反向疫苗学及其筛选保护性抗原应用进展

近年发展起来的反向疫苗学,是现代疫苗学研究的一种新策略,使疫苗学研究进入了一个新时期。这种以“序列-结构-功能”思想为依据,以免疫信息学、计算机预测设计以及高通量的各种组学（包括基因组学、转录本组学、蛋白质组学等）综合集成技术为核心的策略,能为各种病原体保护性抗原候选分子的发现提供一条新途径,可以提高疫苗筛选效率。     

疟疾子孢子疫苗的研究进展

本文系统地回顾了疟疾疫苗的发展史，将疫苗研究的发展分为与生物技术的发展密切相关的三个时期；重点阐述了疟疾子孢子疫苗在不同时期的研究进展，并分析了疟疾疫苗研究的现状和面临的困难。     

Immunoglobulin-binding proteins in ticks: new target for vaccine development against a blood-feeding parasite

Humans have a long history of trying to control ticks. At first, attempts focused on modifying the habitat, whereas later efforts relied heavily on the use of chemicals. Current research is directed at finding a vaccine against ticks. A strategy of targeting 'concealed antigens' succeeded with the first commercialised vaccine against the cattle tick Boophilus microplus. However, vaccine development against other tick species appears unsatisfactory to date. Vaccination depends on a specific antibody-mediated immunoreaction that damages the parasite. Immunoglobulin molecules of vertebrate hosts can pass through gut barriers into the haemolymph of ectoparasites while retaining antibody activity. Research on the ixodid tick Rhipicephalus appendiculatus revealed that host immunoglobulin-G in the parasite was excreted via salivation, during feeding. Immunoglobulin-binding proteins in tick haemolymph and salivary glands are thought to be responsible for such excretion. The discovery of an immunoglobulin excretion system in ticks indicates that they have a highly developed mechanism to protect themselves from their host's antibody attack. Such a mechanism questions whether immunization strategies will be effective against ticks, unless they circumvent or disable the ticks' immunoglobulin excretion system.     

Sul meccanismo di azione della vaccinoterapia nella infezione tifoidea

Summary Having observed before that the blood serum of typhoid patients acquires under the stimulus of the vaccine an evident bacteriolytic action on the typhoid bacillus, we have studied variations brought about by the vaccine stimulus in the blood of the patients as to the redox-potential and to the glutathione in the blood.It has been seen that under vaccine stimulus there is a rapid increase of redox-potential and of the glutathione in the blood: lasting in the cases which tend to recovery, temporary in the cases in which the illness takes its natural course.The values of the total glutathione increase more than those of reduced glutathione, so that an increase of the values of the oxidized glutathione is found.The variations of the values of the redox-potential and of the oxidized glutathione brought about by the vaccine reaction in the blood of the patients leads us to consider the mechanism of the action of vaccine therapy in typhoid infection, on the same principle described by us regarding the action of penicillin.     

Biological weapons

Anthrax has been a major cause of death in grazing animals and an occasional cause of death in humans for thousands of years. Since the late 1800s there has been an exceptional international history of anthrax vaccine development. Due to animal vaccinations, the rate of infection has dropped dramatically. Anthrax vaccines have progressed from uncharacterized whole-cell vaccines in 1881, to pXO2-negative spores in the 1930s, to culture filtrates absorbed to aluminum hydroxide in 1970, and likely to recombinant protective antigen in the near future. Each of these refinements has increased safety without significant loss of efficacy. The threat of genetically engineered, antibiotic and vaccine resistant strains of Bacillus anthracis is fueling hypothesis-driven research and global techniques--including genomics, proteomics and transposon site hybridization--to facilitate the discovery of novel vaccine targets. This review highlights historical achievements and new developments in anthrax vaccine research.     

SV40 association with human malignancies and mechanisms of tumor immunity by large tumor antigen

SV40 was discovered as a contaminate of poliovirus vaccine lots distributed to millions of individuals in the United States between 1955 and 1963 while contaminated vaccine batches were later circulated worldwide. After SV40 was observed to cause in vitro animal and human cell transformations and in vivo tumor formations in animals, the search for a connection between the virus and human malignancies has continued to the present day. Different molecular methods have been used to detect SV40 gene products in a variety of human cancers, though SV40 causality in these tumor types has yet to be established. These data, however, are not without controversial issues related to inconclusive SV40 serological and epidemiological evidence alongside tools and methodologies that may contribute to false-positive results in human specimens. This review will also explore how vaccination against SV40 protein products may be used to help prevent and treat individuals with SV40-expressing cancers. Received 19 September 2006; received after revision 8 November 2006; accepted 13 December 2006     

