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  1. Science & Research (Biologics)

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

 

Mustafa Akkoyunlu, MD, PhD

Mustafa Akkoyunlu, MD, PhD

Office of Vaccines Research and Review
Division of Bacterial, Parasitic, and Allergenic Products
Laboratory of Bacterial Polysaccharides

Mustafa.Akkoyunlu@fda.hhs.gov


Biosketch

Dr. Mustafa Akkoyunlu is a Senior Investigator at the Laboratory of Bacterial Polysaccharides (LBP), Center for Biologics Evaluation and Research (CBER), FDA. He leads the Cellular Immunology section of LBP, where he investigates the mechanisms of antibody development against bacterial polysaccharide vaccines for pediatric pathogens such Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae.

Dr. Mustafa Akkoyunlu is a graduate of Tarsus American College, Tarsus, Turkey. He earned his medical doctor degree from Ankara University Medical School, Ankara, Turkey. In 1997, he completed his Ph.D. training in Microbiology/Immunology at Lund University, Sweden, under the mentorship of Dr. Arne Forsgren. During his graduate work, Dr. Akkoyunlu developed an interest in immunobiological events surrounding the interface of host-microbe interactions. In Sweden, Dr. Akkoyunlu demonstrated the vaccine potential of an H. influenzae membrane molecule, protein D, against otitis media caused by nontypeable H. influenzae. Protein D is now used as a component of the vaccine Synflorix®, which is indicated to prevent systemic pneumococcal disease and bacterial otitis media. In 1997, Dr. Akkoyunlu started his postdoctoral fellowship in Dr. Erol Fikrig’s laboratory at Yale University, where he studied the immunopathogenesis of the tick-borne bacterial disease human granulocytic anaplasmosis. His research at Yale University helped understand the dissemination mechanisms employed by Anaplasma phagocytophilum, the causative agent of anaplasmosis.

Since establishing his own laboratory at FDA in 2002, the primary focus of Akkoyunlu laboratory has been to study the cell-specific function of transmembrane-activator and calcium-modulator and cyclophilin ligand-interactor (TACI), a member of the B lymphocyte activating factor (BAFF) system molecules. Areas of focus include TACI’s role in the generation of antibody responses to polysaccharide vaccines and in mediating signals that govern macrophage phenotype. In addition to receiving numerous awards for his contribution to regulatory reviews, Dr. Akkoyunlu received the “CBER Scientific Achievement Award” in 2016.


General Overview

Our laboratory studies how the immune system responds to bacterial polysaccharide vaccines. Certain types of bacteria are covered with a capsule that is composed of a type of carbohydrate moiety called polysaccharides. The polysaccharide capsule is important for the initiation of bacterial infection, because it protects bacteria from a person’s immune system. Polysaccharide vaccines are made by purifying the capsules from the bacteria. When injected into individuals, the vaccine is intended to stimulate the immune system (namely B cells) to make antibodies targeting the capsular polysaccharide of the bacteria and block infection. Among these 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 neonates and infants, the age group that is most susceptible to infections with encapsulated bacteria. 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, while conjugate vaccines can elicit protective antibody responses in adults after one dose, infants have to be administered four doses starting from two months until 15 months of age in order to elicit levels of antibodies that are protective. As a result of this delay, infants remain only partially protected until they receive the full 4 doses. Our laboratory aims to improve the immunogenicity of polysaccharide vaccines for children, so that vaccines elicit protective antibodies after one or two immunizations instead of four.

An important obstacle to improving pediatric vaccines is the gap in our knowledge of the underlying reasons for the inability of neonates and infants to mount sufficient amounts of protective antibodies. Therefore, we are investigating the critical steps involved in the development of antibodies in response to conjugate polysaccharide vaccines. Important early events in the initiation of host immune response to vaccines are the capture, uptake, and presentation of vaccine antigens by antigen-presenting cells such as dendritic cells and macrophages. The T cells that recognize the vaccine antigens presented on macrophages become activated. Further interactions between activated T cells and B cells are required to induce the expansion of high-quality antibody secreting B cells. Our aim is to identify key differences between neonatal and adult immune systems that can explain the unresponsiveness of neonates to vaccines. Identification of mechanisms governing neonatal immune systems will help devise innovative approaches to improve the pediatric vaccines. For example, studies may suggest ways to modulate neonatal immune systems with molecules that can correct the shortcomings. Invention of fast-acting vaccines can not only be lifesaving during incidents like pandemic flu, when rapid development of immune responses is essential, but also would provide logistical advantages. Truncated immunization schedules can lead to better compliance and help save money by decreasing costs. In addition, improved understanding of the steps required for optimal immune responses in infants could provide better tools for evaluating vaccines submitted for approval to FDA.


