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Influenza Vaccines Review Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for ‘Universal’ Influenza Vaccines Maya Sangesland and Daniel Lingwood * The Ragon Institute of MGH, MIT, and Harvard, 400 Technology Square, Cambridge, MA 02139, USA; [email protected] * Correspondence: [email protected] Abstract: Influenza virus remains a serious public health burden due to ongoing viral evolution. Vaccination remains the best measure of prophylaxis, yet current seasonal vaccines elicit strain- specific neutralizing responses that favor the hypervariable epitopes on the virus. This necessitates yearly reformulations of seasonal vaccines, which can be limited in efficacy and also shortchange pandemic preparedness. Universal vaccine development aims to overcome these deficits by redi- recting antibody responses to functionally conserved sites of viral vulnerability to enable broad coverage. However, this is challenging as such antibodies are largely immunologically silent, both following vaccination and infection. Defining and then overcoming the immunological basis for such subdominant or ‘immuno-recessive’ antibody targeting has thus become an important aspect of universal vaccine development. This, coupled with structure-guided immunogen design, has led to proof-of-concept that it is possible to rationally refocus humoral immunity upon normally ‘unseen’ broadly neutralizing antibody targets on influenza virus. Keywords: influenza virus; antibody response; universal vaccine; immunodominance; broadly neutralizing antibodies; B cell immunology Citation: Sangesland, M.; Lingwood, D. Antibody Focusing to Conserved Sites of Vulnerability: The Immunological Pathways for 1. Introduction—The Need for Universal Influenza Vaccines ‘Universal’ Influenza Vaccines. Viral pathogens such as smallpox and measles have been completely or nearly eradi- Vaccines 2021, 9, 125. https:// cated on a global scale owing to the remarkable success of vaccines; however, influenza doi.org/10.3390/vaccines9020125 virus continues to remain a critical public health issue, as repeated exposure through infection or yearly vaccination has yet to yield long-lasting and durable protection [1–5]. Academic Editor: Yoichi Furuya This inability to generate broadly protective herd immunity imposes a significant burden Received: 11 January 2021 to healthcare systems, where influenza virus is responsible for roughly 3–5 million cases of Accepted: 2 February 2021 Published: 5 February 2021 infection globally with up to 650,000 annual deaths [6,7]. Influenza viruses belong to the family Orthomyxoviridae, which are enveloped viruses Publisher’s Note: MDPI stays neutral containing segmented RNA genomes that can infect across avian and mammalian species, with regard to jurisdictional claims in including humans [8] (Figure1A). Of the four influenza genera (A, B, C, and D), influenza A published maps and institutional affil- and B viruses are responsible for infections in humans. However, influenza A viruses (IAVs) iations. tend to receive more concern, as they evolve faster, incur higher rates of morbidity and mortality, and harbor potential for future pandemic outbreaks [9,10]. IAVs are segregated into subtypes based on the antigenic and phylogenetic characteristics of the two surface gly- coproteins hemagglutinin (HA) and neuraminidase (NA). The CDC currently designates 18 hemagglutinin (H1–H18) and 11 neuraminidase (N1–N11) subtypes that combine to form Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. the viral subtype (e.g., H1N1), with the potential for 198 IAV subtype combinations [11]. This article is an open access article HA can be further subdivided into Group 1 or Group 2 based on further antigenic variation distributed under the terms and (Figure1B). Of the influenza subtypes, H1N1 and H3N2 strains routinely co-circulate in conditions of the Creative Commons the human population, and, along with influenza B, are responsible for yearly seasonal Attribution (CC BY) license (https:// epidemics [7,12]. Current seasonal vaccines consist of a trivalent or quadrivalent formu- creativecommons.org/licenses/by/ lation which includes two influenza A strains (H1N1 and H3N2) and one or two strains 4.0/). from the influenza B lineages (Yamagata and Victoria) (Figure1B). Annual vaccination Vaccines 2021, 9, 125. https://doi.org/10.3390/vaccines9020125 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, x 2 of 19 Vaccines 2021, 9, 125 2 of 20 two strains from the influenza B lineages (Yamagata and Victoria) (Figure 1B). Annual vac- cination remains the best countermeasure against disease, yet efficacy can range from 10% to 60% in a given year and offers little protection from novel pandemic strains [13,14]. remainsVariability the in best seasonal countermeasure