Strategies for development of vaccines for control of ixodid tick species

Ticks are distributed worldwide and impact human and animal health, as well as food animal production. Control of ticks has been primarily by application of acaricides, which has resulted in selection of resistant ticks and environmental pollution. Vaccines have been shown to be a feasible tick control method that offers a cost-effective, environmentally friendly alternative to chemical control. However, identification of tick-protective antigens remains the limiting step in vaccine development. Tick antigens exposed naturally to the host during tick feeding and those concealed have both shown promise as candidate vaccine antigens. Development of vaccines against multiple tick species may be possible using highly conserved tick-protective antigens or by antigens showing immune cross-reaction to different tick species. Vaccines made from a combination of key protective antigens may greatly enhance vaccine efficacy. Preliminary studies have suggested the possibility of vaccine strategies directed toward both tick control and the blocking of pathogen transmission. Characterization of the tick genomes will have a great impact on the discovery of new protective antigens. The future of research directed toward tick vaccine development is exciting because of new and emerging technologies for gene discovery, and vaccine formulation and delivery.     

弓形虫抗原主要功能和免疫特性

研制安全有效的弓形虫疫苗一向是弓形虫病研究的重点,所以我们非常有必要对可能诱导宿主产生保护性免疫应答的弓形虫抗原进行广泛地筛选并对疫苗候选抗原进行科学合理的评价。因此,本文着重对具有致病性,免疫原性和多阶段有效性等重要特征的候选疫苗的抗原进行综述,旨在为将来寻找最佳的抗原,研制有效的疫苗提供较为准确的信息。     

Prevention of lyme disease and other tick-borne infections

Prevention is the best method for avoiding potentially serious complications of Lyme and other tick-borne diseases. In this article, we discuss preventative measures that can be used by individuals or communities. Among the topics discussed are personal protective measures, tick reduction, reservoir reduction, and vaccination. Additionally, new preventative measures that are in development-including new Lyme disease vaccines, antitick vaccines, and reservoir-targeted vaccination-are discussed.     

Isolation and characterization of salivary antigens from the female tick, Dermacentor andersoni

The salivary glands of ixodid ticks are complex organs which are known to contain the antigens responsible for tick resistance in animals. We have identified a large number of proteins from salivary gland extracts (SGE), at least some of which are immunologically recognized by tick resistant animals and which are therefore presumed to be secreted salivary components. During the 6 to 10 day feeding process, a number of these antigens alter in concentration according to individual kinetics, and some of these changes correlate with the kinetics of skin test reactivity of SGE obtained at different times throughout the feeding period. By use of immunoaffinity chromatography we have isolated large quantities of many of the salivary antigens (SGA) contained in SGE, and found that they contain several esterase activities. SGA stimulates both immediate and delayed skin reactions in tick resistant guinea-pigs, and these reactions are about 200-fold more intense, per unit protein, than those elicited by SGE. The skin reactions to SGA are basophil-mediated and have many features in common with the cutaneous basophil hypersensitivity reactions of tick resistant animals. The demonstrated antigenic complexity of the glands may have profound implications for attempts to develop anti-tick vaccines, as it may eventually be found that candidate vaccines will have to incorporate more than one tick antigen in order to be effective.     

Larval membrane antigens protect Hereford cattle against infestation with Boophilus microplus

Hereford cattle (Bos taurus) were immunized with antigens solubilized with Triton X-100 from larval membranes of the cattle tick (Boophilus microplus). Based on tick egg production compared to control cattle, vaccinated cattle were protected (78%) against challenge with 2 x 20,000 tick larvae. The soluble Triton X-100 extract of tick larval membranes was further purified by immunoaffinity chromatography, using immunoglobulin ligands (IgG1 and IgG2) from three immune steers, previously vaccinated with membrane antigens from the midgut of partly engorged adult female ticks. Cattle vaccinated with these purified antigens were protected in two separate experiments (80 and 89% respectively), against challenge with 2 x 20,000 larval ticks compared to control cattle. Whole larval membranes used as vaccines in cattle reduced the amount of eggs produced from ticks by 47% compared to control cattle, but this difference was not significant.     

Arthropod vaccines

Antigens located in the midgut of the tick are hidden from the host's immune system. Egg production of ticks can be reduced when ticks are fed on animals vaccinated with midgut antigens of the tick, and a subunit vaccine formulated with the recombinant antigen Bm86 is now available that can reduce the number of ticks infesting cattle grazing on pasture. Midgut antigens used in vaccines against insects that transmit pathogenic organisms to humans have not been as effective in reducing insect fecundity and an alternative approach may be necessary. Transmission-blocking vaccines directed at interfering with the vector-pathogen interaction could result in loss of vector competence and block the spread of disease-causing organisms.     

