Immunotherapy for Infectious Diseases

50 Boyaka and McGhee
Immunostimulating DNA Sequences and Saponin Derivatives
Immunostimulatory DNA Sequences
Bacterial but not eukaryotic DNA contain immunostimulatory sequences consisting
of short palindromic nucleotides centered around a CpG dinucleotide core, e.g., 5�purine-purine-CG-pyrimidine-pyrimidine-3�
or CpG motifs (164). It is now clear that
CpG motifs can induce B-cell proliferation and Ig synthesis as well as cytokine secretion
(i.e., IL-6, IFN-�, IFN-�, IFN-�, IL-12, and IL-18) by a variety of immune cells
(165). Since CpG motifs create a cytokine microenvironment favoring Th1-type
responses, they can be used as adjuvants to stimulate antigen-specific Th1-type
responses or to redirect harmful allergic or Th2-dominated autoimmune responses.
Indeed, coinjection of bacterial DNA or CpG motifs with a DNA vaccine or with a protein
antigen promotes Th1-type responses even in mice with a preexisting Th2-type of
immunity (166,167). In addition, vaccination of mice with hen egg lysozyme (HEL)
and a CpG oligonucleotide in incomplete Freund’s adjuvant induced a Th1-type
response comparable to that achieved by injecting HEL in complete Freund’s adjuvant
(168). It has also been reported that CpG motifs can enhance systemic as well as
mucosal immune responses when given intranasally to mice (169). The observation that
these CpG motifs can also function as mucosal adjuvants was confirmed by the finding
that delivery to lungs of hepatitis B surface antigen (HBsAg) with CpG DNA
resulted in high HBsAg-specific mucosal and systemic immune responses (170).
Saponin Derivatives
Immunostimulating complexes (ISCOMs) are cage-like particules generated after
addition of cholesterol to the Quil A from the bark of the Quillaja saponaria Molina tree
(171). Since antigens can be incorporated into ISCOMs, these particules represent good
delivery systems for mucosal vaccines. In fact, ISCOMs are effective oral delivery systems
that promote mucosal and systemic immunity (172). It is believed that the cage-like
structure of ISCOMs protects both the antigen and Quil A from degradation in the GI
tract. However, ISCOMs appeared to be toxic after parenteral immunization of experimental
animals. It is possible that ISCOMs are less toxic after oral delivery. This point
will need to be carefully addressed before considering a broader use of ISCOMs.
QS-21 is a highly purified complex triterpene glycoside isolated from the bark of
the Quillaja saponaria Molina tree (173,174). This molecule promotes both humoral
and cell-mediated immunity when added to systemic vaccine formulations (175–177)
and is now being tested in several parenteral vaccine formulations (173). QS-21 was
reported to act as an adjuvant for both systemic and mucosal immunity to a nasally
administered DNA vaccine (178). More recently, it has been shown that QS-21 also
acts as adjuvant when administered by the oral route (179). Interestingly, low oral QS-
21 doses promoted mucosal S-IgA Abs responses, whereas no S-IgA responses were
induced by high oral QS-21 (179). On the other hand, stronger Th1-type responses
were seen after immunization with high oral QS-21 doses (179).
CONCLUSIONS
The increasing numbers of bacteria that are resistant to antibiotic therapy and the
inefficiency of antiviral drugs to resolve virus infections leave vaccines as the most
promising immunoprophylactic approach against infectious diseases. Mucosal sur-