The Specificity of Targeted Vaccines for APC Surface Molecules Influences the Immune Response Phenotype

Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA) to different surface molecules on antigen presenting cells (APC). We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8⁺/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m) delivery as compared to intradermal (i.d.) vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA) demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs.     

DNA vaccines: successes and limitations in cancer and infectious disease

Vaccination with plasmid DNA is an active area of investigation that is being applied to diseases including cancer and microbial pathogens associated with infectious diseases. Since its discovery, great progress has been made with the administration of DNA vaccines to initiate specific and effective immune responses against targeted illnesses. However, many obstacles still face its use in prophylactic and therapeutic vaccination scenarios. The nature of these difficulties alongside the successes and future of plasmid DNA will be discussed.     

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.     

DNA vaccines: future strategies and relevance to intracellular pathogens

Increasing awareness of microbial threat has rekindled interest in the great potential of vaccines for controlling infectious diseases. The fact that diseases caused by intracellular pathogens cannot be overcome by chemotherapy alone has increased our interest in the generation of highly efficacious novel vaccines. Vaccines have proven their efficacy, as the immunoprotection they induce appears to be mediated by long-lived humoral immune responses. However, there are no consistently effective vaccines available against diseases such as tuberculosis and HIV, and other infections caused by intracellular pathogens, which are predominantly controlled by T lymphocytes. This review describes the T-cell populations and the type of immunity that should be activated by successful DNA vaccines against intracellular pathogens. It further discusses the parameters that need to be fulfilled by protective T-cell Ag. We then discuss future approaches for DNA vaccination against diseases in which cell-mediated immune responses are essential for providing protection.     

Intranasal Immunization with DOTAP Cationic Liposomes Combined with DC-Cholesterol Induces Potent Antigen-Specific Mucosal and Systemic Immune Responses in Mice

Despite the progress made by modern medicine, infectious diseases remain one of the most important threats to human health. Vaccination against pathogens is one of the primary methods used to prevent and treat infectious diseases that cause illness and death. Vaccines administered by the mucosal route are potentially a promising strategy to combat infectious diseases since mucosal surfaces are a major route of entry for most pathogens. However, this route of vaccination is not widely used in the clinic due to the lack of a safe and effective mucosal adjuvant. Therefore, the development of safe and effective mucosal adjuvants is key to preventing infectious diseases by enabling the use of mucosal vaccines in the clinic. In this study, we show that intranasal administration of a cationic liposome composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 3β-[N-(N'',N''-dimethylaminoethane)-carbamoyl] (DC-chol) (DOTAP/DC-chol liposome) has a potent mucosal adjuvant effect in mice. Intranasal vaccination with ovalbumin (OVA) in combination with DOTAP/DC-chol liposomes induced the production of OVA-specific IgA in nasal tissues and increased serum IgG1 levels, suggesting that the cationic DOTAP/DC-chol liposome leads to the induction of a Th2 immune response. Additionally, nasal-associated lymphoid tissue and splenocytes from mice treated with OVA plus DOTAP/DC-chol liposome showed high levels of IL–4 expression. DOTAP/DC-chol liposomes also enhanced OVA uptake by CD11c⁺ dendritic cells in nasal-associated lymphoid tissue. These data demonstrate that DOTAP/DC-chol liposomes elicit immune responses via an antigen-specific Th2 reaction. These results suggest that cationic liposomes merit further development as a mucosal adjuvant for vaccination against infectious diseases.     

Innate endogenous adjuvants prime to desirable immune responses via mucosal routes

Vaccination is an effective strategy to prevent infectious or immune related diseases, which has made remarkable contribution in human history. Recently increasing attentions have been paid to mucosal vaccination due to its multiple advantages over conventional ways. Subunit or peptide antigens are more reasonable immunogens for mucosal vaccination than live or attenuated pathogens, however adjuvants are required to augment the immune responses. Many mucosal adjuvants have been developed to prime desirable immune responses to different etiologies. Compared with pathogen derived adjuvants, innate endogenous molecules incorporated into mucosal vaccines demonstrate prominent adjuvanticity and safety. Nowadays, cytokines are broadly used as mucosal adjuvants for participation of signal transduction of immune responses, activation of innate immunity and polarization of adaptive immunity. Desired immune responses are promptly and efficaciously primed on basis of specific interactions between cytokines and corresponding receptors. In addition, some other innate molecules are also identified as potent mucosal adjuvants. This review focuses on innate endogenous mucosal adjuvants, hoping to shed light on the development of mucosal vaccines.     

