Predictive markers of safety and immunogenicity of adjuvanted vaccines

Vaccination represents one of the greatest public health triumphs; in part due to the effect of adjuvants that have been included in vaccine preparations to boost the immune responses through different mechanisms. Although a variety of novel adjuvants have been under development, only a limited number have been approved by regulatory authorities for human vaccines. This report reflects the conclusions of a group of scientists from academia, regulatory agencies and industry who attended a conference on the current state of the art in the adjuvant field. Held at the U.S. Pharmacopeial Convention (USP) in Rockville, Maryland, USA, from 18 to 19 April 2013 and organized by the International Association for Biologicals (IABS), the conference focused particularly on the future development of effective adjuvants and adjuvanted vaccines and on overcoming major hurdles, such as safety and immunogenicity assessment, as well as regulatory scrutiny. More information on the conference output can be found on the IABS website, http://www.iabs.org/.     

Economic migrants and the labour market in Spain and Portugal

Within the last fifteen years Spain and Portugal have begun to experience a phenomenon that occurred in northern Europe three or four decades earlier. Rising prosperity, an ageing population, and growing labour shortages have triggered a demand for foreign labour in the Iberian economies. This survey article identifies the changing trends and developments of recent immigration to two southern European countries, and the problems of labour market integration. It compares and contrasts the insertion process in Spain and Portugal and highlights the policy dilemma that, like most of the rest of the EU, the Iberian economies require immigrant workers, but have yet to develop effective mechanisms for integrating them. It argues that the labour market is not only the principal mechanism by which immigrants are integrated, but is beginning to transform attitudes towards immigration. Employer organizations have played a lead role in pressing for a shift from restriction and control to the management of immigrant integration. However, the needs of employers, who require a supply of cheap, flexible labour clashes with the government's exclusion policy, as the case study based on Lorca, Spain demonstrates.     

A DNA vaccine against cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) prevents tumor growth

Co-stimulatory signaling pathway triggered by the binding of B7.1/B7.2 (CD80/86) of antigen-presenting cells (APCs) to CD28 of T cells is required for optimal T-cell activation. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is a negative regulator of T cell activation, which competes with CD28 for B7.1/B7.2 binding with a greater affinity. Ipilimumab, a monoclonal antibody against CTLA-4, has shown positive efficacy in a pivotal clinical trial for the treatment of metastatic melanoma and was approved by FDA. However, the cost of monoclonal antibody-based therapeutics might limit the number of patients treated. To develop a novel therapeutics specifically targeting CTLA-4, we constructed a DNA vaccine by cloning the sequence of CTLA-4 fused with a transmembrane domain sequence of placental alkaline phosphatase (PLAP) into a mammalian expression plasmid, pVAC-1. Immunization with the resulting construct, pVAC-1-hCTLA-4, elicited antibody specific to human CTLA-4 with cross reactivity to murine CTLA-4, which was sufficient for inhibiting B16F10 tumor growth in c57BL/6 mice in the absence of measurable toxicity. Coupling liposome with pVAC-1-mCTLA-4 could break tolerance to self-antigen in BALB/c mice and induce potent immunity against murine CTLA-4, and suppress growth of subcutaneous renal cell carcinoma (Renca).     

Immunisation against a serine protease inhibitor reduces intensity of Plasmodium berghei infection in mosquitoes

The mosquito innate immune response is able to clear the majority of Plasmodium parasites. This immune clearance is controlled by a number of regulatory molecules including serine protease inhibitors (serpins). To determine whether such molecules could represent a novel target for a malaria transmission-blocking vaccine, we vaccinated mice with Anopheles gambiae serpin-2. Antibodies against Anopheles gambiae serpin-2 significantly reduced the infection of a heterologous Anopheles species (Anopheles stephensi) by Plasmodium berghei, however this effect was not observed with Plasmodium falciparum. Therefore, this approach of targeting regulatory molecules of the mosquito immune system may represent a novel approach to transmission-blocking malaria vaccines.     

2016—2018年辽源市0～6岁儿童疑似预防接种异常反应监测分析

目的分析辽源市2016-2018年0~6岁人群疑似预防接种异常反应(adverse events following immunization, AEFI)的发生特征,评价AEFI监测信息管理系统运转情况。方法通过中国免疫规划信息管理系统收集辽源市2016-2018年报告的0~6岁人群AEFI个案数据,采用描述性流行病学方法进行分析。结果 2016-2018年辽源市共报告306例0~6岁人群AEFI个案,一般反应占97.06%,异常反应占1.96%,AEFI报告发生率为62.73/10万剂次;年度AEFI发生率差异有统计学差异(χ2=27.09,P<0.05),月平均报告例数显示,3月、7月和10月是AEFI发生率报告例数的3个高峰;不同地区间AEFI发生率差异有统计学差异(χ2=16.89,P<0.05),以东丰县最高;男女差异无统计学意义(χ2=0.003,P>0.05),各年龄组差异有统计学意义(χ2=226.07,P<0.05),年龄分布主要分布于2岁以下;疫苗分布以吸附无细胞百白破疫苗发生率(148.90/10万剂次)最高;转归情况除2例正在治疗中外,其余均已痊愈;2017年应调查的AEFI报告后48 h内调查率未达标,其余指标均达到方案要求。结论辽源市AEFI监测系统运转良好,监测水平正在逐步提高;国家计划和非计划免疫疫苗的安全性良好。     

