St. Jude Children’s Research Hospital scientists have reduced transmission of pneumococci in mice using an experimental vaccine that targets proteins on the surface of the bacteria.
The research appears online today in the journal Cell Host & Microbe.
The results suggest a possible strategy for eliminating Streptococcus pneumoniae (pneumococcus) with combination vaccines that block bacterial transmission and prevent invasive disease.
Current vaccines have helped reduce pneumococcal disease, but have done little to stop bacterial transmission.
S. pneumoniae is the most common cause of sepsis, pneumonia, meningitis and middle ear infections in young children.
Cancer patients, people 65 and older and others are also at an increased risk of invasive disease.
“A key aspect of pneumococci’s success is the ability to transmit from one host to another, yet that process and the factors involved are not well understood,” said corresponding author Jason Rosch, Ph.D., an associate member of the St. Jude Department of Infectious Diseases.
“These data suggest that rationally designed combination vaccines may offer a way to disrupt the spread and eliminate invasive disease that threatens young and old alike.”
S. pneumoniae lives in the nasal passages of most people at some point in their life, often beginning at an early age.
Once pneumococcus has colonized a host, the germ can infect others or move deeper into the body and cause invasive disease.
Vaccines are available to prevent invasive disease, but they are not as effective at blocking transmission.
Streptococcus pneumoniae is a common cause of community-acquired pneumonia (CAP), septicemia, and meningitis (1), as well as of noninvasive diseases, such as acute otitis media (AOM) and bronchitis (2).
Over 90 different serotypes of S. pneumoniae, determined by the characteristics of the capsular polysaccharide (CPS), have been identified (3).
There are currently two vaccines available to prevent S. pneumoniaeinfections: the pneumococcal polysaccharide vaccine (PPV) and the pneumococcal conjugate vaccine (PCV).
Each consists of capsular polysaccharide antigen from a limited panel of S. pneumoniae serotypes.
In the United Kingdom, PPV remains the first choice for adult vaccination (4), and PCV is routinely included in childhood immunization schedules worldwide, as it has greater efficacy than PPV in infants.
Unfortunately, in developing countries the high cost of PCV restricts its availability, and in addition, serotype coverage is reduced, as PCV was designed to include the most prevalent serotypes in North America (5).
Furthermore, serotype replacement in response to PCV vaccination alters the ecology of S. pneumoniae, reducing the efficacy of polysaccharide vaccines over time (6).
A vaccine based on protein antigens may provide a low-cost alternative approach capable of inducing cross-serotype protection (7, 8).
One vaccine approach dependent on protein antigens is a whole-cell approach, a cost-effective method of immunizing with a large number of potential protein antigens to potentially induce serotype-independent protective immunity.
In addition, a whole-cell approach could target both humoral and cellular host immunity (9, 10), potentially enabling clearance of both disease and colonization.
Several groups have therefore studied a whole-cell vaccine approach against S. pneumoniae, including progression to early-phase clinical trials (11–13).
An alternative to maintaining protein antigens as part of the whole S. pneumoniae bacterium is using a bacterial lysate as a vaccine, which could result in a more stable preparation that is better suited to vaccine delivery than a whole bacterium.
However, the antigenicity of whole-cell lysates may be weak and require enhancement (14).
One method of enhancing immunogenicity is altering the preparation of the lysate to ensure increased representation of immunoprotective proteins.
This can be partially achieved using anion-exchange chromatography with a pH 8.0 buffer to preferentially capture several well-known S. pneumoniae antigens, all of which have a pI of 7.5 or lower, including PiuA, PiaA, PsaA, RrgA, RrgB, ClpP, PspA, and Ply.
In addition, growth under stress conditions, such as high temperatures, to induce heat shock proteins (Hsps) could increase antigenicity (15), as Hsps facilitate the cross-presentation of peptides (16, 17) and act as natural adjuvants by stimulating macrophages and dendritic cells to cause cytokine secretion (18–20)
As a result, Hsps have been studied as vaccines that protect against cancer as well as microbial pathogens (21), with a number of bacterial Hsps showing promise as vaccine candidates (22–24), including in models of lethal lung infection (25–27).
For example, mice intranasally immunized with the S. pneumoniae Hsp DnaJ (Hsp40) or Hsp caseinolytic protease P (ClpP) were protected from S. pneumoniae infection, including against systemic challenge with a panel of heterologous strains (28).
Hence, Hsps are potential vaccine antigens with advantageous immunomodulatory properties that could be used as a component of a broadly protective S. pneumoniae vaccine.
Transmission essentials
Rosch and his colleagues used high-throughput genetic screening of more than 65,000 S. pneumoniae mutants to search for factors required for transmission.
Using a model developed by St. Jude biostatisticians, the researchers identified about 70 bacterial proteins that played an important role in transmission from infected to uninfected ferrets. Investigators confirmed the findings in mice.
Many of the proteins were involved in metabolism, transcriptional regulation and competency (bacterial exchange of genetic material).
The transmission factors also included surface proteins—PiaA and CppA. Vaccinating female mice with either or both proteins blocked transmission of pneumococcus to their offspring compared to those born to mice who received a current vaccine.
More information: Hannah M. Rowe et al. Bacterial Factors Required for Transmission of Streptococcus pneumoniae in Mammalian Hosts, Cell Host & Microbe (2019). DOI: 10.1016/j.chom.2019.04.012
Journal information: Cell Host & Microbe
Provided by St. Jude Children’s Research Hospital
