Laura Sticchi

MF59®-Adjuvanted H5N1 Vaccine Induces Immunologic Memory and Heterotypic Antibody Responses in Non-Elderly and Elderly Adults

Background Pathogenic avian influenza virus (H5N1) has the potential to cause a major global pandemic in humans. Safe and effective vaccines that induce immunologic memory and broad heterotypic response are needed. Methods and Findings Healthy adults aged 18–60 and >60 years (n = 313 and n = 173, respectively) were randomized (1∶1) to receive two primary and one booster injection of 7.5 μg or 15 μg doses of a subunit MF59-adjuvanted H5N1 (A/Vietnam/1194/2004) (clade 1) vaccine. Safety was monitored until 6 months after booster. Immunogenicity was assessed by hemagglutination inhibition (HI), single radial hemolysis (SRH) and microneutralization assays (MN). Mild injection-site pain was the most common adverse reaction. No serious adverse events relating to the vaccine were reported. The humoral immune responses to 7.5 μg and 15 μg doses were comparable. The rates for seroprotection (HI>40; SRH>25mm2; MN ≥40) after the primary vaccination ranged 72–87%. Six months after primary vaccination with the 7.5 μg dose, 18% and 21% of non-elderly and elderly adults were seroprotected; rates increased to 90% and 84%, respectively, after the booster vaccination. In the 15 μg group, seroprotection rates among non-elderly and elderly adults increased from 25% and 62% after primary vaccination to 92% and 88% after booster vaccination, respectively. A heterologous immune response to the H5N1/turkey/Turkey/05 strain was elicited after second and booster vaccinations. Conclusions Both formulations of MF59-adjuvanted influenza H5N1 vaccine were well tolerated. The European Union requirement for licensure for pre-pandemic vaccines was met by the lower dose tested. The presence of cross-reactive antibodies to a clade 2 heterologous strain demonstrates that this vaccine may be appropriate for pre-pandemic programs. Trial Registration ClinicalTrials.gov NCT00311480

Cross-protection by MF59-adjuvanted influenza vaccine: neutralizing and haemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses.

Adjuvants enhance antibody response against vaccination. We compared the ability of MF59-adjuvanted and non-adjuvanted subunit influenza vaccines, containing A/Wyoming/3/03(H3N2), to confer cross-protection against four consecutive drifted strains in the elderly. Neutralizing and haemagglutination-inhibiting antibody were measured. MF59-adjuvanted vaccine induced a stronger booster response against A/Panama/2007/99(H3N2) than non-adjuvanted vaccine. A/Panama/2007/99(H3N2) circulated widely during the previous 5 years and was included in vaccines over four consecutive seasons. Broader serological protection against drifted strains that circulated 1 and 2 years after vaccination with A/Wyoming/3/03(H3N2) was observed with MF59-adjuvanted vaccine. Thus, MF59-adjuvanted vaccine confers greater immunogenicity than non-adjuvanted vaccines in vulnerable populations.

Universal childhood immunisation against Streptococcus pneumoniae: The five-year experience of Liguria Region, Italy

Liguria was the first Italian Administrative Region, since 2003, to actively recommend free-of-charge immunisation, of all infants, with heptavalent Pneumococcal Conjugate Vaccine (PCV-7), within a research pilot-project. Vaccination coverage among infants rapidly increased from 42.8% in 2003 to 83.3% in 2004, progressively reaching levels of 93.4% in 2007. Two scientific projects have been carried out, aimed: (i) to assess the immunogenicity of PCV-7 and of a hexavalent vaccine Diphtheria-Tetanus-Trivalent Acellular Pertussis-Hepatitis B-Inactivated Polio Virus-Haemophilus influenzae type B (DTaP-HBV-IPV-Hib) when co-administered to healthy infants at 3, 5 and 11-12 months of age (routine schedule), and (ii) to evaluate the effect of the immunisation campaign in preventing pneumococcal-associated hospitalisations. Results in 151 infants showed the high immunogenicity of the vaccines, seroprotection rates, measured 1 month after the third dose, ranging between 97.3% (serotype 6 B) and 100% (serotypes 4 and 9 V) for PCV-7 and between 99.3% and 100% against common antigens of hexavalent vaccine. Monitoring nearly 70,000 children, aged 0-24 months, during the period 2000-2007, and comparing hospitalisation rates occurred in subjects belonging to birth cohorts before and after the introduction of widespread immunisation, a significant decline for all-cause and pneumococcal pneumonia and for acute otitis media was observed, with preventive fractions of 15.2%, 70.5% and 36.4%, respectively.

Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy

Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it.

Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immunodeficiency virus type 1-seropositive and -seronegative adults.

ABSTRACT The objective of this study was to evaluate and compare both the safety and tolerability and the humoral and cell-mediated immune responses for two influenza virus subunit vaccines, one with MF59 adjuvant (Fluad) and one without an adjuvant (Agrippal), in healthy and in human immunodeficiency virus type 1 (HIV-1)-infected adult individuals. To achieve this aim, an open, randomized, comparative clinical trial was performed during the 2005-2006 season. A total of 256 subjects were enrolled to receive one dose of vaccine intramuscularly. Blood samples were taken at the time of vaccination and at 1 and 3 months postvaccination. A good humoral antibody response was detected for both vaccines, meeting all the criteria of the Committee for Medical Products for Human Use. After Beyers correction for prevaccination status, Fluad exhibited better immunogenicity than Agrippal, as shown from the analysis of the geometric mean titers, with significant differences for some virus strains; however, no definitive conclusions on the clinical significance of such results can be drawn, because the method used to estimate antibody response is currently nonstandard for influenza virus vaccines. Significant induction of an antigen-specific CD4+ T-lymphocyte proliferative response was detected at all time points after immunization, for both the vaccines, among HIV-1-seronegative subjects. This was different from what was observed for HIV-1-infected individuals. In this group, significance was not reached at 30 days postvaccination (T30) for those immunized with Agrippal. Also when data were compared between treatment groups, a clear difference in the response at T30 was observed in favor of Fluad (P = 0.0002). The safety profiles of both vaccines were excellent. For HIV-1-infected individuals, no significant changes either in viremia or in the CD4+ cell count were observed at any time point. The results showed good safety and immunogenicity for both vaccines under study for both uninfected and HIV-1-infected adults, confirming current recommendations for immunization of this high-risk category.