Scientific Overview

BAFF system molecules. (A) BAFF system molecules are composed of two ligands (BAFF and APRIL) and three receptors (BAFF -R, TAC!, and BCMA). BAFF and APRIL are primarily expressed by myeloid cells. Both BAFF and APRIL have membrane-bound (mBAFF, mAPR[L) and soluble forms (sBAFF, sAPRIL ). The soluble forms are produced by the cleavage ·with furin convertase. sBAFF exists in a homotrimcric (3-mcr) or oligomeric (60-mer) fonn. Similar to BAFF, soluble APRIL fonns a homolrinlL'T or pai1ners with heparan sulfate proteoglycan (H SPG) to form multimers. All three membrane receptors can be cleaved. to produce their soluble fonns. The cleaved ectodomains of the three receptors may function as soluble decoy receptors (sBAFF-R, sT ACl, and sBCMA) for BAFF and APRil,. (B) BAFF engagement ofBAFF-R is essential fort he survival and development ofB cells beyond the immature Tl B cell stage. T ACI is mooUy ex-pressed on marginal zone (MZ) B cells, follicular (FO) B cells, and plasma cells. BCMA expression is increased on plasmabla,,-isand plasma cells. B.1.FF and APRIL also act on macrophages to stimulate the expression of molecules as,,ociated ,?ith the inflammatory M 1 phenotype. BM, bone mmrow; BCR, B cell receptor, DC, deudrilic cell; iNOS, inducible nitric oxide synthase; TNFo, twnor necrosis factor alpha.

Our laboratory studies the mechanisms of antibody development against polysaccharide vaccines. We are especially interested in understanding the biological functions of TACI, since TACI is essential in response to polysaccharide vaccines. TACI interacts with its ligands, BAFF and a proliferation inducing ligand called APRIL. Polysaccharides are poorly immunogenic antigens and do not elicit antibody responses in neonates and infants. We have previously shown that weak responses to polysaccharides in neonates are largely due to severely reduced expression of TACI on neonatal B cells. Understanding how TACI expression is regulated can help devise strategies to improve pediatric vaccines. B cell receptor (BCR) engagement induces TACI expression in adult B cells but not in neonates. We are currently studying the BCR signaling pathways in neonates to identify molecular and biochemical events that prevent TACI expression. We are also investigating TACI function in aged mice, because we suspect that age-associated changes in the expression and function of TACI may be responsible for the rapid decline of anti-vaccine antibody levels following 23-valent polysaccharide vaccination in this age group.

More recently, we have discovered a new role for TACI in mediating signals that drive the classically activated (M1) macrophage phenotype. Consequently, TACI deficient macrophages adopt the alternatively activated (M2) phenotype and render mice susceptible to cutaneous Leishmania infection. By using a murine high fat diet-induced obesity model, we described a central role for TACI-deficient macrophages that prevents the development of insulin resistance by suppressing adipose tissue inflammation. The discovery of a role for TACI in mediating inflammation-promoting signals in obesity may have additional implications for neonates, since TACI expression is severely reduced in neonates. We have determined that neonatal macrophages exhibit an M2-like phenotype. The reduced expression of TACI may therefore protect neonates from metabolic diseases associated with inflammatory macrophage responses. Conversely, diminished TACI-mediated inflammatory signals may leave neonates susceptible to infections by blunting antimicrobial activities of macrophages. The knowledge gained from these studies can help devise disease-specific interventions during early childhood.

