Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model

Abstract

Otitis media (OM) is a common pediatric disease, and nontypeable Haemophilus influenzae (NTHI) is the predominant pathogen in chronic OM, recurrent OM, and OM associated with treatment failure. OM is also a polymicrobial disease, wherein an upper respiratory tract viral infection predisposes to ascension of NTHI from the nasopharynx, the site of colonization, to the normally sterile middle ear, resulting in disease. Using a clinically relevant viral-bacterial coinfection model of NTHIinduced OM, we performed transcutaneous immunization (TCI) via a band-aid delivery system to administer each of three promising NTHI vaccine candidates derived from bacterial adhesive proteins and biofilm mediators: recombinant soluble PilA (rsPilA), chimV4, and integration host factor. Each immunogen was admixed with the adjuvant LT(R192G/L211A), a double mutant of Escherichia coli heat-labile enterotoxin, and assessed for relative ability to prevent the onset of experimental OM. For each cohort, the presence of circulating immunogen-specific antibody-secreting cells and serum antibody was confirmed prior to intranasal NTHI challenge. After bacterial challenge, blinded video otoscopy and tympanometry revealed a significant reduction in the proportion of animals with signs of OM compared to levels in animals receiving adjuvant only, with an overall vaccine efficacy of 64 to 77%. These data are the first to demonstrate the efficacy afforded by TCI with a band-aid vaccine delivery system in a clinically relevant polymicrobial model of OM. The simplicity of TCI with a band-aid and the significant efficacy observed here hold great promise for reducing the global burden of OM in the pediatric population.KEYWORDS IHF, biofilms, chimV4, nontypeable Haemophilus influenzae, rsPilA T ranscutaneous immunization (TCI) is a noninvasive strategy to induce an immune response by engagement of the numerous antigen-presenting cells within the dermis and epidermis (1, 2). This regime results in both systemic and mucosal immune responses, important outcomes as the mucosae serve as critical defensive barriers to antigenic insult and bacterial disease (3, 4). TCI is needle free, which is expected to aid in patient compliance, to limit risks associated with both administration and waste, and to reduce costs related to formulation and delivery (5). Thus, TCI promises to facilitate greater vaccine distribution.Otitis media (OM) is a disease of the uppermost respiratory tract mucosa and is one of the most common bacterial diseases of childhood due to a multifactorial combination of anatomical, immunological, and environmental factors (6). OM is also a polymicrobial disease caused by one or more of several bacterial species that typically reside within the human nasopharynx. The ability of nontypeable Haemophilus influenzae (NTHI), Streptococcus pneumoniae, and Moraxella catarrhalis to ascend from the nasopharynx through the Eustachian tube and gain access to the normally sterile middle ear space is facilitated by perturbation of the physical and inn...

A Bacterial Epigenetic Switch in Non-typeable Haemophilus influenzae Modifies Host Immune Response During Otitis Media

“…However, there was a consistent increase in mucosal biofilm burden from 2 to 5 days post challenge and 5 to 14 days post challenge, irrespective of modA2 status. These results were similar to biofilm formation reported during experimental otitis media induced by other NTHi strains (Hong et al, 2009(Hong et al, , 2019Novotny et al, 2017). Representative images of middle ears challenged with the modA2 OFF or modA2 ON variants are shown in Figure 1C.…”

Targeting a bacterial DNABII protein with a chimeric peptide immunogen or humanised monoclonal antibody to prevent or treat recalcitrant biofilm-mediated infections

“…An established adenovirus-NTHI polymicrobial challenge model [32] was employed to assess efficacy of the tip chimeric peptide when delivered as a pre-clinical vaccine antigen. Chinchillas were randomly divided into three cohorts of eight animals each based on body weight and immunised by rubbing vaccine formulations on to the unabraded skin behind each pinna (post-auricular region) [33].…”

“…This superinfection model is designed to mimic "My child gets a cold, then a week later has an ear infection". Thus, animals were first actively immunised with the tip or tail chimeric peptide to induce the appropriate immune response [31,33,35,38]. Subsequently, chinchillas were challenged first with adenovirus, then 7-days later with NTHI, after which they were monitored for relative development of ascending OM.…”

Current therapies in treatment and prevention of fracture wound biofilms: why a multifaceted approach is essential for resolving persistent infections

“…In this approach, vaccines against major matrix components are administered after the identification of a persistent infection. Recent studies have shown that these vaccines may stimulate the immune system to disperse the biofilm through sequestration of matrix materials 210 , 211 . For S. aureus , therapeutic use of a conjugate capsular polysaccharide and protein vaccine conferred protection in a rat model of osteomyelitis 212 .…”