Michela Basileo

Effects of Repeated Annual Influenza Vaccination on Antibody Responses against Unchanged Vaccine Antigens in Elderly Frail Institutionalized Volunteers

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.

The good use of plasma. A critical analysis of five international guidelines

BACKGROUND The clinical use of fresh-frozen plasma (FFP) is progressively increasing both nationally and internationally, despite the fact that many studies have shown the weaknesses of the indications for its use. Guidelines on the good use of plasma have, therefore, been adopted in various countries. The aim of the present study was to analyse some of the existing guidelines on the good use of plasma, applying a scientifically validated method, as a preliminary step in the implementation of Regional guidelines. METHODS Abibliographic search (1990-2006) was conducted in databases, websites, and the archives of scientific societies. Relevant articles were recovered in full. The selected guidelines were evaluated using theAGREE instrument, which assesses the completeness and structural quality of the guidelines and, in some aspects, the contents of the recommendations. The project, co-ordinated by the Regional Centre for Co-ordination and Compensation (CRCC) and carried out by four Services of Immunohaematology and Transfusion (SIT) in Umbria, was funded by the Region of Umbria and approved by the four health care institutions involved. RESULTS The bibliographic search yielded 3067 abstracts of which 239 were considered relevant. The analysis of these led to the recovery of 11 guidelines, among which five were selected: those from the British Committee for Standards in Haematology, theAgence Française de Securité Sanitaire de Produits de Sante, the Canadian Members of the Expert Working Group, the American Society of Anesthesiologists Task Force on Blood Component Therapy and the National Health and Medical Research Council (NHMRC)/Australasian Society of Blood Transfusion. CONCLUSIONS None of the guidelines analysed obtained a score higher than 50% in all the domains of the AGREE score. There was no evidence of a tendency to improvement over time in the guidelines analysed. Objective evaluation of the guidelines analysed could provide the starting point for the subsequent production of similar documents.

An influenza B outbreak during the 2007/2008 winter among appropriately immunized elderly people living in a nursing home.

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.

Influenza viruses and cross-reactivity in healthy adults: Humoral and cellular immunity induced by seasonal 2007/2008 influenza vaccination against vaccine antigens and 2009 A(H1N1) pandemic influenza virus

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.

Immunogenicity of intramuscular MF59-adjuvanted and intradermal administered influenza enhanced vaccines in subjects aged over 60: A literature review

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 15mcg®, 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.

Influenza Vaccination and Vitamin K Antagonist Treatment: A Placebo-Controlled, Randomized, Double-blind Crossover Study

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.

Antibody Responses after Influenza Vaccination in Elderly People: Useful Information from a 27-Year Study (from 1988– 1989 to 2014–2015)

Elderly people are more likely than younger people to get flu complications and respond suboptimally to influenza vaccination because of the presence of comorbidities and immunosenescence. In order to collect information about this issue, we evaluated data obtained in 27 winters of study, from 1988–1989 to 2014–2015, in frail elderly institutionalized people (≥60 years) vaccinated with commercially available seasonal trivalent inactivated influenza vaccines. The antibody response was examined comparing hemagglutination inhibition antibody titers in sera collected from 4461 volunteers before and 30 days after vaccination. Examining the results as crude mean responses, we evidenced the ability of influenza vaccines to induce significant increases in antibody titers against all the three vaccine antigens satisfying at least one of the three criteria of the Committee for Medical Products for Human Use (CHMP). Higher responses were found against A/H3N2 vaccine components and, examining different subgroups, in volunteers receiving 45 μg vaccine as compared with 30 μg and in female as compared with male subjects. Very elderly people (>75 years) gave better responses than younger elderly (≤75 years) at least against A/H1N1 strain and the last licensed potentiated vaccines (MF59-adjuvanted and intradermal) were more immunogenic than traditional vaccines (whole, subunit, and split).

An Observational Retrospective Study Provide Information on Hospitalization and Severe Outcomes of the 2009 A(H1N1) Infection in Italy

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.

Immunogenicity of modified vaccinia virus Ankara expressing the hemagglutinin stalk domain of pandemic (H1N1) 2009 influenza virus

Abstract Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Partial Protection Induced by 2011–2012 Influenza Vaccine Against Serologically Evidenced A(H3N2) Influenza Virus Infections in Elderly Institutionalized People

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.