Malaria vaccine

Summary Among infectious diseases caused by protozoa, malaria is still the greatest killer of children. Mortality in adults living in endemic areas is significantly lower because they frequently acquire partial or complete immunity to the major pathogen,Plasmodium falciparum. This natural protection indicates that vaccination may be possible, and the first candidate antigens were cloned with the use of human immune sera as probes. Genetic and biochemical analysis of the parasite proteins revealed that they are polymorphic, and frequently gene sequences were discovered which were specific for a particular parasite isolate, which eliminated most antigens for purposes of vaccine development. The most promising candidate antigens today are the major surface proteins of sporozoites and blood stage parasites. However, the immune response against those is not sufficient for complete protection, and additional, intensive research is necessary to identify new molecules to be included in a vaccine cocktail against malaria. The current spread of the disease due to increasing drug resistance of parasites and mosquito vectors emphasizes the urgent need for a vaccine.     

Malaria vaccine

Among infectious diseases caused by protozoa, malaria is still the greatest killer of children. Mortality in adults living in endemic areas is significantly lower because they frequently acquire partial or complete immunity to the major pathogen, Plasmodium falciparum. This natural protection indicates that vaccination may be possible, and the first candidate antigens were cloned with the use of human immune sera as probes. Genetic and biochemical analysis of the parasite proteins revealed that they are polymorphic, and frequently gene sequences were discovered which were specific for a particular parasite isolate, which eliminated most antigens for purposes of vaccine development. The most promising candidate antigens today are the major surface proteins of sporozoites and blood stage parasites. However, the immune response against those is not sufficient for complete protection, and additional, intensive research is necessary to identify new molecules to be included in a vaccine cocktail against malaria. The current spread of the disease due to increasing drug resistance of parasites and mosquito vectors emphasizes the urgent need for a vaccine.     

Our impasse in developing a malaria vaccine

Malaria presents a challenge to world health that to date has been beyond the abilities of researchers to conquer. This critique presents some of the strategies employed by the parasite to overcome immunity and the immunological challenges that we face to develop vaccines. A conclusion is that a vaccine must identify novel antigens or epitopes that are not normally immunogenic and which are therefore not under immune pressure and most likely to be conserved between different strains. Such antigens are most likely to be targets of cellular immunity. The case for a whole parasite blood stage vaccine is presented based on these premises.     

Towards progress on DNA vaccines for cancer

Cancer immunotherapy faces many obstacles that include eliciting immune reactions to self antigens as well as overcoming tumor-derived immunosuppressive networks and evasion tactics. Within the vaccine arsenal for inhibiting cancer proliferation, plasmid DNA represents a novel immunization strategy that is capable of eliciting both humoral and cellular arms of the immune response in addition to being safely administered and easily engineered and manufactured. Unfortunately, while DNA vaccines have performed well in preventing and treating malignancies in animal models, their overall application in human clinical trials has not impacted cancer regression to date. Since the establishment of these early trials, progress has been made in terms of increasing DNA vaccine immunogenicity and subverting the suppressive properties of tumor cells. Therefore, the success of future plasmid DNA use in cancer patients will depend on combinatorial strategies that enhance and direct the DNA vaccine immune response while also targeting tumor evasion mechanisms. Received 2 April 2007; received after revision 14 May 2007; accepted 21 May 2007     

The use of cyclophosphamide as an enhancer of the vaccine against foot-and-mouth disease

The immunization of biungulate animals with killed foot-and-mouth disease virus (FMDV) requires periodic vaccinations due to a low vaccine immunogenicity. Therefore, FMDV antigens need to be combined with adjuvants such as aluminum hydroxide, saponin or oil emulsions. Animal handling for periodic inoculations, and the repeated doses of vaccines that have to be administered increase the commercialization costs. Moreover, the use of adjuvants may induce adverse effects.In the present work we show that it is possible to increase the life span of neutralizing antibodies in serum when a single dose of cyclophosphamide (Cy) is administered four days before vaccination with aluminum hydroxidesaponin FMDV vaccine.     

