Enhanced passive safety surveillance of a quadrivalent inactivated split virion influenza vaccine in Finland during the influenza season 2020/21.

BACKGROUND: The European Medicines Agency (EMA) requires enhanced safety surveillance to be conducted for annual seasonal influenza vaccines with the aim of rapidly detecting any potential new safety concerns before the peak immunisation period of the vaccine in any given year. The aim of this study was to detect any clinically significant change in the frequency or severity of expected reactogenicity of the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunisation in Finland for the 2020/21 season. The primary objective was to investigate the frequency of suspected adverse drug reactions (ADRs) occurring within 7 days following vaccination. METHODS: Enhanced passive safety surveillance of individuals vaccinated with IIV4 was conducted from October 9, 2020 to November 30, 2020 across seven sites in Finland. The vaccinee reporting rate and ADR reporting rate were calculated and compared with known or expected safety data in order to identify any clinically significant changes. RESULTS: Data were collected from 1008 individuals with 29 vaccinees reporting 82 suspected ADRs. Of these, 28 people reported 79 suspected ADRs within 7 days following vaccination, corresponding to a vaccinee reporting rate of 2.78% (95% CI: 1.85, 3.99) (ADR reporting rate, 7.84% [95% CI: 6.25, 9.67%]). The most frequently reported ADRs were injection site reactions (vaccination site pain, vaccination site erythema and vaccination site swelling) (n = 46, 2.28%), myalgia (n = 9, 0.89%) and headache (n = 8, 0.79%). No serious suspected adverse events were reported at any point post-vaccination and ADR reporting rates were in general lower compared to those reported for IIV4 in the 2019/20 surveillance study. CONCLUSION: No clinically significant changes in what is known or expected for IIV4 were reported for the 2020/21 season which supports the safety profile of this vaccine and will help maintain public confidence in influenza vaccination.

Enhanced passive safety surveillance of the quadrivalent inactivated split-virion influenza vaccine (IIV4) in Finland during the 2019/20 influenza season.

BACKGROUND AND AIMS: The Enhanced Passive Safety Surveillance is a requirement of the European Medicines Agency (EMA) for seasonal influenza vaccines, aiming to rapidly detect any significant change in frequency or severity of expected reactogenicity or allergic events prior to widespread use of a vaccine in any particular year. The aim of this surveillance was to assess the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunization in Finland, as per the national immunization program for 2019/20. The primary objective was to investigate the suspected adverse drug reactions (ADR) occurring within 7 days following vaccination. METHODS: Passive surveillance of individuals vaccinated with IIV4 was conducted within the first 4 to 6 weeks of the influenza season in Finland. Potential ADRs were reported via phone or posted adverse event forms. The vaccinee reporting rate and ADR reporting rate were calculated and compared with the known or expected safety data in order to identify any change which was clinically significant. RESULTS: Data were collected from 939 individuals, with 56 reports received for 163 suspected ADRs. Of these, 38 individuals reported 117 suspected ADRs within 7 days following vaccination, corresponding to an ADR reporting rate of 12.46% (95% CI: 10.41, 14.74%); vaccination-site pain, vaccination-site reaction, and pyrexia were the most frequently reported ADRs. The 18-to-65 years of age category had an ADR reporting rate of 12.56%, the over-65 years of age category had an ADR reporting rate of 16.22%, and no ADRs were reported for individuals aged 6 months to 18 years. No serious suspected ADRs were reported at any time post-vaccination, and the ADR rates were comparable to those reported for IIV4 in the 2018/19 seasonal assessment. The frequency of suspected ADRs was generally aligned with those reported in the Summary of Product Characteristics (SmPC), with the exception of asthenia, somnolence, and erythema, which were slightly higher. No reporting pattern by type, frequency, or severity was identified for the suspected ADRs. CONCLUSIONS: No clinically significant changes in what is known or expected for IIV4 was reported for the 2019/20 season, which supports the overall safety profile.

Monitoring vaccine and non-vaccine HPV type prevalence in the post-vaccination era in women living in the Basilicata region, Italy.

