Immunity to : Catching a Moving Target To Improve Vaccine Design Catharine I. Paules, Adrian B. McDermott and Anthony S. Fauci This information is current as of September 23, 2021. J Immunol 2019; 202:327-331; ; doi: 10.4049/jimmunol.1890025 http://www.jimmunol.org/content/202/2/327 Downloaded from

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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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Immunity to Influenza: Catching a Moving Target To Improve Vaccine Design Catharine I. Paules,* Adrian B. McDermott,† and Anthony S. Fauci‡

n sharp contrast to viruses such as measles, in which in two key viral surface proteins, hemagglutinin (HA) and a single exposure generates long-lasting immunity, (NA) (10). Consistent mutability combined I individuals are repeatedly exposed to influenza viruses with strong Ab-mediated selective immune pressure at the throughout their lifetime without developing broad and population level leads to important antigenic changes from durable protection against infection. As a consequence, sub- year to year, termed “.” Despite this evident stantial worldwide morbidity and mortality associated with problem of antigenic drift, our current vaccination strategy influenza infection remain, as herd immunity by natural in- primarily targets the highly variable head of the HA molecule. Downloaded from fection is never established to protect the population at large. This strain-specific approach relies heavily on an exact match In this regard, influenza epidemics (caused by influenza A and between the HA of the vaccine virus and that seen in circu- B viruses) account for an estimated 291,243–645,832 respi- lating viral strains. If antigenic change occurs in circulating ratory deaths worldwide each year (1), including z12,000– viral HAs, new vaccines must be developed to keep pace with 56,000 deaths in the United States (2). Additionally, influenza this viral evolution. Furthermore, IAVs from other animal

A viruses (IAVs) have caused severe worldwide pandemics of species can sporadically infect humans de novo or recombine http://www.jimmunol.org/ varying degrees of mortality, the most devastating of which segments of their genomes with circulating human IAVs, occurred in 1918 and resulted in an estimated 50–100 million leading to the evolution and transmission of an IAV with deaths worldwide (3). an entirely antigenically novel HA (). Pan- The mainstay of seasonal influenza prevention and control is demics can result from outbreaks of influenza viruses that vaccination. Influenza vaccines are important tools in our manifest antigenic shift. Thus, to protect susceptible popula- armamentarium against influenza infection and disease. They tions from the effects of “antigenic shift,” entirely new influ- reduce infection rate and influenza-related complications and enza vaccines must be developed specifically to target the

