Otitis media and other illnesses caused by nontypeable Haemophilus influenzae (NTHi) remain significant health problems for children and a vaccine for prevention of disease is much needed. Our long-term objectives are to identify surface-exposed antigens of NTHi that are important in a protective immune response, and ultimately, to determine whether a vaccine composed of such antigens would be protective against NTHi disease. In early work, we identified the HMW1/HMW2 and Hia families of proteins as major targets of the human antibody response following natural infection. We later demonstrated a critical role for both protein families in adhesion of NTHi to human eukaryotic cells. Virtually all NTHi express either HMW/HMW2-like or Hia-like adhesins. We later demonstrated the vaccine potential of prototype HMW1/HMW2 proteins in immunization studies in which chinchillas immunized parenterally were protected against NTHi otitis media caused by the homologous strain. We also demonstrated that naturally-acquired human antibodies specific for the HMW1/HMW2-like proteins and polyclonal antisera raised against these proteins are opsonophagocytic for both homologous and heterologous HMW1/HMW2-expressing strains. In more recent work on the Hia proteins, we demonstrated that antibodies specific for the Hia-like proteins are also opsonophagocytic for homologous and heterologous Hia-expressing NTHi. Taken together, these data suggest that proteins from both the HMW1/HMW2 and Hia families, most likely in combination, deserve serious consideration as vaccine candidates for prevention of NTHi disease. Direct mucosal immunization is thought by many experts in the field to be critical to development of a successful otitis media vaccine. In our very recent work, we constructed recombinant adenovirus vectors expressing either HMW1/HMW2 or Hia proteins and demonstrated the immunogenicity of these constructs in the chinchilla otitis model. In the proposed work, we will build upon these earlier studies and determine whether the HMW1/HMW2- and Hia-like proteins can move forward as viable NTHi vaccine candidates. First, we will define the contribution of human antibodies produced against the HMW1/HMW2- and Hia-like proteins to the opsonophagocytic activity that develops in convalescent sera of children with acute NTHI otitis media. Next, we will map the regions of the HMW1/HMW2- and Hia-like proteins that express epitopes recognized by antibodies capable of mediating opsonophagocytic activity against both homologous and heterologous NTHi. Finally, we will assess the ability of recombinant adenovirus vectors expressing the HMW1/HMW2- or Hia-like proteins to provide protection against NTHi disease in the chinchilla model of experimental otitis media. Our proposed studies are innovative for the field both in terms of the promising vaccine antigens under study and in terms of the novel mucosal immunization strategy being investigated. The resulting information will move us further towards our ultimate goal of developing effective vaccines for prevention of NTHi otitis media and other diseases in young children.
Ear infections caused by nontypeable Haemophilus influenzae bacteria are a major problem for children everywhere. The objective of our work is to develop a vaccine for prevention of these Haemophilus ear infections. We previously identified two related bacterial proteins that are very promising vaccine candidates and we will further assess their vaccine potential in the studies proposed in this grant.
|Atack, John M; Day, Christopher J; Poole, Jessica et al. (2018) The HMW2 adhesin of non-typeable Haemophilus influenzae is a human-adapted lectin that mediates high-affinity binding to 2-6 linked N-acetylneuraminic acid glycans. Biochem Biophys Res Commun 503:1103-1107|
|Barenkamp, Stephen J; Chonmaitree, Tasnee; Hakansson, Anders P et al. (2017) Panel 4: Report of the Microbiology Panel. Otolaryngol Head Neck Surg 156:S51-S62|
|Winter, Linda E; Barenkamp, Stephen J (2017) Immunogenicity of Nontypeable Haemophilus influenzae Outer Membrane Vesicles and Protective Ability in the Chinchilla Model of Otitis Media. Clin Vaccine Immunol 24:|
|Pettigrew, Melinda M; Alderson, Mark R; Bakaletz, Lauren O et al. (2017) Panel 6: Vaccines. Otolaryngol Head Neck Surg 156:S76-S87|
|Winter, Linda E; Barenkamp, Stephen J (2016) Naturally Acquired HMW1- and HMW2-Specific Serum Antibodies in Adults and Children Mediate Opsonophagocytic Killing of Nontypeable Haemophilus influenzae. Clin Vaccine Immunol 23:37-46|
|Atack, John M; Winter, Linda E; Jurcisek, Joseph A et al. (2015) Selection and Counterselection of Hia Expression Reveals a Key Role for Phase-Variable Expression of Hia in Infection Caused by Nontypeable Haemophilus influenzae. J Infect Dis 212:645-53|
|Barenkamp, Stephen J (2015) Editorial commentary: Respiratory viruses and otitis media in young children. Clin Infect Dis 60:10-1|
|Atack, John M; Srikhanta, Yogitha N; Fox, Kate L et al. (2015) A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae. Nat Commun 6:7828|
|Winter, Linda E; Barenkamp, Stephen J (2014) Antibodies to the HMW1/HMW2 and Hia adhesins of nontypeable haemophilus influenzae mediate broad-based opsonophagocytic killing of homologous and heterologous strains. Clin Vaccine Immunol 21:613-21|
|Barenkamp, Stephen J (2013) A new human colonization model for nontypeable Haemophilus influenzae. J Infect Dis 208:717-9|
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