Children get the flu more often than adults do, a new study finds. 
 
 Kids typically catch the flu once every two years, whereas adults over age 30 get the flu about twice a decade, a study of people living in China found. 
 
 "There's a lot of debate in the field as to how often people get flu, as opposed to flu-like illness caused by something else," said Adam Kucharski, the study's lead researcher and a fellow at the London School of Hygiene &Tropical Disease in the United Kingdom. Some people who think they have the flu may actually have a cold, whereas other people may truly have the flu and not know it, he said. [6 Flu Vaccine Myths] 
 
 To know for sure whether someone had the flu, researchers search the blood for antibodies against the flu virus. 
 
 When people get sick with the flu, their immune systems produce antibodies that target proteins on the virus surface, and after a person recovers, "the infection will show up when a blood sample is subsequently tested," Kucharski said. In other words, the blood retains a memory of the flu strains that have infected a person in the past. 
 
 In the study, the researchers focused on influenza A (H3N2), a dominant strain of flu virus that sickens and kills the most people worldwide, Kucharski said in a statement. They looked at blood samples from 151 people living in southern China, testing each one against a panel of nine strains of H3N2 that were in circulation between 1968 and 2009, according to the study published today (March 3) in the journal PLOS Biology. 
 
 By comparing people's antibodies with the dates that each flu strain was known to circulate, the researchers were able to figure out how often, on average, people really get the flu. This is the first time that anyone has reconstructed a group's history of flu infection from modern-day blood samples, Kucharski said. 
 
 It's unclear why children are sickened with the flu more often than adults, but the scientists had several ideas. Perhaps children and teenagers interact with more people, and so they may be exposed to more germs, said Stephen Riley, the study's senior researcher and a faculty member at the Medical Research Council Centre for Outbreak Analysis and Modeling at Imperial College London in the United Kingdom. 
 
 "The exact frequency of infection will vary depending on background levels of flu and vaccination," Riley said. 
 
 The researchers, from the U.K., the United States and China, also examined how flu immunity changes in people as they age and encounter different strains of the virus. 
 
 Using a mathematical model, they found that people have stronger immune responses to the flu earlier in life than they do as they get older — a finding that is supported by other studies, Kucharski said. 
 
 "It does seem to be the infections you see later in life, you don't have as great an immune response to," he told Live Science. 
 
 The findings will help scientists understand how a population's immunity influences the flu as the virus evolves, and may help researchers predict how the circulating strains of virus may change in the future, the researchers said. It may also help researchers examine how immunity to historical strains interacts with new vaccines, and how effective new vaccines may be. 
 
 "What we’ve done in this study is to analyze how a person's immunity builds up over a lifetime of flu infections," Kucharski said. "This information helps us understand the susceptibility of the population as a whole, and how easy it is for new seasonal strains to spread through the population." 
 
 Follow Laura Geggel on Twitter @LauraGeggel. Follow Live Science @livescience, Facebook & Google+. Original article on Live Science. ||||| Abstract The immunity of a host population against specific influenza A strains can influence a number of important biological processes, from the emergence of new virus strains to the effectiveness of vaccination programmes. However, the development of an individual’s long-lived antibody response to influenza A over the course of a lifetime remains poorly understood. Accurately describing this immunological process requires a fundamental understanding of how the mechanisms of boosting and cross-reactivity respond to repeated infections. Establishing the contribution of such mechanisms to antibody titres remains challenging because the aggregate effect of immune responses over a lifetime are rarely observed directly. To uncover the aggregate effect of multiple influenza infections, we developed a mechanistic model capturing both past infections and subsequent antibody responses. We estimated parameters of the model using cross-sectional antibody titres to nine different strains spanning 40 years of circulation of influenza A(H3N2) in southern China. We found that “antigenic seniority�? and quickly decaying cross-reactivity were important components of the immune response, suggesting that the order in which individuals were infected with influenza strains shaped observed neutralisation titres to a particular virus. We also obtained estimates of the frequency and age distribution of influenza infection, which indicate that although infections became less frequent as individuals progressed through childhood and young adulthood, they occurred at similar rates for individuals above age 30 y. By establishing what are likely to be important mechanisms driving epochal trends in population immunity, we also identified key directions for future studies. In particular, our results highlight the need for longitudinal samples that are tested against multiple historical strains. This could lead to a better understanding of how, over the course of a lifetime, fast, transient antibody dynamics combine with the longer-term immune responses considered here. 
 
