Towards a blood-stage vaccine for malaria: are we following all the leads?

Although the malaria parasite was discovered more than 120 years ago, it is only during the past 20 years, following the cloning of malaria genes, that we have been able to think rationally about vaccine design and development. Effective vaccines for malaria could interrupt the life cycle of the parasite at different stages in the human host or in the mosquito. The purpose of this review is to outline the challenges we face in developing a vaccine that will limit growth of the parasite during the stage within red blood cells--the stage responsible for all the symptoms and pathology of malaria. More than 15 vaccine trials have either been completed or are in progress, and many more are planned. Success in current trials could lead to a vaccine capable of saving more than 2 million lives per year.     

Immuno-informatics: Mining genomes for vaccine components

The complete genome sequences of more than 60 microbes have been completed in the past decade. Concurrently, a series of new informatics tools, designed to harness this new wealth of information, have been developed. Some of these new tools allow researchers to select regions of microbial genomes that trigger immune responses. These regions, termed epitopes, are ideal components of vaccines. When the new tools are used to search for epitopes, this search is usually coupled with in vitro screening methods; an approach that has been termed computational immunology or immuno-informatics.Researchers are now implementing these combined methods to scan genomic sequences for vaccine components. They are thereby expanding the number of different proteins that can be screened for vaccine development, while narrowing this search to those regions of the proteins that are extremely likely to induce an immune response.As the tools improve, it may soon be feasible to skip over many of the in vitro screening steps, moving directly from genome sequence to vaccine design. The present article reviews the work of several groups engaged in the development of immuno-informatics tools and illustrates the application of these tools to the process of vaccine discovery.     

Protection from infection or disease? Re-evaluating the broad immunogenicity of inactivated SARS-CoV-2 vaccines

How do we measure vaccine efficacy? The strictest but also easiest parameter to determine vaccine efficacy is its ability to block infection. Indeed, if a vaccine is able to block infection, this necessarily follows that it will also prevent both disease development and viral transmission. As a consequence, antibodies, specifically neutralising antibodies, have been used as the “gold standard” correlate of protection to measure SARS-CoV-2 vaccine efficacy, given their ability to block infection. Since SARS-CoV-2 infects cells by the binding of its spike protein to the host ACE-2 receptor, a vaccine that is able to induce a large quantity of antibodies able to block the interaction between the ACE-2 receptor and spike protein should theoretically be highly efficacious. Given this “antibody-centric” method of evaluating of a vaccine, it is clear why spike mRNA vaccines have to date been regarded the most effective COVID-19 vaccine in the market.     

疫苗诱导机体免疫应答机制研究

人类接种疫苗已有200多年的历史,疫苗的应用使得历史上流行的多种传染病得以消灭或控制,挽救了无数人的生命。疫苗免疫机制是全世界疫苗研究者亟待解决的问题。对疫苗免疫机制的一些新认识,极大地促进了疫苗研发。对疫苗天然免疫机制的揭示,在疫苗株的筛选、疫苗免疫效果预测等方面展现了巨大的应用价值。某些疫苗在接种后存在的低应答与无应答现象,在对其免疫机制的探索中得到了解释。此外,对疫苗佐剂免疫机制的揭示,加速了新型疫苗佐剂的研发与应用。对疫苗免疫机制研究中的一些新进展进行了综述。     

人呼吸道合胞病毒活疫苗研究进展

人呼吸道合胞病毒是引起婴幼儿支气管炎和肺炎的主要原因,也可导致免疫缺陷病人及老年人群显著发病和死亡.人呼吸道合胞病毒疫苗已被世界卫生组织(World Health Organization,WHO)列为全球最优先发展的疫苗之一.经过50多年的研究,尤其是随着重组技术和反向遗传学的出现,对RSV疫苗的研究取得了重要进展,...     

