The intense influenza activity in England during the 2010-11 winter resulted from a combination of factors. Population-based seroepidemiology confirms that the third wave of influenza A(H1N1)pdm09 virus circulation was associated with a shift in age groups affected, with the highest rate of infection in young adults

Andrews, Nick

Baguelin, Marc

Ellis, Joanna

Galiano, Monica

Hoschler, Katja

Miller, Elizabeth

Pebody, Richard

Stanford, Elaine

Thompson, Catherine

Zambon, Maria

Emerging Infectious Diseases

PubMed

Katja Hoschler

Catherine Thompson

Nick Andrews

Monica Galiano

Richard Pebody

Joanna Ellis

Elaine Stanford

Marc Baguelin

Elizabeth Miller

Maria Zambon

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Seroprevalence of Influenza A(H1N1)pdm09 Virus Antibody, England, 2010 and 2011

The intense influenza activity in England during the 2010–11 winter resulted from a combination of factors. Population-based seroepidemiology confirms that the third wave of influenza A(H1N1)pdm09 virus circulation was associated with a shift in age groups affected, with the highest rate of infection in young adults

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Hoschler, K; Thompson, C; Andrews, N; Galiano, M; Pebody, R;Ellis, J; Stanford, E; Baguelin, M; Miller, E; Zambon, M (2012)Seroprevalence of influenza A(H1N1)pdm09 virus antibody, England,2010 and 2011. Emerging infectious diseases, 18 (11). pp. 1894-7.ISSN 1080-6040 DOI: 10.3201/eid1811.120720Downloaded from: http://researchonline.lshtm.ac.uk/1236294/DOI: 10.3201/eid1811.120720Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alterna-tively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by/2.5/Seroprevalence of Infl uenza A(H1N1)pdm09 Virus Antibody, England, 2010 and 2011Katja Hoschler, Catherine Thompson, Nick Andrews, Monica Galiano, Richard Pebody, Joanna Ellis, Elaine Stanford, Marc Baguelin, Elizabeth Miller, and Maria ZambonThe intense infl uenza activity in England during the 2010–11 winter resulted from a combination of factors. Population-based seroepidemiology confi rms that the third wave of infl uenza A(H1N1)pdm09 virus circulation was as-sociated with a shift in age groups affected, with the highest rate of infection in young adults.Seroepidemiologic data collected in England during the fi rst 2 infl uenza pandemic waves suggested that another wave of infection with infl uenza A(H1N1)pdm09 virus was unlikely during 2010–11 (1). However, a sub-stantial third wave occurred that affected persons in older age groups (2). Severity indicators suggested a higher level of illness and death, with increased cases in critical care and deaths. We conducted further seroepidemiologic study in England during 2010–11 to identify possible rea-sons for these observations.The StudyThis observational study used anonymized, residual serum samples from routine microbiological testing. Pa-tient age and sex, date of sample collection, and source laboratory information were available (3).Samples were from patients 0–99 years of age, of whom 53% were female. Samples were grouped accord-ing to collection date: pre–fi rst wave (before April 2009 [1,403 samples]) and post–fi rst wave (August–October 2009 [3,091 samples]); post–second wave (January–April 2010 [2,225 samples]); and pre–third wave (June–Octo-ber 2010 [1,782 samples]) and post–third wave (Febru-ary–April 2011 [1,257 samples]) (Figure 1). Availability of samples by region and patient age was not consistent. With the objective of measuring age-dependent incidence, we prioritized serum samples by patient age. Samples were spread across 7 age groups (<5, 5–14, 15–24, 25–44, 45–64, 65–74, and >75 years) and came from the 9 regions of England (East, East Midlands, London, North East, North West, South East, South West, West Midlands, and York-shire and Humber).Viruses were characterized and sequenced as de-scribed (4). All samples were tested by