 |
Although a very effective vaccine exists for HBV, researchers are constantly looking for new possibilities to increase its efficiency and to create new therapeutic vaccines. Additionally, the current HBV vaccine is three doses over about 8 months, which makes it more difficult to get high rates of delivery in many parts of the world. A vaccine that required no boosters or only one booster stands to increase the percentage of people who would be vaccinated. Such a vaccine also has the possibility of being less expensive, making it available to a larger portion of the world's population.
In January 2000, the FDA approved a new two-dose regiment of the standard Merck Recombivax HBV vaccine for adolescents 11-15 years old to be used in place of the traditional three-dose regimen. Because of the busy schedules of adolescents, 25% do not finish the three-dose regimen, and almost all (94%) of those who do finish it do so behind schedule. With a two-dose regimen, a larger proportion of these adolescents will finish the two-dose regimen, which is especially advantageous given that 90% of all HBV cases occur in adolescents and young adults. This new approval is one way to increase the public health effects of an existing vaccine. See our Vaccine Issues page. www.psigroup.com
Other than modifying the existing vaccine, researchers are also looking to make novel vaccines. One form of technology that is being used extensively at this stage of development is recombinant DNA technology. The basic idea of recombinant DNA technology is to insert a piece of DNA from one organism into the genome of another, creating a chimeric DNA molecule. This way, a vector could be made whereby the protein expressed from the DNA would include the immunogenic portion of a protein from a bacteria or virus. If the immunogenic portion could induce an immune response without causing disease, then the recombinant technology could be used to create a vaccine, which is exactly what was done in the case of HBV using the HBsAg (hepatits B surface antigen, see our Virus and Vaccine pages). This same technology has been used to create a more effective vaccine for the advantage of the 5%-10% of people who do not respond to the current vaccine.One research group (the Wyeth Ayerst Research group) from Philadelphia attempted to improve the efficacy of the HBsAg vaccine by adding epitopes to the HBsAg molecule. Rather than adding more of the HBV genome, though, this group decided to generate a novel HBsAg molecule that contains a Th epitope from tetanus toxoid (TT) using recombinant DNA technology. It is significant that the TT epitope included is a Th cell epitope because this chimeric molecule now has the opportuity to induce more T helper cells in order to amplify the humoral, B cell response. Using this method, researchers created a segment of DNA that included the TT Th epitope in the coding sequence of the HBsAg molecule. In doing so they created a new, chimeric protein whose DNA sequence was inserted into an adenovirus vector. In the course of this experiment, the adenovirus vector was then inserted into cells, and the protein encoded was secreted in 22-nm particles, similar to those found in the course of a natural HBV infection. After purification of these particles, they were then injected into mice to determine their immunogenicity and the response of the mice to these particles in comparison to native HBsAg. Interestingly, the anti-HBsAg response to the HBsAg-TT Th conjugate was several fold higher than the anti-HBsAg response to the native protein. The anti-HBsAg titers were anywhere from 5.1-137 fold higher in the mice immunized with the conjugate protein in reference to the mice immunized with native HBsAg. Additionally, mice immunized with the conjugate protein responded with significant antibody titers at significantly lower doses of antigen than did mice immunized with the native antigen. Furthermore, it was found that if these mice were first primed with a dose of TT, their response was increased even further. This was true of mice in both inbred and outbred populations, which contributes to the idea that this conjugate has potential to work in a diverse genetic population as the Th epitope from TT was recognized by several different classes of MHC molecules. Thus, conjugating a Th epitope to the HBsAg is one way to improve the efficacy of the current vaccine. (Chengalvala, et al. 1999). 7.
Electron microscopy of HBsAG conjugaed with a portion of the tetanus toxoid at 125,000x.
Adding foreign epitopes to HBsAg, such as those on tetanus toxoid, may hold the key for eliciting a larger Th response in unresponsive individuals in order to facilitate greater B cell activation.
image from Chengalvala, et. al. in Vaccine, 1999. 7. Researchers have shown that it is possible to immunize with DNA itself. It has been shown that it is possible to delete segments of the genome that pertain to the virulence of certain bacteria in order to make an attenuated strain that retains its immunogenicity but is no longer virulent. Clearly, these organisms are a great source for possible vaccines as they pose no danger to the host but extract an immune response that theoretically will protect the host from exposure to the natural pathogen. In the case of HBV, a DNA vaccine has been engineered in the form of a DNA plasmid containing the genes that encode for HBsAg. This vaccine is injected intramuscularly and has been shown to confer protection in mice after a single injection. The humoral response to this DNA vaccine is comparable to the response to natural infection with HBV. In both cases, IgM can be detected about 1 week after injection with IgG detected about 2 weeks after injection. Importantly, injection with DNA produces not just a humoral response, but a strong CTL response as well, involving the T cells in the immunity. The CTL precursors that are seen after injection of the DNA have been shown to induce specific lysis of HBV infected cells. A vaccine that induces a T cell response in addition to a B cell response may be effective in a larger percentage of people and also may contribute to long-lasting immunity. Although this technology and the results in mice are encouraging, DNA vaccination has its own series of obstacles. First, the DNA that is injected is not always actively transcribed. In other words, the gene transfer is not always complete, rendering the vaccine ineffective. Second, when gene transfer does occur, foreign DNA is inserted into the host's genome and there is no way of controlling where it is inserted, placing the host is at risk for problematic mutations in its genome. Lastly, there is no control over how long the foreign DNA is expressed, and depending on the duration of this expression, it is possible that rather than inducing an immune response in the host, the host could instead become tolerized to the antigen, making it more susceptible to infection rather than less so. Thus, this technology must be improved before it can have human application. (Gregoriadis, 1995, 12.).
Other groups have looked into the case of chronic HBV carriers, those people who are unable to clear the viral infection more than 6 months after HBsAg appears in their serum. These researchers have found that chronic carriers are lacking in their Th response to the virus. This lack of Th response is what causes the lack of humoral response to this antigen. In order to investigate this problem, a cohort of chronic carriers was given the standard yeast recombinant vaccine to see if it had any therapeutic effect. Approximately 50% of those tested did respond to the vaccine and proceeded to clear the infection. Why the vaccine worked for some people and not the others is not clear. Theoretically, the vaccine exposes the host to the same immunogen that the natural virus does; it is the natural virus that the chronic carriers can not clear, yet somehow the vaccine had a therapeutic effect for some of these people but not others. The first question that was asked was whether or not therapeutic success of the vaccine had any correlation with specific MHC haplotypes. Although this would have provided a satisfactory explanation for the reactivity to the vaccine or lack thereof, this was not the case, and response or lack of response to the vaccine had no correlation to MHC haplotypes. At this point, it is not understood why 50% of chronic carriers responded to the vaccine while the other 50% did not. (Couillin, et al. 1999, 8).
Epidemiology Virus Pathology and Treatment
The Vaccine The Vaccine Future Vaccine Issues
References Back to Front Links