vaccine efficacy against is, in disease, large part, yet efficacy linked to can the range highly from mutable 10% tonature 60% inof athe given virus, year which and offersencodes little an protection error-prone from RNA novel polymerase, pandemic resulting strains [13 in,14 the]. Variabilityaccumula- intion seasonal of mutations vaccine in efficacy the two is, major in large surface part, antigens, linked to hemagglutini the highly mutablen and neuraminidase, nature of the virus,through which a process encodes known an error-prone as antigenicRNA drift [15,16]. polymerase, By introducing resulting both in the strain accumulation and subtype of mutationsvariability, in antigenic the two majordrift complicates surface antigens, traditional hemagglutinin vaccine approaches and neuraminidase, by supporting through viral a processescape from known pre-existing as antigenic immunity drift [15,16 [15–19].]. By introducing Vaccines are both thus strain reformulated and subtype yearly variability, based antigenicon surveillance drift complicates measures traditionaland predictions vaccine pu approachesblished by bythe supportingWorld Health viral Organization escape from pre-existing[20], yet as breadth immunity of [protec15–19].tion Vaccines from seasonal are thus reformulated vaccinations yearlyis often based narrow on surveillance and largely measuresstrain-specific, and predictions efficacy suffers published in years by when the World formulations Health Organization are discordant [20 ],with yet ascirculating breadth ofstrains protection [13,21,22]. from seasonal vaccinations is often narrow and largely strain-specific, efficacy suffers in years when formulations are discordant with circulating strains [13,21,22]. FigureFigure 1.1. StructureStructure andand diversitydiversity ofof influenzainfluenza virus.virus. ((AA)) InfluenzaInfluenza isis anan envelopedenveloped virusvirus containingcontaining aa segmentedsegmented RNARNA genome.genome. TheThe surfacesurface glycoproteinsglycoproteins hemagglutininhemagglutinin (HA)(HA) andand neuraminidaseneuraminidase (NA),(NA), alongalong withwith thethe M2M2 ionion channel,channel, whichwhich spansspans thethe viralviral envelope,envelope, serveserve asas potentialpotential universaluniversal vaccinevaccine targets.targets. ((BB)) InfluenzaInfluenza AA (IAV)(IAV) hemagglutininhemagglutinin isis subdividedsubdivided intointo GroupGroup 11 andand GroupGroup 2 2 based based on on antigenic antigenic variability. variability. PandemicPandemic strainsstrains cancan emerge emerge through through antigenic antigenic shift, shift, a processa process by by which which two two different differ- IAVent IAV strains strains of zoonotic of zoonotic origin origin (including (including avian avian and and swine swine species) species) combine combine to to form form aa newnew subtypesubtype thatthat isis infectiousinfectious inin humans.humans. This can bebe extremelyextremely dangerousdangerous asas newlynewly emergingemerging subtypessubtypes areare oftenoften antigenicallyantigenically novelnovel with nono pre-existingpre-existing immunity [[23,24].23,24]. Indeed,Indeed, inin thethe lastlast ~100 ~100 years, years, four four major major IAV IAV pandemics pandemics have have occurred: occurred: the the H1N1 H1N1 Spanish Span- influenzaish influenza (1918), (1918), the H2N2 the H2N2 Asian Asian influenza influenza (1957), (1957), the H3N2 the H3N2 Hong KongHong influenza Kong influenza (1968), and(1968), most and recently, most recently, the H1N1 the swine H1N1 influenza swine infl inuenza 2009. in In 2009. each ofIn theeach above of the examples, above exam- the pandemicples, the pandemic arose either arose directly either from directly an avian from host an avian into humans host into (1918 humans pandemic) (1918 orpandemic) through reassortmentor through reassortment events between events avian–human between avia virusesn–human (1957 viruses and 1968 (1957 pandemics) and 1968 pandemics) or between swine–avian–humanor between swine–avian–human viruses (2009 pandemic)viruses (200 [259 –pandemic)28]. Ongoing [25–28]. pandemic Ongoing concerns pandemic center onconcerns the emergence center on of novelthe emergence H5N1 and of H7N9 novel viruses H5N1 originatingand H7N9 from viruses avian originating species, which from haveavian already species, caused which isolatedhave already spillover caused events isol andated disease spillover outbreaks events and in humans disease [outbreaks29,30]. Given the limitations of seasonal vaccines and the continual threat of pandemic IAVs, in humans [29,30]. the development of universal influenza vaccination strategies remain a priority [4,31–36]. A Given the limitations of seasonal vaccines and the continual threat of pandemic IAVs, the central
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