Angela Bechini

Impact of universal vaccination programmes on the epidemiology of hepatitis B: 10 years of experience in Italy.

Ten years have elapsed since routine vaccination of infants and of 12-year-old adolescent was implemented in Italy. In this period, evidence has accumulated on the epidemiological impact of universal immunisation. Coverage is on average >90% and is >or=95% in many areas of the country. Incidence of acute hepatitis B, that was already declining before 1991, was further decreased by routine vaccination programmes. This is particularly evident in adolescents and young adults (cohorts involved by mandatory vaccination), while incidence shows little changes in older subjects according to data of the last years. Prevalence of hepatitis B virus (HBV) markers detected by sero-epidemiological studies on anonymous sera confirms both the very high coverage with hepatitis B vaccination and the virtual absence of chronic HBsAg carriers in cohorts involved by routine vaccination programmes. The system of passive surveillance on adverse events following hepatitis B vaccination supports the excellent safety record of hepatitis B vaccines. In a hyperendemic area of Southern Italy, where a pilot programme was firstly implemented, it was also possible to document the decline of the involvement of hepatitis B in chronic liver pathologies (from 48% in 1982 to 18% in 1997). If coverage rates are maintained at the present levels, elimination of HBV transmission in Italy may be envisaged in few decades.

Multidrug-resistant commensal Escherichia coli in children, Peru and Bolivia.

Healthy children in urban areas have a high prevalence of fecal carriage of drug-resistant E. coli.

Efficacy, duration of immunity and cross protection after HPV vaccination: A review of the evidence

The efficacy and immunogenicity of HPV vaccines has proven excellent in several phase 2 and phase 3 trials involving tens of thousand women. A decrease in antibody titres was observed in follow-up studies of vaccinees, with initial sharp decline reaching a plateau in the longer term. Only few subjects lost their antibodies during the 5-6 years after vaccination. However, no breakthrough disease occurred even in those subjects. The administration of a challenge dose of quadrivalent vaccine at month 60 of follow-up resulted in a strong anamnestic response. The mechanism by which vaccination confers protection and the reasons for continuing vaccine efficacy remain to be elucidated. The same applies to the possibility of inducing an anamnestic response following viral challenge via genital mucosa. Data strongly suggest that both vaccines can have a variable level of cross protection against HPV types genetically and antigenically-closely related to vaccine types. Demonstration of cross protection against combined endpoints (CIN2/3 and AIS) for combined HPV types, and, as a single type, for HPV-31, has been reached for the quadrivalent vaccine, and there is evidence of cross protection against HPV 31 and 45 persistent infections (as single types) for the bivalent vaccine. Assays used for antibody detection were different for the two vaccines, and standardisation of methods for anti-HPV L1 protein detection is presently underway. The possibility to use universally accepted tests for antibody measurement would make comparison between vaccines and among different studies much easier.

An overview on the implementation of HPV vaccination in Europe

The discovery that the Human PapillomaVirus (HPV) is the necessary cause of cervical cancer has led to the development of prophylactic vaccines. Cervical cancer is the second most common cause of death from cancer among young women in Europe: mortality is still high, despite its important reduction due to screening programs for early detection. Besides cervical cancer, HPV is responsible for a significant proportion of other anogenital cancers and an increasing number of oropharyngeal cancers, representing together an at least equal burden compared to cervical cancer. HPV is also responsible for conditions such as condyloma acuminata (genital warts) and recurrent respiratory papillomatosis. Organized vaccination programs against HPV have the potential to prevent about 70% of cervical cancers and the vast majority of the other HPV-related conditions. Recommendations for HPV vaccination of at least one cohort of females have been issued in nearly all western European countries, and national/regional publicly funded vaccination programs have been introduced in most of them. Different approaches have been chosen for the implementation of HPV vaccination, based on the organization of each countrys health care system. A brief outline of these programs in Europe is presented. As for all preventive public health interventions, high coverage of the target population with HPV vaccines pre-exposure is essential to achieve maximum reduction of cases: therefore, in order to obtain the maximum and most equitable coverage and future benefit, programs targeting adolescents before exposure to HPV should be preferred and population-based. Catch-up programs should also be implemented wherever possible, in order to deliver more and even earlier benefits, and effective communication strategies need to be adopted.

