Long-term safety follow-up of children from a randomized-controlled phase Ⅱb proof-of-concept efficacy study of the live,attenuated,tetravalent dengue vaccine (CYD-TDV) in Thailand

Objective:To investigate the long-term safety of a tetravalent dengue vaccine(CYD-TDV)in children in a phase Ⅱ b follow-up study in Thailand.Methods:In the phase Ⅱb study,children aged 4-11 years were randomized(2:1)to receive three injections of CYD-TDV or serve as control at 6-month intervals,with 25 months’ active follow-up(active phase).This study was an additional four-year passive surveillance for hospitalized virologically-confirmed dengue(VCD;hospital phase).Cases of hospitalized VCD,severe hospitalized VCD,vaccine-related serious adverse events,and deaths were reported for the total population,with post-hoc analyses by enrollment age(<9 and≥9 years).Results:Of 3 997 participants receiving≥1 injection,80.1% were recruited to the hospital phase[2 131(CYD-TDV);1 072(control)].Eighty-five hospitalized VCD cases were reported in the CYD-TDV group and 46 in the control group during the four-year hospital phase[relative risk(RR):0.93,95% confidence interval(Cl):0.64-1.36].The RR over six years of follow-up was 0.77(95% CI:0.57-1.05).In those aged≥9 years,the cumulative RRs in the active phase,hospital phase,and entire six years were 0.28(95% CI:0.08-0.81),0.51(95% CI:0.25-1.05),and 0.42(95% CI:0.24-0.75),respectively.In the overall population,there were ten severe hospitalized VCD cases in the CYD-TDV group and five in the control group over six years(RR:1.00,95% CI:0.31-3.75).Conclusions:Over six years of follow-up,in children aged ≥9 years,CYD-TDV administration is associated with a reduced risk of hospitalized VCD.

Concordance Between Laboratories Testing Clinical Samples and Its Impact on Vaccine Booster Thresholds

Concordance study between two laboratories testing clinical samples is important to a clinical program to assess the comparability of test results, especially when the two laboratories performed the same test at different locations. Assays that measure immune response should not be compared using the simple linear regression model; instead literature publications recommend an ＂errors-in-variables＂ model that accounts for the variability in these assays （Home, 1998）. In this paper, concordance slope and intercept was estimated using the statistical linear relationship （Tan and Iglewicz, 1999） for various tests between laboratories. The confidence bounds for the concordance line were used to assess the impact on vaccine booster thresholds when a consistent bias was observed between the results generated by two laboratories.

The Economic Burden of Head and Neck Cancers in Denmark

Introduction: The incidence of head and neck cancers has increased markedly over the last decade. A Danish study of the costs of head and neck cancers has not been undertaken. Such studies have again become relevant due to the development of the HPV vaccines, as some cases are attributable to high-risk HPV 16 or 18. The objective of study was to estimate the incidence of head and neck cancers and their health care costs. Methods: Data on incidence and health care use related to head and neck cancer were obtained from Danish health care registers. New cancer patients were identified in the Danish National Cancer Register. Resource use per year in the hospital sector was estimated using data from the National Patient Register applying charges as cost estimates. Health care consumption by cancer patients was compared with that by an age- and sex-matched cohort without cancer. Results: We found that nearly 1000 new cases of oral cavity, oropharyngeal, hypopharyngeal and laryngeal cancer are diagnosed annually. In total the cost of these cancers to the Danish hospital sector constituted 31.6 million Euros per year, with the majority of costs (74%) occurring in men. The total costs associated with HPV16/18-related head and neck cancers were estimated to be 6.1 million Euros per year. Conclusion: This study provides the first Danish estimates of the costs associated with non-cervical and non-genital HPV-related cancers based on very reliable, individual-based data. It is expected that the current HPV vaccination programme will reduce this burden.

