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. 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 antigen presenting cells such as 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 polysaccharide vaccines. 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). Polysaccharides are poorly immunogenic antigens and they do not elicit antibody response in infants. In previous years, we had shown that weak response to polysaccharides in newborns is largely due to severely reduced expression of TACI on newborn B cells. Understanding how TACI expression is regulated may help devise strategies to improve pediatric vaccines. 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. Our goal is to identify molecular and biochemical events that prevent TACI expression in newborns. The discovery of a central role for TACI in mediating polysaccharide vaccine responses warrants the study of BAFF system molecules in aged population since polysaccharide vaccines are used to prevent pneumococcal diseases in the aged population. We will explore the involvement TACI in vaccine responses in elderly by using aged mice.
More recently, we have discovered a role for TACI in mediating signals that drive the classically-activated (M1) macrophage phenotype. Conversely, in the absence of TACI, macrophages adapted the alternatively-activated (M2) phenotype and rendered otherwise resistant C57BL/6 mice susceptible to Leishmania major 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 responses to vaccines. We will also investigate the protective role of M2 polarized macrophages in a high fat diet induced obesity and metabolic disease model in TACI KO mouse since M1 polarized macrophages are responsible for the development of insulin resistance following obesity. These studies will lay the ground work for subsequent studies where we will investigate the immune system of newborns born to obese mice. Emerging evidence suggests that infants born to obese mothers are prone to metabolic diseases. We hypothesize that maternal obesity may influence the responses of infants to vaccines by altering their immune system.
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.
Clin Vaccine Immunol 2017 Feb 6;24(2):e00457-16
Assignment of opsonic values to pneumococcal reference serum 007sp for use in opsonophagocytic assays for 13 serotypes.
Burton RL, Antonello J, Cooper D, Goldblatt D, Kim KH, Plikaytis BD, Roalfe L, Wauters D, Williams F, Xie GL, Nahm MH, Akkoyunlu M
J Immunol 2016 Jun 1;196(11):4614-21
Distinct mechanisms underlie boosted polysaccharide-specific IgG responses following secondary challenge with intact gram-negative versus gram-positive extracellular bacteria.
Kar S, Arjunaraja S, Akkoyunlu M, Pier GB, Snapper CM
PLoS One 2016 May 5;11(5):e0154518
MRL Strains Have a BAFFR Mutation without Functional Consequence.
Allman WR, Liu L, Coleman AS, Akkoyunlu M
Ann N Y Acad Sci 2015 Dec;1362(1):57-67
BAFF receptor and TACI in B-1b cell maintenance and antibacterial responses.
Dickinson GS, Akkoyunlu M, Bram RJ, Alugupalli KR
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