(175am) Engineering a Next-Generation Vaccine: Targeting Pneumococcal Disease in an Aging Population

Streptococcus pneumoniae (S. pneumoniae) also known as pneumococcus is a lancet-shaped, Gram-positive, anaerobic bacteria and is the causative agent for pneumococcal disease [1]. Pneumococcal disease is the name given to the spectrum of diseases and conditions that can arise due to an infection with S. pneumoniae. This disease is typically classified into two groups: non-invasive or mucosal pneumococcal disease, which results in conditions like bacterial pneumonia, otitis media (middle ear infection), or sinusitis; and the more severe invasive pneumococcal disease (IPD) which causes conditions like meningitis and bacteremia [1]. Most S. pneumoniae strains are encapsulated by a complex capsular polysaccharide (CPS) shell, which also acts as one of the main virulence factors for this organism [2]. Different capsular polysaccharide shells present on the surface of S. pneumoniae constitute different serotype versions of this organism. Currently, there are over 100 recognized S. pneumoniae serotypes with 7 of those serotypes causing 80% of infections in children five and under and over 50% of infections in older children and adults [1].

Lower respiratory tract infections are a leading cause of illness worldwide, with an estimated 2.4 million deaths in 2019 alone [3]. In 2016, pneumococcal pneumonia was responsible for 1,189,937 deaths globally as well as 197.05 million incidents of disease. Of these deaths, 341,029 occurred in children (<5 years) and 494,340 deaths occurred in the elderly (>70 years) [4]. In the US in 2004 there was an estimated $5.2 billion in direct medical costs (adjusted for inflation) for 4 million cases of pneumococcal disease, with pneumonia accounting for 22% of those cases and 72% of the direct medical costs [5]. Among adults >65 years, pneumonia accounted for most cases (58%) with 80% of those cases requiring hospitalization. In the same study it was found that children <5 years suffer far more from acute otitis media, accounting for 74% of cases in that age group [5]. Additionally, in the US in 2019 there was an estimated 502,600 pneumococcal pneumonia cases, 29,500 invasive pneumococcal disease cases, and 25,400 pneumococcal disease related deaths in adults (>50 years) [6].

Due to the deadly nature of pneumococcal disease and more specifically pneumococcal pneumonia, many efforts have been taken to combat this disease. Vaccination is one of the best ways to prevent disease, with the first attempts to vaccinate against this disease occurring in the early 1900s [7]. In more recent years, there have been successful attempts to create vaccines based on the capsular polysaccharides of S. pneumoniae. Some of those vaccines include Prevnar 13^® (PCV13) or Pneumovax 23^® (PPV23). Both vaccines have moderate efficacy in non-elderly populations against pneumococcal pneumonia; however, the elderly population has a markedly lower vaccine efficacy with PPV23 having a 33% efficacy against pneumococcal pneumonia and PCV13 having a 45% efficacy against pneumococcal pneumonia [8, 9].

To improve upon this, our group has developed a new approach to pneumococcal pneumonia vaccination with a particular focus upon older populations. In our approach, we use lipid nanoparticle as the vehicle for the pneumococcal antigens present in our vaccine formulation. Foundational logic for this delivery approach is co-localizing two types of antigens within the lipid nanoparticle framework, thus, mimicking polyconjugate vaccines, like PCV13, which have shown the best clinical responses to pneumococcal disease. This lipid nanoparticle vaccine has been termed Liposomal Encapsulation of Polysaccharide (LEPS).

The current formulation of the LEPS vaccine consists of one polysaccharide antigen from the pneumococcal capsular polysaccharide (CPS) of S. pneumoniae located in the aqueous core of the lipid nanoparticle and a second surface-exposed S. pneumoniae protein antigen, recombinantly produced, attached to the surface of the lipid nanoparticle. With these two antigens present in the vaccine, the design allows for economy in production, greater vaccine effectiveness, and broader protection against S. pneumoniae serotypes. One of the main advantages of using liposomal delivery of antigens when compared to other methods is the extreme customizability of these particles. The size, surface charge, lipid composition, and antigen composition can all be easily controlled to achieve desired characteristics. In our vaccine formulation, we have the potential to include over 100 different capsular polysaccharides (CPS) in one vaccine dose, thus, enabling broad vaccine coverage against S. pneumoniae serotypes.

[1] M. A. P. W. Ryan Gierke, MD; and Miwako Kobayashi, MD, MPH. "Pinkbook: Pneumococcal disease." Centers for Disease Control and Prevention. https://www.cdc.gov/vaccines/pubs/pinkbook/pneumo.html#streptococcus-pneumoniae (accessed.

[2] K. A. Geno et al., "Pneumococcal Capsules and Their Types: Past, Present, and Future," (in eng), Clin Microbiol Rev, vol. 28, no. 3, pp. 871-99, Jul 2015, doi: 10.1128/cmr.00024-15.

[3] S. Safiri et al., "Global burden of lower respiratory infections during the last three decades," (in eng), Front Public Health, vol. 10, p. 1028525, 2022, doi: 10.3389/fpubh.2022.1028525.

[4] "Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016," (in eng), Lancet Infect Dis, vol. 18, no. 11, pp. 1191-1210, Nov 2018, doi: 10.1016/s1473-3099(18)30310-4.

[5] S. S. Huang et al., "Healthcare utilization and cost of pneumococcal disease in the United States," (in eng), Vaccine, vol. 29, no. 18, pp. 3398-412, Apr 18 2011, doi: 10.1016/j.vaccine.2011.02.088.

[6] R. E. Thomas, "Pneumococcal Pneumonia and Invasive Pneumococcal Disease in Those 65 and Older: Rates of Detection, Risk Factors, Vaccine Effectiveness, Hospitalisation and Mortality," (in eng), Geriatrics (Basel), vol. 6, no. 1, Feb 4 2021, doi: 10.3390/geriatrics6010013.

[7] S. Lister, "The use of pneumococcal vaccine," South African Med Record, vol. 22, no. 6, pp. 115-22, 1924.

[8] C. H. van Werkhoven, S. M. Huijts, M. Bolkenbaas, D. E. Grobbee, and M. J. M. Bonten, "The Impact of Age on the Efficacy of 13-valent Pneumococcal Conjugate Vaccine in Elderly," Clinical Infectious Diseases, vol. 61, no. 12, pp. 1835-1838, 2015, doi: 10.1093/cid/civ686.

[9] M. J. Bonten et al., "Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults," (in eng), N Engl J Med, vol. 372, no. 12, pp. 1114-25, Mar 19 2015, doi: 10.1056/NEJMoa1408544.