BACKGROUND: A large free-of-charge quadrivalent HPV (qHPV) vaccination program, covering four cohorts annually (women 11, 14, 17 and 24 years), has been implemented in Basilicata since 2007. This study evaluated vaccine and non-vaccine HPV prevalence 5-7 years post-vaccination program implementation in vaccinated and unvaccinated women. METHODS: This population-based, cross-sectional study was conducted in the public screening centers of the Local Health Unit in Matera between 2012 and 2014. Cervical samples were obtained for Pap and HPV testing (HC2, LiPA Extra® assay) and participants completed a sociodemographic and behavioral questionnaire. Detailed HPV vaccination status was retrieved from the official HPV vaccine registry. HPV prevalence was described overall, by type and vaccination status. The association between HPV type-detection and risk/protective factors was studied. Direct vaccine protection (qHPV vaccine effectiveness [VE]), cross-protection, and type-replacement were evaluated in cohorts eligible for vaccination, by analyzing HPV prevalence of vaccine and non-vaccine types according to vaccination status. RESULTS: Overall, 2793 women (18-50 years) were included, 1314 of them having been in birth cohorts eligible for the HPV vaccination program (18- to 30-year-old women at enrolment). Among the latter, qHPV vaccine uptake was 59% (at least one dose), with 94% completing the schedule; standardized qHPV type prevalence was 0.6% in vaccinated versus 5.5% in unvaccinated women (P <0.001); adjusted VE against vaccine type infections was 90% (95% CI: 73%-96%) for all fully vaccinated women and 100% (95% CI not calculable) in women vaccinated before sexual debut. No statistically significant difference in overall high-risk HPV, high-risk non-vaccine HPV, or any single non-vaccine type prevalence was observed between vaccinated and unvaccinated women. CONCLUSIONS: These results, conducted in a post-vaccine era, suggest a high qHPV VE and that a well-implemented catch-up vaccination program may be efficient in reducing vaccine-type infections in a real-world setting. No cross-protective effect or evidence of type-replacement was observed a few years after HPV vaccine introduction.

DTaP-IPV-HB-Hib vaccine (Hexaxim): an update 10 years after first licensure.

INTRODUCTION: Hexaxim® is fully liquid, hexavalent, combination vaccine that provides immunization against diphtheria, tetanus, pertussis (whooping cough), polio, hepatitis B, and invasive diseases caused by Haemophilus influenzae type b. Combination vaccines such as Hexaxim reduce the number of injections needed, improving both vaccination compliance and operational efficiency. AREAS COVERED: Safety and immunogenicity data were reviewed from >25 clinical trials involving approximately 7200 infants/toddlers, identified using PubMed searches to April 2023. These trials have evaluated a diverse range of primary series and booster schedules, including antibody persistence, co-administration of Hexaxim with other routine pediatric vaccines, and specific populations (born to Tdap-vaccinated women, preterm, and immunocompromised infants). Lastly, post-marketing surveillance and real-world effectiveness data were assessed. EXPERT OPINION: An extensive program of clinical development prior to licensure demonstrated favorable vaccine safety and good immunogenicity of each antigen, and Hexaxim was first approved for use in 2012. In the 10 years since licensure, Hexaxim has been adopted widely, with more than 180 million doses distributed worldwide. The widespread use of this hexavalent vaccine is a crucial tool in the ongoing and future control of six pediatric infectious diseases globally.

Prevalence and genotype distribution of human papillomavirus infection of the cervix in Spain: the CLEOPATRE study.

Human papillomavirus (HPV) infection is a necessary cause of cervical cancer. The aim of this study was to estimate the prevalence of cervical HPV infection and HPV type-specific distribution among women attending cervical cancer screening in Spain during 2007 and 2008. Women aged 18-65 years were recruited according to an age-stratified sampling method. Liquid-based cervical samples were collected and analyzed for cytology, HPV detection, and genotyping. HPV genotyping was determined using the INNO-LiPA HPV Genotyping Extra Reverse Hybridization Line Probe Assay. Prevalence estimates were age-standardized using 2001 Spanish census data. The present study included 3,261 women. Age-standardized HC2-based HPV prevalence was 14.3% (95% CI, 13.1-15.5) among women aged 18-65 years, and 28.8% (26.6-31.1) among women aged 18-25 years. High-risk HPV types were detected in 12.2% (95% CI, 11.1-13.4) of HPV-tested women, representing 84.0% of HPV-positive samples. Multiple infections were present in 4.1% (95% CI, 3.4-4.8) of HPV-tested women (25.0% of HPV-positive samples). The most common high-risk HPV-types among HPV-tested women were 16 (2.9%), 52 (1.8%), 51 (1.6%), 31 (1.3%), and 66 (1.2%). HPV-type 16 was present in 16.9% of HPV-positive samples. One or more of the HPV vaccine types 6/11/16/18 were detected in 3.8% of HPV-tested women (22.1% of HPV-positive samples). Though not a true population-based survey, this study provides valuable baseline data for future assessment of the impact of current HPV vaccination programs in Spain. The high prevalence of HPV infection among young women may reflect recent changes in sexual behavior.

