Complement and Immunity to Polysaccharide Vaccines

The Complement System

The complement system consists of over 30 proteins present either in the bloodstream or on the surface of cells.  Complement receptors on the surface of cells can either regulate the activity of plasma complement proteins or act as receptors to bind fragments of blood complement proteins.  As part of the innate immune system, the complement system originally evolved to kill bacteria directly in the absence of antibody.  However, complement also has important effects on the adaptive immune response.  When a foreign substance (antigen) is introduced into the body, complement is activated and C3 is cleaved to C3b, which becomes covalently coupled to the antigen.  The C3b then undergoes a number of degradation steps ultimately resulting in the generation of C3dg and C3d.  In the mouse, B lymphocytes and follicular dendritic cells bind C3dg and C3d via complement receptor type 2 (CR2, CD21).  Simultaneous binding of antigen and C3d by B cells results in much stronger activation of the cells than binding of antigen alone and has a number of enhancing effects on the antibody response to the antigen.

Polysaccharide vaccines

Polysaccharides are found in the capsule of a number of clinically important bacteria.  These bacteria include Haemophilus influenzae type b (Hib), Neisseria meningitidis (meningococcus), and Streptococcus pneumonie (pneumococcus).  Infections caused by these bacteria include otitis media, meningitis, pneumonia, and septicemia and are a major cause of serious illness and death in children and adults worldwide.  Antibodies against the capsular polysaccharides protect against infection; therefore, the polysaccharides have been used in vaccines against these bacteria.

Because polysaccharide vaccines do not work well in children under 2 years of age and this age group is particularly susceptible to infections with encapsulated bacteria, there has been extensive research on ways to produce vaccines that will be effective in infants and young children.  Polysaccharides are generally classified as T cell-independent type 2 antigens and stimulate an antibody response that does not require MHC II-restricted T cell help, in contrast to T-dependent protein antigens.  Thus, to improve polysaccharide vaccines, protein molecules have been chemically coupled to the sugars.  These conjugate vaccines are now being successfully used to immunize young children against Haemophilus influenzae type B and against the pneumococcus.  In mice, conjugate vaccines induce a vastly superior antibody response compared with vaccines containing unmodified polysaccharides.