A review of the changes to the licensing of influenza vaccines in Europe

In 2014, the European Committee for Medicinal Products for Human Use (CHMP) published a draft regulatory guideline for the evaluation of influenza vaccines. Following a public consultation round, the final guidance will be published in the near future. Here, we highlight the main changes in the clinical section in this guideline and discuss the background to these changes and whether the new consolidated guidance document can be expected to achieve a better understanding of the performance of seasonal, zoonotic and pandemic influenza vaccines during the regulatory licensing process. The new influenza guideline reflects a changed approach to the regulatory assessment of influenza vaccines, resulting in the abolition of serological criteria, known as the CHMP criteria, which have been the mainstay for evaluating the influenza vaccine immunogenicity for several decades. The new guideline adopts a more diversified approach to the measurement and reporting of the immune response to influenza vaccines and sets a requirement to conduct clinical outcome trials in young children. Importantly, more emphasis is placed on the post-licensure monitoring of the benefit risk of influenza vaccines, including a request for continuous monitoring of efficacy and enhanced safety surveillance. Despite the improvements these new requirements will expectedly bring to the regulatory assessment of influenza vaccines, major challenges remain which cannot be overcome by new guidance alone. Ongoing initiatives in which academia, manufacturers, public health institutes and regulators work together to address these challenges are central to the development of robust tools to evaluate and monitor performance of influenza vaccines in the future

Influenza Vaccination in Community Dwelling Elderly Persons

An influenza epidemic was first described in 1173, although there are reports of influenza as early as 412 BC. Recurrent epidemics and incidental pandemics caused by influenza virus are documented since the last 400 years. These were based upon clinical observation and epidemiology. Although a virus was suspected to be the cause of influenza infections, it was not until 1933 that influenza viruses were first isolated during an influenza epidemic in London. Only recently the virus causing the 1914-1918 pandemic (“Spanish flu”) was isolated from conserved lung tissue of an American soldier. The first influenza vaccine was licensed in 1945

Effectiveness of MF59™ Adjuvanted Influenza A(H1N1)pdm09 Vaccine in Risk Groups in the Netherlands

Background:The aim of the present study was to estimate the effectiveness of the MF59™-adjuvanted influenza A(H1N1)pdm09 vaccine against medically attended influenza-like illness and RT-PCR confirmed influenza in the at-risk population and persons over 60 in the Netherlands.Methods:We conducted a retrospective cohort study in a Dutch based GP medical record database between 30 November 2009 and 1 March 2010 to estimate the vaccine effectiveness against influenza-like illness. Within the cohort we nested a test negative case-control study to estimate the effectiveness against laboratory confirmed influenza.Results:The crude effectiveness in preventing diagnosed or possible influenza-like illness was 17.3% (95%CI: -8.5%-36.9%). Of the measured covariates, age, the severity of disease and health seeking behaviour through devised proxies confounded the association between vaccination and influenza-like illness. The adjusted vaccine effectiveness was 20.8% (95%CI: -5.4%, 40.5%) and varied significantly by age, being highest in adults up to 50 years (59%, 95%CI: 23%, 78%), and non-detectable in adults over 50 years. The number of cases in the nested case control study was too limited to validly estimate the VE against confirmed influenza.Conclusions:With our study we demonstrated that the approach of combining a cohort study in a primary health care database with field sampling is a feasible and useful option to monitor VE of influenza vaccines in the future

Performance of Zika Assays in the Context of Toxoplasma gondii, Parvovirus B19, Rubella Virus, and Cytomegalovirus (TORCH) Diagnostic Assays.

Infections during pregnancy that may cause congenital abnormalities have been recognized for decades, but their diagnosis is challenging. This was again illustrated with the emergence of Zika virus (ZIKV), highlighting the inherent difficulties in estimating the extent of pre- and postnatal ZIKV complications because of the difficulties in establishing definitive diagnoses. We reviewed the epidemiology, infection kinetics, and diagnostic methods used for Toxoplasma gondii, parvovirus B19, rubella virus, and cytomegalovirus (TORCH) infections and compared the results with current knowledge of ZIKV diagnostic assays to provide a basis for the inclusion of ZIKV in the TORCH complex evaluations. Similarities between TORCH pathogens and ZIKV support inclusion of ZIKV as an emerging TORCH infection. Our review evaluates the diagnostic performance of various TORCH diagnostic assays for maternal screening, fetal screening, and neonatal screening. We show that the sensitivity, specificity, and positive and negative predictive value of TORCH complex pathogens are widely variable, stressing the importance of confirmatory testing and the need for novel techniques for earlier and accurate diagnosis of maternal and congenital infections. In this context it is also important to acknowledge different needs and access to care for different geographic and resource settings

Case of seasonal reassortant A(H1N2) influenza virus infection, the Netherlands, March 2018.

