Xin-Xing Gu, M.D.

Acting Chief
Vaccine Research Section

Research Statement

The Vaccine Research Section is seeking to develop vaccines against otitis media in children. The emphasis of this section is on (1) identification of bacterial antigens and/or virulence factors that may be used as vaccine candidates, (2) characterization of these potential vaccines in vitro and in animal models, (3) investigation of the mechanisms of protective immunity in vivo, and (4) clinical trials.

Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (M. cat.) are major causes of otitis media in children and lower respiratory tract diseases in older individuals. Several lines of evidence have shown that lipooligosaccharide (LOS), a major surface antigen on bacterial outer membrane, is not only a virulence factor but also a potential protective antigen, and can be expected to confer immunity to both pathogens. However, the LOS molecule is too toxic to be administered to humans, and detoxified LOS does not elicit antibodies in vivo. To overcome these problems, detoxified LOS was convalently bound to antigenic proteins. Such conjugate vaccines elicit long-lasting antibodies with bactericidal activities against NTHi and M. cat., and confer protection against bacterial challenges in animal models.

Recently, intramural scientists have successfully accomplished a Phase I clinical trial for evaluating safety and immunogenicity of a NTHi conjugate vaccine in human volunteers. Currently, new vaccine candidates such as different types of LOS based conjugate vaccines, outer membrane protein based conjugate vaccines, peptide vaccines, and DNA vaccines are being investigated and developed.

Selected Publications

• Peng D, Hong W, Choudhury BP, Carlson RW, Gu XX. Moraxella catarrhalis bacterium without endotoxin, a potential vaccine candidate. Infecton and Immunity 73(11):7569–77, 2005.
• Wu T, Chen J, Murphy TF, Green BA, Gu XX. Investigation of non-typeable Haemophilus influenzae outer membrane protein P6 as a new carrier for lipooligosaccharide conjugate vaccines. Vaccine 23(44):5177–85, 2005.
• Peng D, Choudhury BP, Petralia RS, Carlson RW, Gu XX. Roles of 3-deoxy-D-manno-2-octulosonic acid transferase from Moraxella catarrhalis in lipooligosaccharide biosynthesis and virulence. Infection and Immunity 73(7):4222–30, 2005.
• Yu S, Gu XX. Synthesis and characterization of lipooligosaccharide-based conjugate vaccines for serotype B Moraxella catarrhalis. Infection and Immunity 73(5):2790–6, 2005.
• Chen R, Lim JH, Jono H, Gu XX, Kim YS, Basbaum CB, Murphy TF, Li JD. Nontypeable Haemophilus influenzae lipoprotein P6 induces MUC5AC mucin transcription via TLR2-TAK1-dependent p38 MAPK-AP1 and IKKbeta-IkappaBalpha-NF-kappaB signaling pathways. Biochemical and Biophysical Research Communications 324(3):1087–94, 2004.
• Hu WG, Berry J, Chen J, Gu XX. Exploration of Moraxella catarrhalis outer membrane proteins, CD and UspA, as new carriers for lipooligosaccharide-based conjugates. FEMS Immunology and Medical Microbiology 41(2):109–15, 2004.
• Gu XX, Rudy SF, Chu C, McCullagh L, Kim HN, Chen J, Li J, Robbins JB, Van Waes C, Battey JF. Phase I study of a lipooligosaccharide-based conjugate vaccine against nontypeable Haemophilus influenzae. Vaccine 21(17–18):2107–2114, 2003.
• Hou Y, Gu XX . Development of peptide mimotopes of lipooligosaccharide from nontypeable Haemophilus influenzae as vaccine candidates. Journal of Immunology 170(8):4373–4379, 2003.
• Hirano T, Hou Y, Jiao X, Gu XX. Intranasal immunization with a lipooligosaccharide-based conjugate vaccine from nontypeable Haemophilus influenzae enhances bacterial clearance in mouse nasopharynx. FEMS Immunology and Medical Microbiology 35(1):1–10, 2003.
• Jiao X, Hirano T, Hou Y, Gu XX. Specific immune responses and enhancement of murine pulmonary clearance of Moraxella catarrhalis by intranasal immunization with a detoxified lipooligosaccharide conjugate vaccine. Infection and Immunity 70(11):5982–5989, 2002.
• Hou Y, Hu WG, Hirano T, Gu XX. A new intra-NALT route elicits mucosal and systemic immunity against Moraxella catarrhalis in a mouse challenge model. Vaccine 20(17–18):2375–2381, 2002.
• Hu WG, Chen J, McMichael JC, Gu XX. Functional characteristics of a protective monoclonal antibody against serotype A and C lipooligosaccharides from Moraxella catarrhalis. Infection and Immunity 69:1358–1363, 2001.
• Shuto T, Xu H, Wang B, Han J, Kai H, Gu XX, Murphy TF, Lim DJ, Li JD. Activation of NF-kB by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKKa/ß-IkBa and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proceedings of the National Academy of Sciences of the USA 98:8774–8779, 2001.
• Hu WG, Chen J, Battey JF, Gu XX. Enhancement of bacterial clearance from murine lungs by immunization of detoxified lipooligosaccharide from Moraxella catarrhalis conjugated to proteins. Infection and Immunity 68:4980–4985, 2000.
• Sun J, Chen J, Cheng Z, Robbins JB, Battey J, Gu XX. Biological activities of antibodies elicited by lipooligosaccharide based-conjugate vaccines of nontypeable Haemophilus influenzae in an otitis media model. Vaccine 18:1264–1272, 2000.
• Hu WG, Chen J, Collins FM, Gu XX. An aerosol challenge mouse model for Moraxella catarrhalis. Vaccine 18:799–804, 1999.
• Rahman MM, Gu XX, Tsai CM, Kolli VS, Carlson RW. The structural heterogeneity of the lipooligosaccharide (LOS) expressed by pathogenic non-typeable Haemophilus influenzae strain 9274. Glycobiology 9:1371–1380, 1999.
• Ueyama T, Gu XX, Tsai CM, Karpas AB, Lim DJ. Identification of common lipooligosaccharide types in isolates from patients with otitis media by monoclonal antibodies against nontypeable Haemophilus influenzae 9274. Clinical and Diagnostic Laboratory Immunology 6:96–100, 1999.
• Wu TH, Gu XX. Outer membrane proteins as a carrier for detoxified lipooligosaccharide conjugate vaccines to nontypeable Haemophilus influenzae. Infection and Immunity 67:5508–5513, 1999.
• Gu XX, Chen J, Barenkamp SJ, Robbins JB, Tsai CM, Lim DJ, Battey J. Synthesis and characterization of lipooligosaccharide-based conjugates as vaccine candidates for Moraxella (Branhamella) catarrhalis. Infection and Immunity 66:1891–1897, 1998.

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