Predictors of human papillomavirus infection in women undergoing routine cervical cancer screening in Spain: the CLEOPATRE study.

BACKGROUND: Human papillomavirus (HPV) is a sexually transmitted infection that may lead to development of precancerous and cancerous lesions of the cervix. The aim of the current study was to investigate socio-demographic, lifestyle, and medical factors for potential associations with cervical HPV infection in women undergoing cervical cancer screening in Spain. METHODS: The CLEOPATRE Spain study enrolled 3 261 women aged 18-65 years attending cervical cancer screening across the 17 Autonomous Communities. Liquid-based cervical samples underwent cytological examination and HPV testing. HPV positivity was determined using the Hybrid Capture II assay, and HPV genotyping was conducted using the INNO-LiPA HPV Genotyping Extra assay. Multivariate logistic regression was used to identify putative risk factors for HPV infection. RESULTS: A lifetime number of two or more sexual partners, young age (18-25 years), a history of genital warts, and unmarried status were the strongest independent risk factors for HPV infection of any type. Living in an urban community, country of birth other than Spain, low level of education, and current smoking status were also independent risk factors for HPV infection. A weak inverse association between condom use and HPV infection was observed. Unlike monogamous women, women with two or more lifetime sexual partners showed a lower risk of infection if their current partner was circumcised (P for interaction, 0.005) and a higher risk of infection if they were current smokers (P for interaction, 0.01). CONCLUSION: This is the first large-scale, country-wide study exploring risk factors for cervical HPV infection in Spain. The data strongly indicate that variables related to sexual behavior are the main risk factors for HPV infection. In addition, in non-monogamous women, circumcision of the partner is associated with a reduced risk and smoking with an increased risk of HPV infection.

Enhanced passive safety surveillance of a trivalent and a quadrivalent influenza vaccine in Denmark and Finland during the 2018/2019 season.

The European Medicines Agency requires Enhanced Passive Safety Surveillance (EPSS) for all seasonal influenza vaccines. Here, we report the EPSS results for the trivalent inactivated influenza vaccine (IIV3; Vaxigrip®) and the quadrivalent inactivated influenza vaccine (IIV4; VaxigripTetraTM) during the 2018/19 influenza season in Denmark and Finland. The primary objective was to estimate the rates of suspected adverse reactions (ARs) occurring within 7 days following routine vaccination. Between October and November 2018, 1000 safety report cards (SRCs) for IIV3 were distributed in Denmark, and 996 SRCs for IIV4 were distributed in Finland. Participants were instructed to report any ARs by telephone or e-mail using the information provided on the SRC. All participants vaccinated with IIV3 were aged ≥18 years. Most participants vaccinated with IIV4 (95.5%) were aged 18 - 65 years, 2.2% were aged 6 months to 17 years, and 2.3% were aged >65 years. Fifty-five ARs were reported by 12 participants (1.2%) vaccinated with IIV3 and 162 ARs were reported by 53 participants (5.3%) vaccinated with IIV4. The most frequent ARs were vaccination site pain and fever for IIV3, and vaccination site pain, vaccination site inflammation, myalgia, and headache for IIV4. The 2018/19 AR rates for IIV3 were comparable to 2017/18 rates. The 2018/19 AR rates for IIV4 were higher than those in 2017/18 but were still lower than the expected AR rates listed in the IIV4 Summary of Product Characteristics. In conclusion, the 2018/19 EPSS showed no clinically significant change from the expected safety profiles of IIV3 and IIV4 vaccines.

Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: a retrospective, population-based study.

