Valentina Parodi

Inactivated influenza vaccines: recent progress and implications for the elderly.

The current public health strategy for the containment of influenza is annual vaccination, which is recommended for the elderly and for those in risk factor categories that present the highest morbidity and mortality. However, because the immune response in the elderly is known to be less vigorous than in younger adults, research in the last decade has focused on improving the immune response to vaccination and increasing the protection of aged populations.The decreased efficacy of vaccines in the elderly is due to several factors, such as a decrease in the number of Langerhans cells, the limited capacity of dendritic cells to present antigen, defects in the expression of Toll-like receptors and the reduced expression of MHC class I and II molecules. Also, production of mature naive T cells by the thymus decreases with age.Among several approaches proposed to address the need for more immunogenic vaccines compared with conventional agents, the most well proven is the use of adjuvants.The first licensed adjuvant, aluminium-based mineral salts (alum), introduced in the 1920s, remains the standard worldwide adjuvant for human use and it has been widely used for almost a century. However, the addition of alum adjuvant to a split or subunit influenza vaccine has induced only marginal improvements. Other adjuvants have been developed and approved for human use since 1997; in particular, MF59, an oil-in-water adjuvant emulsion of squalene, which is able to increase immunogenicity of seasonal, prepandemic and pandemic subunit vaccines while maintaining acceptable safety and tolerability profiles. More recently, another oil-in-water emulsion, AS03, has been approved as a component of pre-pandemic H5N1 and pandemic H1N1 2009 vaccines.Besides adjuvants, several other strategies have been assessed to enhance antibody response in the elderly and other less responsive subjects, such as high-dose antigen vaccines, carrier systems (liposomes/virosomes) and the intradermal route of immunization. In particular, the potential of intradermal vaccination is well documented and the recent availability of an appropriate injection system, which combines simplicity, safety and ease of use, has allowed evaluation of the tolerability, safety and immunogenicity of the intradermal influenza vaccine in large numbers of subjects. Data that emerged from large clinical trials showed an improved immunogenicity compared with that of standard vaccine.Observational studies or comparisons between adjuvanted, intradermal or high-dose versus conventional vaccines are needed to evaluate whether the greater immunogenicity observed in a number of recent studies is correlated with greater protection against influenza and influenza-related complications and death.

Adjuvanted seasonal influenza vaccines and perpetual viral metamorphosis: The importance of cross-protection

Vaccination is considered the most effective means of reducing influenza burden, providing substantial benefits in terms of reduction of morbidity, complications, hospitalizations and deaths, even if vaccines have been associated with a reduced immune response and lower effectiveness in older adults, in particular when a mismatch between the vaccine and the circulating virus strains occurred. Several strategies have been proposed to enhance vaccine protection against drifted strains, including the use of adjuvants. Among oil-emulsion adjuvants, MF-59 was approved for human use more than a decade ago and it is largely used for adjuvantation of influenza vaccine. Recent studies have demonstrated that addition of the MF-59 to subunit influenza vaccine can lead to higher haemagglutination-inhibiting seroprotection rates and to higher neutralization antibody titers against drifted strains not included in the vaccine respect to non-adjuvanted vaccine. Promising results were obtained using a new generation of oil-in-water emulsion adjuvants, named AS, offering cross-protection against heterologous challenge in ferrets.

Head-to-head comparison of an intradermal and a virosome influenza vaccine in patients over the age of 60: Evaluation of immunogenicity, cross-protection, safety and tolerability

In the present study we first compare immunogenicity against vaccine and heterologous circulating A(H1N1)pdm09 strains, tolerability and safety of intradermal Intanza® 15 μg and of virosomal adjuvanted, intramuscularly delivered influenza vaccine, Inflexal® V, in healthy elderly volunteers. Five-hundred participants were enrolled in the study and randomly assigned to the two vaccine groups to receive either one dose of Intanza® 15 μg or Inflexal® V vaccine. All subjects reported solicited local and systemic reactions occurred within 7 d after vaccination and unsolicited adverse events up to 21 d post-immunization and any serious adverse event appeared during the study. A subset of 55 participants was randomly selected for immunogenicity and cross-protection evaluations. Serum samples were collected before and 1 and 3 mo after immunization. Antibody responses were measured using hemagglutination inhibition (HI) against all viruses used in the study and neutralization (NT) assays against A(H1N1)pdm09 strains. At least one of the CHMP criteria for influenza vaccine approval in the elderly was met by virosomal vaccine against all the tested viruses; intradermal vaccine met all criteria against all strains. Several parameters of immune response against strains with a different antigenic pattern from that of vaccine A/California/04/09(H1N1)pdm09 were significantly higher in the intradermal vaccine group compared with the virosomal group. Safety and systemic tolerability of both vaccines were excellent, but injection site reactions occurred significantly more frequently in the intradermal vaccination group. Immunogenicity of Intanza® 15 μg intradermal vaccine tended to be higher than that of Inflexal® V against heterologous strains in healthy elderly.

