typical vaccine development will augment either humoral or cellular immunity. However, multipronged approaches that target several Ags may limit the gener- ation of viral escape mutants. There are few vaccine platforms that can deliver multiple Ags and generate robust cellular and humoral immunity. In this article, we describe a novel vaccination strategy, tested preclinically in mice, for the delivery of novel bivalent viral-vectored vaccines. We show this strategy elicits potent T cell responses toward highly conserved internal Ags while simultaneously inducing high levels of Abs toward hemagglutinin. Importantly, these humoral responses generate long-lived http://www.jimmunol.org/ plasma cells and generate Abs capable of neutralizing variant hemagglutinin-expressing pseudotyped lentiviruses. Significantly, these novel viral-vectored vaccines induce strong immune responses capable of conferring protection in a stringent influenza A virus challenge. Thus, this vaccination regimen induces lasting efficacy toward influenza. Importantly, the simultaneous delivery of dual Ags may alleviate the selective pressure that is thought to potentiate antigenic diversity in avian influenza viruses. The Journal of Immunology, 2017, 199: 1333–1341. easonal influenza A virus (IAV) infections cause signifi- tensive care unit (1–3). For the past 70 y, vaccination has been the cant morbidity and mortality worldwide and remain a mainstay healthcare strategy against influenza infection (4–6). by guest on September 28, 2021 S major public health concern. The novel avian-origin in- However, traditional inactivated influenza vaccines (IIVs) confer fluenza A strain (H7N9), initially identified in 2013, is now cir- strain-specific protection and do not typically induce the broad- culating with almost annual frequency and almost one-third of all spectrum immunity needed in the face of a newly emergent IAV H7N9 cases occurred in the 2016/2017 influenza season. Most (7–9). Therefore, the possible threat of a pandemic outbreak has worringly, the case-fatality rate for this virus exceeds 40% (1–3). catalyzed the development of broadly protective IAV vaccines. In addition, H7N9 influenza viruses have recently been assessed as Recent strategies to augment and broaden vaccine efficacy have having the highest potential pandemic risk of any novel IAV; this shifted toward the development of “universal” vaccines capable of assessment is based on recent studies indicating that H7N9 viruses providing heterosubtypic protection against multiple, or possibly have increased genetic diversity and wider geographical distri- all, subtypes of IAV. Although humoral and cellular immunity can bution; additionally, in recent outbreaks, a significantly higher mediate heterosubtypic responses, inducing Abs against the more proportion of H7N9-infected patients have needed care in an in- conserved stalk domain of hemagglutinin (HA) has been the recent focus of many vaccine programs (10, 11). However, multipronged approaches that target several Ags that induce humoral and cellular *Jenner Institute, University of Oxford, Oxford OX3 7DQ, United Kingdom; †Peter Medawar Building for Pathogen Research, University of Oxford, Oxford responses may limit the generation of viral escape mutants com- OX1 3SY, United Kingdom; ‡Department of Microbiology, Icahn School of Medicine pared with vaccines that target a limited number of protective at Mount Sinai, New York, NY 10029; and xPseudotype Unit, School of Pharmacy, University of Kent, Chatham Maritime, Kent ME4 4TB, United Kingdom epitopes on the HA stalk. There are few vaccine technologies that ORCIDs: 0000-0002-4404-0229 (S.C.); 0000-0002-4973-1520 (F.F.); 0000-0002- will facilitate the delivery of multiple Ags to generate robust 6823-9750 (S.C.G.); 0000-0001-7711-897X (T.L.). cellular and humoral immunity toward infectious disease Ags. Received for publication June 1, 2016. Accepted for publication June 14, 2017. Viral-vectored vaccines have been developed for the induction This work was supported by Wellcome Trust Grant 097113/Z/11/ BVRVBZO. of strong humoral and potent cellular immunity toward encoded Address correspondence and reprint requests to Dr. Teresa Lambe, Jenner Institute, Ags. An added benefit of this platform is that viral vectors can University of Oxford, Old Road Campus Research Building, Oxford, Oxfordshire accommodate more than one Ag (12). Typically, for heterologous OX3 7DQ, United Kingdom. E-mail address: [email protected] prime-boost vaccination strategies, one viral vector (e.g., Chim- Abbreviations used in this article: ASC, Ab-secreting cell; BEI Resources, Biode- panzee adenovirus [ChAd]) encoding the target Ag(s) is used for fense and Emerging Infections Research Resources Repository; ChAd, chimpanzee adenovirus; HA, hemagglutinin; IAV, influenza A virus; IIV, inactivated influenza the priming vaccination, and a different platform, most often vaccine; i.m., intramuscularly; LLPC, long-lived plasma cell; MVA, modified vac- modified vaccinia Ankara (MVA), is used for the boost or repeat cinia Ankara; SFU, spot-forming unit. vaccination. In the current study, we describe novel ChAd- and Copyright Ó 2017 by The American Association of Immunologists, Inc. 0022-1767/17/$30.00 MVA-vectored vaccines that are designed to simultaneously www.jimmunol.org/cgi/doi/10.4049/jimmunol.1600939 1334 BIVALENT VACCINES PROTECT AGAINST INFLUENZA CHALLENGE induce heterosubtypic and protective B and T cell responses against alone was used as a negative control, and pools of overlapping peptides three influenza A Ags: HA, NP, and M1. Using a heterologous prime- (H7HA) and NP147–158 (TYQRTRALV) were typically added at 2 mg/ml. boost strategy, we induce high levels of heterosubtypic and homol- ELISA ogous immune responses targeting the major virion surface protein HA and the conserved internal viral Ags NP and M1. We dem- ELISA was performed essentially as described (14). Nunc MaxiSorp 96- well plates were coated with 0.1 mg of recombinant protein [H7HA protein onstrate protection, after prime-boost vaccination, in a stringent was produced in-house, as described (16)] and recombinant H5HA protein challenge model of mouse-adapted avian IAV. (A/Vietnam/1203/2004 [H5N1], recombinant from baculovirus, BEI Re- sources NR-10510) per well, and plates were washed until the fifth dilution of the reference standard (1:1600 dilution) reached an approximate OD450 Materials and Methods value of 1. This point was defined as one relative ELISA Unit, and relative Recombinant ChAd and MVA vaccines ELISA units of test sera were calculated, essentially as described (14, 17). The construction of ChAdOx1 NP+M1 has been described previously IgG Ab-secreting cell ELISPOT assay (13). Details of the viral-vectored vaccines used in these studies are as described in Table I. A bone marrow IgG Ab-secreting cell (ASC) ELISPOT assay was per- formed as described (18, 19) using ∼1
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