Malaria vaccine development: current status

The development of an effective malaria vaccine represents one of the most important approaches that would provide a cost-effective intervention for addition to currently available malaria control strategies. Here, Howard Engers and Tore Godal review recent advances. Over the past decade there has been considerable progress in the understanding of immune mechanisms involved in conferring protection to malaria and in the identification of vaccine candidate antigens and their genes. Several new vaccines have entered Phase I/II trials recently, new adjuvants have been developed for human use and new approaches, such as DNA vaccines and structural modification of antigens to circumvent some of the strategies the parasite uses to avoid the immune response, are being applied. Thus, from the TDR perspective, global malaria vaccine development is entering a crucial period with unprecedented opportunities.     

畜禽疫苗佐剂研究进展

畜禽用疫苗主要是亚单位疫苗、减毒或灭活细菌/病毒疫苗,为了使疫苗对动物能达到长效持久的保护,必须使用有效的佐剂.根据不同的作用方式,目前可将佐剂主要分为2大类:疫苗传递系统的佐剂、免疫刺激作用佐剂.本探讨了近年来畜禽用疫苗佐剂的功能及其发展趋势,概述了其应用研究的进展.     

Recent advances in veterinary vaccine adjuvants

Next generation veterinary vaccines are going to mainly comprise of either subunit or inactivated bacteria/viruses. These vaccines would require optimal adjuvants and delivery systems to accord long-term protection from infectious diseases in animals. There is an urgent need for the development of new and improved veterinary and human vaccine adjuvants. Adjuvants can be broadly divided into two classes, based on their principal mechanisms of action: vaccine delivery systems and 'immunostimulatory adjuvants'. Vaccine delivery systems are generally particulate e.g. emulsions, microparticles, ISCOMS and liposomes, and mainly function to target associated antigens into antigen presenting cells (APC). In contrast, immunostimulatory adjuvants are predominantly derived from pathogens and often represent pathogen associated molecular patterns, e.g. LPS, MPL and CpG DNA, which activate cells of the innate immune system. Recent progress in innate immunity is beginning to yield insight into the initiation of immune responses and the ways in which immunostimulatory adjuvants might enhance this process in animals and humans alike.     

Red blood cells as an antigen-delivery system.

The use of adjuvants is usually required to induce strong immunological responses to protein antigens. However, in many cases these adjuvants cannot be extensively applied in human and veterinary vaccinations because of associated inflammatory reactions or granuloma formation. We show here that protein antigens (bovine serum albumin, hog liver uricase, and yeast hexokinase), coupled to autologous red blood cells by way of a biotin-avidin-biotin bridge, elicit an immunological response in mice similar to or higher than that obtained by the use of Freund's adjuvant. Quantities as low as 0.5 micrograms/mouse are high enough to generate these immunological responses. Furthermore, splenocytes of mice immunized by red blood cell-coupled antigens can be used to generate hybridomas secreting monoclonal antibodies. Thus, the delivery of antigens by autologous red blood cells is an effective way to avoid the use of adjuvants for producing anti-peptide antibodies and possibly to generate peptide vaccines.     

Vaccines and global health

Vaccines have made a major contribution to global health in recent decades but they could do much more. In November 2011, a Royal Society discussion meeting, 'New vaccines for global health', was held in London to discuss the past contribution of vaccines to global health and to consider what more could be expected in the future. Papers presented at the meeting reviewed recent successes in the deployment of vaccines against major infections of childhood and the challenges faced in developing vaccines against some of the world's remaining major infectious diseases such as human immunodeficiency virus (HIV), malaria and tuberculosis. The important contribution that development of more effective veterinary vaccines could make to global health was also addressed. Some of the social and financial challenges to the development and deployment of new vaccines were reviewed. The latter issues were also discussed at a subsequent satellite meeting, 'Accelerating vaccine development', held at the Kavli Royal Society International Centre. Delegates at this meeting considered challenges to the more rapid development and deployment of both human and veterinary vaccines and how these might be addressed. Papers based on presentations at the discussion meeting and a summary of the main conclusions of the satellite meeting are included in this issue of Philosophical Transactions of the Royal Society B.     

