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Research
Meningococcal Disease

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.

A variety of problems have made developing a MenB vaccine difficult. In principle, the human immune system should be able to mount a response against proteins on the surface of the bacteria as well as the capsule that encases the bacteria. However, the capsule is made from sialic acid, a sugar also found on human cells, so the human immune system often does not recognize it as foreign. In addition, variation in both the expression and sequence of bacterial surface proteins make it difficult to elicit “universal” immunity against all substrains.

 

Structure of the meningococcal cell wall. Capsular polysaccharides and outer membrane proteins are the target of ongoing vaccine research.

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.

Structure of poly alpha (2®8) N-acetyl neuraminic acid, also known as polysialic acid (PSA).

 

Structure of poly alpha (2®8) N-acetyl neuraminic acid, also known as polysialic acid (PSA).

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.

Fluorescence micrograph of human complement proteins (green fluorescence) deposited on the surface of MenB bacteria resulting from antibodies binding to the bacteria. The antibodies were produced by immunizing with a candidate vaccine developed in our laboratory.

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.

Laser scanning confocal fluorescence microscopy of a dividing cancer cell and a monoclonal antibody that recognizes N-acetyl/de-N-acetyl PSA. The antibody is stained red and the nuclear DNA is stained blue.

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.

These data suggest that PSA may have a role in cell division and might provide new opportunities for the treatment and prevention of cancer.

 

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