Identification of Neospora antigens recognized by CD4+ T cells and immune sera from experimentally infected cattle

Neospora caninum is recognized as a major cause of infectious abortion in cattle. Very little is known about immunity to Neospora . Cell mediated responses have previously been shown to be important in the development of protective immunity to the closely related parasite Toxoplasma gondii , and may therefore be an important component in the immune response to Neospora . In this paper we report that a group of low molecular weight NC1 strain tachyzoite antigens (≤ 30 kDa) separated by SDS PAGE and bound to nitrocellulose membrane stimulated proliferation in vitro of CD4+ T cells from calves experimentally infected with N. caninum . Proliferation was accompanied by production of high concentrations of IFNγ. Several of these antigens were also recognized by antibody produced in these animals. As the most effective vaccines require the stimulation of both humoral and cell mediated immune responses, these antigens may be important in the development of a vaccine against neosporosis.     

The roles of latency-associated antigens in tuberculosis vaccines

Tuberculosis (TB) is a re-emerging disease and is caused by Mycobacterium tuberculosis (M. tuberculosis). TB is currently one of the leading causes of morbidity and mortality, worldwide. The only available vaccine against TB infection, Bacillus Calmette–Guérin (BCG), fails to adequately protect against reactivation of latent infections in adults. Furthermore, recently developed subunit vaccines, which are in various stages of clinical trials, are all prophylactic vaccines based on proteins expressed in replicating stage of M. tuberculosis and they are not preventive of reactivation of latent TB infection. Thus, an appropriate subunit post-exposure vaccine needs to be developed to control all forms of TB infection. To produce a multi-stage subunit vaccine, scientists should combine the early secreted M. tuberculosis antigens with latency antigens. For this purpose, some latency proteins are known which could be important antigens in the production of specific humoral and cellular immune responses in latent M. tuberculosis infected individuals. Several studies have evaluated the immunogenicity of these proteins in improving the TB vaccines. The present study is a comprehensive review of several studies on the role of the latency antigens in the development of TB vaccines. Overall, the studies indicate that the latency-associated antigens including the resuscitation-promoting factors, the Dormancy of survival regulon (DosR) proteins and the starvation stimulant proteins are potential candidates for the development of subunit vaccines against TB infection.     

斑点热疫苗研究进展

斑点热是斑点热群立克次体引起的一类重要传染病,接种疫苗仍是预防斑点热的一种重要措施. 灭活立氏立克次体接种能够刺激实验动物产生特异性体液和细胞免疫,有效对抗该立克次体的致死性攻击,但对人体免疫的保护效果并不理想. 目前已发现的斑点热群立克次体的保护性抗原主要有外膜蛋白A、外膜蛋白B、YbgF和Adr2等表面蛋白,是研发斑点热分子疫苗的潜在候选分子. 单个保护性抗原免疫虽然能够诱导动物产生良好的特异性体液和细胞免疫应答,但是不能提供完全保护. 多个保护性抗原组合或保护性抗原的T和B淋巴细胞表位组合是研发斑点热分子疫苗的有效途径.     

Detection of Jingmenviruses in Japan with Evidence of Vertical Transmission in Ticks

Jingmen tick virus (JMTV) and the related jingmenvirus-termed Alongshan virus are recognized as globally emerging human pathogenic tick-borne viruses. These viruses have been detected in various mammals and invertebrates, although their natural transmission cycles remain unknown. JMTV and a novel jingmenvirus, tentatively named Takachi virus (TAKV), have now been identified during a surveillance of tick-borne viruses in Japan. JMTV was shown to be distributed across extensive areas of Japan and has been detected repeatedly at the same collection sites over several years, suggesting viral circulation in natural transmission cycles in these areas. Interestingly, these jingmenviruses may exist in a host tick species-specific manner. Vertical transmission of the virus in host ticks in nature was also indicated by the presence of JMTV in unfed host-questing Amblyomma testudinarium larvae. Further epidemiological surveillance and etiological studies are necessary to assess the status and risk of jingmenvirus infection in Japan.     

Lyme disease and the Lyme disease vaccines.

Both OspA vaccines, with or without adjuvant, are effective and safe. People must receive repeated doses of the vaccine, however, to receive effective protection. If the vaccines are to be part of a Lyme disease prevention strategy, doctors and patients must pay attention to booster shot timing. Maximum public health benefit can be achieved only if the Lyme disease vaccines are integrated into broad individual and community-based efforts to prevent Lyme disease and other tick-borne diseases. Only people at significant risk of contracting Lyme disease should consider vaccination, and vaccination should merely complement--not replace--personal precautions for avoiding tick bites.     

