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Evaluation of Southern Hemisphere Influenza Vaccine Recommendations
Abstract
In 1999, the World Health Organization switched from annual to semi-annual recommendations for influenza vaccine composition. We compared the antigenic match between recommendations and circulating viruses before and after 1999, in the Northern and Southern Hemispheres. Vaccine match proportion for A/H3N2 viruses increased from 31% to 59% in the Southern Hemisphere (P<0.05), and is now comparable to that in the Northern Hemisphere. Vaccine match for influenza B decreased from approximately 100% to 33-54% in both hemispheres (P<0.05), following the unexpected resurgence of influenza B/Victoria in 1997. No estimate was available for influenza A/H1N1. We conclude that semi-annual vaccine recommendations are useful overall and discuss potential ways forward, including a recommendation for the improvement of vaccination policy and influenza surveillance in tropical areas.
... Since 1999, the World Health Organization has issued semi-annual recommendations for the composition of influenza vaccines to be used in the Southern and Northern hemispheres [7][8], but they do not currently issue specific recommendations for the inter-tropical belt [9]. The 2012 recommendations of the World Health Organization Strategic Advisory Group of Experts identified the highest priority groups for influenza vaccination in countries with no vaccination programmes [10]. ...
... Alternatively, the recommendation may be to simply vaccinate at any time of the year [12]. In fact, in countries where influenza circulates year-round, vaccinating twice per year may be worth considering [7], at least for at-risk groups. ...
[This corrects the article DOI: 10.1371/journal.pone.0152310.].
... Since 1999, the World Health Organization has issued semi-annual recommendations for the composition of influenza vaccines to be used in the Southern and Northern hemispheres [7][8], but they do not currently issue specific recommendations for the inter-tropical belt [9]. The 2012 recommendations of the World Health Organization Strategic Advisory Group of Experts identified the highest priority groups for influenza vaccination in countries with no vaccination programmes [10]. ...
... Alternatively, the recommendation may be to simply vaccinate at any time of the year [12]. In fact, in countries where influenza circulates year-round, vaccinating twice per year may be worth considering [7], at least for at-risk groups. ...
Introduction:
Determining the optimal time to vaccinate is important for influenza vaccination programmes. Here, we assessed the temporal characteristics of influenza epidemics in the Northern and Southern hemispheres and in the tropics, and discuss their implications for vaccination programmes.
Methods:
This was a retrospective analysis of surveillance data between 2000 and 2014 from the Global Influenza B Study database. The seasonal peak of influenza was defined as the week with the most reported cases (overall, A, and B) in the season. The duration of seasonal activity was assessed using the maximum proportion of influenza cases during three consecutive months and the minimum number of months with ≥80% of cases in the season. We also assessed whether co-circulation of A and B virus types affected the duration of influenza epidemics.
Results:
212 influenza seasons and 571,907 cases were included from 30 countries. In tropical countries, the seasonal influenza activity lasted longer and the peaks of influenza A and B coincided less frequently than in temperate countries. Temporal characteristics of influenza epidemics were heterogeneous in the tropics, with distinct seasonal epidemics observed only in some countries. Seasons with co-circulation of influenza A and B were longer than influenza A seasons, especially in the tropics.
Discussion:
Our findings show that influenza seasonality is less well defined in the tropics than in temperate regions. This has important implications for vaccination programmes in these countries. High-quality influenza surveillance systems are needed in the tropics to enable decisions about when to vaccinate.
... National references laboratories provide more specific information, such as the strain of influenza virus (e.g., A(H1N1), A(H3N2), or B) and its susceptibility to antivirals. Surveillance data also provide valuable information to WHO Collaborating Centers 8 for the antigenic and genetic analyses that are required to develop future vaccine formulation recommendations (16). This type of surveillance information should be collected, analyzed, and reported regularly so that the information is available throughout the year. ...
... Before 1999, worldwide vaccines were limited to Northern Hemisphere strains. Improved surveillance since then has resulted in the implementation of WHO recommendations that both Northern and Southern Hemisphere strains be included in the vaccines, which has improved the match between the vaccines and the circulating wild strains (16). For some countries in tropical areas of Latin America, the decision of whether to use a Northern or Southern Hemisphere vaccine remains unclear (25). ...
In Latin America, adult influenza is a serious disease that exacts a heavy burden in terms of morbidity, mortality, and cost. Although much has been written about the disease itself, relatively little information has been compiled on what could be done to reduce its impact across the region, particularly from the perspective of clinicians with firsthand experience in confronting its effects. To fill this data gap, in 2011, the Pan American Health and Education Foundation (PAHEF) and the U.S.-based nonprofit Fighting Infectious Diseases in Emerging Countries (FIDEC) organized a conference and convened a panel of Latin American scientistclinicians with experience and expertise in adult influenza in the region to 1) discuss the major issues related to the disease and 2) develop and produce a consensus statement summarizing its impact as well as current efforts to diagnose, prevent, and treat it. The consensus panel concluded a more concerted and better-coordinated effort was needed to reduce the adverse impact of seasonal influenza and future pandemics, including more surveillance, more active involvement by both governmental and nongovernmental organizations, and a much greater effort to vaccinate more adults, especially those at high risk of contracting the disease. In addition, a new approach for diagnosing influenza was recommended.
... For reasons that are poorly understood, influenza and respiratory syncytial virus (RSV) exhibit distinct winter seasonality in temperate latitudes, while patterns of activity are more diverse in tropical locations [1][2][3][4][5][6]. A better understanding of influenza seasonality is useful to inform the timing and composition of vaccine recommendations and monitor the emergence of new virus variants [7][8]. Influenza vaccines have become increasingly available in middle-income countries, but the complex seasonal patterns of virus activity complicate the design of effective vaccination campaigns. ...
... The median length of the 85 country-specific time series meeting our minimum sample size criteria was 9 yrs (range [3][4][5][6][7][8][9][10][11][12][13][14], and the median number of positive specimens isolated per single respiratory season and country was 453 (range 53-25,050). ...
There is limited information on influenza and respiratory syncytial virus (RSV) seasonal patterns in tropical areas, although there is renewed interest in understanding the seasonal drivers of respiratory viruses.We review geographic variations in seasonality of laboratory-confirmed influenza and RSV epidemics in 137 global locations based on literature review and electronic sources. We assessed peak timing and epidemic duration and explored their association with geography and study settings. We fitted time series model to weekly national data available from the WHO influenza surveillance system (FluNet) to further characterize seasonal parameters.Influenza and RSV activity consistently peaked during winter months in temperate locales, while there was greater diversity in the tropics. Several temperate locations experienced semi-annual influenza activity with peaks occurring in winter and summer. Semi-annual activity was relatively common in tropical areas of Southeast Asia for both viruses. Biennial cycles of RSV activity were identified in Northern Europe. Both viruses exhibited weak latitudinal gradients in the timing of epidemics by hemisphere, with peak timing occurring later in the calendar year with increasing latitude (P
... Likewise, for the Southern hemisphere, Influenza virus circulation patterns are reviewed each September, so that vaccination can takes place between March and April of the following year. The current six-month delay between the WHO expert recommendations and vaccine availability is due to limitations of the current technology used in the manufacturing process, which represents a severe challenge for vaccine efficacy (Richard et al., 2010). For these reasons, it is important to investigate national patterns of Influenza virus circulation in tropical countries in order to estimate the most appropriate timing for administering the most appropriate Influenza vaccine. ...
To study the spatial and temporal patterns of influenza A virus (IAV) is essential for an efficient control of the disease caused by IAV and efficient vaccination programs. However, spatiotemporal patterns of spread as well as genetic lineage circulation of IAV on a countrywide scale have not been clearly determined for many tropical regions of the world. In order to gain insight into these matters, the spatial and temporal patterns of IAV in six different geographic regions of Ecuador, from 2011 to 2021, were determined and the timing and magnitude of IAV outbreaks in these localities investigated. The results of these studies revealed that although Ecuador is a South American country situated in the Equator line, its IAV epidemiology resembles that of temperate Northern Hemisphere countries. Phylogenetic analysis of H1N1pdm09 and H3N2 IAV strains isolated in five different localities of Ecuador revealed that provinces in the south of this country have the largest effective population size by comparison with provinces in the north, suggesting that the southern provinces may be acting as a source of IAV. Co-circulation of different H1N1pdm09 and H3N2 genetic lineages was observed in different geographic regions of Ecuador.
... The WHO releases semiannual recommendations for influenza vaccine formulations, in preparation for the peak influenza seasons in the northern and the southern hemispheres respectively. The composition of annual vaccinations patients receive prior to the peak season in each hemisphere are therefore based on information only 8 months old [55]. If Chinese VFR Travel health and Chinese international students travellers travel to China in December or January and obtain influenza vaccination in Australia before they travel, they would still be receiving the southern hemisphere vaccine for the previous season. ...
Background
International students frequently return to their country of origin to visit friends and relatives (VFR), and are at increased risk of travel-associated infections. Little is known of their travel health seeking behaviours. China is the biggest source of international students studying in Australia and the unprecedented epidemic of COVID-19 in China makes this an important area of research.
Methods
Focus groups of Chinese international students were conducted to explore travel health-related knowledge, attitudes and practices. Eligible participants were studying in Sydney, and had travelled to China and Hong Kong to visit friends and relatives in the preceding 18 months. A variety of topics were explored, using a focus group guide. Thematic analysis was undertaken on the transcripts using nVivo software. The list of codes and themes were not pre-determined but developed through content analysis.
Results
Two focus groups were held with a total of 28 participants. Risk perception about VFR travel was generally low among Chinese international students. Pre-travel healthcare was not sought. Students strongly relied on the Internet, social media, parents and friends in China for travel health advice.
Conclusions
This research provides insights into Chinese international students as VFR travellers. It confirms students could be a risk population for importations of infections such as COVID-19 because of low risk perception and lack of seeking travel health advice. This can inform health promotion strategies for students.
