Protective Efficacy in Sheep of Adenovirus-Vectored Vaccines against Bluetongue Virus Is Associated with Specific T Cell Responses

Bluetongue virus (BTV) is an economically important Orbivirus of the Reoviridae family that causes a hemorrhagic disease in ruminants. Its control has been achieved by inactivated-vaccines that have proven to protect against homologous BTV challenge although unable to induce long-term immunity. Therefore, a more efficient control strategy needs to be developed. Recombinant adenovirus vectors are lead vaccine candidates for protection of several diseases, mainly because of their potency to induce potent T cell immunity. Here we report the induction of humoral and T-cell mediated responses able to protect animals against BTV challenge by recombinant replication-defective human adenovirus serotype 5 (Ad5) expressing either VP7, VP2 or NS3 BTV proteins. First we used the IFNAR^(-/-) mouse model system to establish a proof of principle, and afterwards we assayed the protective efficacy in sheep, the natural host of BTV. Mice were completely protected against BTV challenge, developing humoral and BTV-specific CD8⁺- and CD4⁺-T cell responses by vaccination with the different rAd5. Sheep vaccinated with Ad5-BTV-VP2 and Ad5-BTV-VP7 or only with Ad5-BTV-VP7 and challenged with BTV showed mild disease symptoms and reduced viremia. This partial protection was achieved in the absence of neutralizing antibodies but strong BTV-specific CD8⁺ T cell responses in those sheep vaccinated with Ad5-BTV-VP7. These data indicate that rAd5 is a suitable vaccine vector to induce T cell immunity during BTV vaccination and provide new data regarding the relevance of T cell responses in protection during BTV infection.     

Intranasal Mucosal Boosting with an Adenovirus-Vectored Vaccine Markedly Enhances the Protection of BCG-Primed Guinea Pigs against Pulmonary Tuberculosis

Background

Recombinant adenovirus-vectored (Ad) tuberculosis (TB) vaccine platform has demonstrated great potential to be used either as a stand-alone or a boost vaccine in murine models. However, Ad TB vaccine remains to be evaluated in a more relevant and sensitive guinea pig model of pulmonary TB. Many vaccine candidates shown to be effective in murine models have subsequently failed to pass the test in guinea pig models.

Methods and Findings

Specific pathogen-free guinea pigs were immunized with BCG, AdAg85A intranasally (i.n), AdAg85A intramuscularly (i.m), BCG boosted with AdAg85A i.n, BCG boosted with AdAg85A i.m, or treated only with saline. The animals were then infected by a low-dose aerosol of M. tuberculosis (M.tb). At the specified times, the animals were sacrificed and the levels of infection in the lung and spleen were assessed. In separate studies, the long-term disease outcome of infected animals was monitored until the termination of this study. Immunization with Ad vaccine alone had minimal beneficial effects. Immunization with BCG alone and BCG prime-Ad vaccine boost regimens significantly reduced the level of M.tb infection in the tissues to a similar extent. However, while BCG alone prolonged the survival of infected guinea pigs, the majority of BCG-immunized animals succumbed by 53 weeks post-M.tb challenge. In contrast, intranasal or intramuscular Ad vaccine boosting of BCG-primed animals markedly improved the survival rate with 60% of BCG/Ad i.n- and 40% of BCG/Ad i.m-immunized guinea pigs still surviving by 74 weeks post-aerosol challenge.

Conclusions

Boosting, particularly via the intranasal mucosal route, with AdAg85A vaccine is able to significantly enhance the long-term survival of BCG-primed guinea pigs following pulmonary M.tb challenge. Our results thus support further evaluation of this viral-vectored TB vaccine in clinical trials.     

