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Current research and future prospects in the development of vaccines against gastrointestinal nematodes in cattle.

Vaccination is being considered as the most feasible alternative for anthelmintic drugs to control gastrointestinal nematode infections in cattle. However, despite the identification of several candidate protective antigens, no vaccines against gastrointestinal nematode parasites are currently available. The main problems that hamper the development of nematode vaccines in ruminants are that vaccination with recombinant nematode proteins produced in bacterial or eukaryotic expression systems did not induce a protective immune response and no suitable antigen delivery system is available for presentation of protective worm antigens to the bovine mucosal immune system. The present review will focus on recent advances and remaining obstacles in vaccine development against gastrointestinal nematodes in cattle, in particular against the abomasal parasite Ostertagia ostertagi.

Animals↗

Immunoparasitology: its contribution to development of new parasite vaccines.

Immunoparasitology--the study of the immunology of host-parasite relationships--can post some notable research successes over the past decade. Progress towards prophylactic molecularly-defined vaccines against human parasitic diseases such as falciparum malaria, schistosomiasis mansoni and cutaneous leishmaniasis, as well as economically-important veterinary parasites, has been good. However, new vaccines are not coming as easily as might be hoped mainly because of several deficiencies in knowledge on the immunology of host-parasite relationships and the unknown relevance of well-characterized model systems to real-life parasitic diseases. In some models, the immunology of resistance and the immunology of disease are understood in broad outline. The availability of isolated antigens and their epitopes has improved quantitation of host immune responses to various life cycle stages of parasites and enabled vaccination efficacy or diagnostic potential to be assessed. One of several major challenges facing the immunoparasitologist interested in vaccine development is overcoming genetically-based unresponsiveness to "oligoepitope", defined-antigen vaccines particularly at the level of helper TH and cytotoxic (Tc) T cells.

Animals↗

Development of an AIDS vaccine. Biological and ethical challenges.

The biologic, ethical, and social obstacles in AIDS vaccine development are explored. Current understanding of the immunodeterminants of HIV-1 pathogenesis is reviewed and ideal biological properties for an AIDS vaccine are proposed. Options for clinical trial design, criteria for entry into clinical trials, and provision for care of volunteers who experience vaccine-associated adversity are discussed.

Acquired Immunodeficiency Syndrome↗

Experimental basis for the development of a synthetic vaccine against Plasmodium falciparum malaria sporozoites.

Malaria continues to cause extensive morbidity and mortality in man. The exact number of individuals affected is not known. Estimates vary from 200 to 400 million, and more than one million die each year. Protective immunity against malaria can be obtained by vaccination with irradiated sporozoites. The protective antigens are polypeptides (circumsporozoite [CS] proteins) which cover the surface membrane of the parasite. CS proteins contain species-specific immunodominant epitopes, formed by tandem repeated sequences of amino acids. The dominant epitope of Plasmodium falciparum is represented in the synthetic peptide asparagine-alanine-asparagine-proline repeated in tandem three times; that is, (NANP)3. Monoclonal antibodies and most or all polyclonal human antibodies to P. falciparum sporozoites react with (NANP)3. Polyclonal antibodies raised against the synthetic peptide (NANP)3 react with the surface of the parasite and neutralize its infectivity. Since (NANP)3 repeats are present worldwide in CS proteins from P. falciparum, this epitope is a logical target for vaccine development.

Animals↗

Rationale for development of a synthetic vaccine against Plasmodium falciparum malaria.

Protective immunity against malaria can be obtained by vaccination with irradiated sporozoites. The protective antigens known as circumsporozoite (CS) proteins, are polypeptides that cover the surface membrane of the parasite. The CS proteins contain species-specific immunodominant epitopes formed by tandem repeated sequences of amino acids. Here it is shown that the dominant epitope of Plasmodium falciparum is contained in the synthetic dodecapeptide Asn-Ala-Asn-Pro-Asn-Ala-Asn-Pro-Asn-Ala-Pro or (NANP)3. Monoclonal antibodies and most or all polyclonal human antibodies to the sporozoites react with (NANP)3, and polyclonal antibodies raised against the synthetic peptide (NANP)3 react with the surface of the parasite and neutralize its infectivity. Since (NANP)3 repeats are present in CS proteins of P. falciparum from many parts of the world, this epitope is a logical target for vaccine development.

