More effective immunization

Immunization activities, in spite of being one of the easiest health components to deliver, are frequently forgotten or relegated to a low priority. One of the major reasons why immunization services have not been more widely implemented in developing countries is that present knowledge is inadequately applied. Although gaps do exist in some technical and operational areas, the most important concern is the application on a larger scale of already available knowledge and technologies. It is emphasized that programming strategies should promote delivery of immunization services to the population groups at highest risk of contracting the target diseases--children less than 1 year old and pregnant women--and that these services can most effectively be delivered as an integral part of the primary health care system. The use of immunization coverage as a simple and meaningful indicator of the extension of coverage of health services is analysed by using data from immunization programmes in two countries of the Americas.     

Immunogenicity and efficacy of oral vaccines in developing countries: lessons from a live cholera vaccine

Oral vaccines, whether living or non-living, viral or bacterial, elicit diminished immune responses or have lower efficacy in developing countries than in developed countries. Here I describe studies with a live oral cholera vaccine that include older children no longer deriving immune support from breast milk or maternal antibodies and that identify some of the factors accounting for the lower immunogenicity, as well as suggesting counter-measures that may enhance the effectiveness of oral immunization in developing countries. The fundamental breakthrough is likely to require reversing effects of the 'environmental enteropathy' that is often present in children living in fecally contaminated, impoverished environments.     

Japanese encephalitis vaccines--needs, flaws and achievements

Japanese encephalitis causes serious health problems in countries in Southeast Asia, where the causative virus is endemic. Whereas most adults living in this region have acquired immunity, children are at high risk of infection. Childhood mass immunization programs with first-generation mouse brain-derived vaccines efficiently reduced Japanese encephalitis incidence in affected countries, but immunization recommendations have mostly been abolished in Japan owing to the occurrence of severe side effects. Thus, there is a pressing need for safer vaccines to keep the disease under control. The safety profile of the current vaccines, together with the relatively low incidence, makes the risk/benefit ratio unfavorable for immunization of travelers to Southeast Asia, despite the high mortality once the clinical disease has developed. As Asian countries become increasingly popular travel destinations, the availability of well-tolerated vaccines would likely shift the ratio towards immunization. Currently, there is one second-generation inactivated cell-culture-grown vaccine in late-stage clinical development that is approaching licensing in developed countries.     

Will Dengue Vaccines Be Used in the Public Sector and if so,How? Findings from an 8-country Survey of Policymakers and Opinion Leaders

Background

A face-to-face survey of 158 policymakers and other influential professionals was conducted in eight dengue-endemic countries in Asia (India, Sri Lanka, Thailand, Vietnam) and Latin America (Brazil, Colombia, Mexico, Nicaragua) to provide an indication of the potential demand for dengue vaccination in endemic countries, and to anticipate their research and other requirements in order to make decisions about the introduction of dengue vaccines. The study took place in anticipation of the licensure of the first dengue vaccine in the next several years.

Methods/Principal Findings

Semi-structured interviews were conducted on an individual or small group basis with government health officials, research scientists, medical association officers, vaccine producers, local-level health authorities, and others considered to have a role in influencing decisions about dengue control and vaccines. Most informants across countries considered dengue a priority disease and expressed interest in the public sector use of dengue vaccines, with a major driver being the political pressure from the public and the medical community to control the disease. There was interest in a vaccine that protects children as young as possible and that can fit into existing childhood immunization schedules. Dengue vaccination in most countries surveyed will likely be targeted to high-risk areas and begin with routine immunization of infants and young children, followed by catch-up campaigns for older age groups, as funding permits. Key data requirements for decision-making were additional local dengue surveillance data, vaccine cost-effectiveness estimates, post-marketing safety surveillance data and, in some countries vaccine safety and immunogenicity data in the local population.

Conclusions/Significance

The lookout for the public sector use of dengue vaccines in the eight countries appears quite favorable. Major determinants of whether and when countries will introduce dengue vaccines include whether WHO recommends the vaccines, their price, the availability of external financing for lower income countries, and whether they can be incorporated into countries'' routine immunization schedules.     