 Author Summary Host immunity against seasonal influenza viruses influences the emergence of new virus strains, the size and severity of “flu�? epidemics, and the effectiveness of vaccination programmes. However, the specific factors that shape the immune response of a single human to a particular strain are little understood because individual infections and the development of immunity over a lifetime in that person are rarely observed directly. To determine the aggregate effect of a lifetime of influenza infections on host immunity, we developed a mathematical model that captures the specific strains with which an individual has been infected and for the corresponding antibody response, the relative contribution of boosting, cross-reactivity, and antigenic seniority to its neutralising ability. Combining the model with data from a survey in southern China that examined antibody levels against nine different influenza strains from 1968 to 2009, we revealed key components of the immune response to influenza virus infection, and obtained estimates of the frequency of influenza infection and the ages at which infection occurred. Our results suggest that “antigenic seniority�?, whereby strains encountered earlier in life gain more “senior�? positions in the immune response, and short-lived cross-reactivity between different strains are important components of the immune response and, therefore, could shape the evolution and emergence of influenza viruses. 
 
 Citation: Kucharski AJ, Lessler J, Read JM, Zhu H, Jiang CQ, Guan Y, et al. (2015) Estimating the Life Course of Influenza A(H3N2) Antibody Responses from Cross-Sectional Data. PLoS Biol 13(3): e1002082. https://doi.org/10.1371/journal.pbio.1002082 Academic Editor: Andrew Fraser Read, The Pennsylvania State University, UNITED STATES Received: April 16, 2014; Accepted: January 16, 2015; Published: March 3, 2015 Copyright: © 2015 Kucharski et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: Data on observed individual titres are available as Dataset S1 in DOI: 10.1371/journal.ppat.1002802. Model estimated titres are available in S1 Data. Funding: This work is supported by the Medical Research Council (UK, Project MR/J008761/1); Wellcome Trust (UK, Project 093488/Z/10/Z); Fogarty International Centre (USA, R01 TW008246-01); Fogarty International Centre with the Science & Technology Directorate, Department of Homeland Security (USA, RAPIDD program); National Institute for General Medical Sciences (US, MIDAS U01 GM110721-01); and National Institute for Health Research (UK, for Health Protection Research Unit funding). JL's work was supported by a grant from NIAID (K22 AI092150-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Abbreviations:: HA, haemagglutinin; HAI, haemagglutination inhibition; NA, neuraminidase 
 