Evaluating Potential Vaccine Antigens in both the <i>Chlamydia trachomatis</i>and <i>Chlamydia muridarum</i>Intravaginal Mouse Challenge Models

Identifying relevant animal challenge models adds to the complexity of human vaccine development. Murine challenge models have been the most utilized animal model for Chlamydia trachomatis vaccine development. The question arises as to whether the C. trachomatis or C. muridarum pre-clinical model is optimal. We compared C. muridarum and C. trachomatis intravaginal challenge models in a combined total of seventy-five studies evaluating potential vaccine candidates. In 100% (42/42) of C. muridarum studies, mice immunized with Chlamydia elementary bodies (EB) demonstrated a significant reduction in urogenital bacterial shedding as measured by qPCR (p C. trachomatis studies. We have evaluated proposed vaccine antigens in both models and observed immunization with Chlamydia major outer membrane protein (MOMP) vaccine formulations to be protective (p C. trachomatis model, and immunization with PmpD p82 translocator domain was not protective in either model. We also observed in both models that depletion of CD4+ T-cells in MOMP-immunized mice resulted in diminished protective immunity but animals were still able to reduce the infection level. In contrast, mice immunized with live EBs by intraperitoneal route did not require CD4+ T-cells to resolve urogenital infection from intravaginal challenge in either model. Overall, we have found the C. muridarum model to be a more robust, reliable, and reproducible model for vaccine antigen discovery.

Evaluation of previous product residue on magnetic bar used for manufacturing of Japanese Encephalitis vaccine

Cleaning validation is one of recommendation from Pharmaceutical Inspection Co-operation Scheme(PIC/S)to avoid contamination of pharmaceutical products.The objective of cleaning validation is to confirm reliability of cleaning procedure for removal of contaminants associated with previous products,residues of cleaning agents and potential microbial contaminants(1)Japanese Encephalitis vaccine is a new product that is prequalified by World Health Organization(WHO)and manufactured at GPO-MBP.

Clinical development update: 1st dengue vaccine candidate

A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in the Asia-Pacific and Latin American countries.We report the results of long-term follow-up interim analyses and integrated efficacy analyses.We are assessing the incidence of hospitalization for virologically confirmed dengues a surrogate safety end point during follow-up in years 3–6 of two phase 3 trials,CYD14 and CYD15,and a phase 2b trial,CYD23/57.We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15.

The Burden of Hospitalisations for Herpes Zoster Ophtalmicus in Spain (1997-2008)

Purpose: This epidemiological retrospective survey aims to provide population-based estimates of the burden of hospitalisation for herpes zoster ophthalmicus in Spain during a twelve-year period (1997-2008). Methods: All hospital discharges and deaths related to herpes zoster ophthalmicus in patients older than 30 years old from 1997 to 2008 in Spain were obtained. Differences in proportions were assessed by the Chi-square test. ANOVA was used for multiple comparisons. Poisson regression was used to assess differences in the rates. Results: A total of 3029 hospital discharges in patients older than 30 years old were coded as herpes zoster ophthalmicus. Of those, 1009 were coded as primary cause of hospitalization. This corresponds to a hospitalization rate of 0.94 and 0.31 hospitalizations per 100,000 for any position and first diagnostic position, respectively. The 75% of the total discharges were in immunocompetent patients. The herpes zoster ophthalmicus hospitalization rate increased significantly during the study period. This increase was also observed for immunocompetent patients. A total of 127 and 21 deaths occurred in patients ≥ 30 year-old hospitalized with herpes zoster ophthalmicus in any diagnostic position and principal diagnostic code, respectively during the 12-year study period. Of them, 70 (53.4%) were in immunocompetent patients, and, of those 11 were in patients with HZO in the first diagnosis position. The hospitalization rate and case-fatality rate increase significantly with age from 50 years old onwards. Conclusion: HZO, a vaccine preventable disease, still causes hospitalization and death in adults in Spain.