反向遗传学技术在猪瘟病毒研究中的应用

猪瘟目前在许多国家流行并对养猪业造成巨大损失。虽然常规疫苗(如中国猪瘟兔化弱毒疫苗,即C株)在猪瘟防控中发挥巨大作用,但近年来在猪瘟防控中出现的新情况,如非典型感染、持续性感染及免疫失败等;同时目前世界上许多国家正开展的猪瘟扑灭计划使得弱毒疫苗的应用受到很大限制。因此,加强猪瘟病毒在致病机理、传播机制等方面的研究以及加快新型猪瘟疫苗的开发是当务之急。近年来,反向遗传学技术的发展为猪瘟病毒基因功能研究和疫苗制备方面开辟了新思路。以下回顾了反向遗传操作技术在猪瘟病毒基因功能研究与标记疫苗株构建方面的研究进展,同时提出了该领域目前面临的问题,并对其未来发展方向进行了展望。     

The immune response of two microbial antigens delivered intradermally,sublingually, or the combination thereof

A key consideration to produce a successful vaccine is the choice of appropriate vaccination route. Though most vaccines are administered parenterally, this route is not effective in producing a robust mucosal or cell-mediated response. Intradermal and sublingual vaccinations have been explored recently as potential needle-free immunization strategies. We explored intradermal and sublingual routes as well as the combination of the two routes in eliciting both systemic and mucosal immune responses. Mice were immunized intradermally or sublingually with dmLT, a mutant of Escherichia coli heat-labile toxin. A systemic IgG response is dominant in intradermal immunization while a mucosal IgA response is dominant in sublingual immunization. When routes were combined, a synergistic response was seen with high titers of anti-dmLT IgG and IgA. IpaB/IpaD antigens of Shigella flexneri type III secretion system, were admixed with dmLT as adjuvant and administered by each route alone or in combination. Again, the intradermal route elicited a systemic response while the sublingual route elicited a mucosal response. When combined, the routes produced a robust synergistic response to both antigens that exhibited a balanced Th1/Th2 response. These results provide a new potential needle-free immunization strategy that will benefit low income countries and increase compliance in industrial countries.     

Perspectives on the Impact of Varicella Immunization on Herpes Zoster. A Model-Based Evaluation from Three European Countries

The introduction of mass vaccination against Varicella-Zoster-Virus (VZV) is being delayed in many European countries because of, among other factors, the possibility of a large increase in Herpes Zoster (HZ) incidence in the first decades after the initiation of vaccination, due to the expected decline of the boosting of Cell Mediated Immunity caused by the reduced varicella circulation. A multi-country model of VZV transmission and reactivation, is used to evaluate the possible impact of varicella vaccination on HZ epidemiology in Italy, Finland and the UK. Despite the large uncertainty surrounding HZ and vaccine-related parameters, surprisingly robust medium-term predictions are provided, indicating that an increase in HZ incidence is likely to occur in countries where the incidence rate is lower in absence of immunization, possibly due to a higher force of boosting (e.g. Finland), whereas increases in HZ incidence might be minor where the force of boosting is milder (e.g. the UK). Moreover, a convergence of HZ post vaccination incidence levels in the examined countries is predicted despite different initial degrees of success of immunization policies. Unlike previous model-based evaluations, our investigation shows that after varicella immunization an increase of HZ incidence is not a certain fact, rather depends on the presence or absence of factors promoting a strong boosting intensity and which might or not be heavily affected by changes in varicella circulation due to mass immunization. These findings might explain the opposed empirical evidences observed about the increases of HZ in sites where mass varicella vaccination is ongoing.     

Experience with the expanded WHO program on immunization against tetanus

According to (WHO) statistics, over 1 million infants in the developing countries die each year from tetanus. The estimated annual occurrence of tetanus in the 3rd World exceeds 2.5 million cases, including approximately 1.3 million newborn infants. In 1974, WHO began an expanded program for the systematic immunization of infants against tetanus and certain other diseases. The program uses 2 approaches for preventing tetanus: 1) immunization of infants under 1 year of age with the AKDS vaccine; and 2) immunization of pregnant women or, if possible, all women, with tetanus anatoxin. The 2nd approach is more effective, especially when 2 doses of tetanus anatoxin are administered within a minimum interval of 4 weeks. The anatoxin has no harmful effects on the fetus and can be used during any stage of pregnancy. The program strives to reduce infant mortality caused by tetanus to less than 1 case in 1000 by 1990, and to 0 by 2000. To attain these goals, systematic immunization should be combined with drastic improvements in delivery techniques and hygiene in developing countries. Specialized surveys indicate that initial steps toward implementation of the program resulted in a significant reduction of infant mortality caused by tetanus. Experience with the expanded WHO program shows that elimination of tetanus in infants is a realistic and attainable goal.     