BACKGROUND: Data on the epidemiology and cost of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in Italy are limited. This retrospective, population-based study was designed to determine the incidence of HZ and the proportion developing PHN in Italy and the associated medical resource utilisation and costs. It focused primarily on immunocompetent patients aged > or = 50 years who would be eligible for preventive vaccination. METHOD: Data were extracted from a primary-care database and national hospital-discharge records covering four major regions in Italy for 2003-2005. Cases of HZ and PHN (1 and 3 months' duration; PHN1 and PHN3) were identified by ICD9-CM codes and, additionally for PHN, prescription of neuropathic pain medication. RESULTS: Over 3 years, 5675 incident cases of HZ were documented in adults, of which 3620 occurred in immunocompetent patients aged > or = 50 years (incidence of 6.31 per 1000 person-years [95% CI: 6.01-6.62]). Of the immunocompetent patients aged > or = 50 years with HZ, 9.4% (95% CI: 8.2-10.7) and 7.2% (95% CI: 6.2-8.2) developed PHN1 and PHN3, respectively. Increasing age, female sex, and being immunologically compromised conferred increased risk for both HZ and PHN. Overall, about 1.3% of HZ and almost 2% of PHN cases required inpatient care, with 16.9% of all HZ-related hospitalisations due specifically to PHN. In patients aged > or = 50 years, mean stay was 7.8 +/- 5.4 days for HZ and 10.2 +/- 8.6 days for PHN, and direct costs associated with inpatient care were more than 20 times outpatient costs per HZ case (mean +/- SD: euro2592 +/- euro1313 vs. euro122.68 +/- euro97.51) and over 5 times more per episode of PHN (mean +/- SD: euro2806 +/- euro2641 vs. euro446.10 +/- euro442.97). Total annual costs were euro41.2 million, of which euro28.2 million were direct costs and euro13.0 million indirect costs. CONCLUSIONS: This study, the largest to date on the epidemiology and economic impact of HZ and PHN in Italy, confirms the considerable disease and economic burden posed by HZ. As HZ and PHN disproportionately affect the elderly, without intervention this problem is likely to grow as the proportion of elderly in the Italian population continues to increase.

Dissection of the HLA-DR4 peptide repertoire in endocrine epithelial cells: strong influence of invariant chain and HLA-DM expression on the nature of ligands.

Class II MHC (MHC II) expression is restricted to professional APCs and thymic epithelium but it also occurs in the epithelial cells of autoimmune organs which are the unique targets of the CD4 autoreactive T cells in endocrine autoimmune diseases. This specificity is presumably conditioned by an epithelium-specific peptide repertoire associated to MHC II at the cell surface. MHC II expression and function is dependent on the action of two main chaperones, invariant chain (Ii) and DM, whose expression is coregulated with MHC II. However, there is limited information about the in vivo expression levels of these molecules and uncoordinated expression has been demonstrated in class II-positive epithelial cells that may influence the MHC-associated peptide repertoires and the outcome of the autoimmune response. We have examined the pool of peptides associated to DR4 molecules expressed by a neuroendocrine epithelial cell and the consequences of Ii and DM coexpression. The RINm5F rat insulinoma cell line was transfected with HLA-DRB1*0401, Ii, and DM molecules in four different combinations: RIN-DR4, -DR4Ii, -DR4DM, and -DR4IiDM. The analysis of the peptide repertoire and the identification of the DR4 naturally processed ligands in each transfected cell were achieved by mass spectrometry. The results demonstrate that 1) the expression of Ii and DM affected the DR4 peptide repertoires by producing important variations in their content and in the origin of peptides; 2) these restrictions affected the stability and sequence of the peptides of each repertoire; and 3) Ii and DM had both independent and coordinate effects on these repertoires.

HLA-DR4 molecules in neuroendocrine epithelial cells associate to a heterogeneous repertoire of cytoplasmic and surface self peptides.

Expression of MHC class II genes by epithelial cells is induced in inflammatory conditions such as autoimmunity and organ transplantation. Class II ligands generated by the epithelial cell processing mechanisms are unknown, although some unique epitopes have been described in epithelial cells that B cells could not generate. Epithelial cells are the targets of autoreactive T cell responses in autoimmune diseases and of transplant rejection processes, which may involve recognition of cell type-specific epitopes. In the present report, we have compared the DR4-associated repertoire and the intracellular distribution of class II, invariant chain (Ii), and DM molecules between a human DR4-, Ii-, and DM-transfected rat neuroendocrine epithelial cell line and a homozygous DR4 (DRB1*0401) lymphoblastoid B cell line, by mass spectrometry sequencing techniques, and immunoelectron microscopy. The epithelial cells chosen for transfection, RINm5F, are rat insular cells widely used for human studies of autoimmune diabetes. The results revealed a remarkably heterogeneous pool of self protein-derived peptides from the cell surface and various intracellular compartments, including the cytosol and secretory vesicles in epithelial cells, compared with a very restricted homogeneous repertoire in lymphoblastoid B cell lines, where few epitopes from surface molecules were predominant. The generation of distinct DR4-associated peptide repertoires in these two cell types could be due to the effect of several factors including differences in subcellular location of Ii and DM molecules, differential DO expression, and cell type-specific mechanisms of class II ligand generation. This is specially relevant to processes involving epithelial T cell interactions such as organ-specific autoimmunity and transplant rejection.