Evaluation of Biomarkers 0f Bacterial Polysaccharide Vaccine Efficacy: The Innate Immune Response

Principal Investigator: Mustafa Akkoyunlu, MD, PhD
Office / Division / Lab: OVRR / DBPAP / LBP

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Overview

Public Health Issue: Bacteria such as Neisseria meningitidis, and Streptococcus pneumoniae cause meningitis, pneumoniae and other serious life-threatening diseases. Vaccines have significant potential to protect against disease and death from these bacteria, but current vaccines provide only partial protection. Vaccinating to develop antibodies against the polysaccharide (PS) coating of these "encapsulated" bacteria could in theory protect against disease, but these PS are poor at stimulating the proper antibody response. Enhancing the immune response by additives to the vaccine (e.g., adjuvants) includes conjugation of PS to protein carriers, which significantly improves the immune response to PSs. However, it is not known how to choose the best protein carriers, since the exact role of the conjugated protein in the vaccine's immune response is not fully understood. Alternative, new methods are being proposed to stimulate the immune system. For example, toll-like receptors (TLR) activation results in stimulation of an "innate" immune response, and, thus, molecules that act to stimulate TLRs (agonists) are being tested as adjuvants in PS vaccines.

Regulatory Contribution: By understanding the effect of TLR agonists on immune system mediators, such as cytokines and cell membrane molecules crucial in the development of antibodies, FDA scientists can support the development of novel vaccine approaches using these adjuvants. When PSs are used together with TLR agonists, delineation of the effect of PSs on immune cells expressing TLRs will help predict the clinical outcomes and support development of appropriate clinical trials to test these products. In addition, we have found that PS vaccines decrease expression of a key molecule on B cells (TACI), and that this impacts the immune response to vaccines. Therefore understanding how TACI expression is modulated may yield new strategies to improve PS vaccines.

Research Approach: Our laboratory studies how antibody response develops against bacterial PS. We have shown that newborns who normally do not respond to PS vaccines express a B lymphocyte molecule (TACI) at very low levels. TACI is shown to be essential for the development of antibody response against PS vaccines and the low expression of TACI appears to be responsible for the unresponsiveness of newborns to PS vaccines. We have determined that the meningococcal type C polysaccharide (MCPS) actively decreases the expression of TACI in adult mouse B cells, suggesting that TACI expression can be modulated developmentally or by bacterial PS. Molecules and events that effect TACI expression impact the capacity of hosts' response to polysaccharide vaccines. Experiments are underway to understand why newborns express low levels of TACI and how MCPS inhibits TACI expression. We are using genetically modified mice lacking certain signaling molecules that may be required for the expression of TACI to elucidate the role of these candidate molecules in controlling TACI expression. Elucidation of the biological consequences of the suppression of TACI expression by MCPS may help understand whether MCPS inhibition of TACI contributes to the weak immune response against PS vaccines. A second immunomodulatory property of MCPS is to inhibit the activation of innate immunity through TLR4. The fact that MCPS inhibits TLR4 activation by binding to CD14 suggests that MCPS may affect other TLRs that also utilize CD14 for successful activation of the host innate immune system. The modulatory affect of MCPS on TLR agonists that use CD14 for the activation of cells are being investigated.

Mission Relevance & Outcomes: Since TLR agonists are increasingly considered as adjuvants/carriers for PS conjugate vaccines, determination of the effect of PSs and TLR agonists on the innate immune system will enhanceevaluation of the vaccine outcomes such as efficacy and safety of PS vaccines, and assist in evaluation of clinical trial design. Understanding the mechanisms of antibody development against PS vaccines may help in improving the existing PS vaccines by including appropriate adjuvants to vaccines that can target the expression of molecules such as TACI.

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Publications

J Immunol 2008 Jul 15;181(2):976-90
Deficient TACI Expression on B Lymphocytes of Newborn Mice Leads to Defective Ig Secretion in Response to BAFF or APRIL.
Kanswal S, Katsenelson N, Selvapandiyan A, Bram RJ, Akkoyunlu M

Eur J Immunol 2007 Jul;37(7):1785-95
Synthetic CpG oligodeoxynucleotides augment BAFF- and APRIL-mediated immunoglobulin secretion.
Katsenelson N, Kanswal S, Puig M, Mostowski H, Verthelyi D, Akkoyunlu M

Cell Microbiol 2007 May;9(5):1297-310
Neisseria meningitidis type C capsular polysaccharide inhibits lipooligosaccharide-induced cell activation by binding to CD14.
Kocabas C, Katsenelson N, Kanswal S, Kennedy MN, Cui X, Blake MS, Segal DM, Akkoyunlu M

FEMS Immunol Med Microbiol 2004 Nov 1;42(3):299-305
Interferon-gamma deficiency reveals that 129Sv mice are inherently more susceptible to Anaplasma phagocytophilum than C57BL/6 mice.
Wang T, Akkoyunlu M, Banerjee R, Fikrig E

Clin Diagn Lab Immunol 2004 Sep;11(5):963-8
CXCR2 blockade influences Anaplasma phagocytophilum propagation but not histopathology in the mouse model of human granulocytic anaplasmosis.
Scorpio DG, Akkoyunlu M, Fikrig E, Dumler JS