For this reason, it is important to combine antibiotics with vaccination in post-exposure therapy . The alternative to antibiotic treatment  may be pre and post-exposure prevention with the use of vaccines. Post-exposure use of vaccines may shorten the prophylaxis time required. Terrorist attacks have forced scientists to take steps to search for an effective, safe, easy-to-administer vaccine, the use of which will provide long-term protection. Currently, the AVA vaccine is available on the US market and the UK AVP [8, 9, 12, 23].
The full virulence of
Anthrax spores enter the body, where they duplicate and transform into vegetative forms capable of producing a toxin consisting of three synergistically acting proteins: protective antigen (PA – 83 kDa); lethal factor (LF – 87 kDa) and edema factor (EF – 89 kDa). LF in combination with PA form lethal toxin and EF in combination with PA form edema toxin [8, 16, 39].
According to the latest research, PA binds to the ATR (anthrax toxin receptor), which is a cellular receptor encoded by the ANTXR1 gene present on the surface of the host cell and is digested by the protease resulting in the removal of 20 kDa fragment. The obtained C – terminal PA fragment (PA63 kDa) acquires the ability to polymerize by forming heptamer. The next step is binding of factors LF and EF. Once (PA63) 7 – LF and (PA63) 7 – EF complexes are formed, they penetrate via ATR-mediated endocytosis into the acid environment of the endosome. . The acidic pH in the endosome induces the incorporation of the PA heptamer into the endosome membrane and translocation of the EF factor into the cytosol of the attacked cell .
Presently, the vaccines against anthrax are produced in the Great Britain and in the USA. The British vaccine AVP (anthrax vaccine precipitated) and the American AVA (anthrax vaccine adsorbed) are licensed.
The AVP vaccine was first licensed in the UK in 1979 and is administered in three doses every three weeks and fourth dose after six months with an additional boost dose every twelve months. The AVA vaccine was registered in 1970 in the USA, at the Michigan Biologic Products Institute, Lansing and it is a cell-free culture adsorbed on aluminum hydroxide. The vaccine was named Biothrax in 2002 [3, 7, 9, 22, 28].
AVA requires a long vaccination schedule which is troublesome to perform and it is marginally reactogenic. It is administered six times in three doses every two weeks, and then three additional doses after six, twelve and eighteen months; plus yearly boosters. Up to 01.03.1999, around 590,000 doses of the anthrax vaccine were administered to American soldiers with no vaccine side effects noted [7, 14, 38].
In research on primates it was shown that administering two doses with two weeks between them, fully protected the animals from infection with air-suspended spores of
In the future, post-exposure antibiotic therapy should be shortened and combined with vaccination which guarantee protection against bacteraemia. A study conducted by Williamson
The US Food and Drug Administration accepted AVA (Anthrax Vaccine Absorbed BioThrax) as anthrax vaccine. In post-exposure prophylaxis (PEP) AVA is recommended to administered three times subcutaneously: zero, fourteen and twenty-eight days, in combination with sixty days of antibiotic therapy [28, 29].
The Advisory Committee on Immunisation Practices (ACIP) recommends that one combines antibiotic therapy followed by vaccine administration in two weeks in post-exposure regimen .
The Centre for Disease Control and Prevention provides Biothrax in 5 ml dose vials. as the cell-filtrate of strain
A study by Sivko
Group of forty-eight cynomolgus macaques were randomized to five group. Next, the AVA vaccine was administered in various mixtures on days zero and fourteen. Then Ames spores of
Animals susceptible to infection can be protected by an approved Sterne vaccine containing live
New generation vaccines containing recombinant peptides can provide solutions to these problems. Recently, the proposed antigen was rPA, BcIA, FIS. The ability to elicit a cellular response by selected antigens was tested on goats and with using a mouse model
A 5% increase in goat survival was observed when FIS was added to the rPA and rBcIA mixture. These results confirmed earlier studies in which goats were vaccinated with rPA and rBcIA as well as rPA, rBcIA with the addition of FIS. The vaccine consists of three antigens for greater protection against
New generation vaccines based on recombinant forms of anthrax toxin are unstable during storage. Research shows that the response to this type of vaccine is directed at non-functional, non-neutralizing sections of anthrax toxin. Neutralization of anthrax toxin occurs by blocking the functional regions and epitopes, antibodies that comprise the PA domain . The AVA and rPA vaccines with Alhydrogel adjuvant used in phase 1 clinical studies in humans and animals gave similar levels of antibodies. .