Monophosphoryl lipid A analogues with varying 3-O-substitution: synthesis and potent adjuvant activity

Structurally defined immunostimulatory adjuvants play important roles in the development of new generation vaccines. Here described are the syntheses of three monophosphoryl lipid A analogues (1-3) with different substitution at 3-O-position of the reducing sugar and their potent immunostimulatory adjuvant activity. The syntheses involve the preparation of glycosylation acceptors benzyl 3,4-di-O-benzyl-2-deoxy-2-[(R)-3-tetradecanoyloxytetradecanamido]-beta-D-glucopyranoside (16) and benzyl 3-O-allyl-4-O-benzyl-2-deoxy-2-[(R)-3-tetradecanoyloxytetradecanamido]-beta-D-glucopyranoside (17). The glycosylation reactions between the donor 4,6-di-O-benzylidene-2-deoxy-2-(2',2',2'-trichloroethoxycarbonylamino)-alpha-d-glucopyranosyl trichloroacetimidate (21) and acceptors 16 and 17 provide the desired beta-(1-->6)-linked disaccharides 22 and 23, respectively. Selective reductive ring opening of the 4,6-di-O-benzylidene group, installation of a phosphate group to the 4'-hydroxyl group, and the final global debenzylation produce the designed monophosphoryl lipid A analogues 1-3. All three synthetic analogues induce antigen specific T-cell proliferation and interferon-gamma (IFN-gamma) production in ex vivo experiments with a totally synthetic liposomal vaccine system. The immunostimulatory potency of compound 1-3 is in the same order of magnitude as that of the detoxified natural lipid A product isolated from Salmonella minnesota R595 (R595 lipid A). The substituent at the 3-O-position of the reducing sugar does not have much effect on the adjuvant activity of monophosphoryl lipid A analogues. The preliminary lethal toxicity study indicates that the 3-O-acylated hepta-acyl monophosphoryl lipid A may not be more toxic than its 3-O-deacylated hexa-acyl analogue.     

Immunodominant Francisella tularensis antigens identified using proteome microarray

Stimulation of protective immune responses against intracellular pathogens is difficult to achieve using non-replicating vaccines. BALB/c mice immunized by intramuscular injection with killed Francisella tularensis (live vaccine strain) adjuvanted with preformed immune stimulating complexes admixed with CpG, were protected when systemically challenged with a highly virulent strain of F. tularensis (Schu S4). Serum from immunized mice was used to probe a whole proteome microarray in order to identify immunodominant antigens. Eleven out of the top 12 immunodominant antigens have been previously described as immunoreactive in F. tularensis. However, 31 previously unreported immunoreactive antigens were revealed using this approach. Twenty four (50%) of the ORFs on the immunodominant hit list belonged to the category of surface or membrane associated proteins compared to only 22% of the entire proteome. There were eight hypothetical protein hits and eight hits from proteins associated with different aspects of metabolism. The chip also allowed us to readily determine the IgG subclass bias, towards individual or multiple antigens, in protected and unprotected animals. These data give insight into the protective immune response and have potentially important implications for the rational design of non-living vaccines for tularemia and other intracellular pathogens.     

Requirements on bacterial polyesters as future substitute for conventional plastics for consumer goods

Bacterial polyesters such as polyhydroxybutyrate (PHB) or polyhydroxyalkanoates (PHAs) have to pass the following requirements to be accepted on a large scale: (i) they have to fulfil an urgent market need: (ii) they require that new and efficient composting systems are installed in urban areas; (iii) they have to complete with the present plastics as far as quality and processing performance are concerned; (iv) they have to meet the requirement for the registration as food packages; and (v) they have to meet competitive price limits. (i) Some 30% of the plastics in the municipal waste originates from goods which are less than 1 year in use and tend to be heavily soiled by food and feed residues. This part is difficult and expensive to dispose of. Biodegradable alternatives could replace a large part of it. The waste could be diverted from landfills and incineration to composting sites near the end user. The savings in costs and frustrations are the source of a pressing demand for biopolymers, especially for producing goods which do not demand longevity and which are likely to end up soiled with organic matters. (ii) Composting infrastructures exist in rural areas. In urban areas new systems for collecting and composting ‘garden and kitchen wastes’ are being installed for reducing landfill problems, especially in Austria, Denmark, Germany and the Netherlands. These installations give biopolymers a competitive edge in the disposal discussion. (iii) Bacterial polyesters meet various quality and processing performances. They are water-resistant, and goods made of the polyesters are water-tight. The material can be processed by injection and by blow moulding. However, the esters are not flexible enough for forming films or foils. They also tend to become brittle and to lose their vapour barrier properties. It is expected that these limits will be overcome by improving blend formulations. (iv) Bacterial polyesters are not yet allowed for use as food package material. Since the esters represent a novel product, the procedure for the registration poses serious, but no insoluble problems. They require long and costly tests. There are no indications that bacterial polyesters would not attain the requirements. However, they are not expected to serve as food packages in the near future. (v) The present prices for bacterial polyesters are far too high to be accepted on a large scale by the processing and packaging industry. Costs are high mainly because of the raw material prices and to the small-scale production units. They can be lowered to accepted levels by investing in larger units in countries where inexpensive raw materials are available. Thus they will be able to meet the price limits. Since bacterial polyesters increasingly meet the requirements for the penetration of a mass market and since more and more consumers accept composting as an environmentally sound way of recycling organic materials, the polyesters are expected to penetrate a significant part of the short-lived and contaminated plastic products markets by the turn of the century.     