Translating innate immunity into immunological memory: implications for vaccine development

Vaccination is the most effective means of preventing infectious diseases. Despite the success of many vaccines, there is presently little knowledge of the immunological mechanisms that mediate their efficacy. Such information will be critical in the design of future vaccines against old and new infectious diseases. Recent advances in immunology are beginning to provide an intellectual framework with which to address fundamental questions about how the innate immune system shapes adaptive immunity. In this review, we summarize current knowledge about how the innate immune system modulates the quantity and quality of long-term T and B cell memory and protective immune responses to pathogens. In addition, we point out unanswered questions and identify critical challenges, the solution of which, we believe, will greatly facilitate the rational design of novel vaccines against a multitude of emerging infections.     

Host responses from innate to adaptive immunity after vaccination: Molecular and cellular events

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of longterm T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.     

Vaccination against the major infectious diseases

The reputation of vaccination rests on a 200-year-old history of success against major infectious diseases. That success has led to the doctrine of 'for each disease, a vaccine'. Although some diseases have proved frustrating, this doctrine carries considerable truth. However, when one reviews the vaccines now available it is apparent that most successes have been obtained when the microbe has a bacteremic or viremic phase during which it is susceptible to the action of neutralizing antibodies, and before replication in the particular organ to which it is tropic. Poliomyelitis and infections by capsulated bacteria are examples where vaccination has worked efficiently. However, some success has also been achieved against agents replicating on respiratory or gastrointestinal mucosae. Influenza, pertussis and rotavirus vaccines are examples of such agents, against which it has been possible to induce immune responses acting locally as well as systemically. In addition, when bacteria produce disease through exotoxins, purification and chemical or genetic inactivation of those toxins has yielded highly efficacious vaccines. Control of intracellular pathogens has not been achieved, except partly with the BCG vaccine against tuberculosis, and modern efforts are directed towards pathogens against which cellular immune responses are critical. In general, two achievements have been crucial to the success of vaccines: the induction of long-lasting immunological memory in individuals and the stimulation of a herd immunity that enhances control of infectious diseases in populations.     

Role of immunostimulatory molecules in poultry vaccines

Immunization by vaccination is the most suitable and safest method for preventing infectious diseases in the poultry worldwide. Vaccines alone cannot effectively protect birds from variety of pathogens under field conditions. The combined use of potent immunostimulants in vaccines is an alternative to increase the efficacy of vaccines that can be achieved by the development of better adjuvant. One such adjuvant is cytokine; cytokines have been used extensively as adjuvant in vaccines and are responsible for the type and extent of an immune response following vaccination. Although the innate immune system in birds is not fully characterized but their immune system is very much similar to that of mammals, and moreover with the recent discovery of a number of avian cytokine genes it is now possible to study their effectiveness in enhancing the immune response during vaccination. This review focuses on the recent studies and developments involving the role of immunomodulating agents especially cytokines of avian origin in poultry vaccines.     

DNA vaccines: a mini review

DNA vaccines are a major breakthrough in the field of vaccination with several advantages over traditional vaccines. Unlike traditional vaccines, DNA vaccines stimulate both arms of the immune system offering long lasting immunity. DNA vaccines not only have the potential to fight against infectious diseases such as influenza and hepatitis but they can also be used to prevent autoimmune diseases such as multiple sclerosis. In general, this article is intended as a mini-review to discuss DNA vaccination, as well as patents on different types of DNA vaccines.     

Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guérin vaccination.

Data obtained in animals indicate that neonatal immune responses are biased toward Th2. This could reduce the efficacy of vaccines against viral and mycobacterial diseases. The ability of human newborns to develop a Th1 immune response upon immunization has not been studied. Since the vaccine Mycobacterium bovis bacillus Calmette-Guérin (BCG) triggers a Th1-type response in adults, we investigated whether it induces a similar response in newborns and whether age at vaccination influences immunogenicity. We found that BCG vaccination at birth induces a memory Th1-type response of similar magnitude to that when given later in life. This study demonstrates that human newborns can be immunized against pathogens controlled by a Th1 immune response.     