hemagglutination-inhibition (HI) assay; samples with suffi cient material also were tested by microneutralization assay according to stan-dard methods (1). Samples with titers >32 or >40 by HI or microneutralization assay, respectively, were considered seropositive.We determined antibody persistence by comparing an-tibody levels in the post–second wave panel with those of the pre–third wave panel on a subset of samples from 3 regions (North East, North West, and South West) where samples were available for both time points. Results were assessed with 95% confi dence intervals. The full analysis of the seroprevalence preceding the 2010–11 season is de-tailed elsewhere (1).In samples from all persons except those in the young-est age group (<5 years), antibody declined from the end of the 2009–10 winter season (post–second wave) to before DISPATCHES1894 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 11, November 2012Author affi liations: Health Protection Agency, London, UK (K. Ho-schler, C. Thompson, N. Andrews, M. Galiano, R. Pebody; J. Ellis, M. Baguelin, E. Miller, M. Zambon); and Health Protection Agency, Manchester, UK (E. Stanford)DOI: http://dx.doi.org/10.3201/eid1811.120720Figure 1. Number of infl uenza A(H1N1)pdm09 virus detections (and percentage positive) detected through a network of Health Protection Agency laboratories (the Respiratory DataMart system) from the start of the pandemic in week 17 (week of April 27) 2009 until the end of the 2010–11 winter season. It demonstrates the 3 waves of pandemic infl uenza activity in summer 2009, autumn 2009, and winter 2010–11 and the key events in relation to the timing of the national infl uenza vaccination program. The timing of the serum collections are illustrated at the bottom of the fi gure. Samples were grouped into panels according to their collection. Light gray, A(H1N1)pdm09 virus; medium gray, untyped infl uenza A virus; black, infl uenza B virus; line, overall percentage positive. Study periods were defi ned as follows: pre–fi rst wave, before April 2009; post–fi rst wave, August–October 2009; post–second wave, January–April 2010; pre–third wave, June–October 2010; and post–third wave, February–April 2011. A(H1N1)pdm09 Virus Antibody, Englandthe onset of the 2010–11 season (pre–third wave). This de-cline was limited (<10% reduction by HI and microneu-tralization assays in persons 5–74 years of age), with the largest reduction in the >75-year group (–15% and –20% by HI and microneutralization assays, respectively). In children <5 years, antibody levels increased (15% and 10% by HI and nicroneutralization assays, respectively) during the same time period (Tables 1,2; Figure 2).We assessed changes in antibody levels during the 2010–11 season using data from all 5 available regions (East, North East, North West, South West, and Yorkshire and Humber) (Tables 1, 2; online Technical Appendix Ta-ble, wwwnc.cdc.gov/EID/pdfs/12-0720-Techapp.pdf). For all age groups, HI and microneutralization assays demon-strated similar trends, although the increase by microneu-tralization assay in elderly persons was lower than by HI assay (48% vs. 28% increase). We found no evidence for association of titer with sex or region.Children in the 2 youngest groups (<14 years) had the highest titers overall and highest percentage of sero-positive samples (Tables 1, 2; Figure 2; online Technical Appendix Table). The highest increases in seroprevalence during the third wave were observed in the oldest age group (>75 years, from 17% to 65% seropositive by HI assay), followed by young adults (15–44 years, from 33% to 66% seropositive by HI assay) (online Technical Ap-pendix Figure).ConclusionsClinical surveillance data obtained during the course of acute illness (2) and seroepidemiology through popula-tion sampling are consistent and together point toward a  Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 11, November 2012 1895Table 