Advances In Vaccine Development Research Articles

Vaccine Development Against Leishmania donovani

Visceral leishmaniasis (VL) caused by Leishmania donovani and Leishmania infantum/chagasi represents the second most challenging infectious disease worldwide, leading to nearly 500,000 new cases and 60,000 deaths annually. Zoonotic VL caused by L. infantum is a re-emergent canid zoonoses which represents a complex epidemiological cycle in the New world where domestic dogs serve as a reservoir host responsible for potentially fatal human infection and where dog culling is the only measure for reservoir control. Life-long immunity to VL has motivated development of prophylactic vaccines against the disease but very few have progressed beyond the experimental stage. No licensed vaccine is available till date against any form of leishmaniasis. High toxicity and increasing resistance to the current chemotherapeutic regimens have further complicated the situation in VL endemic regions of the world. Advances in vaccinology, including recombinant proteins, novel antigen-delivery systems/adjuvants, heterologous prime-boost regimens and strategies for intracellular antigen presentation, have contributed to recent advances in vaccine development against VL. Attempts to develop an effective vaccine for use in domestic dogs in areas of canine VL should be pursued for preventing human infection. Studies in animal models and human patients have revealed the pathogenic mechanisms of disease progression and features of protective immunity. This review will summarize the accumulated knowledge of pathogenesis, immune response, and prerequisites for protective immunity against human VL. Authors will discuss promising vaccine candidates, their developmental status and future prospects in a quest for rational vaccine development against the disease. In addition, several challenges such as safety issues, renewed and coordinated commitment to basic research, preclinical studies and trial design will be addressed to overcome the problems faced in developing prophylactic strategies for protection against this lethal infection.

Enhanced transgene expression improves immune responses following DNA vaccination (53.1)

Abstract Plasmid DNA (pDNA)-based gene delivery has the potential to advance vaccine development due to advantages such as low cost, ease of production, safety (e.g. pDNA does not cause insertional mutagenesis), and the flexibility to introduce several genes at once. To date, there are more than 300 clinical trials involving pDNA-based gene transfer. Although promising, these trials have revealed that poor transfection efficiency, transient protein production, and low immunogenicity limit therapy efficacy. We are investigating the use of minicircle (MC) DNA as a means of circumventing these limitations. MC vectors contain the expression cassette of full-length plasmids, but lack the bacterial backbone sequences that are targeted for transcriptional repression in mammalian cells. Removal of these plasmid backbone sequences is achieved via site-specific recombination in Escherichia coli prior to episomal (i.e. MC) DNA isolation. The absence of these prokaryotic elements also reduces MC size relative to its parental pDNA, leading to enhanced transfection efficiencies. Data will be presented showing that vaccination with MC DNA results in significantly higher and more prolonged reporter transgene expression. Furthermore, we compare specific responses of adoptively transferred and endogenous CD8+ T cells following vaccination of mice with either parental pDNA or MC-encoded antigen.

How To Become a Top Model: Impact of Animal Experimentation on Human Salmonella Disease Research

Salmonella serotypes are a major cause of human morbidity and mortality worldwide. Over the past decades, a series of animal models have been developed to advance vaccine development, provide insights into immunity to infection, and study the pathogenesis of human Salmonella disease. The successive introduction of new animal models, each suited to interrogate previously neglected aspects of Salmonella disease, has ushered in important conceptual advances that continue to have a strong and sustained influence on the ideas driving research on Salmonella serotypes. This article reviews important milestones in the use of animal models to study human Salmonella disease and identify research needs to guide future work.

