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Influence of disease burden, public perception, and other factors on new vaccine development, implementation, and continued use.

The development, implementation, and continued use of new vaccines depends on several factors. Although disease burden seems like an obvious quantitative measure for setting priorities for new vaccine development and use, resources are not always allocated proportionately. This is particularly evident for diseases that are unique (or largely limited) to people in developing countries. Public pressure based on perceptions of the risks associated with a disease or vaccine, the cost of new vaccines, and the ability to incorporate them into existing vaccination programmes also need to be considered in the decision to introduce new vaccines. Vaccine manufacturers play an important part in development of new vaccines, and therefore, the issues that are important to them, namely, production, intellectual property rights, and product liability, must be addressed. By advocating rational decisions, supported by accurate information, scientists and public-health professionals can have an important role in transforming the potential of new vaccines into the reality of new vaccine-preventable diseases.

Animals↗

Diarrheal disease. Established pathogens, new pathogens, and progress in vaccine development.

Although much progress has been made in reducing the morbidity and mortality of infectious diarrhea through the use of oral rehydration, progress in preventive measures, such as vaccine development, has been slow. Despite the plethora of candidate vaccines developed, there has not been an effective vaccine ready for general use, particularly in developing countries, during the past decade, perhaps in part because of the as-yet-undefined pathophysiology of many of these pathogens, as well as the complexity of the gastrointestinal immune system. It is hoped that more rapid progress will be made during the next decade as our understanding of these factors increases.

Animals↗

Avian gut-associated immune system: implication in coccidial vaccine development.

Host responses to coccidia are complex and involve both humoral and cellular immune mechanisms. Convincing evidence exists for a major role of cell-mediated immunity in anticoccidial resistance. With an increasing need for the development of coccidial vaccine, understanding of the intestinal immune system is crucial. To provide increased insight into the immune mechanisms involving mucosal immune response to coccidia, cellular events involved in the maturation of intestinal immune system were studied. Postnatal development of various T lymphocyte subpopulations expressing CD3, CD8, CD4, and antigen-specific T cell receptor (TCR) heterodimers expressing gamma delta (TCR1) or alpha beta (TCR2) was investigated in chickens. Intraepithelial lymphocytes (IEL) expressing the CD8 antigen increased gradually following hatching and subsequently declined with age. The CD4+ cells represented a minor subpopulation among the IEL. The ratios of IEL T cells expressing gamma delta (TCR1) or alpha beta (TCR2) in the intraepithelium of chickens gradually increased after hatching. These results indicate maturational changes of intestinal immune system that should be considered in the development of vaccine against coccidia.

Animals↗

Bacterial otitis media: current vaccine development strategies.

Otitis media is the most common reason for children less than 5 years of age to visit a medical practitioner. Whilst the disease rarely results in death, there is significant associated morbidity. The most common complication is loss of hearing at a critical stage of the development of speech, language and cognitive abilities in children. The cause and pathogenesis of otitis media is multifactorial. Among the contributing factors, the single most important are viral and bacterial infections. Infection with respiratory syncytial virus, influenza viruses, para-influenza viruses, enteroviruses and adenovirus are most commonly associated with acute and chronic otitis media. Streptococcus pneumoniae, non-typeable Haemophilus influenzae and Moraxella catarrhalis are the most commonly isolated bacteria from the middle ears of children with otitis media. Treatment of otitis media has largely relied on the administration of antimicrobials and surgical intervention. However, attention has recently focused on the development of a vaccine. For a vaccine to be effective against bacterial otitis media, it must, at the very least, contain antigens that induce a protective immune response in the middle ear against the three most common infecting bacteria. Whilst over the past decade there has been significant progress in the development of vaccines against invasive S. pneumoniae disease, these vaccines are less efficacious for otitis media. The search for candidate vaccine antigens for non-typeable H. influenzae are well advanced whilst less progress has been made for M. catarrhalis. No human studies have been conducted for non-typeable H. influenzae or M. catarrhalis and the concept of a tribacterial vaccine remains to be tested in animal models. Only when vaccine antigens are determined and an understanding of the immune responses induced in the middle ear by infection and immunization is gained will the formulation of a tribacterial vaccine against otitis media be possible.