... Further, since 2001, the 2 B strain lineages have co-circulated with varying prevalence, making it difficult to predict the next season's dominant lineage. 100,101 The result has been frequent mismatches between the B strain lineage in influenza vaccines and the B strain lineage circulating in the community. Between 1999-2000 and 2012-2013, the B strain lineage in trivalent influenza vaccines has not matched the dominant circulating strain in half of the influenza seasons. ...
Influenza is a highly contagious respiratory acute viral disease which imposes a very heavy burden both in terms of epidemiology and costs, in the developed countries as well as in the developing ones. It represents a serious public health concern and vaccination constitutes an important tool to reduce or at least mitigate its burden. Despite the existence of a broad armamentarium against influenza and despite all the efforts and recommendations of international organisms to broaden immunization, influenza vaccination coverage is still far from being optimal. This, taken together with logistic and technical difficulties that can result into vaccine shortage, makes intra-dermal (ID) vaccines, such as Fluzone® ID and Intanza®, particularly attractive. ID vaccines are comparable and, in some cases, superior to intra-muscular/sub-cutaneous vaccines in terms of immunogenicity, safety, reactogenicity, tolerability and cross-protection profiles, as well as in terms of patient preference, acceptance and vaccine selection. Further advances, such as Fluzone® ID with alternative B strains and Quadrivalent Fluzone® ID or the possibility of self-administering the vaccines, make influenza ID vaccines even more valuable.
... Evaluating the cost-effectiveness of the QIV used in a developing country such as Thailand will be required to formulate a sound public health policy. Finally, alternating the inclusion of B/Yam and B/Vic strains in the annual vaccine from year to year should also be considered [39,40]. ...
Influenza B viruses comprise two lineages, Victoria (B/Vic) and Yamagata (B/Yam), which co-circulate globally. The surveillance data on influenza B virus lineages in many countries often underestimate the true prevalence due to the lack of a rapid, accurate, and cost-effective method for virus detection. We have developed a real-time PCR with melting curve analysis for lineage-specific differential detection of influenza B virus. By amplifying a region of the hemagglutinin gene using real-time PCR with SYBR Green I dye, B/Vic and B/Yam could be differentiated based on their melting temperature peaks. This method was efficient (B/Vic = 93.2 %; B/Yam 97.7 %), sensitive (B/Vic, 94.6 %; B/Yam, 96.3 %), and specific (B/Vic, 97.7 %; B/Yam, 97.1 %). The lower detection limit was 10(2) copies per microliter. The assay was evaluated using 756 respiratory specimens that were positive for influenza B virus, obtained between 2010 and 2015. The incidence of influenza B virus was approximately 18.9 % of all influenza cases, and the percentage was highest among children aged 6-17 years (7.57 %). The overall percentage of mismatched influenza B vaccine was 21.1 %. Our findings suggest that real-time PCR with melting curve analysis can provide a rapid, simple, and sensitive lineage-specific influenza B virus screening method to facilitate influenza surveillance.
... Detailed antigenic characterization should also be performed whenever possible in order to carefully study the temporal patterns of emergence of novel drift variants in each hemisphere and each country and the match with vaccine strains (e.g. 8,21 ). It is important to note that seasonality is not well defined (or inexistent) in many tropical regions 1,19 . ...
Both the Northern and the Southern Hemisphere annual WHO influenza vaccine recommendations are designed to ensure vaccine delivery before the winter-time peak of viral circulation in each hemisphere. However, influenza seasonal patterns are highly diverse in tropical countries and may be out of phase with the WHO recommendations for their respective hemisphere. We modelled the peak timing of influenza activity for 125 countries using laboratory-based surveillance data from the WHO’s FLUNET database and compared it with the influenza hemispheric recommendations in place. Influenza vaccine recommendations for respectively 25% and 39% of the Northern and Southern Hemisphere countries were out of phase with peak influenza circulation in their corresponding hemisphere (62% and 53%, respectively, when the analysis was limited to the 52 countries in the tropical belt). These results indicate that routine influenza immunization efforts should be closely tailored to local patterns of viral circulation, rather than a country’s hemispheric position.
... Between 1999 and 2009, four seasonal vaccine formulations selected for implementation in the northern hemisphere failed to adequately match the epidemic strain because a new antigenic variant emerged after the vaccine strain composition decision was made [7]. Mismatch events have occurred at a similar frequency in the southern hemisphere in recent years [8]. ...
Vaccination is the most effective strategy for prevention and control of influenza. Timely production and deployment of seasonal influenza vaccines is based on an understanding of the epidemiology of influenza and on global disease and virologic surveillance. Experience with seasonal influenza vaccines guided the initial development of pandemic influenza vaccines. A large investment in pandemic influenza vaccines in the last decade has resulted in much progress and a body of information that can now be applied to refine the established paradigm. Critical and complementary considerations for pandemic influenza vaccines include improved assessment of the pandemic potential of animal influenza viruses, proactive development and deployment of pandemic influenza vaccines, and application of novel platforms and strategies for vaccine production and administration.
... The GROG is a network of general practitioners and paediatricians that routinely collects biological samples from patients presenting with ARI, allowing the IBVD study to rely on a very Yamagata lineage viruses were found to be the dominant B lineage, without any tendency for either one to prevail or wane in the long run, thus making it difficult to predict which lineage would be dominant during next season [23]. ...
Studies that aimed at comparing the clinical presentation of influenza patients across virus types and subtypes/lineages found divergent results, but this was never investigated using data collected over several years in a countrywide, primary care practitioners-based influenza surveillance system.
The IBVD (Influenza B in Vircases Database) study collected information on signs and symptoms at disease onset from laboratory-confirmed influenza patients of any age who consulted a sentinel practitioner in France. We compared the clinical presentation of influenza patients across age groups (0-4, 5-14, 15-64 and 65+ years), virus types (A, B) and subtypes/lineages (A(H3N2), pandemic A(H1N1), B Victoria, B Yamagata).
Overall, 14,423 influenza cases (23.9% of which were influenza B) were included between 2003-2004 and 2012-2013. Influenza A and B accounted for over 50% of total influenza cases during eight and two seasons, respectively. There were minor differences in the distribution of signs and symptoms across influenza virus types and subtypes/lineages. Compared to patients aged 0-4 years, those aged 5-14 years were more likely to have been infected with type B viruses (OR 2.15, 95% CI 1.87-2.47) while those aged 15-64 years were less likely (OR 0.83, 95% CI 0.73-0.96). Males and influenza patients diagnosed during the epidemic period were less likely to be infected with type B viruses.
Despite differences in age distribution, the clinical illness produced by the different influenza virus types and subtypes is indistinguishable among patients that consult a general practitioner for acute respiratory infections.
... 1 In recent years, 2 major subtypes of influenza A (H1N1 and H3N2) and 2 lineages of influenza B (Yamagata and Victoria) have been circulating. 2 The current seasonal trivalent influenza vaccine (TIV) includes one strain of A/H1N1, one strain of A/H3N2 and a strain from one of the 2 lineages of influenza B. Vaccination has been a key recommended measure against influenza, 3,4 however, due to antigenic drift, novel strains are generated against which many people lack immunity. The vaccine is updated annually, based on the most likely circulating strains. ...
The trivalent seasonal influenza vaccine is expected to provide optimum protection if the vaccine strains match the circulating strains. The effect of worldwide mismatch between the vaccine strains and extant strains on travellers attending Hajj pilgrimage is not known. Annually 2-3 million Muslims coming from north and south hemispheres congregate at Hajj in Mecca, Saudi Arabia, where intense congestion amplifies the risk of respiratory infection up to eight fold. In order to estimate, to what extent mismatching increases the risk of vaccine failure in Hajj pilgrims, we have examined the global data on influenza epidemiology since 2003, in light of the available data from Hajj. These data demonstrate that globally mismatching between circulating and vaccine strains has occurred frequently over the last 12 years, and the mismatch seems to have affected the Hajj pilgrims, however, influenza virus characteristics were studied only in a limited number of Hajj seasons. When the vaccines are different, dual vaccination of travelers by vaccines for Southern and Northern hemispheres should be considered for Hajj pilgrims whenever logistically feasible. Consideration should also be given to the use of vaccines with broader coverage, i.e. quadrivalent, or higher immunogenicity. Continuous surveillance of influenza at Hajj is important.
... The World Health Organization recommends trivalent influenza virus vaccine composition on a semiannual basis. Influenza virus vaccination control in Malaysia follows the Southern Hemisphere recommendations (6), but we found mismatches in 3 of 8 years (37.5% mismatch rate) for which sequence data were available in Kuala Lumpur (Fig. 1B), compared with global vaccine mismatch rates of 38 to 54% for influenza B virus (17,18). However, influenza virus vaccination rates are low in Southeast Asian countries, including Malaysia (19). ...
Influenza B virus causes significant disease but remains understudied in tropical regions. We sequenced 72 influenza B viruses collected in Kuala Lumpur, Malaysia from 1995-2008. The predominant circulating lineage (Victoria or Yamagata) changed every 1-3 years, and these shifts were associated with increased incidence of influenza B. We also found poor lineage matches with recommended influenza vaccine strains. While most influenza B lineages in Malaysia were short-lived, one circulated for 3-4 years.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
... Vaccination is the main strategy to reduce the public health burden caused by influenza. However, its effectiveness depends on how close the HA sequences of the virus strains used in the vaccine are to those circulating in the same influenza season [7]. Sequence analysis of the glycoprotein genes allows the identification of new strains and may also reveal geographical regions where the detected strains have circulated. ...
BACKGROUND: Influenza remains a major health problem due to the seasonal epidemics that occur every year caused by the emergence of new influenza virus strains. Hemagglutinin (HA) and neuraminidase (NA) glycoproteins are under selective pressure and subjected to frequent changes by antigenic drift. Therefore, our main objective was to investigate the influenza cases in Uberlândia city, Midwestern Brazil, in order to monitor the appearance of new viral strains, despite the availability of a prophylactic vaccine.
