Mark James Cayabyab, PhD

Recent advances in vaccine technology provide new hope for infectious diseases and cancer. The promise of effective vaccines has the potential to save countless lives worldwide from HIV/AIDS, malaria, tuberculosis and other diseases impacting public health. The fields of microbial pathogenesis, immunology and vaccinology offer opportunities to develop vaccine strategies that will elicit protective immune responses. The Cayabyab lab focuses on vaccine vector development, as well as the role of innate immunity in the induction of protective memory immune responses. The overall goal of this research is to enhance basic knowledge of immunology and aid in the development of effective vaccines against infectious diseases and cancer.

Development of recombinant oral bacteria and mycobacteria as vaccine vectors
A vaccine vector is a weakened version of a virus or bacterium that carries an inserted antigen from a disease causing agent to the person being vaccinated. The vaccine vector delivers the antigen in a natural way into the body and stimulates the immune system into acting against the infection. Commensal nonpathogenic oral bacteria and mycobacteria are attractive vaccine vector candidates. Studies have shown that some strains of commensal oral bacteria and mycobacteria are safe and elicit potent mucosal immune responses. Importantly, with the genome of several important mycobacteria and oral bacteria species completely sequenced, we can genetically manipulate these microorganism for expressing protective vaccine antigens. We have begun to conduct research on developing these harmless microorganisms as vaccine vector against  infectious agents such as the Human Immunodeficiency Virus (HIV-1). Initial studies demonstrate that recombinant mycobacteria are promising vaccine vector candidates. Despite these advances in recombinant oral vaccine research, tremendous work is still needed to generate a viable recombinant oral vaccine vector for clinical use.

Role of Toll-like and NOD receptors in the innate and adaptive immune response to mycobacteria and other vaccine vectors
A number of vaccine studies suggest that stimulation of Toll-like receptors (TLRs) can have a positive influence on the magnitude and the quality of antigen-specific T cell responses. The likely explanation for these observations is that the innate immune response mediated by TLRs has a profound influence on the adaptive immune response. The surface membrane-bound TLRs as well as the cytosolic NOD receptors are two major classes of pattern recognition receptors (PRRs) that can recognize conserved structures on the invading microbe and mediate innate immunity against bacteria and viruses. Previous studies have revealed a critical role for some of these innate molecules in controlling certain viral and bacterial infections. However, the relevance of these molecules in immune responses to mycobacteria and other vectors has not been fully addressed. Interestingly, mycobacteria and many vaccine vectors express ligands that could interact with either TLR or NOD receptors, and therefore we will test whether the TLR and NOD signaling pathways play an important role in the generation of innate and adaptive memory immune responses to vaccine vectors.

The role of Natural Killer (NK), Treg and TH17 cells in the generation of innate and adaptive immune response
NK cells play a critical role in innate immunity by their ability to secrete cytokines and chemokines, as well as directly kill infected host cells. NK cells are thought to link the innate and adaptive immune systems and have been implicated in protection against pathogens and tumors. Natural T regulatory (Treg) are CD25+FoxP3+CD4+ T cells that are critical for peripheral tolerance and the prevention of autoimmunity. Tregs inhibit the effector function of T cells, NKT cells, B cells and antigen presenting cells. TH17 cells are a subset of T helper cells that play a crucial role in infectious, inflammatory, autoimmune diseases and cancer. TH17 cells mainly secrete the proinflammatory cytokines IL-17, IL-17F and IL-22 and have emerged as major players in inflammatory and autoimmune processes. We are interested in delineating the role of NK, Treg and TH17 cells in the innate and adaptive immune responses to mycobacteria and other vaccine vectors because there is growing interest in this field of study. Our research plan includes the use of depleting monoclonal antibodies that regulate NK, Treg and TH17 cell activity and knockout mice that have alterations in the functional capacities of these cells to determine the role these regulatory cells play in the innate and adaptive memory immune response to mycobacteria and other vaccine vectors. The goal of these research efforts is to address important scientific gaps in the understanding of early mycobacterial control as well as factors that help shape primary and memory immune responses to mycobacteria and other vectors, thus providing critical information to drive vaccine development.

Selected Publications

Cayabyab MJ, Korioth-Schmitz B, Sun Y, Carville A, Balachandran H, Miura A, Carlson KR, Buzby AP, Haynes BF, Jacobs WR, Letvin NL. (2009) Recombinant Mycobacterium bovis BCG prime-recombinant adenovirus boost vaccination in Rhesus monkeys elicits robust polyfunctional simian immunodeficiency virus-specific T-cell responses. J. Virol. 83:5505-5513.

Hovav AH, Cayabyab MJ, Panas MW, Santra S, Greenland J, Geiben R, Haynes BF, Jacobs WR Jr, Letvin NL. (2007) Rapid memory CD8+ T-lymphocyte induction through priming with recombinant Mycobacterium smegmatis. J. Virol. 81:74-83.

Qin L, Greenland JR, Moriya C, Cayabyab MJ, Letvin NL. (2007) Effects of type I interferons on the adjuvant properties of plasmid granulocyte-macrophage colony-stimulating factor in vivo. J. Virol. 81:10606-10613.  

Hovav AH, Panas MW, Rahman S, Sircar P, Gillard G, Cayabyab MJ, Letvin NL. (2007) Duration of antigen expression in vivo following DNA immunization modifies the magnitude, contraction, and secondary responses of CD8+ T lymphocytes. J. Immunol. 179:6725-6733.  

Cayabyab MJ, Hovav AH, Hsu T, Krivulka GR, Lifton MA, Gorgone DA, Fennelly GJ, Haynes BF, Jacobs WR Jr, Letvin NL. (2006) Generation of CD8+ T-cell responses by a recombinant nonpathogenic M. smegmatis vaccine vector expressing human immunodeficiency virus type 1 Env. J. Virol. 80:1645-1652.

Cayabyab MJ, Hovav AH, Hsu T, Krivulka GR, Lifton MA, Gorgone DA, Fennelly GJ, Haynes BF, Jacobs WR Jr, Letvin NL. (2006) Generation of CD8+ T-cell responses by a recombinant nonpathogenic smegmatis vaccine vector expressing human immunodeficiency virus type 1. Env. J. Virol. 80:1645-1652.

Yu JS, Peacock JW, Vanleeuwen S, Hsu T, Jacobs WR Jr, Cayabyab MJ, Letvin NL, Frothingham R, Staats HF, Liao HX, Haynes BF. (2006) Generation of mucosal anti-human immunodeficiency virus type 1 T-cell responses by recombinant Mycobacterium smegmatis. Clin. Vaccine Immunol. 13:1204-1211.