Antoni Torres, Respiratory Intensive Care Unit, Department of Pneumology and Respiratory Allergy, Hospital Clinic of Barcelona, University of Barcelona, Spain, opened the symposium, noting that pneumococcal conjugate vaccines (PCV) have reduced pneumococcal disease through direct and indirect effects. However, the burden of pneumococcal disease remains substantial in adults, supporting the importance of further reducing vaccine-preventable disease and its impact on healthcare resource utilisation and public health. Mário Ramirez, Faculty of Medicine, University of Lisbon, Portugal, and Molecular Microbiology and Infection Laboratory, Institute of Molecular Medicine, University of Lisbon, Portugal, reviewed the changing serotype epidemiology of pneumococcal disease in Europe, and described important differences between pneumococcal polysaccharide vaccines and PCVs. He detailed the dramatic direct impact of PCVs in children in decreasing the burden of vaccine-type (VT) pneumococcal disease, as well as indirect effects in unvaccinated populations, particularly adults. Residual VT-disease and increases in non-PCV13 disease underscore the need for additional disease coverage that may be afforded by higher-valent PCVs. Charles Feldman, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa, reviewed the considerable worldwide burden of lower respiratory tract infections (LRTI), including pneumococcal pneumonia. He noted that indirect effects in adults may be suboptimal, and herd effects may have reached their limit.
Feldman described adult populations that should be prioritised for pneumococcal vaccination based on risk factors, and stressed the importance of a comprehensive approach to increase adult vaccination. Finally, Wendy Watson, Vaccines Clinical Research, Pfizer, Collegeville, USA, described the adult PCV20 clinical development programme, emphasising that it was built on the well-established PCV13 platform. In the Phase III clinical trial programme, PCV20 was well tolerated, with a safety profile similar to PCV13, regardless of prior pneumococcal vaccination history. Importantly, it was immunogenic across all ages studied and in those with chronic medical conditions. Wendy Watson concluded that PCV20 has the potential to simplify adult vaccination and help reduce the burden of adult pneumococcal disease.
Changing Serotype Epidemiology of Pneumococcal Disease in Europe
Ramirez noted that more than 100 pneumococcal serotypes have now been identified, which is most likely the result of increased serotyping rates and greater interest in serotypes rather than the result of vaccine-associated selection pressure.1,2 Knowledge of serotype epidemiology remains essential, both to monitor effects of vaccination on pneumococcal disease, including serotype elimination and replacement, and to assess potential unmet vaccination needs.
Ramirez emphasised the importance of capsular serotypes as a determinant of virulence.3 Notably, “all serotypes are not equal.” They are associated with different types and severity of disease, with varying degrees of morbidity and mortality, and with differing age groups and patient characteristics.4
Ramirez noted that although all pneumococcal vaccines target specific serotypes, key differences characterise pneumococcal polysaccharide vaccines (e.g., 23-valent pneumococcal polysaccharide vaccine [PPV23]) and PCVs. PCVs induce a more robust and longer-lasting immune response that includes recruitment of T helper cells and formation of memory B cells.5,6 In contrast, PPV23 induces a shorter-lived T cell–independent response that lacks immune memory.5,6 Importantly, from a public health perspective, PCVs, unlike the polysaccharide vaccine, can interfere with asymptomatic carriage, which can lead to reduced transmission of vaccine serotypes in the community.7
Pneumococcal Disease Remains an Ongoing Burden: Epidemiology
Ramirez noted that PCVs are highly effective, resulting in dramatic reductions in the burden of VT invasive pneumococcal disease (IPD) in children directly targeted for vaccination.8,9 He pointed out that after the introduction of PCV7 and PCV13 in children, reductions in the incidence of IPD were also seen in adults.9
Ramirez went on to detail three components of the remaining burden of pneumococcal disease in Europe, which supports the need for expanded-valent vaccines (Box 1).
A closer look at serotypes responsible for IPD after PCV introduction shows that PCV7 serotypes have been almost eliminated or occur at very low levels in countries with mature vaccination programmes (e.g., France, England and Wales, Germany, and Spain), although there are important differences among countries.9,10-12 For example, in Germany, the proportion of IPD cases due to PCV7 serotypes is approximately 3% in young children versus nearly 6% in France for the same age group.10,12 Ramirez described Portugal as an outlier, with PCV7 serotypes accounting for approximately 13% of all IPD in those aged ≤17 years; much of this appears to be associated with antibiotic resistance.13,14
The additional serotypes contained in PCV13 remain an important cause of IPD in Europe. Again, significant differences among countries have been reported. In France, additional PCV13 serotypes accounted for approximately 9% of IPD in young children compared with approximately 10–16% in Germany.10,12 In Portugal, although the number of adult PCV13 cases is similar to other European countries, more than 30% of cases of paediatric IPD are due to the additional PCV13 serotypes.13,14 Overall, serotypes 3 and 19A account for a substantial portion of the remaining PCV13 disease.9,11,12
Ramirez noted that in the period preceding PCV10/13, the overall incidence of IPD in older adults declined in some countries while remaining stable in others.15 Overall declines in adult IPD through 2014 were followed by rebounds through 2018, which appear to be largely due to non-VT serotypes, with similarities and differences associated with the use of PCV13 versus PCV10.15 Ramirez stressed that “the benefits of group protection that were seen in adults by children vaccination are being compromised by an increase in non-PCV13 disease in adults.”
