Re: WER. Seroepidemiological studies of pandemic influenza A (H1N1) 2009 virus
Seroepidemiological studies of pandemic influenza A (H1N1) 2009 virus (WER, edited)
[Source: World Health Organization, Full PDF Document (
LINK). Extract, edited.]
Weekly epidemiological record
Relev? ?pid?miologique hebdomadaire
11 JUNE 2010, 85th YEAR / 11 JUIN 2010, 85e ANN?E
No. 24, 2010, 85, 229?236
http://www.who.int/wer
Seroepidemiological studies of pandemic influenza A (H1N1) 2009 virus
Background
A great deal of information has been generated as the 1-year anniversary of the start of the influenza A (H1N1) 2009 pandemic approaches, yet there remain many questions regarding the infectivity and epidemiology of pandemic influenza A (H1N1) 2009 virus. Under the surveillance system for pandemic influenza, the incidence of infection for many countries was calculated using data that captured only the number of people seeking medical care for illness, while those with asymptomatic or mild infections were not counted, leading to an underestimation of the actual number of infections. Influenza-specific antibodies are regarded as markers of past infection, and the detection of significant antibody titres against a specific strain of the virus may also reflect partial or complete protection against that virus. Therefore, measurements of antibody in serum samples obtained from populations before and after circulation of pandemic influenza A (H1N1) 2009 virus can be used to estimate the extent of infection in the population.
These data may inform decision-making on public health policy and help quantify the effectiveness of interventions.(1,2)
In this review the methods and results of 9 studies of the seroprevalence of pandemic influenza A (H1N1) 2009 virus that have been published in peer-reviewed journals are examined, and the implications of such studies (Table 1) are discussed. These studies include data from 7 countries: China; China, Province of Taiwan; Finland; Germany; Singapore; the United Kingdom; and the United States of America. The studies were designed to determine the prevalence of cross-reactive antibodies to the pandemic influenza virus prior to its appearance and to estimate the proportion of the population that was infected.
Methods: populations studied and laboratory procedures
Eight of the seroepidemiological studies provided baseline estimates of the prevalence of pandemic A (H1N1) 2009 virus cross-reactive antibodies. All 8 used serum samples collected prior to the appearance of the virus in the community but represent different subsets of the population. For example, Singapore evaluated samples from healthy volunteers, most of whom were born before 1958,(3) and from military personnel, hospital staff and residents in a long-term care facility before community transmission was recognized in the country;(4) China sampled farmers from Guangxi Province who had no previous history of vaccination plus a small number of people from Guangdong Province;(5) the United States used stored serum samples from vaccine trials conducted in 1976 and from academic, industry or government personnel collected between 2005 and prior to the pandemic in 2009;(6) the United Kingdom used serum samples from 9 regions across England collected in 2008;(7) Germany used serum from healthy blood donors collected between 2007 and 2008;(8) and Finland used serum samples collected from the virus diagnostic unit at Helsinki University Hospital between 2004 and 2005.(9)
In addition, 5 of the studies also provided additional serological data for specimens collected after the appearance of pandemic A (H1N1) 2009 virus. These include samples from inpatients or ambulatory patients,(8,10) health-care workers,(4,11) participants in vaccine trials,(6) and military personnel.(4)
In the studies evaluated in this report, the serological tests used to measure influenza antibodies in human serum samples included both microneutralization assays and haemagglutination inhibition assays (Table 1).
The studies that used haemagglutination inhibition assays followed the standard protocol as described by the United States Centers for Disease Control and Prevention.(12)
Each study used a different reference strain of the pandemic A (H1N1) 2009 virus for the tests.