Plants as bioreactors for the production of vaccine antigens

Plants have been identified as promising expression systems for commercial production of vaccine antigens. In phase I clinical trials several plant-derived vaccine antigens have been found to be safe and induce sufficiently high immune response. Thus, transgenic plants, including edible plant parts are suggested as excellent alternatives for the production of vaccines and economic scale-up through cultivation. Improved understanding of plant molecular biology and consequent refinement in the genetic engineering techniques have led to designing approaches for high level expression of vaccine antigens in plants. During the last decade, several efficient plant-based expression systems have been examined and more than 100 recombinant proteins including plant-derived vaccine antigens have been expressed in different plant tissues. Estimates suggest that it may become possible to obtain antigen sufficient for vaccinating millions of individuals from one acre crop by expressing the antigen in seeds of an edible legume, like peanut or soybean. In the near future, a plethora of protein products, developed through ‘naturalized bioreactors’ may reach market. Efforts for further improvements in these technologies need to be directed mainly towards validation and applicability of plant-based standardized mucosal and edible vaccines, regulatory pharmacology, formulations and the development of commercially viable GLP protocols. This article reviews the current status of developments in the area of use of plants for the development of vaccine antigens.     

Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB.     

Pneumococcal Virulence Factors: Structure and Function

The overall goal for this review is to summarize the current body of knowledge about the structure and function of major known antigens of Streptococcus pneumoniae, a major gram-positive bacterial pathogen of humans. This information is then related to the role of these proteins in pneumococcal pathogenesis and in the development of new vaccines and/or other antimicrobial agents. S. pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections and meningitis in children. The present vaccine for the pneumococcus consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, who are normally at low risk of serious disease, it is only about 60% effective in the elderly. In children younger than 2 years the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the pneumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk from pneumococcal disease. Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets. Essentially all of these antigens have been or are being investigated on a structural level in addition to being characterized biochemically. Recently, three-dimensional structures for hyaluronate lyase and pneumococcal surface antigen A became available from X-ray crystallography determinations. Also, modeling studies based on biophysical measurements provided more information about the structures of pneumolysin and pneumococcal surface protein A. Structural and biochemical studies of these pneumococcal virulence factors have facilitated the development of novel antibiotics or protein antigen-based vaccines as an alternative to polysaccharide-based vaccines for the treatment of pneumococcal disease.     

Pneumococcal virulence factors: structure and function.

The overall goal for this review is to summarize the current body of knowledge about the structure and function of major known antigens of Streptococcus pneumoniae, a major gram-positive bacterial pathogen of humans. This information is then related to the role of these proteins in pneumococcal pathogenesis and in the development of new vaccines and/or other antimicrobial agents. S. pneumoniae is the most common cause of fatal community-acquired pneumonia in the elderly and is also one of the most common causes of middle ear infections and meningitis in children. The present vaccine for the pneumococcus consists of a mixture of 23 different capsular polysaccharides. While this vaccine is very effective in young adults, who are normally at low risk of serious disease, it is only about 60% effective in the elderly. In children younger than 2 years the vaccine is ineffective and is not recommended due to the inability of this age group to mount an antibody response to the pneumococcal polysaccharides. Antimicrobial drugs such as penicillin have diminished the risk from pneumococcal disease. Several pneumococcal proteins including pneumococcal surface proteins A and C, hyaluronate lyase, pneumolysin, autolysin, pneumococcal surface antigen A, choline binding protein A, and two neuraminidase enzymes are being investigated as potential vaccine or drug targets. Essentially all of these antigens have been or are being investigated on a structural level in addition to being characterized biochemically. Recently, three-dimensional structures for hyaluronate lyase and pneumococcal surface antigen A became available from X-ray crystallography determinations. Also, modeling studies based on biophysical measurements provided more information about the structures of pneumolysin and pneumococcal surface protein A. Structural and biochemical studies of these pneumococcal virulence factors have facilitated the development of novel antibiotics or protein antigen-based vaccines as an alternative to polysaccharide-based vaccines for the treatment of pneumococcal disease.     

