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Vaccination offers protection against influenza, although current vaccines need to be reformulated each year. The development of a broadly protective influenza vaccine would guarantee the induction of heterosubtypic immunity also against emerging influenza viruses of a novel subtype. Vaccine candidates based on the stalk region of the hemagglutinin (HA) have the potential to induce broad and persistent protection against diverse influenza A viruses.Modified vaccinia virus Ankara (MVA) expressing a headless HA (hlHA) of A/California/4/09 (CA/09) virus was used as a vaccine to immunize C57BL/6 mice. Specific antibody and cell-mediated immune responses were determined, and challenge experiments were performed by infecting vaccinated mice with CA/09 virus.Immunization of mice with CA/09-derived hlHA, vectored by MVA, was able to elicit influenza-specific broad cross-reactive antibodies and cell-mediated immune responses, but failed to induce neutralizing antibodies and did not protect mice against virus challenge.Although highly immunogenic, our vaccine was unable to induce a protective immunity against influenza. A misfolded and unstable conformation of the hlHA molecule may have affected its capacity of inducing neutralizing antiviral, conformational antibodies. Design of stable hlHA-based immunogens and their delivery by recombinant MVA-based vectors has the potential of improving this promising approach for a universal influenza vaccine.

Background: Concern about the possibility that annually repeated influenza immunizationmayinduce a lower antibody response than first vaccination. Objective: To ascertain the cumulative effects of yearly vaccination on serological response to unaltered vaccine antigens in the elderly. Methods: The haemagglutination-inhibiting (HI) antibody response was examined in 158 elderly institutionalized frail volunteers subdivided in 3 groups according to the sequential winters in which each subject received a trivalent inactivated influenza vaccine. The study, conducted over 5 consecutive winters (from 1998/99 to 2002/03), reports the antibody response only for sequential years (2 or 3) in which the vaccine strain examined was not altered. Results: Significant increases in the values of HI antibody titres were observed after vaccination in each year examined against the different influenza vaccine strains used, except against B antigen in the second of the 3 winters studied (1999/00). The antibody responses found were not always adequate, i.e. at levels above the currently requested values for commercial vaccines (post-vaccination seroprotection rate ≧1:40, increases in geometric mean titres ≧2, positive responses ≧30% compared with pre-vaccination), probably because of old age (mean age ≧81 years) and the presence of underlying diseases in a high percentage of volunteers (≧86%). The most frequent chronic diseases found werecardiovascular diseases (48%), endocrine disorders (19%), functional disability (10%) and pulmonary diseases (4%). The post-vaccination values observed in the sequential years were in general similar for A/H3N2 and A/H1N1 vaccine strains. A decrease, however, for some parameters at statistically significant levels, was observed against B antigen following repeated vaccine administrations. Conclusion: Our data seem to support the possibility of a slight impairment of HI antibody response against unaltered influenza vaccine antigens, especially for influenza strains that have circulated for prolonged periods of time. Indeed a tendency to a lower response was found only against B/Beijing antigen, introduced in the vaccine composition in the winter 1995/96, but not against the A/H3N2 and A/H1N1 vaccine strains, which weremore frequently changed.

Ninety-two institutionalized elderly subjects were vaccinated with trivalent influenza inactivated vaccine available for the 2011-2012 season, characterized by a prevalent circulation of A(H3N2) influenza viruses (A/Victoria/208-clade) presenting antigenic and genetic patterns different from the A(H3N2) vaccine component (A/Perth/16/2009-clade). Haemagglutination inhibiting (HI) antibody titers were determined in sera collected before, 1 and 6 months after vaccination and patients were considered positive for serological evidence of recent infection if they had a seroconversion on comparing HI titers found in sera collected 1 and 6 months after vaccination. No seroconversions were found against A(H1N1) and B vaccine components. Instead 17 volunteers seroconverted against all or at least some of the different A(H3N2) antigens examined, i.e. the 2011-2012 (A/Perth/16/2009) and the 2012-2013 (A/Victoria/361/2011) vaccine strains and four drifted viruses belonging to the A/Victoria/208-clade circulating in the area were the elderly people were living. The results obtained suggest that influenza infections in the vaccinated volunteers might be due both to a poor match between vaccine and circulating A(H3N2) viruses, since 1 month after vaccination 15 of the 17 volunteers had post-vaccination HI titers considered protective (≥40) against the A(H3N2) vaccine antigen, but not always against the epidemic strains, and to a waning of vaccine induced immune response, since 6 months after vaccination HI titers of non-infected volunteers were found to be decreased as compared with those found 1 month after vaccination.