... V accines based on inactivated or attenuated influenza viruses are an effective strategy to prevent influenza disease, but they rely on an appropriate choice of strains to be used for the vaccine before the season commences (1,2). The annual selection of vaccine strains in the Northern and Southern hemispheres is necessitated by the continuous antigenic evolution of influenza viruses, which contributes to seasonal differences in the distribution of subtypes and strains as well as the appearance of new subtypes and strains (3)(4)(5)(6)(7)(8). Vaccine failure may arise from the emergence of mismatched strains antigenically drifted or unrelated to the vaccine strains (7,9,10). ...
The estimation of the effectiveness of vaccination against seasonal influenza is guided by the comparison of antigenicities between influenza virus isolates from clinical breakthrough cases with strains included in the vaccine. This study examined whether the prediction of antigenicity using sequence analysis of the hemagglutinin (HA) gene-encoded HA1-domain could be a simpler alternative to using the conventional hemagglutination inhibition (HI) assay, which requires influenza virus culturing. Specimens were taken from breakthrough cases that occurred in a trivalent influenza vaccine efficacy trial involving over 43000 participants during the 2008-2009 season. A total of 498 influenza viruses were successfully subtyped as A(H3N2) (380), A(H1N1) (29), B(Yamagata) (23) and B(Victoria) (66), from 603 PCR- or culture-confirmed specimens. Unlike the B-strain, most A(H3N2) (377) and all A(H1N1) viruses were designated as homologous to the respective vaccine strains based on the HA1-domain nucleic acid sequence. HI titers relative to the respective vaccine strains and PCR subtyping were determined for 48% (182/380) of A(H3N2) and 86% (25/29) of A(H1N1) viruses. Eighty-four percent of the A(H3N2) and A(H1N1) viruses designated as homologous by sequence were matched to the respective vaccine strains by HI testing. However, these homologous A(H3N2) and A(H1N1) viruses displayed a wide range of relative HI titers. Therefore, although PCR was a sensitive diagnostic method to confirm influenza cases, HA1 sequence analysis appeared to be of limited value in accurately predicting antigenicity and hence may be inappropriate to classify clinical specimens as homologous or heterologous to the vaccine-strain for estimating vaccine efficacy in a prospective clinical trial.
... Influenza vaccine effectiveness varies from year to year, depending in part on the match between circulating influenza viruses and vaccine strains 22 ; effectiveness also can vary among specific populations. Hara and colleagues found decreased immunogenicity to the 2009 H1N1 vaccine among individuals with severe motor and intellectual disability. ...
Children With Special Health Care Needs and Preparedness: Experiences From Seasonal Influenza and the 2009 H1N1 Influenza Pandemic - Volume 6 Issue 2 - Georgina Peacock, Cynthia Moore, Timothy Uyeki
... Given our inability to predict future candidate pandemic strains or their drift during an actual pandemic, understanding how T-cells respond when primed with one Ag and are then boosted by a heterosubtypic Ag is important to improve the design of an effective vaccine. In fact, from 1991 to 2007, only a 55-69% match was achieved by licensed vaccine components that target the rapidly drifting seasonal H3N2 Ags (60). ...
The major antigenic component of licensed influenza vaccines, hemagglutinin (HA), elicits predominantly type-specific antibody responses, thus necessitating frequent antigenic updates to the annual vaccine. However, accumulating evidence suggests that influenza vaccines can also induce significant cross-reactive T-cell responses to highly divergent, heterosubtypic HA antigens not included in the vaccine. Influenza vaccines are less effective among the elderly and studies that characterize cross-reactive T-cell immunity in this vulnerable population are much needed. Here, we systematically compare the ex vivo frequency, cytokine profile and phenotype of vaccine-elicited HA-specific T-cell responses among a cohort of young (18-49 years old) and elderly (≥70 years old) vaccinees, as well as the maturation and activation phenotype of total CD4(+) and CD8(+) T-cells. IFN-γ production after in vitro expansion and HA-specific Ab titers were also determined. We find that vaccine-elicited ex vivo frequencies of CD4(+) T-cells elicited by vaccination reactive to any given homo- or heterosubtypic Ag were comparable across the two age groups. While, no differences were observed between age groups in the phenotype of Ag-specific or total CD4(+) T-cells, PBMC from young adults were superior at producing IFN-γ after short-term Ag-specific culture. Significantly, while vaccine-elicited T-cell responses were durable among the younger vaccinees, they were short-lived among the elderly. These results have important ramifications for our understanding of vaccine-induced changes in the magnitude and functionality of HA-specific CD4(+) T-cells, as well as age-related alterations in response kinetics.
... To keep in step with these amino-acid adaptations, a constant updating and remodelling of HA-and NAfocussed vaccines is necessary on an annual or even biannual basis. 15,16 Broader-acting, small-molecule antiviral drugs that target the functional sites of NA and surface ion channel protein M2 of influenza provide an additional line of defence. [17][18][19] Vaccination is effectively a pre-infection strategy designed currently to block the spread of an already known and characterized circulating strain, while smallmolecule antivirals in clinical use are post-infection strategies, capable of broader strain inhibition. ...
Fundamentally new approaches are required for the development of vaccines to pre-empt and protect against emerging and pandemic influenzas. Current strategies involve post-emergent homotypic vaccines that are modelled upon select circulating 'seasonal' influenzas, but cannot induce cross-strain protection against newly evolved or zoonotically introduced highly pathogenic influenza (HPI). Avian H5N1 and the less-lethal 2009 H1N1 and their reassortants loom as candidates to seed a future HPI pandemic. Therefore, more universal 'seasoned' vaccine approaches are urgently needed for heterotypic protection ahead of time. Pivotal to this is the need to understand mechanisms that can deliver broad strain protection. Heterotypic and heterosubtypic humoral immunities have largely been overlooked for influenza cross-protection, with most 'seasoned' vaccine efforts for humans focussed on heterotypic cellular immunity. However, 5 years ago we began to identify direct and indirect indicators of humoral-herd immunity to protein sites preserved among H1N1, H3N2 and H5N1 influenzas. Since then the evidence for cross-protective antibodies in humans has been accumulating. Now proposed is a rationale to stimulate and enhance pre-existing heterotypic humoral responses that, together with cell-mediated initiatives, will deliver pre-emptive and universal human protection against emerging epidemic and pandemic influenzas.
Background
Hong Kong’s seasonal influenza schedule follows the World Health Organization’s northern hemisphere vaccine composition recommendations but with year-round influenza activity there is the potential to implement routine age- and gestation-based schedules utilising both northern and southern hemisphere vaccines for children aged 6 months to 2 years and for pregnant women. This study assessed the potential feasibility of such schedules.
Methods
A literature review was conducted and in-depth interviews with vaccine experts, policy makers and nurses were undertaken.
Results
The following schedules were proposed and assessed for perceived feasibility: 1) a four-dose schedule in the first two years of life requiring an additional unscheduled clinic visit at 7 months; 2) a three-dose schedule excluding the 4-week booster after the first dose; 3) a two-dose schedule for pregnant women involving a dose at the booking visit and a dose with pertussis vaccine at 7 months gestation; and 4) a one-dose schedule at 7 months gestation.
Conclusions
Age- and gestation-based routine influenza vaccination schedules are theoretically feasible for both young children and pregnant women. The three-dose paediatric and one-dose obstetric schedules were assessed in interviews with vaccine experts, policy makers and nurses to be most acceptable. Further clinical studies are required to determine whether such schedules are non-inferior to current seasonal-based schedules in terms of vaccine effectiveness and vaccine uptake.
We monitored the circulating strains and genetic variation among seasonal influenza A and B viruses in Thailand between July 2017 and March 2020. The hemagglutinin gene was amplified and sequenced. We identified amino acid (AA) changes and computed antigenic relatedness using the P epitope model. Phylogenetic analyses revealed multiple clades/subclades of influenza A(H1N1)pdm09 and A(H3N2) were circulating simultaneously and evolved away from their vaccine strain, but not the influenza B virus. The predominant circulating strains of A(H1N1)pdm09 belonged to 6B.1A1 (2017–2018) and 6B.1A5 (2019–2020) with additional AA substitutions. Clade 3C.2a1b and 3C.2a2 viruses co-circulated in A(H3N2) and clade 3C.3a virus was found in 2020. The B/Victoria-like lineage predominated since 2019 with an additional three AA deletions. Antigenic drift was dominantly facilitated at epitopes Sa and Sb of A(H1N1)pdm09, epitopes A, B, D and E of A(H3N2), and the 120 loop and 190 helix of influenza B virus. Moderate computed antigenic relatedness was observed in A(H1N1)pdm09. The computed antigenic relatedness of A(H3N2) indicated a significant decline in 2019 (9.17%) and 2020 (− 18.94%) whereas the circulating influenza B virus was antigenically similar (94.81%) with its vaccine strain. Our findings offer insights into the genetic divergence from vaccine strains, which could aid vaccine updating.
Background:
The importance of influenza viruses in respiratory infections in sub-Saharan Africa has been historically overlooked, including in Burkina Faso. This study therefore aimed at evaluating the prevalence and seasonal occurrence of influenza viruses in children under five years old, at risk of influenza-related complications, presenting with influenza-like illness (ILI) or severe acute respiratory infection (SARI). The study also aimed at identifying the periods with increased influenza transmission for vaccination recommendations in Burkina Faso.
Methods:
From January 2014 to December 2015, ILI and SARI (2015 only) patients were recruited in six healthcare centers in Burkina Faso. Influenza A and B molecular detection and subtyping was performed. Clade clustering of a subset of A(H1N1)pdm09 and A(H3N2) strains was deduced by performing phylogenetic analyses on hemagglutinin gene sequences. Weekly surveillance data from FluNet (2011-2013; 2016) and this study (2014-2015) were used to identify periods of increased influenza activity.