Immune responses of cattle to biochemically modified antigens from the midgut of the cattle tick, Boophilus microplus

Treatment of membrane antigens of the midgut (GM) of the cattle tick, Boophilus microplus with sodium metaperiodate (periodate), pronase and lipase significantly inhibited the reactivity of the GM with antibodies in the sera of 57 cattle vaccinated with GM. Treatment of GM with periodate only removed the correlation between antibody reactivity of sera and protection against infestation with ticks. A monoclonal antibody (MoAb QU13), which recognises protective antigens solubilized from GM (Lee + Opdebeeck 1991), did not react with GM treated with periodate. Cattle vaccinated with GM extracts were significantly protected against infestation with cattle ticks (P less than 0.05), whereas cattle vaccinated with either GM extracts treated with periodate or with antigens precipitated from GM extracts with MoAb QU13 and also treated with periodate, were not protected against infestation. These studies provide preliminary evidence that protective antigens in the tick midgut membrane either are carbohydrate or are dependent on carbohydrate for their specificity.     

Peripheral cellular and humoral responses to infestation with the cattle tick Rhipicephalus microplus in Santa Gertrudis cattle

Resistance to cattle tick infestation in single‐host ticks is primarily manifested against the larval stage and results in the immature tick failing to attach successfully and obtain a meal. This study was conducted to identify immune responses that characterize the tick‐resistant phenotype in cattle. Thirty‐five tick‐naïve Santa Gertrudis heifers were used in this study, thirty of which were artificially infested for thirteen weeks with tick larvae while five animals remained at a tick‐free quarantine property to serve as a control group. Following thirteen weeks of tick infestation, the animals in this trial exhibited highly divergent tick‐resistant phenotypes. Blood samples collected throughout the trial were used to measure peripheral immune parameters: haematology, the percentage of cellular subsets comprising the peripheral blood mononuclear cell (PBMC) population, tick‐specific IgG₁ and IgG₂ antibody titres, IgG1 avidity for tick antigens and the ability of PBMC to recognize and proliferate in response to stimulation with tick antigens in vitro. The tick‐susceptible cattle developed significantly higher tick‐specific IgG₁ antibody titres compared to the tick‐resistant animals. These results suggest that the heightened antibody response either does not play a role in resistance or might contribute to increased susceptibility to infestation.     

Live oral Salmonella vaccines: potential use of attenuated strains as carriers of heterologous antigens to the immune system

Live attenuated strains of salmonellae are showing promise as live oral vaccines against human typhoid fever and other Salmonella infections of man and animals. Attenuation can be achieved by introducing genetically defined, non-reverting mutations into specific genes on the Salmonella chromosome. Mutations in the gal E or aroA genes of Salmonella inhibit the ability of the bacteria to grow in vivo, and strains carrying such lesions are effective vaccines against salmonellosis. Genetic determinants encoding for the expression of potentially protective antigens from heterologous, non-Salmonella pathogens can be readily introduced into these attenuated Salmonella strains. Expression of the heterologous antigen does not affect the ability of the Salmonella host to be used as a Salmonella vaccine. Mice infected orally with a Salmonella typhimurium aroA vaccine expressing the Escherichia coli heat-labile toxin B subunit developed both a secretory and serum antibody response to this antigen. These serum antibodies were able to neutralise the activity of E. coli heat-labile toxin in tissue culture assays. A humoral and cell-mediated (DTH) immune response was detected against beta galactosidase, an intracellular antigen, in mice infected with an aroA vaccine expressing this cloned antigen. The prospects for the development of live Salmonella vaccines as a method for delivering heterologous antigens derived from bacteria, viruses and parasites is discussed.     

DNA vaccine against visceral leishmaniasis: a promising approach for prevention and control

The visceral leishmaniasis (VL) caused by Leishmania donovani parasite severely affects large populations in tropical and subtropical regions of the world. The arsenal of drugs available is limited, and resistance is common in clinical field isolates. Therefore, vaccines could be an important alternative for prevention against VL. Recently, some investigators advocated the protective efficacy of DNA vaccines, which induces the T cell‐based immunity against VL. The vaccine antigens are selected as conserved in various Leishmania species and provide a viable strategy for DNA vaccine development. Our understanding for DNA vaccine development against VL is not enough and much technological advancement is required. Improved formulations and methods of delivery are required, which increase the uptake of DNA vaccine by cells; optimization of vaccine vectors/encoded antigens to augment and direct the host immune response in VL. Despite the many genes identified as vaccine candidates, the disappointing potency of the DNA vaccines in VL underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the design, strategy, safety issues, varied candidates, progress and challenges that play a role in their ability against VL.     