Global Distribution of Campylobacter jejuni Penner Serotypes: A Systematic Review

Penner serotyping has been the principal method for differentiating Campylobacter isolates since its inception. Campylobacter capsule polysaccharide (CPS), the principal serodeterminant on which Penner serotyping is based, is presently of interest as a vaccine component. To determine the required valency of an effective CPS-based vaccine, a comprehensive understanding of CPS distribution is needed. Because of the association between Penner serotype and CPS, we conducted a systematic review to estimate the frequency and distribution of Penner serotypes associated with cases of Campylobacteriosis. In total, more than 21,000 sporadic cases of C. jejuni cases were identified for inclusion. While regional variation exists, distribution estimates indicate that eight serotypes accounted for more than half of all sporadic diarrheal cases globally and three serotypes (HS4 complex, HS2, and HS1/44) were dominant inter-regionally as well as globally. Furthermore, a total of 17 different serotypes reached a representation of 2% or greater in at least one of the five regions sampled. While this review is an important first step in defining CPS distribution, these results make it clear that significant gaps remain in our knowledge. Eliminating these gaps will be critical to future vaccine development efforts.     

新城疫疫苗研究进展

新城疫（Newcastle disease,ND）是禽类的病毒性疾病之一,能引发禽类神经系统、消化系统和呼吸系统损伤,死亡率高达30%,对家禽养殖形成了严重制约,因此,研究ND具有重要的经济意义。合理使用疫苗是防控新城疫疫情的主要方法。自1950年以来,新城疫减毒活疫苗和灭活疫苗已被广泛使用,之后载体疫苗也进入商业化应用阶段。此外,疫苗佐剂的选择以及递送途径的优化也进入研究人员的视野。基于此,分析了新城疫传统疫苗、载体疫苗、病毒样颗粒疫苗的研发现状及前景,介绍了纳米粒子和新型免疫佐剂在新城疫疫苗研发过程中的应用进展,并总结了目前国内外常见的新城疫商业化疫苗,旨在为研制更高效、廉价的新城疫疫苗提供参考,从而进一步控制当前新城疫疫情的蔓延。     

Vaccines against malaria

There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.     

Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL

Expression of NY-ESO-1 in a high proportion of different human tumors makes this protein a very attractive vaccine target. NY-ESO-1 peptides, recognized by HLA-A2-restricted CTL, have recently been described. However, it remains unclear how efficiently tumors generate these epitopes, and whether peptide analogues can be used for optimal expansion and activation of NY-ESO-1-specific HLA-A2-restricted CTL. By generating unique CTL clones, we demonstrate that NY-ESO-1-positive tumor cells are efficiently killed by HLA-A2-restricted CTL specific for the peptide epitope NY-ESO-1 157-165. Presentation of this epitope is not affected by the presence or absence of the proteasome subunits low molecular proteins 2 and 7 and is not blocked by proteasome inhibitors, while it is impaired in the TAP-deficient cell line LBL 721.174. NY-ESO-1 157-165 peptide analogues were compared for their antigenicity and immunogenicity using PBL from melanoma patients. Three peptides, containing the carboxyl-terminal cysteine substituted for either valine, isoleucine, or leucine, were recognized at least 100 times more efficiently than the wild-type peptide by specific CTL. Peptide analogues were capable of stimulating the expansion of NY-ESO-1-specific CTL from PBL of melanoma patients much more efficiently than wild-type peptide. These findings define the processing requirements for the generation of the NY-ESO-1 157-165 epitope. Identification of highly antigenic NY-ESO-1 peptide analogues may be important for the development of vaccines capable of expanding NY-ESO-1-specific CTL in cancer patients.     