 Introduction The immunity of a host population against specific influenza A strains can influence a number of important biological processes. It can affect the emergence of new virus strains, and hence shape the evolution of the disease [1,2]. It can also influence the size and severity of a pandemic [3–6], and the effectiveness of vaccination programmes [7]. There are two main ways to measure the adaptive immune response against influenza viruses [8]. In microneutralisation assays, a mixture of virus and diluted serum is used to infect cell cultures; the titre is the highest dilution for which virus infection is blocked. Microneutralisation titres therefore measure the overall neutralising antibody response. Such a response can include several components. Some antibodies are specific to antigenic sites on the globular head of the haemagglutinin (HA) surface protein. These sites are highly variable: the HA undergoes frequent mutation, enabling the virus to escape existing antibody responses [9]. There is also evidence that antibodies target conserved epitopes on the stalk of the HA protein or the neuraminidase (NA) surface protein [10–12]. Alternatively, haemagglutination inhibition (HAI) assays measure the extent to which antibodies inhibit binding of the HA protein to red blood cells. Whereas microneutralisation titres likely capture more of the total antibody response, the HAI assay is a more sensitive measure of antibodies that are specific for antigenic sites on the head of the HA protein [13]. The ability of human sera to neutralise current and historical influenza strains exhibits substantial variation between individuals and with age [10,13–15]. These patterns are likely to be influenced by a number of factors. First, neutralisation titres to a particular strain depend on the immune response following exposure to that virus: after infection or vaccination, the immune response to a particular virus can be boosted [5]. Although the initial response may decay to a lower level after a short period of time [16,17], there is evidence that the subsequent level of response can persist for several decades [18]. Observed titres can also depend on the order and number of influenza infections. Francis [14] coined the term “original antigenic sin�? to describe the phenomenon by which HAI titres to the first influenza infection of a lifetime were apparently higher than titres to other strains. Upon subsequent infection, it has been suggested that the original response can be enhanced [14,19–21] and the antibody response to the new strain reduced [22–26]; for original antigenic sin to occur, there is evidence that the original and new strain must be antigenically related [26,27]. Recent work has refined the original antigenic sin hypothesis, proposing that serological patterns should be described in terms of “antigenic seniority�? [13,15]. As with original antigenic sin, the primary infection gains the most “senior�? position in the immune response, but—as a key refinement to the original sin hypothesis—the hierarchy of responses continues with each subsequent infection, as each strain takes a less senior position in the response. As well as boosting and original antigenic sin/antigenic seniority, observed serological responses can also depend on cross-reactivity between strains and temporal waning of responses. Even if hosts have not been exposed to a given strain, they can have a raised titre against the virus if the test strain is similar to those already encountered [5,18]. Establishing the contribution of different mechanisms to neutralisation titres remains challenging, however, because the aggregate effect of immune responses over a lifetime are rarely observed directly [13,24]. Moreover, observed titres not only depend on the relationship between infection and immune response: they are also influenced by the specific strains a host has been infected with. It has been suggested that certain age groups are infected more often than others [28,29], but the true frequency of influenza infection cannot be easily measured [30]. To explore the effects of past infections and subsequent immune responses on observed microneutralisation titres, we fitted a mechanistic model of within-host serological dynamics to data from a cross-sectional survey based in southern China [31]. In the study, 151 individuals’ sera were tested against a panel of nine different influenza A(H3N2) strains isolated between 1968 and 2008. Six of these strains corresponded to representative viruses from every second “antigenic cluster�? that appeared between 1968 and 2003; in total there were 11 such clusters of antigenically similar strains during this period [32]. The other three test viruses were strains that circulated in southern China between 2003 and 2008. We used the mechanistic model to assess the relative contribution of boosting, cross-reactivity, and antigenic seniority to observed neutralisation titres, and estimated key immunological parameters. We also estimated which specific strains each individual had been infected with, and hence assembled infection histories for each individual in the study population. This made it possible to calculate the frequency of infection for influenza A(H3N2) in the host population, and to establish how the infection rate varied with age. 
 
