Findings about serological variations observed in patients during the 2009 pandemic in England (UK) – fresh assessment of the evidenceArchived

Assessment of baseline age-specific antibody prevalence and incidence of infection to novel influenza A H1N1 2009Hardelid P, Andrews NJ, Hoschler K, et al.Health Technol Assess. 2010 Dec; 14(55):115-92

The rationale behind this large influenza serology study, carried out in England (United Kingdom) during and after the 2009 pandemic, was based on the necessity that exists of conducting timely sero-epidemiological surveys able to provide information on the age-specific incidence of influenza infection, which in view of the authors is essential for the calculation of the true denominator for markers of severity – such as case fatality and hospitalisation rates – and for estimating key transmission parameters such as the basic reproductive number (or Ro), which is the average number of secondary cases generated from a single index case. The main aim pursued by the authors was to calculate the incidence of influenza A(H1N1)2009 infection during successive waves of the 2009 pandemic by means of calculating the pre-2009 pandemic baseline immunity and the prevalence of antibodies anti-influenza A(H1N1)2009 in the English population selected as sample for the study. The question the authors tried to answer, in the shape of specific objectives, was double. Firstly, they tried to document the prevalence of cross-reactive antibodies to influenza A(H1N1)2009 by age-group in the population of England before the start of the 2009 pandemic. A second objective was to document the age-specific incidence of infection by month of onset as the pandemic progressed by measuring the increases in the proportion of individuals with antibodies to A(H1N1)2009 stratified by age, during the period August 2009 to April 2010.Although the study was carried out during and after the 2009 pandemic, the serum samples used originated from a variety of sources within the English health system. The specimens collected during and after the 2009 pandemic came from microbiology and chemical pathology laboratories whereas those samples collected before the pandemic came from serum banks from the Health Protection Agency (HPA) serological surveillance programme. All these serum panels were then assembled and tested with specific serological assays with the purpose of providing an assessment of the level of influenza A(H1N1)2009-specific protective antibody in the English population. The samples stored in the serum banks consisted of age-group defined residual serum aliquots submitted during 2008 to 16 microbiology laboratories in 8 regions in England. These stored sera were used to document age-stratified prevalence of antibodies to A(H1N1)2009 prior to the arrival of the 2009 pandemic in the UK. The estimation of the monthly incidence as the 2009 pandemic progressed was calculated from changes in prevalence between time points, supplemented by a likelihood-based approach. Despite several technical challenges the authors faced, haemagglutination inhibition (HI) and micro-neutralisation (MN) assays were developed and used to document the baseline cross-reactive antibodies in the population prior to the arrival of the 2009 pandemic and the spread of the virus in the population after the first and second waves. In addition, the authors compared the serological data extracted in this way with virological and clinical incidence surveillance data derived from laboratory confirmation of acute pandemic influenza A(H1N1)2009 infections with the purpose of obtaining a more accurate picture of the impact of the pandemic across age groups.The results of the baseline prevalence survey showed that 29.8% of older adults (individuals born before 1940) had pre-existing cross-reactive antibodies capable of neutralising the influenza A(H1N1)2009 pandemic virus and were spared for infection during the first and subsequent waves in the pandemic. The researchers also found that younger age groups had the lowest level of pre-existing cross-reactive antibodies, thus, being the most susceptible group from a serological point of view. This explains the observed highest attack rates in the <15 year-old population and the contribution of school closures to interrupting transmission in the early stages of the pandemic. The authors also state that these observations are congruent with observations from previous pandemics in the sense that they had a bigger impact on young people and caused more severe morbidity and mortality than seasonal influenza epidemics. These serological studies showed the ten-fold overestimation of cases that happened during the first 2009 pandemic wave due to ‘consultation’ bias, as opposed to classical statistical models of estimation of cases based on the assessment of clinical presentations, but this overestimation was much smaller during the second wave. From a regional perspective, London suffered the first big wave before the rest of the country, particularly hitting school-age children, and although the regional gap was reduced later on, the incidence in this city remained high throughout the pandemic.The authors of this report have come up with a set of important recommendations to follow, in particular (sic):• ‘Investment in seroepidemiological studies for seasonal influenza to improve understanding of its epidemiology and the impact of vaccination, including investment in infrastructure for  storage and investigation of alternative modalities of collection such as dried blood spots’• ‘Detailed analysis of surveillance data from A(H1N1)2009 to ensure legacy systems which can provide information about propensity to consult are developed for use in seasonal influenza’• ‘Development of more rapid serological assays that can measure recent infection and do not require collection of convalescent sera’• ‘Investment in technologies and scientific resources in emerging technologies which address the questions of immune repertoire of anti influenza antibodies in older individuals to determine key cross reactive protective antibodies and their likely genesis’• ‘Further work to develop greater understanding of serological correlates of protection’• ‘Further snapshot of population immunity at regular intervals during the next 5 years to track the waning of immunity to pandemic influenza in the affected ages and investigate the interplay with immunity arising from seasonal circulating viruses’• ‘Further development of statistical methods, such as likelihood-based estimation, that can facilitate the rapid interpretation of serological data for “real time” model parameterisation’