1. Seroprevalence of influenza A(H1N1)pdm09 virus antibody, England, 2010 and 2011* CharacteristicNo. seropositive samples/no. total samples† (% seropositive samples, 95% CI) Post–second wave‡ Pre–third Post–third wave HI MN HI MN HI MN Age group, y        <5 36/98 (0.37, 0.27–0.47) 31/77 (0.4, 0.29–0.52) 94/182 (0.52, 0.44–0.59) 88/174 (0.51, 0.43–0.58) 99/160 (0.62, 0.54–0.69) 93/150 (0.62, 0.54–0.7)  5–14 132/213 (0.62, 0.55–0.69) 69/107 (0.64, 0.55–0.73) 142/244 (0.58, 0.52–0.64) 152/237 (0.64, 0.58–0.7) 155/200 (0.78, 0.71–0.83) 146/199 (0.73, 0.67–0.79)  15–24 68/154 (0.44, 0.36–0.52) 44/101 (0.44, 0.34–0.54) 152/405 (0.38, 0.33–0.42) 156/400 (0.39, 0.34–0.44) 216/320 (0.68, 0.62–0.73) 188/311 (0.6, 0.55–0.66)  25–44 66/200 (0.33, 0.27–0.4) 31/83 (0.37, 0.27–0.49) 106/370 (0.29, 0.24–0.34) 114/370 (0.31, 0.26–0.36) 187/294 (0.64, 0.58–0.69) 155/283 (0.55, 0.49–0.61)  45–64 59/220 0.27, 0.21–0.33) 42/110 (0.38, 0.29–0.48) 69/320 (0.22, 0.17–0.26) 93/318 (0.29, 0.24–0.35) 62/138 (0.45, 0.36–0.54) 52/135 (0.39, 0.3–0.47)  65–74 36/145 (0.25, 0.18–0.33) 27/87 (0.31, 0.22–0.42) 35/168 (0.21, 0.15–0.28) 42/167 (0.25, 0.19–0.32) 38/74 (0.51, 0.39–0.63) 38/74 (0.51, 0.39–0.63)  >75 55/172 (0.32, 0.25–0.4) 77/163 (0.47, 0.39–0.55) 16/93 (0.17, 0.1–0.26) 25/92 (0.27, 0.18–0.37) 46/71 (0.65, 0.53–0.76) 39/71 (0.55, 0.43–0.67) Region§     Total 1,202 1,782 1,257  North West 561 624 337  South West 404 232 265  North East 237 526 179  East 0 292 122  Yorkshire and   Humber 0 108 354 *HI, hemagglutination inhibition assay; MN, microneutralization assay. †Samples with titers >32 by HI or >40 by MN, ‡For data consistency, samples from only North West, South West, and North East regions were included in this analysis because these regions also were among the 5 regions in pre– and post–third wave samples. §Numbers by region describe total available number of samples (all analyzed at least by HI assay). Table 2. Seroincidence estimates of influenza A(H1N1)pdm09 virus antibody, England, 2010 and 2011 Age group, y Change in antibody level, % (95% CI) Post–second wave to pre–third wave* Pre–third wave to post–third wave† Hemagglutination inhibition Microneutralization Hemagglutination inhibition Microneutralization <5 15 (3–27) 10 (–3 to 24) 10 (0–21) 11 (1–22) 5–14 –4 (–13 to 5) 0 (–11 to 11) 19 (11–28) 9 (1–18) 15–24 –7 (–16 to 3) –5 (–15 to 6) 30 (23–37) 21 (14–29) 25–44 –4 (–12 to 4) –7 (–18 to 5) 35 (28–42) 24 (16–31) 45–64 –5 (–13 to 2) –9 (–19 to 1) 23 (15–33) 9 (0–19) 65–74 –4 (–13 to 5) –6 (–18 to 6) 31 (18–43) 26 (13–39) >75 –15 (–25 to –4) –20 (–32 to –8) 48 (34–61) 28 (13–42) *Antibody levels at the end of the 2009–10 winter season compared with those before the 2010–11 season. †Antibody levels before and after the 2010–11 season. shift in the age range for infection with A(H1N1)pdm09 in the fi rst season after the 2009 pandemic. This fi nding is similar to those in earlier pandemics (5) and other countries (6). Historical data, including from 1918, suggest that the initial impact in children is followed by a dramatic shift in age distribution of infected persons, with the probability of infection in adults exceeding those of children until the age distribution returns to the normal seasonal pattern (5,7). This adaptation process may take 3–10 years (7).The rates of decline in antibody to A(H1N1)pdm09 from the 2009–10 to the 2010–11 winters are similar to historic data (8) and A(H1N1)pdm09 vaccine trials (9,10). The implications of such reduction are uncertain. The se-roprevalence data suggested susceptibility in young adults pre–third wave, but not in children who were targeted by an extended vaccination program in the United Kingdom from January 2010. Up to 30% of children <5 years were vaccinated (11).During the 2010–11 season, antibody was acquired primarily by young and old adults. The largest increase in antibody levels after the 2010–11 winter occurred in persons >75 years of age. Clinical surveillance data sug-gests that elderly persons (>65 years of age) were relatively spared from infection with A(H1N1)pdm09 virus (12). We propose that the increase resulted primarily from seasonal infl uenza vaccination in 2010–11 with vaccine uptake of 72.8% (13). In young adults (15–44 years), we believe that acquisition of antibody occurred as susceptible persons be-came infected during the winter. Children were relatively spared from infection with A(H1N1)pdm09 during winter 2010–11; their high rate of infection in the 2 previous pan-demic waves, together with vaccination, left a limited num-ber of susceptible persons (Figure 2) .Our study design—a retrospective, periodic, cross-sectional collection—has certain limitations. We analyzed similar but not identical groups and persons at different time points. For each sample, only limited information was available. Without information about vaccination status or infl uenza exposure history during the season, our interpre-tation of antibody levels and their changes has to be taken with caution. However, in this descriptive analysis we also used supportive evidence from UK infl uenza surveillance programs and take into account the date of vaccination tim-ing and uptake, which strengthens our interpretation of the serologic data.The collections for each sample set were distributed over time periods of up to 21 weeks, during which antibody levels would have changed, depending on the combined ef-fects of seroconversion, antibody waning and availability of vaccination. A novel likelihood-based approach, described previously has therefore been developed to overcome some of the limitations of the conventional statistical method (1).We found no evidence of substantial antigenic drift in circulating viruses that could affect seroepidemiology re-sults (online Technical Appendix Table). We conclude that the intense A(H1N1)pdm09 virus activity in the England during the 2010–11 winter must have resulted from a com-bination of factors.DISPATCHES1896 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 11, November 2012Figure 2. Percentage of samples with hemagglutination-inhibition titer >32 during consecutive waves of infl uenza activity, England, summer 2009 and 2009–10 and 2010–11 infl uenza seasons. Data were plotted from all available results determined by hemagglutination-inhibition assay on samples from all regions. A) Children <5 years old. B) Children 5–14 years old. C) Persons 15–24 years old. D) Persons 25–44 years old. E) Persons 45–64 years old. F) Persons 65–74 years old. G) Persons >75 years old. Black line, results from all regions; gray line, results from the North West and South West regions, which provided samples throughout the entire period. Error bars indicate 95% confi dence intervals.A(H1N1)pdm09 Virus Antibody, EnglandThe change in age distribution of infection is likely to have caused increased severity, resulting from a larger number of patients with underlying concurrent conditions (12) or from age-dependent changes in pathology. Defi ning antibody correlates of protection becomes more complex with rising patient age as other immune mechanisms in-creasingly contribute to protection, e.g., CD4+ T cells, as demonstrated in human challenge experiments (14). More-over, a murine model identifi ed the role of age in suscep-tibility to pathogenesis and transmission of infl uenza virus infection (15). These observations might help to provide some mechanistic insights for the shift in age distribution of infection and severity in the season after the 2009 pan-demic. Genetic drift in circulating virus over time affecting human airway adaptation and varying climatic conditions during different pandemic waves also should be investi-gated.AcknowledgmentsWe thank the Health Protection Agency Regional Microbiol-ogy Network and National Health Service laboratories that collect samples for the