Universal Noncapsular Pneumococcal Vaccine – A New Answer to Serotype Substitution?
Christopher J. Harrison, MD, FAAP, FPIDS | Director, Infectious Diseases Research Laboratory | Director, Vaccine and Treatment Evaluation Unit | Professor of Pediatrics, UMKC School of Medicine
Current pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccines (PCV7 and PCV13) have had great success. They target capsular polysaccharides of serotypes previously determined to be the most common among the known 94 serotypes. These antibodies prevent recently acquired or colonizing pneumococci from causing disease. The mechanism involves serotype-specific antibodies in secretions, serum or tissue fluid attaching to the specific capsules and facilitating elimination of the bacteria from tissues and often from mucosal surfaces.
However, this success has been somewhat marred by serotype substitution, or as some have called it “the whack-a-mole phenomenon,”1 i.e., successful vaccines aimed at the most common serotypes allow emergence of previously infrequent serotypes (19F decreasing, but 19A emerging) as causes of invasive and noninvasive disease. Even more insidious is capsular switching, where the disease-producing machinery of a virulent serotype, e.g., 19A adopts a new external capsule, 15B, to evade PCV13-induced antibodies,2 akin to people changing to heavier clothing in cold weather.
Given that the serotype targets keep shifting with each new vaccine, we can try to keep adding more serotypes to PCV13 (there are candidate vaccines with up to a total of 20 serotypes under study). However, there is likely a maximum number of serotypes that can be packaged into one vaccine. As an alternative, there is ongoing research for a universally “conserved” antigen target common to all pneumococcal strains, regardless of capsular serotype.
One potential candidate protein is elongation factor Tu (EF-Tu). It is one of those antigens that causes tissue-injuring inflammation during infection. During autolysis when pneumococci fall apart if packed too close together with limited nutrition (think purulent collections in pneumonia or meningitis), pneumococci release EF-Tu, which appears to trigger local innate inflammatory immune responses via toll-like receptor 4 (TLR4), enhancing tissue injury. You may remember TLR4 as the potent innate immune responder to the LPS in capsules of Gram negative rods.
A group of Japanese investigators recently published in vitro and animal data to suggest EF-Tu could indeed represent a new target for a universal vaccine to replace or complement current PCV vaccines.3 They confirmed that EF-Tu is common to all pneumococcal strains tested, and that it is found both on the pathogen’s surface and intracellularly.
They immunized mice with a recombinant EF-Tu (rEF-Tu). The mice produced IgG1 and IgG2a antibodies to EF-Tu and increased numbers of CD4+ T-cells. Serum from immunized mice increased phagocytosis of S. pneumoniae by macrophages regardless of serotype. The best news was that immunized mice had less tissue injury and inflammation and were significantly protected against lethal challenge when inoculated with two serotypes not currently in PCV13, (2 and 15A). In other words, the protection was not serotype-specific.
Therefore, pneumococcal EF-Tu could be a candidate for the serotype-independent vaccine against invasive disease. The mechanism of protection by this vaccine is not exclusively destruction of the bacteria, but adds a neutralizing effect for a toxic bacterial component that is generated during infection. Yet, it still may not be sufficient as a solo vaccine. Its best use may be to complement vaccines whose antibodies directly attack the pneumococcus.
Another issue to be examined is whether EF-Tu would affect non-invasive disease, e.g., acute otitis media or sinusitis, which are primarily mucosal infections whose root cause is dysfunction of middle ear or sinus-cleansing mechanisms.
Nevertheless, this is an example of new initiatives to answer an old problem noted even in cinema about the unintended consequences of human interventions, i.e., that despite our best intentions “nature finds a way.” - Jeff Goldblum in the original Jurassic Park
Playing “Whack-a-Mole” with Pneumococcal Serotype Eradication. Swanson D, Harrison C. Pediatrics. 2017 Oct 4. pii: e2017-2034. [Epub ahead of print]. PMID: 28978717.
Whole Genome Sequencing of 39 Invasive Streptococcus Pneumoniae Sequence Type 199 Isolates Revealed Switches from Serotype 19A to 15B. PLoS One. Makarewicz O, Lucas M, Brandt C, et al. 2017 Jan 3;12(1): e0169370.
Immunization with Pneumococcal Elongation Factor Tu Enhances Serotype-independent Protection Against Streptococcus Pneumoniae Infection. Nagai K, Domon H, Maekawa T, et al. Vaccine. 2019 Jan 3;37(1):160-168. Epub 2018 Nov 13.