Plant‐based oral vaccines against zoonotic and non‐zoonotic diseases

The shared diseases between animals and humans are known as zoonotic diseases and spread infectious diseases among humans. Zoonotic diseases are not only a major burden to livestock industry but also threaten humans accounting for >60% cases of human illness. About 75% of emerging infectious diseases in humans have been reported to originate from zoonotic pathogens. Because antibiotics are frequently used to protect livestock from bacterial diseases, the development of antibiotic‐resistant strains of epidemic and zoonotic pathogens is now a major concern. Live attenuated and killed vaccines are the only option to control these infectious diseases and this approach has been used since 1890. However, major problems with this approach include high cost and injectable vaccines is impractical for >20 billion poultry animals or fish in aquaculture. Plants offer an attractive and affordable platform for vaccines against animal diseases because of their low cost, and they are free of attenuated pathogens and cold chain requirement. Therefore, several plant‐based vaccines against human and animals diseases have been developed recently that undergo clinical and regulatory approval. Plant‐based vaccines serve as ideal booster vaccines that could eliminate multiple boosters of attenuated bacteria or viruses, but requirement of injectable priming with adjuvant is a current limitation. So, new approaches like oral vaccines are needed to overcome this challenge. In this review, we discuss the progress made in plant‐based vaccines against zoonotic or other animal diseases and future challenges in advancing this field.     

DNA vaccination strategies against infectious diseases

DNA immunisation represents a novel approach to vaccine and immunotherapeutic development. Injection of plasmid DNA encoding a foreign gene of interest can result in the subsequent expression of the foreign gene products and the induction of an immune response within a host. This is relevant to prophylactic and therapeutic vaccination strategies when the foreign gene represents a protective epitope from a pathogen. The recent demonstration by a number of laboratories that these immune responses evoke protective immunity against some infectious diseases and cancers provides support for the use of this approach. In this article, we attempt to present an informative and unbiased representation of the field of DNA immunisation. The focus is on studies that impart information on the development of vaccination strategies against a number of human and animal pathogens. Investigations that describe the mechanism(s) of protective immunity induced by DNA immunisation highlight the advantages and disadvantages of this approach to developing vaccines within a given system. A variety of systems in which DNA vaccination has resulted in the induction of protective immunity, as well as the correlates associated with these protective immune responses, will be described. Particular attention will focus on systems involving parasitic diseases. Finally, the potential of DNA immunisation is discussed as it relates to veterinary medicine and its role as a possible vaccine strategy against animal coccidioses.     

The evolutionary consequences of alternative types of imperfect vaccines

The emergence and spread of mutant pathogens that evade the effects of prophylactic interventions, including vaccines, threatens our ability to control infectious diseases globally. Imperfect vaccines (e.g. those used against influenza), while not providing life-long immunity, confer protection by reducing a range of pathogen life-history characteristics; conversely, mutant pathogens can gain an advantage by restoring the same range of traits in vaccinated hosts. Using an SEIR model motivated by equine influenza, we investigate the evolutionary consequences of alternative types of imperfect vaccination, by comparing the spread rate of three types of mutant pathogens, in response to three types of vaccines. All mutant types spread faster in response to a transmission-blocking vaccine, relative to vaccines that reduce the proportion of exposed vaccinated individuals becoming infectious, and to vaccines that reduce the length of the infectious period; this difference increases with increasing vaccine efficacy. We interpret our results using the first published Price equation formulation for an SEIR model, and find that our main result is explained by the effects of vaccines on the equilibrium host distribution across epidemiological classes. In particular, the proportion of vaccinated infectious individuals among all exposed and infectious hosts, which is relatively higher in the transmission-blocking vaccine scenario, is important in explaining the faster spread of mutant strains in response to that vaccine. Our work illustrates the connection between epidemiological and evolutionary dynamics, and the need to incorporate both in order to explain and interpret findings of complicated infectious disease dynamics.     