Designing the next generation of vaccines for global public health

Vaccine research and development are experiencing a renaissance of interest from the global scientific community. There are four major reasons for this: (1) the lack of efficacious treatment for many devastating infections; (2) the emergence of multidrug resistant bacteria; (3) the need for improving the safety of the more traditional licensed vaccines; and finally, (4) the great promise for innovative vaccine design and research with convergence of omics sciences, such as genomics, proteomics, immunomics, and vaccinology. Our first project based on omics was initiated in 2000 and was termed reverse vaccinology. At that time, antigen identification was mainly based on bioinformatic analysis of a singular genome. Since then, omics-guided approaches have been applied to its full potential in several proof-of-concept studies in the industry, with the first reverse vaccinology-derived vaccine now in late stage clinical trials and several vaccines developed by omics in preclinical studies. In the meantime, vaccine discovery and development has been further improved with the support of proteomics, functional genomics, comparative genomics, structural biology, and most recently vaccinomics. We illustrate in this review how omics biotechnologies and integrative biology are expected to accelerate the identification of vaccine candidates against difficult pathogens for which traditional vaccine development has thus far been failing, and how research will provide safer vaccines and improved formulations for immunocompromised patients in the near future. Finally, we present a discussion to situate omics-guided rational vaccine design in the broader context of global public health and how it can benefit citizens in both developed and developing countries.     

Developments in the production and quality control of poliovirus vaccines -- historical perspectives.

Using virus grown in monkey kidney cells, Salk and his colleagues developed an inactivated poliovirus vaccine (IPV) in 1952. A large-scale field trial showed the vaccine to be safe and highly immunogenic in children, but soon after the vaccine became generally available in 1955, cases of paralytic disease were reported in recipients. Investigations showed that almost all the cases occurred in children who had received vaccine from one particular manufacturer. Extensive studies attributed the disaster to problems with inactivation. Addition of a Seitz filtration step midway during formalin inactivation and extension of the inactivation period resulted in a safe vaccine. No further paralytic cases were observed following the use of several hundred million doses of this improved vaccine. Thus, IPV was safe and caused a dramatic decline in the incidence of poliomyelitis in countries where it was used. A second generation IPV is produced in fermentors using well-characterized cell strains or continuous cell lines. The major breakthrough in the development of live poliovirus vaccine was the application of tissue culture methods for virus attenuation. By 1959 several candidate live oral poliovirus vaccines (OPV) had been developed. These were clinically tested in millions of individuals and found to be safe and effective. Since the attenuated virus strains developed by Koprowski and Cox were more neurotropic in monkeys than the Sabin strains, only the latter was licensed in the USA in 1961 and endorsed shortly after by the World Health Organization (WHO). The widespread use of Sabin's OPV in many countries hastened the development of International Requirements by WHO for OPV in 1962 to define the criteria that ensured the uniformity of batches produced by different manufacturers. These have been updated continuously in light of new information and quality control procedures. Extensive field trials have shown the risk of OPV associated polio to be less than 0.3 per million doses administered.     

Tuberculosis Vaccines and Prevention of Infection

SUMMARY

Tuberculosis (TB) is a leading cause of death worldwide despite the availability of effective chemotherapy for over 60 years. Although Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination protects against active TB disease in some populations, its efficacy is suboptimal. Development of an effective TB vaccine is a top global priority that has been hampered by an incomplete understanding of protective immunity to TB. Thus far, preventing TB disease, rather than infection, has been the primary target for vaccine development. Several areas of research highlight the importance of including preinfection vaccines in the development pipeline. First, epidemiology and mathematical modeling studies indicate that a preinfection vaccine would have a high population-level impact for control of TB disease. Second, immunology studies support the rationale for targeting prevention of infection, with evidence that host responses may be more effective during acute infection than during chronic infection. Third, natural history studies indicate that resistance to TB infection occurs in a small percentage of the population. Fourth, case-control studies of BCG indicate that it may provide protection from infection. Fifth, prevention-of-infection trials would have smaller sample sizes and a shorter duration than disease prevention trials and would enable opportunities to search for correlates of immunity as well as serve as a criterion for selecting a vaccine product for testing in a larger TB disease prevention trial. Together, these points support expanding the focus of TB vaccine development efforts to include prevention of infection as a primary goal along with vaccines or other interventions that reduce the rate of transmission and reactivation.     

