Live attenuated influenza virus increases pneumococcal translocation and persistence within the middle ear

Infection with influenza A virus (IAV) increases susceptibility to severe lower and upper respiratory tract (URT) bacterial infections, resulting in complications such as pneumonia, bacteremia, sinusitis, and bacterial acute otitis media (AOM) [1]; the latter is a major contributor to the global burden of pediatric disease and remains one of the most common diagnoses leading to the prescription of antimicrobial agents in the United States [2]. While bacterial AOM often occurs in isolation, increasing evidence suggests that primary or concurrent viral respiratory infections of the URT may play uniquely important roles in enhancing bacterial acquisition, colonization, and, ultimately, progression from asymptomatic bacterial carriage to AOM [3], notably from Streptococcus pneumoniae and Staphylococcus aureus [1, 4]. Although the mechanisms underlying influenza virus–mediated susceptibility to bacterial AOM are not entirely defined, they likely include a combination of IAV-mediated cytotoxic breakdown of mucosal and epithelial barriers of the URT [5–8] and aberrant innate immune responses to bacterial invaders in the immediate postinfluenza state, characterized by uncontrolled proinflammatory and antiinflammatory cytokine production, excessive leukocyte recruitment, and immunopathology [1, 9–13]. When coupled with diminished mucosal defenses, such an environment becomes increasingly hospitable for bacterial pathogens to flourish and cause clinical disease in the days and weeks following influenza virus infection. Increasing evidence links the early innate immune response triggered by vaccination to long-term vaccine efficacy [14]. Thus, a goal of vaccination is to elicit an immune response as close to that elicited by the pathogen itself, without subsequent disease. The intranasally administered live attenuated influenza vaccine (LAIV) is composed of 1:1:6 reassortant viruses containing the hemagglutinin (HA) and neuraminidase (NA) surface proteins from wild-type viruses on a temperature-sensitive and attenuated backbone designed to enable efficient viral replication in the cooler temperatures of the URT but not the warmer temperatures of the lower respiratory tract (LRT) [15, 16]. Through selective replication in the URT, LAIV proteins are exposed to the host immune system in their native conformation, eliciting highly robust immunoglobulin A (IgA), serum immunoglobulin G (IgG), and cellular immune responses mimicking those of the pathogenic virus itself [17], without subsequent virus-mediated disease in the LRT [18, 19]. Recently, we demonstrated that LAIV, while safely providing long-term immunity against influenza and significantly reducing postinfluenza secondary bacterial infections [20], inadvertently enhances the duration and density of bacterial carriage in the nasopharynx of mice [21], a finding that has since been shown in humans [22]. Importantly, in contrast to wild-type IAV infections, LAIV did not alter bacterial outgrowth in the LRT and demonstrated no increases in the incidences of bacterial pneumonia or bacteremia. What is not known is whether LAIV virus replication in the URT may, like that of the wild-type IAV, inadvertently catalyze bacterial migration from the nasopharynx, where it is largely asymptomatic, into the middle ear, where it can increase the risk of symptomatic AOM [13, 23, 24]. Such an effect of the attenuated virus could result from LAIV-mediated inflammation of the epithelial cells of the pharyngotympanic tube [13] or from elevated bacterial density within the nasopharynx [25].