A narrative review on the effectiveness of PPSV23 vaccination in adults in China

ABSTRACT

Pneumococcal Polysaccharide Vaccine (PPSV23) is available for free in some Chinese cities for elderly patients and those with comorbidities. However, there is a lack of studies summarizing its preventive effect specifically in Chinese adults. This review aims to discuss the epidemiology of pneumococcal disease, coverage and effectiveness of PPSV23 vaccination, elderly individuals and patients with comorbidities, coadministration of PPSV23 vaccine with other vaccines, and future directions for its use in China. It was found that the PPSV23 vaccination rate among the elderly ranged from 1.2% to 42.1% depending on location, with an effectiveness of 9.34%(95%CI: 2.05%, 16.62%) to 57.7%(95%CI: 20.7%, 77.5%). There is a need to raise awareness of pneumococcal disease and its prevention, especially in China. To better manage pneumococcal disease in China, developing new vaccines for common serotypes and continuously monitoring serotype distribution associated with the disease is also needed.

Introduction

Pneumococcal infections are caused by Streptococcus pneumoniae (pneumococcus), a common opportunistic pathogen. Occasionally, it can invade the lower respiratory tract or the bloodstream and can lead to various diseases such as meningitis, bacteremia, and pneumonia. Invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) are caused by S. pneumoniae, resulting in significant morbidity and mortality.¹ Pneumococcal invasive (such as bacteremia/sepsis and meningitis) and noninvasive infections involving non-bacteremic pneumococcal pneumonia (NBPP) commonly affect elderly patients. Having said that, the total number of cases is also higher among older adults and children, hence remain a major public health issue with high morbidity and mortality.^2,3

As per WHO, pneumococcal diseases were one of the deadliest diseases with mortality killing 2.6 million people globally and more than 3,00,000 children age <5 years every year.^4,5 In China, pneumonia is the fourth leading cause of death, accounting for 125,000 deaths in the elderly population and 30,000 deaths in children aged <5 years every year with infection rates varying from 28.0% to 71.5%.^6–8

Vaccination is critical for the reduction of mortality and morbidity related to pneumococcal pneumonia. There is even more urgency to manage pneumococcal diseases through vaccination due to the increasing antibiotic resistance of S pneumoniae.⁹ Previous studies have shown that reduced consumption of antibiotics resulted in a significant decrease in macrolide resistance, and the introduction of pneumococcal vaccination decreased the development of antimicrobial resistance. Increasing the coverage of pneumococcal vaccination could even lead to major annual cost savings due to averted antimicrobial resistance, hence its increased uptake has been highly favored.¹⁰

At present, 2 different pneumococcal vaccines are approved for use in the elderly population: a pneumococcal polysaccharide vaccine (PPV) and a pneumococcal conjugate vaccine (PCV). The only available formulation containing 23 different capsular polysaccharides (serotypes) of S pneumoniae (23-valent pneumococcal polysaccharide vaccine [PPSV23]; Pneumovax or Pnu-Immune) is licensed for its use in adult patients and has been widely used for the immunity against the most common cause of pneumococcal disease since 1980s.¹¹ Polysaccharide vaccines primarily induce a B-cell-dependent immune response via the release of immunoglobulins. However, these polysaccharide vaccines are not recommended for use in children aged <2 years, probably due to their immature immune system. However, non-responders to immunization are especially frequent in older patients.¹¹ Vaccination for adults with polysaccharide vaccines requires revaccination after 5 to 6 years.

