Abstract
Influenza virus infections continue to pose a major public health threat worldwide associated with seasonal epidemics and sporadic pandemics. Vaccination is considered the first line of defense against influenza. Live attenuated influenza virus vaccines (LAIVs) may provide superior responses compared to inactivated vaccines because the former can better elicit a combination of humoral and cellular responses by mimicking a natural infection. Unfortunately, during the 2013-2014, 2014-2015, and 2015-2016 seasons, concerns emerged about the effectiveness of the only LAIV approved in the United States that prevented the Advisory Committee on Immunization Practices (ACIP) from recommending its use. Such drawbacks open up the opportunity for alternative LAIV strategies that could overcome such concerns. Previously, we developed a combined strategy of temperature-sensitive mutations in the PB2 and PB1 segments and an epitope tag in the C terminus of PB1 that effectively attenuates influenza A viruses of avian and mammalian origin. More recently, we adopted a similar strategy for influenza B viruses. The resulting attenuated (att) influenza A and B viruses were safe, immunogenic, and protective against lethal influenza virus challenge in a variety of animal models. In this report, we provide evidence of the potential use of our att strategy in a quadrivalent LAIV (QIV) formulation carrying H3N2 and H1N1 influenza A virus subtype viruses and two antigenic lineages of influenza B viruses. In naive DBA/2J mice, two doses of the QIV elicited hemagglutination inhibition (HI) responses with HI titers of ≥40 and effectively protected against lethal challenge with prototypical pandemic H1N1 influenza A and influenza B virus strains.IMPORTANCE Seasonal influenza viruses infect 1 billion people worldwide and are associated with ∼500,000 deaths annually. In addition, the never-ending emergence of zoonotic influenza viruses associated with lethal human infections and of pandemic concern calls for the development of better vaccines and/or vaccination strategies against influenza virus. Regardless of the strategy, novel influenza virus vaccines must aim at providing protection against both seasonal influenza A and B viruses. In this study, we tested an alternative quadrivalent live attenuated influenza virus vaccine (QIV) formulation whose individual components have been previously shown to provide protection. We demonstrate in proof-of principle studies in mice that the QIV provides effective protection against lethal challenge with either influenza A or B virus.
Highlights
Influenza virus infections continue to pose a major public health threat worldwide associated with seasonal epidemics and sporadic pandemics
Wild-type A/turkey/Ohio/313053/2004 generated by reverse genetics Mouse-adapted A/California/04/2009 generated by reverse genetics B/Brisbane/60/2008 carrying the PB2 Y406 mutation generated by reverse genetics Wild-type B/Wisconsin/01/2010 att virus Ty/04 with PB1 E391, G581, T661, HA tag, and PB2 S265 mutations; other gene segments from wild-type Ty/04; generated by reverse genetics Reassortant att virus with PB1 and PB2 gene segments from Ty/04 att; other gene segments from ma-Ca/04; generated by reverse genetics B/Brisbane/60/2008 with PB1 G580, A660, and HA tag; other gene segments from unmodified wild-type B/Bris strain (PB2 F406); generated by reverse genetics Reassortant att virus carrying HA and NA gene segments from B/Wisc and remaining genes from B/Bris att; generated by reverse genetics
During the 2013–2014, 2014 –2015, and 2015–2016 seasons, a number of issues emerged that called into question the effectiveness of the only FDAapproved Live attenuated influenza virus vaccines (LAIVs) in the U.S market
Summary
Influenza virus infections continue to pose a major public health threat worldwide associated with seasonal epidemics and sporadic pandemics. During the 2013–2014, 2014 –2015, and 2015–2016 seasons, concerns emerged about the effectiveness of the only LAIV approved in the United States that prevented the Advisory Committee on Immunization Practices (ACIP) from recommending its use. We provide evidence of the potential use of our att strategy in a quadrivalent LAIV (QIV) formulation carrying H3N2 and H1N1 influenza A virus subtype viruses and two antigenic lineages of influenza B viruses. The never-ending emergence of zoonotic influenza viruses associated with lethal human infections and of pandemic concern calls for the development of better vaccines and/or vaccination strategies against influenza virus. The most widely used influenza virus vaccine is IIV, which can elicit protective humoral immunity by inducing the production of neutralizing antibodies that target epitopes on the virus HA (and, to a lesser extent, the neuraminidase [NA] surface protein). In the United States, the only FDA-approved LAIV consists of viruses carrying a series of mutations in the internal gene segments of the master donor viruses (MDVs) (A/Ann Arbor/6/60 [H2N2] [MDV-A] and B/Ann Arbor/1/66 [MDV-B]) [20,21,22]
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