ECDC Comment (03rd March 2011):

Serological reports of appropriately structured, age stratified and geographically representative samples like the one described here [1] can provide an immense amount of information to set in context other measures of pandemic impact in a population, and provide the most accurate measures of population exposure. There are other studies similar to this one that have shown matching conclusions, particularly in relation to the cross-protective immunity features among different age groups associated with the 2009 pandemic. One of these studies carried out in the UK found that around one child in every three was infected with A(H1N1)2009 in the first wave of infection in regions with a high incidence, ten times more than estimated from clinical surveillance. In addition, the study found that pre-existing antibody in older age groups protects against infection. [2]. Another study described the infection rates of four different groups among the population of Thailand (from Bangkok and its surroundings) by measuring the antibodies present in blood after the first 2009 pandemic wave had passed [3]. It was found that blood donors had a lower infection rate than health care workers (7% vs. 12.8%) and, among the general population, the infection rate observed in children was much higher than that of adults (58.6% vs. 3.1%). These results are congruent with the HTA report with regards to the findings in the general population.But most probably, the first national representative seroprevalence cross-sectional study of the 2009 pandemic in the general population following a full pandemic wave was carried out in New Zealand [4]. ECDC published a Scientific Advance based on this study, along with a WHO review back in July 2010 [5]. The New Zealand survey was undertaken to evaluate immunity and incidence of infection in populations, identification of protective or risk factors (including the groups at higher risk) and the provision of evidence for decisions on effective vaccination and other public health interventions. The overall community seroprevalence for the study population was 26.7% but varied with age and ethnicity; for instance, children aged 5-19 years had the highest seroprevalence (46.7%), significantly higher than their baseline immunity of 14%; they were closely followed by pre-school children aged 1-4 years, which seroprevalence was 29.5%, also high when compared to their age-specific baseline immunity of 6%; finally, the seroprevalence and the baseline immunity observed in people aged 60 or more were of similar value around 24%.

References

1. Hardelid P, Andrews NJ, Hoschler K, Stanford E, Baguelin M, Waight PA, et al. Assessment of baseline age-specific antibody prevalence and incidence of infection to novel influenza AH1N1 2009. Health Technol Assess 2010;14(55):115–192
2. Elizabeth, M., H. Katja, et al. (2010). "Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study." The Lancet 375(9720): 1100-1108
3. Lerdsamran H, Pittayawonganon C, Pooruk P, Mungaomklang A, Iamsirithaworn S, et al. (2011) Serological Response to the 2009 Pandemic Influenza A (H1N1) Virus for Disease Diagnosis and Estimating the Infection Rate in Thai Population. PLoS ONE 6(1): e16164
4. Bandaranayake D, Huang S, Bissielo A and Wood T. Seroprevalence of the 2009 influenza A(H1N1) pandemic in New Zealand. Ministry of Health, Client report FW10057. Available at: http://www.moh.govt.nz/moh.nsf/pagesmh/10124/$File/seroprevalence-flu-2…
5. ECDC Scientific Advance, 6 July 2010 ‘Seroepidemiological studies of 2009 influenza A(H1N1) pandemic – A WHO Review and a subsequent publication from New Zealand’.