LONDON — The search for vaccines to protect against certain types of meningitis and septicemia has received added impetus from the discovery of a means of boosting the immune response to the bacterial pathogens that cause these diseases.
The finding could represent a powerful method for protecting vulnerable groups such as infants from several serious infections for which there are currently few effective vaccines.
Many bacteria — such as Streptococcus pneumoniae and Neisseria meningitidis, both of which cause meningitis — are covered with a thick polysaccharide capsule. Unfortunately, the polysaccharide, when incorporated in a vaccine, fails to stimulate a strong immune response. However, a new approach to developing vaccines to protect against such pathogens, reported in the January edition of Nature Medicine, could overcome this problem.
Andrew Heath, lecturer at the division of Molecular and Genetic Medicine and Sheffield Institute for Vaccine Studies at the University of Sheffield Medical School, in the U.K., and colleagues described their discovery in a paper titled: "Enhancement of T cell-independent immune responses in vivo by CD40 antibodies."
Heath told BioWorld International: "This work points the way toward a possible effective and inexpensive means of protecting susceptible groups against important bacterial pathogens."
The reason why the polysaccharide capsule of the bacteria in question fails to stimulate a strong immune response is that it is not made of protein. Proteins can be taken up by antigen-presenting cells. Those cells break them down into peptides which they present on their surfaces in conjunction with the molecules of the major histocompatibility complex. Such peptides are capable of stimulating T cells, which in turn help B cells to produce the appropriate class and type of antibodies.
The mechanism by which the T cell helps the B cell is as follows. The activated T cell expresses a molecule on its surface called the CD40 ligand. As its name suggests, this molecule binds to the CD40 molecule, which is present on B cells. But without stimulation of the T cell by antigen-presenting cells, this mechanism is absent.
Antigens such as polysaccharides have therefore been called "T cell-independent antigens." When used in candidate vaccines, they stimulate only a weak antibody response; and the boost to the immune response which is normally seen on second exposure to the antigen does not occur.
Heath and his colleagues have shown, however, that it is possible to circumvent the need for T cell help, and stimulate B cells in the appropriate way using antibodies to CD40. They immunized mice with a mixture of CD40 antibodies and polysaccharide from S. pneumoniae. The mice produced a strong antibody response. Significantly, the animals produced the full range of immunoglobulin G (IgG) antibodies which are required for effective immunity, rather than the limited range of IgM and IgG3 antibodies which would have appeared if they had been immunized with the polysaccharide alone.
The team went on to challenge the immunized mice with wild-type S pneumoniae. Five of eight animals survived the challenge, compared with only one of six which received polysaccharide plus a control monoclonal antibody, and none of 11 which received polysaccharide alone.
Heath's group also studied a strain of mice called CBA/N, which do not respond at all to T cell-independent antigens. To some extent, these animals provide a model of human infants, who also do not respond to such antigens. Tests showed these mice also produced a strong antibody response.
Heath said: "This work shows that it is possible to bypass the need for T cell help by putting in this anti-CD40 antibody with the polysaccharide antigen." The problem at present, he added, is that the doses of antibody being used in mice are very high — much higher than could be tolerated in humans.
To overcome this difficulty, the team next will endeavor to formulate a vaccine co-localizing the antibody and the polysaccharide, which should make it possible to reduce greatly the dose of antibody used. If tests of this strategy in mice go well, Heath said, "We would hope, along with a partner, to attempt some clinical trials using anti-human CD40."