Cross-protection against drifted influenza viruses: Options offered by adjuvanted and intradermal vaccines

Antigenic drift, the evolutionary mechanism of influenza viruses, results in an increased susceptibility of vaccinated subjects against circulating viruses. New vaccines able to grant a broader and cross-reactive immune response against drifted influenza variants are needed. Several strategies were explored to enhance the immunogenicity of plain vaccines: adjuvants, carriers and intradermal administration of influenza vaccine emerge as a promising options. To evaluate the ability of a MF59™-adjuvanted and intradermal influenza vaccine to elicit an effective antibody response against circulating viruses presenting antigenic patterns different from those of the vaccine strains, we compared antibody responses elicited by “implemented” vaccines and conventional intramuscular trivalent inactivated vaccine against heterologous circulating influenza A viruses. Different studies, simulating different epidemiological pictures produced by the natural antigenic drift of seasonal influenza viruses, highlighted the superior cross-reactivity of the antibodies elicited by MF59™ and intradermal vaccines, compared with subunit or split vaccine against heterologous viruses.

Syndrome surveillance and molecular epidemiology for early detection and tracing of an outbreak of measles in Liguria, Italy.

The performances of surveillance systems for measles in Europe are poorly investigated, despite the fundamental role they should play in the early detection of outbreaks and in the assessment of the progress towards elimination. A new chief complaint syndrome surveillance system has been developed in Genoa, Italy, using data from the Emergency Department records of the regional reference university hospital and its ability to early detect an outbreak of measles that began during the winter months of 2007/2008 was evaluated. For the 23‐month period from January 2007 to November 2008, the Emergency Department registration and triage software was used to obtain the time series of daily counts, that were related with cases notified by the statutory notification system and detection and characterization data from the measles regional reference laboratory. One hundred fifty five cases of measles‐like illness were identified by the syndrome surveillance system. Two epidemic threshold breakthroughs were able to anticipate the first notified case by 54 and 11 days. Globally, the new syndrome surveillance system allows the activation of the alert state with a specificity of 94.3% and a sensitivity of 91%. Molecular investigation showed the spread of the virus from United Kingdom to Piemonte and then to Liguria and allowed us to exclude the re‐ circulation of strains circulating in Northern Italy during the previous seasons. Syndrome surveillance integrated with a rapid detection and characterization of the agent responsible for the disease could be an effective, specific and sensitive tool for measles surveillance. J. Med. Virol. 81:1807–1813, 2009.

Phase 4 randomized trial of intradermal low-antigen-content inactivated influenza vaccine vs. standard-dose intramuscular vaccine in HIV-1-infected adults

This study evaluated safety, tolerability and immunogenicity of intradermal (ID) trivalent inactivated split influenza vaccine, with a lower antigen content (9 µg HA per strain) than the conventional intramuscular one (15 µg), in HIV-1-infected adults younger than 60 y. A total of 54 HIV-1-positive participants were enrolled and randomly assigned to receive a single dose of either ID-administered low-antigen-content split inactivated vaccine or intramuscularly-administered (IM) standard-dose inactivated split vaccine. Subjects were provided with a diary to monitor any local and/or systemic reactions to the vaccine for 7 d following vaccination. Serum samples were collected before, 28 d and 90 d after immunization. The plasma HIV-RNA and CD4+ T-lymphocyte count were checked at day 0 and day 90. Serum hemagglutination-inhibition (HI) activity for the three influenza strains included in the vaccine composition was measured to assess the antibody response at one month and 3 mo after vaccination. Both vaccines showed optimal safety and tolerability profiles. All the three Committee for Medicinal Products for Human Use immunogenicity criteria for vaccine approval in adults younger than 60 were met by both vaccines against A(H1N1) and A(H3N2) viruses. Both vaccines met mean-fold-increase and seroprotection criteria but failed seroconversion criteria against B virus. No difference in terms of post-vaccination geometric mean titers, mean fold increase, seroprotection and seroconversion rates were found comparing ID and IM vaccines. In conclusion, the recently available low-antigen-content ID vaccine is safe, well-tolerated and as immunogenic as IM standard-dose influenza vaccine.

Indoor Radon Exposure in Italian Schools

Background: The aim of the study was to assess radon concentration in schoolrooms in a city located in the midwest of Italy. Methods: A two-phase environmental study was carried out in 19 school buildings of 16 primary, secondary, and tertiary schools. Results: Median (interquartile range—IQR) indoor radon concentration in schoolrooms was 91.6 (45.0–140.3) Bq/m3. The highest (median 952.8 Bq/m3) radon concentration was found in one (3.6%) classroom, located in a building of a primary school whose median concentration was 185 Bq/m3. Radon concentration was significantly correlated with the number of students and teachers, foundation wall construction material, and with the absence of underground floors. A geopedological survey was performed close to the building with highest radon level, showing the presence of granite and tonalithic granodiorite in the soil. Conclusions: Radon levels should be routinely assessed where individuals live or work. Schools are susceptible targets, because of childhood stay and the long daily stay of occupants. Low-cost interventions, such as implementation of natural air ventilation and school maintenance, can reduce radon levels, limiting individual exposure.