 Materials and Methods Ethics Statement Study protocols and instruments were approved by the following institutional review boards: Johns Hopkins Bloomberg School of Public Health, University of Liverpool, University of Hong Kong, Guangzhou No. 12 Hospital, and Shantou University. Written informed consent was obtained from all participants over 12 y of age, and verbal assent was obtained from participants 12 y of age or younger. Written permission of a legally authorised representative was obtained for all participants under the age of 18 y. Data Participants were recruited from five study locations, with 20 households randomly selected in each location (further details given in Lessler et al. [31]). Participants’ sera were tested against nine representative influenza A(H3N2) strains using a virus neutralisation assay. The strains included six vaccine strains: A/Hong Kong/1/1968, A/Victoria/3/1975, A/Bangkok/1/1979, A/Beijing/353/1989, A/Wuhan/359/1995, and A/Fujian/411/2002. Three strains that circulated in southern China in the years preceding the study were also tested: A/Shantou/90/2003, A/Shantou/806/2005, and A/Shantou/904/2008. Titres were measured using serial 2-fold dilutions from 1:10 to 1:1,280 in duplicate. In our analysis, we represented the results in terms of log neutralisation titres. A log titre of c corresponded to a dilution of 10 × 2(c−1). Hence, there were nine possible log titres: the lowest was 0, which corresponded to a dilution <1:10; the highest was 8, which corresponded to a dilution of 1:1,280. Model of Serological Dynamics We took an “epochal�? view of infection [32,33], with individuals either infected or not during each antigenic epoch; we assumed there were 14 such epochs between 1968 and 2008. We modelled serological titres by assuming that the mean neutralisation titre to a specific strain depended on both individual infection history and a combination of serological mechanisms. We considered four specific mechanisms: boosting from infection with the test strain, cross-reactivity from antigenically similar strains, boosting of earlier responses as a result of subsequent infection, and suppression of subsequent responses as a result of prior immunity. The final two mechanisms have been suggested as potential explanations for observed patterns of antigenic seniority [13,15]. We included the four main mechanisms in the model as follows. Suppose an individual has an infection history that consists of a set of strains X (note that we do not distinguish between live infection and vaccination in the model). We assumed that if an individual had been infected with only one strain, they would exhibit a fixed log titre against that strain, controlled by a single parameter, μ. In the absence of antigenic seniority or cross-reactivity, the individual would therefore have titre equal to μ for every strain in their infection history, and zero for all other strains (Fig. 1A). However, if the individual had been infected with more than one strain, titres against earlier strains could be higher than those against later strains as a result of antigenic seniority. PPT PowerPoint slide 
 
 PowerPoint slide PNG larger image 
 
 larger image TIFF original image Download: Fig 1. Schematic of mechanisms that shape observed titres in the model. (A) Simple boosting. In the absence of cross-reactivity and antigenic seniority, if an individual had been infected with a particular strain, they exhibited a fixed response to that strain equal to μ. This was controlled by a single parameter in the model. In the figure, strains are sorted by date of isolation, with serological samples taken in present day. Strains the host has been infected with are shown in red; coloured bars show the magnitude of observed log titre as a result of past infection with each strain. (B) Boosting of prior responses via antigenic seniority. Infections boosted observed titres to earlier infecting strains by a certain scaling factor, controlled by the parameter τ1. The magnitude of titre to a particular strain therefore depends on the number of infections that occurred after infection with that strain. (C) Suppression of new responses via antigenic seniority. The response to each strain was reduced as a result of immunity generated by previous infections. This reduction was controlled by the parameter τ2. The titre to a particular strain therefore depended on the number of infections that occurred before that strain circulated. (D) Cross-reactivity. In the absence of antigenic seniority, the observed titre to a test strain depended on the response as a result of infection with that strain, plus cross-reactive responses from infection with other strains. These cross-reactive responses decreased with the distance (measured in years) between each infection and the test strain. Strains that circulated further from the test strain in time contributed less to the observed response. https://doi.org/10.1371/journal.pbio.1002082.g001 Two mechanisms have been proposed to explain observed patterns of antigenic seniority: previous responses might be boosted as a result of subsequent infections, or subsequent responses might be reduced as a result of previous immunity [15]. To evaluate the contribution of these two mechanisms, we specified the model so that—depending on parameter values—both, one, or neither mechanism could contribute to measured titres. During the fitting process, model outputs could therefore be compared to observed serological data to establish which mechanism(s) were most plausible given the data. First, we assumed each infection could boost titres against strains encountered previously by a parameter τ 1 (Fig. 1B). Hence the titre μ was scaled by a factor s 1 (X, j) = (1 + τ 1 )|X|−N j where N j is the number of the strain in the infection history (i.e., the first strain is 1, the second is 2, etc.) and |X| is the total number of infections. If τ 1 = 0, then there was no boosting as a result of subsequent infection. This mechanism, in which observed titres to a particular strain depended on the number of subsequent infections, was also proposed by Miller et al. [13] following a longitudinal study of influenza A infections. Second, we assumed prior immunity could reduce observed titres against strains encountered later in life (Fig. 1C). The titre against a particular strain would therefore be scaled by a factor . Here, observed titres to each strain depended on how many infections had occurred previously. When τ 2 = 0, prior infections did not lead to reduced responses against later strains. When τ 2 was large, the formulation was equivalent to a model of original antigenic sin, in which immunity from the primary infection suppressed all subsequent responses [28,34]. Finally, we incorporated cross-reactivity by assuming that mean titre against a specific strain was equal to the sum of cross-reactive responses to all strains in an individual’s infection history. We assumed that the contribution made by each strain depended on the temporal distance between the strain in the infection history and the test strain (Fig. 1D). The level of cross-reaction between a test strain j and infecting strain m was given by d(j, m) = e−σ|t m −t j |, where |t m − t j | was the number of years between strains j and m, and σ was a parameter to be fitted. If σ was large, it was equivalent to having no cross-reactivity between strains. To combine the four mechanisms in the model, we assumed that the log titre individual i has against a strain j was Poisson distributed with the following mean: (1) As d(j, m), s 1 (X, m), or s 2 (X, m) could equal 1 for certain parameter values, the model was capable of omitting certain mechanisms if necessary. We also accounted for potential observation error by assuming that there was a uniform probability of observing a titre different to the true one. Hence, the likelihood of observing titre c j against test strain j was equal to the sum over all possible true titres: (2) We estimated model parameters using Markov chain Monte Carlo (details in S1 Text; dataset and model outputs in S1 Data). As a sensitivity analysis, we also included the waning of antibody responses in our model. This was achieved by modifying Equation 1: (3) where w was a waning parameter that we fixed. The formulation meant that waning reduced titres to strains in the infection history by a factor e−w per year. If w = 0, then we recovered the model given by Equation 1. 
 
