Cristiano Alicino

Adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine

Vaccination is universally considered as the principal measure for the control of influenza, which represents a significant burden worldwide, both from a health-care and a socio-economic viewpoint. Conventional non-adjuvanted trivalent influenza vaccines (TIVs) have been recognized as having some deficiencies, such as suboptimal immunogenicity particularly in the elderly, in patients with severe chronic diseases and immunocompromized, indeed, those groups of the population at higher risk of developing severe complications following influenza infection, when compared to healthy adults. Moreover, the protection offered by conventional vaccines may be reduced by periodic antigenic drifts, resulting in a mismatch between the circulating and vaccinal viral strains. Another gap regarding currently available vaccines is related to the egg-based manufacturing system for their production: not only the length of time involved with the latter but also the limited capacity of this platform technology represent a major limitation for the active prevention of influenza, which is particularly important in the case of a new pandemic strain. New technologies used in vaccine composition, administration and manufacture have led to major advances during the last few years, and clinical researchers have continued to work hard, investigating several different strategies to improve the performance of influenza vaccines: namely, the addition of different adjuvants (i.e., MF59- and AS03-vaccines, virosomal formulations), the use of alternative routes of administration or manufacture (i.e., intradermal, nasal and oral vaccines and cell culture- and reverse genetic-based vaccines) or of high doses of antigen, and the development of DNA-vaccines, or the use of conserved viral epitopes (i.e., the extracellular portion of the M2 protein, the nucleoprotein and some domains of the hemagglutinin), in the attempt to produce a “universal target” antigen vaccine. The knowledge acquired represents a fundamental challenge for the control of influenza. An overview of the most recent and interesting results, some of which gained from our own research experience, particularly concerning two successful approaches, of those outlined above, namely the use of: (i) the oil-in-water MF59-adjuvant, and (ii) the intradermal (ID) route for vaccine administration, through a novel microinjection system, will be reported and discussed, together with the possible implications and perspectives to optimize immunization policies against influenza in the near future.

Assessing Ebola-related web search behaviour: insights and implications from an analytical study of Google Trends-based query volumes

BackgroundThe 2014 Ebola epidemic in West Africa has attracted public interest worldwide, leading to millions of Ebola-related Internet searches being performed during the period of the epidemic. This study aimed to evaluate and interpret Google search queries for terms related to the Ebola outbreak both at the global level and in all countries where primary cases of Ebola occurred. The study also endeavoured to look at the correlation between the number of overall and weekly web searches and the number of overall and weekly new cases of Ebola.MethodsGoogle Trends (GT) was used to explore Internet activity related to Ebola. The study period was from 29 December 2013 to 14 June 2015. Pearson’s correlation was performed to correlate Ebola-related relative search volumes (RSVs) with the number of weekly and overall Ebola cases. Multivariate regression was performed using Ebola-related RSV as a dependent variable, and the overall number of Ebola cases and the Human Development Index were used as predictor variables.ResultsThe greatest RSV was registered in the three West African countries mainly affected by the Ebola epidemic. The queries varied in the different countries. Both quantitative and qualitative differences between the affected African countries and other Western countries with primary cases were noted, in relation to the different flux volumes and different time courses. In the affected African countries, web query search volumes were mostly concentrated in the capital areas. However, in Western countries, web queries were uniformly distributed over the national territory. In terms of the three countries mainly affected by the Ebola epidemic, the correlation between the number of new weekly cases of Ebola and the weekly GT index varied from weak to moderate. The correlation between the number of Ebola cases registered in all countries during the study period and the GT index was very high.ConclusionGoogle Trends showed a coarse-grained nature, strongly correlating with global epidemiological data, but was weaker at country level, as it was prone to distortions induced by unbalanced media coverage and the digital divide. Global and local health agencies could usefully exploit GT data to identify disease-related information needs and plan proper communication strategies, particularly in the case of health-threatening events.

