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Broadly Protective Influenza Vaccines: Design and Production Platforms Available online at www.sciencedirect.com ScienceDirect Broadly protective influenza vaccines: design and production platforms Husni Elbahesh, Giulietta Saletti, Thomas Gerlach and Guus F Rimmelzwaan Effective vaccines are the cornerstone of our defenses against and patients with chronic diseases, vaccination against acute influenza virus infections that result in 500 000 annual influenza is recommended [4]. Thus, the availability of deaths worldwide. For decades, an on-going concerted effort efficacious vaccines is important in mitigating the potential has been to develop a universal influenza vaccine to combat impact of seasonal and future pandemic outbreaks. This the looming threat of potentially pandemic emerging and re- was exemplified in 2009, when a novel swine origin qua- emerging influenza viruses. To address the need for rapid druple reassortant virus of the H1N1 subtype caused a efficacious vaccines that could mitigate the impact of seasonal pandemic outbreak.Despite huge efforts, vaccines became and future pandemics, multiple platforms are under available after the peak of the pandemic in many countries, development and/or investigation. What is clear is that any which is obviously an unwanted scenario. universal vaccine must provide long-lasting cross-protective immunity that can induce both B and T cell responses. This Although IAV of the H1N1 subtype circulated in the review will explore some of the universal influenza vaccine human population before 2009, these viruses were anti- platforms in the contexts of their ability to induce long-lasting genically different from the pandemic strain and conse- and cross-protective T cell immunity. quently, the majority of individuals did not have virus neutralizing (VN) antibodies to the H1N1pdm09 strain. In contrast however, H1N1 viruses that circulated Address between 1918 and 1957 resemble the 2009 pandemic University of Veterinary Medicine (TiHo), Research Center for Emerging Infections and Zoonoses (RIZ), Bu¨ nteweg 17, 30559 Hannover, Germany strain antigenically. Consequently, individuals born before 1957 had been exposed to these viruses and Corresponding author: developed antibodies that cross-reacted with the Rimmelzwaan, Guus F ([email protected]) 2009 pandemic strain and were spared from infection to a certain extent [5–8]. Current Opinion in Virology 2019, 34:1–9 Current vaccine strategies typically aim at the induction This review comes from a themed issue on Emerging viruses: inter- species transmission of VN antibodies that are directed to epitopes located in close vicinity of the receptor binding site of hemaggluti- Edited by Adolfo Garcı´a-Sastre and Juergen A Richt nin (HA), the receptor binding protein of influenza For a complete overview see the Issue and the Editorial viruses. However, update of the vaccine strains is Available online 27th November 2018 required almost annually to match the epidemic strains https://doi.org/10.1016/j.coviro.2018.11.005 antigenically. Furthermore, the seasonal vaccine will offer little protection against pandemic or zoonotic influenza 1879-6257/ã 2018 Elsevier B.V. All rights reserved. viruses with an antigenically distinct HA, often of an alternative subtype. In contrast, IAV infections induce a certain level of immunity against IAVs of other subtypes (heterosubtypic immunity) (reviewed in Ref. [9 ]) and experiments in both mouse and primate models of infec- Introduction tion demonstrated that cross-reactive virus-specific CD8+ Influenza viruses are major cause of acute respiratory tract T-cells in particular contribute to this type of protective infections. Both influenza A and B viruses (IAV or IBV, immunity [10–14]. In humans, it was also shown that the respectively) cause annual epidemics in humans with sub- presence of virus-specific CD8+ T-cells induced by infec- stantial morbidity and mortality. In addition, IAV have tion with seasonal IAV strains correlated with protection caused pandemic outbreaks of variable severity [1]. While against pandemic and zoonotic viruses [15,16 ,17]. seasonal IAV are currently of the H1N1 and H3N2 sub- Therefore, developing vaccines that can induce potent types, zoonotic infections with IAV of other subtypes, like T cell responses could overcome limitations of antibody- H5N1 and H7N9, continue to be detected. It has been mediated immunity by providing heterotypic cross-pro- demonstrated that some avian viruses only require a few tection through recognition of highly conserved internal adaptive mutations to become transmissible between proteins. In this review, we discuss current and future mammals and therefore pose a pandemic threat [2,3]. To universal vaccine platforms (Figure 1) with consideration protect selected high risk groups, like