Adult↗

New adjuvants for parenteral and mucosal vaccines.

Developing efficient adjuvants for human vaccines, in order to elicit broad and sustained immune responses at systemic or mucosal levels, remains a challenge for the vaccine industry. Conventional approaches in the past have been largely empirical and partially successful. Selection was based on the balance between toxicity and adjuvanticity, first in an animal model, and then in clinical trials. The advent of improved biochemical techniques has allowed for the purification or construction of new and well characterised adjuvants. In addition, recent advances in our understanding of the immune system, most particularly with respect to early proinflammatory signals, have led to the identification of new biological targets for vaccine adjuvants. In particular, one can now choose adjuvants able to selectively induce T helper (Th)-1 and/or Th2 responses, according to the vaccine target and the desired immune response. As our knowledge of the cell types and cytokines interacting in the immune responses increases, so does our understanding of the mode of action of adjuvants, as well as the way in which they produce adverse effects.

Adjuvants, Immunologic↗

Development of vaccines against sea lice.

A review of efforts to develop a vaccine against sea lice is presented together with analysis of the rationale behind the approaches and potential future directions. Vaccines against the caligid copepod, Lepeophtheirus salmonis, have the potential to be a cost-effective means of controlling the infection and avoid many of the disadvantages of medicine treatments. However, research towards such vaccines is in its infancy and approaches so far used have met with little or no success. Most strategies for sea louse vaccines have adopted methods used for vaccines against other ectoparasites. A vaccine against the cattle tick (Boophilus microplus) is in field use while other vaccines such as the sheep blowfly (Lucilia cuprina) vaccine are at an earlier stage of development. These haematophageous parasites ingest host antibody as part of a large blood meal which can target antigenic sites in the gut. However, the assumption that arachnid and insect physiology are directly comparable with that of sea lice is not proven, and this may partly explain the slow progress this approach has had with sea lice. Success in developing a louse vaccine will depend upon a better understanding of louse digestive biology, particularly an evaluation of whether the cattle tick model is applicable to the development of a louse vaccine. If the louse gut is to be targeted immunologically, critical antigens will need to be identified and evaluated, bearing in mind that an economic vaccine must include recombinant proteins or be a DNA vaccine. Alternatives to the louse gut as a target are also worth consideration. Antibodies could target critical host-parasite interactions that are amenable to disruption, although no such targets have been identified.

Animals↗

Prospects for the use of new vaccines in developing countries: cost is not the only impediment.

Global immunization programs represent a great public health success story. Evidence from every region documents substantial reductions in morbidity and mortality following widespread use of vaccines developed years ago. Development and introduction of new vaccines and vaccine combinations aimed at the industrialized world market are occurring at a fast pace. A number of political and economic factors will influence the rate at which developing country immunization programs incorporate those new vaccines that could have a major public health impact. Perhaps the greatest determinant of this rate is the extent to which international and bilateral agencies and national governments appreciate the potential value of new vaccines.

Costs and Cost Analysis↗

Progress in development of liver fluke vaccines.

Infection of ruminants by Fasciola spp continues to cause large economic losses worldwide. Recent results from several laboratories have demonstrated that animals can be significantly protected against infection by vaccination with defined Fasciola antigens. Apart from reducing fluke burdens, some vaccines can elicit a concurrent reduction in parasite egg production. The expectation of a commercially feasible vaccine that might also reduce parasite transmission in the field is now realistic, although major hurdles still exist. Here, Terry Spithill and John Dalton review the results of several recent vaccine trials and discuss the future prospects for vaccine development.