Adherence to international and national recommendations for the prevention of surgical site infections in Italy: Results from an observational prospective study in elective surgery

BACKGROUND An observational prospective study of the perioperative procedures for prevention of surgical site infections (SSIs) was carried out in a tertiary referral teaching hospital in Liguria, Italy, to evaluate their adherence to international and national standards. METHODS A 1-month survey was performed in all surgical departments, monitored by turns by trained survey teams. Data regarding presurgical patient preparation and intraoperative infection control practices were collected. RESULTS A total of 717 elective interventions were actively monitored in 703 patients who underwent surgery. Hair-shaving was performed mainly using a razor (92%) by the nurses (72.8%) on the day before the operation (83.5%). All of the patients showered, either with a common detergent (87%) or with an antiseptic solution (13%). Antimicrobial prophylaxis was administered properly in 75.7% of the patients at induction of anaesthesia; however, according to current Italian guidelines, inappropriate prophylaxis was provided in 55.2% patients. Appropriate antisepsis of the incision area was done in 97.4% of the operations, and nearly 90% of the interventions lasted less than the respective 75th percentile. The doors of the operating theatres were mostly open during the duration of the operation in 36.3% of the cases. CONCLUSIONS This review of infection control policies identified significant opportunities for improving the safety and the quality of routine surgical practice.

Epidemiology of HBV S-gene mutants in the Liguria Region, Italy: Implications for surveillance and detection of new escape variants.

HBV surface antigen (HBsAg) variants may impair diagnosis or allow the virus to escape vaccine-induced immunity and their circulation in the population can represent a Public Health threat. Their prevalence, however, is not yet completely established. Evidence indicates that amino acid substitutions within HBsAg can lead to conformational changes which allow mutated HBV to escape the vaccine-induced antibodies used in the screening tests. In such scenario, the aim of this study was to investigate the prevalence of HBV S-Gene escape mutants by sequencing the gene in a cohort of Ligurian patients monitored for viral load, genotype and drug resistance and to evaluate the risk of false negative HBsAg detection by routine screening tests. From 2007 to 2011, in 256 consecutive samples from Ligurian HBV positive patients sequencing assay for detection of RT/S-Gene mutations using Trugene® HBV Genotyping kit (Siemens Healthcare Diagnostics Inc., Tarrytown, NY) was performed. Serological HBV tests and viral load were also performed. Analyzed sequences revealed G145R mutation in 8/256 (3.1%) examined sequences, it was alone in 5 patients and accompanied by other HBsAg mutations in 3 samples. HBsAg resulted undetectable by 3 of the 8 samples, derived from patients with multiple mutations: T126I-T131A-C139Y-E/D144G, T126I-M133L, and P120Q-T126I. The emergence of these mutants, at least the G145R, has already been addressed as a public health concern because of its capability of escaping the immune system. In the present study we point out a second aspect connected with their existence and with similar potential negative impact on public health, that is their capability of escape punctual detection.

Acceptance and Safety of the Intradermal Influenza Vaccine Among the Elderly in Italy: an On-Field National Study

IntroductionAn observational multicenter study was carried out in Italy, to evaluate the acceptability and safety of the new intradermal (ID) influenza vaccine (Intanza Sanofi Pasteur SA, Lyon, France) among subjects aged ≥ 60 years, compared with that of other intramuscular (IM) influenza vaccines. Compliance with the use of the ID vaccine by healthcare professionals was also assessed.MethodsA previously validated and self-administered questionnaire, Vaccinees’ Perception of Injection (VAPI®), consisting of 21 questions, mainly focused on four dimensions (bother, arm movements, sleep, and acceptability), was administered to > 1,600 individuals with spontaneous access to outpatient clinics, located in Northern, Central, and Southern Italy, to evaluate the acceptance of the vaccines. Occurrence of solicited and unsolicited side effects and of serious adverse events was assessed in a subset of subjects (n = 500), using a clinical diary filled in by vaccinees following immunization. Compliance with the new ID vaccine by healthcare professionals was investigated using an ad-hoc questionnaire.ResultsA very favorable opinion concerning the acceptability of both the vaccines under survey, with the most positive answers ranging between 75.5% and 94.9%, was registered within the study population. Also the compliance by healthcare professionals (n = 130) with the novel ID vaccine was favorable. No serious adverse event occurred during the 6-month follow-up period. The frequency of solicited systemic reactions was comparable between the two study groups, while solicited local reactions were significantly higher in the ID-vaccine group than in the IM-vaccine group, even if at values lower than those reported in phase 3 clinical trials (ranges = 18.5–32.6% vs. 29.5–70.9%). These local events were mild and transient, thus without any clinical relevance.ConclusionThe novel ID influenza vaccine can be widely recommended in clinical practice, representing a useful tool to improve immunization coverage rates, and thus the control of influenza.