Results:
Influenza A and B viruses were detected in 15.1% (112/743) of ILI and 6.6% (12/181) of SARI patients. Overall, influenza A viruses were largely predominant (81/124, 65.3%), with 69.1% of A(H3N2) and 30.9% of A(H1N1)pdm09 strains. Four waves of increased transmission were identified in 2014-2015, each dominated by different influenza subtypes and clades. Between 2011 and 2016, periods of increased influenza activity varied in their frequency, duration and timing.
Conclusions:
Influenza A and B viruses were detected in a substantial number of ILI and SARI cases in Burkina Faso. Vaccination in September-October would likely protect the highest number of patients. This article is protected by copyright. All rights reserved.
Influenza infection in pregnancy can have adverse impacts on maternal, fetal, and infant outcomes. Influenza vaccination in pregnancy is an appealing strategy to protect pregnant women and their infants. The Bill & Melinda Gates Foundation is supporting three large, randomized trials in Nepal, Mali, and South Africa evaluating the efficacy and safety of maternal immunization to prevent influenza disease in pregnant women and their infants <6 months of age. Results from these individual studies are expected in 2014 and 2015. While the results from the three maternal immunization trials are likely to strengthen the evidence base regarding the impact of influenza immunization in pregnancy, expectations for these results should be realistic. For example, evidence from previous influenza vaccine studies - conducted in general, non-pregnant populations - suggests substantial geographic and year-to-year variability in influenza incidence and vaccine efficacy/effectiveness. Since the evidence generated from the three maternal influenza immunization trials will be complementary, in this paper we present a side-by-side description of the three studies as well as the similarities and differences between these trials in terms of study location, design, outcome evaluation, and laboratory and epidemiological methods. We also describe the likely remaining knowledge gap after the results from these trials become available along with a description of the analyses that will be conducted when the results from these individual data are pooled. Moreover, we highlight that additional research on logistics of seasonal influenza vaccine supply, surveillance and strain matching, and optimal delivery strategies for pregnant women will be important for informing global policy related to maternal influenza immunization.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
Evidence has shown that quadrivalent influenza vaccines containing all four subtypes are safe and immunogenic. However, to date there have been few published studies exploring the population-level clinical and economic impact of quadrivalent compared to trivalent influenza vaccines. Economic evaluation studies need to be conducted in order to inform country-level decision making about whether (and how to) introduce and replace the current trivalent influenza vaccines with quadrivalent influenza vaccination programs. Several key issues associated with estimating the clinical and economic impact of the trivalent versus quadrivalent vaccines are discussed in this article, particularly the complexities involved in estimating the incremental preventable disease and economic burden. Other factors, such as the indirect (herd) protection from quadrivalent influenza vaccination and the timing of the replacement of trivalent influenza vaccination programs are also discussed.
Influenza is a worldwide public health concern. Since the introduction of trivalent influenza vaccine in 1978, vaccination has been the primary means of prevention and control of influenza. Current influenza vaccines have moderate efficacy, good safety, and acceptable tolerability; however, they have unsatisfactory efficacy in older adults, are dependent on egg supply for production, and are time-consuming to manufacture. This review outlines the unmet medical needs of current influenza vaccines. Recent developments in influenza vaccines are also described.
Since the 1980s, 2 antigenically distinct influenza B lineages have cocirculated in the world: B/Victoria/2/87 (first appeared in the 1980s) and B/Yamagata/16/88 (became predominant in the 1990s). B/Victoria/2/87 isolates were geographically restricted to eastern Asia during 1991-2000. During 2000-2001 and 2001-2002, B/Victoria/2/87 isolates reemerged in North America, Europe, and South America, and then spread globally. During influenza virus surveillance, season 2002, an outbreak of acute respiratory illness, which quickly spread among the population, has been notified by public health authorities living in Araraquara, São Paulo, Brazil. Instituto Adolfo Lutz and Secretariat of Health of São Paulo state teams initiate an investigation towards to describe the pattern of infection in this population temporally and by age and to characterize the strains by virus isolation and hemagglutination inhibition assay. The outbreak lasted approximately 10 weeks; many cases occurred between mid-August and mid-September. Children younger than 13 years were the most affected; the elderly were mostly immune to infection. Analysis of the clinical respiratory samples helped in identifying the B/Hong Kong/330/2001 and B/Brisbane/32/2002 subtypes-recent variants of B/Victoria/02/88, a lineage restricted to Southeast Asia until 2001. The Araraquara outbreak confirms the reemergence of the B/Victoria viruses in South America and highlights the importance of monitoring local circulating strains, especially in light of the absence of cross-protection between antigenically distinct influenza lineages. Based on influenza virus surveillance, public health authorities worldwide should decide whether trivalent vaccines or quadrivalent vaccines (containing both influenza virus B lineages) are to be used in each country. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
In Latin America, adult influenza is a serious disease that exacts a heavy burden in terms of morbidity, mortality, and cost. Although much has been written about the disease itself, relatively little information has been compiled on what could be done to reduce its impact across the region, particularly from the perspective of clinicians with first-hand experience in confronting its effects. To fill this data gap, in 2011, the Pan American Health and Education Foundation (PAHEF) and the U.S.-based nonprofit Fighting Infectious Diseases in Emerging Countries (FIDEC) organized a conference and convened a panel of Latin American scientist-clinicians with experience and expertise in adult influenza in the region tol) discuss the major issues related to the disease and 2) develop and produce a consensus statement summarizing its impact as well as current efforts to diagnose, prevent, and treat it. The consensus panel concluded a more concerted and better-coordinated effort was needed to reduce the adverse impact of seasonal influenza and future pandemics, including more surveillance, more active involvement by both governmental and nongovernmental organizations, and a much greater effort to vaccinate more adults, especially those at high risk of contracting the disease. In addition, a new approach for diagnosing influenza was recommended.
Fluarix® is a trivalent, inactivated, split-virion influenza vaccine containing 15 μg haemagglutinin from each of the three influenza virus strains (including an H1N1 influenza A virus subtype, an H3N2 influenza A virus subtype and an influenza B virus) that are expected to be circulating in the up-coming influenza season.
Fluarix® is highly immunogenic in healthy adults and elderly, and exceeds the criteria that make it acceptable for licensure in various regions (including the US and Europe). In a large, phase III, placebo-controlled, double-blind trial conducted in the US (2004/2005) in subjects aged 18–64 years, postvaccination sero-conversion rates against the H1N1, H3N2 and B antigens were 60–78% and respective postvaccination seroprotection rates were 97–99% in Fluarix® recipients. Another phase III trial conducted in the US (2005/2006) established the noninferiority of Fluarix® versus another trivalent inactivated influenza virus vaccine in subjects aged ≥18 years, including a subgroup of elderly subjects. In annual European registration trials, Fluarix® has consistently exceeded the immunogenicity criteria set by the EU Committee for Medicinal Products for Human Use for adults and the elderly. Fluarix® demonstrated immunogenicity in small, open-label studies in at-risk subjects.
During a year when the vaccine was well matched to the circulating strain, Fluarix® demonstrated efficacy against culture-confirmed influenza A and/or B in a placebo-controlled trial in adults aged 18–64 years. In addition, Fluarix® vaccination of pregnant women demonstrated efficacy in reducing the rate of laboratory-confirmed influenza in the infants and reducing febrile respiratory illnesses in the mothers and their new-born infants in a randomized trial.
Fluarix® was generally well tolerated in adults and the elderly in well designed clinical trials and in the annual European registration trials, with most local and general adverse events being transient and mild to moderate in intensity. The most common adverse reactions in recipients of Fluarix® were pain, redness or swelling at the injection site, muscle aches, fatigue, headache and arthralgia.
In conclusion, Fluarix® is an important means of decreasing the impact of seasonal influenza viruses on adults and the elderly.
Data on influenza in tropical countries remain scarce compared with that in temperate countries. However, the emergence of avian influenza virus (H5N1) and the 2009 pandemic represented a major stimulus for advances in knowledge about influenza in many of these countries. This review summarizes recent data on viral and epidemiologic aspects of the condition in tropical countries.
Avian influenza and the influenza pandemic of 2009 have contributed to pioneer production of data on influenza in the tropical settings. Preliminary data on epidemiology, genetic diversity, and antiviral resistance of influenza viruses (seasonal and pandemic) in tropical countries have been published recently.
The seasonality of influenza is very diverse in tropical countries. Recent studies on the subject confirm the year-round activity of these viruses in many countries and the regular occurrence of epidemic outbreaks in others. The use of molecular diagnostic methods has led to prevalence rates comparable to those seen in temperate countries. Phylogenetic analysis of hemagglutinin of influenza isolates allows understanding of the evolution and divergence of avian (H5N1) and human influenza viruses (A/H1N1, A/H3N2, and B) in tropical settings. Influenza viruses resistant to oseltamivir and zanamivir have been detected in tropical countries despite the rare use of these drugs in the treatment of influenza in people living in these areas.
The evolutionary interaction between influenza A virus and the human immune system, manifest as 'antigenic drift' of the viral haemagglutinin, is one of the best described patterns in molecular evolution. However, little is known about the genome-scale evolutionary dynamics of this pathogen. Similarly, how genomic processes relate to global influenza epidemiology, in which the A/H3N2 and A/H1N1 subtypes co-circulate, is poorly understood. Here through an analysis of 1,302 complete viral genomes sampled from temperate populations in both hemispheres, we show that the genomic evolution of influenza A virus is characterized by a complex interplay between frequent reassortment and periodic selective sweeps. The A/H3N2 and A/H1N1 subtypes exhibit different evolutionary dynamics, with diverse lineages circulating in A/H1N1, indicative of weaker antigenic drift. These results suggest a sink–source model of viral ecology in which new lineages are seeded from a persistent influenza reservoir, which we hypothesize to be located in the tropics, to sink populations in temperate regions.
