• Antiviral susceptibility profile of influenza A viruses; keep an eye on immunocompromised patients under prolonged treatment.

      Kossyvakis, A; Mentis, A-F A; Tryfinopoulou, K; Pogka, V; Kalliaropoulos, A; Antalis, E; Lytras, T; Meijer, A; Tsiodras, S; Karakitsos, P; et al. (2017-02)
      There was an increase in severe and fatal influenza cases in Greece during the 2011-2015 post-pandemic period. To investigate causality, we determined neuraminidase (NA) inhibitor susceptibility and resistance-conferring NA and hemagglutinin (HA) mutations in circulating influenza type A viruses during the pandemic (2009-2010) and post-pandemic periods in Greece. One hundred thirty-four influenza A(H1N1)pdm09 and 95 influenza A(H3N2) viruses submitted to the National Influenza Reference Laboratory of Southern Greece were tested for susceptibility to oseltamivir and zanamivir. Antiviral resistance was assessed by neuraminidase sequence analysis, as well as the fluorescence-based 50 % inhibitory concentration (IC50) method. Five influenza A(H1N1)pdm09 viruses (2.2 %) showed significantly reduced inhibition by oseltamivir (average IC50 300.60nM vs. 1.19nM) by Gaussian kernel density plot analysis. These viruses were isolated from immunocompromised patients and harbored the H275Y oseltamivir resistance-conferring NA substitution. All A(H1N1)pdm09 viruses were zanamivir-susceptible, and all A(H3N2) viruses were susceptible to both drugs. Oseltamivir-resistant viruses did not form a distinct cluster by phylogenetic analysis. Permissive mutations were detected in immunogenic and non immunogenic NA regions of both oseltamivir- resistant and susceptible viruses in the post-pandemic seasons. Several amino acid substitutions in the HA1 domain of the HA gene of post-pandemic viruses were identified. This study indicated low resistance to NAIs among tested influenza viruses. Antiviral resistance emerged only in immunocompromised patients under long-term oseltamivir treatment. Sequential sample testing in this vulnerable group of patients is recommended to characterise resistance or reinfection and viral evolution.
    • Estimated incidence and number of outpatient visits for seasonal influenza in 2015-2016 in Beijing, China.

      Wu, S; Van Asten, L; Wang, L; McDonald, S A; Pan, Y; Duan, W; Zhang, L; Sun, Y; Zhang, Y; Zhang, X; et al. (2017)
      Information on morbidity burden of seasonal influenza in China is limited. A multiplier model was used to estimate the incidence and number of outpatient visits for seasonal influenza by age group for the 2015-2016 season in Beijing, the capital of China, based on reported numbers of influenza-like illness consultations and proportions of positive cases from influenza surveillance systems in Beijing, general consultation rates and other parameters from previous studies, surveys and surveillance systems. An estimated total of 1 190 200 (95% confidence interval (CI) 830 400-1 549 900) cases of influenza virus infections occurred in Beijing, 2015-2016 season, with an attack rate of 5·5% (95% CI 3·9-7·2%). These infections resulted in an estimated 468 280 (95% CI 70 700-606 800) outpatient visits, with an attack rate of 2·2% (95% CI 0·3-2·8%). The attack rate of influenza virus infections was highest among children aged 0-4 years (31·9% (95% CI 21·9-41·9%)), followed by children aged 5-14 years (18·7% (95% CI 12·9-24·5%)). Our study demonstrated a substantial influenza-related morbidity in Beijing, China, especially among the preschool- and school-aged children. This suggests that development or modification of seasonal influenza targeted vaccination strategies need to recognize that incidence is highest in children.
    • Excess all-cause and influenza-attributable mortality in Europe, December 2016 to February 2017.

      Vestergaard, Lasse S; Nielsen, Jens; Krause, Tyra G; Espenhain, Laura; Tersago, Katrien; Bustos Sierra, Natalia; Denissov, Gleb; Innos, Kaire; Virtanen, Mikko J; Fouillet, Anne; et al. (2017-04-06)
      Since December 2016, excess all-cause mortality was observed in many European countries, especially among people aged ≥ 65 years. We estimated all-cause and influenza-attributable mortality in 19 European countries/regions. Excess mortality was primarily explained by circulation of influenza virus A(H3N2). Cold weather snaps contributed in some countries. The pattern was similar to the last major influenza A(H3N2) season in 2014/15 in Europe, although starting earlier in line with the early influenza season start.
    • Heterosubtypic cross-reactivity of HA1 antibodies to influenza A, with emphasis on nonhuman subtypes (H5N1, H7N7, H9N2).