Animals↗

Extraintestinal isolates of Escherichia coli: identification and prospects for vaccine development.

Extraintestinal pathogenic Escherichia coli (ExPEC) cause a wide variety of infections that are responsible for significant morbidity, mortality and costs to our healthcare system. Thereby, the development of an efficacious ExPEC vaccine will minimize disease and may be cost-effective in selected patient groups. Surface polysaccharides, such as capsule, have been traditional targets for vaccine development. Considering that significant antigenic heterogeneity exists among surface polysaccharides present in various ExPEC strains, their use as vaccine candidates will be challenging. Therefore, alternative vaccine candidates/approaches are being identified and evaluated and are discussed in this review. The authors envision that an efficacious ExPEC vaccine will consist of either a polyvalent subunit vaccine or a genetically engineered killed whole-cell vaccine.

Animals↗

The role of nonhuman primate models in AIDS vaccine development.

Although animal models have been useful in guiding vaccine development, HIV/AIDS models have not yielded a clear correlate of immunity nor given consistent results on the potential efficacy of various vaccine approaches. Further development and improved uniformity in the use of animal models would maximize their potential to meet the urgent worldwide need for a safe and effective HIV vaccine.

AIDS Vaccines↗

Cell-mediated immunity and the challenges for vaccine development.

One of the hallmarks of successful vaccination is the induction of strong and persistent memory T cell responses, a process that involves striking changes in the number and functional properties of T cells. Many questions pertaining to this complex, multifaceted process remain unanswered. Some of the key issues and challenges to optimize memory T cell responses and foster vaccine development include the optimization of effector T cell burst sizes, the use of adjuvants, cytokines and co-stimulatory molecules, epitope enhancement and the standardization of techniques to detect specific T cells. Age also has an impact on vaccine design because of the physiological changes in cell-mediated immunity that occur throughout life.

Aging↗

The present status of rabies vaccine development and clinical experience with rabies vaccine.

Attempts to control human rabies have a long history: animal and human vaccines provide efficient weapons for prevention. In this presentation, we would like to consider the different rabies vaccines available for human use, and particularly the modern vaccines produced in cell culture. Rabies virus is considered as an unique virus, but in fact, 5 groups of rabies fixed strains are used throughout the world to produce human rabies vaccines: Pasteur, Beijing, Flury, Fuenzalida and SAD strains. The Pasteur-derived strains, designated PV or PM, are the most widely used for the production of traditional vaccines of the Semple or Suckling Mouse Brain (SMB) types, but also for the production of modern cell culture vaccines: Human Diploid and Purified Vero Cell vaccines (HDCV and PVRV). The different rabies vaccines should be classified according to the cell system used to cultivate the virus: animal systems are still employed to produce the old traditional vaccines-Semple and SMB-which continue to be produced in several countries; Primary cell systems, particularly Hamster Kidney and Chick embryo cells, are used; Cell lines are presently the most interesting approach for vaccine production. The use of the human diploid cell system permitted the development of the HDCV, the most widely distributed cell culture rabies vaccine, and today considered as the reference vaccine. The heteroploid VERO cell line was introduced in 1982 to the production of inactivated rabies vaccine; it retained all the advantages of the Human Diploid Cell system, while offering the possibility of the large scale industrial production of PVRV. For both HDCV and PVRV, production security is guaranteed by the existence of a master cell seed and working cell bank, with a complete history of the cell, a limited number of passages and permanent and total quality control of the cell substrate. The principal human rabies vaccines produced worldwide at present using cell culture are compared, in terms of their technical characteristics and their capacity economically to face worldwide vaccine needs. The greatest needs are today in tropical countries, where only a limited amount of modern cell culture vaccines are used.

Animals↗

Contraceptive vaccine development.