不同DNA疫苗联合接种可有效增强免疫效果

造反乙型肝炎（乙肝）病毒核心抗原（ＨＢｃＡｇＡ）、ｅ抗原（ＨＢｅＡｇ）及单纯疱疹病毒ｇＤ抗原（ＨＳＶ－１－ｇＤ）基因为目的基因,进行ＤＮＡ疫苗联合免疫的研究。通过对不同基因片段的表达研究,选择了能在哺乳动物细胞中高效表达乙肝病毒核心抗原、ｅ抗原和单纯疱疹病毒ｇＤ抗原的质粒ＤＮＡ免疫Ｂａｌｂ／ｃ小鼠。结果显示：表达乙肝病毒核心抗原和单纯疱毒ｇＤ抗原的ＤＨＡ疫苗单独免疫,能有效刺激机体产生体液免疫和细     

Prion疾病疫苗研究策略

朊病毒病是一类侵袭人类及多种动物中枢神经系统的致死性退行性脑病,目前缺乏有效的预防和治疗方法。朊病毒病的重组蛋白亚单位疫苗、DNA疫苗、合成肽疫苗、病毒样颗粒疫苗、树突状细胞疫苗、黏膜免疫疫苗等已取得一定进展,但现有的免疫策略仅能部分克服免疫耐受,诱导较低或中等滴度的抗体,对PrPSc感染动物模型只能提供部分保护,Prion疫苗研究任重而道远。     

Vaccines against Chlamydia: approaches and progress

Infections of the eye and genital tract with the bacterium Chlamydia trachomatis are a major cause of morbidity worldwide and are costly to treat. Development of a vaccine capable of protecting against infection or severe disease presents special challenges but would be the most effective long-term option for control of chlamydial disease. Progress has been made in understanding protective and pathological immune mechanisms in these infections, and a number of potential vaccine candidates have been developed.     

金黄色葡萄球菌疫苗及其免疫治疗进展

具有多重抗生素耐药性的金黄色葡萄球菌是导致医院感染最常见的致病菌,而目前高致病性耐甲氧西林菌株(MRSA)在社区中的传播使得健康人群也面临极大威胁,因此针对金黄色葡萄球菌的疫苗和免疫治疗的研究迫在眉睫。多数的研究以金黄色葡萄球菌细胞壁锚定蛋白、荚膜多糖、外毒素等为靶点,虽然在一些临床前试验中显示出疫苗和免疫治疗对金葡菌感染具有保护性,但是目前临床试验结果却并不乐观,还没有一个经得起临床检验的疫苗。本文章从临床前试验和临床试验两个方面综述了目前关于金黄色葡萄球菌的疫苗和免疫治疗进展。     

Env-Independent Protection Induced by Live, Attenuated Simian Immunodeficiency Virus Vaccines

Live attenuated simian immunodeficiency viruses (SIV), such as nef deletion mutants, are the most effective vaccines tested in the SIV-macaque model so far. To modulate the antiviral immune response induced by live attenuated SIV vaccines, we had previously infected rhesus monkeys with a nef deletion mutant of SIV expressing interleukin 2 (SIV-IL2) (B. R. Gundlach, H. Linhart, U. Dittmer, S. Sopper, S. Reiprich, D. Fuchs, B. Fleckenstein, G. Hunsmann, S. Stahl-Hennig, and K. Überla, J. Virol. 71:2225–2232, 1997). In the present study, SIV-IL2-infected macaques and macaques infected with the nef deletion mutant SIVΔNU were challenged with pathogenic SIV 9 to 11 months postvaccination. In contrast to the results with naive control monkeys, no challenge virus could be isolated from the SIV-IL2- and SIVΔNU-infected macaques. However, challenge virus sequences could be detected by nested PCR in some of the vaccinated macaques. To determine the role of immune responses directed against Env of SIV, four vaccinated macaques were rechallenged with an SIV-murine leukemia virus (MLV) hybrid in which the env gene of SIV had been functionally replaced by the env gene of amphotropic MLV. All vaccinated macaques were protected from productive infection with the SIV-MLV hybrid in the absence of measurable neutralizing antibodies, while two naive control monkeys were readily infected. Since the SIV-MLV hybrid uses the MLV Env receptor Pit2 and not CD4 and a coreceptor for virus entry, chemokine inhibition and receptor interference phenomena were not involved in protection. These results indicate that the protective responses induced by live attenuated SIV vaccines can be independent of host immune reactions directed against Env.     

