Neisseria meningitidis is a major cause of bacterial meningitis and bacteremia in otherwise healthy infants and young adults. Bacterial meningitis—an inflammation of the meninges which surround the spinal cord and brain—is a rare but extremely dangerous, rapidly progressing disease. It can become life-threatening within hours after the first symptoms appear. Even with proper antibiotic treatment, 10 to 14% of patients die, and an equal number are left with permanent neurologic damage such as hearing loss, paralysis, and mental retardation.
N. meningitidis also causes bacteremia, a disease in which bacteria multiply uncontrollably in the bloodstream. Bacteremia can lead to septic shock, organ failure, loss of limbs, and death.
Developing a Vaccine Against Neisseria meningitidis group B
To date, there is no broadly protective vaccine for MenB. The lack of a MenB vaccine seriously limits our ability to control meningococcal disease since MenB strains account for ~20% of meningococcal infections in North America and up to 80% in Northern Europe.
Testing MenB Vaccines Based on Sialic Acid Derivatives
Since it was observed that antibodies against a mixed N-acetyl/de-N-acetyl derivative of PSA can kill MenB, we have begun studying whether antibodies elicited by other PSA derivatives can also protect against meningococcal disease.
Five PSA derivatives were synthesized, conjugated to a carrier protein, and tested in mice. Groups of ten mice were given each vaccine and two or three booster shots. Ten days after each injection, blood samples were drawn and the immune response was examined. All five vaccines produced a strong immune response, eliciting antibodies capable of recognizing the bacteria. All the vaccine-elicited antibodies were also able to trigger the deposition of complement proteins on the surface of the bacteria, an important characteristic because complement is the primary mechanism of protection against meningococcal disease. In addition, antibodies from some of the vaccines were able to protect against MenB disease in an infant rat model of meningococcal bacteremia when the infant rats were injected with MenB bacteria.
De-N-Acetyl Sialic Acid and Immunotherapeutic Approaches to Cancer
It has long been recognized that cancer cells often over-express Sia on their surface. Recently, we discovered that many human cancers express previously unrecognized N-acetyl/de-N-acetyl PSA antigens. For example, melanoma, leukemia and neuroblastoma cell lines express PSA antigens that are reactive with anti-N-acetyl/de-N-acetyl PSA antibodies. Interestingly, in some cancer cells the antigens seem to be found only on the surface of dividing cells. Furthermore, the binding of the antibodies causes the cells to stop growing and undergo programmed cell death. Thus, the antibodies have the potential to inhibit the growth and metastasis of tumors.
Vaccines that elicited such antibodies would have the potential to prevent or treat certain cancers. To study this idea, we obtained sera from mice that had been vaccinated with the PSA derivatives and tested them against human cancer tissues and healthy human tissues. These sera contained a high level of antibodies elicited by the vaccines. We found that antibodies in some of the sera bound to human cancer tissues but not to healthy tissues.