Adoption costs of new vaccines-A Stackelberg dynamic game with risk-perception transition states

Vaccination has become an integral part of public health,since an increase in overall vaccination in a given population contributes to a decline in infectious diseases and mortality.Vaccination also contributes to a lower rate of infection even for nonvaccinators due to herd immunity((Brisson and Edmunds,2002)).In this work we model human decision-making(with respect to a vaccination program in a single-payer health care provider country)using a leader-follower game framework.We then extend our model to a discrete dynamic game,where time passing is modelled by risk perception changes among population groups considering whether or not to vaccinate.The risk perception changes are encapsulated by probability transition matrices.We assume that the singlepayer provider has a given fixed budget which would not be sufficient to cover 100%of a new vaccine for the entire population.To increase the potential coverage,we propose the introduction of a partial vaccine adoption policy,whereby an individual would pay a portion of the vaccine price and the single payer would support the rest for the entire population.We show how this policy,together with changes in risk perceptions regarding vaccination,impact the strategic decisions of individuals in each group,the policy cost under budgetary constraints and,ultimately,how it impacts the overall uptake of the vaccine in the entire population.

Large-scale frequent testing and tracing to supplement control of Covid-19 and vaccination rollout constrained by supply

Non-pharmaceutical interventions(NPI)were implemented all around the world in the fight against COVID-19:Social distancing,shelter-in-place,mask wearing,etc.to mitigate transmission,together with testing and contact-tracing to identify,isolate and treat the infected.The majority of countries have relied on the former measures,followed by a ramping up of their testing and tracing capabilities.We present here the cases of South Korea,Italy,Canada and the United States,as a look back to lessons that can be drawn for controlling the pandemic,specifically through the means of testing and tracing.By fitting a disease transmission model to daily case report data in each of the four countries,we first show that their combination of social-distancing and testing/tracing have had a significant impact on the evolution of their first wave of pandemic curves.We then consider the hypothetical scenario where the only NPI measures implemented past the first pandemic wave consisted of isolating individuals due to repeated,country-scale testing and contact tracing,as a mean of lifting social distancing measures without a resurgence of COVID-19.We give estimates on the average isolation rates needed to occur in each country.We find that testing and tracing each individual of a country,on average,every 4.5 days(South Korea),5.7 days(Canada),6 days(Italy)and 3.5 days(US),would have been sufficient to mitigate their second pandemic waves.We also considered the situation in Canada to see how a frequent large-scale asymptomatic testing and contact tracing could have been used in combination with vaccination rollout to reduce the infection in the population.This could offer an alternative approach towards preventing and controlling an outbreak when vaccine supply is limited,while testing capacity has been increasingly enhanced.

脊髓灰质炎病毒灭活疫苗：全球消灭脊髓灰质炎的必然选择

在人类抗击脊髓灰质炎的斗争中，脊髓灰质炎病毒灭活疫苗（IPV）是最早使用的疫苗。虽然在20世纪60年代和70年代被口服脊髓灰质炎减毒活疫苗（OPV）取代，但随着人们认识到继续使用OPV存在的风险，IPV的使用成为必然。继Jonas Salk对IPV开展的先驱性工作并建立了该疫苗的关键原则之后，用灭活野毒株研制的现代型含Salk IPV疫苗多年来已经在许多国家常规应用，并且积累了相当多的使用经验。接种IPV可以使机体产生循环抗体，该抗体可以阻止病毒的感染，进而对麻痹产生非常好的保护作用。暴露于脊髓灰质炎病毒野毒株或疫苗株（OPV）可以产生黏膜抗体和细胞免疫，使机体获得不同程度对抗黏膜感染（以及因此导致的传播）的保护能力。因此使用IPV续接OPV的序贯免疫程序具有既能消除疫苗相关性麻痹型脊髓灰质炎（VAPP）的风险，又能限制疫苗衍生株脊髓灰质炎病毒（VDPV）风险的优势。Sabin IPV作为刚上市的新疫苗，已经开始产生数据以证明其性能。IPV将在全球消灭脊髓灰质炎中发挥无可替代的作用。