Towards an AIDS vaccine: challenges and prospects

Since the human immunodeficiency virus (HIV) started its spread through the human population, the AIDS epidemic has steadily increased on all continents unchecked by any therapeutic or preventive intervention, except for education. The search for an AIDS cure is facing great difficulties as HIV, a human retrovirus, is able to integrate and remain latent in the human genome for years. An effective vaccine thus remains the only foreseeable way to control and eventually eradicate AIDS. The unique pathogenicity and variability of HIV have raised new challenges in vaccine design, testing and evaluation. The status of the intense research efforts undertaken to solve these problems were assessed at a recent workshop on the AIDS vaccines.     

Viral vaccines: achievements and challenges

In this review the present state of vaccination as a means to control viral diseases is discussed, and the needs and directions for future investigations are considered. The history of viral vaccines already in use is surveyed for guidance in what steps and background knowledge of the viral agents and the host responses to infection were necessary to their successful development. The steps requisite for demonstrating efficacy and safety of a viral vaccine also are summarized, and the features of the target populations to be protected are noted as they affect the final requirement for a successful vaccine: that it be administered in proper dosage and potency to those who need it. General remarks on the proper use of current vaccines are followed by an overview of various developments toward prospective vaccines, along with the predicted time-frames for their coming into general use. Vaccines considered include vaccines to be administered locally at the portal of entry, subunit vaccines, viruses attenuated by genetic manipulation, use of viral vectors, vaccines developed by means of recombinant DNA, synthetic peptides, and anti-idiotype vaccines, as well as new vaccines being developed by more conventional methods.     

The challenges of host and viral diversity in HIV vaccine design

Rational HIV vaccine design is crucially dependent on a number of factors, including a detailed understanding of the immune responses that control infection in individuals that have non-progressing disease, the impact of host genetics on these responses, and the degree of immunological cross-reactivity between the vaccine immunogen and the encountered virus antigens. Significant progress has been made in a number of these areas over the past five years, which might help in the generation of a more effective immunogen design and will provide opportunities for novel vaccine delivery options. However, the understanding of immune response(s) that can mediate protection from infection or, if infection ensues, that slow the rate of HIV disease progression is still incomplete and will require detailed studies in unprecedentedly large populations infected with different HIV clades, combining advances in virology, immunology, human host genetics and bioinformatics analyses for the optimal design of vaccine immunogens.     

Prospects for an AIDS vaccine

Recent developments, in both animal systems and human trials, have provided encouraging results to counter the pessimism that has prevailed concerning the likelihood of obtaining an effective AIDS vaccine. This review summarizes these findings and their impact on defining and focusing the research agenda for the immediate future.     

Progress and challenges toward an AIDS vaccine: Brother,can you spare a paradigm?

The development of a safe and effective vaccine for prevention of AIDS has thus far proven to be exceedingly difficult due to the complexities associated with HIV pathogenesis including but not limited to antigenic hypervariability, multiple routes and modes of transmission, a lack of defined correlates of protective immunity, and a tropism for infection of immunoregulatory cells which are essential for orchestrating an effective host immune response. Recent observations, including the identification of significant differences between primary isolates of HIV circulating in the population and laboratoryadapted isolates, animal model protection studies demonstrating prevention of AIDS-like disease progression in nonhuman primates in the absence of sterilizing immunity, and epidemiologic studies which question the current dogma surrounding HIV variation and control, have led to the development of novel approaches for antigen presentation and adjuvant development targeted at AIDS vaccine development. The goal of developing a safe and effective AIDS vaccine will likely occur when continued advances in understanding the immunopathogenesis of HIV is balanced with a healthy dose of empirical testing of innovative candidate AIDS vaccines.     

Malaria vaccine development: persistent challenges

There is no licensed vaccine against any human parasitic disease and apicomplexan parasites cause enormous human suffering; the malaria parasite alone kills approximately one million people annually and is the cause of the majority of infection-related deaths in the young. A malaria vaccine is essential if the goal of malaria eradication is to be achieved. Decades ago it was shown that attenuated malaria parasites could induce sterile immunity to infection but progress towards efficacious vaccines for malaria has been slow. However, recent studies have begun to tease out the immune correlates of vaccine-induced sterile protection and essential research on animal models of disease continues to guide vaccine design. Whole parasite approaches to vaccine design through attenuation as well as subunit vaccine development continue to move forward to clinical trials and are showing promising results.     

Viral sensors: diversity in pathogen recognition

Summary:  Innate sensors of viral infection detect viral products and initiate the signal cascades that lead to the antiviral response. Several proteins have been identified to play a role in this process, mostly members of the Toll-like receptor and retinoic acid-inducible gene I-like receptor families. These receptors have been demonstrated to function in part by recognizing a diverse yet unique repertoire of nucleic acid substrates. Upon recognition of their ligands, these sensors activate distinct signaling pathways that lead to the secretion of type I interferon and inflammatory cytokines. It remains to be seen, however, if these sensors are redundant or whether each serves a unique function. In this work, we review the current knowledge of viral sensors, speculate on how they may function in vivo , and explore the potential reasons for their diversity.     