New developments in flavivirus vaccines with special attention to yellow fever

PURPOSE OF REVIEW: Here we review recent epidemiological trends in flavivirus diseases, findings related to existing vaccines, and new directions in flavivirus vaccine research. We emphasize the need for stepped-up efforts to stop further spread and intensification of these infections worldwide. RECENT FINDINGS: Although the incidence and geographic distribution of flavivirus diseases have increased in recent years, human vaccines are available only for yellow fever, Japanese encephalitis, tick-borne encephalitis and Kyasanur forest disease. Factors contributing to resurgence include insufficient supplies of available vaccines, incomplete vaccination coverage and relaxation in vector control. Research has been underway for 60 years to develop effective vaccines against dengue, and recent progress is encouraging. The development of vaccines against West Nile, virus recently introduced to North America, has been initiated. In addition, there is considerable interest in improving existing vaccines with respect to increasing safety (e.g. eliminating the newly recognized syndrome of yellow fever vaccine-associated viscerotropic adverse disease), and to reducing the cost and number of doses required for effective immunization. SUMMARY: Traditional approaches to flavivirus vaccines are still employed, while recent advancements in biotechnology produced new approaches to vaccine design, such as recombinant live virus, subunit and DNA vaccines. Live chimeric vaccines against dengue, Japanese encephalitis and West Nile based on yellow fever 17D virus (ChimeriVax) are in phase I/II trials, with encouraging results. Other chimeric dengue, tick-borne encephalitis and West Nile virus candidates were developed based on attenuated dengue backbones. To further reduce the impact of flavivirus diseases, vaccination policies and vector control programs in affected countries require revision.     

Prospects for recombinant vaccines against Babesia bovis and related parasites

Babesial parasites infect cattle in tropical and temperate regions of the world and cause significant morbidity and mortality. Discovery of protective antigens that could be used in a killed vaccine has been slow and to date there are few promising vaccine candidates for cattle Babesia. This review describes mechanisms of protective innate and adaptive immune responses to babesial parasites and different strategies to identify potentially protective protein antigens of B. bovis, B. bigemina, and B. divergens. Successful parasites often cause persistent infection, and this paper also discusses how B. bovis evades and regulates the immune response to promote survival of parasite and host. Development of successful non-living recombinant vaccines will depend on increased understanding of protective immune mechanisms and availability of parasite genomes.     

Genetic diversity and malaria vaccine design, testing and efficacy: preventing and overcoming 'vaccine resistant malaria'

The development of effective malaria vaccines may be hindered by extensive genetic diversity in the surface proteins being employed as vaccine antigens. Understanding of the extent and dynamics of genetic diversity in vaccine antigens is needed to guide rational vaccine design and to interpret the results of vaccine efficacy trials conducted in malaria endemic areas. Molecular epidemiological, population genetic, and structural approaches are being employed to try to identify immunologically relevant polymorphism in vaccine antigens. The results of these studies will inform choices of which alleles to include in multivalent or chimeric vaccines; however, additional molecular and immuno-epidemiological studies in a variety of geographic locations will be necessary for these approaches to succeed. Alternative means of overcoming antigenic diversity are also being explored, including boosting responses to critical conserved regions of current vaccine antigens, identifying new, more conserved and less immunodominant antigens, and developing whole-organism vaccines. Continued creative application and integration of tools from multiple disciplines, including epidemiology, immunology, molecular biology, and evolutionary genetics and genomics, will likely be required to develop broadly protective vaccines against Plasmodium and other antigenically complex pathogens.     

Upcoming and future strategies of tick control: a review

Ticks are distributed worldwide and significantly impact human and animal health. Due to severe problems associated with the continuous use of acaricides on animals, integrated tick management is recommended. Increasing public health concern over the tick-borne diseases demands the strategic control of ticks on animals that transmit diseases to human beings. Immunological control of tick vector of Kyasanur Forest Disease (KFD) on cattle and other wild reservoir hosts is one of the possible alternative strategy for reducing the transmission of KFD to man. Chemical-vaccine synergies have been demonstrated and a combination of chemical and vaccine for tick and tick-borne disease control has been identified as a sustainable option. Studies have suggested the possibility of vaccine strategies directed towards both tick control and transmission of pathogens. Besides tick vaccine, use of endosymbionts, which are essential for the survival of arthropod hosts, for the control of tick vectors will be one of the targeted areas of research in near future. India with huge natural resources of herbs and other medicinal plants, the possibilities of developing herbal acaricides is discussed. The future of research directed towards target identification is exciting because of new and emerging technologies for gene discovery and vaccine formulation.     

HspX的功能及其在结核疫苗研制中的应用进展

研制安全有效的结核疫苗一直是结核病研究的重点,因此,有必要对其主要致病菌结核分枝杆菌(Mycobacterium tuberculosis,Mtb)抗原进行科学合理的评价。本文综述了潜伏性结核感染重要抗原HspX的致病机制及其在结核疫苗研制中的应用进展,探讨了HspX抗原在不同类型疫苗研制中的作用,旨在为将来研制有效的结核疫苗提供较准确的信息。