 Discussion We have examined how past infections with influenza A(H3N2) strains influence observed cross-sectional neutralisation titres. We found that “antigenic seniority�? and quickly decaying cross-reactivity were important components of the immune response. The order in which an individual is infected with influenza strains was therefore important in dictating observed titres to a particular virus: titres appeared to be the result of a combination of strain-specific boosting, cross-reactivity, and suppression of subsequent responses as a result of antigenic seniority (Fig. 5). PPT PowerPoint slide 
 
 PowerPoint slide PNG larger image 
 
 larger image TIFF original image Download: Fig 5. Schematic of mechanisms that shape observed titres. Our model suggests that the expected magnitude of titres that result from a sequence of infections depends on three of the four mechanisms described in Fig. 1: simple boosting, suppression of subsequent responses as a result of antigenic seniority, and cross-reaction. The contribution from infecting strains to observed titres is influenced by simple boosting and suppression via antigenic seniority (A). These contributions, as well as cross-reaction between similar strains, influence final observed titres (B). For illustrative purposes, strains here appear in 3-y-long epochs, and have circulated over a 40-y period. Strains the host has been infected with are shown in red; coloured bars show the magnitude of observed log titre as a result of past infection with each strain. https://doi.org/10.1371/journal.pbio.1002082.g005 Our results emphasise the importance of understanding how currently unobserved mechanisms shape the dynamics of influenza for individuals over the course of their lifetime. Traditionally, analysis of serological data has been descriptive rather than mechanistic. It has therefore been challenging to distinguish between different hypotheses that could describe observed patterns. In particular, we evaluated two antigenic seniority mechanisms that have been proposed as explanations for why individuals exhibit raised titres to strains encountered earlier in life [15]: earlier responses could be boosted by subsequent infections, or subsequent responses could be reduced as a result of prior immunity. There is an apparent discrepancy between our main parameter estimates for antigenic seniority and empirical observations of boosting of antibodies to early infections. Our baseline results (in the absence of waning) suggest that while there is a reduction in the magnitude of response to later infections, the boosting component of antigenic seniority has a negligible effect on observed long-term titres. However, several studies have found evidence for boosting of existing responses following influenza infection [13,14,19–21]. There were two mechanisms in our model that could potentially lead to increased titres to previously encountered strains after subsequent infections. The first was cross-reaction: in our framework, individuals who had been infected with few strains (Fig. 3A) had lower titres than those who had been infected with several strains that are antigenically related (Fig. 3C). We assumed cross-reaction was symmetric in the model, and made the same contribution to titres regardless of infection order. In contrast, we did not find evidence for boosting of earlier responses as a result of antigenic seniority. In order to investigate this further, we considered the possibility of waning antibodies as a sensitivity analysis. Unfortunately, with cross-sectional data, the boosting and waning processes were not identifiable. Therefore, we assumed a plausible single overall rate of antibody waning and found evidence for boosting as part of an antigenic seniority process. However, although it was possible to force boosting into the model, we suggest that the identifiability issues between boosting and waning and the discrepancy between the model parameters and observed boosting are both consequences of the different timescales on which these immunological processes occur. Boosting and waning are both likely to contribute to the hierarchal nature of antibody responses to influenza. But while waning of elevated titres has been observed over periods of less than a year [35–38], it is not clear precisely how boosted antibody responses persist over time in the absence of infection [41]. Based on our model results, we suggest that repeated boosting of long-lived antibody responses in the absence of waning is unlikely: such a process would lead to either extremely high titres in older individuals or very low rates of infection, neither of which seem credible. Therefore, in essence, we believe our model provides a plausible description of the acquisition of a stable set of persistent antibodies. The apparent discrepancies between observed boosting and relatively low titres to historical strains further highlight the need for studies that take repeated measurements of the serological response of individuals against a panel of historical influenza strains [42]. With such data, the mechanistic model presented here could be expanded to explore both the short- and long-term dynamics of influenza immunity. This would help elucidate the precise role of boosting and suppression in antigenic seniority. We found that cross-reactivity decayed quickly with time, with a half-life of 2.4 y. Hence, there was little cross-reaction between influenza A(H3N2) strains that circulated several years apart. We also considered a model that included broad cross-reactivity between strains, but when we fitted this model to data, the parameter estimate for broad cross-reactivity was zero, indicating that this additional component was not necessary to reproduce observed serological patterns. However, there is evidence that individuals are capable of producing broadly cross-reactive antibodies following infection with a pandemic strain [12,40], and