Ramirez then focused on non-PCV13 serotypes causing IPD in paediatric and adult populations in Europe. He stated that although causative serotypes overlap between adults and children, the paediatric population displays greater serotype diversity than adults across countries. He detailed the most common serotypes associated with IPD in Europe, which mainly reflect the larger adult population. Notably, serotypes 8 and 3 have been increasing (2014–2018).16 Next, he posed the question of what gains in protection might be expected from the higher-valent PCV15 and PCV20 vaccines now entering the market. By way of illustration, Ramirez showed the potential additional protection that might be anticipated when going to higher-valent PCVs.10,13 For example, in adults in Portugal, going from PCV13 to PCV15 could provide additional coverage of approximately 8%, while PCV20 could provide additional coverage beyond PCV15 of 28%.13
Moving from IPD to community-acquired pneumonia (CAP), Ramirez noted that although CAP is the most common manifestation of pneumococcal disease in adults, 50% or more of its aetiology remains unknown despite advances in diagnostic methods.17 Nevertheless, pneumococci remain the primary bacterial agent identified in CAP in developed countries, accounting for 33–50% of cases in which the aetiology was established.17
Comparisons of Serotypes in Non-invasive Pneumococcal Pneumonia and Invasive Pneumococcal Disease
In adults, serotype distribution in non-invasive pneumococcal pneumonia (NIPP) and IPD (including bacteraemic CAP) can differ.18 Data from Portugal showed that PCV13 serotypes declined moderately for NIPP in adults.18 A systematic review and meta-analysis as well as country-specific studies show that non-invasive VT-CAP remains a considerable burden in adults, despite childhood immunisation programmes. Substantial proportions are due to PCV13 serotypes as well, depending on the geographic location.7,19,20 Because serotype distribution for NIPP and IPD differ, serotype surveillance for IPD cannot be used to fully estimate the burden of NIPP.
Summary and Conclusions
Ramirez concluded by stating that although paediatric PCV use has been effective in decreasing VT-IPD in children and adults, a significant burden of VT and non-VT disease remains. Importantly, the benefits of PCV13 vaccination in children may be eroding due to increases in non–PCV13-type disease. In adults, NIPP serotype epidemiology may differ from that of bacteraemic CAP. Furthermore, there is a decrease in some but not all PCV13 serotypes. Consequently, specific surveillance for NIPP is necessary to understand the burden of disease in adults. Taken together, these observations on the epidemiology of pneumococcal serotypes reinforce the need for expanded-valent vaccines and direct adult vaccination to address the still significant burden of pneumococcal disease.
What Can We Learn from the Pneumococcal Conjugate Vaccine Experience to Date?
Feldman detailed the substantial burden of LRTIs on healthcare systems worldwide, with pneumonia remaining one of the leading causes of hospitalisation, resource utilisation, and death.21,22 With hospitalisations for pneumonia increasing, coupled with declines in available beds, the ability of healthcare systems to deal with resource demand is limited.23-25 Moreover, the COVID-19 pandemic has turned a spotlight on and exacerbated limitations of healthcare systems globally,2526 and it has had a negative impact on routine vaccination with attendant public health consequences.27,28
Global Epidemiology of Lower Respiratory Tract Infections
Pneumococcal infections continue to be associated with significant morbidity and mortality, with Streptococcus pneumoniae contributing to more deaths globally than all other pathogens in the study combined. Despite reductions in LRTI rates, the burden of disease remains substantial, particularly in older individuals and in some geographic locations, underscoring the need to further reduce vaccine-preventable disease.21
Overall Impact of Pneumococcal Conjugate Vaccines in Europe
Feldman went on to describe milestones in the development of pneumococcal vaccines, including recent approvals of the higher-valent PCV15 and PCV20 vaccines.29,30 He then reviewed data on the effectiveness of PCVs over time against IPD and non-bacteraemic pneumonia in various age groups and settings, including substantial reductions in paediatric IPD after the introduction of PCV7 and PCV13.9,31 Feldman also noted that the reductions in IPD were apparent via direct effects in children and indirect effects (i.e., herd protection) in adults ≥50 years of age.31 He attributed this to the ability of conjugate vaccines to reduce nasopharyngeal colonisation and subsequent transmission, as also mentioned by Ramirez.7,33 Indirect effects of infant PCV13 vaccination have also been seen through declines in pneumococcal CAP in hospitalised adults, particularly non-bacteraemic pneumonia.32 Across 13 sites in 10 European countries, IPD incidence rates in older individuals varied but generally declined after the introduction of PCV10 and PCV13.15 Feldman stated that several factors may influence variability across countries, including population characteristics, underlying risk factors, and the specific conjugate vaccine given to children. Regardless of the country, however, residual disease remained.