Immunologic Monitoring of Cellular Immune Responses in Cancer Vaccine Therapy

Immunologic Monitoring of Cellular Immune Responses in Cancer Vaccine Therapy

Rinderpest and Peste des Petits Ruminants: Virus Plagues of Large and Small Ruminants

In Rinderpest and Peste des Petits Ruminants: Virus Plagues of Large and Small Ruminants, Tom Barrett (now deceased), of the Institute for Animal Health, Pirbright Laboratory, Surrey, UK, and his co-editors have subtly presented the main developments in the quest to conquer these diseases. The instructive text, which touches on the key dynamics of both deadly diseases, incorporates considerable historical detail, infection biology, and information on disease diagnosis, control, and eradication. This book consists of high quality scientific and historical research based on the editors’ experience with morbilliviruses and collaborations with other researchers worldwide. In total, 22 scientists have contributed their expertise on various infectious diseases to the monograph’s 17 chapters. Throughout, the contributors have tried to maintain an appropriate balance between peste des petits ruminants (PPR) and rinderpest (RP). This hypothesis-based balancing act is important to understand PPR. A future significance of PPR can be realized by the phrase stated by the editors, “If rinderpest becomes a disease of the past, PPR is certainly a disease of the future.” The book starts with an historical account of the RP and PPR diseases accompanied by photographs from the 18th century. These photographs are detailed, illustrative, and fascinating. Of particular interest are a condolence letter, written by Emile Roux from Institute Pasteur to the widow of Joseph Hamoir, with whom Emile Roux worked on rinderpest, and a group photo, including Robert Koch, of his visit to the Imperial Veterinary Laboratory (currently Indian Veterinary Research Institute, Mukteshwar, India) in 1897 where he conducted experiments to immunize cattle with the bile taken from an animal that had succumbed in a virulent outbreak of rinderpest. The book focuses on the following issues: relative position of each member in the genera, comparative molecular biology, pathophysiology of the infectious diseases, global epidemiologic patterns, contribution of countries in the eradication of the disease under the Pan African Rinderpest Campaign Programme and the Pan African Programme for the Control of Epizootics, viral immune suppression, and molecular diagnostic approaches being developed. For all these issues, the importance for clinicians of accurate diagnosis and management and prevention of infectious diseases is highlighted. Because of the current sensitivity about an emergence of PPR and the successful Global Rinderpest Eradication Programme, the contributors believe that PPR can be controlled similarly and its spread prevented. Thus, the last 7 chapters emphasize the traditional prophylactic measures, potency of vaccines and possibility of vaccine use, the history of vaccine improvement, recent advances in vaccine development, implementation of international control campaigns for the eradication of RP and PPR by using vaccine, and a brief overview of the pathogenesis and eradication of measles virus. Finally, the editors assess the real cost and benefits of the Global Rinderpest Eradication Programme campaign and predict that the world will soon be free of RP, at comparatively little cost. Although the book discusses many aspects of the current situation, such as epidemiological distribution, progress in vaccine development, and advances in the diagnosis of PPR diagnostic procedures, information regarding the most recent developments is lacking; a few chapters were written in ≈2000 before the increase in PPR research. Still, I consider this to be the only book that comprehensively describes PPR. It is suitable not only for academics and researchers, but also for virologists, infectious disease specialists, vaccine researchers, and clinicians. Moreover, this book provides appropriate scientific source material suitable for undergraduate and graduate studies.

100th Anniversary of the death of Ricketts: Howard Taylor Ricketts (1871–1910). The namesake of the Rickettsiaceae family

The US American pathologist and microbiologist Howard Taylor Ricketts died 100 years ago. He is renowned for discovering the causative organism and the transmission route of Rocky Mountain spotted fever and of tabardillo – an epidemic louse-borne typhus occurring especially in Mexico. He also found that both diseases were caused by related infectious agents ( Rickettsia rickettsii and Rickettsia prowazekii). The scientific community therefore named both a taxonomic family (Rickettsiaceae) and an order (Rickettsiales) after the scientist. Ricketts’ work on immunity and serums became the basis for further advances in vaccine development.

PHILANTHROPY Gates pledges $10 billion for vaccine research and distribution in poor countries

The Bill & Melinda Gates Foundation has pledged $10 billion over 10 years to support vaccine R&D and the delivery of new vaccines—for ailments such as malaria, diarrheal diseases, and tuberculosis—to the world’s poorest countries. This latest round of funding comes on top of $4.5 billion that the foundation has already given to this cause. “Vaccines already save and improve millions of lives in developing countries,” Microsoft founder Bill Gates said at the World Economic Forum meeting in Davos, Switzerland, on Jan. 29. “Innovation will make it possible to save more children than ever before.” He called on governments and the private sector to invest in R&D and immunization programs. In announcing the funding, Melinda Gates pointed to record rates of vaccinations in the developing world and dramatic decreases in deaths from preventable diseases, such as measles. She also noted advances in vaccine development, with more candidates reaching late-stage clinical trials and new vaccines ...