Flu's Tricky Tricks
After vaccination against influenza A virus, single-point mutations are selected in hemagglutinin (the virus molecule that binds to sialic acid molecules on the surface of host cells) that escape neutralization by polyclonal antibody responses. Hensley et al. (p. 734 ) have discovered that in mice these mutations increased the virus's avidity for sialic acid. Amino acid substitutions that occur during reiterations of immune escape and avidity modulation can thus drive antigenic variation. This constant evolution of influenza viruses requires us to change vaccine components annually, and, for equine influenza, Park et al. (p. 726 ) show that as the match between virus and vaccine strains drifts apart with time, the probability of becoming infected and the length of the infectious period increase to the point where outbreaks occur. Nevertheless, even imperfect vaccines may be of benefit to a population because increasing the proportion of vaccinated individuals can supply enough herd immunity to offset a poor antigenic match, especially if used in conjunction with antiviral drugs. For humans, Yang et al. (p. 729 , published online 10 September) estimate that the rate of transmission within U.S. households puts influenza A 2009 H1N1 (the current pandemic “swine flu”) in the higher range of transmissibility, compared to past seasonal and pandemic strains. Thus, to achieve mitigation this fall, children should be the first recipients of vaccine, followed by adults—aiming overall for 70% coverage of the population.
A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups. To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups.
Using a microneutralization assay, we measured cross-reactive antibodies to pandemic H1N1 virus (2009 H1N1) in stored serum samples from persons who either donated blood or were vaccinated with recent seasonal or 1976 swine influenza vaccines.
A total of 4 of 107 persons (4%) who were born after 1980 had preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children between the ages of 6 months and 9 years, in 12 to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. Vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to 2009 H1N1 in adults.
Vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies.
Examination of the evolutionary dynamics of complete influenza viral genomes reveals that other processes, in conjunction with antigenic drift, play important roles in viral evolution and selection, but there is little biological evidence to support these genomic data. Previous work demonstrated that after the A/Fujian/411/2002-like H3N2 influenza A epidemic during 2003-2004, a preexisting nondominant Fujian-like viral clade gained a small number of changes in genes encoding the viral polymerase complex, along with several changes in the antigenic regions of hemagglutinin, and in a genome-wide selective sweep, it replaced other co-circulating H3N2 clades.
Representative strains of these virus clades were evaluated in vitro and in vivo.
The newly dominant 2004-2005 A/California/7/2004-like H3N2 clade, which featured 2 key amino acid changes in the polymerase PA segment, grew to higher titers in MDCK cells and ferret tissues and caused more-severe disease in ferrets. The polymerase complex of this virus demonstrated enhanced activity in vitro, correlating directly to the enhanced replicative fitness and virulence in vivo.
These data suggest that influenza strains can be selected in humans through mutations that increase replicative fitness and virulence, in addition to the well-characterized antigenic changes in the surface glycoproteins.
Background:
Acute respiratory illnesses and influenza-like illnesses (ILI) are a significant source of morbidity and mortality worldwide. Despite the public health importance, little is known about the etiology of these acute respiratory illnesses in many regions of South America. In 2006, the Peruvian Ministry of Health (MoH) and the US Naval Medical Research Center Detachment (NMRCD) initiated a collaboration to characterize the viral agents associated with ILI and to describe the clinical and epidemiological presentation of the affected population.
Methodology/principal findings:
Patients with ILI (fever > or =38 degrees C and cough or sore throat) were evaluated in clinics and hospitals in 13 Peruvian cities representative of the four main regions of the country. Nasal and oropharyngeal swabs, as well as epidemiological and demographic data, were collected from each patient. During the two years of this study (June 2006 through May 2008), a total of 6,835 patients, with a median age of 13 years, were recruited from 31 clinics and hospitals; 6,308 were enrolled by regular passive surveillance and 527 were enrolled as part of outbreak investigations. At least one respiratory virus was isolated from the specimens of 2,688 (42.6%) patients, with etiologies varying by age and geographical region. Overall the most common viral agents isolated were influenza A virus (25.1%), influenza B virus (9.7%), parainfluenza viruses 1, 2, and 3, (HPIV-1,-2,-3; 3.2%), herpes simplex virus (HSV; 2.6%), and adenoviruses (1.8%). Genetic analyses of influenza virus isolates demonstrated that three lineages of influenza A H1N1, one lineage of influenza A H3N2, and two lineages of influenza B were circulating in Peru during the course of this study.
Conclusions:
To our knowledge this is the most comprehensive study to date of the etiologic agents associated with ILI in Peru. These results demonstrate that a wide range of respiratory pathogens are circulating in Peru and this fact needs to be considered by clinicians when treating patients reporting with ILI. Furthermore, these data have implications for influenza vaccine design and implementation in South America.
Since 1999 the World Health Organization issues annually an additional influenza vaccine composition recommendation. This initiative aimed to extend to the Southern Hemisphere (SH) the benefits-previously enjoyed only by the Northern Hemisphere (NH)--of a vaccine recommendation issued as close as possible to the moment just before the onset of the influenza epidemic season. A short time between the issue of the recommendation and vaccine delivery is needed to maximize the chances of correct matching between putative circulating strains and one of the three strains present in the vaccine composition. Here we compare the effectiveness of the SH influenza vaccination adopted in Brazil with hypothetical alternative scenarios defined by different timings of vaccine delivery and/or composition. Scores were based on the temporal overlap between vaccine-induced protection and circulating strains. Viral data were obtained between 1999 and 2007 from constant surveillance and strain characterization in two Brazilian cities: Belém, located at the Equatorial region, and São Paulo, at the limit between the tropical and subtropical regions. Our results show that, among currently feasible options, the best strategy for Brazil would be to adopt the NH composition and timing, as in such case protection would increase from 30% to 65% (p<.01) if past data can be used as a prediction of the future. The influenza season starts in Brazil (and in the equator virtually ends) well before the SH winter, making the current delivery of the SH vaccination in April too late to be effective. Since Brazil encompasses a large area of the Southern Hemisphere, our results point to the possibility of these conclusions being similarly valid for other tropical regions.
Although information about seasonality and prevalence of influenza is crucial for development of effective prevention and control strategies, limited data exist on the epidemiology of influenza in tropical countries. To better understand influenza in Nicaragua, we performed a prospective 2-year cohort study of influenza-like illness (ILI) involving 4,276 children, 2-11 years of age, in Managua, during April 2005-April 2007. One peak of ILI activity occurred during 2005, in June-July; 2 peaks occurred during 2006, in June-July and November-December. The rate of ILI was 34.8/100 person-years. A household risk factor survey administered to a subset (61%) of participants identified the following risk factors: young age, asthma, and increasing person density in the household. Influenza virus circulation was confirmed during each ILI peak by laboratory testing of a subset of samples. Our findings demonstrate a high rate of ILI, with seasonal peaks, in children in Nicaragua.
Seminal models of herd behaviour and informational cascades point out existence of negative information externalities, and propose to ?destroy? information in order to achieve social improvements. Although in the last years many features of herd behaviour and informational cascades have been studied, this particular aspect has never been extensively analysed. In this article we try to fill this gap, investigating both theoretically and experimentally whether and to which extent destroying information can improve welfare. Our empirical results show that this decisional mechanism actually leads to a behaviour pattern more consistent with the theory that in turn produces the predicted efficiency gain. --
We estimated the effectiveness of inactivated influenza vaccines for the prevention of laboratory-confirmed, medically attended influenza during 3 seasons with variable antigenic match between vaccine and patient strains.
Patients were enrolled during or after a clinical encounter for acute respiratory illness. Influenza infection was confirmed by culture or reverse-transcriptase polymerase chain reaction. Case-control analyses were performed that used data from patients who were ill without influenza (hereafter, "test-negative control subjects") and data from asymptomatic control subjects from the population (hereafter, "traditional control subjects"). Vaccine effectiveness (VE) was estimated as [100 x (1-adjusted odds ratio)]. Influenza isolates were antigenically characterized.
Influenza was detected in 167 (20%) of 818 patients in 2004-2005, in 51 (14%) of 356 in 2005-2006, and in 102 (11%) of 932 in 2006-2007. Analyses that used data from test-negative control subjects showed that VE was 10% (95% confidence interval [CI], -36% to 40%) in 2004-2005, 21% (95% CI, -52% to 59%) in 2005-2006, and 52% (95% CI, 22% to 70%) in 2006-2007. Using data from traditional control subjects, VE for those seasons was estimated to be 5% (95% CI, -52% to 40%), 11% (95% CI, -96% to 59%), and 37% (95% CI, -10% to 64%), respectively; confidence intervals included 0. The percentage of viruses that were antigenically matched to vaccine strains was 5% (3 of 62) in 2004-2005, 5% (2 of 42) in 2005-2006, and 91% (85 of 93) in 2006-2007.
Influenza VE varied substantially across 3 seasons and was highest when antigenic match was optimal. VE estimates that used data from test-negative control subjects were consistently higher than those that used data from traditional control subjects.
To investigate the epidemiology of and mortality from cryptosporidiosis in young children in Guinea Bissau, West Africa.
Three year community study of an open cohort followed up weekly.
301 randomly selected houses in a semi-urban area in the capital, Bissau.
1315 children aged less than 4 years.
Cryptosporidium infection detected by examination of stools during episode of diarrhoea and death of a child.
Cryptosporidium spp were found in 239 (7.4%) out of 3215 episodes of diarrhoea. The parasite was most common in younger children (median age 12 months) and at the beginning of the rainy seasons. The prevalence of cryptosporidiosis was 15% (77/513) in cases of persistent diarrhoea compared with 6.1% (148/2428) in diarrhoea lasting less than two weeks (p < 0.0001). Cryptosporidiosis was associated with excess mortality in children who had the infection in infancy, and this excess mortality persisted into the second year of life (relative mortality 2.9 (95% confidence interval 1.7 to 4.9)). The excess mortality could not be explained by malnutrition, or by socioeconomic factors, hygienic conditions, or breast feeding.
