Despite use of influenza vaccines for more than 65 y, influenza and its complications are a major cause of morbidity and mortality worldwide. Most deaths during influenza virus infections are due to underlying co-morbidities or secondary bacterial pneumonia. The measures of immune response currently used for licensure of influenza vaccines are relevant mainly for protection from viral infection in healthy adults. Development of new or improved influenza vaccines will require a definition of novel, and specific correlates of protection. These correlates should associate immune responses with outcomes that are relevant to specific risk groups, such as asthma exacerbation, hospitalization or disruptions to care or daily activities. Assessment of vaccine effectiveness for both viral and bacterial vaccines should include measures of impact on secondary bacterial pneumonia.

Secondary bacterial infections contribute to morbidity and mortality from influenza. Vaccine effectiveness is typically assessed using prevention of influenza, not secondary infections, as an endpoint. We vaccinated mice with formalin-inactivated influenza virus vaccine preparations containing disparate HA and NA proteins and demonstrated an ability to induce the appropriate anti-HA and anti-NA immune profiles. Protection from both primary viral and secondary bacterial infection was demonstrated with vaccine-induced immunity directed toward either the HA or the NA. This finding suggests that immunity toward the NA component of the virion is desirable and should be considered in generation of influenza vaccines.

The newest type of influenza virus, influenza D virus (IDV), was isolated in 2011. IDV circulates in several animal species worldwide, causing mild respiratory illness in its natural hosts. Importantly, IDV does not cause clinical disease in humans and does not spread easily from person to person. Here, we review what is known about the host–pathogen interactions that may limit IDV illness. We focus on early immune interactions between the virus and infected host cells in our summary of what is known about IDV pathogenesis. This work establishes a foundation for future research into IDV infection and immunity in mammalian hosts.

A combination of viral, bacterial, and host factors contributes to the severity and overall mortality associated with influenza virus-bacterium superinfections. To date, the virulence associated with the recently identified influenza virus protein PB1-F2 has been largely defined using models of primary influenza virus infection, with only limited assessment in models of Streptococcus pneumoniae superinfection. Specifically, these studies have incorporated isogenic viruses that differ in the PB1-F2 expressed, but there is still knowledge to be gained from evaluation of natural variants derived from a nonhuman host species (swine). Using this rationale, we developed the hypothesis that naturally occurring viruses expressing variants of genes, like the PB1-F2 gene, can be associated with the severity of secondary bacterial infections. To test this hypothesis, we selected viruses expressing variants in PB1-F2 and evaluated outcomes from superinfection with three distinct Gram-positive respiratory pathogens: Streptococcus pneumoniae , Staphylococcus aureus , and Streptococcus pyogenes . Our results demonstrate that the amino acid residues 62L, 66S, 75R, 79R, and 82L, previously proposed as molecular signatures of PB1-F2 virulence for influenza viruses in the setting of bacterial superinfection, are broadly associated with enhanced pathogenicity in swine in a bacterium-specific manner. Furthermore, truncated PB1-F2 proteins can preferentially increase mortality when associated with Streptococcus pyogenes superinfection. These findings support efforts to increase influenza virus surveillance to consider viral genotypes that could be used to predict increased severity of superinfections with specific Gram-positive respiratory pathogens.

Influenza virus infections remain a significant health burden worldwide, despite available vaccines. Factors that contribute to this include a lack of broad coverage by current vaccines and continual emergence of novel virus strains. Further complicating matters, when influenza viruses infect a host, severe infections can develop when bacterial pathogens invade. Secondary bacterial infections (SBIs) contribute to a significant proportion of influenza-related mortality, with Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, and Haemophilus influenzae as major coinfecting pathogens. Vaccines against bacterial pathogens can reduce coinfection incidence and severity, but few vaccines are available and those that are, may have decreased efficacy in influenza virus-infected hosts. While some studies indicate a benefit of vaccine-induced immunity in providing protection against SBIs, a comprehensive understanding is lacking. In this review, we discuss the current knowledge of viral and bacterial vaccine availability, the generation of protective immunity from these vaccines, and the effectiveness in limiting influenza-associated bacterial infections.