deaths in some populations. However, they are less efficacious novel strain. Traditionally, theories regarding suboptimal in- by guest on September 23, 2021 than vaccines for many other infectious diseases. For example, fluenza VE have centered on antigenic mismatch between in the United States, influenza vaccine effectiveness (VE) circulating viral strains and the vaccine strain (11). Therefore, against medically attended illness ranges between 10% and it seems logical that VE data for any given population should 60% depending on the season (4). Additionally, as a result be fairly predictable from year to year based solely on char- of time constraints imposed by current manufacturing prac- acteristics of the circulating viral strain and its relationship to tices, influenza vaccines have historically had limited public the vaccine virus. However, VE estimates show remarkably health impact during pandemics (5). complex temporal and demographic trends that differ from season to season, vary among age cohorts within a season, Antigenic drift and shift and seem to be influenced by prior vaccination history (11). One fundamental stumbling block in the current approach to Hence, to better understand the limitations of our current influenza vaccine design is that the virus itself is a constantly influenza vaccines, we must first acknowledge that influenza moving target, often driven by immune pressure from previous immunity is unlikely to be static and that immunological exposures (6–9). IAVs rapidly escape preexisting immunity memory generated through both natural infection and vacci- because of the evolution of an error-prone RNA polymer- nation may impact all subsequent influenza exposures. ase that lacks proofreading capacity and garners mutations Immunologic history When we are exposed to or infected with a virus such as *Milton S. Hershey Medical Center, Penn State College of Medicine, Hershey, measles, which remains fairly constant over time, each sub- PA 17033; †Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and ‡National Institute sequent exposure generally elicits consistent and reproducible of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD B cell responses (12). However, with a constantly moving 20892 target such as influenza, each re-exposure to an antigenically Address correspondence and reprint requests to Dr. Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Office of the Director, Building 31, distinct variant elicits mostly recall responses and usually to a Room 7A03, 31 Center Drive, MSC 2520, Bethesda, MD 20892. E-mail address: lesser degree, some novel Ab and B cell responses (13–15). [email protected] Practically, this means that the immune response to each Abbreviations used in this article: HA, hemagglutinin; IAV, influenza A virus; NA, re-exposure will only be slightly different from the previous neuraminidase; OAS, original antigenic sin; VE, vaccine effectiveness. immune response. The dynamics of these differential re- Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 sponses, in particular, pertaining to competitive dominance, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1890025 328 INVITED COMMENTARY are postulated to have critical implications for understanding avian influenza viral subtypes if they are in the same phylo- protective immune responses to influenza. In this regard, it genetic group. has been hypothesized that a preferential boosting of Ab and From an immunological perspective, it would be important B cell responses against influenza viruses encountered in early to determine the basis of OAS and to modify this phenomenon life occurs with each subsequent influenza exposure. This to improve influenza vaccine approaches (21). During an concept was first postulated 50 y ago by T. Francis (16), initial influenza encounter, an individual develops Abs and who analyzed serologic data from several human cohorts in memory B cell responses that target multiple different epi- the 1940s–1950s (15). At the time, Francis and others (16) topes. Upon subsequent exposures, there is a recall of humoral noted that Ab patterns varied among birth cohorts, that the and memory B cells to conserved epitopes that were likely breadth of Ab responses increased with age, and that influenza initially elicited by the priming virus and that predominate vaccination preferentially boosted Ab levels to historical influ- and perhaps skew the overall response to the newly encoun- enza strains. These findings led to the theory that Ab first tered strain (15, 21, 22). It is uncertain whether this phe- established by childhood influenza infection will continue to nomenon is unique and defined entirely by the first influenza characterize and dominate subsequent immune responses to encounter, be it infection or vaccination; defined by the first influenza both for the individual and the entire birth cohort influenza encounter within a subtype or phylogenetic group; within the general population. Francis (16) proposed the or a result of cumulative experiences over time. This question phrase “original antigenic sin” (OAS) to describe this phe- is currently a subject of intense scrutiny. nomenon. Recently, this theory has been revisited as a poten- In any case, preexisting immunity to influenza viruses can Downloaded from tial explanation for the complexities seen in VE data as well as have unforeseen consequences when the conserved epitopes age-specific mortality patterns seen with influenza infection generating the focus of the Ab-mediated immune response mu- (15). Immunological and epidemiologic evidence is accumu- tate. For example, during the 2013–2014 H1N1 influenza lating to lend credibility to both the positives and negatives of season, middle-aged adults were surprisingly disproportion- the OAS hypothesis, although the mechanisms involved in the ately affected. A particular mutation, K166Q, occurred in process and how much impact every re-exposure plays in the H1N1 HA head (23). This region of the HA was con- http://www.jimmunol.org/ shaping subsequent immune responses are largely unknown. served between H1N1 strains circulating in the late 1970s and Birth cohort data showing differential protection by age the pandemic H1N1 strain that emerged in 2009. Conse- against influenza have long suggested that OAS may impact quently, a substantial proportion of middle-aged adults gen- immunity throughout one’s lifetime. Mortality data from the erated a focused Ab response to this region in response to the 1918 influenza pandemic revealed that the majority of deaths 2009 influenza pandemic, which protected them during the occurred in individuals 20–40 y of age. This is unlike mor- 2009 H1N1 pandemic and any subsequent H1N1 exposures tality associated with seasonal influenza, which is typically (23). However, the mutation at position 166 may explain why