The Relationship between Anti-merozoite Antibodies and Incidence of Plasmodium falciparum Malaria: A Systematic Review and Meta-analysis

One of the criteria to objectively prioritize merozoite antigens for malaria vaccine development is the demonstration that naturally acquired antibodies are associated with protection from malaria. However, published evidence of the protective effect of these antibodies is conflicting. We performed a systematic review with meta-analysis of prospective cohort studies examining the association between anti-merozoite immunoglobin (Ig) G responses and incidence of Plasmodium falciparum malaria. Two independent researchers searched six databases and identified 33 studies that met predefined inclusion and quality criteria, including a rigorous definition of symptomatic malaria. We found that only five studies were performed outside sub-Saharan Africa and that there was a deficiency in studies investigating antibodies to leading vaccine candidates merozoite surface protein (MSP)-1(42) and erythrocyte binding antigen (EBA)-175. Meta-analyses of most-studied antigens were conducted to obtain summary estimates of the association between antibodies and incidence of P. falciparum malaria. The largest effect was observed with IgG to MSP-3 C terminus and MSP-1(19) (responders versus nonresponders, 54%, 95% confidence interval [CI] [33%-68%] and 18% [4%-30%] relative reduction in risk, respectively) and there was evidence of a dose-response relationship. A tendency towards protective risk ratios (RR<1) was also observed for individual study estimates for apical membrane antigen (AMA)-1 and glutamate-rich protein (GLURP)-R0. Pooled estimates showed limited evidence of a protective effect for antibodies to MSP-1 N-terminal regions or MSP-1-EGF (epidermal growth factor-like modules). There was no significant evidence for the protective effect for MSP-2 (responders versus nonresponders pooled RR, MSP-2(FC27) 0.82, 95% CI 0.62-1.08, p = 0.16 and MSP-2(3D7) 0.92, 95% CI 0.75-1.13, p = 0.43). Heterogeneity, in terms of clinical and methodological diversity between studies, was an important issue in the meta-analysis of IgG responses to merozoite antigens. These findings are valuable for advancing vaccine development by providing evidence supporting merozoite antigens as targets of protective immunity in humans, and to help identify antigens that confer protection from malaria. Further prospective cohort studies that include a larger number of lead antigens and populations outside Africa are greatly needed to ensure generalizability of results. The reporting of results needs to be standardized to maximize comparability of studies. We therefore propose a set of guidelines to facilitate the uniform reporting of malaria immuno-epidemiology observational studies. Please see later in the article for the Editors' Summary.

RB-Finder: An Improved Distance-Based Sliding Window Method to Detect Recombination Breakpoints

Recombination detection is important before inferring phylogenetic relationships. This will eventually lead to a better understanding of pathogen evolution, more accurate genotyping, and advancements in vaccine development. In this paper, we introduce RB-Finder, a fast and accurate distance-based window method to detect recombination in a multiple sequence alignment. Our method introduces a more informative distance measure and a novel weighting strategy to reduce the window size sensitivity problem and hence improve the accuracy of breakpoint detection. Furthermore, our method is faster than existing phylogeny-based methods since we do not need to construct and compare complex phylogenetic trees. When compared with the current best method Pruned-PDM, our method is a few hundred times more efficient. Experimental evaluation of RB-Finder using synthetic and biological datasets showed that our method is more accurate than existing phylogeny-based methods. We also show how our method has potential use in other related applications such as genotyping.

Better Influenza Vaccines for Older People: What Will It Take?

