PLoS Medicine
(Accessed 23 November 2013)
http://www.plosmedicine.org/

Research Article
Characterization of Regional Influenza Seasonality Patterns in China and Implications for Vaccination Strategies: Spatio-Temporal Modeling of Surveillance Data
Hongjie Yu, Wladimir J. Alonso, Luzhao Feng, Yi Tan, Yuelong Shu, Weizhong Yang, Cécile Viboud
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001552
Abstract
Background
The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs.

Methods and Findings
We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005–2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%-151%] in the north versus 37% [95% CI 27%-47%] in the south, p<0.0001). Epidemics peaked in January–February in Northern China (latitude ≥33°N) and April–June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January–February and June–August (periodicity ratio >0.6 in provinces located within 27.4°N-31.3°N, slope of latitudinal gradient with latitude -0.016 [95% CI -0.025 to -0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces.

Conclusions
Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4–6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics.

Editors’ Summary
Background
Every year, millions of people worldwide catch influenza, a viral disease of the airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because antigenic drift—frequent small changes in the viral proteins to which the immune system responds—means that an immune response produced one year provides only partial protection against influenza the next year. Annual vaccination with a mixture of killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces the risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. Because the immune response induced by vaccination decays within 4–8 months of vaccination and because of antigenic drift, it is important that these programs are initiated only a few weeks before the onset of local influenza activity. Thus, vaccination starts in early autumn in temperate zones (regions of the world that have a mild climate, part way between a tropical and a polar climate), because seasonal influenza outbreaks occur in the winter months when low humidity and low temperatures favor the transmission of the influenza virus.

Why Was This Study Done?
Unlike temperate regions, seasonal influenza patterns are very diverse in tropical countries, which lie between latitudes 23.5°N and 23.5°S, and in the subtropical countries slightly north and south of these latitudes. In some of these countries, there is year-round influenza activity, in others influenza epidemics occur annually or semi-annually (twice yearly). This complexity, which is perhaps driven by rainfall fluctuations, complicates the establishment of effective routine immunization programs in tropical and subtropical countries. Take China as an example. Before a national influenza vaccination program can be established in this large, climatologically diverse country, public-health experts need a clear picture of influenza seasonality across the country. Here, the researchers use spatio-temporal modeling of influenza surveillance data to characterize the seasonality of influenza A and B (the two types of influenza that usually cause epidemics) in China, to assess the role of putative drivers of seasonality, and to identify broad epidemiological regions (areas with specific patterns of disease) that could be used as a basis to optimize the timing of future Chinese vaccination programs.

What Did the Researchers Do and Find?
The researchers collected together the weekly reports of laboratory-confirmed influenza prepared by the Chinese national sentinel hospital-based surveillance network between 2005 and 2011, data on population size and density, mobility patterns, and socio-economic factors, and daily meteorological data for the cities participating in the surveillance network. They then used various statistical modeling approaches to estimate influenza seasonal characteristics, to assess predictors of influenza seasonal characteristics, and to identify epidemiologically relevant regions. These analyses indicate that, over the study period, northern provinces (latitudes greater than 33°N) experienced winter epidemics of influenza A in January–February, southern provinces (latitudes less than 27°N) experienced peak viral activity in the spring (April–June), and provinces at intermediate latitudes experienced semi-annual epidemic cycles with infection peaks in January–February and June–August. By contrast, influenza B activity predominated in the colder months throughout China. The researchers also report that minimum temperatures, hours of sunshine, and maximum rainfall were the strongest predictors of influenza seasonality.

What Do These Findings Mean?
These findings show that influenza seasonality in China varies between regions and between influenza virus types and suggest that, as in other settings, some of these variations might be associated with specific climatic factors. The accuracy of these findings is limited by the short surveillance period, by sparse surveillance data from some southern and mid-latitude provinces, and by some aspects of the modeling approach used in the study. Further surveillance studies need to be undertaken to confirm influenza seasonality patterns in China. Overall, these findings suggest that, to optimize routine influenza vaccination in China, it will be necessary to stagger the timing of vaccination over three broad geographical regions. More generally, given that there is growing interest in rolling out national influenza immunization programs in low- and middle-income countries, these findings highlight the importance of ensuring that vaccination strategies are optimized by taking into account local disease patterns.