Because of the age-related immune system decline, 2 potentiated influenza vaccines were specifically licensed for the elderly: Fluad(®), an MF59-adjuvanted vaccine administered intramuscularly (IM-MF59), and Intanza 15 mcg(®), a non adjuvanted vaccine administered intradermally (ID). The objective of this paper was to conduct a systematic review of studies that evaluated antibody responses in the elderly following immunization with IM-MF59 or ID vaccines. The two potentiated vaccines induced immune responses satisfying, in most instances, the European Medicine Agency immunogenicity criteria, both against vaccine antigens and heterovariant drifted strains. Considering pooled data reported in the articles analyzed and papers directly comparing the 2 vaccines, the antibody responses elicited by IM-MF59 and ID were found to be generally comparable. The use of IM-MF59 and ID vaccines can be proposed as an appropriate strategy for elderly seasonal influenza vaccination although further studies are required for a more complete characterization of the 2 vaccines.

Ninety-two institutionalized elderly subjects were vaccinated with trivalent influenza inactivated vaccine available for the 2011-2012 season, characterized by a prevalent circulation of A(H3N2) influenza viruses (A/Victoria/208-clade) presenting antigenic and genetic patterns different from the A(H3N2) vaccine component (A/Perth/16/2009-clade). Haemagglutination inhibiting (HI) antibody titers were determined in sera collected before, 1 and 6 months after vaccination and patients were considered positive for serological evidence of recent infection if they had a seroconversion on comparing HI titers found in sera collected 1 and 6 months after vaccination. No seroconversions were found against A(H1N1) and B vaccine components. Instead 17 volunteers seroconverted against all or at least some of the different A(H3N2) antigens examined, i.e. the 2011-2012 (A/Perth/16/2009) and the 2012-2013 (A/Victoria/361/2011) vaccine strains and four drifted viruses belonging to the A/Victoria/208-clade circulating in the area were the elderly people were living. The results obtained suggest that influenza infections in the vaccinated volunteers might be due both to a poor match between vaccine and circulating A(H3N2) viruses, since 1 month after vaccination 15 of the 17 volunteers had post-vaccination HI titers considered protective (≥40) against the A(H3N2) vaccine antigen, but not always against the epidemic strains, and to a waning of vaccine induced immune response, since 6 months after vaccination HI titers of non-infected volunteers were found to be decreased as compared with those found 1 month after vaccination.

Background The age-related weakening of the immune system makes elderly subjects less responsive to influenza vaccination. In the last years, two “enhanced vaccines” were licensed for individuals aged ≥65 years, one being a subunit vaccine (Fluad®) containing the MF59 adjuvant administered intramuscularly (IM-MF59) and the other one a split non-adjuvanted vaccine administered intradermally (Intanza® 15mcg) (ID). In the present study, we evaluated and compared the antibody responses against the three vaccine antigens and heterovariant A(H3N2) circulating viruses induced by IM-MF59 and ID influenza vaccines in 80 elderly institutionalized volunteers (40 per group) during the Winter season 2011–2012. Results Hemagglutination inhibiting (HI) antibody titers were assessed in blood samples collected before, 1 and 6 months after vaccination. One month after vaccination both the IM-MF59 and ID vaccines induced increases in HI titers against all the three vaccine strains. The results in the two groups were similar against the A(H3N2) and A(H1N1) strains. Responses against the B strain typically tended to be higher after ID than IM-MF59, yet both vaccines stimulated lower responses against the B strain than against the two A strains. The two vaccines induced favorable results also against four epidemic drifted A(H3N2) viruses circulating in Winter 2011–2012. Six months after vaccination, the HI titers decreased in both groups. Conclusion The responses induced by IM-MF59 and ID vaccines in institutionalized elderly people were similar against the A(H3N2) and A(H1N1) strains but frequently higher, for the ID, against the B strain. The two vaccines induced positive responses against drifted A(H3N2) circulating viruses.

