Status and Future Trends of Pneumococcal Vaccination in Chronic Obstructive Pulmonary Disease

"Vaccines are the tugboats of preventive health." -William Foege Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction that is typically progressive. The disease is punctuated by exacerbations, which are often produced by bacterial infections, contributing to morbidity, mortality, and decreased life expectancy due to the progression of the disease. COPD is the third-most common cause of mortality globally with more than 3 million deaths each year with most deaths happening in low- and middle-income countries; hence, the prevention of COPD exacerbation with vaccination is important.[1] COPD patients are susceptible to infections due to multiple reasons. This includes the aberrant phagocytic activity of macrophages to common bacteria, impaired immune response, and marked airway inflammation with the recruitment of neutrophils and macrophages. Inhaled noxious particles, such as tobacco smoke, elevate the risk of bacterial infections mainly by disrupting mucociliary clearance, impairing airway epithelium, and altering microbiome composition. Moreover, inhaled corticosteroid usage to prevent frequent exacerbations potentially increases the rate of lung infections. Given the susceptibility of COPD patients to common bacterial pathogens, vaccinations are recommended. Community-acquired pneumonia (CAP) associated with COPD exacerbation has a worse outcome compared to exacerbations without pneumonia in terms of increased mortality (both during the hospital stay and short-term posthospitalization period), duration of hospital stays, and frequency of readmission.[2] As Streptococcus pneumoniae is the most frequent cause of CAP irrespective of age and comorbidity,[3] the prevention of pneumococcal pneumonia is an important step in reducing the incidence of exacerbations of COPD. Current pneumococcal vaccines use pneumococcal capsular polysaccharides as antigens to generate serotype-specific antibodies, which facilitate serotype-specific clearance of pneumococci through opsonophagocytosis. Commercially available pneumococcal vaccines are either polysaccharide conjugate vaccines (PCV13, PCV15, and PCV20) or pneumococcal polysaccharide vaccines (PPSV23). PPSV23 covers a wide range of serotypes of pneumococci that are responsible for most of the invasive pneumococcal pneumonia, and clinical trials have shown its effectiveness in preventing severe pneumococcal pneumonia. On the other hand, PPSV23 has shown less effectiveness in protecting against pneumonia on a long-term basis and in immunocompromised persons or individuals with other potential risk factors.[4] Pneumococcal Conjugate vaccines (PCVs) induce a T-cell-dependent response. The antigen binds to the B-cells, and the peptides from the carrier protein are presented to carrier-peptide–specific helper T-cells. These helper T-cells enhance the immune response by the B-cells, and memory B-cells also are created. On the other hand, PPSV imparts a T-cell-independent immune response that evokes immediate B-cell response only. There is evidence that in COPD patients, PCVs impart better immunogenicity which can persist longer.[5] The effectiveness of PPSV23 has been in doubt for many years in elderly or at-risk individuals. Trials have shown decreased efficacy of PPSV23 to prevent pneumonia in the elderly.[6] A post hoc analysis of the large randomized placebo-controlled trial (CAPiTA study) has suggested that PCV13 has long-term efficacy in the elderly population aged above 65 years with or without comorbidities including COPD.[7] Limited data are available comparing the duration of immunogenicity of conjugated and polysaccharide vaccines in COPD. As per one prospective observational cohort study in COPD patients aged more than 55 years, during the 1st year, both vaccines imparted protective effects against exacerbations. However, from the 2nd year, the PPSV23 group showed a gradual decline, reaching the level of the control group by year 5 postvaccination. Furthermore, after year 1, the PPSV23 group had shown a higher pneumonia incidence rate compared to even the control group (P < 0.001). To conclude, the trial demonstrated that PCV13 is associated with long-term protection, lasting at least 5 years, against episodes of pneumonia or COPD exacerbations.[8] In recent years, there has been a need to develop novel PCV vaccines, as new S. pneumoniae serotypes appeared to cause pneumococcal diseases, and antibiotic resistance was also associated with these serotypes.[9] In 2021, a 20-valent (PCV20) and a 15-valent (PCV15) pneumococcal vaccine were licensed for usage. The CDC's Advisory Committee on Immunization Practices recommendations specify the use of either PCV20 alone or PCV15 in series with PPSV23 for all adults aged ≥65 years and for adults aged 19–64 years with certain underlying medical conditions or other risk factors who have not received a PCV or whose vaccination history is unknown.[10] Indian guideline recommends a single dose of PCV13 followed by PPSV23 ≥ 8 weeks later for adults aged 19–64 years with underlying chronic lung diseases. In individuals above 65 years, the decision to administer a dose of PCV13 preceding PPSV23 should be taken jointly by the physician and the patient on a case-to-case basis.[11] There is evidence for an additive benefit when the influenza vaccine is administered simultaneously with the pneumococcal vaccine. A recent study supported the favorable effects of influenza and PPSV23 vaccinations, resulting in a reduced frequency of exacerbation in the following year, with an odds ratio (OR) of 1.06 (95% confidence interval [CI]: 0.84–1.34) for PPSV23 alone and an OR of 2.37 (95% CI: 1.39–4.08) for patients who were administered both vaccines.[12] There is emerging evidence that nonvaccine, unencapsulated serotypes of S. pneumoniae are related to COPD exacerbations and invasive pneumococcal diseases.[13] The Centers for Disease Control and Prevention (CDC) reported that only <25% of the total number of invasive pneumococcal disease cases in immunocompromised patients were caused by PPSV23-covered S. pneumoniae serotypes. This indicates the need for the development of new vaccines not dependent on the polysaccharide antigen alone. Thus, new vaccine development approaches include vaccine candidates against pneumococcal proteins through new protein antigens or genetic manipulations of the main pneumococcal proteins.[14] Identifying key potential virulence factors for developing new pneumococcal vaccines is under study. This includes pneumococcal surface protein A, choline-binding protein A (previously known as pneumococcal surface protein C), pneumolysin, pneumococcal histidine triad protein D, and so on. In addition, there are several ongoing studies to develop vaccines based on diminishing autolysin using genetically modified live attenuated whole-cell vaccines or creating nanovaccines. In the current edition of this journal, an original study is described where the authors compare pneumococcal vaccinated with unvaccinated patients regarding the severity of COPD exacerbation in terms of multilobar consolidation, need for intensive care unit care, occurrence of type 2 respiratory failure, and presence of features of sepsis.[15] All these parameters are found to be better in terms of severity of illness in previously vaccinated patients. This further emphasizes the advantages of pneumococcal vaccination in COPD patients. Thus, guidelines recommend sequential vaccination with both PCVs and PPSV23 for COPD patients, and there are evidence to support these recommendations to prevent COPD exacerbations and CAP. Due to the emergence of pneumococcal pneumonia with nonvaccine serotypes, novel pneumococcal vaccines against pneumococcal proteins are required, and shortly, we are optimistic to get the commercial availability of these types of vaccines.