Recent advances in antigen definition and production have made the development of a contraceptive vaccine more attainable. Such a vaccine must evoke an immune response that blocks an indispensable step in the reproductive process. Vaccine research involves many approaches to fertility prevention. Vaccines are being developed that could interrupt fertility by inhibition of gonadotrophin release, the function of follicle-stimulating hormone or the effects of human chorionic gonadotrophin (hCG); alternatively, they may prevent fertilization by interfering with the transport of spermatozoa or with sperm-zona pellucida binding. The most advanced prototype is a vaccine based on antibodies to beta hCG. Such vaccines are being studied for clinical efficacy. Many hurdles remain in contraceptive vaccine development. Since the antigens are peptides or small proteins, the resultant immune response is usually moderate, and better adjuvants and delivery systems must be developed to enhance and maintain the immune response. Improvement of the mucosal immune response may be necessary for vaccines incorporating sperm antigens. Research on vaccines that control fertility has resulted in a fascinating base of scientific knowledge that, it is hoped, can be converted into products that will allow another option for individuals who wish to control their fertility.

Animals↗

An attenuated West Nile prototype virus is highly immunogenic and protects against the deadly NY99 strain: a candidate for live WN vaccine development.

In a short time, West Nile virus has developed into a nationwide health and veterinary problem. The high virulence of the circulating virus and related lineage 1 WN strains hinders development of an attenuated live vaccine. We describe an attenuated WN isolate, WN1415, which is a molecularly cloned descendant of the WN prototype B956 strain. The parent virus belongs to lineage 2, members of which have not been associated with epidemic or epizootic outbreaks. A set of non-conservative mutations, mostly in non-structural protein genes, distinguishes the WN1415 isolate from the parent B956 prototype strain. Immunization with WN1415 (55-550,000 pfu) established a potent immunity, which protected the majority of mice against lethal challenge with WN NY99. The attenuated nature of the isolate and its excellent growth characteristics combined with the availability of a highly stable infectious clone make the isolate an attractive candidate for live WN vaccine development.

Amino Acid Substitution↗

Vaccine development for an imminent pandemic: why we should worry, what we must do.

The avian H5N1 virus continues to evolve and poses an imminent pandemic threat. Pandemic vaccine development, however, has progressed slowly. For it to succeed, it must be based on a public health perspective that reflects the arithmetic of pandemic vaccine demand, especially by countries without vaccine companies. Clinical trials of H5N1 vaccines have been discouraging, and we must understand why the H5N1 virus is so poorly immunogenic. Antigen-sparing pandemic vaccines will be required, and future trials must identify the most effective adjuvant and determine whether whole virus vaccines will be needed. Problems related to intellectual property and concerns about several regulatory issues must be resolved. Public funding for clinical trials must be provided and firm leadership and coordination exercised by national and international (WHO) public health officials. Vaccination for an imminent pandemic requires a global perspective not only for vaccine development but also for vaccine production and distribution.

Clinical Trials as Topic↗

How reliable are models for malaria vaccine development? Lessons from irradiated sporozoite immunizations.

Models occupy a key position in the development of anti-parasitic vaccines, yet their relevance has been seldom addressed. It is customary to admit that malaria vaccine development requires easy-to-handle, laboratory models. Animal models involving predominantly inbred rodents and primates as parasite hosts are currently the basic tools for the study of host-parasite interactions. Literature however indicates that the induction of host protection is more difficult in natural host-parasite pairs than in experimental models of parasite infection. Moreover different models delineate a wide range of host-pathogen relationship profiles providing a mosaic of contradictory informations, yet there is little incentive to delineate their relevance or to exploit recent advances to develop improved model systems. In this context the analysis of natural host-parasite interactions between Plasmodium berghei and its mammalian host and reservoir, the tree rat Grammomys surdaster could ge of relevance in the study of host-parasite interactions.

Animals↗

Issues in tick vaccine development: identification and characterization of potential candidate vaccine antigens.

It is well established that acquired immunity against tick infestation can be induced by repeated tick infestation or by active immunization with either crude or purified native as well as recombinant antigens. This review provides insights into the development of tick vaccines with reference to identification, purification and molecular cloning of candidate target antigens.

Animals↗

New approaches in vaccine development.

