Comparison of clinical effectiveness of vaccines for preventing pneumonia, as well as their mediated effect on the health status of COPD patients, demonstrated that both PCV13 and PPV23 are effective during the first 1–2 years after the vaccination. However, the effectiveness of PPV23 decreases noticeably over time: PPV23 ensured proper protection only within two years after vaccination, while PCV13 exhibited a high level of protection during the entire follow-up. Furthermore, the risk of complications in patients vaccinated with PPV23 increased after 3 years after the vaccination compared to vaccine-naïve patients.
Vaccination effectiveness directly depends on various factors, such as the serotypic pattern, patients' age, and the health status at baseline. Many researchers have mentioned the positive effect of vaccination on the outcomes (13) and cost effectiveness of vaccination (14) for PPV23 and PCV13 (7). However, the follow-up period was limited (3 years after the vaccination) for most studies where the vaccines were compared directly. This fact does not allow one to take into account the effect of the decline in effectiveness of vaccination with PPV23 and PCV13 over time. Hence, the question regarding the long-term vaccination effectiveness still remains open. This question becomes especially relevant in the presence of risk factors, such as smoking, FEV1(15), cardiovascular pathology(16), and other factors(12, 17) worsening the prognosis for developing severe forms of pneumonia. In current study, all patients had high risk factors for developing severe pneumonia: age > 45 years; smoking; and dyspnea severity grade assessed using the MMRC scale ≥ 2. Nevertheless, pneumococcal vaccination was shown to effectively prevent pneumonia in these patients.
The previous studies assessing the effectiveness of PPV23 showed that the patients differed in terms of clinical effectiveness of vaccination depending on their age (4). The risk of vaccine failure increased significantly in patients older than 65 years. Our study has confirmed this observation and demonstrated that this effect is valid only for the polysaccharide vaccine. For PCV13, patient's age was not a significant factor affecting vaccine effectiveness. Our study found no evidence for the earlier demonstrated influence of FEV1 on vaccine effectiveness. This was probably because only 2.9% of patients in our sample had FEV < 40%, which was regarded as the threshold level for this parameter.
Although the primary objective of vaccination is to reduce the risk of pneumonia in patients with COPD, it also indirectly affects the patients' overall health status. The study (7)] demonstrated that vaccination with PCV13 reduced the risk of hospitalization (for any reasons) in stable patients having no exacerbations (non-exacerbators), but not in patients having COPD exacerbations within the previous year. In our study, we found that vaccination with PCV13 was associated with the significant overall decline in the exacerbation and hospitalization rates. Before enrollment, the rate of hospitalization because of COPD exacerbation was > 90%. Administration of any pneumococcal vaccine reduced the exacerbation rate over fourfold during the first year. Hence, pneumococcal vaccination has a positive effect on the course of COPD, which includes reduced exacerbation rate and improved overall quality of life. However, reduced hospitalization rates were stably observed only for PCV13, while the exacerbation rate and the rate of exacerbation-related hospitalizations increased abruptly as early as two years after vaccination with PPV23.
The observed decline in tolerance to pneumonia and the increasing percentage of patients with severe pneumonia in the PPV23 group after three-year follow-up is potentially related to hyporesponsiveness. Polysaccharide vaccines stimulate the short-lived B-cell response as they influence the terminal differentiation of the existing memory B-cells into plasma cells, thus depleting the memory B-cell pool (18). This process is not confined to hyporesponsiveness to subsequent vaccination but causes an overall decline in immune response. In combination with the elderly age and the numerous risk factors in COPD patients, this process increases pneumonia severity and the frequency of pneumonia episodes in patients 3–5 years after vaccination with PPV23 even compared to vaccine-naïve patients.
Our study has a number of limitations. First, it has a non-randomized design due to ethical considerations: only patients having additional administrative reasons and warned about the potential risks were enrolled to form vaccine-naïve groups. In order to minimize the risk of bias associated with the non-randomized study design, we employed the PSM methods to select matching patient groups. Second, the size of patient groups differed significantly. Third, the study involved PP analysis rather than ITT one. Nevertheless, this study was the first study to analyze long-term (5-year) clinical effectiveness of vaccination with PCV13 and PPV23 in patients with COPD. Further trials involving large cohorts and registries will make it possible to assess additional risks associated with the long-term effect of hyporesponsiveness in patients after vaccination with PPV23 and its potential effect on quality of life and the risks of unfavorable outcomes.