As a result of these concerns, a lot of effort has been invested in production and testing of the immunological efficiency of rPA (recombinant PA protein).
The vaccine containing the recombinant PA protein elicited a strong immune response producing a high neutralizing antibody titer providing protection against attenuated
The rPA protein can be used to produce anthrax vaccine due to its
Both inhalation anthrax and pneumonic plague can be prevented simultaneously using a new form of vaccine presented in another research publication. A new study reports the development of a vaccine which allows targeting three antigens, F1 and V from
Tested animals proved a full protection from a simultaneous challenge with
Another example of a nanoparticle vaccine directed against both anthrax and plague is a product based on bacteriophage T4 as a platform. The strong immune response, which is specific for anthrax and plague, was triggered by virus particles. Moreover, nanoparticles tested on animal models such as rabbits, mice and rats, protected them against inhalational anthrax and pulmonary form of plague.
Despite administrating simultaneously a lethal dose of both anthrax toxin and
The mucosal and systemic compartments were tested for the immunological memory response by Sun-Je Woo et al., who have investigated intranasal immunisation of rPA of
Moreover, use of the mentioned intranasal immunisation of rPA and CT, resulted in formation of effector memory CD4+ T cells in the lungs. As the result Th1 and Th17 – type cytokines in the lungs expanded their expression. However, this do not hold for the spleen or CLNs. From the results it can be assumed that the PA-mediated immunity through nasal route, may become an promising agent to protect from anthrax, as there is direct correlation between protective immunity and the PA-specific antibodies. In conclusion, nasal route appears to be the most promising platform for the vaccine delivery, and produces a long-term immunity against anthrax .
Vaccination with the anthrax capsule – a naturally occurring component of the bacterium that causes the disease – completely protected monkeys from lethal anthrax infection. These results indicate that anthrax capsule is a highly effective vaccine component that should be considered for incorporation in future generation anthrax vaccines .
Research concerning the new anti-capsule vaccine development becomes an interesting topic, judging by the current results. Significant antibody responses where observed for the outer membrane protein complex (OMPC) of
Currently most of the available anthrax vaccines work only against the single PA immunogen of
However, the higher dosage of 50 µg of the capsule conjugated vaccine resulted in a full protection of rhesus macaques against inhalation anthrax. Therefore, the promising results indicate that this conjugated capsule vaccine could become a promising drug in fighting anthrax challenge.
From the current studies, it can be observed that large doses of conjugate capsule-OMPC vaccine, can deliver a full protection in the rhesus macaques, animal model of inhalation anthrax. In fact, the promising results of the non-human primate model can suggest that the conjugated vaccine of immunogenic capsule with PA in prospect anthrax vaccines can possibly boost the effectiveness of PA-based vaccines [5, 6].
Vaccines development, diagnostic assays and the post exposure therapy are the main areas PA antigen is targeted in research. It takes ten to eleven days from the first symptoms of cutaneous anthrax for the immune system reaction to be detectable, and it continues to be recognizable for the following eight to sixteen months.
Intoxication by anthrax toxin is a large process where each part of PA has a defined role. The second domain (PAD2), which is responsible for membrane insertion and heptamerisation of PA, generated the largest immune response. Another significant response was detected against domain 4 (PAD4), that has generally higher presence in the course of heptamerisation. However, the highest immune response was caused by the domain 1 in a mouse model, in comparison to domains 2 and 4 which were significantly less efficient in triggering the larger antibody titer.
In conclusion, the individual domain 2 and 4 may become interesting targets for vaccine development through generating the chimeric protein with different applicable proteins, due to significant immunoreactivity observed on human cutaneous anthrax . The results of the research of Gubbins
The main disadvantage of PA based vaccines is a short shelf life which restrains their usage, although they are currently the most efficient drug fighting against
In conclusion, this study described the development of a new generation vaccine for fighting against anthrax, by chimeric protein fusion of immunodominant epitopes of PA and N-terminal domain of LF (LFn) .
The threat of