A Bivalent Vaccine Based on a Replication-Incompetent Influenza Virus Protects against Streptococcus pneumoniae and Influenza Virus Infection

Abstract

Streptococcus pneumoniae is a major causative pathogen in community-acquired pneumonia; together with influenza virus, it represents an important public health burden. Although vaccination is the most effective prophylaxis against these infectious agents, no single vaccine simultaneously provides protective immunity against both S. pneumoniae and influenza virus. Previously, we demonstrated that several replication-incompetent influenza viruses efficiently elicit IgG in serum and IgA in the upper and lower respiratory tracts. Here, we generated a replication-incompetent hemagglutinin knockout (HA-KO) influenza virus possessing the sequence for the antigenic region of pneumococcal surface protein A (PspA). Although this virus (HA-KO/ PspA virus) could replicate only in an HA-expressing cell line, it infected wild-type cells and expressed both viral proteins and PspA. PspA-and influenza virus-specific antibodies were detected in nasal wash and bronchoalveolar lavage fluids and in sera from mice intranasally inoculated with HA-KO/PspA virus, and mice inoculated with HA-KO/PspA virus were completely protected from lethal challenge with either S. pneumoniae or influenza virus. Further, bacterial colonization of the nasopharynx was prevented in mice immunized with HA-KO/PspA virus. These results indicate that HA-KO/PspA virus is a promising bivalent vaccine candidate that simultaneously confers protective immunity against both S. pneumoniae and influenza virus. We believe that this strategy offers a platform for the development of bivalent vaccines, based on replication-incompetent influenza virus, against pathogens that cause respiratory infectious diseases. IMPORTANCEStreptococcus pneumoniae and influenza viruses cause contagious diseases, but no single vaccine can simultaneously provide protective immunity against both pathogens. Here, we used reverse genetics to generate a replication-incompetent influenza virus carrying the sequence for the antigenic region of pneumococcal surface protein A and demonstrated that mice immunized with this virus were completely protected from lethal doses of infection with either influenza virus or Streptococcus pneumoniae. We believe that this strategy, which is based on a replication-incompetent influenza virus possessing the antigenic region of other respiratory pathogens, offers a platform for the development of bivalent vaccines.

The role of influenza in the epidemiology of pneumonia

“…In particular, we find a presence of an epidemiological impact of influenza on pneumonia. This suggests that interventions targeted at reducing the risk of pneumonia, either via vaccines targeted towards bacterial sources of pneumonia 47 or against influenza, which are particularly effective in reducing the risk of subsequent risk of pneumonia 48 49 , are likely to be more effective compared to post hoc treatment and case management. Furthermore, given that the interaction operates at short time scales, antiviral treatment of influenza patients may not be as efficacious in preventing secondary bacterial infections 39 .…”

Development and applications of single-cycle infectious influenza A virus (sciIAV)

“…Whether these bivalent sciIAV had different protective efficacies than reporter-expressing sciIAV was not addressed (Masic et al, 2013; Uraki et al, 2013). Amenability of sciIAV as a bivalent vaccine was further shown when Streptococcus pneumoniae surface protein A (PspA), HPIV-3 HN protein, or RSV F protein replaced the reporter gene in sciIAV (Fonseca et al, 2014; Katsura et al, 2014; Kobayashi et al, 2013). All of these vaccines could induce Abs and reduce the burden against the heterologous pathogen while retaining their ability to protect against influenza challenge.…”

Next generation protein basedStreptococcus pneumoniaevaccines

“…Spn infection almost always follows a viral upper respiratory infection (URI). Therefore animal co-infection models have been used to study co-pathogenesis of Spn with viruses such as human influenza virus, [42][43][44][45][46][47] respiratory syncytial virus, 48 adenovirus, 49,50 metapneumovirus, 51 parainfluenza virus. 52 The most well-investigated bacterialviral interaction is the synergism between influenza virus and Spn 23 and the interaction has been shown to be strongly associated with Spn dissemination from the NP and subsequent local or systemic invasion.…”