New Approaches In Vaccine Development Research Articles

497. Fecal cytokine profiling and markers of intestinal inflammation in Aotus nancymaae diarrhea model for enteropathogens

Abstract Background Naval Medical Research Unit 6 (NAMRU-6) established an animal model that closely resembles diarrheal diseases caused by Shigella, Campylobacter, and enterotoxigenic Escherichia coli (ETEC) in humans. These enteropathogens cause considerable mortality due to diarrhea in children and morbidity in travelers and military personnel deployed to regions of high prevalence. The successful oral challenge model developed in Aotus nancymaae, a New World monkey species, for Shigella, Campylobacter, and ETEC results in reproducible diarrhea attack rates of ≥70%. This model has been fundamental for the development and evaluation of new vaccine candidates. Many new approaches in vaccine development focus on stimulating antibodies against specific antigens expressed by these enteropathogens. Recent studies use the Aotus diarrhea model to evaluate new passive therapeutic and prophylactic treatments to prevent infection, inflammation, or diarrhea. However, the immune response and intestinal inflammation by the main enteropathogens are not clearly defined. Methods This study investigates how the cytokines and fecal markers of intestinal inflammation respond to gastroenteritis caused by Shigella, Campylobacter and ETEC in Aotus. Twenty-nine fecal cytokines (FC) were measured during diarrhea induced by Shigella flexneri (N = 8), Campylobacter jejuni (N=8), and ETEC (N = 8). Results Of note, both IL-1β and IL-15 were significantly increased at 24 hours after ETEC challenge. In contrast, when an infection with Shigella flexneri occurs, a significant increase in cytokines and chemokines such as MIF, MIP-1α and MIP-1β are observed 24 hours after challenge. While animals challenged with Campylobacter jejuni produce an increase in IL-1β 24 hours after challenge and an increase in cytokines MIF, MIP-1α and MIP-1β 4 days after challenge. Conclusion There is nonspecific upregulation of TH1/TH17 effector cytokines and those known to mediate intestinal barrier damage. The FC profiles have a different behavior between the three enteropathogens. This provides new insights into gut-specific immune alterations in the Aotus diarrhea model, which will help improve the design of new prophylactic and therapeutic treatments against diarrhea. Disclosures All Authors: No reported disclosures.

Current approaches to HIV vaccine development: a narrative review.

IntroductionThe development of an effective vaccine to protect against HIV is a longstanding global health need complicated by challenges inherent to HIV biology and to the execution of vaccine efficacy testing in the context of evolving biomedical prevention interventions. This review describes lessons learnt from previous efficacy trials, highlights unanswered questions, and surveys new approaches in vaccine development addressing these gaps.MethodsWe conducted a targeted peer‐reviewed literature search of articles and conference abstracts from 1989 through 2021 for HIV vaccine studies and clinical trials. The US National Library of Medicine's Clinical Trials database was accessed to further identify clinical trials involving HIV vaccines. The content of the review was also informed by the authors’ own experience and engagement with collaborators in HIV vaccine research.DiscussionThe HIV vaccine field has successfully developed multiple vaccine platforms through advanced clinical studies; however, the modest efficacy signal of the RV144 Thai trial remains the only demonstration of HIV vaccine protection in humans. Current vaccine strategies include prime‐boost strategies to improve elicitation of immune correlates derived from RV144, combination mosaic antigens, novel viral vectors, antigens designed to elicit broadly neutralizing antibody, new nucleic acid platforms and potent adjuvants to enhance immunogenicity across multiple classes of emerging vaccine candidates.ConclusionsHIV vaccine developers have applied lessons learnt from previous successes and failures to innovative vaccine design approaches. These strategies have yielded novel mosaic antigen constructs now in efficacy testing, produced a diverse pipeline of early‐stage immunogens and novel adjuvants, and advanced the field towards a globally effective HIV vaccine.

Cutaneous leishmaniasis: immune responses in protection and pathogenesis.

Cutaneous leishmaniasis is a major public health problem and causes a range of diseases from self-healing infections to chronic disfiguring disease. Currently, there is no vaccine for leishmaniasis, and drug therapy is often ineffective. Since the discovery of CD4(+) T helper 1 (TH1) cells and TH2 cells 30 years ago, studies of cutaneous leishmaniasis in mice have answered basic immunological questions concerning the development and maintenance of CD4(+) T cell subsets. However, new strategies for controlling the human disease have not been forthcoming. Nevertheless, advances in our knowledge of the cells that participate in protection against Leishmania infection and the cells that mediate increased pathology have highlighted new approaches for vaccine development and immunotherapy. In this Review, we discuss the early events associated with infection, the CD4(+) T cells that mediate protective immunity and the pathological role that CD8(+) T cells can have in cutaneous leishmaniasis.

