of this decade. However, far more information is needed on the safety and antigenicity of the polyvalent vaccine.
Other approaches under investigation might also provide good results, including subunit vaccine, plasma DNA vaccine, and infectious cloned vaccine (e.g., chimeric dengue-4 backbone), and recombinant dengue vaccine containing NS-1 (which is a potent antigen in experimental vaccines against yellow fever). However, there appears to be no practical way to produce neutralizing antibodies without at least some enhancing activity; this will be a safety concern in all dengue vaccines.
Another major concern is the duration of protection. Most cases of DHF occur between ages 3 and 15, at which point children seem to develop an immunity. Hence, dengue vaccines should have a very solid long-term memory, with the ability to induce both B-cell and T-cell responses, as well as good antibody response.
One of the biggest barriers to vaccine development is that there is no suitable animal model for DHF. One team looked at over 100 primate species and couldn’t find a model. Primates can be infected, and they develop viremia, but they don’t progress to the more serious syndrome of DHF.
In response to questions from the audience, Dr. Ennis added the following:
Although T-cell activation is V-beta-17 specific, it does not appear to be a super-antigen effect. Instead, host factors such as HLA seem to be contributing to increased risk. HLA typing of the children in Thailand should shed light on this question.
Antigenic variation doesn’t seem to be a major issue. There are four serotypes, but within the serotypes there doesn’t seem to be much drift in the antigens or epitopes.
Immune response to primary infection is serotype-specific, with antibodies appearing after a day or two, about when the virus is cleared. At the beginning of a secondary infection, therefore, the only antibodies that will recognize the new virus will be the crossreactive antibodies. Hence, the triggering of the increased number of infected cells takes place before the antibody response.
The risk of DHF increases with secondary infection, but it does not appear to increase further when the subject is infected with a third serotype. In fact, risk seems to go down after the second infection, possibly because of cross-neutralization.
While there is a strong emphasis on developing a quadravalent vaccine, additional studies will be needed to develop a combination vaccine that has 95 percent neutralizing-antibody responses to all four serotypes, instead of 60 percent for one and 95 percent for another.
Greater knowledge about the polymorphic nature of T-cell response should make it possible to engineer vaccines that contain T-cell epitopes as well as neutralizing epitopes.