Economic aspects of vaccines and immunizations

Several techniques are used to estimate whether investing in vaccines and immunization is worthwhile, including cost analysis, cost-benefit analysis, cost-effectiveness analysis, and cost-utility analysis. At least 162 published economic evaluations of vaccines have been carried out from 1969 to 1998. They consistently show that immunization is an excellent investment--highly cost-effective and usually cost-saving--for vaccines that are currently recommended for universal use. Although prices of newer vaccines are higher than prices of traditional vaccines, they are still highly cost-effective. The World Health Organization, UNICEF, and vaccine manufacturers have developed approaches to make newer vaccines available to developing countries at reduced prices. Sustainability of immunization programs (the ability of a country to continue its immunization program in the absence of external support) is an increasingly important goal. However, external assistance will be essential in the short term to ensure that all the world's people benefit fully from the new vaccines.     

A global health partnership's use of time-limited support to catalyze health practice change: the case of GAVI's Injection Safety Support

This paper presents the findings of a study to assess the effectiveness and sustainability of a GAVI (Global Alliance of Vaccines and Immunization) sponsored, time-limited Injection Safety (INS) support. The support came in two forms: 1) in-kind, in the form of AD syringes and safety boxes, and 2) in cash, for those countries that already had a secure, multi-year source of AD syringes and safety boxes, but proposed to use INS support to strengthen their injection safety activities. In total, GAVI gave INS support for a three-year period to 58 countries: 46 with commodities and 12 with cash support. To identify variables that might be associated with financial sustainability, frequencies and cross-tabulations were run against various programmatic and socio-economic variables in the 58 countries. All but two of the 46 commodity-recipient countries were able to replace and sustain the use of AD syringes and safety boxes after the end of their GAVI INS support despite the fact that standard disposable syringes are less costly than ADs (10-15 percent differential). In addition, all 12 cash-recipient countries continued to use AD syringes and safety boxes in their immunization programs in the years following GAVI INS assistance. At the same time, countries were often not prepared for the increased waste management requirements associated with the use of the syringes, suggesting the importance of anticipating challenges with the introduction of new technologies. The sustained use of AD syringes in countries receiving injection safety support from GAVI, in a majority of cases through government financing, following the completion of three years of time-limited support, represents an early indication of how GHPs can contribute to improved health outcomes in immunization safety in the world's poorest countries in a sustainable way.     

Enteroviruses in the XX and XXI centuries

The modern view of the role of enteroviruses in the eradication of poliomyelitis is presented. Enteroviruses were discovered in the XX century. In the 1950s they caused great epidemics of poliomyelitis and serous meningitis in many countries of the world. The introduction of oral poliomyelitis vaccine (OPV) into medical practice made it possible to eliminate the epidemics of poliomyelitis in a short time. Poliomyelitis morbidity was reduced to sporadic cases and in a number of regions disappeared. OPV produced non-specific influence also on the epidemics of serous meningitis, as well as on a case incidence. The eradication of poliomyelitis viruses and the cessation of immunization with OPV will not result in eradication of paralytic diseases. Paralytogenic viruses of 20 serotypes circulate in nature, and some of these viruses are capable of causing the outbreaks of severe paralytic diseases. The authors propose either to retain immunization with OVP as tour immunizations with monovaccine of type 2, or to create new live enterovirus vaccines on the basis of avirulent enterovirus strains.     