Of all infectious diseases, influenza is foremost in its association with an agerelated increase in serious consequences leading to hospitalization, debilitating complications, and death. Current influenza vaccines are both effective [1] and cost saving [2]; however, in spite of widespread influenza vaccination programs, rates of hospitalization for acute respiratory illnesses and cardiovascular diseases have been increasing in the population aged ^65 years during the influenza season [3]. Given that current influenza vaccines are only 30%40% effective in this population, there appears to be a considerable margin for improvement. However, in spite of recent advances in vaccine development, the same technology has been used to produce seasonal influenza vaccines for the past 40 years.

Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms

Parasites from the protozoan phylum Apicomplexa are responsible for diseases, such as malaria, toxoplasmosis and cryptosporidiosis, all of which have significantly higher rates of mortality and morbidity in economically underdeveloped regions of the world. Advances in vaccine development and drug discovery are urgently needed to control these diseases and can be facilitated by production of purified recombinant proteins from Apicomplexan genomes and determination of their 3D structures. To date, both heterologous expression and crystallization of Apicomplexan proteins have seen only limited success. In an effort to explore the effectiveness of producing and crystallizing proteins on a genome-scale using a standardized methodology, over 400 distinct Plasmodium falciparum target genes were chosen representing different cellular classes, along with select orthologues from four other Plasmodium species as well as Cryptosporidium parvum and Toxoplasma gondii. From a total of 1008 genes from the seven genomes, 304 (30.2%) produced purified soluble proteins and 97 (9.6%) crystallized, culminating in 36 crystal structures. These results demonstrate that, contrary to previous findings, a standardized platform using Escherichia coli can be effective for genome-scale production and crystallography of Apicomplexan proteins. Predictably, orthologous proteins from different Apicomplexan genomes behaved differently in expression, purification and crystallization, although the overall success rates of Plasmodium orthologues do not differ significantly. Their differences were effectively exploited to elevate the overall productivity to levels comparable to the most successful ongoing structural genomics projects: 229 of the 468 target genes produced purified soluble protein from one or more organisms, with 80 and 32 of the purified targets, respectively, leading to crystals and ultimately structures from one or more orthologues.

Immunization update and hot topics in clinical immunology: How does this relate to my practice?

The prevention of infectious diseases by the use of vaccines represents one of medicine's greatest triumphs during the 20th century. This era has witnessed the global eradication of smallpox as a result of Jennerian cowpox vaccination, the elimination of paralytic poliomyelitis from the western hemisphere, and within 5-10 years the anticipated eradication of poliomyelitis worldwide as a result of the poliovirus vaccines. Next slated for worldwide eradication is measles, the great killer of infants and children, which each year extracts a global mortality of one million victims. Throughout the 20th century the percutaneous (i.e., subcutaneous or intramuscular) route has almost exclusively been the preferred way to administer vaccines. However, as a result of several important scientific discoveries made during the 20th century, including new tissue-culturing techniques, the development of recombinant DNA technology, and genetic sequencing, a whole new generation of tailor-made modern vaccines has become available, including DNA vaccines and transgenic plant vaccines. Moreover, it became apparent that alternative routes of administration of vaccines, such as by aerosol immunization might be more appropriate and more effective than immunization via the parenteral route. The overall success in vaccine development, however, has not been without cost. For every new vaccine that has been developed, an adverse effect has been seen. Thus, although modern vaccines are extremely safe and effective, they are neither completely safe nor completely effective. The goal of vaccine development, therefore, is to achieve the highest degree of protection and the lowest rate of adverse effects. This paper describes some of the recent advances in vaccine development and will focus on some hot topics relating to the recent development and use of respiratory aerosolized vaccines.

Tick control: further thoughts on a research agenda

Tick control is a subject that has stimulated intense interest for more than a century. This article is a commentary on the research needs for tick control proposed in Peter Willadsen's recent article and it calls attention to tick control strategies that were either poorly represented or omitted from the latter. Special consideration is given to host-targeted devices to control disease vector ticks infesting wildlife, to pheromone-impregnated decoys for attracting and killing ticks in the natural environment and on hosts, and to more up-to-date advances in vaccine development.

