Vaccines, Blood & Biologics
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
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 composed of a type of carbohydrate called polysaccharides. The polysaccharide capsule provides protection for the bacteria and is important in initiating bacterial infections. Polysaccharide vaccines are made by removing the capsules of these bacteria and purifying the polysaccharide. When injected into individuals, the vaccine stimulates the immune system (namely B cells) to make antibodies targeting the capsular polysaccharide of the bacteria. Among such bacteria are those that cause serious infections such as meningitis and pneumonia.
Bacterial polysaccharides cannot trigger strong immune reactions in adults. More importantly they do not induce sufficient antibody responses in newborns and infants, the age group that is most susceptible to infections with encapsulated bacteria. In order to make polysaccharide vaccines more effective, researchers developed ways to link (conjugate) polysaccharides to protein carriers. These carrier molecules improve the ability of vaccines to stimulate the immune system. Meningococcal and pneumococcal conjugate vaccines are examples of such vaccines. However, these vaccines still have to be administered 4 times during the first 15 months of life in order to elicit levels of antibodies that are protective. Our laboratory aims to improve the immunogenicity of polysaccharide vaccines so that they can elicit protective antibodies after one or two immunizations instead of four.
An important obstacle in improving the pediatric vaccines is the gap in our knowledge of the underlying reasons for the inability of newborns and infants to mount sufficient amounts of antibodies that are protective. Therefore, we are studying to understand the critical steps involved in the development of antibodies in response to polysaccharide vaccines. These steps are the uptake and presentation of vaccine antigen by macrophages. Macrophages typically process the vaccines and stimulate T cells while presenting the processed antigen. Further interactions between activated T cells and B cells are required to induce the generation of antibody secreting B cells. Our aim is to identify key differences between newborn and adult immune system that can explain the unresponsiveness of newborns to vaccines. We aim to use this information to improve the pediatric vaccines by testing molecules that can correct the shortcomings of newborn immune system. Invention of fast acting vaccines not only can be lifesaving during incidents like pandemic flu when rapid development immune response is essential but also would provide logistical advantages. Truncated immunization schedules can also lead to better compliance and help save money by decreasing the costs. In addition, improved understanding of steps required for optimum immune response could provide better tools for evaluating vaccines submitted for approval to FDA.
Our laboratory focuses on the mechanisms of antibody development against vaccines for pediatric population, including polysaccharide vaccines that are regulated by the Laboratory of Bacterial Polysaccharides.
We are particularly interested in understanding the biological functions of the tumor necrosis factor family member receptor, TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) since TACI has been shown to be essential in response to polysaccharide vaccines. TACI on B cells interacts with its ligands B lymphocyte activating factor (BAFF) and a proliferation inducing ligand (APRIL). Although polysaccharides can induce antibody responses in adults, this response is weak and transient in newborns. In previous years, we had shown that newborn B cells express low levels of TACI and as a result, newborn B cells do not respond to BAFF and APRIL. We also showed that the TLR9 ligand CpG ODN improves the responses to polysaccharide vaccines by up-regulating TACI and sensitizing B cells to BAFF and APRIL. These results suggest that limited availability of TACI appear to be responsible for the unresponsiveness of newborns to polysaccharide vaccines. Identification of low TACI expression as an obstacle in front of generating optimum immune response to vaccines warrants investigation to identify the underlying biological reasons for diminished TACI expression in newborns. A biological signal that induces TACI expression is the B cell receptor (BCR) engagement. In newborn mouse, the increase in TACI expression remains limited after BCR stimulation. One of our current research interests is to study the differences between newborn and adult BCR signaling pathways. We focus on four known pathways downstream of BCR and aim to identify molecular and biochemical events that prevent TACI expression.
More recently, we have discovered a role for TACI in macrophage phenotype determination. We observed that in the absence of TACI, macrophages adapt the alternatively activated (M2) phenotype. TACI ligands BAFF and APRIL appear induce the development of classically activated (M1) macrophage phenotype. As expected, both BAFF and APRIL induced M1 polarization led to the elimination of intracellular parasite Leishmania major in macrophages. Furthermore, we showed that TACI KO macrophages are sufficient to render the resistant mouse strain susceptible to cutaneous Leishmania infection. These data are significant and may have implications for explaining the shortcomings of newborn immune system since TACI expression is severely reduced in newborns. Our future focus will be to explore the implications of TACI mediated M2 polarization of newborn macrophages in newborn responses to vaccines.
Continuing on the objective to delineate the differences in newborn and adult immune system, we have been studying the phenotypic and functional properties of newborn follicular helper T (Tfh) cells. Tfh development and germinal center (GC) formation is essential for optimum immune response against T cell dependent vaccines. So far, we have shown that newborn Tfh development and GC formation is limited after vaccination. Understanding the specific reasons for diminished Tfh development and GC formation may help devise novel strategies to improve vaccines.
Proc Natl Acad Sci U S A 2015 Jul 28;112(30):E4094-103
TACI deficiency leads to alternatively activated macrophage phenotype and susceptibility to Leishmania infection.
Allman WR, Dey R, Liu L, Siddiqui S, Coleman AS, Bhattacharya P, Yano M, Uslu K, Takeda K, Nakhasi HL, Akkoyunlu M
J Immunol 2014 Apr 15;192(8):3582-95
Impaired B cell receptor signaling is responsible for reduced TACI expression and function in X-linked immunodeficient mice.
Uslu K, Coleman AS, Allman WR, Katsenelson N, Bram RJ, Alugupalli KR, Akkoyunlu M
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.
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.
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