Human papilloma virus vaccination: impact and recommendations across the world

Human papilloma virus (HPV) vaccination has been implemented in several countries for about the past 7 years, mainly in the adolescent female population, with varying coverage results. Although the impact of immunization on cervical and other HPV-related cancers will be evident in the next decades, a marked decrease of prevalent HPV infections, precancerous lesions and genital warts is already dramatic in the vaccinated cohorts, and also in their sexual partners, thus providing clear evidence of the effectiveness of HPV vaccination, including a herd-protection effect. Today, recommendations and implementation of universal HPV vaccination for adolescent girls are a public-health priority in all countries of the world. Countries with limited resources are presently involved in demonstration projects and, in some cases, have launched national programmes with the help of international agencies and alliances. Extension of immunization offer to young women and to adolescent male subjects has become an important additional opportunity for several countries, with a special focus needed on homosexual men with HIV infection who are at particularly increased risk of HPV-related diseases. Public-health authorities are confronted with the need to enlarge HPV-vaccination offer to all target groups, especially pre-adolescent girls, so that they can be saved from dreadful cancers by reaching high immunization coverage.

Increasing Resistance in Commensal Escherichia coli, Bolivia and Peru

To the Editor: The global increase of antimicrobial-drug resistance, including resistance to the new and most potent antimicrobial agents, is a major public health concern. In low-resource countries, where bacterial infections are still among the major causes of death, especially for children, it is of particular concern (1). ANTRES (Towards Controlling Antimicrobial Use and Resistance in Low-income Countries—An Intervention Study in Latin America) is a research project on antimicrobial-drug use and resistance in low-resource countries of Latin America (see www.unifi.it/infdis/antres/default.htm). In 2002, the baseline ANTRES study showed a high rate of fecal carriage of Escherichia coli with acquired resistance to several antimicrobial drugs, especially older drugs (e.g., ampicillin, trimethoprim-sulfamethoxazole, tetracycline, streptomycin, and chloramphenicol), in preschool children from 4 urban settings in Bolivia and Peru (2). We report the results of a second cross-sectional study, conducted in 2005, that evaluated the evolution of antimicrobial-drug resistance in the studied areas. We studied healthy children 6–72 months of age from each of 4 urban areas: 2 in Bolivia (Camiri, Santa Cruz Department; Villa Montes, Tarija Department) and 2 in Peru (Yurimaguas, Loreto Department; Moyobamba, San Martin Department). The study design, sampling and inclusion criteria, methods, and ethical issues were the same as those of the baseline study (2). The study was carried out over 4 months (September–December 2005), the same seasonal period as in the previous study. No significant differences in sex ratios were found among children enrolled from the different areas, whereas minor differences were found for age. No statistical differences were found between the 2002 baseline study and the 2005 study results in terms of numbers of children (3,193 vs. 3,174) and sex ratios (0.94 vs. 0.95) (Table). Statistical analyses were performed by using Stata 9.0 (Stata Corp., College Station, TX, USA). Logistic regression models were used to compare the antimicrobial-drug resistance rates in 2002 and 2005, considering the combined influences of age, sex, city, and country. Table Antimicrobial drug–resistance rates of Escherichia coli as part of commensal flora in children, Bolivia and Peru, 2002 and 2005* *Expanded Table available online at www.cdc.gov/EID/content/14/2/338-T.htm. Data from the 2005 survey confirmed high resistance rates for ampicillin, trimethoprim-sulfamethoxazole, tetracycline, streptomycin, and chloramphenicol. The differences in resistance rates observed between 2002 and 2005 for these drugs, although sometimes statistically significant, are probably of limited epidemiologic relevance due to the high rates of antimicrobial-drug resistance found in the E. coli population in both surveys. The most relevant finding of the 2005 survey was the remarkable increase since 2002 in the resistance rates to fluoroquinolones and expanded-spectrum cephalosporins (Table). Molecular analysis showed that the dramatic increase in rates of resistance to expanded spectrum cephalosporins was mostly the result of dissemination of CTX-M-type extended-spectrum β-lactamase determinants (3). Concerning the association between sex and resistance rates, the higher resistance rates observed for some agents and in some settings for boys in the baseline study were not confirmed, except in 1 case (kanamycin in Camiri, p = 0.04) (2). Analysis by age (not performed for amikacin due to low numbers of resistant isolates) confirmed the occurrence of higher resistance rates for the youngest age group and an overall decreasing trend by age for all agents, except ciprofloxacin and gentamicin. For these 2 agents, resistance rates increased, although not significantly (p = 0.95 and p = 0.55, respectively) (2). Although we did not specifically address factors potentially involved in this phenomenon, we will address them in future investigations. Increasing resistance to fluoroquinolones and expanded-spectrum cephalosporins among E. coli clinical isolates has been observed in several parts of the world and complicates the management of infections (4,5). Recently, intestinal colonization with fluoroquinolone-resistant or extended-spectrum β-lactamase–producing E. coli of nonhospitalized persons has been described as an emerging phenomenon (6–9). Although the exact clinical implications of this phenomenon are not clearly established, colonization by these resistant strains is a public health threat at the community and hospital levels (8,9). The reasons for the increased prevalence of fecal carriage of these resistant E. coli strains by children from the studied areas are not clear. Data collected about household use of antimicrobial drugs excluded previous use of fluoroquinolones and expanded-spectrum cephalosporins (C. Kristiansson et al., unpub. data). The increased prevalence of resistant E. coli strains in preschool children most likely reflects increased exposure within a contaminated household setting, in the food chain, or both (6,8,10). Our findings support the need to continue monitoring the evolution of resistance in commensal E. coli, to evaluate the effects of these important reservoirs of resistance genes distributed in the community, to investigate the epidemiologic relationship with clinical isolates, and to define the role of the food supply. Investigation into whether carriage of resistant strains in adults correlates with data on antimicrobial-drug use in hospitals and in the community would also be of interest.

