In a recent study published in the journal Npj Vaccines, researchers reviewed the immune mechanisms employed by existing vaccines for invasive pneumococcal disease (IPD).
They discussed upcoming vaccine strategies, as well as challenges associated with serotype selectivity and the usage of pneumococcal-derived proteins as alternative antigens in vaccine development.
Despite the implementation of worldwide vaccination programs, IPD caused by the bacterial pathogen Streptococcus pneumoniae, continues to cause widespread illness and has a fatality rate of close to 5%. Streptococcus pneumoniae asymptomatically colonizes the host nasopharynx and subsequently causes invasive disease since the human immune system’s ability to counteract S. pneumoniae virulence factors such as the capsular polysaccharide (CPS) coat protein is reduced.
The ability of the bacterium to use the heterogeneous monosaccharide building blocks of CPS and link and modify them also results in serotyping, with almost 90% of all IPD cases being attributed to 20 to 25 serotypes. The common manifestations of IPD are lung infection and pneumonia, with continued infection resulting in acute blood infection, bacteremia, septicemia, and infections of the spinal cord and brain, and eventually meningitis. IPD in patients hospitalized with coronavirus disease 2019 (COVID-19) or influenza also increases the fatality rate.
Given the fact that IPD still accounts for a substantial proportion of lower respiratory infections (15 cases out of every 100,000 people every year) with about 1.1 million fatalities each year, the development of more effective vaccines against S. pneumoniae continues to be a priority.
Existing pneumococcal vaccines
The primary immune clearance method of pneumococcal colonization is phagocytosis, and the CPS inhibits complement activation and helps S. pneumoniae evade immune clearance. However, the distinct structure of CPS and its surface exposure also provide vaccines with a suitable antigen to target and induce opsonophagocytic clearance of the bacteria.
The initiation of vaccination programs in the 20th century using the CPS expressed in the most prevalent serotypes has seen considerable success. However, the use of bacterial-derived, purified CPS cannot initiate the host’s adaptive immune response and only generates low-affinity, short-lived immunoglobulin M (IgM) responses that wane in six months.
CPS antigens can only be recognized by specific B cells, resulting in the secretion of IgM antibodies, with no activation of T-cell-induced antibody class switching and affinity maturation, leading to an absence of the memory B or T cells required for long-term protection.
Glycoconjugate vaccine technology, in which CPS is conjugated with a carrier protein with immunogenic properties, has helped induce adaptive immune responses that target CPS, causing class switching of IgM to IgG and affinity maturation, resulting in immune memory. However, despite their success in inducing long-term immunity, the inconsistencies across different vaccine batches and variations in immunogenicity continue to present challenges.
The development of conjugate vaccines also presents some hurdles since CPS is chemically activated for the carrier protein to be covalently attached to it, and this activation method could play a deleterious role. Furthermore, the non-specific conjugation of CPS and the carrier protein could result in an inability to present the key antigens to the major histocompatibility complex (MHC). Current vaccine technology is focused on the formulation of conjugate vaccines where the structural homogeneity and immunogenicity are not affected.
A recently developed 10-valent conjugate vaccine — Pneumosil, which does not use the peroxide oxidation method to attach CPS to the carrier protein covalently — has shown comparable efficacy to other approved pneumococcal vaccines.
Another 24-valent vaccine, VAX-24, conjugates CPS with a proprietary carrier protein, which is modified to allow site-selective conjugation and enriches the CPS conjugate epitope sites while keeping the tertiary structure of CPS intact.
The researchers also discussed other recent vaccine formulations that aim to circumvent the challenges presented by the traditional conjugation methods. Furthermore, the heterogeneity in the prevalence of serotypes across the globe and the problem of capsular switching, which present further challenges to the development of effective pneumococcal vaccines, were also discussed.
Alternate antigen targets
The focus of vaccine technology on CPS and serotype-specific vaccines reduces the scope of vaccine application since it can only induce immunity against the specific serotypes included in the formulation.
The emergence of non-encapsulated S. pneumoniae strains is also involved in the increased incidence of IPD cases. The researchers suggest a different approach in which vaccines target conserved surface proteins of S. pneumoniae.
Proteins such as pneumolysin, a cholesterol-dependent cytolysin, have long been studied and have been found in every S. pneumoniae strain that causes IPD.
While full-length pneumolysin protein was found to protect against a wide range of S. pneumoniae serotypes, it was also associated with cytotoxicity. However, mutated versions of pneumolysin with reduced toxicity, as well as other proteins such as pneumococcal surface protein A and pneumococcal histidine triad surface protein D are promising potential vaccine antigen targets.
To summarize, the review discussed the existing state of pneumococcal vaccines and the challenges related to serotype heterogeneity, vaccine conjugation processes, and capsular switching. These challenges continue to present roadblocks to developing vaccines that are effective against a wide range of S. pneumoniae serotypes whilst providing long-lasting immunity.
The researchers also discussed other potential vaccine antigens, such as surface proteins that are conserved across numerous S. pneumoniae strains.