Estimating age-specific cumulative incidence for the 2009 influenza pandemic: a meta-analysis of A(H1N1)pdm09 serological studies from 19 countries

Abstract

Background: The global impact of the 2009 influenza A(H1N1) pandemic (H1N1pdm) is not well understood.

Objectives: We estimate overall and age-specific prevalence of cross-reactive antibodies to H1N1pdm virus and rates of H1N1pdm infection during the first year of the pandemic using data from published and unpublished H1N1pdm seroepidemiological studies.

Methods: Primary aggregate H1N1pdm serologic data from each study were stratified in standardized age groups and evaluated based on when sera were collected in relation to national or subnational peak H1N1pdm activity. Seropositivity was assessed using well-described and standardized hemagglutination inhibition (HI titers ≥ 32 or ≥ 40) and microneutralization (MN ≥ 40) laboratory assays. The prevalence of cross-reactive antibodies to the H1N1pdm virus was estimated for studies using sera collected prior to the start of the pandemic (between 2004 and April 2009); H1N1pdm cumulative incidence was estimated for studies in which collected both pre- and post-pandemic sera; and H1N1pdm seropositivity was calculated from studies with post-pandemic sera only (collected between December 2009-June 2010).

Results: Data from 27 published/unpublished studies from 19 countries/administrative regions - Australia, Canada, China, Finland, France, Germany, Hong Kong SAR, India, Iran, Italy, Japan, Netherlands, New Zealand, Norway, Reunion Island, Singapore, United Kingdom, United States, and Vietnam - were eligible for inclusion. The overall age-standardized pre-pandemic prevalence of cross-reactive antibodies was 5% (95%CI 3-7%) and varied significantly by age with the highest rates among persons ≥ 65 years old (14% 95%CI 8-24%). Overall age-standardized H1N1pdm cumulative incidence was 24% (95%CI 20-27%) and varied significantly by age with the highest in children 5-19 (47% 95%CI 39-55%) and 0-4 years old (36% 95%CI 30-43%).

Conclusions: Our results offer unique insight into the global impact of the H1N1 pandemic and highlight the need for standardization of seroepidemiological studies and for their inclusion in pre-pandemic preparedness plans. Our results taken together with recent global pandemic respiratory-associated mortality estimates suggest that the case fatality ratio of the pandemic virus was approximately 0.02%.

Keywords: A(H1N1)pdm09; H1N1pdm; cross-reactive antibodies; cumulative incidence; seroprevalence.

Figure 1

(a) Review process of published and unpublished H1N1pdm serologic literature search. (b) Example of the characterization of timing of sera collection in relation to national H1N1pdm virus activity. N.B. Characterization of sera timing was conducted using the national, or subnational when available, epidemic curve separately for each country that provided serological data, Time period A indicates the time period prior to the reporting of the first H1N1pdm cases in North America and start of the 2009 influenza pandemic. Time period B indicates the time period after the H1N1pdm virus was identified in North America, but before wide‐spread circulation of the virus occurred in each country. This assessment was made for each individual country or subnational geographic area if subnational virologic data were available. Time period C indicated the time after the national or subnational peak in H1N1pdm virologic activity was over, but not completely back to baseline levels. Time period D indicates the national or subnational time when H1N1pdm virus circulation was clearly over. Shaded area indicates example of peak H1N1pdm virologic activity. Studies that collected sera during peak activity were excluded from the analyses.

Figure 2

Geographic distribution of included study populations.

Figure 3

Cumulative incidence of H1N1pdm infection in studies with pre‐ and post‐pandemic sera collection. Each dot represents the unadjusted point estimate with 95% confidence bounds for a study that provided data from all age groups. Individual study estimates are unadjusted; the pooled estimate is age‐adjusted. There was heterogeneity in the overall rates variance estimates for the random effects for the pre‐pandemic overall estimates (A) P = 0·024 and post‐pandemic seroprevalence rates (C) P = 0·09; and the I ² for the overall cumulative incidence rates (B) =98·1%.

Figure 4

Age‐specific (A) prevalence of cross‐reactive antibodies from baseline pre‐pandemic sera, (B) cumulative incidence of H1N1pdm infection using pre‐ and post‐pandemic sera and (C) H1N1pdm seroprevalence from post‐pandemic sera. Point estimates indicate pooled estimate and lines represent relevant 95%CI. Each line represents unadjusted age‐specific results from individual studies. See Tables S1–S3 for studies included in each estimate.