Effectiveness of a 23-valent polysaccharide vaccine in preventing pneumonia and non-invasive pneumococcal infection in elderly people: a large-scale retrospective cohort study.

This retrospective cohort study evaluated the effectiveness of a 23-valent pneumococcal polysaccharide vaccine in reducing hospital admission for pneumonia, otitis media and exacerbation of asthma or other syndromes due to Streptococcus pneumoniae in 9170 high-risk individuals. Cohort members were followed from 1 January 1998 to 31 December 2002. With regard to preventing hospitalization due to pneumonia, we observed a decrease in the incidence of 1/10 000 person-months and a reduction in the relative risk of 38% in the vaccinated cohort compared with the non-vaccinated subjects. A decrease in the risk of hospital admission for asthma, acute otitis media, chronic obstructive pulmonary disease and other respiratory infections was also observed in vaccinated compared with non-vaccinated subjects. The specificity of these findings was confirmed by the lack of a protective effect from vaccination for those outcomes, such as hospitalization ‘for all causes’ and ‘other otorhinolaryngological diagnoses’, that were not directly related to pneumococcal disease.

Decline in pneumonia and acute otitis media after the introduction of childhood pneumococcal vaccination in Liguria, Italy.

The effect of the pneumococcal conjugate vaccine immunization programme on pneumococcal-associated or potentially pneumococcal-associated hospital admissions in the Italian region of Liguria was assessed. Hospital admission rates were compared in subjects belonging to birth cohorts before and after the introduction of widespread immunization for 0 − 2-year old children with a seven-valent conjugate vaccine (PCV7). Significant reductions in hospitalization rates for all-cause and pneumococcal pneumonia and for acute otitis media were observed in subjects born after widespread uptake of the vaccine. The preventive fraction (a measure of vaccine effectiveness) ranged from 15.2% for all-cause pneumonia to 70.5% for pneumococcal pneumonia. This study contributes to the growing body of information that supports the beneficial effect of PCV7 vaccination.

Cost-benefit evaluation of influenza vaccination in the elderly in the Italian region of Liguria

Influenza causes considerable morbidity and mortality and the damage to public health can be considerable. The most effective measures available for the prevention of influenza is vaccination. In most industrialised countries the objective of vaccination is to limit the disease among individuals at risk, especially the elderly. During the winter of 2000/2001, General Practitioners (GPs) monitored 14,818 elderly individuals. The objective was to evaluate the weekly incidence of the disease. Furthermore, we carried out a prospective study on 512 elderly individuals, arranged according to vaccination (304 vaccinated and 208 non-vaccinated), with the main objective of assessing the costs of the disease and the efficacy of vaccination. Finally, in order to assess the percentage of vaccinated elderly individuals, we carried out a telephone survey on 500 subjects. Our clinical surveillance study enabled us to establish that morbidity was particularly low in elderly individuals.The results of the prospective study allowed us to estimate the cost-benefit ratio at 8.22, with a net saving of 110.20 Euros for each vaccinated subject. We were also able to establish that the vaccine coverage among elderly individuals was 63%. Our study, though carried out during a low epidemic year, confirms the economic advantage of vaccination in the elderly.

Flu vaccination with a virosomal vaccine does not affect clinical course and immunological parameters in scleroderma patients.

Safety and efficacy of adjuvanted vaccines in autoimmune individuals raises growing clinical and scientific interest. Protection from influenza would bring particular benefits in these patients with common cardiac and respiratory impairment. This study evaluates efficacy, clinical safety and immune effects of the administration of a single dose of a virosomal flu vaccine in 46 scleroderma patients. The following parameters were evaluated before and after administration of Inflexal: clinical conditions, inflammation and autoimmunity parameters, humoral response, lymphocyte proliferation and cytokine production upon flu antigen stimulation by specific and non-specific cells. Inflexal was found effective in scleroderma patients. In no subject was worsening of clinical conditions, inflammation and immunological parameters observed.

Safety and Immunogenicity of Conventional Subunit and MF59-adjuvanted Influenza Vaccines in Human Immunodeficiency Virus-1-seropositive Patients

In this study of influenza vaccination, 37 human immunodeficiency virus (HIV)-1-seropositive patients were randomized to receive either a vaccine with a conventional subunit or one adjuvanted with MF59. Blood samples were collected at the time of vaccination, and then 30 and 180 days later, to evaluate immunogenicity, CD4+ T-lymphocyte count and HIV-1 RNA levels. Seroconversion rates against the three viral strains included in the vaccine ranged between 44% and 72% and 53% and 68% for the adjuvanted vaccine and the subunit vaccine, respectively. Other criteria of the European Medicines Evaluation Agency were also met. Vaccination was not associated with serious adverse events. Local and systemic effects were mild and of short duration. CD4+ T-lymphocyte counts and viraemia levels were not negatively affected by vaccination. These results confirmed the safety and immunogenicity of these currently available vaccines in HIV-1-seropositive patients, thus supporting the recommendation for influenza immunization in this high-risk category.