concentrated among infants and the elderly (17). To further they were disproportionately affected during the 2013–2014 by guest on September 23, 2021 underscore this point, the elderly actually had less influenza- H1N1 season. related mortality during the 1918 pandemic than in any of Another example of how the immune response can be af- the preceding influenza seasons (1911–1917). A potential ex- fected by a seemingly innocuous single amino acid change planation for these observations centers on the concept of arises from the vaccine manufacturing process itself. The OAS. Elderly individuals and the very young may have been majority of the world’s influenza vaccine supply is still gen- relatively more protected from the 1918 H1N1 pandemic erated in eggs, and during this process, mutations can occur in than other demographic groups because of an early-life expo- areas of the HA head that help adapt the virus to grow better sure to an antigenically related H1 virus (15). Young adults, in eggs but have the collateral effect of impacting an indi- in contrast, were more likely exposed to an H3 virus in child- vidual’s immune response to the vaccine (24). For example, a hood, potentially hindering robust immunity to H1N1 influ- recent study by Garretson et al. (25) showed that 5% of enza during 1918 and explaining their more severe clinical a 159-person cohort had a $4-fold higher Ab response to a courses. Similarly, during the 2009 H1N1 pandemic, el- single egg-adapted mutation in the HA head of the egg- derly individuals again had a decreased incidence of disease, adapted H1N1 vaccine strain than to the circulating H1N1 suggesting that they were protected by exposure to H1N1 influenza strain. Historically, it is not known whether such viruses circulating prior to 1957 (18). Individuals born after egg-adapted Ab responses impact overall immunity. However, 1977, when H1N1 viruses returned to human circulation, did based on recent data, we can speculate that Ab responses fo- not (as a birth cohort) have the same level of protection cused on an egg-adapted mutation in the 2016–2017 H3N2 against pandemic H1N1. This may have resulted from the influenza vaccine strain may have contributed to an overall fact that only a proportion of this age group would have had decrease in VE against that strain (24). an initial encounter with H1N1 viruses when H3N2 viruses were cocirculating at the time. This observation may also be HA stem immunity related to the degree of antigenic similarity between the post- Thus far, our discussion of OAS has focused primarily on 1977 priming virus and the 2009 H1N1 pandemic strain or neutralizing Ab responses to highly mutable regions of the HA alternatively be related to some yet-undefined factor (18, 19). head, which is arguably the dominant protective response Interestingly, age-specific mortality patterns have also been against influenza and the best understood mechanism of im- seen in individuals infected with H5N1 (phylogenetic group munity. However, protection seen against extremely divergent 1) and H7N9 (phylogenetic group 2) avian influenza viruses viral strains, such as the 2009 H1N1 pandemic strain, and the (20). These data suggest that early-life exposure to seasonal cross-group protection described by Gostic et al. (20), suggest human influenza strains can lend protection against divergent that, at least in some cases, conserved regions of the influenza The Journal of Immunology 329 virus play a critical role in defining the immune response. In ideal influenza vaccination strategy would be a “universal” this regard, functional Ab responses do occur to less-mutable influenza vaccine approach that targets the immutable com- regions of the HA, such as the HA stem. This region of the ponents of influenza and puts us one step ahead of this elusive HA remains relatively unchanged from year to year despite virus. Such a vaccine would ideally give $75% protection antigenic drift and is conserved between influenza subtypes against symptomatic influenza disease caused by both group I within the two respective phylogenetic HA groups. Despite and group II IAVs, have a durability of at least 1 y and repeated exposures to antigenically drifted influenza viruses, preferably much longer, and be effective in all demographic most individuals have low levels of these HA stem Abs in groups (33). To achieve this goal, we must improve our re- serum (21), suggesting an immunologic hierarchy in which search tools and fill the knowledge gaps in our scientific un- HA head Abs are generally immunodominant. Conversely, derstanding (33). First, our current animal models for when exposed to more-divergent viruses created by antigenic studying influenza are for the most part immunologically shift, HA stem responses may be more pronounced. This was naive with regard to influenza. One problem with this ap- recognized following the 2009 H1N1 pandemic when in- proach has been illustrated in the past by surveillance data fected individuals had increased HA stem–specific serum Ab collected by the World Health Organization and its collabo- and higher memory B cell frequencies because the HA head rating centers. Historically, antigenic distance between cir- epitopes antigenically shifted, whereas the HA stem region culating and vaccine viruses was judged using ferret sera remained antigenically similar (13, 26). However, evidence (animals without preexisting influenza immunity) and, in suggests that HA stem responses are transient in circulation, some cases, produced very distinct results from those gener- Downloaded from dissipating quickly following influenza exposure, yet they gen- ated using human sera (15). This also has important impli- erally accumulate with increasing age (15). Therefore, it is cations for developing new vaccination strategies as a vaccine unclear from currently available data whether functional Ab may work well in the context of a naive host; however, it may responses directed toward the HA stem are protective and, more fail to protect in the setting of historical immunity. Second, so, if they are durable without a specific boosting strategy (27). vaccine efficacy is often linked to the HAI titer, which is the