that individuals can exhibit a longitudinal increase in neutralising titres against pandemic strains that are no longer circulating [13]. Again, this highlights the need for longitudinal studies of serological responses against a panel of historical influenza strains. Such data would make it possible to jointly examine the contribution of broad and strain-specific immune responses, and understand how cross-reactive antibodies and antigenic seniority influence observed serological patterns over multiple timescales. As well as comparing the effects of different immune mechanisms, we estimated infection histories for each individual in our study population. We used this information to measure how frequency of infection varied with age. Although infections became less frequent as individuals progressed through childhood and young adulthood, they occurred at similar rates for individuals above age 30 y (Fig. 4A). It has been suggested that influenza transmission is driven by intense social contacts among younger age groups [43]. The decline in frequency of infection with age may be the result of age-specific differences in social behaviour. A study conducted in the same area of southern China as our serological survey found intense mixing within the under-20-y age groups, which could mean the force of infection was higher within these groups [44]. Unfortunately, we had limited serological data for very young individuals (the youngest participant in the study was aged 7 y); it would be interesting to see how the frequency of infection changes from birth through childhood. There are some additional limitations to the work described here. We made no prior assumptions about different age groups’ rate of infection, and hence infection history, in the model. An important next step would be to develop an approach that could measure force of infection from cross-sectional data [45]. This could be explored using a model that accounted for population transmission dynamics as well as serological responses. Moreover, we examined serological data from only 151 participants in southern China. It would therefore be helpful to test similar models of serodynamics against observed titres in other populations [42]. We also focused on responses against a panel of A(H3N2) influenza strains. Unlike group 1 influenza viruses such as A(H1N1), A(H1N1p), and A(H2N2), no group 2 viruses other than A(H3N2) have caused a pandemic; it has been suggested that this is why antibody titres specific to HA stalks might be lower for group 2 viruses than for the more antigenically diverse set of group 1 viruses that have circulated in humans [13]. We also do not distinguish between live infection and vaccination in the model; different routes of exposure could influence the process of antigenic sin/seniority in different ways [12,24]. The model we present offers a novel method for simultaneously investigating immune responses and past infections. Studies looking at the antigenic relationship between different influenza strains typically examine cross-reactivity using ferret sera [9,32]. However, the transmission dynamics of influenza is mediated not just by antigenic change in the virus, but also by underlying immunity in the host population. To analyse the evolutionary trajectory of influenza viruses using human sera, it would be necessary to account for past infections, and how these shape the immune response. We propose that a model of serodynamics, as outlined in this paper, would provide the theoretical foundation required to tackle this problem. Our results also have implications for the analysis of control measures. By considering how a lifetime of infection shapes cross-sectional sera, we have measured the relative importance of different immune mechanisms and past infections in measured serological responses to influenza. As well as influencing the evolution of influenza, such mechanisms could have an impact on the effectiveness of vaccination programmes [7]. We found that the model had limited capacity to accurately predict the magnitude of observed titres to strains that circulated several years before or after the strains to which the model was fitted (S8 Fig.). This is likely the result of the fast decay in cross-reactivity between strains over time. However, the model could generally predict age-specific trends in titres to unencountered strains, even those far from the strain used for fitting. It also reproduced the observed titre levels accurately when fitted strains were close to the test strains in time. This suggests that sufficient representation of past strains, perhaps from every antigenic epoch, would be needed to reproduce all responses accurately. Further, our results were based on neutralisation titres. Similar results are likely to be obtained using HAI, albeit with lower specificity for lower titre values [15,42]. Also, future studies may be able to take advantage of emerging immunological technology based on high throughput protein microarrays [46] and sequence-based measures of B cell diversity [47]. Using a model of cross-sectional serological responses, we have assessed the relative importance of different immune mechanisms and the timing of influenza infection in shaping observed neutralisation titres across the lifetime of an individual. To our knowledge, these two key factors have not previously been combined to fit immunological data. As well as characterising different aspects of the immune response, we have generated individual-level estimates of the frequency and age distribution of influenza infection from cross-sectional serological data. These results demonstrate the value of interpreting immune responses in the context of a lifetime of infection. Integrating the life course of immunity into future analyses of influenza dynamics could therefore lead to a better understanding of population susceptibility and the potential transmissibility of new seasonal strains. 
 