Economic evaluation of varicella vaccination in Italian children and adolescents according to different intervention strategies: the burden of uncomplicated hospitalised cases.

An economic evaluation of universal varicella vaccination in Italy was performed to assess the potential clinical and economic effects of three different strategies versus no vaccination. By means of the EVITA model, vaccination with two doses in toddlers only (1-1.5 years), adolescents only (13 years) and toddlers with adolescents catch-up programmes were simulated. All universal varicella vaccination strategies including toddlers (with or without an adolescent catch-up programme) turned out to be highly effective in reducing the burden of disease due to varicella. In addition, they lead to significant net savings from the societal perspective but to higher costs compared to return of investment from National Health Service perspective. The huge economic burden of hospitalised uncomplicated varicella cases registered in Italy can partially explain these highly beneficial findings for the societal perspective. Overall, our analysis confirmed the favourable clinical and economic impact of routine varicella vaccination with two doses of vaccine in Italy.

Cost-effectiveness of new adult pneumococcal vaccination strategies in Italy.

Community-acquired pneumonia (CAP) and invasive pneumococcal disease (IPD) are very relevant pathologies among elderly people (≥ 65 y old), with a consequent high disease burden. Immunization with the 23-valent pneumococcal polysaccharide vaccine (PPV23) has been differently implemented in the Italian regions in the past years, reaching overall low coverage rates even in those with medical indications. In 2010, the 13-valent pneumococcal conjugate vaccine (PCV13) became available and recommended in the universal Italian infant immunization program. Since October 2012, indications for use of PCV13 were extended to subjects ≥ 50 y to prevent invasive pneumococcal diseases. The Italian decision makers should now revise regional indications for the prevention of pneumococcal diseases in the elderly. Pharmaco-economic analyses represent a useful tool to value the feasibility of new immunization programs and their sustainability. Therefore, an ad hoc population model was developed in order to value the clinical and economic impact of an adult pneumococcal vaccination program in Italy. Particularly, different immunization scenarios were modeled: vaccination of 65 y-olds (1 cohort strategy), simultaneous vaccination of people aged 65 and 70 y (double cohort strategy) and, lastly, immunization of people aged 65, 70 and 75 y (triple cohort strategy), thus leading to the vaccination of 5, 10 and 15 cohorts during the 5 y of the program. In addition, the administration of a PPV23 dose one year after PCV13 was evaluated, in order to verify the economic impact of the supplemental serotype coverage in elderly people. The mathematical model valued the clinical impact of PCV13 vaccination on the number of bacteraemic pneumococcal pneumonia (BPP) and pneumococcal meningitis (PM) cases, and related hospitalizations and deaths. Although PCV13 is not yet formally indicated for the prevention of pneumococcal CAP by the European Medicine Agency (differently from FDA, whose indications include all pneumococcal diseases in subjects ≥ 50 y), the model calculated also the possible impact of vaccination on CAP cases (non-bacteraemic), considering the rate of this disease due to S. pneumoniae. The results of the analysis show that, in Italy, an age-based PCV13 vaccination program in elderly people is cost-effective from the payer perspective, with costs per QALY ranging from 17,000 to 22,000 Euro, according to the adopted vaccination strategy. The subsequent PPV23 offer results in an increment of costs per QALY (from 21,000 to 28,000 Euro, according to the vaccination strategy adopted). Pneumococcal vaccination using the conjugate vaccine turned out to be already favorable in the second year of implementation, with incremental costs per QALY comparable to those of other already adopted prevention activities in Italy (for instance, universal HPV vaccination of 12 y-old girls), with further benefits obtained when extending the study period beyond the 5-y horizon of our analysis.