Journal Article↗

High immunogenic enterovirus 71 strain and its production using serum-free microcarrier Vero cell culture.

Developing an effective vaccine against enterovirus 71 (EV71) infection provides the best means to control the disease. We have previously reported that large-scale preparation of a low immunogenic EV71 strain can be achieved using serum free microcarrier Vero cell culture in a 2-l bioreactor [Wu SC, Liu CC, Lian WC. Optimization of microcarrier cell culture process for the inactivated enterovirus type 71 vaccine development. Vaccine 2004;22:3858-64]. This present work further investigated the virus growth and the immunogenicity of two high immunogenic strains (EV71-075 and EV71-117) prepared in serum-free microcarrier cell cultures. Our results showed that serum free culture increased cell death rate after infection, reduced the virus specific productivity, but resulted in elicitation of higher neutralizing titers in immunized mice as compared to that parallel obtained in serum-containing cultures. Therefore, serum-free microcarrier culture is a valuable process for developing inactivated EV71 vaccines.

Amino Acid Sequence↗

A vaccine against Asian schistosomiasis.

There is continued transmission of schistosomiasis japonica in China and Philippines despite highly effective control programs that focus on the application of the highly effective drug praziquantel (PZQ). The massive Three Gorges Dam across the Yangtze River in Southern China, soon to be completed, is expected to significantly increase schistosomiasis transmission and introduce the disease into areas currently unaffected. After long-term experience it is generally accepted that PZQ chemotherapy, although the cornerstone of current control programs, does have significant limitations. Furthermore, efficient drug delivery requires a substantial infrastructure to regularly cover all parts of an endemic area. Although there is not yet clear-cut evidence for the existence of PZQ-resistant schistosome strains, decreased susceptibility to the drug has been observed in several countries. As a result, a protective vaccine represents an essential component for the long-term control of schistosomiasis. This article briefly reviews aspects of anti-schistosome protective immunity that are important in the context of vaccine development. The current status in the development of vaccines against Schistosoma japonicum will then be discussed as will new approaches that may improve on the efficacy of available vaccines, and aid in the identification of new targets for immune attack. With new and extensive data becoming available from the S. japonicum genome project, the prospects for developing an effective vaccine are encouraging. The challenges that remain are many but it is crucial that the momentum towards developing effective anti-schistosome vaccines is maintained.

Animals↗

Proteomics reveals that proteins expressed during the early stage of Bacillus anthracis infection are potential targets for the development of vaccines and drugs.

In this review, we advance a new concept in developing vaccines and/or drugs to target specific proteins expressed during the early stage of Bacillus anthracis (anthrax) infection and address existing challenges to this concept. Three proteins (immune inhibitor A, GPR-like spore protease, and alanine racemase) initially identified by proteomics in our laboratory were found to have differential expressions during anthrax spore germination and early outgrowth. Other studies of different bacillus strains indicate that these three proteins are involved in either germination or cytotoxicity of spores, suggesting that they may serve as potential targets for the design of anti-anthrax vaccines and drugs.

Alanine Racemase↗

State of the art in developing allergen vaccines in Cuba: prospects of novel adjuvanted vaccines.

Standardized allergen vaccines have been developed and registered as biopharmaceutical products in Cuba. Three different vaccines were obtained from the most relevant allergenic mite species: Dermatophagoides pteronvssinus, Dermatophagoides siboney, and Blomia tropicalis. Immuno-analytical methods based on murine monoclonal antibodies and human IgE antibodies were developed for assessing allergenic potency, composition, and stability. Preclinical and clinical studies showed efficacy and safety in diagnostic prick-tests and subcutaneous immunotherapy in asthmatic patients. New approaches are now undertaken in order to develop new adjuvanted formulations based on liposomes or proteoliposomes from Neisseria meningitidis, and purified allergens; aiming to overcome the drawbacks of conventional immunotherapy.

Adjuvants, Immunologic↗

New carriers and adjuvants in the development of vaccines.