Prospects of the use of bacteriophage-based virus-like particles in the creation of anthrax vaccines

The profitability of vaccine production is less than that of other pharmaceutical goods worldwide. Thus, the cost of the vaccine substance determines the range of vaccines available for use. This is of particular importance for veterinary vaccines. In this review, we have surveyed the published data on exploited vaccines and concluded that the immunogenicity of antigen substances based on whole virions is higher than that of soluble antigens. The physiological basis of this phenomenon remains unknown; however, it may explain why most of the described recombinant vaccines have not yet been put into practice. All practically implemented antiviral vaccines (except that for hepatitis B) are based on viral substances produced by conventional cultural technologies. In light of this observation, an approach to the development of a universal platform for recombinant vaccines produced in the form of virus-like particles is suggested. To this end, a technique of designing fused bifunctional derivatives of bacteriophage proteins containing antigens of interest should be involved. The approach is depicted with the use of the protective anthrax antigen, a conventional vaccine antigen.     

Accelerating vaccine development and deployment: report of a Royal Society satellite meeting

The Royal Society convened a meeting on the 17th and 18th November 2010 to review the current ways in which vaccines are developed and deployed, and to make recommendations as to how each of these processes might be accelerated. The meeting brought together academics, industry representatives, research sponsors, regulators, government advisors and representatives of international public health agencies from a broad geographical background. Discussions were held under Chatham House rules. High-throughput screening of new vaccine antigens and candidates was seen as a driving force for vaccine discovery. Multi-stakeholder, small-scale manufacturing facilities capable of rapid production of clinical grade vaccines are currently too few and need to be expanded. In both the human and veterinary areas, there is a need for tiered regulatory standards, differentially tailored for experimental and commercial vaccines, to allow accelerated vaccine efficacy testing. Improved cross-fertilization of knowledge between industry and academia, and between human and veterinary vaccine developers, could lead to more rapid application of promising approaches and technologies to new product development. Identification of best-practices and development of checklists for product development plans and implementation programmes were seen as low-cost opportunities to shorten the timeline for vaccine progression from the laboratory bench to the people who need it.     

Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens,Providing Sterile Immunity to Challenge Infection

Over 25% of the world''s population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM⁺GFP⁺ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations.     

Efficacy model for mosquito stage transmission blocking vaccines for malaria

Vaccines that target antigens found on the mosquito stages of Plasmodium falciparum and Plasmodium vivax parasites are under development as transmission blocking vaccines. Antisera from vaccinated animals and humans are able to block oocyst development in artificially fed mosquitoes but it is not clear from these data what level of antibody response would be required for a useful vaccine in a field setting. This paper describes a mathematical model that takes into account the relationship between antibody levels and blocking of oocyst levels in artificial feeds, the distribution of antibody responses seen in human populations and the distribution of oocyst densities in infected mosquitoes in the field to calculate the levels of antibody in the host population that would be required to achieve a level of herd immunity in a vaccinated human population that would give an operationally useful level of transmission blocking. The model predicts that current formulations of Pfs25 are likely to achieve useful reductions in transmission when tested in human field trials.     

Immune response against Mycobacterium tuberculosis: implications for vaccine development

Tuberculosis remains a major health problem globally. Although this threat would best be controlled by a combination of chemotherapy and vaccination, satisfactory vaccines are not available yet. Rational design of a novel vaccine generation against tuberculosis has become possible on the basis of recent achievements in molecular genetics of the pathogen and immunology of the host. Currently, two different strategies are pursued. First, the subunit vaccine approach attempting to induce efficacious immunity by unique antigens in defined adjuvants. Second, the whole bacterial vaccine approach relying on multiple antigens and built-in adjuvanticity. Time will tell which type of vaccine is best suited for eradication of tuberculosis.     

Q Fever Knowledge,Attitudes and Vaccination Status of Australia’s Veterinary Workforce in 2014

Q fever, caused by Coxiella burnetii, is a serious zoonotic disease in humans with a worldwide distribution. Many species of animals are capable of transmitting C. burnetii, and consequently all veterinary workers are at risk for this disease. An effective Q fever vaccine has been readily available and used in Australia for many years in at-risk groups, and the European Centre for Disease Prevention and Control has recently also called for the use of this vaccine among at-risk groups in Europe. Little is known about attitudes towards this vaccine and vaccine uptake in veterinary workers. This study aimed to determine the Q fever vaccination status of veterinarians and veterinary nurses in Australia and to assess and compare the knowledge and attitudes towards Q fever disease and vaccination of each cohort. An online cross-sectional survey performed in 2014 targeted all veterinarians and veterinary nurses in Australia. Responses from 890 veterinarians and 852 veterinary nurses were obtained. Binary, ordinal and multinomial logistic regression were used to make comparisons between the two cohorts. The results showed that 74% of veterinarians had sought vaccination compared to only 29% of veterinary nurses. Barriers to vaccination among those not vaccinated did not differ between cohorts, and included a lack of perceived risk, financial expense, time constraints, and difficulty in finding a vaccine provider. Poor knowledge and awareness of Q fever disease and vaccination were additional and notable barriers for the veterinary nursing cohort, suggesting veterinary clinics and veterinarians may not be meeting their legal responsibility to educate staff about risks and risk prevention. Further evaluation is needed to identify the drivers behind seeking and recommending vaccination so that recommendations can be made to improve vaccine uptake.     

