Interchangeability of two Enterovirus 71 inactivated vaccines in Chinese children: A phase IV,open-label,and randomized controlled trial

BackgroundIn China, three inactivated Enterovirus 71 (EV71) vaccines have been approved. Although the vaccines in an immunization series should be from a single manufacture, children sometimes have to receive EV71 vaccines from more than one manufacturers. The aim of this study was to evaluate the interchangeability and safety of vaccination with EV71 vaccines from two manufacturers among Chinese children.MethodsWe conducted an open label and randomized controlled study among children aged 6–35 months from November 2018 to January 2019. The participants were randomly assigned (1:1:1:1) to receive EV71 vaccines in one of the four different schedules (two using a single vaccine for all doses from one manufacture, and two mixed schedules using vaccines from two manufactures). Blood samples were collected pre-vaccination (Day 0) and one month after the second dose (Day 60) for neutralizing antibody assay. Immunogenicity was assessed in the per-protocol cohort and safety was assessed in the total vaccinated cohort.ResultsA total of 300 children were enrolled and randomized, of whom 89.0% (267/300) were included in the per-protocol cohort for immunogenicity analysis. The seroconversion rates of the EV71 neutralizing antibody in four groups ranged from 98.4% to 100.0%, and were not significantly different among the groups. Compared with other groups, geometric mean titer was higher in group D, in which the participants received Institute of Medical Biology Chinese Academy of Medical Sciences (CAMS) vaccine in the first dose and the Sinovac vaccine in the second dose. Safety profiles were similar among the four groups and no serious adverse events related to the vaccination were reported.ConclusionsInterchangeability of EV71 vaccines from two manufactures to complete an immunization series showed good immunogenicity and safety. The antibody response levels may vary by vaccination sequences of EV71 vaccines from the two manufacturers.Trial registration: ClinicalTrials.govNCT03873740.     

MMV020275 and MMV020490, promising compounds from malaria box for the treatment of equine piroplasmosis

Equine piroplasmosis is a tick-transmitted disease that is considered one of the most serious infectious diseases affecting equines. Searching for novel antipiroplasm drugs remains indispensable due to the emergence and spreading of resistant piroplasm parasites against the limited currently used drugs, diminazene aceturate and imidocarb dipropionate. Therefore, novel drugs with specified targets need to be identified and exploited. The inhibitory effects of Medicines for Malaria Venture (MMV) Malaria Box compounds with potent in vitro anti-equine piroplasmosis activity were evaluated against the growth of B. microti in mice in this study. Using a nested PCR assay targeting the B. microti ss-rRNA gene, we investigated the far-reaching impacts of effective combinations to inhibit parasite recrudescence. Using real-time PCR, this study revealed potential targets for the found potent compounds. When used as monotherapy, screening the Malaria Box against the in vivo growth of the B. microti parasite resulted in the discovery of new, potent antipiroplasm medicines, such as MMV020275 and MMV020490. In MMV020275-treated Theileria equi in vitro culture, a statistically significant difference (P<0.05) in the cGMP-dependent protein kinase (PKG) mRNA level was identified as a down-regulation in contrast to non-treated cultures. In conclusion, new potent antipiroplasm drugs, including MMV020275 and MMV020490 are identified. MMV020275 significantly down-regulate the mRNA levels of the PKG gene. Clofazimine enhanced the inhibitory efficacy of MMV compounds which is suggested to use in treatment of animal or human babesiosis in the future.     

Access and Unmet Needs of Orphan Drugs in 194 Countries and 6 Areas: A Global Policy Review With Content Analysis

ObjectivesThree hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs.MethodsPharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis.ResultsOne hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001).ConclusionsGlobally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.     

Choosing between 7-, 10- and 13-valent pneumococcal conjugate vaccines in childhood: A review of economic evaluations (2006–2014)

BackgroundSeven-valent pneumococcal conjugate vaccines (PCV7) have been used in children for more than a decade. Given the observed increase in disease caused by pneumococcal serotypes not covered by PCV7, an increasing number of countries are switching from 7-valent to 10- and 13-valent PCVs (“PCV10” and “PCV13”). Economic evaluations are important tools to inform decisions and price negotiations to make such a switch.ObjectiveThis review aims to provide a critical assessment of economic evaluations involving PCV10 or PCV13, published since 2006.MethodsWe searched Scopus, ISI Web of Science (SCI and SSCI) and Pubmed to retrieve, select and review relevant studies, which were archived between 1st January 2006 and 31st January 2014. The review protocol involved standard extraction of assumptions, methods, results and sponsorships from the original studies.ResultsSixty-three economic evaluations on PCVs published since January 2006 were identified. About half of these evaluated PCV10 and/or PCV13, the subject of this review. At current prices, both PCV13 and PCV10 were likely judged preferable to PCV7. However, the combined uncertainty related to price differences, burden of disease, vaccine effectiveness, herd and serotype replacement effects determine the preference base for either PCV10 or PCV13. The pivotal assumptions and results of these analyses also depended on which manufacturer sponsored the study.ConclusionA more thorough exploration of uncertainty should be made in future analyses on this subject, as we lack understanding to adequately model herd and serotype replacement effects to reliably predict the population impact of PCVs. The introduction of further improved PCVs in an environment of evolving antibiotic resistance and under the continuing influence of previous PCVs implies that the complexity and data requirements for relevant analyses will further increase. Decision makers using these analyses should not just rely on an analysis from a single manufacturer.     