Health Protection Agency seroepidemiology pro-gram. We are grateful for the technical support provided by Janice Baldevarona, Surita Gangar, Paola Barbero, Dipa Lakhman, Ray Borrow, Kevin Potts, and Sam Tomes.This study was funded by the National Institute for Health Research Health Technology Assessment Programme and the De-partment of Health.Dr Hoschler is Advanced Clinical Scientist at the Respira-tory Virus Unit, Microbiology Services–Colindale, Health Pro-tection Agency, UK. Her research is focused on infl uenza serol-ogy, including the investigation of natural and vaccine responses, infl uenza seroepidemiology and development of new diagnostic serologic assays.References  1.  Hardelid P, Andrews NJ, Hoschler K, Stanford E, Baguelin M, Waight PA, et al. Assessment of baseline age-specifi c antibody prev-alence and incidence of infection to novel infl uenza A/H1N1 2009. Health Technol Assess. 2010;14:115–92.  2.  Presanis AM, Pebody RG, Paterson BJ, Tom BD, Birrell PJ, Charlett A, et al. Changes in severity of 2009 pandemic A/H1N1 infl uenza in England: a Bayesian evidence synthesis. BMJ. 2011;343:d5408.http://dx.doi.org/10.1136/bmj.d5408  3.  Health Protection Agency. Seroepidemiology Programme. Lon-don [cited 2012 May 14]. http://www.hpa.org.uk/Topics/InfectiousDiseases/InfectionsAZ/SeroepidemiologyProgramme/  4.  Galiano M, Agapow PM, Thompson C, Platt S, Underwood A, Ellis J, et al. Evolutionary pathways of the pandemic infl uenza A (H1N1) 2009 in the UK. PLoS ONE. 2011;6:e23779. http://dx.doi.org/10.1371/journal.pone.0023779  5.  Simonsen L, Clarke MJ, Schonberger LB, Arden NH, Cox NJ, Fu-kuda K. Pandemic versus epidemic infl uenza mortality: a pattern of changing age distribution. J Infect Dis. 1998;178:53–60. http://dx.doi.org/10.1086/515616  6.  Viasus D, Cordero E, Rodriguez-Bano J, Oteo JA, Fernandez-Na-varro A, Ortega L, et al. Changes in epidemiology, clinical features and severity of infl uenza A (H1N1) 2009 pneumonia in the fi rst post-pandemic infl uenza season. Clin Microbiol Infect. 2012;18:E55–62.http://dx.doi.org/10.1111/j.1469-0691.2011.03753.x  7.  Saglanmak N, Andreasen V, Simonsen L, Molbak K, Miller MA, Viboud C. Gradual changes in the age distribution of excess deaths in the years following the 1918 infl uenza pandemic in Copen-hagen: using epidemiological evidence to detect antigenic drift. 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Pandemic H1N1 (swine) infl uenza vac-cine uptake amongst patient groups in primary care in England 2009/10 [cited 2012 May 14]. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/@ps/documents/digitalasset/dh_121014.pdf12.  Health Protection Agency. Surveillance of infl uenza and other respira-tory viruses in the UK: 2010–2011 report [cited 2012 May 14]. http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/129668741415413.  Health Protection Agency. Seasonal infl uenza vaccine uptake amongst GP patient groups in England. Winter season 2010–11 [cit-ed 2012 May 14]. http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_129856.pdf14.  Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, et al. Preexisting infl uenza-specifi c CD4(+) T cells correlate with disease protection against infl uenza challenge in humans. Nat Med. 2012;18:274–80. http://dx.doi.org/10.1038/nm.261215.  Sun S, Zhao G, Xiao W, Hu J, Guo Y, Yu H, et al. Age-related sensitivity and pathological differences in infections by 2009 pan-demic infl uenza A (H1N1) virus. Virol J. 2011;8:52. http://dx.doi.org/10.1186/1743-422X-8-52Address for correspondence: Katja Hoschler, Respiratory Virus Unit, Virus Reference Department, Microbiology Services–Colindale, Health Protection Agency, 61 Colindale Ave, London, NW9 5HT, UK; email: katja.hoschler@hpa.org.uk Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 18, No. 11, November 2012 1897Search past issues of EID at www.cdc.gov/eid

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