children, the elderly to induction of lasting and cross-reactive T cell responses. www.sciencedirect.com Current Opinion in Virology 2019, 34:1–9 2 Emergining virus: intraspecies transmission Figure 1 LAIV Broadly Protective IIV Immunity RNA Vaccine Recombinant/VLP (mRNA/SAM-mRNA) DNA Vaccine Influenza virus gene Cellular correlates Vectored-Vaccine Antibody correlates of protection of protection Influenza virus gene Expression of Expression of internal proteins surface proteins (M1, NP) (HA, NA, M2e) Current Opinion in Virology Schematic of current and future ‘universal’ influenza vaccine platforms under investigation with respective consideration of the type of lasting immunity and correlates of protection induced. Current vaccines Both inactivated influenza virus (IIV) and live attenu- Design and production ated influenza virus (LAIV) vaccines make up the The global influenza vaccination program is a major effort majority of IV vaccines being used, both of which are with more than 400 million doses administered every largely produced in embryonated chicken eggs. Vaccine year [18]. Because seasonal influenza viruses undergo strains used for vaccine production are typically antigenic drift, the vaccine composition requires frequent obtained by genetic reassortment. The gene segments updates for the vaccine to maintain efficacy. The recom- encoding HA and NA of defined antigenicity are com- mendation of strains to be used for vaccine production bined with those obtained from an egg adapted strain relies on a vast global network of surveillance, the and confer a high yield phenotype or for LAIV, with WHO’s Global Influenza Surveillance and Response gene segments that confer the vaccine strains an atten- System (GISR). Together with national centers in more uated cold-adapted and temperature-sensitive pheno- than 100 countries, GISR is tasked with identifying type. The production and characterization of high yield circulating strains, their global distribution patterns and reassortant strains is time-consuming. In addition, dur- most importantly, their antigenic similarity to previous ing passaging in embryonated chicken eggs the vaccine vaccine strains. strains may acquire adaptive changes in the HA, which Current Opinion in Virology 2019, 34:1–9 www.sciencedirect.com Development of universal influenza vaccines Elbahesh et al. 3 may affect its antigenicity and consequently its effec- are typically used in children. Reports of reduced vac- tiveness [19–23]. Egg-independent vaccine production cine efficacy in children between 2 and 17 years old using mammalian cell-culture is an attractive alterna- prompted the American Centers for Disease Control and tive [24–27] and the production of recombinant HA in Prevention to recommend that LAIV should not be used insect cells by a baculovirus expression system has also in this age group during the 2016/2017 and 2017/2018 received FDA approval [24–28]. Regardless of the seasons. However, the CDC did recommend the Flu- vaccine production system, the major antigenic target Mist LIAV for the 2018/2019 season after manufacturers of these vaccines is the viral HA; specifically the glob- showed increased efficacy by replacing the H1N1 vac- ular head of the HA which contains at least 5 antigenic cine component with a different strain (A/Slovenia/2903/ sites that surround the receptor binding site [29]. HA- 2015) [49–51]. specific antibodies directed to these antigenic sites can neutralize the virus by preventing binding of the virus Considering the above, there is a clear need for alterna- to its receptor, provided that they match the virus tive influenza vaccines that can induce broadly protec- antigenically. The acquisition of amino acid changes tive immunity. During a pandemic outbreak, the prior at these positions can result in evasion from recognition use of these vaccines would reduce morbidity and mor- by VN antibodies. tality in the population and would buy some time until tailor made vaccines against the emerging pandemic Challenges and limitations strains become available. The development of such The emergence of viruses with novel HA and/or NA ‘universal’ influenza vaccines has been high on the genes derived from animal influenza viruses is of great research agenda for some years now and some advance- concern, because these reassortant viruses are well ments have been made [52]. adapted to replicate in humans and VN antibodies to their membrane glycoproteins are virtually absent in the human population. Consequently these viruses have the Universal vaccines potential to cause a pandemic outbreak, which has indeed Design and limitations occurred four times in the last century, in 1918 (H1N1), The largest efforts in designing a ‘universal’ influenza 1957 (H2N2), 1968 (H3N2) and 2009 (H1N1). In addi- vaccine
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