轮状病毒疫苗研究现状

轮状病毒自上世纪70年代初发现至今,仍是婴幼儿病毒性腹泻最主要的病原体。每年约60万婴幼儿因轮状病毒感染导致严重脱水死亡。轮状病毒疫苗从上世纪90年代初开始研制,至今已有三种疫苗用于预防轮状病毒感染。这三种疫苗均为减毒活疫苗:其中包括单一血清型Rotarix、罗特威和重组5价疫苗RotaTeq。它们已在全球多国使用,有些国家已将其纳入免疫规划。疫苗的使用使人群轮状病毒感染下降,特别是死亡率明显减少。但也出现了一些问题,因此除了减毒活疫苗,也有一些实验室研究其他形式的疫苗,例如重组疫苗、灭活疫苗等。本文主要介绍轮状病毒疫苗的研究现状,为我国轮状病毒疫苗的研究、使用和推广提供一定理论依据。     

Live oral typhoid vaccine Ty 21 a. An original method of manufacturing and distribution

Oral immunization against typhoid using Ty 21 a strain did not meet the anticipated success. This vaccine is too expensive for countries which actually need immunization. The suitable form of the vaccine is not yet clearly defined. Our proposal therefore is to give up freeze-drying and to use fresh suspended live bacilli. We have established that this form is stable enough (at least one week at + 4 degrees C) to allow necessary controls and good dispatch. More, the colonization of digestive tract should be easier when the vaccine is given as a liquid than as capsules with a dry content.     

The cluster method in conducting epidemiological research

The Expanded Programme on Immunization (EPI) whose goal is to reduce morbidity and mortality by providing children with immunizations against diphtheria, pertussis, tetanus, poliomyelitis, measles, and tuberculosis continually faces the problem of documenting immunization coverage rates. Therefore the EPI seeks simple, effective, and inexpensive methods of evaluation which could be implemented in different countries. An example of such a method is a simplified cluster sampling technique of estimation of immunization coverage through the examination of 210 children, selected randomly as 30 groups of 7 children each. In 1978-1984 more than 1000 immunization coverage surveys were performed all over the world, mainly in developing countries. In a modified way this method is also used to collect data on morbidity and mortality of certain EPI target diseases as well as diarrhoeal diseases.     

Production of monoclonal antibody to bovine leukemia virus glycoprotein gp51 by in vitro immunization

The monoclonal antibody against glycoprotein gp51 of bovine leukemia virus (BLV) envelope antigen was produced by in vitro immunization. This monoclonal antibody reacted with viral antigen was observed at the 69 kilodalton (kDa) glycoprotein. However, this monoclonal antibody was not involved in neutralizing. It was shown that in comparison with in vivo immunization, in vitro immunization has some advantages, namely a short immunization period and a small antigen quantity.     

DNA Immunization with Japanese Encephalitis Virus Nonstructural Protein NS1 Elicits Protective Immunity in Mice

Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, is a zoonotic pathogen that is prevalent in some Southeast Asian countries and causes acute encephalitis in humans. To evaluate the potential application of gene immunization to JEV infection, we characterized the immune responses from mice intramuscularly injected with plasmid DNA encoding JEV glycoproteins, including the precursor membrane (prM) plus envelope (E) proteins and the nonstructural protein NS1. When injected with the plasmid expressing prM plus E, 70% of the immunized mice survived after a lethal JEV challenge, whereas when immunized with the plasmid expressing NS1, 90% of the mice survived after a lethal challenge. As a control, the mice immunized with the DNA vector pcDNA3 showed a low level (40%) of protection, suggesting a nonspecific adjuvant effect of the plasmid DNA. Despite having no detectable neutralizing activity, the NS1 immunization elicited a strong antibody response exhibiting cytolytic activity against JEV-infected cells in a complement-dependent manner. By contrast, immunization with a construct expressing a longer NS1 protein (NS1′), containing an extra 60-amino-acid portion from the N terminus of NS2A, failed to protect mice against a lethal challenge. Biochemical analyses revealed that when individually expressed, NS1 but not NS1′ could be readily secreted as a homodimer in large quantity and could also be efficiently expressed on the cell surface. Interestingly, when NS1 and NS1′ coexisted in cells, the level of NS1 cell surface expression was much lower than that in cells expressing NS1 alone. These data imply that the presence of partial NS2A might have a negative influence on an NS1-based DNA vaccine. The results herein clearly illustrate that immunization with DNA expressing NS1 alone is sufficient to protect mice against a lethal JEV challenge.     