Vaccine outlooks

After negative publicity and a series of setbacks over HIV/AIDS and influenza, the prospects for research on new vaccines are improvingVaccine research is at a crossroads between renewed optimism created by fundamental scientific advances, and pessimism from a series of scientific and publicity setbacks over the past decade. Early successes in the field against acute viral diseases, such as smallpox and polio, raised hopes that more serious infectious diseases could be controlled or even eradicated by vaccination, just as it was once thought that penicillin would eradicate major bacterial diseases such as tuberculosis and leprosy....it became clear that many viruses were much tougher nuts to crack in terms of vaccine development...However, it became clear that many viruses were much tougher nuts to crack in terms of vaccine development than had been thought, and it also emerged that not all vaccines were equally safe. Indeed, mounting concerns over the safety of vaccines culminated in the infamous Wakefield paper published in the Lancet in 1998 that associated the MMR vaccine—against measles, mumps and rubella—with autism and inflammatory bowel disease in children. After several studies failed to reproduce these results, the Lancet eventually retracted this paper in 2010, but not before considerable damage had been done to public confidence in vaccination as a whole. Other factors have also sapped confidence in the field—notably the continuing failure to develop an effective vaccine against HIV/AIDS, 15 years after the first hopeful reports that a breakthrough might be imminent (Gorse et al, 1995).Researchers have since developed a string of HIV/AIDS vaccine candidates, some of which have entered clinical trials, but none of which have been sufficiently efficient and safe. The gloom has deepened further after the failure of a vaccine candidate developed by the pharmaceutical company Merck in 2007, that had high hopes for success. This vaccine, called V520, used a weakened adenovirus that carries three HIV genes, to stimulate host production of T cells that it was hoped would kill HIV-infected cells. Early small trials had detected cellular immune responses, but these largely failed to materialize in a subsequent phase II clinical trial. The recombinant vaccine triggered a rapid immune response against itself that actually impaired the T-cell response against the HIV antigens. As a result, the trial was halted in September 2007 (Anon, 2007).Controversially, it has since been suggested that V520 rendered some individuals more liable to subsequent infection, although views on this finding are polarized. According to Steven Patterson, a research fellow specializing in HIV at Imperial College, London, “there was a greater incidence of infection in those individuals who had immunity to adenovirus type 5 before vaccination. Some scientists argue that the numbers [of people who suffered infection during the trial] are relatively low, the results represent a statistical anomaly and that the effect gradually disappeared, suggesting that it was not a real effect. Others, including ourselves, think that in adenovirus type 5-immune individuals the vector activated pre-existing memory CD4 cells migrate to mucosal tissue. Then, because the virus preferentially replicates in activated CD4 T cells and the number of HIV susceptible cells is increased at the site of HIV infection, there is an increase in the number of infections. With time the activated cells return to a resting state which would explain why the effect of adenovirus vaccination gradually disappeared.”Whatever the truth in this case, it highlighted the setbacks in HIV/AIDS research and increased negative sentiments both among the public and, more crucially, funding agencies. “The devastating impact of HIV and its lethality have placed research on vaccines and other preventative measures under an unfamiliar spotlight,” said Colonel Jerome Kim, HIV vaccines product manager for the US Army from the Walter Reed Army Institute of Research. “This has tended to exaggerate both the incremental successes and failures of HIV-1 vaccine research.”The devastating impact of HIV and its lethality have placed research on vaccines and other preventative measures under an unfamiliar spotlightThis might have contributed to a decline in public funding that has been combined with a continuing lack of investment from the private sector (AVERT, 2010). More worryingly, there have been signs that governments are withdrawing funding from vaccine research (Médecins Sans Frontières, 2009). In fact, the US government—through the National Institutes of Health—and the Bill and Melinda Gates Foundation—the charitable trust established in 1994 by Microsoft founder Bill Gates—accounted for 79% of the world''s US$868 million funding for HIV/AIDS vaccine research in 2008 (HIV Vaccines and Microbicides Resource Tracking Working Group, 2010).Other areas of vaccination research have also contributed to negative sentiments towards the field. A universal vaccine against influenza has proved similarly elusive, given the mutability of the virus. The recent swine flu pandemic—the severity of which fell short of many pessimistic expectations—left many governments having spent huge sums on vaccines that they never needed. Furthermore, had swine flu become as virulent as it might have, these vaccine stockpiles might still have been only partially effective.More worryingly, there have been signs that governments are withdrawing funding from vaccine researchAll of these factors are fuelling groups who are opposed to vaccine research for various