Risk in Vaccine Research and Development Quantified

To date, vaccination is the most cost-effective strategy to combat infectious diseases. Recently, a productivity gap affects the pharmaceutical industry. The productivity gap describes the situation whereby the invested resources within an industry do not match the expected product turn-over. While risk profiles (combining research and development timelines and transition rates) have been published for new chemical entities (NCE), little is documented on vaccine development. The objective is to calculate risk profiles for vaccines targeting human infectious diseases. A database was actively compiled to include all vaccine projects in development from 1998 to 2009 in the pre-clinical development phase, clinical trials phase I, II and III up to Market Registration. The average vaccine, taken from the preclinical phase, requires a development timeline of 10.71 years and has a market entry probability of 6%. Stratification by disease area reveals pandemic influenza vaccine targets as lucrative. Furthermore, vaccines targeting acute infectious diseases and prophylactic vaccines have shown to have a lower risk profile when compared to vaccines targeting chronic infections and therapeutic applications. In conclusion; these statistics apply to vaccines targeting human infectious diseases. Vaccines targeting cancer, allergy and autoimmune diseases require further analysis. Additionally, this paper does not address orphan vaccines targeting unmet medical needs, whether projects are in-licensed or self-originated and firm size and experience. Therefore, it remains to be investigated how these - and other - variables influence the vaccine risk profile. Although we find huge differences between the risk profiles for vaccine and NCE; vaccines outperform NCE when it comes to development timelines.     

Inulin-derived adjuvants efficiently promote both Th1 and Th2 immune responses

There has been a recent resurgence of interest into new and improved vaccine adjuvants. This interest has been stimulated by the need for new vaccines to combat problematic pathogens such as SARS and HIV, and to counter potential bioterrorist attacks. A major bottleneck in vaccine development is the low immunogenicity of purified subunit or recombinant proteins, creating the need for safe human adjuvants with high potency. A major problem in the search for the ideal adjuvant is that adjuvants that promote cell-mediated (Th1) immunity (e.g. Freund's complete adjuvant) generally have unacceptable local or systemic toxicity that precludes their use in human vaccines. There is a need for a safe, non-toxic adjuvant that is able to stimulate both cell-mediated and humoral immunity. Inulin-derived adjuvants that principally stimulate the innate immune system through their ability to activate the alternative complement pathway have proven ability to induce both cellular and humoral immunity. With their excellent tolerability, long shelf-life, low cost and easy manufacture, they offer great potential for use in a broad range of prophylactic and therapeutic vaccines. Based on successful animal studies in a broad range of species, human trials are about to get underway to validate the use of inulin-based adjuvants in prophylactic vaccines against hepatitis B, malaria and other pathogens. If such trials are successful, then it is possible that inulin-derived adjuvants will one day replace alum as the adjuvant of choice in most human prophylactic vaccines.     

Nanogel-based antigen-delivery system for nasal vaccines

Nasal vaccination is considered a potent and practical immunization route for the induction of effective immunity to infectious diseases. Successful nasal vaccines require efficient delivery to, and retention of antigens within, nasal mucosa, including both the inductive (e.g., nasopharynx-associated lymphoid tissues) and effector (e.g., turbinate covered with single-layer epithelium) tissues, where antigen-specific immune responses are initiated and executed, respectively. We developed an approach towards successful nasal vaccination by using self-assembled nano-sized hydrogel particles, known as nanogels, which are composed of a cationic type of cholesteryl group-bearing pullulan. Here, we review the merging of nanotechnological and immunological concepts leading to the development of next-generation nasal vaccines, and demonstrate the applicability of novel nanogel-based vaccine for the prevention of infectious diseases.     

Multiple alternating immunizations with DNA vaccine and replication incompetent adenovirus expressing gB of pseudorabies virus protect animals against lethal virus challenge

The prime-boost vaccination with DNA vaccine and recombinant viral vector has emerged as an effective prophylactic strategy to control infectious diseases. Here, we compared the protective immunities induced by multiple alternating immunizations with DNA vaccine (pCIgB) and replication-incompetent adenovirus (Ad-gB) expressing glycoprotein gB of pseudorabies virus (PrV). The platform of pCIgB-prime and Ad-gB-boost induced the most effective immune responses and provided protection against virulent PrV infection. However, priming with pCIgB prior to vaccinating animals by the DNA vaccine-prime and Ad-boost protocol provided neither effective immune responses nor protection against PrV. Similarly, boosting with Ad-gB following immunization with DNA vaccine-prime and Ad-boost showed no significant responses. Moreover, whereas the administration of Ad-gB for primary immunization induced Th2-type-biased immunity, priming with pCIgB induced Th1-type-biased immunity, as judged by the production of PrV-specific IgG isotypes and cytokine IFN-gamma. These results indicate that the order and injection frequency of vaccine vehicles used for heterologous prime-boost vaccination affect the magnitude and nature of the immunity. Therefore, our demonstration implies that the prime-boost protocol should be carefully considered and selected to induce the desired immune responses.