Results
The result of the baseline surveys of samples collected before the start of the pandemic provide evidence that the proportion of individuals with pre-existing antibodies that cross-reacted with pandemic A (H1N1) 2009 influenza viruses increases with age (Table 2). Although the 2 studies from Singapore found no individuals(3) or a low proportion(4) of individuals with cross-reactive antibodies, 4 other studies (from Finland, Germany, the United Kingdom and the United States) reported a relatively high proportion of individuals aged >60 years with pre-existing cross-reactive antibodies when compared with younger age groups. For the studies that examined antibody titres after the appearance of the pandemic virus, samples taken during the acute phase and during convalescence were available for testing in only 1 study.(4) Two additional studies compared the proportion of the population that was seropositive for pandemic A (H1N1) 2009 virus before and after circulation to estimate the proportion that became infected during the pandemic. The remaining studies reported seropositivity rates after pandemic A (H1N1) 2009 virus had been circulating but did not have baseline comparisons.
The studies consistently found that young children and young adults had the highest rates of seropositivity to the pandemic A (H1N1) 2009 virus after the arrival of pandemic virus in the community, or the greatest increase in seropositivity rates compared with baseline (Table 2).
Discussion
The microneutralization test is a sensitive and specific assay for detecting the total functional antibodies that neutralize infectivity of the virus. The assay measures antibodies against a number of different antigenic targets including those on the haemagglutinin surface protein and the neuraminidase surface protein. The microneutralization test provides information on whether a person has antibodies that can neutralize the infectivity of a given virus strain; this is used as an indicator of protection from infection. However the correlation of microneutralization titres to clinical protection has not been established. Performing the assay involves handling live viruses; this may require stringent laboratory biosafety practices and may be impossible for laboratories that lack such facilities.
The haemagglutination inhibition assay is used to measure antibodies that can bind to the virus surface protein haemagglutinin, which is responsible for attaching the virus to cells to initiate the infection cycle. In the absence of antibodies that bind the haemagglutinin, the protein will cause clumping, or agglutination, of red blood cells. The test does not specifically measure neutralizing antibodies but is considered a surrogate test for virus neutralization. The correlation between the haemagglutination inhibition titre and clinical protection has been documented for seasonal influenza viruses; a haemagglutination inhibition titre of 32 or 40 is generally accepted to be associated with a 50% reduction in the risk of influenza infection or disease in a population.(13,14,15,16)
However, results of the haemagglutination inhibition assay are highly dependent on the type of red cells used in the assay.
Reports from clinical vaccine trials suggest that haemagglutination inhibition and microneutralization assays provide comparable sensitivity to detect people who have protective immunity against the pandemic A (H1N1) 2009 virus.(17,18)
Results from 3 of the studies reviewed here also demonstrated that both assays correlated well and yielded similar results in serological surveys.(19,20,21)
The interpretation and direct comparison of the results of the 9 studies is complicated because: they used different cut-off values to represent a positive result; they were implemented during different stages of the pandemic; there is a lack of strain-specific laboratory tests for antibodies against pandemic A (H1N1) 2009 virus that clearly distinguish pandemic infection from previous infection with other H1N1 viruses or previous vaccinations; and the studies used different population groups. Studies attempted to compensate for the lack of preinfection sera from individuals by using prepandemic titres of antibodies in the population. However, even this method was complicated by the need to use serum samples for baseline estimates from study populations that were not representative of the general population, such as people who donated to blood banks.
Given these inherent limitations in the data, however, some consistent observations have been noted. The results of the baseline seroepidemiological surveys provided reasonably consistent evidence that cross-protective immunity from previously circulating H1N1 strains increases with age, with the highest levels occurring in individuals aged >60 years. This finding may explain the low observed rates of illness in this group. In addition, the results from studies carried out after the appearance of pandemic A (H1N1) 2009 virus support the observation that infection rates were highest among school-aged children and young adults. Additional findings from individual studies include evidence that the virus had different rates of infectivity geographically during the same time periods, at least during the early period of out-of-season transmission. The seropositivity rate of antibodies against the pandemic A (H1N1) 2009 virus in first-line hospital staff in China, Province of Taiwan, was higher than that in second-line workers who had less exposure to patients and than in the general population of patients. This was thought to reflect a higher infection risk resulting from patient contact, and highlights the need for health-care workers to be vaccinated.(11)
Based on the results of these studies it is still not possible to accurately estimate the true global attack rate of the pandemic. Data from more studies, preferably those that used standardized methods, are needed because it is unclear whether the wide variation in the level of seropositivity among studies was caused by differences in methods or regional differences in the attack rate. Seroepidemiological studies are ongoing in approximately 24 countries. Results from these studies, in addition to the studies presented in this review, will provide a better composite picture of the attack rates of pandemic A (H1N1) 2009 virus. In addition to the limitations described above, the timing of sample collection in relation to the circulation of the virus and initiation of vaccination against pandemic influenza in the areas studied needs to be carefully considered when interpreting future studies. WHO is fostering efforts to standardize methods so that the comparability of data will be improved in the future.