Thinking globally, acting locally: harnessing the immune system to deal with recalcitrant pathogens.

ABSTRACTTraditional approaches to harnessing the immune system to confront infectious diseases depend on vaccines, which have generally proven highly effective, but for many infections these either are not available or are of limited effectiveness. Although antibiotic therapy has been extremely successful in reducing the burden of bacterial disease, the emergence of resistance among several important pathogens threatens to undermine this accomplishment, and despite some successes chemotherapeutic treatments for viral, fungal, and parasitic infections are more limited. Understanding the mechanisms whereby pathogens manipulate the immune system to favor their survival, or exploit weaknesses in host immunity, can lead to novel approaches for the treatment of infections by redirecting host immune responses against the pathogen. Such treatments may be most effectively applied at the mucosal locations which are frequently the sites of initial infection and may also suggest new approaches for vaccine development.

Hepatitis C Virus - Proteins, Diagnosis, Treatment and New Approaches for Vaccine Development

Hepatitis C virus (HCV) causes acute and chronic human hepatitis infection and as such is an important global health problem. The virus was discovered in the USA in 1989 and it is now known that three to four million people are infected every year, WHO estimating that 3 percent of the 7 billion people worldwide being chronically infected. Humans are the natural hosts of HCV and this virus can eventually lead to permanent liver damage and carcinoma. HCV is a member of the Flaviviridae family and Hepacivirus genus. The diameter of the virus is about 50-60 nm and the virion contains a single-stranded positive RNA approximately 10,000 nucleotides in length and consisting of one ORF which is encapsulated by an external lipid envelope and icosahedral capsid. HCV is a heterogeneous virus, classified into 6 genotypes and more than 50 subtypes. Because of the genome variability, nucleotide sequences of genotypes differ by approximately 31-34%, and by 20-23% among subtypes. Quasi-species of mixed virus populations provide a survival advantage for the virus to create multiple variant genomes and a high rate of generation of variants to allow rapid selection of mutants for new environmental conditions. Direct contact with infected blood and blood products, sexual relationships and availability of injectable drugs have had remarkable effects on HCV epidemiology. Hundreds of thousands of people die each year from hepatitis and liver cancer caused by HCV virus infection. Approximately 80% of patients with acute hepatitis C progress into a chronic disease state leading to serious hepatic disorders, 10-20% of which develop chronic liver cirrhosis and hepatocellular carcinoma. The incubation period of HCV is 6-8 weeks and the infection is often asymptomatic so it is very hard to detect at early stages, making early treatment very difficult. Therefore, hepatitis C is called a "silent disease". Neutralizing antibodies are produced against several HCV proteins during infection but the virus mutates to escape from antibodies. Some patients with chronic hepatitis C may have some symptoms such as fatigue, muscle aches, nausea and pain. Autoimmune and immunecomplex-mediated diseases have also been reported with chronic HCV infection.

A MRSA-terious enemy among us: Boosting MRSA vaccines

Infection with methicillin-resistant Staphylococcus aureus (MRSA) can cause symptoms ranging from mild skin infections to more severe disease in various organs, even among healthy individuals. The ability of this pathogen to escape our immune arsenal and overcome antibiotic therapy poses a challenge to preventing their spread and treating the related symptoms. In 'Bench to Bedside', Scott Kobayashi and Frank DeLeo explore new approaches for vaccine development that focus on antigens required for establishment of disease. Studies with infected mice immunized against S. aureus coagulases—important for abscess formation and bloodstream infection—suggest such an approach may be used to reduce bacterial load and protect against severe disease in humans. In 'Bedside to Bench', Michael Otto examines a large human study where the presence of genes encoding Panton-Valentine leukocidin toxin (PVL) in community-associated MRSA did not correlate with complicated skin structure infections—a result opposing the widespread notion that PVL is the primary CA-MRSA virulence factor.