reasons, according to Joachim Hombach, at the World Health Organization''s Initiative for Vaccine Research in Geneva. “There are certain groups, particularly in the industrialised world, that have an anti-vaccine attitude, and these kinds of cases find very fertile ground there,” he said, referring in particular to the Lancet MMR article. “There is also a different story relating to general attitudes towards acceptance of absolutely no risk associated with vaccines or other medical interventions.” This risk-averse culture exposes vaccines to public scrutiny when side effects occur during trials or afterwards, and has even been spreading to developing countries. “This creates a challenging climate for vaccine research,” said Hombach.There are still strong grounds for optimism, as huge strides have been made in understanding the relationship between viruses and the immune response, which is more subtle and diverse than has been previously appreciated. In a sense, diseases such as polio represent the low-hanging fruit in the orchard of infectious disease; early successes in vaccine development have perhaps created a false sense of optimism. “Diseases that are more chronic, where you have a very delicate balance between the pathogen and the immune response, are very difficult to prevent with vaccines,” Hombach said. “HIV is not the only one and there is also TB for instance, which is quite difficult. It is much easier to develop vaccines against acute diseases.”There is accordingly a need to educate the public about these difficulties, commented Tomáš Hanke, Nuffield professor of medicine specializing in HIV research at Oxford University. “Public confidence is a matter of public education and understanding of the process of scientific discovery,” he said. “The more challenging the aim is, the more explaining the public needs.”Researchers disagree about the major problems hindering the development of new vaccines. In the case of HIV, Kim identified the elimination of CD4⁺ helper T cells by the virus as one of the major problems, because these cells are at the centre of immune control and influence the activities of other cells. It is this disabling of helper T cells that weakens the immune response to other diseases in those who have AIDS.Patterson believes that the greatest problem is the virus''s mutability. “The ability of the virus to quickly mutate and escape from responses that are mounted against specific domains of the virus that are recognized by the immune system is, I think, the major hurdle that we need to overcome,” he said. This is one reason why the traditional strategy of inducing protective antibodies by administering an attenuated virus has not worked for HIV.There are two further problems. First, important regions of the HIV virus are shielded by sugars and second, although antibodies that disable a broad range of HIV viruses have been identified, these tend to be produced too late in the immune response, when infection is already well established. For this reason, there has been increased focus on T-cell vaccines that can recognize and kill infected cells, rather than on efforts to prevent infection in the first place. Crucially though, as Patterson pointed out, this approach still faces the problem of mutation, because this can enable the virus to escape recognition by T cells.This, in turn, suggests that vaccines must target regions of the virus that are well conserved. “A normal T cell immune response tends to be against a small number of so-called dominant epitopes and in the case of HIV these are often against the more variable regions the virus can afford to mutate without any cost to itself,” Patterson explained. “To avoid immune escape, we probably need to induce a T cell response against a number of conserved virus epitopes that the virus could not afford to mutate without severely impairing its replication capacity. I believe this aim is achievable.”While the battle against HIV/AIDS has been catching most of the headlines, a lesser known viral disease, dengue, has been rising quickly up the research agendaMore fundamental research at the molecular level is needed to achieve this goal. Robin Weiss, professor of viral oncology at University College London, leads one team who are trying to identify antigens or targets that might one day become useful in vaccine design. Weiss does not claim to be near an imminent breakthrough, but he believes that a major step might be made soon towards developing a broad-spectrum vaccine that could prevent HIV infection in the first place. The problem, as Weiss pointed out, is not that individuals with HIV fail to produce antibodies, but that HIV elicits too many different ones, nearly all of which are ineffective. Only a few HIV-infected individuals produce potent antibodies and even then, these are often in insufficient concentrations. Now that the crystal structure of the potent antibodies has been defined, this vital molecular information could be used to design new vaccines that elicit production of these antibodies in the host.Valuable information has also come from a US Army sponsored clinical trial in Thailand that studied more than 16,000 healthy individuals between 2003 and 2006. A vaccine containing genetically engineered versions of three HIV genes was used, with an inert form of the bird virus canary pox as the vector. In December 2009, the sponsors reported that the rate of HIV infection among volunteers who received the experimental vaccine was 31% lower than among those who received a placebo (Rerks-Ngarm et al, 2009). “[The trial] showed, for the first time, that a vaccine is able to reduce the risk of