The reduced immunogenicity and effectiveness of influenza vaccines in subjects presenting high risk of influenza-related complications, hospitalization and death, led the innovative drive to search for new strategies to implement the immune response elicited by influenza vaccines including addition of adjuvants, and use of alternative routes of antigen delivery.In this study we evaluated and compared the immune antibody response induced in 252 elderly volunteers living in nursing homes after immunization with three different 2012-2013 seasonal trivalent inactivated influenza vaccines: a conventional split vaccine (n=26), and two potentiated vaccines (a subunit vaccine adjuvanted with MF59 (n=137) or a split vaccine administered intradermally (n=89)), specially licensed for elderly people. Haemagglutination inhibiting (HI) antibody titers were assessed in blood samples collected before and one month after vaccination.The results were evaluated as increase in HI titers found comparing pre- and post-vaccination sera and according to the Committee for Medicinal Products for Human Use (CHMP) criteria for approval of influenza vaccines in the elderly. Significant antibody increases and fulfillment of all the three CHMP requirements were observed against A/H3N2 and B antigens following immunization with the two potentiated vaccines. After immunization with conventional vaccine responses were lower against A/H3N2 and equivalent against the B antigen. The two potentiated vaccines induced significant antibody increases against A/H1N1 antigen, however, only one of the CHMP criteria was reached. The HI antibody increases after conventional vaccine were significant only for the geometric mean titer and none of the CHMP criteria was fulfilled. The antibody responses induced by the two potentiated vaccines against the three vaccine antigens wereequivalent although post-vaccination titers against the B antigen tended to be higher in subjects vaccinated with intradermal vaccine than in individuals receiving MF59-adjuvanted vaccine. In conclusion the use of MF59 adjuvant and intradermal vaccination appear to be appropriate strategies to address the challenge of declining immune response in the elderly after influenza vaccination.

Background: The aim of this study was to try to ascertain whether, in the absence of a pre-organized programme, locally collected data might provide information about the epidemiological and clinical characteristics of the recent A(H1N1) pandemic in Italy. Methods: The study was an observational retrospective analysis of the clinic-epidemiological features performed by reviewing medical charts from 141 hospitalized patients with laboratory confirmed pandemic A(H1N1) infection in Umbria, a region of central Italy, in the period July 2009 to March 2010. Results: The pandemic virus was found capable of inducing severe illness requiring hospitalization or intensive care unit admission (ICU), or resulting in death. Age and comorbidity were found to be potential risk factors for severe disease. The mean age of the hospitalized patients was 37 years (range 0 - 93 yrs), however the mean age of ICU admitted patients, including people who did not survive, was higher as compared with those admitted to general medical ward (54 vs 35 yrs). The highest incidence of hospitalization was observed in the youngest group (0 - 17 yrs), the greatest rate of ICU admission in adults (18 - 64 years), and the risk of death in the oldest population ( ≥ 65 yrs). Comorbity conditions were present in some (55%), but not all hospitalized patients and increased with the age and the severity of the illness. Conclusions: The data obtained are compatible with the identified epidemiological characteristics of the A(H1N1) pandemic derived from partial information previously collected in Italy and from studies conducted in other European and non European countries. The results of our retrospective observational study suggest that locally organized data collection may give information on the epidemiological and clinical characteristics of a pandemic that are compatible with those obtained from more complex and complete studies . doi: http://dx.doi.org/10.4021/jocmr883w

We analyzed humoral and cellular immune responses against vaccine antigens and the new A(H1N1) virus in healthy adults before and after immunization with the 2007/2008 commercially available trivalent subunit MF59-adjuvanted influenza vaccine during the Fall 2007, prior to the emergence of the new virus. Antibody titers were significantly boosted only against the three vaccine antigens. Seasonal vaccination boosted pre-existing cellular responses upon stimulation of peripheral blood mononuclear cells not only with the homologous three vaccine antigens, but also with the heterologous new 2009 A(H1N1) and with a highly conserved peptide present in the stalk region of hemagglutinin (HA). These results show that cross-reactive cell responses against the new virus were present before the circulation of the virus and were boosted by seasonal vaccination. The cross-reactivity of cellular responses might, at least in part, explain the low pathogenicity of the new pandemic virus. The finding of cellular immunity, that can be increased by seasonal vaccination, against the conserved HA peptide, underline the potential use, in human vaccines, of conserved peptides of the stalk region of HA characterized by broad immunogenicity in experimental systems.