Does PCV13 Provide Protection Against Invasive Pneumococcal Disease and Bacteraemic and Non-bacteraemic Community-acquired Pneumonia in Older Adults: The CAPiTA Study
The CAPiTA study demonstrated that PCV13 provided significant protection in adults aged ≥65 years against VT-IPD and VT-CAP as well as non-bacteraemic VT-CAP.34 Reductions in VT-CAP and VT-IPD were seen across age groups, including those aged 75–84 years.35 Real-world data also demonstrated substantial reductions in PCV13 VT-CAP (both bacteraemic and non-bacteraemic) in older adults, including those with immunocompromising conditions.36
Susceptibility to Streptococcus pneumoniae Is Influenced by the Host and Environmental Factors
Feldman highlighted the array of risk factors that influence susceptibility to S. pneumoniae, including age, chronic medical conditions in immunocompetent individuals, immunocompromising conditions, environmental factors, and behavioural factors.37-40 He shared data that show the increased incidence of pneumococcal pneumonia hospitalisations associated with chronic medical and immunocompromising conditions, such as chronic lung disease, HIV infection, severe renal disease, and immunosuppressive therapy.41 Notably, the risk of pneumonia in adults, regardless of age group, increases as the number of comorbidities increase.42 In fact, the risk of CAP in adults in the presence of multiple underlying medical conditions, sometimes called ‘risk stacking’, is often as high as that in immunocompromised individuals.42,43
Current Considerations for Adult Vaccine Programmes
Feldman pointed out that the COVID-19 pandemic and associated lockdowns have reduced routine vaccination rates, including PCV13 priming and booster doses in paediatric populations.27,28 This is likely to cause decrements in herd protection. He emphasised the importance of the various factors to be considered in developing and establishing effective vaccine programmes and guidelines for adults, such as regional differences in population characteristics and residual burden of pneumococcal disease; the occurrence of serotype replacement disease; potential underestimation of disease burden by conventional microbiological methods; and limits of herd protection levels.44-46 He cited data suggesting that herd protection may have reached its limits in some countries.19,44,47,48
After describing serotypes covered in the new, higher-valent PCVs, Feldman summarised updated adult pneumococcal vaccine recommendations from the Centers for Disease Control and Prevention (CDC) as well as recommendations from Europe, pointing out the considerable variability across countries.49,50 The key CDC recommendations for adults ≥19 years who are PCV-naïve or whose history is unknown are in Box 2.49
In discussing vaccine coverage rates, Feldman stressed that the concentration on childhood vaccination has resulted in variable suboptimal vaccination coverage in adults, which may be exacerbated by inadequate physician knowledge about adult pneumococcal vaccination.51 Feldman emphasised that to be successful, a vaccination programme must involve multiple stakeholders, including the government, the public, healthcare professionals, and the media, which can help reinforce accurate and appropriate recommendations.52
Feldman specified key takeaways for healthcare professionals to promote appropriate vaccination for adults, including ensuring routine assessment, making appropriate vaccine recommendations, and documenting each patient’s vaccinations.
In conclusion, Feldman reiterated that the global burden of LRTI remains high, with pneumococcal disease a significant cause of morbidity and mortality, particularly in some locations and among those with risk factors. Despite the reduction of disease associated with PCV13 in both children and adults, PCV vaccination of adults, including the use of higher-valent PCVs, such as PCV20, can further reduce the disease burden.
Addressing a New Era to Help Protect Against Pneumococcal Disease in Adults
Watson introduced PCV20, explaining that it was built on the Pfizer PCV13 platform and contains seven additional serotypes to broaden serotype coverage. It is approved in Europe for the prevention of IPD and pneumonia caused by the PCV20 serotypes in adults ≥18 years of age.29 Watson went on to describe the clinical development programme for PCV20 and key Phase III study results.