Dengue epidemiology and pathogenesis:images of the future viewed through a mirror of the past

Every year, millions of individuals throughout the world are seriously affected by dengue virus. The unavailability of a vaccine and of anti-viral drugs has made this mosquito-borne disease a serious health concern. Not only does dengue cause fatalities but it also has a profoundly negative economic impact. In recent decades, extensive research has been performed on epidemiology, vector biology, life cycle, pathogenesis, vaccine development and prevention. Although dengue research is still not at a stage to suggest definite hopes of a cure, encouraging significant advances have provided remarkable progress in the fight against infection. Recent developments indicate that both anti-viral drug and vaccine research should be pursued, in parallel with vector control programs.     

Potential therapeutic applications of PHA-L4, the mitogenic isolectin of phytohemagglutinin

Assuming that the attributes of the mitogenic-leukoaggglutinating (L4) isolectin of phytohemagglutinin as a proposed ideal biologic response modifier can be confirmed, it could prove to be a highly versatile agent with broad therapeutic potential for several areas of management including cancer and cancer surgery adjuvant, critical infections (including that with the human immunodeficiency viruses), vaccine adjuvant, allograft transplantations, aplastic anemias, and extensive burns. The isolectin is predictably more likely to be effective as an adjuvant or adjunctive agent than as an induction agent. Initial evaluation in dogs would serve the double purpose of establishing a presumptive key role in veterinary medicine and expediting the development of its use in humans.     

Aspects of cancer immunotherapy

Cancer immunotherapy has traditionally undergone a 'revolution' every decade, from the use of Bacille Calmette-Guérin by scarification in the 1970s, to interleukin-2 therapies in the 1980s, and monoclonal antibody treatments in the early 1990s. Usually the early reports on the use of such agents were encouraging, but when more patients were studied in multiple centres, the initial promising results could not be confirmed. Now in a new century, we have more reagents and methods available than ever before - indeed, with such a plethora of reagents it is difficult to envisage them being fully and appropriately tested within the next decade, by which time there will be even more reagents to test. However, there have been three major advances which should lead to substantial progress in cancer immunotherapy: (1) the widespread use of genetic engineering, enabling identification of candidate vaccine proteins and manipulation of their sequences; (2) the production of antigens, antibodies and cytokines in large amounts by recombinant technologies, and (3) an understanding of the mode of presentation of peptides by major histocompatibility complex Class I and Class II molecules and their recognition by T cells. Despite these advances, there are major problems facing cancer immunotherapy, such as the ability of tumours to mutate and evade the immune system and the difficulty of precisely defining the interactions of effector cells in mediating 'rejection' or destruction of a tumour. There are clearly immunological similarities with diseases such as malaria and schistosomiasis, where the invading foreign organisms can use a variety of strategies to resist an elicited immune response. The failure to find a suitable vaccine for these diseases must lead to some pessimism for the development of immunotherapy for an autologous tumour. However, there are promising studies now in progress which should give an indication of the most important directions to follow. This review provides a commentary on aspects of cancer immunotherapy and in particular will deal with: (1) the selection of antigens as vaccine components; (2) the modes of presentation of antigens, particularly by major histocompatibility complex Class I molecules; and (3) new modes of delivery of vaccine immunogens.     

Recent progress in the development and testing of vaccines against human tuberculosis

The growing pandemic of human tuberculosis has not been affected significantly by the widespread use of the only currently available vaccine, bacille Calmette Guerin. Bacille Calmette Guerin protects uniformly against serious paediatric forms of tuberculosis and against adult pulmonary tuberculosis in some parts of the world, but there are clearly populations in high-burden countries which do not benefit from the current vaccination regimen. New tuberculosis vaccines will be essential for the ultimate control of this ancient disease. Research over the past 10 years has produced literally hundreds of new tuberculosis vaccine candidates representing all of the major vaccine design strategies; protein/peptide vaccines in adjuvants, DNA vaccines, naturally and rationally attenuated strains of mycobacteria, recombinant mycobacteria and other living vaccine vectors expressing genes coding for immunodominant mycobacterial antigens, and non-peptide vaccines. Many of these vaccines have been tested for immunogenicity and protective efficacy in mouse and guinea pig models of low-dose pulmonary tuberculosis. In addition, alternative routes of tuberculosis vaccine delivery (e.g. oral, respiratory, gene gun) and various combinations of priming or boosting an experimental vaccine with bacille Calmette Guerin have been examined in relevant animal models. One of the most promising of these vaccines is currently in Phase I trials in human subjects, and others are expected to follow in the near future. This review will summarise the most recent progress made toward the development and preclinical evaluation of novel vaccines for human tuberculosis.     