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases

Case of seasonal reassortant a(H1N2) influenza virus infection, the Netherlands, March 2018

A seasonal reassortant A(H1N2) influenza virus harbouring genome segments from seasonal influenza viruses A(H1N1)pdm09 (HA and NS) and A(H3N2) (PB2, PB1, PA, NP, NA and M) was identified in March 2018 in a 19-months-old patient with influenza-like illness (ILI) who presented to a general practitioner participating in the routine sentinel surveillance of ILI in the Netherlands. The patient recovered fully. Further epidemiological and virological investigation did not reveal additional cases

Risk factors of vitamin B12 deficiency in patients receiving metformin

Background Identification of risk factors for metformin-related vitamin B12 deficiency has major potential implications regarding the management of diabetes mellitus. Methods We conducted a nested case-control study from a database in which the source population consisted of subjects who had levels of both serum vitamin B12 and hemoglobin A1c checked in a central laboratory. We identified 155 cases of diabetes mellitus and vitamin B12 deficiency secondary to metformin treatment. Another 310 controls were selected from the cohort who did not have vitamin B12 deficiency while taking metformin. Results A total of 155 patients with metformin-related vitamin B12 deficiency (mean \ub1 SD serum vitamin B12 concentration, 148.6 \ub1 40.4 pg/mL [110 \ub1 30 pmol/L]) were compared with 310 matched controls (466.1 \ub1 330.4 pg/mL [344 \ub1 244 pmol/L]). After adjusting for confounders, we found clinically important and statistically significant association of vitamin B12 deficiency with dose and duration of metformin use. Each 1-g/d metformin dose increment conferred an odds ratio of 2.88 (95% confidence interval, 2.15-3.87) for developing vitamin B12 deficiency (P<.001). Among those using metformin for 3 years or more, the adjusted odds ratio was 2.39 (95% confidence interval, 1.46-3.91) (P =3D .001) compared with those receiving metformin for less than 3 years. After exclusion of 113 subjects with borderline vitamin B12 concentration, dose of metformin remained the strongest independent predictor of vitamin B12 deficiency. Conclusions Our results indicate an increased risk of vitamin B12 deficiency associated with current dose and duration of metformin use despite adjustment for many potential confounders. The risk factors identified have implications for planning screening or prevention strategies in metformin-treated patients

Annual influenza vaccination in community-dwelling elderly individuals and the risk of lower respiratory tract infections or pneumonia

Background Influenza vaccination has been associated with a reduction in the number of hospitalizations for respiratory conditions in elderly persons over the period from 1996 to 2002. Little is known, however, about the effect of influenza vaccination on the whole range of severity of respiratory tract infections. Methods We investigated the effect of annual influenza vaccination on the occurrence of lower respiratory tract infections (LRTIs) in community-dwelling elderly individuals. From 1996 to 2002, we performed a population-based cohort study, using the computerized Integrated Primary Care Information database in the Netherlands, of community-dwelling subjects who were 65 years or older on January 1 of the year of study entry. For each year, the individual cumulative exposure to influenza vaccination since study entry was computed. We compared the risk of LRTI after a first vaccination or revaccination with the risk for no vaccination using a time-varying multivariate Cox proportional hazard model, adjusted for age, sex, smoking, and underlying disease. Results In the study population of 26 071 subjects, 3412 developed LRTIs during follow-up. During the influenza epidemic periods, a first vaccination did not reduce risk for LRTI. In the total population, the hazard ratio following a first vaccination was 0.86 (95% confidence interval [CI], 0.71 to 1.05); in the population without or with comorbidity, these ratios were 0.90 (95% CI, 0.56 to 1.45) and 0.83 (95% CI, 0.66 to 1.04), respectively. During epidemic periods, revaccination reduced risk of LRTI by 33% (95% CI, 8% to 52%) in individuals without comorbidity. In individuals with comorbidity, the risk reduction of 5% was nonsignificant (95% CI, \u9610% to 18%). Conclusion In this study, annual influenza revaccination was associated with a reduction in LRTI in community-dwelling elderly individuals

Effectiveness of MF59™ adjuvanted influenza A(H1N1)pdm09 vaccine in risk groups in the Netherlands.

BACKGROUND: The aim of the present study was to estimate the effectiveness of the MF59™-adjuvanted influenza A(H1N1)pdm09 vaccine against medically attended influenza-like illness and RT-PCR confirmed influenza in the at-risk population and persons over 60 in the Netherlands. METHODS: We conducted a retrospective cohort study in a Dutch based GP medical record database between 30 November 2009 and 1 March 2010 to estimate the vaccine effectiveness against influenza-like illness. Within the cohort we nested a test negative case-control study to estimate the effectiveness against laboratory confirmed influenza. RESULTS: The crude effectiveness in preventing diagnosed or possible influenza-like illness was 17.3% (95%CI: -8.5%-36.9%). Of the measured covariates, age, the severity of disease and health seeking behaviour through devised proxies confounded the association between vaccination and influenza-like illness. The adjusted vaccine effectiveness was 20.8% (95%CI: -5.4%, 40.5%) and varied significantly by age, being highest in adults up to 50 years (59%, 95%CI: 23%, 78%), and non-detectable in adults over 50 years. The number of cases in the nested case control study was too limited to validly estimate the VE against confirmed influenza. CONCLUSIONS: With our study we demonstrated that the approach of combining a cohort study in a primary health care database with field sampling is a feasible and useful option to monitor VE of influenza vaccines in the future