Cryptosporidiosis is an important cause of death in otherwise healthy children in developing countries.
To determine risk factors for diarrhea, the authors followed an open cohort of 1,314 children from Guinea-Bissau by weekly diarrhea recall interviews between April 1987 and March 1990. Data on feeding practices and measles infection were available for all children and, for 531 children, comprehensive data on explanatory variables were recorded. Of 57 variables, seven were independently associated with an increased incidence of diarrhea. These were a recent (in the past 14 days) diarrheal episode, male sex, being weaned from breast milk, not being looked after by the mother, head of the household being < 30 years old, eating cold leftovers, and drinking water from an unprotected public water supply. In breastfed children, only three variables were associated with diarrhea, including prior diarrhea, male sex, and not being looked after by the mother. Among weaned children, six variables delineated increased rates of diarrhea, including unprotected public water supply, eating of cold leftovers, and lack of maternal education. Major determinants of persistent diarrhea included weaning, lack of maternal education, and having pigs in the home. It is concluded that, in addition to the promotion of breastfeeding, important interventions against diarrhea include improvements in water supply, hygiene, and food handling. However, because of effect modification by breastfeeding, the largest effects of these interventions will probably be among weaned children.
Although the surface proteins of human influenza A virus evolve rapidly and continually produce antigenic variants, the internal viral genes acquire mutations very gradually. In this paper, we analyze the sequence evolution of three influenza A genes over the past two decades. We study codon usage as a discriminating signature of gene- and even residue-specific diversifying and purifying selection. Nonrandom codon choice can increase or decrease the effective local substitution rate. We demonstrate that the codons of hemagglutinin, particularly those in the antibody-combining regions, are significantly biased toward substitutional point mutations relative to the codons of other influenza virus genes. We discuss the evolutionary interpretation and implications of these biases for hemagglutinin's antigenic evolution. We also introduce information-theoretic methods that use sequence data to detect regions of recent positive selection and potential protein conformational changes.
Surveillance for influenza in Australia in 2002 was based on notifications to the National Notifiable Diseases Surveillance system from all states and territories, national and state-based sentinel practice consultations for influenza-like illness and reports of influenza virus isolations from a laboratory network. The impact of influenza was assessed by absenteeism data from a major national employer. Influenza A was the dominant type, 99 per cent of which were subtype H3N2 with only a single H1 isolate, which was identified as H1N2. The H3N2 isolates were closely related to the vaccine strain A/Moscow/10/99 and the A/Panama/2007/99, with less than one per cent showing genetic variation. Influenza B made up 21 per cent of circulating influenza and the majority of B strains were of the B/Victoria lineage, but had a haemagglutinin closely related to the B/Hong Kong/330/2001 strain. This strain was associated with two outbreaks but a proportion of vaccinees with the 2002 vaccine showed protective antibody titres. The 2002 influenza vaccine was given to 77 per cent of Australians over 65 years.
Observational studies report that influenza vaccination reduces winter mortality risk from any cause by 50% among the elderly. Influenza vaccination coverage among elderly persons (> or =65 years) in the United States increased from between 15% and 20% before 1980 to 65% in 2001. Unexpectedly, estimates of influenza-related mortality in this age group also increased during this period. We tried to reconcile these conflicting findings by adjusting excess mortality estimates for aging and increased circulation of influenza A(H3N2) viruses.
We used a cyclical regression model to generate seasonal estimates of national influenza-related mortality (excess mortality) among the elderly in both pneumonia and influenza and all-cause deaths for the 33 seasons from 1968 to 2001. We stratified the data by 5-year age group and separated seasons dominated by A(H3N2) viruses from other seasons.
For people aged 65 to 74 years, excess mortality rates in A(H3N2)-dominated seasons fell between 1968 and the early 1980s but remained approximately constant thereafter. For persons 85 years or older, the mortality rate remained flat throughout. Excess mortality in A(H1N1) and B seasons did not change. All-cause excess mortality for persons 65 years or older never exceeded 10% of all winter deaths.
We attribute the decline in influenza-related mortality among people aged 65 to 74 years in the decade after the 1968 pandemic to the acquisition of immunity to the emerging A(H3N2) virus. We could not correlate increasing vaccination coverage after 1980 with declining mortality rates in any age group. Because fewer than 10% of all winter deaths were attributable to influenza in any season, we conclude that observational studies substantially overestimate vaccination benefit.
We used a regression model to examine the impact of influenza on death rates in tropical Singapore for the period 1996-2003. Influenza A (H3N2) was the predominant circulating influenza virus subtype, with consistently significant and robust effect on mortality rates. Influenza was associated with an annual death rate from all causes, from underlying pneumonia and influenza, and from underlying circulatory and respiratory conditions of 14.8 (95% confidence interval 9.8-19.8), 2.9 (1.0-5.0), and 11.9 (8.3-15.7) per 100,000 person-years, respectively. These results are comparable with observations in the United States and subtropical Hong Kong. An estimated 6.5% of underlying pneumonia and influenza deaths were attributable to influenza. The proportion of influenza-associated deaths was 11.3 times higher in persons age >65 years than in the general population. Our findings support the need for influenza surveillance and annual influenza vaccination for at-risk populations in tropical countries.
Viboud and colleagues discuss the implications of a new study by Peiris et al. that assesses the burden of influenza in Hong Kong.
The impact of influenza on morbidity and hospitalization in the tropics and subtropics is poorly quantified. Uniquely, the Hong Kong Special Administrative Region has computerized hospital discharge diagnoses on 95% of total bed days, allowing disease burden for a well-defined population to be accurately assessed.
Influenza-associated morbidity and hospitalization was assessed by Poisson regression models for weekly counts of hospitalizations in Hong Kong during 1996 to 2000, using proportions of positive influenza types A (H1N1 and H3N2) and B isolations in specimens sent for laboratory diagnosis as measures of influenza virus circulation. We adjusted for annual trend, seasonality, temperature, and relative humidity, as well as respiratory syncytial virus circulation. We found that influenza was significantly associated with hospitalization for acute respiratory disease (International Classification of Diseases version 9 codes [ICD9] 460-466 and 480-487) and its subcategory pneumonia and influenza (ICD9 480-487) for all age groups. The annual rates of excess hospitalization per 100,000 population for acute respiratory diseases for the age groups 0-14, 15-39, 40-64, 65-74, and 75+ were 163.3 (95% confidence interval [CI], 135-190), 6.0 (95% CI, 2.7-8.9), 14.9 (95% CI, 10.7-18.8), 83.8 (95% CI, 61.2-104.2), and 266 (95% CI, 198.7-330.2), respectively. Influenza was also associated with hospitalization for cerebrovascular disease (ICD9 430-438) for those aged over 75 y (55.4; 95% CI, 23.1-87.8); ischemic heart disease (ICD9 410-414) for the age group 40-64 y (5.3; 95% CI, 0.5-9.5) and over 75 y (56.4; 95% CI, 21.1-93.4); and diabetes mellitus (ICD9 250) for all age groups older than 40 y.
Influenza has a major impact on hospitalization due to cardio-respiratory diseases as well as on cerebrovascular disease, ischemic heart disease, and diabetes mellitus in the tropics and subtropics. Better utilization of influenza vaccine during annual epidemics in the tropics will enhance global vaccine production capacity and allow for better preparedness to meet the surge in demand that is inevitable in confronting a pandemic.
Asymptomatic enteric infections are important where sequelae or protection from subsequent illness is an outcome measure. The use of reverse transcription-polymerase chain reaction (RT-PCR) to identify asymptomatic enteric infections in a birth cohort followed for rotaviral infections in a south Indian urban slum is reported. Of 1191 non-diarrhoeal samples from 371 children collected in May-June 2003, 22 (1.9%) were positive by ELISA. A total of 147 (40.6%) of 362 samples tested by VP6 RT-PCR were positive. In those samples that could be typed, a high diversity of G types including G1, G2, G4, G8, G9 and G10, and a high proportion (34.4%) of mixed infections were detected. Noroviruses were identified in 6/28 (21.4%) samples tested. The identification of infections undetectable by conventional techniques indicates the importance of the use of sensitive diagnostic techniques in research studies. Asymptomatically infected children may also act as a source of infection for other susceptible hosts.
Antigenic and genetic analysis of the hemagglutinin of ∼13,000 human influenza A (H3N2) viruses from six continents during
2002–2007 revealed that there was continuous circulation in east and Southeast Asia (E-SE Asia) via a region-wide network
of temporally overlapping epidemics and that epidemics in the temperate regions were seeded from this network each year. Seed
strains generally first reached Oceania, North America, and Europe, and later South America. This evidence suggests that once
A (H3N2) viruses leave E-SE Asia, they are unlikely to contribute to long-term viral evolution. If the trends observed during
this period are an accurate representation of overall patterns of spread, then the antigenic characteristics of A (H3N2) viruses
outside E-SE Asia may be forecast each year based on surveillance within E-SE Asia, with consequent improvements to vaccine
strain selection.
Annual influenza epidemics in humans affect 5–15% of the population, causing an estimated half million deaths worldwide per year [Stohr K. Influenza—WHO cares. Lancet Infectious Diseases 2002;2(9):517]. The virus can infect this proportion of people year after year because the virus has an extensive capacity to evolve and thus evade the immune response. For example, since the influenza A(H3N2) subtype entered the human population in 1968 the A(H3N2) component of the influenza vaccine has had to be updated almost 30 times to track the evolution of the viruses and remain effective. The World Health Organization Global Influenza Surveillance Network (WHO GISN) tracks and analyzes the evolution and epidemiology of influenza viruses for the primary purpose of vaccine strain selection and to improve the strain selection process through studies aimed at better understanding virus evolution and epidemiology. Here we give an overview of the strain selection process and outline recent investigations into the global migration of seasonal influenza viruses.