      Te Beest, Dennis E; de Bruin, Erwin; Imholz, Sandra; Koopmans, Marion; van Boven, Michiel (2017)
      Epidemics of influenza A vary greatly in size and age distribution of cases, and this variation is attributed to varying levels of pre-existing immunity. Recent studies have shown that antibody-mediated immune responses are more cross-reactive than previously believed, and shape patterns of humoral immunity to influenza A viruses over long periods. Here we quantify antibody responses to the hemagglutinin subunit 1 (HA1) across a range of subtypes using protein microarray analysis of cross-sectional serological surveys carried out in the Netherlands before and after the A/2009 (H1N1) pandemic. We find significant associations of responses, both within and between subtypes. Interestingly, substantial overall reactivity is observed to HA1 of avian H7N7 and H9N2 viruses. Seroprevalence of H7N7 correlates with antibody titers to A/1968 (H3N2), and is highest in persons born between 1954 and 1969. Seroprevalence of H9N2 is high across all ages, and correlates strongly with A/1957 (H2N2). This correlation is most pronounced in A/2009 (H1N1) infected persons born after 1968 who have never encountered A/1957 (H2N2)-like viruses. We conclude that heterosubtypic antibody cross-reactivity, both between human subtypes and between human and nonhuman subtypes, is common in the human population.
    • Influenza vaccine effectiveness estimates in the Dutch population from 2003 to 2014: The test-negative design case-control study with different control groups.

      van Doorn, Eva; Darvishian, Maryam; Dijkstra, Frederika; Donker, Gé A; Overduin, Pieter; Meijer, Adam; Hak, Eelko (2017-05-15)
      Information about influenza vaccine effectiveness (IVE) is important for vaccine strain selection and immunization policy decisions. The test-negative design (TND) case-control study is commonly used to obtain IVE estimates. However, the definition of the control patients may influence IVE estimates. We have conducted a TND study using the Dutch Sentinel Practices of NIVEL Primary Care Database which includes data from patients who consulted the General Practitioner (GP) for an episode of acute influenza-like illness (ILI) or acute respiratory infection (ARI) with known influenza vaccination status. Cases were patients tested positive for influenza virus. Controls were grouped into those who tested (1) negative for influenza virus (all influenza negative), (2) negative for influenza virus, but positive for respiratory syncytial virus, rhinovirus or enterovirus (non-influenza virus positive), and (3) negative for these four viruses (pan-negative). We estimated the IVE over all epidemic seasons from 2003/2004 through 2013/2014, pooled IVE for influenza vaccine partial/full matched and mismatched seasons and the individual seasons using generalized linear mixed-effect and multiple logistic regression models. The overall IVE adjusted for age, GP ILI/ARI diagnosis, chronic disease and respiratory allergy was 35% (95% CI: 15-48), 64% (95% CI: 49-75) and 21% (95% CI: -1 to 39) for all influenza negative, non-influenza virus positive and pan-negative controls, respectively. In both the main and subgroup analyses IVE estimates were the highest using non-influenza virus positive controls, likely due to limiting inclusion of controls without laboratory-confirmation of a virus causing the respiratory disease.
    • Influenza-like Illness Incidence Is Not Reduced by Influenza Vaccination in a Cohort of Older Adults, Despite Effectively Reducing Laboratory-Confirmed Influenza Virus Infections.

      van Beek, Josine; Veenhoven, Reinier H; Bruin, Jacob P; van Boxtel, Renée A J; de Lange, Marit M A; Meijer, Adam; Sanders, Elisabeth A M; Rots, Nynke Y; Luytjes, Willem (2017-08-15)
      Data on the relative contribution of influenza virus and other respiratory pathogens to respiratory infections in community-dwelling older adults (≥60 years) are needed.
    • Variation in loss of immunity shapes influenza epidemics and the impact of vaccination.

      Woolthuis, Rutger G; Wallinga, Jacco; van Boven, Michiel (2017-09-19)
      Protective antibody immunity against the influenza A virus wanes in 2-7 years due to antigenic drift of the virus' surface proteins. The duration of immune protection is highly variable because antigenic evolution of the virus is irregular. Currently, the variable nature of the duration of immunity has had little attention in analyses of the impact of vaccination, including cost-effectiveness studies.