The number of patients on oral anticoagulant therapy has increased in recent years, and this trend is expected to continue. The increased workload for physicians has led to the development of computerized systems to make organizational workflow more efficient. These programs may include algorithms to propose a weekly dosage and timing for the following visit. Before introducing a new algorithm in clinical practice, its safety and efficacy must be validated. We undertook a retrospective simulation study to test a new algorithm for the TAOnet system. The main outcome was the percentage of concordant and discordant proposals between manual- and algorithm-based prescriptions. Pairs of computerized and physician prescriptions were assessed. They were categorized as 0.1-5, 5.1-10 and >10% if the dose was different, and assigned as "algorithm better" or "manual better" dependent upon the subsequent international normalized ratio value. In 61.0% of cases, the manual and computerized weekly dosage assignments were identical; in 15.3% of cases, the difference was between 0.1 and 5%; in 14.7 of cases, it was between 5.1 and 10%; and in 9.0% of cases, it was >10%. The algorithm did better in 43.9% of discordant pairs, generally due to less frequent under-dosing. In conclusion, the new algorithm proved to consistently overlap with the manual method. The algorithm is useful but must be tested in a multi-center, prospective, interventional study.

The study evaluated the immunogenicity and efficacy of a trivalent subunit MF59-adjuvanted influenza vaccine (A/Wisconsin/67/05 (H3N2), A/Solomon Islands/3/06 (H1N1) and B/Malaysia/2506/04) in preventing serologically diagnosed infections in a group of 67 institutionalized elderly volunteers during 2007/2008 winter, characterized by co-circulation of drifted A/H3N2, A/H1N1 and B influenza viruses. Influenza vaccination induced a significant increase in the amounts of hemagglutination inhibiting antibodies, both against the vaccine and the epidemic drifted strains. However, vaccination did not prevent the circulation of the new drifted influenza B virus (B/Florida/4/06-like), belonging to the B/Yamagata/16/88-lineage, antigenically and genetically distinct from B/Victoria/2/87-lineage viruses from which the vaccine B strain was derived.

Background Among millions of persons vaccinated against influenza virus each year, many are older patients treated with several drugs, including vitamin K antagonists (VKAs), among which warfarin is the most commonly used. Due to high interpatient and intrapatient variability, the therapeutic dose of VKA has to be individualized by monitoring of international normalized ratio (INR) values. The objectives of this study were to evaluate variation in the INR and warfarin weekly dose variation after influenza vaccination administration and to follow up patients for related hemorrhagic and thrombotic events to evaluate the safety of the influenza vaccine and to assess the immunogenicity of the influenza vaccination in patients receiving VKAs. Methods One hundred four patients on a stable VKA regimen and with an indication for influenza vaccination were randomized to receive influenza vaccination and subsequent placebo administration, or vice versa. All patients were tested for coagulation variables, clinical events, and antibody response against vaccine components. Results Similar mean prothrombin times, expressed as the INR and VKA weekly dose, were found in patients after receiving vaccine or placebo. The absence of any vaccination effect on VKA treatment was confirmed using a linear mixed-effects model. The percentages of time that patients were in therapeutic range were 70.7% after receiving vaccine and 72.4% after receiving placebo ( P = .57). There were no fatal or major bleeding events and 11 minor mucocutaneous hemorrhagic events. After vaccination, the percentage of seroprotected patients ranged from 92.0% to 100.0% depending on the vaccine antigen examined. Conclusions Influenza vaccination had no significant effect on INR values or warfarin sodium weekly doses. Close monitoring of INR values is not required after influenza vaccination in patients on stable long-term VKA regimens. Trial Registration clinicaltrials.gov Identifier:NCT00222638

The BD Phoenix system was compared to the cefoxitin disk diffusion test for detection of methicillin (meticillin) resistance in 1,066 Staphylococcus aureus and 1,121 coagulase-negative staphylococcus (CoNS) clinical isolates. The sensitivity for Phoenix was 100%. The specificities were 99.86% for S. aureus and 88.4% for CoNS.