Determinants of adherence to seasonal influenza vaccination among healthcare workers from an Italian region: results from a cross-sectional study

Objectives Notwithstanding decades of efforts to increase the uptake of seasonal influenza (flu) vaccination among European healthcare workers (HCWs), the immunisation rates are still unsatisfactory. In order to understand the reasons for the low adherence to flu vaccination, a study was carried out among HCWs of two healthcare organisations in Liguria, a region in northwest Italy. Methods A cross-sectional study based on anonymous self-administered web questionnaires was carried out between October 2013 and February 2014. Through univariate and multivariate regression analysis, the study investigated the association between demographic and professional characteristics, knowledge, beliefs and attitudes of the study participants and (i) the seasonal flu vaccination uptake in the 2013/2014 season and (ii) the self-reported number of flu vaccination uptakes in the six consecutive seasons from 2008/2009 to 2013/2014. Results A total of 830 HCWs completed the survey. Factors statistically associated with flu vaccination uptake in the 2013/2014 season were: being a medical doctor and agreeing with the statements ‘flu vaccine is safe’, ‘HCWs have a higher risk of getting flu’ and ‘HCWs should receive flu vaccination every year’. A barrier to vaccination was the belief that pharmaceutical companies influence decisions about vaccination strategies. Discussion All the above-mentioned factors, except the last one, were (significantly) associated with the number of flu vaccination uptakes self-reported by the respondents between season 2008/2009 and season 2013/2014. Other significantly associated factors appeared to be level of education, being affected by at least one chronic disease, and agreeing with mandatory flu vaccination in healthcare settings. Conclusions This survey allows us to better understand the determinants of adherence to vaccination as a fundamental preventive strategy against flu among Italian HCWs. These findings should be used to improve and customise any future promotion campaigns to overcome identified barriers to immunisation.

Influenza vaccination among healthcare workers in Italy.

Influenza vaccination is a fundamental tool for the prevention of influenza in healthcare settings and its administration to healthcare workers (HCWs) is recommended in more than 40 countries including United States of America and many countries of the European Union. Despite these recommendations, the compliance of HCWs to influenza vaccination is largely inadequate in Italy. Since 2005/06 season, a comprehensive multifaceted intervention project aimed at increasing the seasonal influenza vaccination coverage rates among HCWs was performed at the IRCCS AOU San Martino IST teaching hospital in Genoa, Italy, the regional tertiary adult acute-care reference center with a 1300 bed capacity. Despite almost a decade of efforts, the vaccination coverage rates registered at our hospital steadily remain unsatisfactory and very distant by the minimum objective of 75% defined by the Italian Ministry of Health. During the last influenza season (2013/14), vaccination coverage rates by occupation type resulted 30% among physicians, 11% among nurses and 9% among other clinical personnel. Further efforts are necessary to prevent the transmission of influenza to patient and novel strategies need to be identified and implemented in order to increase the compliance of HCWs, particularly nurses, with the seasonal influenza vaccination.

The Molecular Epidemiology and Evolutionary Dynamics of Influenza B Virus in Two Italian Regions during 2010–2015: The Experience of Sicily and Liguria