Modelling hospital admissions for lower respiratory tract infections in the elderly in England

Despite the importance of lower respiratory-tract infection (LRI) in causing hospitalizations in elderly patients (>or=65 years of age) and recent advances in vaccine development, a complete picture of the causative organisms is not available. All hospital discharge diagnoses (ICD-10 code) for LRI in elderly patients in England during 1995-1998 were reviewed. Using known seasonality in potential causative agents of LRI, the contribution of different respiratory pathogens to hospitalizations coded as 'unspecified LRI' was estimated by multiple linear regression analysis. Ninety-seven per cent of 551633 LRI-associated diagnoses had no specific organism recorded. From the statistical model the estimated proportions of admissions attributable to different pathogens were applied to calculate estimated hospitalization rates: 93.9 hospitalizations/10000 population aged >or=65 years due to S. pneumoniae, 22.9 to influenza virus, 22.3 to H. influenzae, 17.0 to whooping cough, and 12.8 to respiratory syncytial virus. There is enormous potential to improve health using existing vaccines and those under development.

Advances in vaccine development against the pre-erythrocytic stage of Plasmodium falciparum malaria

With approximately 2.4 billion people at risk, Plasmodium falciparum malaria infection caused by an infectious bite of an Anopheles mosquito continues to be a major cause of mortality and morbidity, mainly in the tropics and subtropics. Measures to control the mosquito vector on a broad scale are expensive and need to be maintained continuously. The rapid emergence of parasite strains that are resistant to affordable drugs highlights the urgent need for a cheap and effective vaccine. Candidate vaccines that have been developed to date target different stages of the parasite life cycle. This review describes the recent advances in the development of a vaccine that aims to terminate the infection at its first stage in the liver. The candidate vaccines that are currently under clinical evaluation are introduced and the results from recent trials discussed. The review aims to explain the immunologic challenges a successful vaccine has to meet, as well as the different strategies that are currently employed in an attempt to induce a protective immune response. Furthermore, an outline of available options to be tested in the near future will be presented.

Prevention of Staphylococcus aureus infections: advances in vaccine development

Staphylococcus aureus is a ubiquitous bacterial species that causes serious disease in a minority of carriers, particularly in hospital settings. S. aureus disease is difficult to treat, and antibiotic-resistant strains have become common. Prevention of S. aureus disease would therefore be the best way to limit the morbidity and mortality caused by this organism, but its virulence is determined by a number of different factors, making design of a widely effective vaccine difficult. Here, various S. aureus virulence factors and attempts to develop vaccines or other protective drugs based on these factors are reviewed. In particular, the results of a Phase III clinical study of a vaccine directed at capsular polysaccharides types 5 and 8 are discussed.

Vaccines for otitis media: proposals for overcoming obstacles to progress

Otitis media is a common problem with enormous morbidity worldwide. The development of vaccines to prevent otitis media would have an important human and economic impact. A striking lack of progress in the development, production and clinical testing of vaccines to prevent otitis media has occurred in the past decade. This review outlines a series of specific proposals intended to advance vaccine development for otitis media.

Human papillomavirus vaccines and prevention of cervical cancer.

Cervical cancer and precancerous cervical lesions constitute a major problem in women's health. Every year 470,000 cases of cervical cancer are diagnosed worldwide, and about half the women afflicted will die. In the United States alone, approximately 14,000 cases of cervical cancer are diagnosed each year despite the availability of screening and access to high-quality gynecological care. With the confirmation that cervical cancer is caused by an infectious agent, human papillomavirus, the possibility of fighting this disease with either prophylactic or therapeutic vaccination arose. This review describes advances in vaccine development and very promising first results for prophylactic vaccination against cervical cancer.

Candidate HIV/AIDS vaccines

Candidate HIV/AIDS vaccines

Capsulate bacteria and the lung.

Capsulate bacteria cause the majority of community-acquired pneumonia presenting to hospital world-wide, at all ages. They are united by the virulence factor of their differing capsular polysaccharides, enabling them to evade phagocytosis. All cause invasive disease beyond the respiratory tract, including septicaemia and central nervous system infection. Recent advances in vaccine development have made the capsular polysaccharide an achievable target for vaccine strategies across all ages, with impacts already seen upon Streptococcus pneumoniae and Haemophilus influenzae type b pneumonia in countries able to afford these new vaccines.