Hepatitis vaccines: recent advances

Despite the availability of hepatitis A vaccines that might provide protection for decades, hepatitis B vaccines that provides protection for at least 15 years and the recent introduction of a combined hepatitis A and B vaccine, these infections continue to spread in both the developed and developing world. Hepatitis A vaccine coverage has been limited to high-risk groups: such a selective immunisation policy is unlikely to have a major impact. If adequate immunogenicity in infants is confirmed, dosing schedules can be improved and the costs of vaccination reduced, universal paediatric immunisation with combined hepatitis A and B products is likely to result in the eventual eradication of these infections. In the interim, novel hepatitis A vaccines are being investigated and additional studies on hepatitis A vaccine immunogenicity in infants are in progress. Worldwide use of hepatitis B vaccines for the newborn, young children and high-risk groups should control this infection and obviate the need for a vaccine against hepatitis D. Newer hepatitis B vaccines that may reduce the likelihood of non-responsiveness and have immunotherapeutic value are under study. A recombinant hepatitis E vaccine for use in endemic regions is currently in clinical trials. The development of an effective hepatitis C vaccine has been agonisingly slow and many impediments have been recognised. These include the lack of a susceptible small animal, a high degree of hepatitis C virus (HCV) genomic diversity and failure to produce high quantities of HCV in tissue culture. The development of a novel HCV replicon system may be a major breakthrough. Nonetheless, it may still be exceedingly difficult to produce a vaccine that uniformly provides sterilising immunity; the possibility of developing a hepatitis C vaccine that can prevent chronic infection is an exciting concept that requires further investigation. Advances in recombinant technology, the use of novel genetic (DNA-based) vaccines, expression of hepatitis antigens in plants and improved adjuvants also hold considerable promise.     

Extraneous agent detection in vaccines--a review of technical aspects

The quality and safety of commercial vaccines have a profound importance. Contrary to all precautions and efforts the use of biological material in vaccine development and production may lead to potential contamination of the vaccines with known and unknown extraneous agents (EAs). In veterinary field official lists of EAs have been compiled as legal framework to describe the potential agents, which must be tested during manufacture of vaccines. Nevertheless, detection of known and unknown contaminants in vaccines is a common duty for manufacturers and authorities of both veterinary and human field sharing similar needs of special technical approaches. State-of-art molecular methods such as randomly primed PCR combined with massive parallel sequencing (MPS) or microarrays may open new perspectives in extraneous agent testing. The robustness and efficacy of this technical approach in vaccine control was clearly demonstrated on a human vaccine example when porcine circovirus type 1 (PCV1) contamination was revealed in Rotarix, a human rotavirus vaccine. The consequences and implications are reviewed hereby from a veterinary regulatory point of view.     

Subunit protein vaccines: theoretical and practical considerations for HIV-1

With the spread of AIDS still rampant in many parts of the world, there is a global urgency to develop a vaccine against HIV-1. Without a doubt, developing an effective vaccine against the virus has been a monumental scientific challenge. Although advances in molecular biology and biotechnology over the years have enabled us to generate "designer antigens," our ability to transform them into successful vaccine candidates has been limiting. This review will be divided into three sections: First, the theoretical benefits and limitations of subunit protein vaccine strategy will be presented. Secondly, recent progress in our understanding of immune responses against AIDS vaccine candidates that incorporate recombinant proteins or peptides will be reviewed, mainly those that are designed to elicit humoral immune responses. Finally, some of the factors that must be considered in designing and evaluating future vaccine candidates will be discussed.     

Mosquito-based transmission blocking vaccines for interrupting Plasmodium development

Reduction of transmission is critical for effective malaria control. Transmission blocking vaccines, which are intended to prevent the parasites from infecting the mosquito vectors, could target mosquito antigens that are required for the successful development of the parasite in its vector. Here we review recent advances in the identification of promising candidate antigens for a mosquito-based transmission blocking vaccine.