靶向寄生虫的核酸适配体应用研究进展

核酸适配体是人工合成的单链DNA或RNA寡核苷酸,经指数富集的配体系统进化技术体外筛选获得。核酸适配体可与病毒、细菌、寄生虫等生物体的蛋白质与其他小分子靶标进行高亲和力和特异性结合。与抗体相比,核酸适配体具有无免疫原性、制备简单、易于批量生产、便于修饰、性能稳定、价格低廉等优点,在疾病诊断和治疗领域具有重要的应用潜力。本文综述了靶向疟原虫、锥虫、利什曼原虫等寄生虫的核酸适配体的研究进展,以期为寄生虫感染的检测和防治提供新策略。     

Immune response to rabies post-exposure prophylaxis in patients with non-HIV secondary immunodeficiencies

BackgroundThis study sought to determine the proportion of individuals with non-HIV secondary immunodeficiencies presenting inadequate antibody titers after rabies post-exposure prophylaxis (PEP) and to identify variables associated with inadequate response.MethodsA retrospective review of the records of immunocompromised patients having received a full course of PEP after a rabies exposure and having been tested for post-PPE antibody titers in two French Antirabies Clinics, between 2013 and 2018, was conducted. Antibody titers < 0.5 EU/ml (ELISA) were classified as inadequate.ResultsA total of 28 individuals were included, 6 had inadequate post-PPE titers. None of the tested variable was independently associated with inadequate titers.ConclusionsInadequate response was unpredictable and not explained either by the characteristics of patients or by the PEP regimen they received. These findings support the WHO recommendation to systematically assess post-PEP response in immunocompromised patients to detect non-responders, who might require an additional dose.     

Social and behavioral determinants of attitudes towards and practices of hepatitis B vaccine birth dose in Vietnam

BackgroundHepatitis B virus (HBV) infection is a significant public health issue in Vietnam. Our goal was to understand the determinants of attitudes towards and practices of hepatitis B vaccine birth dose (HepB-BD) in certain regions of Vietnam.MethodA rapid qualitative assessment was conducted in three geographically diverse provinces that reported low coverage (<50%) of HepB-BD. Using purposive sampling of participants, 29 focus group discussions and 20 in-depth interviews were held with caregivers (n = 96), healthcare providers (n = 75), and healthcare administrators (n = 16). Summary notes from these were translated, and inductive coding was used to derive themes. The SAGE Vaccine Hesitancy Determinants Matrix was used as a theoretical framework to organize barriers and facilitators associated with the themes into three levels of influence.ResultsAt the individual and group level, caregivers who had higher levels of knowledge about HepB-BD sought the vaccine proactively, while others with lower knowledge faced barriers to the vaccine. Some caregivers reported a negative attitude toward health services because of a language barrier or had generalized concerns about HepB-BD due to media reporting of the past adverse events. Distress arising from potential adverse events was equally common among healthcare providers. At the contextual level, the physical environment made it difficult for caregivers to access healthcare facilities and for providers to conduct outreach. Home births posed a challenge for timely administration of HepB-BD, while health facility births facilitated it. Vaccination-specific barriers included misinterpretation of pre-vaccination screening criteria and asking for the consent of caregivers. Inadequate resources for service delivery negatively influenced HepB-BD attitudes and practices.ConclusionGiven the diversity of barriers associated with attitudes towards and practices of HepB-BD in the three provinces, tailored interventions will be necessary for both demand- and supply-side factors. Rural areas, often with more home births and geographic barriers, may require focused attention.     

Impact of pneumococcal conjugate vaccine on pneumonia hospitalization and mortality in children and elderly in Ecuador: Time series analyses

BackgroundPneumococcal conjugate vaccines (PCV) reduce the burden of invasive pneumococcal disease and pneumonia hospitalizations. However, there is limited evidence of the effect of PCVs on pneumonia mortality in children. It is anticipated that indirect effects resulting from PCV use among children might further reduce the remaining burden of adult pneumococcal disease caused by pneumococcal serotypes contained in PCV. Whether this will result in reduced pneumonia mortality in children and adults is still not known.MethodsWe investigated the impact of PCV on pneumonia hospitalization and mortality in in Ecuador, where PCV was introduced in 2010, considering national data from secondary data sources from 2005 to 2015. Time series analysis using regression models were used to evaluate the decline in the number of all-cause pneumonia hospitalizations and deaths in the period post-PCV introduction. The target populations were children under 5 years and adults aged 50 years and over. Outcomes of interest were hospitalizations and mortality in which the main cause of hospital admission and death, respectively, were coded as ICD10 codes J12-18 (pneumonia). Three different models were fitted.ResultsWe demonstrate a sizeable impact of PCV in pneumonia hospitalization in children < 1 year (27% reduction, 95%CI 12–42%), and < 5 years of age (33% reduction, 95%CI 11–43%). The estimated impact of PCV in pneumonia mortality was a reduction of 14% in < 1 year (95%CI 0–33%), 10% in < 5 years (95%CI 0–25%), and 22% (95%CI 7–34%) in adults aged 50–64 years. Little evidence of a change was detected in elderly ≥ 65 years.ConclusionThis study is the first to report on the impact of PCV in pneumonia morbidity and mortality in children and older adults, being relevant to policy makers and global donors. Findings were consistent when using different models. Additional studies on the indirect effect of PCV in older adults are needed.