Anthrax vaccination strategies.

Traditional vaccination with whole pathogens or pathogen-derived subunits has completely eliminated diseases like smallpox, and has greatly limited the incidence, morbidity and mortality associated with many other infectious diseases. Unfortunately, a large burden of infectious disease remains that may be preventable through vaccination. For many of these, more focused and innovative approaches may be essential for the development of effective vaccines.

The promise and challenge of epitope-focused vaccines.

The management of anthrax remains a top priority among the biowarfare/bioterror agents. It was the Bacillus anthracis spore attack through the US mail system after the September 11, 2001, terrorist attacks in the USA that highlighted the potential of B. anthracis as a bioterrorism agent and the threat posed by its deliberate dissemination. These attacks invigorated the efforts toward understanding the anthrax pathogenesis and development of more comprehensive medical intervention strategies for its containment in case of both natural disease and manmade, accidental or deliberate infection of a non-suspecting population. Currently, efforts are directed toward the development of safe and efficacious vaccines as well as intervention tools for controlling the disease in the advanced fulminant stage when toxemia has already developed. This work presents an overview of the current understanding of anthrax pathogenesis and recent advances made, particularly after 2001, for the successful management of anthrax and outlines future perspectives.

Anthrax vaccines: present status and future prospects.

The terrorism events of September 11, 2001, and the subsequent B. anthracis spore attacks through the U.S. mail system have demonstrated their feasibility as a bioterrorism weapon. Moreover, they have shown that the West needs to be prepared for an increasing number of terrorist attacks, which may include the use of biological warfare. In the absence of specific intelligence and integrated real-time detection systems, the unpredictable nature of bioterrorism events calls for the development of medical countermeasures, which will enable the authorities to treat the exposed individuals. 1,2 Following a biological anthrax attack, vaccination in conjunction with antibiotic administration appears to be the most effective and economical form of mass protection. However, such a countermeasure is not as effective as it may seem because the current vaccines have drawbacks and the interval between initial exposure and the onset of treatment can be lengthy 3 as well. For these reasons, therapeutic strategies that emphasize toxin inactivation are seen to be worth pursuing. At present, physicians have antibiotic options at their disposal to eliminate an anthrax infection, but they have no therapeutic options to combat the lethal factor (LF a ) mediated toxemia and tissue destruction or the residual toxemia that persists even after the bacteria have been eliminated by antibiotics. 4 New details regarding anthrax pathogenesis and host responses have emerged since the terrorist attack in 2001, which demonstrate that not only a better understanding of the biology of virulence factors but also their interaction with the host during infection could lead to the development of improved options against anthrax. 5,6 Research efforts for the development of improved treatment modalities have increased dramatically, leading to a huge expansion in the existing literature, and it is precisely this that makes reviewing such a topic so difficult. The present study focuses on the most important medical countermeasures against inhalational anthrax that have been developed mainly since 2001 and also highlights current problems and the possible development of improved human anti-infective strategies.

Current and Future Medical Approaches To Combat the Anthrax Threat

Trichinellosis is one of the most important food-borne parasitic zoonoses throughout the world Because infected pigs are the major source of human infections, and China is becoming the largest international producer of pork, the development of a transmission-blocking vaccine to prevent swine from being infected is urgently needed for trichinellosis control in China Our previous studies have demonstrated that specific Trichinella spiralis paramyosin (Ts-Pmy) and Ts-87 antigen could provide protective immunity against T spiralis infection in immunized mice Certain protective epitopes of Ts-Pmy and Ts-87 antigen have been identified To identify more Ts-Pmy protective epitopes, a new monoclonal antibody, termed 8F12, was produced against the N-terminus of Ts-Pmy This antibody elicited significant protective immunity in mice against T spiralis infection by passive transfer and was subsequently used to screen a random phage display peptide library to identify recognized epitopes Seven distinct positive phage clones were identified and their displayed peptides were sequenced Synthesized epitope peptides conjugated to keyhole limpet hemocyanin were used to immunize mice, four of which exhibited larval reduction (from 187% to 263%, respectively) in vaccinated mice in comparison to the KLH control To increase more effective protection, the epitope 8F7 that was found to induce the highest protection in this study was combined with two other previously identified epitopes (YX1 from Ts-Pmy and M7 from Ts-87) to formulate a multi-epitope vaccine Mice immunized with this multi-epitope vaccine experienced a 350% reduction in muscle larvae burden after being challenged with T spiralis larvae This protection is significantly higher than that induced by individual-epitope peptides and is associated with high levels of subclasses IgG and IgG1 These results showed that a multi-epitope vaccine induced better protective immunity than an individual epitope and provided a feasible approach for developing a safer and more effective vaccine against trichinellosis

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Protective Immunity against Trichinella spiralis Infection Induced by a Multi-Epitope Vaccine in a Murine Model

Current evidence suggests that protective antigen (PA)-based anthrax vaccines may elicit a narrow neutralizing antibody repertoire, and this may represent a vulnerability with PA-based vaccines. In an effort to identify neutralizing specificities which may complement those prevalent in PA antiserum, we evaluated whether sequences within the 2β2-2β3 loop of PA, which are apparent in the crystal structure of heptameric but not monomeric PA, might represent a target for an epitope-specific vaccine for anthrax and, further, whether antibodies to these sequences are induced in rabbits immunized with monomeric PA. We evaluated the immunogenicity in rabbits of a multiple antigenic peptide (MAP) displaying copies of amino acids (aa) 305 to 319 of this region. Overall, four out of six rabbits vaccinated with the MAP peptide in Freund's adjuvant developed high-titer, high-avidity antibody responses which cross-reacted with the immobilized peptide sequence comprising aa 305 to 319 and with PA, as determined by an enzyme-linked immunosorbent assay, and which displayed potent and durable neutralization of lethal toxin (LeTx) in vitro, with peak titers which were 452%, 100%, 67%, and 41% of the peak neutralization titers observed in positive-control rabbits immunized with PA. Importantly, analysis of sera from multiple cohorts of rabbits with high-titer immunity to PA demonstrated a virtual absence of this potent antibody specificity, and work by others suggests that this specificity may be present at only low levels in primate PA antiserum. These results highlight the potential importance of this immunologically cryptic neutralizing epitope from PA as a target for alternative and adjunctive vaccines for anthrax.

Te Hui Liu

Papers

Synthetic Peptide Vaccine Targeting a Cryptic Neutralizing Epitope in Domain 2 of Bacillus anthracis Protective Antigen

Genetic vaccines for anthrax based on recombinant adeno-associated virus vectors.