Atraumatic oral spray immunization with replication-deficient viral vector vaccines

The development of needle-free vaccines is one of the recently defined “grand challenges in global health” (H. Varmus, R. Klausner, R. Klausner, R. Zerhouni, T. Acharya, A. S. Daar, and P. A. Singer, Science 302:398-399, 2003). To explore whether a natural pathway to the inductive site of the mucosa-associated lymphatic tissue could be exploited for atraumatic immunization purposes, replication-deficient viral vector vaccines were sprayed directly onto the tonsils of rhesus macaques. Tonsillar immunization with viral vector vaccines encoding simian immunodeficiency virus (SIV) antigens induced cellular and humoral immune responses. Viral RNA levels after a stringent SIV challenge were reduced, providing a level of protection similar to that observed after systemic immunization with the same vaccines. Thus, atraumatic oral spray immunization with replication-deficient vectors can overcome the epithelial barrier, deliver the vaccine antigen to the mucosa-associated lymphatic tissue, and avoid induction of tolerance, providing a novel approach to circumvent acceptability problems of syringe and needle vaccines for children and in developing countries.     

Quantitative estimation of diphtheria and tetanus toxoids. 4. Toxoids as international reference materials defining Lf-units for diphtheria and tetanus toxoids

The Lf-unit, which is used in the control of diphtheria and tetanus toxoid production and in some countries also to follow immunization of horses for production of antitoxins, has hitherto been defined by means of antitoxin preparations. A diphtheria toxoid and a tetanus toxoid preparation, both freeze-dried, were examined in an international collaborative study for their suitability to serve as reference reagents in the flocculation tests and for defining the Lf-units. It was shown that flocculation tests using the reference toxoids are very reproducible and reliable and the WHO Expert Committee on Biological Standardization established: the toxoid called DIFT as the International Reference Reagent of Diphtheria Toxoid for Flocculation Test with a defined content of 900 Lf-units of diphtheria toxoid per ampoule; and the toxoid called TEFT as the International Reference Reagent of Tetanus Toxoid for Flocculation Test with a defined content of 1000 Lf-units of diphtheria toxoid per ampoule.     

Abating Mercury Exposure in Young Children Should Include Thimerosal-Free Vaccines

Pediatric immunization is essential to prevent, control and eradicate children`s infectious diseases. Newborns and infants in less developed countries have a concentrated schedule of Thimerosal-containing vaccines (TCVs); pregnant mothers are also immunized with TCVs. Metabolic changes during early development are demonstrably an important risk factor for ethylmercury (EtHg) effects on neurodevelopment, while exposure to Thimerosal sensitizes susceptible individuals to life-long contact dermatitis. Concerns regarding toxicity of Hg have moved rich nations to withdraw it from medicines and, in particular, Thimerosal from pediatric vaccines; it has been more than 20 years since rich countries started using Thimerosal-free vaccines. TCVs and Thimerosal-free vaccines show dissimilar profiles of adverse effects. Thimerosal-free vaccines have shown a decrease in contact dermatitis, while TCVs showed a significant association with increased risk of tic disorders; in some circumstances, EtHg in combination with other neurotoxic substances negatively impacted neurobehavioral tests. In studies that explored vaccines and risk of tics, Thimerosal was a necessary factor. However, when the binary exposure to organic Hg forms (TCV–EtHg and fish-MeHg) was considered, effects on neurobehavioral tests were inconsistent. Conclusions: (a) The indiscriminate use of pediatric-TCVs in less developed countries carries an unjustifiable and excessive EtHg exposure with an unnecessary risk of neurotoxicity to the developing brain; (b) measurable benefits (of Thimerosal-free) and measurable risks of tic disorders have been associated with the (Thimerosal-containing) type of vaccine; (c) Thimerosal-free vaccines are clinically and toxicologically justifiable and they should be available to children in less developed countries.     

我们离麻疹消除还有多远?

中国麻疹发病率自2008年起出现大幅度下降,但2012年底以来麻疹发病疫情呈上升趋势,部分城市出现了以成人为主的疫情暴发。导致麻疹疫情再次上升的一个可能原因是中国的麻疹疫苗实际接种率低于报告接种率,常规免疫有不到位的情况。同时,中国存在部分麻疹免疫空缺人群,既未接种过麻疹常规疫苗,也没有参加过2004—2010年的补充免疫活动。这类人群积累到一定程度后,可引起聚集性的疫情暴发。中国在消除麻疹方面虽已取得显著进展,但近年来疫情再次抬头值得警惕。进一步增加常规麻疹两剂疫苗接种率,对重点地区和人群适当增加补充免疫活动,更好地落实麻疹应急预案等,将有助于控制并消除麻疹疫情。