Hepatitis E Virus: An emerging enigmatic and underestimated pathogen

Hepatitis E virus (HEV) is an RNA virus causing hepatitis E disease. The virus is of one serotype but has diverse genotypes infecting both humans and animals. Based on evidence from seroprevalence studies, about 2 billion people are estimated to have been infected with HEV globally. HEV, therefore, poses a significant public health and economic challenge worldwide. HEV was discovered in the 1980s and was traced back to the 1955 – 1956 outbreak of hepatitis that occurred in India. Subsequently, several HEV epidemics involving thousands of individuals have occurred nearly annually in different countries in Asia and Africa. Initially, the virus was thought to be only enterically transmitted, and endemic in developing countries. Due to the environmental hygiene and sanitation challenges in those parts of the world. However, recent studies have suggested otherwise with the report of autochthonous cases in industrialised countries with no history of travel to the so-called endemic countries. Thus, suggesting that HEV has a global distribution with endemicity in both developing and industrialised nations. Studies have also revealed that HEV has multiple risk factors, and modes of transmission as well as zoonotic potentials. Additionally, recent findings have shown that HEV leads to severe disease, particularly among pregnant women. In contrast to the previous narration of a strictly mild and self-limiting infection. Studies have likewise demonstrated chronic HEV infection among immunocompromised persons. Consequent to these recent discoveries, this pathogen is considered a re – emerging virus, particularly in the developed nations. However, despite the growing public health challenges of this pathogen, the burden is still underestimated. The underestimation is often attributed to poor awareness among clinicians and a lack of routine checks for the disease in the hospitals. Thus, leading to misdiagnosis and underdiagnosis. Hence, this review provides a concise overview of epidemiology, diagnosis, and prevention of hepatitis E.     

Predictors of healthcare workers' intention to vaccinate against COVID-19: A cross sectional study from Saudi Arabia

BackgroundVaccination is considered the best way to prevent the spread of COVID-19 and to prevent the complications of the disease. Nevertheless, no awareness campaigns were conducted in Saudi Arabia until March 1, 2021, when the Vaxzevria, or ChAdOx1 nCoV-19 (AZD1222), vaccine became available.ObjectivesThis study aims to determine the factors that can predict healthcare workers’ acceptance of the COVID-19 vaccine.MethodsA cross-sectional study was conducted from July to September 2021, in our university tertiary hospital (King Saud University Medical City [KSUMC]), Riyadh, Saudi Arabia. The study targeted potential participants among healthcare workers at KSUMC. We assessed healthcare workers’ perceptions and beliefs about the COVID-19 vaccine via a questionnaire that was distributed via social media applications such as WhatsApp, Twitter, and Google. Participants were informed about the questionnaire before they filled it out, and they were asked to respond to three screening questions before beginning the main questionnaire. These screening questions ensured that the participants met the inclusion criteria. Included participants were over the age of 18, agreed to answer the questions, and were residents of Saudi Arabia. The participants filled out the self-administered questionnaire.ResultsA total of 529 participants completed the questionnaires. All participants were vaccinated, 68% were female, 55% were married, 35% had been working for less than five years, and 65% had a bachelor’s degree. More than half of participants had not previously been infected with COVID-19, and most did not interact with COVID-19 patients. More convenient access to the vaccine increased the odds ratio of participant vaccination by 0.39. An increase in the number of vaccinated friends and family members increased the odds ratio of participant vaccination by 0.30. However, COVID- 19 vaccination mandates decreased the odds ratio of participant vaccination by 0.27. The fitted linear regression model explained 32% of the variation observed in the dependent variable, acceptance of the COVID-19 vaccine, and the adjusted R squared was 0.32. The fitted regression model was statistically significant at a 95% confidence interval; the p-value was 0.00001.ConclusionIn Saudi Arabia, there is an immense need to increase uptake of the COVID-19 vaccine. This requires encouraging more positive beliefs and attitudes regarding vaccination in general and the COVID-19 vaccine in particular.