HIV infection in humans,” said Kim. “Although our results were modest, they are providing a great deal of information to inform the field. For example, the protection appeared highest at 6–12 months based on post-hoc analysis. If we can sustain or increase this effect, that would be a great accomplishment.”While the battle against HIV/AIDS has been catching most of the headlines, a lesser known viral disease, dengue fever, has been rising quickly up the research agenda. Dengue fever is caused by four related strains of flavivirus that are transmitted by mosquitoes. The disease affects 50–100 million people annually, mostly in urban tropical areas, where an estimated 2.5 billion are at risk (Webster et al, 2009), largely because of growing urban populations. Attempts to develop a vaccine have been inhibited by the host immune response to the vaccine, according to Sarah Rowland-Jones, professor of immunology at the Weatherall Institute of Molecular Medicine in Oxford, UK. “It is a tough target for vaccine development principally because of the possibility that immune mechanisms contribute to pathogenesis, so researchers have to be particularly careful that a dengue vaccine does not make disease more likely because of the kind of immune response it stimulates, rather than leading to protection from infection,” she said.The fact that there are four viruses is another problem, especially as a vaccine protecting against one might actually prime individuals for another serotype. “The best hypothesis for severe dengue is that following a first infection, an individual gains immunity against that serotype but becomes more prone to a second infection with a different serotype,” said Jeremy Farrar, Director of the Wellcome Unit in Vietnam and a professor of tropical medicine at Oxford University. “With that second infection against another serotype, more severe disease develops. Obviously this makes vaccine development difficult as one worries individuals will be ‘primed'' by the vaccine and, when they get a natural infection will have more severe disease.”...the effect of each nucleotide change on virus activity is very small, but the cumulative impact of hundreds of such changes causes strong attenuationHowever, Farrar believes this problem has been fixed with the new generation of ‘chimeric vaccines'' that offer protection against all four serotypes. These are based on an exisiting vaccine against the related disease yellow fever, incorporating a part of the dengue virus that triggers an immune response. This chimeric approach has the potential to be extended to develop vaccines against other diseases.This begs the question of why a dengue virus vaccine has not been developed already, given that the related yellow fever vaccine has been available for years. Part of the reason is that dengue is a tougher target, involving four serotypes, but it is also because its mortality is much lower than the 50% rate of yellow fever. “Dengue hasn''t been top of the agenda because it hasn''t caused so much mortality, but there is a lot of morbidity, and it puts a lot of stress on health authorities and has an epidemic potential,” Hombach said. For this reason it has received more funding recently, with phase III clinical trials likely to begin soon, according to Farrar.An entirely different approach for engineering vaccines might also be emerging. Traditional vaccines use mutated virus strains with limited replication abilities, in order to stimulate the immune system. The main drawback of this approach is that many attenuated strains fail to elicit adequate immunity, and it takes a long time to develop such strains. However, Eckard Wimmer and colleagues at Stony Brook University in New York, have developed a computer-aided approach to create attenuated strains without changing the composition and amino-acid sequence of the virus''s proteins (Mueller et al, 2010).They exploit the redundancy of the genetic code; 64 codons code for just 20 amino acids. As most amino acids are coded for by several codons, it is possible to introduce single-nucleotide changes without altering which proteins are expressed, thereby retaining all antigens that might generate an adaptive immune response. Crucially, however, this alters the expression of some genes, which reduces the ability of the virus to replicate. As Wimmer pointed out, the effect of each nucleotide change on virus activity is very small, but the cumulative impact of hundreds of such changes causes strong attenuation. “We call this ‘death by a thousand cuts'',” he said.Moreover, subsequent natural mutations will probably change only one or two of these nucleotide substitutions back to the original, so the chance that the virus will regain its former virulence is very small. The greatest advantage of this approach, however, is speed. “Clearly, such recoded genomes can only be produced by chemical synthesis,” said Wimmer. “They can be designed rapidly—much faster than any other live vaccine that was isolated after long trials of selection.” This, argues Wimmer, makes the approach ideal for countering emerging pandemics when time is short, especially those caused by influenza. Indeed, Wimmer has demonstrated his approach by designing an influenza vaccine (Mueller et al, 2010).Even if this synthetic approach can generate new vaccine candidates more quickly, it will still require development time and clinical trials to assess their efficacy and safety—as is the case for other emerging techniques. New knowledge and new technologies are filtering through to vaccine development; while the disappointments of the past have provided valuable lessons.     