Background:
Different types of influenza vaccines are currently produced worldwide. Vaccination of pregnant women is recommended internationally, while healthy adults are targeted in North America.
Objectives:
To identify, retrieve and assess all studies evaluating the effects (efficacy, effectiveness and harm) of vaccines against influenza in healthy adults, including pregnant women.
Search methods:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2), MEDLINE (January 1966 to May 2013) and EMBASE (1990 to May 2013).
Selection criteria:
Randomised controlled trials (RCTs) or quasi-RCTs comparing influenza vaccines with placebo or no intervention in naturally occurring influenza in healthy individuals aged 16 to 65 years. We also included comparative studies assessing serious and rare harms.
Data collection and analysis:
Two review authors independently assessed trial quality and extracted data.
Main results:
We included 90 reports containing 116 data sets; among these 69 were clinical trials of over 70,000 people, 27 were comparative cohort studies (about eight million people) and 20 were case-control studies (nearly 25,000 people). We retrieved 23 reports of the effectiveness and safety of vaccine administration in pregnant women (about 1.6 million mother-child couples).The overall effectiveness of parenteral inactivated vaccine against influenza-like illness (ILI) is limited, corresponding to a number needed to vaccinate (NNV) of 40 (95% confidence interval (CI) 26 to 128). The overall efficacy of inactivated vaccines in preventing confirmed influenza has a NNV of 71 (95% CI 64 to 80). The difference between these two values depends on the different incidence of ILI and confirmed influenza among the study populations: 15.6% of unvaccinated participants versus 9.9% of vaccinated participants developed ILI symptoms, whilst only 2.4% and 1.1%, respectively, developed laboratory-confirmed influenza.No RCTs assessing vaccination in pregnant women were found. The only evidence available comes from observational studies with modest methodological quality. On this basis, vaccination shows very limited effects: NNV 92 (95% CI 63 to 201) against ILI in pregnant women and NNV 27 (95% CI 18 to 185) against laboratory-confirmed influenza in newborns from vaccinated women.Live aerosol vaccines have an overall effectiveness corresponding to a NNV 46 (95% CI 29 to 115).The performance of one-dose or two-dose whole virion pandemic vaccines was higher, showing a NNV of 16 (95% CI 14 to 20) against ILI and a NNV of 35 (95% CI 33 to 47) against influenza, while a limited impact on hospitalisation was found (NNV 94, 95% CI 70 to 1022).Vaccination had a modest effect on time off work and had no effect on hospital admissions or complication rates. Inactivated vaccines caused local harms. No evidence of association with serious adverse events was found, but the harms evidence base was limited.The overall risk of bias in the included trials is unclear because it was not possible to assess the real impact of bias.
Authors' conclusions:
Influenza vaccines have a very modest effect in reducing influenza symptoms and working days lost in the general population, including pregnant women. No evidence of association between influenza vaccination and serious adverse events was found in the comparative studies considered in the review. This review includes 90 studies, 24 of which (26.7%) were funded totally or partially by industry. Out of the 48 RCTs, 17 were industry-funded (35.4%).
This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]). Information on vaccination issues related to the recently identified novel influenza A H1N1 virus will be published later in 2009. The 2009 seasonal influenza recommendations include new and updated information. Highlights of the 2009 recommendations include 1) a recommendation that annual vaccination be administered to all children aged 6 months-18 years for the 2009-10 influenza season; 2) a recommendation that vaccines containing the 2009-10 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; and 3) a notice that recommendations for influenza diagnosis and antiviral use will be published before the start of the 2009-10 influenza season. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Approximately 83% of the United States population is specifically recommended for annual vaccination against seasonal influenza; however, <40% of the U.S. population received the 2008-09 influenza vaccine. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates or supplements that might be required during the 2009-10 influenza season also can be found at this website. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.
This report updates the 2007 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine and antiviral agents (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2007;56[No. RR-6]). The 2008 recommendations include new and updated information. Principal updates and changes include 1) a new recommendation that annual vaccination be administered to all children aged 5--18 years, beginning in the 2008--09 influenza season, if feasible, but no later than the 2009--10 influenza season; 2) a recommendation that annual vaccination of all children aged 6 months through 4 years (59 months) continue to be a primary focus of vaccination efforts because these children are at higher risk for influenza complications compared with older children; 3) a new recommendation that either trivalent inactivated influenza vaccine or live, attenuated influenza vaccine (LAIV) be used when vaccinating healthy persons aged 2 through 49 years (the previous recommendation was to administer LAIV to person aged 5--49 years); 4) a recommendation that vaccines containing the 2008--09 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Florida/4/2006-like antigens be used; and, 5) new information on antiviral resistance among influenza viruses in the United States. Persons for whom vaccination is recommended are listed in boxes 1 and 2. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. This report and other information are available at CDC's influenza website (http://www.cdc.gov/flu), including any updates or supplements to these recommendations that might be required during the 2008--09 influenza season. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.
During 1988-1989 two highly distinct antigenic variants of influenza type B were recognized in hemagglutination-inhibition tests with postinfection ferret serum. These viruses were antigenically related to either B/Victoria/2/87, the most recent reference strain, or B/Yamagata/16/88, a variant that was isolated in Japan in May 1988. All influenza B viruses isolated in the United States during an epidemic in the winter of 1988-1989 were antigenically related to B/Victoria/2/87. However, in several countries in Asia, both B/Victoria/2/87-like viruses and B/Yamagata/16/88-like viruses were isolated. Sequence analysis of the hemagglutinin (HA) genes of several influenza B isolates from 1987 to 1988 indicated that the HA1 domains of the B/Yamagata/16/88-like viruses and B/VI/87-like viruses isolated in 1988 differed by 27 amino acids. Evolutionary relationships based on this sequence data indicated that the B/Yamagata/16/88-like viruses were more closely related to epidemic viruses from 1983 (B/USSR/100/83-like viruses) than to more recent reference strains such as B/Victoria/2/87. All other Asian strains, as well as selected isolates from the United States in 1988, were confirmed by sequence analysis as being genetically related to B/Victoria/2/87. These data provide clear evidence that two parallel evolutionary pathways of influenza type B have existed since at least 1983 and that viruses from each of the separate lineages were isolated from cases of influenza B in 1988. This finding is similar to earlier observations for type A H1N1 and H3N2 influenza viruses.
The unexpectedly low efficacy of influenza vaccine during school outbreaks of influenza B virus in the spring of 1987 in Japan was probably attributable to a poor antibody response of vaccinees to the epidemic viruses. An antigenic analysis of the causative B viruses isolated in 1987 and 1988 showed much variation in hemagglutination inhibition patterns. The nucleotide sequences that code for the HA1 domain of B/Fukuoka/c-27/81, B/Ibaraki/2/85, B/Nagasaki/1/87, and B/Yamagata/16/88 viruses were determined and compared with those of the previously reported hemagglutinin genes. The nucleotide sequences of the hemagglutinin gene of a new variant, B/Yamagata/16/88, had only 93.4% homology with those of two other viruses from the same epidemic. An analysis of nucleotide and amino acid substitutions of the hemagglutinin genes of influenza B viruses revealed that new and some old variants could cocirculate in the same epidemic. A phylogenetic tree constructed by the neighbor-joining method allowed estimation of an evolutionary rate of 2.3 x 10(-3) synonymous (silent) substitutions per nucleotide site per year in the hemagglutinin gene.
Eighteen codons in the HA1 domain of the hemagglutinin genes of human influenza A subtype H3 appear to be under positive selection
to change the amino acid they encode. Retrospective tests show that viral lineages undergoing the greatest number of mutations
in the positively selected codons were the progenitors of future H3 lineages in 9 of 11 recent influenza seasons. Codons under
positive selection were associated with antibody combining site A or B or the sialic acid receptor binding site. However,
not all codons in these sites had predictive value. Monitoring new H3 isolates for additional changes in positively selected
codons might help identify the most fit extant viral strains that arise during antigenic drift.
Influenza is an acute respiratory illness of global importance that causes considerable morbidity and mortality every year. At the beginning of the millennium, influenza will still be an emergent or re-emergent infection because of the viral ability to mutate. Global influenza surveillance indicates that influenza viruses may vary within a country and between countries and continents during an influenza season. Virologic surveillance is of critical importance in monitoring antigenic shift and drift. Disease surveillance is important in assessing the impact of the epidemics. Both types of information provide the basis of vaccine composition and the correct use of antivirals. Laboratory diagnosis is of critical importance for the global surveillance of influenza and may allow the timely use of antiviral drugs. Viral isolation remains the gold standard for laboratory diagnosis; however, several new rapid diagnostic tests are available or in development. The clinical spectrum of the disease varies from asymptomatic infection to the classic flu syndrome, and respiratory and nonrespiratory complications are observed particularly in high-risk groups. Current inactivated influenza vaccines have shown efficacy and effectiveness in preventing influenzalike illness, hospitalization for pneumonia, and death and in reducing health care costs. Because of the annual administration of the vaccine and the short period of time where it can be administered, strategies directed at improving vaccine coverage are of critical importance. In this sense, experiences obtained in different countries, such as with the National Immunization Campaigns developed in Argentina, provide one model of massive vaccine administration. In addition to current vaccines, new live attenuated vaccines will permit a most effective prevention of influenza in the community in the near future. A new type of antiviral, neuraminidase inhibitors, offers valuable benefits in the prevention and treatment of influenza A and B. A future pandemic of influenza seems inevitable. There is wide recognition that preparation for the next pandemic requires that infrastructure be in place during interpandemic periods for implementing preventive and therapeutic measures. The WHO has established a pandemic influenza task force, and a number of countries in Latin America have developed formal pandemic plans. These national and international efforts are essential to reduce the mortality and morbidity in the next influenza pandemic.
