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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Evaluating the Host and Microbial Factors That Impact the Efficacy of Polysaccharide Vaccines

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


General Overview

Our laboratory studies how the immune system responds to bacterial polysaccharide vaccines regulated by FDA. Certain types of bacteria have an outer layer called a capsule that is formed from a type of carbohydrate called polysaccharides. The polysaccharide capsule provides protection to the bacteria and is important in initiating bacterial infections. Polysaccharide vaccines are made by removing the capsule of these bacteria and purifying the polysaccharide. When injected into individuals, the vaccine stimulates the immune system to make antibodies against bacteria with polysaccharide capsules. Among such bacteria are those that cause meningitis and pneumonia. The immune system cells that produce antibodies in response to both vaccines and real infections are called B cells.

Bacterial polysaccharides cannot trigger strong immune reactions in adults, nor do they induce sufficient antibody response in newborns and infants, the age group that is most susceptible to infections with encapsulated bacteria. In order to make polysaccharides more effective, researchers developed ways to link (conjugate) polysaccharides to molecules called protein carriers. These carrier molecules improve the ability of vaccines to stimulate the immune system. However, they still have to be administered at least 3 to 4 times during the first 15 months of life in order to obtain protective antibody levels. Therefore, we are trying to improve the immunogenicity of polysaccharide vaccines in order to reduce the number of times newborns and infants must receive them.

Our laboratory studies a critical step in the process in which B cells become activated to make antibodies in response to polysaccharide vaccines. The process of B cell activation requires interaction between specific molecules on B cells and different immune system cells. We are trying to understand the role this interaction plays in triggering B cell activation. Such new information might give valuable insights into how researchers can improve the ability of polysaccharides to stimulate B cells and thus reduce the number of vaccinations that newborns and infants need. In addition, improved understanding of how these molecules trigger B cell activation and protective immune responses to bacterial polysaccharides could provide better tools for evaluating new vaccines submitted for approval to FDA.


Scientific Overview

Our laboratory focuses on the mechanisms of antibody development against bacterial polysaccharide vaccines. We also pay special attention to the humoral immune response to vaccines in newborns and infants as infections with encapsulated bacteria are especially prevalent in these age groups.

We are trying to understand the role of the tumor necrosis factor receptor family member TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor). TACI on B cells interacts with its ligand, B lymphocyte activating factor, which belongs to the TNF family and is expressed by different immune system cells. Our laboratory is specifically interested in the role of TACI in response to polysaccharides, since TACI is essential for the development of antibody responses against polysaccharides.

Our previous research showed that newborn mice B cells express low levels of TACI and they do not respond to the TACI ligands BAFF and a proliferation inducing ligand (APRIL). We also showed that the TLR9 ligand CpG ODN improves the response to polysaccharide vaccines by up-regulating TACI and sensitizing B cells to BAFF and APRIL. These results suggest that the lack of TACI appear to be responsible for the unresponsiveness of newborns to polysaccharide vaccines. More importantly, experiments with the adjuvant CpG ODN suggest that up-regulation of TACI in newborns leads to improved response to polysaccharides.

During the next fiscal year we will explore why newborn mice express low levels of TACI and how TACI expression is regulated. We will initially focus on the role of commensal bacteria because our research has shown that toll like receptor agonists strongly upregulate TACI expression. Our hypothesis is based on the fact that the sterile born mice gut is rapidly colonized with bacteria that are rich in toll-like receptor agonists. We will test whether the colonization with bacteria that carry the toll-like receptors stimulate the expression of TACI as the mice age.

Our laboratory has also investigated the cause of the weak immunogenicity of polysaccharides. We showed that incubation of the capsular polysaccharide of meningococcal type C (MCPS) with B cells strongly down-regulates TACI. Moreover, B cells exposed to MCPS do not respond to the ligands BAFF or APRIL. We hypothesize that bacterial polysaccharides target B cells to suppress the development of antibody response during infection. In the next fiscal year, we will study the mechanisms of MCPS-mediated suppression of TACI on B cells, focusing on MCPS-mediated signaling and MCPS-mediated apoptosis of B cells. We will also monitor the effect of MCPS on B cell molecules other than TACI.

We plan to continue to study B cell suppression and to initiate a new project to understand the poor immune response against protein antigens in newborns.


Publications

J Infect Dis 2013 Mar;207(5):872-3
Bacterial polysaccharide mediated downregulation of TACI and B cell apoptosis contribute to the hyporesponsiveness against bacterial polysaccharides vaccines.
Coleman AS, Akkoyunlu M

Scand J Immunol 2012 Mar;75(3):368
TACI expression is low both in human and mouse newborns.
Akkoyunlu M

Clin Vaccine Immunol 2011 Oct;18(10):1728-36
Establishment of a new human pneumococcal standard reference serum, 007sp.
Goldblatt D, Plikaytis BD, Akkoyunlu M, Antonello J, Ashton L, Blake M, Burton R, Care R, Durant N, Feavers I, Fernsten P, Fievet F, Giardina P, Jansen K, Katz L, Kierstead L, Lee L, Lin J, Maisonneuve J, Nahm MH, Raab J, Romero-Steiner S, Rose C, Schmidt D, Stapleton J, Carlone GM

Vaccine 2011 Jul 18;29(32):5294-303
A host-restricted viral vector for antigen-specific immunization against Lyme disease pathogen.
Xiao S, Kumar M, Yang X, Akkoyunlu M, Collins PL, Samal SK, Pal U

Vaccine 2011 Apr 5;29(16):2834
Detection of naturally occurring antibodies against Protein D of Haemophilus influenzae.
Akkoyunlu M

J Immunol 2011 Feb 15;186(4):2430-43
Suppressive effect of bacterial polysaccharides on BAFF system is responsible for their poor immunogenicity.
Kanswal S, Katsenelson N, Allman W, Uslu K, Blake MS, Akkoyunlu M

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

     
 

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