Clinical benefits using PCV13 in adults are controversial [8,9,10,11]. We undertook a large population-based cohort study to investigate the clinical effectiveness of PCV13 vaccination in preventing hospitalisations for pneumococcal and all-cause pneumonia among middle-aged and older adults in Catalonia. To our knowledge, apart from the CAPITA trial, [8] this is the first large prospective study evaluating this issue in practice.

As main findings, PCV13 vaccination did not emerge effective to prevent pneumonia and/or death in our study population. In the initial unadjusted analyses, crude incidence rates for all analysed outcomes were largely greater in PCV13 vaccinated than in PCV13 unvaccinated subjects, reflecting the baseline excess risk of vaccinated (who had higher prevalence of underlying risk conditions than unvaccinated subjects). After multivariable adjustments we found that PCV13 vaccination did not alter significantly the risk of hospitalisation for pneumococcal pneumonia and/or all-cause death, but it remained significantly associated with an increased risk of hospitalisation for all-cause pneumonia (mHR: 1.69; 95% CI: 1.48–1.94) considering the total study cohort. In stratified analyses focused on immunocompromised persons and elderly individuals, main target groups where PCV13 is currently recommended, [4, 5] the PCV13 did not emerge effective either. In fact, excluding middle-aged individuals, PCV13 vaccination appeared significantly associated with an increased risk of all-cause pneumonia in all analysed strata.

Although apparently opposite, our data does not fully disagree with data reported in the CAPITA trial (the unique RCT that has evaluated the clinical efficacy of the PCV13 in adults to date) [8]. Concretely, the CAPITA study (large RCT comparing PCV13 vs placebo among 84,496 individuals ≥65 years in the Netherlands) reported a significant PCV13 efficacy of 45.6% (95% CI: 21.8% to 62.5%) against vaccine-type pneumococcal pneumonia but did not show any significant efficacy of PCV13 against all-cause pneumonia, death from pneumonia and all-cause death [8]. The reported PCV13 efficacy against all-type pneumococcal pneumonia was 30.6% (95% CI: 9.8% to 46.7%) in the CAPITA trial, [8] which overlaps with data observed in the present study (mHR: 1.17; 95% CI: 0.75–1.83). On other hand, considering all-cause pneumonia, we note that a null or negative effect of PCV13 against all-cause community-acquired pneumonia was not fully excluded among the general elderly population in the CAPITA study (PCV13 efficacy: − 5%to 14%) [8].

We highlight that comparison is difficult due to important methodological and epidemiological differences between both studies. Indeed, while no routine antipneumococcal vaccination for adults and/or children had been introduced in the Netherlands when the CAPITA trial started, [20] the PPsV23 for adults and the PCV7/PCV13 for children had been used in Catalonia since the 2000s [12, 13]. Thus, the PCV13 efficacy estimates in a population with an expected greater prevalence of circulating PCV13 serotypes can not be fully compared with the PCV13 effectiveness in a population with a minor prevalence of circulating PCV13-serotypes (if a herd effect from PCV’s childhood immunisation may be expected) [21].

At present, because the risk of immunization is believed to be very small, many experts and clinicians recommend pneumococcal vaccination for all persons with an increased risk of infection or death (i.e, high-risk adults and elderly persons) [4, 5, 22, 23]. However, we note that having an increased risk of suffering a pneumococcal infection (e.g. immunocompromising or other risk conditions) does not necessarily imply that vaccination of these persons will be an effective measure in the practice [24,25,26]. According to our results, the possibility of a harm effect of PCV13 vaccination (increasing the risk of all-cause pneumonia) may not be completely excluded. Hypothetically, since PCV13 vaccination may reduce pneumococcal carriage/colonization and this could alter the nasopharyngeal/respiratory tract flora, an increase in infections by other microorganisms (especially in high-risk or elderly individuals) could be a possible explanation for this unexpected finding.

The authors underline the importance of RCT data, and note the limited amount of such data regarding clinical efficacy of PCV13 in adults. Clinical outcomes of patients are affected by many factors, being antibody production and associated phagocyte stimulation only one aspect, which incompletely represent the immune response overall (especially aging immune response) and may not adequately reflect the potential impact of the vaccine on clinical outcomes [2, 3, 27].

Major strengths in this study were the large size and representativity of the study cohort (involving more than 2 million people, almost 80% of overall population over 50 years in Catalonia), and the use of survival analysis methods to estimate PCV13 effectiveness against public healt relevant outcomes such as hospitalisation from pneumococcal or all-cause pneumonia and all-cause death. Although it is not a RCT, the large size of the study population together with the adjustment of major possible confounding variables (e.g, history of previous pneumococcal disease or pneumonia, comorbidities and underlying risk conditions, PPsV23 and influenza vaccination status) in the multivariable analyses may provide an acceptable basis to assess the potential effects of PCV13 vaccination in adults at present.

Major limitations in this study are related with its observational nature: mainly, the non-randomised vaccination and the scarce PCV13 coverage in the study population (which limits statistical power to evaluate vaccination effectiveness against uncommon events, especially in subgroups analyses). The authors recognize these inherent limitations but note that, opposite to “vaccine efficacy” that must be evaluated by trials with controlled conditions, “vaccination effectiveness” may be evaluated by observational studies conducted in the real-practice conditions (i.e., study populations where the vaccine is not routinely used or it is more frequently prescribed for persons with underlying risk conditions as in the present study).

In this study, the large differences in outcomes between PCV13 vaccinated and unvaccinated suggest that vaccinated persons were sicker. The large differences observed in crude incidence rates between vaccinated and unvaccinated mostly resolved in the multivariable analysis, although a residual confounding due to unobserved factors (as all observational studies) may not be completely excluded [19]. In favour of a non important residual confounding in the final PCV13 effectiveness estimates, we note that the adjusted risk of all-cause death did not significantly differ between vaccinated and unvaccinated (mHR: 1.07; 95% CI: 0.97–1.18; p = 0.190), despite crude mortality had been more than double in vaccinated (5944 per 100,000) than in unvaccinated (2354 per 100,000).

Our study is not able to assess the possible overall effect of PCV13 against all pneumonia (including outpatient cases) because only hospitalisations from pneumonia were included. We note that pneumonia cases managed outside the hospital could represent approximately a 25% of overall pneumonia cases in older adults and this was not evaluated in the present study.

In the present study, comorbidities/underlying risk conditions for pneumococcal disease were considered only at baseline. Incident comorbidities occurred after study start were not assessed, which could affect vaccination effectiveness estimates for the subgroup of patients who developed later any of these comorbidities/risk conditions considered as an indication for PCV13 vaccination. Basically, this could affect to immunocompromising conditions (although their expected incidence would be small). We note that the majority of comorbidities/risk conditions related to PCV13 indication are prevalent conditions (mainly chronic illnesses), which were established at baseline and little incidence of new cases would be expected throughout one-year period after study start.

On other hand, although the validity of clinical data source was previously checked, [16] information bias may have occurred if some vaccinations and/or comorbidities/underlying conditions were not recorded. We do not have available data for pneumococcal serotypes (which is not reflected in the Spanish CMBD system) and, consequently, vaccination effectiveness against vaccine-type pneumococcal infections (the most specific outcome evaluating vaccine efficacy) can not be assessed in the present study. We note, however, that the expected incidence of this outcome is low (10.2 cases per 100,000 elderly population-year according to laboratory-based epidemiological data in Catalonia during 2014) [28] and underline the fact that our study provides other very important data from a clinical and public health point of view (such as hospitalisation for pneumococcal and all-cause pneumonia, death from pneumonia and death from any cause).