Overview of the PCV20 Phase III Clinical Development Programme
The Phase III clinical development programme included three studies that evaluated safety and immunogenicity. The studies comprised more than 4,000 adults who were immunocompetent and were either healthy or had stable underlying chronic medical conditions, as well as individuals with prior pneumococcal vaccination.29 Watson noted that because PCV20 is based on the legacy of PCV13, studies were not conducted in individuals with immunocompromising conditions; specifically, the immunogenicity and safety of PCV13 has been formally studied in those with HIV infection and stem cell
Watson explained that immunologic comparisons were the basis for inferring efficacy, as agreed to with both the U.S. Food and Drug Administration (FDA) and the regulatory authority in Europe, in the PCV20 Phase III programme.29 Primary immunologic comparisons were based on serotype-specific opsonophagocytic activity (OPA) geometric mean titres (GMT), and were measured 1-month post-vaccination.29 She emphasised, however, that no specific OPA level or minimal response that predicts clinical protection against pneumococcal disease have been established for adults, and that potential vaccine benefits involve more than just antibody levels. Consistent with the PCV13 licensure programme in adults, comparisons involved statistical non-inferiority analyses for each of the 20 serotypes in PCV20 compared with the corresponding control. It is important to understand, however, that missing non-inferiority for a given serotype does not translate directly into lower disease protection. As discussed with regulatory agencies, the totality of data from immunogenicity analyses for that serotype could still be used to provide evidence of protection.
Phase III Programme: Pivotal Study
Watson reviewed the pivotal Phase III study, which enrolled nearly 4,000 adults into three age groups (≥60, 50–59, and 18–49 years), approximately 3,000 of whom were ≥60 years of age. The study randomised participants ≥60 years of age to either PCV20/saline or PCV13/PPV23. At 1-month post-vaccination, those who received PCV20 received saline whereas those randomised to PCV13 received PPV23. Immunogenicity of PCV20 was compared with PCV13 for the shared 13 serotypes and with PPV23 for the seven additional serotypes. The two younger cohorts, adults aged 50–59 years and 18–49 years, were randomised to PCV20 or PCV13.53 As Watson explained, an age-bridging strategy was conducted, comparing the immunogenicity of PCV20 in participants 60–64 years of age to that in the two younger cohorts, a strategy also used in the PCV13 development programme.53 Safety analyses included local and systemic reactions as well as adverse events (AE), including serious AEs and newly diagnosed chronic medical conditions.53
Demographic characteristics were similar across the vaccine groups included in the study. Risk factors, including age and underlying conditions, were well represented.15 The safety profile of PCV20 was similar to that of PCV13; most reported events were local reactions across all age groups.53 Any systemic events, such as fatigue, headache, muscle pain, and joint pain were mild or moderate; no serious vaccine-related AEs were reported.29,53
PCV20 induced robust immune responses to all 20 serotypes in adults ≥60 years of age and was non-inferior to PCV13 for all 13 matched serotypes;53 slight decrements in OPA GMTs for PCV20 compared with PCV13 “were not considered clinically meaningful.” In comparison with PPV23 for the seven shared serotypes, non-inferiority of PCV20 was narrowly missed for serotype 8 (lower 95% confidence interval: 0.49), but other data showed evidence of a clear response to serotype 8 after PCV20. For example, from baseline to 1 month after PCV20 vaccination, 78% of participants had at least a four-fold rise in OPA titres, which was well within the range (54–84%) observed for the 13 shared serotypes after PCV13.53 Watson stated that “overall the data supports the potential for PCV20 to elicit protective responses across all vaccine serotypes.”
PCV20 immune responses in adults aged 50–59 years or 18–49 years met non-inferiority criteria for immune responses in adults aged 60–64 years.53 Immunogenicity in the younger age groups was similar to or higher than in the 60–64-year-old cohort, establishing a bridge to support use in adults ≥18 years of age.53 Finally, in the pivotal study, a post hoc analysis demonstrated that the pattern of immune responses and OPA GMTs to PCV20 in adults aged 18–64 years with chronic medical conditions were robust, supporting its use in adults aged <65 years at increased risk of pneumococcal disease.54
Additional Clinical Programme Data: Older Adults with Prior Pneumococcal Vaccination
Watson described an open-label descriptive study conducted in adults ≥65 years of age who had previously received PPV23, PCV13, or PCV13/PPV23.55 For each of these cohorts, PCV20 elicited responses to all 20 vaccine serotypes.55 Regardless of prior pneumococcal vaccination history, safety and tolerability of PCV20 were similar in each group.55
Summary and Conclusion
In the PCV20 Phase III clinical trial programme, built on the foundation of the PCV13 programme, PCV20 was demonstrated to be well tolerated, with a safety profile similar to PCV13, regardless of prior pneumococcal vaccination. It was also immunogenic across all ages and in those with chronic medical conditions. PCV20, therefore, offers a potentially simplified and impactful approach to the prevention of pneumococcal disease in adults.
Prescribing information for Pfizer products mentioned in this article: APEXXNAR▼(pneumococcal polysaccharide conjugate vaccine (20-valent, adsorbed)) can be found here, Prevenar 13 (pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed)) can be found here.