1) Lipsitch M et al. Managing and reducing uncertainty in an emerging influenza pandemic. New England Journal of Medicine, 2009, 361:112?115.
2) The WHO informal network for mathematical modelling for pandemic influenza H1N1 2009 (working group on data needs). Studies needed to address public health challenges of the 2009 H1N1 influenza pandemic: insights from modeling. Public Library of Science Currents: Influenza, 2009, Dec 17: RRN1135 (
LINK), accessed May 2010).
3) Tang J et al. Cross?reactive antibodies to pandemic (H1N1) 2009 virus, Singapore. Emerging Infectious Diseases, 2010, 16:874?876.
4) Chen M et al. 2009 influenza A(H1N1) seroconversion rates and risk factors among distinct adult cohorts in Singapore. Journal of the American Medical Association, 2010, 303:1383?1391.
5) Chen H et al. Serologic survey of pandemic (H1N1) 2009 virus, Guangxi Province, China. Emerging Infectious Diseases, 2009, 15:1849?1850.
6) Hancock K et al. Cross?reactive antibody responses to the 2009 pandemic H1N1 influenza virus. New England Journal of Medicine, 2009, 361:1945?1952.
7) Miller E et al. Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study. Lancet, 2010, 375:1100?1108.
8) Allwinn R et al. Determination of serum antibodies against swine-origin influenza A virus H1N1/09 by immunofluorescence, haemagglutination inhibition, and by neutralization tests: how is the prevalence rate of protecting antibodies in humans? Medical Microbiology Immunology, 2010, 199:117?121.
9) Ikonen N et al. High frequency of cross-reacting antibodies against 2009 pandemic influenza A(H1N1) virus among the elderly in Finland. Eurosurveillance, 2010, 15(5)
ii=19478 (also available from:
LINK).
10) Ross T et al. Seroprevalence following the second wave of pandemic 2009 H1N1 influenza. Public Library of Science Currents: Influenza, 2010, Feb 24: RRN1148.
11) Chan Y et al. Seroprevalence of antibodies to pandemic (H1N1) 2009 influenza virus among hospital staff in a medical center in Taiwan. Journal of the Chinese Medicine Association, 2010, 73:62?66.
12) Kendal AP, Pereira MS, Skehel JJ. Concepts and procedures for laboratory?based influenza surveillance. Atlanta, GA, United States Centers for Disease Control and Prevention, 1982.
13) Hobson D et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. Journal of Hygiene (London), 1972, 70:767?777.
14) De Jong JC et al. Haemagglutination?inhibiting antibodies to influenza virus. Developmental Biology (Basel), 2003, 115:63?73.
15) Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Research, 2004, 103: 133?138.
16) Wood JM et al. Comparison of influenza serology techniques by international collaborative study. Vaccine, 1994, 12:167?174.
17) Clark et al. Trial of 2009 influenza A (H1N1) monovalent MF59?adjuvanted vaccine. New England Journal of Medicine, 2009, 361:2405?2413.
18) Greenberg ME et al. Response after one dose of a monovalent influenza A (H1N1) 2009 vaccine ? preliminary report. New England Journal Medicine, 2009, 361:2405?2413.
19) Hancock et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. New England Journal of Medicine, 2009, 361:1945?1952.
20) Miller et al. Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross?sectional serological study. Lancet, 2010, 375:1100?1108.
21) McCullers et al. Recipients of vaccine against the 1976 ?swine flu? have enhanced neutralization responses to the 2009 novel H1N1 influenza virus. Clinical Infectious Diseases, 2010, 50:1487?1492.
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