Immunization. Update: search for an AIDS vaccine

Identifying a successful HIV preventive vaccine is among the highest research priorities of the US NIH. While therapies for HIV have brought hope to those who are already HIV-infected, stopping the worldwide epidemic will require safe, effective HIV vaccines. Here, we describe scientific and other obstacles to attaining that goal and provide a brief synopsis of clinical trial results, recent preclinical results, and future priorities.     

Viral diversity in asthma

Asthma exacerbations are precipitated primarily by respiratory virus infection and frequently require immediate medical intervention. Studies of childhood and adult asthma have implicated a wide variety of respiratory viruses in exacerbations. By focusing on both RNA and DNA respiratory viruses and some newly identified viruses, this review illustrates the diversity and highlights some of the uncertainties that exist in our understanding of virus-related asthma exacerbations.     

Dengue determinants: Necessities and challenges for universal dengue vaccine development

Dengue illness can range from mild illness to life-threatening haemorrhage. It is an Aedes-borne infectious disease caused by the dengue virus, which has four serotypes. Each serotype acts as an independent infectious agent. The antibodies against one serotype confer homotypic immunity but temporary protection against heterotypic infection. Dengue has become a growing health concern for up to one third of the world's population. Currently, there is no potent anti-dengue medicine, and treatment for severe dengue relies on intravenous fluid management and pain medications. The burden of dengue dramatically increases despite advances in vector control measures. These factors underscore the need for a vaccine. Various dengue vaccine strategies have been demonstrated, that is, live attenuated vaccine, inactivated vaccine, DNA vaccine, subunit vaccine, and viral-vector vaccines, some of which are at the stage of clinical testing. Unfortunately, the forefront candidate vaccine is less than satisfactory, and its performance depends on serostatus and age factors. The lessons from clinical studies depicted ambiguity concerning the efficacy of dengue vaccine. Our study highlighted that viral structural heterogeneity, epitope accessibility, autoimmune complications, genetic variants, genetic diversities, antigen competition, virulence variation, host-pathogen specific interaction, antibody-dependent enhancement, cross-reactive immunity among Flaviviruses, and host-susceptibility determinants not only influence infection outcomes but also hampered successful vaccine development. This review integrates dengue determinants allocated necessities and challenges, which would provide insight for universal dengue vaccine development.     

Viral vectors as vaccine platforms: deployment in sight

A little more than a decade after the explosion of research into recombinant live-attenuated or replication-deficient viruses as vaccine platforms, many viral vector-based vaccines have been licensed for animals. Progress has been slower for humans but 2011 will see the licensure of the first viral-vectored vaccine for humans, against Japanese Encephalitis. In addition a vaccine with a viral-vectored component showed efficacy against HIV infection in humans. Viral-based vaccines have an excellent safety profile but must deal with the potential problem of pre-existing anti-vector immunity. Recent successes reflect diverse improvements such as development of new adenovirus serotypes and better prime-boost approaches, suggesting that many viral vectors are approaching their final years as vaccine 'candidates' rather than vaccines.     

Emerging respiratory viruses: challenges and vaccine strategies

The current threat of avian influenza to the human population, the potential for the reemergence of severe acute respiratory syndrome (SARS)-associated coronavirus, and the identification of multiple novel respiratory viruses underline the necessity for the development of therapeutic and preventive strategies to combat viral infection. Vaccine development is a key component in the prevention of widespread viral infection and in the reduction of morbidity and mortality associated with many viral infections. In this review we describe the different approaches currently being evaluated in the development of vaccines against SARS-associated coronavirus and avian influenza viruses and also highlight the many obstacles encountered in the development of these vaccines. Lessons learned from current vaccine studies, coupled with our increasing knowledge of the host and viral factors involved in viral pathogenesis, will help to increase the speed with which efficacious vaccines targeting newly emerging viral pathogens can be developed.     

Delipidation of a hepadnavirus: Viral inactivation and vaccine development

Many viruses including HIV, hepatitis C and hepatitis B, have an outer lipid envelope which maintains inserted viral peptides in the "correct" functional conformation and orientation. Disruption of the lipid envelope by most solvents destroys infectivity and often results in a loss of antigenicity. This communication outlines a novel approach to viral inactivation by specific solvent delipidation which modifies the whole virion rendering it non-infective, but antigenic. Duck hepatitis B virus (DHBV) was delipidated using a diisopropylether (DIPE) and butanol mixture and residual infectivity tested by inoculation into day-old ducks. Delipidation completely inactivated the DHBV (p < 0.001). Delipidated DHBV was then used to vaccinate ducks. Three doses of delipidated DHBV induced anti-DHBs antibody production and prevented high dose challenge infection in five out of six ducks. In comparison, five of six ducks vaccinated with undelipidated DHBV and four of four ducks vaccinated with glutaraldehyde inactivated DHBV were unprotected (p < 0.05). Although this solvent system completely inactivated DHBV, viral antigens were retained in an appropriate form to induce immunity. Delipidation of enveloped viruses with specific organic solvents has potential as the basis for development of vaccines.