Using a mouse-adapted LAIV [live attenuated influenza vaccine] against influenza A (H3N2) virus carrying the same mutations as the human FluMist vaccine, we find that LAIV vaccination reverses normal bacterial clearance from the nasopharynx and significantly increases bacterial carriage densities of the clinically important bacterial pathogens Streptococcus pneumoniae and Staphylococcus aureus within the upper respiratory tract of mice.
Vaccination with LAIV also resulted in 2- to 5-fold increases in mean durations of bacterial carriage.
Furthermore, we show that the increases in carriage density and duration were nearly identical in all aspects to changes in bacterial colonizing dynamics following infection with wild-type (WT) influenza virus.
Here we show, in mice, that vaccination with LAIV primes the upper respiratory tract for increased bacterial growth and persistence of bacterial carriage, in a manner nearly identical to that seen following wild-type influenza virus infections.
In the respiratory tract, for example, viral infections are known to predispose to secondary bacterial invasive disease and pneumonia from pathogens that are most commonly benign but occasionally become virulent, particularly following a viral infection. A well-known example is the often lethal synergy between influenza virus and pneumococcal or staphylococcal bacterial secondary infections.
Infection with influenza viruses increases susceptibility to severe lower and upper respiratory tract (LRT and URT, respectively) bacterial infections resulting in complications, such as pneumonia, bacteremia, sinusitis, and acute otitis media.
Increasingly, evidence is linking the early innate immune response triggered by infection or vaccination to sustained adaptive immunity. Thus, a broad goal of vaccination is to elicit an immune response analogous to that of the pathogen itself, without subsequent disease.
Although an innate immune response to vaccination is beneficial for long-term protection from influenza virus and influenza virus-bacterial coinfections, the direct consequences of such a response to a viral vaccine, with respect to secondary colonization and disease due to entirely unrelated bacterial pathogen species, are unknown.
As increased susceptibility to and transmission of bacterial pathogens following influenza are due in large part to the innate immune response and breakdowns of the epithelial barriers of the URT, it is important to understand whether similar effects, elicited by live attenuated virus replication, may also predispose to bacterial infection.
Using a live attenuated influenza A virus vaccine, (LAIV), which contains many of the same mutations and demonstrates similar growth dynamics to those in the commercially available human FluMist vaccine… we evaluated the effects of LAIV… on Streptococcus pneumoniae (the pneumococcus) and Staphylococcus aureus replication and disease.
LAIV is restricted in growth in the lower but not the upper respiratory tract.
LAIV enhances pneumococcal bacterial dynamics in the URT in a manner highly analogous to WT influenza virus.
Following vaccination, normal bacterial clearance from the [nasopharynx] was halted, and bacteria reverted to exponential growth within 3 days postvaccination.
Receipt of LAIV significantly increased the density of bacterial carriage and extended the mean duration of colonization from 35 to 57 days. Of particular importance, these effects were nearly identical in all aspects to the effects of the WT influenza virus on bacterial carriage density and duration.
[V]accination in the presence of bacterial colonization resulted in very mild, though sustained weight loss relative to colonized, unvaccinated controls that corresponded with time of greatest excess bacterial proliferation.
Early vaccination or infection with WT virus led to immediate excess bacterial outgrowth…
This increase was generally more pronounced following LAIV vaccination relative to WT virus infection, but the difference only reached statistical significance at day 1 post-bacterial infection.
[T]he effects of vaccination on distinct pathogen species unrelated to vaccine-targeted pathogens have, until now, remained entirely unexplored.
[E]nhanced bacterial load in the URT following LAIV may agree with human data, where LAIV has been associated with increases in adverse upper respiratory tract symptoms.
[A]dverse URT symptoms following administration of FluMist… are most evident in children <5 years of age, where rates of bacterial carriage are greatest.
Potentially corroborating this are data from a large prospective double-blind trial of FluMist that assessed reactogenicity and adverse URT events within the first 28 days following vaccination in ~3,000 children between the ages of 6 and 59 months. This trial demonstrated a bimodal increase in URT symptoms following FluMist vaccination, the first between days 2 and 4 post-vaccination and the second between days 5 and 10 post-vaccination.
In the context of the current findings, the first peak may correspond with viral replication, while the second, more sustained peak may, at least in part, be driven by symptoms due to excess bacterial carriage.
[T]he broad implications suggest that live attenuated viral vaccines may have unintended consequences on important human bacterial pathogens unrelated to the vaccine target species.