Before World War I, influenza was not considered a particularly serious problem. The great pandemic of 1918-1919 changed all that, and the possibility that such a catastrophe could occur again has conditioned all subsequent developments. In epidemiological terms, the hallmark of an influenza is the excess mortality that it causes combined with an enormous burden of ill-health that saps the energy of individuals, families and communities throughout the whole world. In order to engage in influenza prevention and control, the global influenza surveillance network was set up by World Health Organization (WHO) in 1948 as a worldwide alert system for the identification of new influenza viruses, gathering information from 110 participating laboratories in 82 countries and four WHO Collaborating Centers for Influenza reference and research: Centers for Disease Control and Prevention, Atlanta (USA), National Institute for Medical Research, London (UK), WHO Collaborating Centre for Influenza Reference and Research, Melbourne (Australia) and the National Institute for Infectious Diseases, Tokyo (Japan). This network helps WHO to monitor influenza activity all over the world and provides the organization with the viral isolates and information it requires to decide which new virus strains will be used to produce influenza vaccines during the following season. Each year, information about the isolates over the previous 12 months is analyzed and used to determine the composition of the influenza vaccine to be administered during the coming influenza season both for the northern and southern hemisphere. If necessary, the recommendations for the southern hemisphere differ from the ones formulated for the northern hemisphere vaccine. The information supplied by this network enables the organization to regularly update its World Wide Web (WWW) site (FluNet), which reports on the situation of diseases. This network will also enable the WHO to detect a new influenza pandemic as early as possible.
Acute viral respiratory tract infections are a significant cause of morbidity worldwide. Information on the epidemiology and seasonality of these infections is important in planning vaccination and treatment strategies. In temperate climes, there are distinct seasonal peaks in the winter months. This paper reviews the seasonal trends of respiratory viral infections in the tropics. Despite the absence of a winter season, consistent seasons of infection, albeit less distinct, have been observed. With few exceptions, respiratory syncytial virus and influenza infections have been observed mainly during the rainy seasons in Asian, African and South American countries.
The antigenic evolution of influenza A (H3N2) virus was quantified and visualized from its introduction into humans in 1968 to 2003. Although there was remarkable correspondence between antigenic and genetic evolution, significant differences were observed: Antigenic evolution was more punctuated than genetic evolution, and genetic change sometimes had a disproportionately large antigenic effect. The method readily allows monitoring of antigenic differences among vaccine and circulating strains and thus estimation of the effects of vaccination. Further, this approach offers a route to predicting the relative success of emerging strains, which could be achieved by quantifying the combined effects of population level immune escape and viral fitness on strain evolution.
Influenza outbreaks have been reported among travelers, but attack rates and incidence are unknown.
A cohort study was conducted. Travelers to subtropical and tropical countries recruited at the University of Zurich Travel Clinic (Switzerland), January 1998 to March 2000, were investigated with pre- and posttravel assessment of hemagglutination inhibition and by questionnaire.
Among 1450 travelers recruited who completed questionnaires and provided serum samples before departure, 289 (19.9%) reported febrile illness during or after traveling abroad; of these, 211 (73.0%) provided paired serum samples. Additionally, paired serum samples were collected from 321 frequency-matched afebrile control subjects among the remaining 1161 subjects of the study population. Seroconversion for influenza virus infection was demonstrated in 40 (2.8%) of all travelers; 18 participants (1.2%) had a > or = 4-fold increase in antibody titers. This corresponds to an incidence of 1.0 influenza-associated events per 100 person-months abroad. Among the 211 febrile participants, 27 (12.8%) had seroconversion, 13 (6.2%) with a > or = 4-fold increase; among the 321 afebrile control subjects, 13 (4.0%) had seroconversion, 5 (1.6%) with a > or = 4-fold increase. Twenty-five seroconverters (62.5%; P = .747) acquired influenza outside of the European epidemic season. Sixteen patients (40.0%) sought medical attention either abroad or at home, and 32 (80.0%) were asymptomatic at the time of completion of the survey.
This survey indicates that influenza is the most frequent vaccine-preventable infection among travelers to subtropical and tropical countries. Infections occur mainly outside the domestic epidemic season, and they have a considerable impact. Pretravel vaccination should be considered for travelers to subtropical and tropical countries.
Influenza circulation and mortality impact in tropical areas have not been well characterized. The authors studied the seasonality of influenza throughout Brazil, a geographically diverse country, by modeling influenza-related mortality and laboratory surveillance data. Monthly time series of pneumonia and influenza mortality were obtained from 1979 to 2001 for each of the 27 Brazilian states. Detrended time series were analyzed by Fourier decomposition to describe the amplitude and timing of annual and semiannual epidemic cycles, and the resulting seasonal parameters were compared across latitudes, ranging from the equator (+5 degrees N) to the subtropics (-35 degrees S). Seasonality in mortality was most pronounced in southern states (winter epidemics, June-July), gradually attenuated toward central states (15 degrees S) (p < 0.001), and remained low near the equator. A seasonal southward traveling wave of influenza was identified across Brazil, originating from equatorial and low-population regions in March-April and moving toward temperate and highly populous regions over a 3-month period. Laboratory surveillance data from recent years provided independent confirmation that mortality peaks coincided with influenza virus activity. The direction of the traveling wave suggests that environmental forces (temperature, humidity) play a more important role than population factors (density, travel) in driving the timing of influenza epidemics across Brazil.
Background:
Three different types of influenza vaccines are currently produced world wide. None is traditionally targeted to healthy adults. Despite the publication of a large number of clinical trials, there is still substantial uncertainty about the clinical effectiveness of influenza vaccines and this has negative impact on the vaccines acceptance and uptake.
Objectives:
To identify, retrieve and assess all studies evaluating the effects of vaccines on influenza in healthy adults. To assess the effectiveness of vaccines in preventing cases of influenza in healthy adults. To estimate the frequency of adverse effects associated with influenza vaccination in healthy adults.
Search strategy:
MEDLINE was searched using the strategy of the Cochrane Acute Respiratory Infections Group. The bibliography of retrieved articles, the Cochrane Controlled Trials Register (CCTR), and EMBASE (1990 to 1997) were also searched. Handsearch of the journal Vaccine from its first issue to the end of 1997 (Jefferson and Jefferson, 1996; Jefferson, 1998). We wrote to vaccine manufacturers and first or corresponding authors of studies in the review.
Selection criteria:
Any randomised or quasi-randomised studies comparing influenza vaccines in humans with placebo, control vaccines or no intervention, or comparing types, doses or schedules of influenza vaccine. Live, attenuated or killed vaccines or fractions thereof administered by any route, irrespective of antigenic configuration were considered. Only studies assessing protection from exposure to naturally occurring influenza in healthy individuals aged 14 to 60 (irrespective of influenza immune status) were considered.
Data collection and analysis:
Both clinically defined cases and serologically confirmed cases of influenza were considered as outcomes according to the authors' definitions. Time off work, complication and hospitalisation rates were considered, together with adverse effects. Vaccine schedules were analysed including one component matching the recommended vaccine (WHO or government recommendations) for the year of the study, and whether they matched the circulating viral subtypes.
Main results:
The recommended live aerosol vaccines reduced the number of cases of serologically confirmed influenza A by 48% (95% confidence interval 24% to 64%), whilst recommended inactivated parenteral vaccines had a vaccine efficacy of 68% (95% confidence interval 49% to 79%). The vaccines were less effective in reducing clinical influenza cases, with efficacies of 13% and 24% respectively. Use of the vaccine significantly reduced time off work, but only by 0.4 days for each influenza episode (95% confidence interval 0.1 to 0.8 days). Analysis of vaccines matching the circulating strain gave higher estimates of efficacy, whilst inclusion of all other vaccines reduced the efficacy.
Reviewer's conclusions:
Influenza vaccines are effective in reducing serologically confirmed cases of influenza A. However, they are not as effective in reducing cases of clinical influenza. The use of WHO recommended vaccines appears to enhance their effectiveness in practice.
Influenza continues to have a major worldwide impact, resulting in considerable human suffering and economic burden. The regular recurrence of influenza epidemics is thought to be caused by antigenic drift, and a number of studies have shown that sufficient changes can accumulate in the virus to allow influenza to reinfect the same host. To address this, influenza vaccine content is reviewed annually to ensure protection is maintained, despite the emergence of drift variants; however, it is not always possible to capture every significant drift, partly due to the timing of the recommendations. Vaccine mismatch can impact on vaccine effectiveness, and has significant epidemiological and economical consequences, as was seen most apparently in the 1997-1998 influenza season. To meet the challenge of antigenic drift, vaccines that confer broad protection against heterovariant strains are needed against seasonal, epidemic and pandemic influenza. In addition to the use of vaccine adjuvants, emerging research areas include development of a universal vaccine and the use of vaccines that exploit mechanisms of cross-protective immunity.
Seasonal influenza affects 5-15% of the world's population annually and is considered to be the second most frequent vaccine-preventable infection in travelers. Despite increasing travel volume worldwide, guidelines on influenza vaccination for international travel are scarce. On the basis of some national recommendations, influenza vaccine should be used based on host criteria to usual risk groups, such as old (>50-65 years) or young (6-23 months) age and those with comorbidities. Additionally, environmental and behavioral factors must be considered. Close contact with high transmission has been documented in cruise ships and during mass gatherings. Travelers crossing to the opposite hemisphere in influenza-peak season may need protection. Those visiting the tropics are at moderate risk of infection and illness during the entire year. A summary on existing traveler recommendations relating to avian influenza is included.
The influenza vaccine failed this winter. Steven Salzberg suggests that future success relies on sharing data more widely and making the virus strain selection process more transparent.
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