The 7-valent pneumococcal conjugate vaccine (PCV7) employs an inactivated diphtheria CRM197 toxoid as the carrier protein for all 7 serotypes was initially used, whichhelps improve its immunogenicity. The currently available PCV formulations include the 10-valent pneumococcal conjugate vaccine (PCV10), the 13-valent pneumococcal conjugate vaccine (PCV13), the 15-valent pneumococcal conjugate vaccine (PCV15), the 20-valent pneumococcal conjugate vaccine (PCV20), and the 21-valent pneumococcal conjugate vaccine (PCV21), with the numbers indicating the number of pneumococcal capsule types included in the vaccine.^12,13 PCVs have shown effectiveness in imparting anti-IPD immunity, specifically in young children. Capsular polysaccharides of PCV-7 are conjugated to cross-reactive material 197 (CRM197), one of the highly immunogenic diphtheria toxoid proteins. After their binding and internalization via polysaccharide-specific IgM antibodies, CRM197-specific type 2 helper (Th2) T cells interact with B cells and subsequently present the processed CRM197 protein, along with MHC II to effector T cells. This type of adaptive immune response is characterized by antibody isotype switching and the generation of memory B cells. Compared to PCVs, PPSV23 is primarily designed for use in older children and adults who are at risk for pneumococcal disease. It is not licensed for use in children aged <2 years.¹¹ PCV13 is primarily recommended to children, initiating with a series of doses at 2, 4, and 6 months, followed by a booster at 12–15 months.¹⁴ Conversely, PPSV23 is recommended for adults, especially those aged >65 and also for patients aged ≥ 2 years with certain high-risk conditions.^15,16 Adult patients receive a single dose, with a second dose after five years for those at highest risk. These immunization programs are crucial in managing and preventing pneumococcal diseases, reflecting an important public health strategy in China.

According to the WHO, the incorporation of pneumococcal-combined vaccine into National Immunization Programs (NIPs) is advisable for all countries with enhanced mortality and morbidity due to pneumococcal diseases. According to the Chinese Preventive Medicine Association (CPMA), the expert consensus on immunoprophylaxis of pneumococcal disease also recommended that priority populations such as infants, children, and the elderly receive pneumococcal vaccination.^14,17 As of 2019, there are 149 countries that have integrated pneumococcal-combined vaccine into their NIP.¹⁸ According to the updated guideline from the CPMA in 2012, PPSV23 has received its regulatory approval and recommendation for elderly individuals and patients with chronic disease in China, when there was no routine PPSV23 vaccination regimen since it is not part of the NIP for adults.¹⁹ At present, older adults have been recommended to first receive 1 dose of PCV13, followed by 1 dose of PPSV23 after 6 months. However, this complicated recommendation has been adopted only by very few developed countries. Earlier, the PPSV23 vaccine was not provided for free in China; individuals had to personally cover the costs of pneumococcal vaccination.²⁰ In 2013, Shanghai became the first city in China to offer free PPSV23 for individuals aged 60 and older. Currently, more than 14 cities in China provide this free vaccination for the same age group. In 2019, among the overall pneumococcal doses released, approximately 16% were provided for free.⁶ Experts within China have also recommended PPSV23 vaccination for routine use in elderly patients and those with comorbidities under special conditions.²¹

Although protective efficacy of PPVs against IPDs has been reported in several previous studies, their effectiveness in preventing pneumonias, and other pneumococcal infections is still not established.^22,23 According to the WHO position paper, previous clinical trials reported the protective effect of PPSV23 vaccination against IPD and all-cause pneumonia among generally young adults and, to a lesser extent, protection against IPD in the general population of elderly people. However, these studies have not demonstrated promising efficacy of PPSV23 against either IPD or all-cause pneumonia in high-risk populations such as adults and children with comorbidities, thereby increasing their risk of pneumococcal disease.²⁴ Moreover, no studies have summarized the preventive effect of the PPSV23 vaccine, specifically in Chinese adults. Thus, a more comprehensive summary on the effectiveness of PPSV23 in Chinese adults is necessary. This review aims to discuss the effectiveness of PPSV23 against pneumococcal diseases. This review summarizes the epidemiology of pneumococcal disease, PPSV23 vaccination coverage, effectiveness of PPSV23 vaccination, elderly individuals and patients with comorbidities, coadministration of PPSV23 vaccine with other vaccines, and future directions for its use in China.

Methods

This review was conducted based on data from articles published from 1981 to 2024 using PubMed and Scopus databases. The following keywords were used for the search- “pneumococcal polysaccharide vaccine,” OR “PPSV23” AND “Chinese adults” AND “serotypes.” Original articles and abstracts including randomized controlled trials, and critical reviews including systematic review and meta-analysis were selected and examined. Trials outside the scope of this review were not considered. References of the retrieved articles were also screened to search for potentially relevant papers (Figure 1)

Figure 1.

Search methodology.