Sexual behaviour and risk factors for the acquisition of human papillomavirus infections in young people in Italy: suggestions for future vaccination policies

BackgroundHuman Papillomavirus (HPV) is the most common sexually transmitted infection. The main risk factors correlated with HPV infection are: early sexual debut, the number of partners, frequency and type of sexual contact and partner’s sexual histories.We surveyed sexual habits among young people in order to provide information that might orient decision-makers in adopting HPV multi-cohort vaccination policies.MethodsWe administered a questionnaire to students (14–24 years old) in five Italian cities.Results7298 questionnaires were analyzed (4962 females and 2336 males); 55.3% of females (95% CI 53.9–56.7) and 52.5% of males (95% CI 50.5–54.5) reported regular sexual activity. The mean age at sexual debut was 15.7 ± 1.6 and 15.6 ± 1.6 for females and males, respectively, and the median age was 16 for both sexes.With regard to contraceptive use during the last year, 63.6% of males and 62.8% of females responded affirmatively; 42.6% of males and 42.8% of females used condoms.ConclusionThe results reveal precocious sexual activity among respondents, with the mean age at first intercourse declining as age decreases. Condom use proved to be scant. Considering lifestyle-related risk factors, males appear to have a higher probability of acquiring HPV infection than females.These data support the importance of promoting multi-cohort HPV vaccination strategies for females up to 25 years of age. It is essential to improve vaccination coverage through different broad-spectrum strategies, including campaigns to increase awareness of sexually transmitted diseases and their prevention.

Impact of universal vaccination against varicella in Italy

In Italy, the introduction of Universal Varicella Vaccination (UVV) has been decided but postponed, as a national programme, until 2015, when data from Regions which have already implemented it will be available. Starting from 2003, eight Italian Regions (Basilicata, Calabria, Friuli Venezia Giulia, Apulia, Sardinia, Sicily, Tuscany and Veneto) have progressively introduced UVV, in their immunization programme, with different schedules in children aged 13–15 months and 5–6 years, currently a two-dose schedule is adopted by all Regions. In June 2013, an Interregional Group on Varicella Vaccination (IGVV) has been established in order to assess the effectiveness of varicella vaccination with standardized and shared tools. The aim of this study was to evaluate the impact of varicella vaccination on the incidence and hospitalizations due to varicella and its complications in the period 2003–2012 in order to support the Italian decision makers on the future national adoption. Preliminary data showed that a general reduction of incidence and hospitalization rates was observed in the study period, resulting in relevant savings for the National Health Service. Immunization coverage with first dose at 24 months of age was high in all Regions (84%–95%) in 2012. Adverse events due to varicella vaccines were rare and without permanent sequelae. Underreporting of varicella cases and delays in the administration of the first dose of varicella vaccines were the main critical issues. In conclusion, solid evidences in support of universal UVV arise from the experiences available today in Italy.