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Perspective
Complex Disease Dynamics and the Design of Influenza Vaccination Programs
Steven Riley
http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001553

For influenza vaccine programs to be optimal from the point of view of the individual at risk of infection, two conditions must be met. First, the vaccine must contain antigens that are well-matched to currently circulating strains [1]. Second, the vaccine must be administered at the right time: early enough that there is sufficient time for antibodies to rise in response to the vaccination, but not so early that protection by the vaccine wanes prior to infectious challenge [2]. The rate of waning of vaccine-induced protection against influenza is particularly high for older adults, one of the groups most at-risk of severe outcomes and often a top priority for national vaccination programs. Therefore, good knowledge of likely temporal trends in the risk of influenza infection is a necessary prerequisite for the design of optimal vaccination programs.

In this week’s PLOS Medicine, Cécile Viboud and colleagues [3] present an extensive analysis of sentinel virological surveillance of influenzas A(H3N2) and B from China with the objective of finding epidemiological patterns that support the design of the country’s first national influenza vaccination program. The authors use time series of viral isolation data from a network of sentinel hospitals, finding strong evidence for key epidemiological features of the incidence of influenza subtypes. Rather than relying on syndromic definitions or excess mortality, these biologically robust outcomes identify the patterns of circulating strains with high specificity.    Despite variability in both the propensity of individuals to seek treatment and the likelihood of them being tested, virological surveillance data accurately describe the timing of peak incidence, the duration of elevated incidence (the influenza season), and periods when influenza is absent (provided testing levels are high year-round).

In many temperate populations such as the United States, knowledge of epidemiological patterns of influenza incidence has facilitated the robust design of vaccination programs [4]: incidence is strongly seasonal, with a very low risk of infection during the summer. The vast majority of infections are focused in a 6–8 week period in the winter months. Therefore, vaccination programs that are expected to last ~6 weeks are initiated ~12 weeks prior to the expected start of the season (the beginning of October in the Northern Hemisphere and the beginning of April in the Southern Hemisphere).

At lower latitudes, patterns are far less clear [5]. Equatorial populations such as Singapore report almost constant year-round incidence of influenza-like illness [6], while some subtropical locations, such as Hong Kong, exhibit weak biennial cycles, with their seasonality characterized primarily by a clear off-season [7]. A study of influenza patterns in Brazil, a country with a large population spanning a wide range of latitudes, revealed wave-like dynamics originating in the less populated equatorial region and travelling out towards larger temperate populations (based on excess pneumonia and influenza mortality) [8].

In their study, Viboud and colleagues were able to separate China into three epidemiological zones for influenza A(H3N2). In the temperate north, incidence peaked sharply during January and February, while in the tropical south, a longer epidemic with a lower peak was observed during April and May. The regions in the middle latitudinal zone exhibited biannual cycles with smaller incidence peaks temporally aligned with their northern and the southern neighbors.

Intriguingly, there were clear differences in the spatial patterns of influenza B compared with those of influenza A. There was little evidence of biannual cycles for influenza B, with the timing of the single peak each year closely correlated with latitude: epidemics occurred first in the north and then progressed steadily to the south. Perhaps most striking, the authors also found that the proportion of samples positive for influenza B increased from less than 20% in the northernmost provinces to almost 50% in the southernmost provinces. These observations point to fundamentally different circulation patterns between influenzas A(H3N2) and B and should motivate systematic phylogeographical and serotype studies of influenza B at the national scale in China.

The observed differences in circulation patterns between influenzas A(H3N2) and B present challenges for the design of vaccination programs at middle and lower latitudes in China. As the authors observe, the timing of peaks in the southernmost provinces is only marginally ahead of Southern Hemisphere populations and suggests that those provinces may wish to follow the Southern Hemisphere timetable. However, such a decision might be slightly premature: genetic data from even a small subset of the viral isolates used for this study could give a definitive picture of the ancestral relationship between viruses circulating in southern China relative to viruses in northern China and Southern Hemisphere populations.

A lasting legacy of the 2009 pandemic is increased interest in novel methods of manufacture for influenza vaccines [9]. Although the vast majority of vaccines delivered today arise from egg-based production systems (not substantially different from those used for the first vaccine trials approx 70 years ago), there are a number of alternative production processes under investigation that may reduce both costs and timelines [10],[11],[12]. When these technologies are fully developed, they could greatly facilitate the redesign of vaccination programs for both seasonal and pandemic influenza. As epidemiological and phylogenetic studies reveal more about the circulation of specific influenza virus subtypes in different regions of the world, it seems likely that the current system of selecting only two official vaccine strain sets per year will be refined. The results presented by Viboud and colleagues [3] suggest that rapidly expanding vaccination programs in populous mid-latitude provinces of China may provide an ideal setting in which to investigate the possible benefits of rapid vaccine production and locally-informed strain selection.