Different approaches are being followed to enhance the immunogenicity of established and newly developed vaccines. Some of them foresee the utilization of carrier molecules recognized by the immune systems of a large proportion of the human population. Others are directed mainly towards the development of improved adjuvants and delivery systems.

Adjuvants, Immunologic↗

Recent advances in the development of HIV-1 Tat-based vaccines.

Over the last two decades most of the efforts in HIV vaccine development have been based on the use of the HIV Env with the goal to induce sterilizing immunity. However, as a result of Env variability disappointing results have been obtained in preclinical and phase III clinical trials. Although the objective of a preventive immunity still remains a priority, secondary endpoints (e.g. block of virus replication and disease onset) are being considered at the present as more achievable end-points in HIV vaccine development. This is based on accumulating evidence indicating that low viral load correlates with maintenance of immune functions and slow progression to disease, and that cell-mediated immunity plays a major protective role in the absence of sterilizing immunity. The promising results obtained in non-human primates with a vaccine based on a native Tat protein (B-clade), which is an early regulatory protein key for HIV replication and AIDS pathogenesis, highlights the importance of targeting the virus very early after infection. In particular, the immune response against Tat appears to modify the virus-host interactions at the very beginning of infection, thus containing the depletion of critical immune cells and the progression of infection. Moreover, since Tat targets and induces maturation of dendritic cells, has immunomodulatory activities and drives Th-1 and CTL responses, immunization with Tat may drive or increase these immune responses also against other HIV antigens to support an effective, long-lasting and hopefully even sterilizing antiviral immunity. Finally, Tat B-clade is similarly recognized by sera from individuals infected by different virus clades (A, B, C, D) supporting the concept of a cross-clade vaccine. Therefore, the Tat-vaccine should contain virus replication protecting from disease progression (non-sterilizing immunity) or even favoring an abortive infection. Although only a phase III clinical trial will establish the efficacy of this vaccine strategy, the Tat-vaccine has recently entered preventive and therapeutic phase I clinical testing in Italy to establish safety (primary-end-point) and immunogenicity (secondary end-point) and phase II studies are being prepared.

AIDS Vaccines↗

Vaccination of adults against travel-related infectious diseases, and new developments in vaccines.

The number of people travelling to tropical or subtropical countries, whether for holidays or for business, is steadily increasing. Many of these travellers are at risk of acquiring an infectious disease. Protection against certain infectious diseases is possible by vaccination. Vaccinations required or recommended for adults are reviewed here. Progress in the refinement of available vaccines, as well as the development of new vaccines, is discussed.

Adult↗

Translational research to assist policy decisions about introducing new vaccines in developing countries.

Few new-generation vaccines have found their way into public-health programmes for the poor in developing countries, and for those that have, delays of years or even decades after their licensure and introduction in industrialized countries have been the rule. Financial constraints and political obstacles have played major roles in delaying the introduction of the vaccines. Also contributing to this situation has been a dearth of needed research. While past analyses have identified inadequate support for conducting Phase 1 studies as an obstacle, other types of translational research are also needed. Vaccines may perform less well in impoverished populations in the developing world than in more affluent populations. Consequently, Phase 2 and Phase 3 trials of new vaccines in developing countries are a second essential type of translational research needed for the introduction of vaccines in developing countries. Moreover, even for vaccines that have performed well in pre-licensure human trials in developing countries, doubts often remain about whether the local disease burden justifies introduction of vaccine, whether the vaccine will be cost-effective, and whether introduction of vaccine will be programmatically feasible, acceptable, and financially sustainable. Because these residual doubts constitute obstacles to the introduction of vaccine, a third type of translational research is needed to provide this evidence required for policy. In this paper, these three types of translational research are illustrated with projects being undertaken in the Diseases of the Most Impoverished Programme. The Programme is conducting translational research to accelerate the rational introduction of new vaccines against cholera, shigellosis, and typhoid fever in developing countries affected by these diseases.

Clinical Trials as Topic↗