best-studied correlate of protection against influenza (33). http://www.jimmunol.org/ Immunity to NA This assay relies entirely on hemagglutination, which is a Abs directed to other influenza proteins may also play a role in property of the HA head, specifically the receptor binding protection against infection and transmission and theoretically site. The HAI titer has a number of limitations, including contribute to shaping an individual’s immunity over time. In no defined threshold for 100% protection, variability between this regard, Ab to NA has emerged as a potentially important age groups and patient populations, and an inability to mea- target of an individual’s immune response to influenza (28). sure other non-HA head components of the immune re- Although Abs to NA are not neutralizing in vitro, they are sponse. To develop and test a universal influenza vaccine,

effective at limiting viral spread. In animal models, NA is we most certainly need novel ways of measuring immu- by guest on September 23, 2021 immunogenic (29) and is able to prevent overt disease despite nity and animal models that can recapitulate the human not leading to sterilizing immunity (28). Multiple clinical experience. trials (28) have shown that the NA inhibition titer is an in- Even if we are able to overcome the limitations in our current dependent predictor of protection against influenza. Addi- immunological tools for assessing influenza vaccines, we must tionally, recent data from human challenge models suggest still address the gaps in scientific knowledge needed to achieve that NA inhibition may actually be more predictive of clinical the ultimate goal of universality. First, we must determine the outcome indicators in this particular setting than measure- choice(s) of antigenic target or targets for vaccine design. It ments that assess Ab responses to the HA head (30) (hem- seems clear that NA is an underused target that could improve agglutination inhibition titer) or HA stem (anti-HA stem Ab the effectiveness and breadth of currently available vaccines. titers) (31). Most seasonal influenza vaccines do contain NA; however, the It has been postulated for decades that NA immunity was NA content for each vaccine is not standardized and may be critical in reducing the severity of infection during the 1968 too low to generate an optimal immune response. This was H3N2 influenza pandemic (28, 29). It is also well established recently illustrated by Chen et al. (34) who demonstrated that that NA drifts over time, again suggesting that it is subject to influenza vaccines rarely induce NA-reactive B cells, whereas immune pressure and is an important target for population natural infection induces an NA-specific B cell response with immunity (28). The role of NA immunity in an individual’s a magnitude similar to that of HA-reactive B cells. A propor- immune history to influenza exposure, including the con- tion of these B cells produced broadly cross-reactive Abs ca- cept of OAS, remains uncertain. However, Rajendran et al. pable of binding a range of IAVs. Because of slower rates of (32) reported that Abs to NA differ in both magnitude and drift, NA epitopes may be more resistant to antigenic change breadth among different age groups. Furthermore, similar to and potentially impact VE in the short term. Ultimately, Abs to the HA head, NA Ab titers in middle-aged adults and however, it seems likely that to overcome selective immune the elderly are highest against HA subtypes encountered in pressure, more conserved epitopes may have to be identified as childhood. Although additional research is needed, this lends either a component of influenza vaccines or as a standalone credibility to the hypothesis that lifelong NA responses are universal vaccine design. In this regard, there is currently also greatly impacted by early influenza infection. significant focus in the influenza research community on targeting conserved epitopes of the HA stem. To successfully Universal influenza vaccine generate immune responses to these epitopes, we will need As discussed above, our current approach to influenza vacci- to overcome the immunodominant response to the HA nation leaves us constantly trying to chase a moving target. The head. This will likely involve presenting the stem (or other 330 INVITED COMMENTARY subdominant epitopes) to the immune system in new ways, hemagglutinin stalk domain. [Published erratum appears in 2018 Sci. Rep. 8: 276; 8: 4265]. Sci. Rep. 7: 14614. either through novel conformational constructs, different 8. Chong, Y., and H. 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