Serotype-independent pneumococcal vaccines

Streptococcus pneumoniae remains an important cause of disease with high mortality and morbidity, especially in children and in the elderly. The widespread use of the polysaccharide conjugate vaccines in some countries has led to a significant decrease in invasive disease caused by vaccine serotypes, but an increase in disease caused by non-vaccine serotypes has impacted on the overall efficacy of these vaccines on pneumococcal disease. The obvious solution to overcome such shortcomings would be the development of new formulations that provide serotype-independent immunity. This review focuses on the most promising approaches, including protein antigens, whole cell pneumococcal vaccines, and recombinant bacteria expressing pneumococcal antigens. The protective capacity of these vaccine candidates against the different stages of pneumococcal infection, including colonization, mucosal disease, and invasive disease in animal models is reviewed. Some of the human trials that have already been performed or that are currently ongoing are presented. Finally, the feasibility and the possible shortcomings of these candidates in relation to an ideal vaccine against pneumococcal infections are discussed.     

Effect of papain on experimental amyloidosis

Experimental amyloidosis was induced in mice by repeated injections of complete Freund's adjuvant (CFA) reinforced with a bacterial vaccine. Papain was administered i.p. at various time intervals during the treatment with CFA. Amyloidosis was found only in the spleen and the liver. No statistically significant differences were found between the papain-treated and the control groups. It is assumed that, although papain releaseed the polysaccharide moiety from the polysaccharide protein complex, the released polysaccharides were most probably bound by electrostatic forces to the amyloid fibres, and did not interfere with amyloidogenesis.     

Effect of papain on experimental amyloidosis

Summary Experimental amyloidosis was induced in mice by repeated injections of complete Freund's adjuvant (CFA) reinforced with a bacterial vaccine. Papain was administered i.p. at various time intervals during the treatment with CFA. Amyloidosis was found only in the spleen and the liver. No statistically significant differences were found between the papain-treated and the control groups. It is assumed that, although papain released the polysaccharide moiety from the polysaccharide protein complex, the released polysaccharides were most probably bound by electrostatic forces to the amyloid fibres, and did not interfere with amyloidogenesis.     

In vitro assessment of anti-Leishmania immunity of man acquired with a vaccine

Monocytes, obtained from a human volunteer immunized with a Leishmania infantum-derived vaccine, when cultured in vitro displayed a strong parasiticidal activity against L. major promastigotes. In addition, immune serum conferred leishmanicidal activities to monocytes of normal, unexposed donors, and to murine macrophages.     

Putting endotoxin to work for us: Monophosphoryl lipid A as a safe and effective vaccine adjuvant

The development of non-infectious subunit vaccines greatly increases the safety of prophylactic immunization, but also reinforces the need for a new generation of immunostimulatory adjuvants. Because adverse effects are a paramount concern in prophylactic immunization, few new adjuvants have received approval for use anywhere in the developed world. The vaccine adjuvant monophosphoryl lipid A is a detoxified form of the endotoxin lipopolysaccharide, and is among the first of a new generation of Toll-like receptor agonists likely to be used as vaccine adjuvants on a mass scale in human populations. Much remains to be learned about this compound’s mechanism of action, but recent developments have made clear that it is unlikely to be simply a weak version of lipopolysaccharide. Instead, monophosphoryl lipid A’s structure seems to have fortuitously retained several functions needed for stimulation of adaptive immune responses, while shedding those associated with pro-inflammatory side effects. Received 25 April 2008; received after revision 05 June 2008; accepted 10 June 2008     

Protective action on mice of acellular extracts from Salmonella typhimurium]

Acellular fractions obtained by saline extraction at 60 or at 100 degree C of Salmonella typhimurium protect mice against an experimental infection with the homologous strain. After purification, these fractions which are complex, might be used for the development of a vaccine.     

Large-scale purification of inactivated influenza vaccine using membrane molecular filtration

Summary A procedure is reported for the elimination of at least 95% of hens' egg protein impurities from inactivated influenza vaccine, by selective molecular filtration through a membrane with a cut-off limit of 1×10⁶ daltons.     

In vitro assessment of anti-Leishmania immunity of man acquired with a vaccine

Summary Monocytes, obtained from a human volunteer immunized with aLeishmania infantum-derived vaccine, when cultured in vitro displayed a strong parasiticidal activity againstL. major promastigotes. In addition, immune serum conferred leishmanicidal activities to monocytes of normal unexposed donors, and to murine macrophages.     

The SARS-CoV S glycoprotein

The severe acute respiratory syndrome-coronavirus (SARS-CoV) spike (S) glycoprotein alone can mediate the membrane fusion required for virus entry and cell fusion. It is also a major immunogen and a target for entry inhibitors. Recent rapid advances in our knowledge of the structure and function of this protein have lead to the development of a number of candidate vaccine immunogens and SARS-CoV entry inhibitors.