Molecular epidemiology of influenza B virus remained poorly studied in Italy, despite representing a major contributor to seasonal epidemics. This study aimed to reconstruct the phylogenetic relationships and genetic diversity of the hemagglutinin gene sequences of 197 influenza B strains circulating in both Southern (Sicily) and Northern (Liguria) Italy between 2010 and 2015. Upper respiratory tract specimens of patients displaying symptoms of influenza-like illness were screened by real-time RT-PCR assay for the presence of influenza B virus. PCR-positive influenza B samples were further analyzed by sequencing. Neighbor-joining phylogenetic trees were constructed and the amino-acid alignments were analyzed. Phylogenetic analysis showed clusters in B/Victoria clade 1A/1B (n = 29, 14.7%), and B/Yamagata clades 2 (n = 112, 56.8%) and 3 (n = 56, 28.4%). Both influenza B lineages were found to co-circulate during the study period, although a lineage swap from B/Victoria to B/Yamagata occurred in Italy between January 2011 and January 2013. The most represented amino-acid substitutions were N116K in the 120-loop (83.9% of B/Yamagata clade 3 strains) and I146V in the 150-loop (89.6% of B/Victoria clade 1 strains). D197N in 190-helix was found in almost all viruses collected. Our findings provide further evidence to support the adoption of quadrivalent influenza vaccines in our country.

Invasive Candida Infections in Liver Transplant Recipients: Clinical Features and Risk Factors for Mortality

Background Invasive fungal infections remain a leading cause of morbidity and mortality among liver transplant recipients (LTRs). In this patient population, invasive Candida infections (ICIs) account for the large majority of cases. To date, only small studies and case-series analysing clinical presentation and risk factors for mortality in LTRs with ICIs are available. Methods We performed a retrospective multicenter multinational study in 10 centers in Europe and Brazil. All consecutive LTRs developing ICIs during the period January 2011 to December 2013 were included in the study. Results A total of 42 LTRs were included. Median age was 52.5 years, and 78.6% of patients were men. Viral hepatitis was the most common cause for liver transplantation (42.9%). Candidemia represented the majority of cases (24, 57.1%), followed by intra-abdominal candidiasis (18, 42.9%). Overall 30-day mortality was 23.8%, with higher mortality in patients with candidemia compared with intra-abdominal candidiasis (37.5% vs 5.6%, P = 0.02). Multivariate analysis showed candidemia to be a risk factor associated with mortality among LTRs presenting ICIs (odds ratio, 11.86; 95% confidence interval, 1.5-280; P = 0.01). Candida albicans represented the most common isolate (59.5%). High rates of antifungal resistances were found, with 16.7% and 4.8% of isolates displaying resistance to azoles and caspofungin, respectively. Conclusions Our study confirms the occurrence of high mortality rates in LTRs developing ICIs. Mortality rates varied according to the type of infection, with candidemia representing a risk factor for mortality. The high rates of antifungal resistance should be considered in the choice of the empiric antifungal regimen.

Impact of a mixed educational and semi-restrictive antimicrobial stewardship project in a large teaching hospital in Northern Italy

AbstractBackgroundThe overuse of antimicrobials favors the dissemination of antimicrobial resistance, as well as invasive fungal diseases and Clostridium difficile infections (CDI). In this study, we assessed the impact of a mixed educational and semi-restrictive antimicrobial stewardship (AMS) project in a large teaching hospital in Italy.MethodsThe AMS project was conducted from May 2014 to April 2016. It consisted of two initiatives in two consecutive periods: (1) educational activities; (2) semi-restrictive control of antimicrobial prescribing through a computerized software. The primary endpoint was consumption of antibacterials and antifungals. Secondary endpoints were incidence of CDI, methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI), carbapenem-resistant Klebsiella pneumoniae (CRKP) BSI, and Candida BSI.ResultsDuring the study period, a statistically significant reduction in consumption was observed for antibacterials (−1.45 defined daily doses (DDD)/1000 patient-days monthly, 95% confidence intervals [CI] −2.38 to −0.52, p 0.004), mainly driven by reductions in the use of fluoroquinolones, third/fourth generation cephalosporins, and carbapenems. No decrease in consumption of antifungals was observed (−0.04 DDD/1000 patient-days monthly, 95% CI −0.34 to +0.25, p 0.750). A statistically significant trend towards reduction was observed for incidence of CRKP BSI (incidence rate ratio 0.96, 95% CI 0.92–0.99, p 0.013). No statistically significant variations in trends were observed for CDI, MRSA BSI, and Candida BSI.ConclusionsThe mixed AMS project was effective in reducing the use of major antibacterials and the incidence of CRKP BSI. Further research is needed to assess the extent of long-term benefits of semi-restrictive approaches.