Vaccines against gastrointestinal nematode parasites of ruminants

A consequence of intensive livestock production is an increase in the incidence and impact of gastrointestinal (GI) parasites. Farmers have sought to redress this shift in the natural host-parasite relationship by chemotherapy. However, with the widespread development of resistance to anthelmintics and the current impetus for sustainable agricultural practices, alternatives such as vaccines are being sought to maintain animal productivity. In this article, David Emery and Barry Wagland discuss recent advances in immunity to nematode infections of ruminants and the development of vaccines made possible by the dogged persistence and ingenuity of cadres of parasitologists who have done more than 'go through the motions'.     

Vaccines against protozoal diseases of veterinary importance

Abstract Protozoan parasites are important animal and human pathogens. At present, most of these infections are controlled by chemotherapy. In addition, vaccines are available for some of these diseases. There is, however, still an urgent need for the development of vaccines against protozoal diseases, since the current array of available vaccines is very limited. This review describes the different approaches that have been taken to develop such vaccines and discusses the difficulties that hampered vaccine development. Many of the problems are related to the complex life cycle of these parasites and the virtual lack of mass in vitro culture systems. We also give an overview of the commercial and non-commercial vaccines that do exist at present. Finally, we describe the future directions of this interesting field. New techniques and strategies include parasite cultivation methods and recombinant-DNA techniques, such as vector vaccines and DNA-vaccines. Moreover, these approaches are complemented by the development of sophisticated adjuvants; the coupling of immunoprotective molecules to entities with adjuvant activity or the use of cytokines, e.g. IL-12. Through these innovations new vaccines against protozoal diseases will become available in the near future.     

Plant-Based Vaccines for Protection Against Infectious and Autoimmune Diseases

Referee: Dr. Yoedono Sovyanhadi, Department of Biological Sciences, Oakwood College, 7000 Adventist Boulevard, NW, Huntsville, AL 35896 Over the last 2 decades, the number of emergent infectious diseases has increased at an alarming rate. Also disheartening is the rise of known infectious pathogens that have acquired extensive drug resistance and reemerged with greater virulence. More recently, the threat of bioweapons has rekindled an urgency for the development of mass immunization programs. In response to this increased infectious disease threat, efforts have been intensified to identify more effective, inexpensive, and more easily deliverable mucosal vaccination methods. One area of research currently under development is the genetic modification of plants for production of immunoprotective proteins. The ability of plants to synthesize complex proteins using the elements of sunlight, soil, air, and water makes them ideal organisms for harvesting large quantities of therapeutic proteins. The introduction of antigen or antibody encoding genes into the genome of a plant through stable transformation enables them to manufacture vaccine proteins that are directly applicable for use in disease treatment, unlike yeast, bacterial, insect or other expression systems that require purification steps before delivery. As an alternative to stable transformation, plants can be used to generate large quantities of vaccines by acting as hosts for genetically altered plant viruses in which antigen proteins can be expressed and later purified from infected plant tissues. In this review, we survey current experimental strategies for using edible plants to achieve passive and active immunization against infectious disease organisms. In addition, methods are described for the construction of transformed plants that can provide protection against autoimmune diseases. Concerns and present obstacles to effective immunization with plant-based vaccines for animals and humans are presented.     

Protection against pertussis by immunisation.

Review of all 126 children admitted to the communicable diseases unit with whooping cough during the epidemic in 1978 showed that two had received two doses of triple vaccine and only one had had full primary immunisation against the disease. None of these three children suffered complications of the disease. Of the 123 children who had not been immunised against pertussis, however, 66 had had one or more complications. In Birmingham the dramatic decline in immunisation against pertussis has been accompanied by a fall in acceptance rates for diphtheria and tetanus immunization. Nevertheless, of the 62 children aged over 1 year in this series, 41 had been so immunised. These findings suggest that the apparently positive decision by parents to omit pertussis immunisation was misplaced, since immunisation does protect against the more serious complications of the disease. Furthermore, there is no firm evidence that pertussis immunisation of children without specific contraindications is associated with serious adverse reactions.