 Author Contributions Conceived and designed the experiments: AJK SR. Performed the experiments: AJK. Analyzed the data: AJK SR. Contributed reagents/materials/analysis tools: JL JMR HZ CQJ YG DATC SR. Wrote the paper: AJK JL JMR DATC SR. Designed the empirical study and collected the data: JL JMR HZ CQJ YG DATC SR.
– Historically, it's been challenging to pinpoint how often people get the flu, in part because most of us can't self diagnose it, thinking we have it when we don't or not knowing we have it when we do. Now researchers say they've found the answer—that kids get the flu on average every two years, adults every five—by studying antibodies in the blood samples of 151 people in southern China to sort out which influenza strains people have become immune to and when. By comparing a person's antibodies against certain strains with the dates those strains circulated, the researchers were able to ascertain when people actually had the flu, the team reports in the journal PLoS Biology. "The exact frequency of infection will vary depending on background levels of flu and vaccination," one researcher tells LiveScience. The researchers, from China, the US, and the UK, say there are several possible reasons why kids get the flu more than twice as frequently as adults, among them being that they are exposed to more germs due to increased interaction with others, and also that they've simply not lived as long and haven't accumulated the same antibodies against influenza strains. Interestingly, though, kids have stronger immune responses to the flu than adults. The findings could help researchers better predict how strains will adapt in the future, as well as how immunity to past strains may influence one's response to new vaccines. (This year's flu vaccine was one of the least effective in the past decade.)