In the last century, vaccines have been one of the most powerful tools for preventing infectious diseases. Smallpox has been eradicated and other diseases such as poliomyelitis or measles have been reduced to very low levels in many regions of the world. However, infectious diseases remain the leading cause of death worldwide. Thus, the development of vaccines to prevent diseases for which no vaccine currently exists such as AIDS or malaria as well as the improvement of efficacy and safety of existing vaccines remains a high priority. Achieving such ambitious goals in a near future will certainly require a strong modification of the methods that have been used so far to identify vaccine candidates. In particular, modern vaccinology could strongly benefit of the latest developments of molecular biology and immunology. Here, we will discuss some potential applications of the increasing knowledge of pathogen genomes as well as the immune system for the discovery of new antigenic targets and the development of new strategies of vaccination.

Acquired Immunodeficiency Syndrome↗

Field studies of cytotoxic T lymphocytes in malaria infections: implications for malaria vaccine development.

The search for a cytotoxic T lymphocyte (CTL)-inducing malaria vaccine has moved forward from epitope identification to planning stages of safety and immunogenicity trials of candidate vaccines. Development of CTL-inducing vaccine candidates has taken center stage based on the observation that CTL-mediated protection might be the dominant mechanism by which sterile immunity is achieved in irradiated sporozoite immunization experiments in humans and laboratory animals. However, studies in naturally infected individuals living in endemic areas, as reviewed here by Michael Aidoo and Venkatachalam Udhayakumar, have revealed that CTL induction might be influenced by factors such as parasite variants, host genes, other infections and transmission patterns. The influence of these factors on CTL induction has been demonstrated individually and in various combinations in controlled animal experiments. However, in naturally infected humans, they are presented in a complex host-parasite-environment interaction, in a manner that is not easily achieved in laboratory-based experiments. Understanding these interactions is crucial for the development and testing of CTL-inducing vaccines for humans.

Amino Acid Sequence↗

India embarks on vaccine-development scheme.

Six diseases are the targets of the vaccine development program in India. The project involves 12 national research institutions and two private companies, Indian Immunologicals and Bharat Biotech, which are both based in Hyderabad, India. Targets of the program are AIDS, cholera, Japanese encephalitis, malaria, rabies, and tuberculosis. In a report in the journal Nature Medicine, K. S. Jayaraman notes that a single agency--the Department of Biotechnology (DBT)--will oversee the project. According to Jayaraman, DBT secretary Manju Sharma predicts the deployment of cholera and rabies vaccines by the year 2002. An oral recombinant cholera vaccine recently proved safe in Phase I trials at the Institute of Microbial Technology, Chandigart, and a promising DNA vaccine for rabies is in late preclinical development at the Indian Institute of Science, Bangalore. The AIDS vaccine initiative, underway at the All India Institute of Medical Sciences, New Delhi, will use a poxvirus construct expressing HIV-I subtype C, the strain most prevalent on the Indian subcontinent. N. K. Vinayak, head of the DBT medical division, told Jayaraman that the HIV vaccine would be ready for animal studies in a year. Funding for the program seems small by Western standards: $4 million over 3 years.

Acquired Immunodeficiency Syndrome↗

[Vaccine development for P. aeruginosa: based on antigen cloning of clinical vaccines][.

For the development of a clinical vaccine against P. aeruginosa infections we cloned the genes for the main outer membrane proteins F and I of P. aeruginosa and characterized protective epitopes by monoclonal antibodies. A recombinant hybrid protein (OprFaa190-342-OprIaa21-83) was expressed in E. coli which represents the protective epitopes. The vaccine showed to be highly protective in mice against experimental P. aeruginosa infections. A phase I trial in human volunteers showed that the vaccine is well tolerated and that high antibody titers against P. aeruginosa were induced.

Antigens, Bacterial↗

Perspectives of HIV vaccine developments.

Human immunodeficiency virus type 1 (HIV-1) may enter the blood stream as free virus or via infected lymphocytes, which poses problems for vaccine development. The classical vaccine designs, attenuated, inactivated, or subunit vaccine will be discussed with regard to HIV. Development of a recombinant subunit vaccine appears to be the most promising approach. Forthcoming results from experiments involving inoculation of chimpanzees should allow evaluation of the feasibility of using a subunit vaccine based on the env-glycoprotein. Also the use of live recombinant vaccinia merits further investigation.

Animals↗