Recent Advances in Understanding Immunity Against Brucellosis: Application for Vaccine Development

Brucellosis is an important zoonotic disease of nearly worldwide distribution. This pathogen causes abortion in cattle and undulant fever, arthritis, endocarditis and meningitis in human. The immune response against B. abortus involves innate and adaptive immunity involving antigen-presenting cells, NK cells and CD4 + and CD8 + T cells. IFN- is a crucial immune component that results from Brucella recognition by host immune receptors such as Toll-like receptors (TLRs) that lead to IL-12 production. Although great efforts to elucidate immunity against Brucella have been employed, the subset of cells and factors involved in host immune response remains not completely understood. Our group and others have been working in an attempt to understand the mechanisms involved in innate responses to Brucella. Understanding the requirements for immune protection can help the design of alternative vaccines that would avoid the drawbacks of currently available vaccines to Brucella. This review discusses recent studies in host immunity to Brucella and new approaches for vaccine development.

Dendritic Compounds as Immune Response Modulators. New Approaches for Vaccine Development

Despite several infectious diseases which have been eradicated or controlled worldwide nowadays, there are still some infectious diseases such as AIDS, caused by HIV, which are supposed to be a serious social health problem and demand the search for new vaccines. A classical approach for generation of vaccines against infection was initially based on the use of killed or attenuated pathogens. With the increase of information about mechanisms governing immune responses after microorganism infection, new approaches have been investigated. The use of dendritic cells (DCs) pulsed with whole pathogen organisms has been considered and explored; however, this approach still presents serious concerns about safety issues. This fact has conducted to a “non-classical” approach where well defined antigens with complete control of molecular design are used. Two strategies are generally envisaged. One is based on the direct stimulation of T and B-cells using immunogenic peptides for producing antibodies and the other one is based on the use of antigen-pulsed dendritic cells producing both cellular and humoral response. This review will be focused on the state of the art of these new approaches for vaccine development to infectious diseases. Synthetic strategies, technical problems, and applications of multivalent dendritic systems will be described and commented. This is a topic of enormous interest which could open interesting alternatives and expectancy in infectious diseases for the development of effective therapies. Keywords: Dendritic Compounds, Vaccine Development, Immune Response, Modulators, infectious diseases, AIDS, HIV, T and B-cells, immunogenic peptides

A plant‐produced influenza subunit vaccine protects ferrets against virus challenge

Influenza A viruses are of major concern for public health, causing worldwide epidemics associated with high morbidity and mortality. Vaccines are critical for protection against influenza, but given the recent emergence of new strains with pandemic potential, and some limitations of the current production systems, there is a need for new approaches for vaccine development. To demonstrate the immunogenicity and protective efficacy of plant-produced influenza antigens. Method We engineered, using influenza A/Wyoming/3/03 (H3N2) as a model virus, the stem and globular domains of hemagglutinin (HA) produced in plants as fusions to a carrier protein and used purified antigens with and without adjuvant for ferret immunization. These plant-produced antigens were highly immunogenic and conferred complete protection against infection in the ferret challenge model. The addition of plant-produced neuraminidase was shown to enhance the immune response in ferrets. Plants can be used as a production vehicle for vaccine development against influenza. Domains of HA can generate protective immune responses in ferrets.

New approaches in vaccine development for parasitic infections

Vaccines have had a tremendous impact on the control of infectious diseases. Not only are vaccines potentially the least expensive mechanism to combat infectious diseases, under optimal conditions, widespread vaccination can result in disease eradication - as in the case of smallpox. Despite this great potential, vaccines have had little impact on human parasitic infections. The reasons for this are many - these eukaryotic pathogens are genetically and biologically complex organisms, some with elaborate life cycles and well-honed immune evasion mechanisms. Additionally, our understanding of the mechanisms of immune control of many parasitic infections -- of what constitutes an effective immune response and of how to induce high-quality immunological memory -- is not fully developed. This review attempts to highlight recent advances that could impact vaccine discovery and development in parasitic infections and proposes areas where future studies may lead to breakthroughs in vaccines for the agents of parasitic diseases. There are several other recent reviews highlighting the results of vaccine trials, specifically in the malaria field.

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.

New approaches in vaccine development

Among the tools available for disease prevention and control, vaccines rank high with respect to effectiveness and economic feasibility. The emergence of new concepts and technologies in biochemistry, genetics and immunology has opened the way for novel approaches to vaccination. A recent meeting 3 The Institut Pasteur EurΩconference on New Trends in Vaccine R & D: Adjuvants, Delivery Systems and Antigen Formulations was held at Paris, France, on 26–28 February 1998. 3 focused on these key new trends in vaccine research and development.