Publics and vaccinomics: beyond public understanding of science

Vaccines have been among the most effective tools for addressing global public health challenges. With the advent of genomics, novel approaches for vaccine discovery are opening up new opportunities for vaccine development and applications, particularly with the expectation of personalized vaccines and the possibility of addressing a broader range of infectious diseases. In this context, it is useful to reflect on the social contexts of vaccine development as these have been influenced by social, ethical, political challenges. This article discusses the historical context of vaccine controversies and factors that help explain public acceptance and resistance, illustrating that these challenges go well beyond simple public misunderstandings. The broader vaccine challenges evident along the innovation trajectory, from development to commercialization and implementation include problems in research and development, organizational issues, and legal and regulatory challenges that may collectively contribute to public resistance or confidence. The recent history of genomics provides further lessons that the developing field of vaccinomics can learn from.     

Potent CTL induction by a whole cell pertussis vaccine in anti-tumor peptide immunotherapy

Promising yet limited clinical responses have been reported for peptide based immunotherapy against tumors. In order to induce more potent cytolytic CD8 T cell responses, we investigated the use of Bordetella pertussis vaccine as an adjuvant for peptide immunization. A whole cell (Wc) vaccine has been known to induce a Th1 biased immune response while an acellular (Ac) vaccine tends to induce that of the Th2 type. Natural infection by B. pertussis helps to maintain a robust Th1 memory in the host population. To examine the adjuvant activity of the pertussis vaccine, we immunized mice with an ovalbumin peptide as a model tumor antigen, and monitored the development of anti-tumor activities. The addition of either the Ac or the Wc vaccine helped expand the specific CD8 T cells. However, there was a marked difference in the induced cytolytic activity where the Wc vaccine was superior to the Ac. The Wc vaccine was also more effective in inducing in vivo tumor rejection. The adjuvant activity was not only effective against ovalbumin, but was also evident when an endogenous tumor antigen, Wilms' tumor 1 gene product, was targeted. These results indicate that, although the Wc vaccine does not share the same antigen specificity with tumor cells, it can aid in the development of highly cytolytic CD8 T cells as an adjuvant at the site of peptide immunization.     

Malaria vaccines

Although the possibility of a live attenuated malaria vaccine has been considered, current malaria vaccine development activities are dominated by attempts to develop a subunit vaccine. Hence, it is entirely appropriate that a session of the Molecular Approaches to Malaria conference, Lorne, Australia, 2-5 February 2000, was devoted to vaccine development. The oral presentations in this session and the relevant poster presentations are outlined here by Robin Anders and Allan Saul.