We studied 91 faecal specimens of 38 children and 53 adults in a five-day epidemiological survey between the end of February and the beginning of March, 2006. The subjects were in- or out-patients of Chacas Hospital, Ancash. The OP were performed with macroscopic evaluation, microscopic (direct and after formalin-ether concentration, FEA) observations and Giemsa permanent stain of all faecal samples. 61 subjects (67.0%) were infected with parasites (25 children, 65.5%, and 36 adults, 67.9%). D. fragilis was prevalent in 30.8% of subjects (28.9% of children, 32.1% of adults); G. duodenalis was observed in 12.1% of cases (21.1% of children and 5.7% of adults); A. lumbricoides was observed in 15.4% of cases (18.4% and 19.9% respectively); other helminths were identified in 7.7% of cases (10.1% and 5.7% respectively); non-pathogenic protozoa alone were observed in 23.1% of cases (28.9% among children and 19.9% among adults). D. fragilis was more frequent among females (44.7% vs. 20.8%), while G. duodenalis and A. lumbricoides among males (13.2% vs. 10.5% and 17.0% vs. 13.2% respectively). We emphasize the usefulness of both FEA and Giemsa permanent stain for a good OP.

The study evaluates the risk/benefit of influenza vaccination in patients on stable long-term oral anticoagulant therapy (OAT). One hundred and four consecutive patients with indication for influenza vaccination were randomized to receive one dose of 2004/2005 influenza vaccine followed by placebo after 6 weeks, or vice versa, in a cross-over blinded trial. All patients were tested for anticoagulation levels and for hemagglutination inhibiting antibody titres against the influenza vaccine antigens. The highly protective antibody titres induced by influenza vaccination and the absence of statistically relevant interactions between vaccination and OAT suggest that influenza vaccination can be used safely and successfully in elderly patients on OAT.

This study examined the antibody response against the three vaccine antigens and the epidemic A/H3N2 drift variant (A/California) and the prevention of laboratory diagnosed influenza infections in a group of elderly institutionalized people vaccinated with the 2004/2005 influenza vaccine. Antibody titres were measured by hemagglutination inhibition (HI) in sera collected before and 1 month after vaccination. Laboratory diagnosis was done examining throat swabs (RT-PCR or MDCK cell culture) or by serology (seroconversion comparing HI titres in sera collected 1 and 5 months after vaccination). Results obtained showed that influenza vaccination induced an adequate immune response against the three vaccine antigens and the epidemic A/H3N2 variant, however it was not capable of preventing an influenza outbreak due to the new A/H3N2 (A/California) variant.

We measured haemagglutination inhibiting (HI) serum antibody titers to vaccine matched A/H1N1 influenza virus strain and to the new pandemic 2009 A/H1N1 (pH1N1) virus in two groups of volunteers prior and after 2003/2004 or 2007/2008 influenza seasonal vaccine administration. The responses were examined considering the overall volunteers studied in the two winters (144 and 79, respectively) and grouping those subjects in birth cohort classes (1903–1919; 1920–1957; 1958–1977). Before vaccination, HI antibody titers were found in all the groups examined and, on comparing the different age-groups, titers were higher in the younger groups as compared with the oldest against the A/H1N1 seasonal strains but titers were higher in the oldest as compared with the younger ones against the pH1N1 strain. Vaccination induced significant increases in HI titers against the matched A/H1N1 vaccine strains in all the groups examined. The responses satisfied the EMEA criteria and were higher in the youngest volunteers as compared with older groups. Increases were also found in the level of cross-reactive HI antibodies to the new pandemic 2009 A/H1N1 virus although in most instances the requirements of the EMEA were not met.