To further delineate the differences in neonatal and adult immune systems, we are characterizing neonatal follicular helper T (Tfh) cells. Tfh-cell development and germinal center (GC) formation is essential for optimum immune responses against T-cell dependent vaccines. To date, we have shown that neonatal Tfh-cell development and GC formation is limited after vaccination. We also demonstrated elevated regulatory Tfh (Tfr) cells in immunized neonates, whose persistence may be responsible for impaired neonatal Tfh-cell development. We will test this hypothesis by employing strategies to deplete Tfr cells in vaccinated neonatal mice. Understanding the specific reasons for diminished Tfh-cell development and GC formation may help devise novel strategies to improve pediatric vaccines.


Important Links

https://orcid.org/0000-0001-9958-4031

https://publons.com/researcher/1744212/mustafa-akkoyunlu/

https://loop.frontiersin.org/people/581332/overview

https://www.researchgate.net/profile/Mustafa-Akkoyunlu


Publications

  1. NPJ Vaccines 2023 Nov 8;8(1):173
    IL6 suppresses vaccine responses in neonates by enhancing IL2 activity on T follicular helper cells.
    Parvathaneni S, Yang J, Lotspeich-Cole L, Sakai J, Lee RC, Akkoyunlu M
  2. Elife 2023 Feb 3;12:e83561
    B cell receptor induced IL-10 production from neonatal mouse CD19(+)CD43(-) cells depends on STAT5 mediated IL-6 secretion.
    Sakai J, Yang J, Chou CK, Wu WW, Akkoyunlu M
  3. J Biol Chem 2021 Sep;297(3):101053
    Circulating CD138 enhances disease progression by augmenting autoreactive antibody production in a mouse model of systemic lupus erythematosus.
    Liu L, Akkoyunlu M
  4. Sci Rep 2021 Jan 8;11(1):90
    Neonatal mice resist Plasmodium yoelii infection until exposed to para-aminobenzoic acid containing diet after weaning.
    Parra M, Yang J, Weitner M, Akkoyunlu M
  5. PLoS One 2020 Sep 4;15(9):e0238493
    Memory CD73+IgM+ B cells protect against Plasmodium yoelii infection and express Granzyme B.
    Parra M, Weitner M, Yang A, Akue A, Liu X, Schmidt T, Allman WR, Akkoyunlu M, Derrick SC
  6. Front Immunol 2020 Jul 28;11:1569
    Disease stage-specific pathogenicity of CD138 (syndecan 1)-expressing T cells in systemic lupus erythematosus.
    Liu L, Takeda K, Akkoyunlu M
  7. Front Immunol 2018 Dec 20;9:3049
    IL-6 impairs vaccine responses in neonatal mice.
    Yang J, Sakai J, Siddiqui S, Lee RC, Ireland DDC, Verthelyi D, Akkoyunlu M
  8. Front Immunol 2018 Nov 9;9:2612
    TACI contributes to Plasmodium yoelii host resistance by controlling T follicular helper cell response and germinal center formation.
    Parra M, Yang J, Weitner M, Derrick S, Yang A, Schmidt T, Singh B, Moreno A, Akkoyunlu M
  9. Diabetes 2018 Aug;67(8):1589-603
    TACI deficient macrophages protect mice against metaflammation and obesity-induced dysregulation of glucose homeostasis.
    Liu L, Inouye KE, Allman WR, Coleman AS, Siddiqui S, Hotamisligil GS, Akkoyunlu M
  10. Allergy 2018 Jun;73(6):1196-205
    Macrophages-common culprit in obesity and asthma.
    Sharma N, Akkoyunlu M, Rabin RL
  11. Sci Rep 2018 Jan 22;8(1):1308
    Delayed onset of autoreactive antibody production and M2-skewed macrophages contribute to improved survival of TACI deficient MRL-Fas/Lpr mouse.
    Liu L, Allman WR, Coleman AS, Takeda K, Lin TL, Akkoyunlu M
  12. Clin Microbiol Rev 2017 Oct;30(4):991-1014
    The role of BAFF system molecules in host response to pathogens.
    Sakai J, Akkoyunlu M
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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

 

 

 
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