Epidemiology of pneumococcal disease

Pneumococcal diseases are more prevalent in extremes of age i.e., ≤5-years and older adults (≥60 years). As aging progresses, complex changes in the immune system are observed in older adults (immunosenescence), making them more vulnerable to pneumococcal and other infectious diseases.²⁵ Compared to young adults, the aged adult population have one or more chronic comorbidities that make the disease more severe. Other risk factors for pneumococcal diseases include smoking, alcohol addiction, air-pollutants, living in crowed places etc.²⁵

S pneumoniae is a highly invasive, gram-positive, extracellular bacterial pathogen. It consists of a surface polysaccharide capsule that inhibits ingestion and killing by leukocytes, which acts as the main virulence factor.²⁶ Each capsular polysaccharide is antigenically unique and represents a different serotype. So far, >100 known serotypes have been described.²⁵ A comparative analysis of the invasive disease isolates and carriage isolates has shown differences in virulence, depending on the capsular serotype of the pathogen as well as age and geographical regions of the patients.²⁷ There are significant differences in these serotypes based on country of origin and patient population.²⁸ Serotypes 1, 3, 7 F, 14, and 19A are the most frequent in European patients;²⁹ serotypes 19 F, 23 F, 19A, 6B, 14, 6A, and 15B occur the most in Chinese patients.³⁰

Serologic immunity against S pneumoniae significantly influences the incidence of IPD and pneumococcal pneumonia. This immunity can be acquired through infection or vaccination and is serotype specific. Pneumococcal vaccines are active vaccines composed of the pneumococcal capsular polysaccharide, thereby preventing pneumococcal diseases.²⁶ By preventing severe disease, pneumococcal vaccination also imparts cardioprotective effects, and these effects reduce the risk of myocardial infarction and mortality.³¹

S. pneumoniae can cause human-to-human transmission via intimate contact or aerosol exposure. Infection by S. pneumoniae can lead to asymptomatic nasopharyngeal carriage, localized respiratory disease (sinusitis, pneumonia, and otitis media), or severe systemic disease. Pneumococcal disease remains as one of the major causes of severe disease in both children and adults, especially in case of IPD, and is associated with bacteremic pneumonia, meningitis, endocarditis, arthritis, or severe non-bacteremic pneumonia. Such severe pneumococcal infections cause substantial morbidity and mortality, with mortality from pneumococcal pneumonia ranging from 5% to 7%.^31,32 In addition, S pneumoniae is the leading cause of bacterial pneumonia globally and is the fourth largest cause for pneumonia-related deaths in China.³²

According to the disease-burden data and epidemiologic studies, pneumococcal disease has been majorly reported in children, as compared with the limited data available in adults, particularly in Asia. Importantly, Asia is the fastest growing population in the world, and identifying key strategies for combating pneumococcal disease has the greatest potential public health impact worldwide. There is little information about the burden of pneumococcus in China although studies conducted in neighboring countries have found larger proportions (eg, 9.1%-65.0% in studies conducted in Japan and 13.5%-60.8% in South Korea).³³ Previous research has suggested that the burden of pneumonia in adults is most likely significantly underestimated. With the increasing burden of aging population in China, the burden caused by pneumococcal pneumonia exacerbated and particularly reinforced by the influence of risk factors such as chronic comorbid conditions.³⁴ Although the incidence of pneumonia has been recognized globally to be an important health concern, the actual disease burden in Chinese population is neither studied nor necessarily reported properly.³⁵ One of the important reasons behind this is the lack of ongoing and systematic surveillance in China, thereby complicating the assessment of pneumonia incidence and mortality.³⁶

Development of pneumococcal vaccines

Vaccination against S pneumoniae induces antibodies targeting capsular polysaccharides as antigens, and pneumococcal vaccines use capsular polysaccharides from pneumococcal serotypes that are commonly responsible for invasive disease. Serum opsonophagocytic activity titers in response to pneumococcal vaccine in adults denote the protection imparted by these vaccines against IPD.³⁷ PPVs and PCVs are 2 types of pneumococcal vaccine available for clinical use. Serotypes and their indications of PPV and PCV are summarized in Table 1. PPVs consist of partially purified pneumococcal capsular polysaccharides, whereas PCVs are inactivated vaccines that consist of type-specific pneumococcal capsular polysaccharides conjugated to a carrier protein or proteins. Pediatric PCVs provide indirect protection by reducing the carriage of vaccine-type pneumococcal serotypes in children, which decreases the transmission of these serotypes to unvaccinated individuals, including other children and adults.^46,47 This phenomenon, known as herd immunity, helps protect the broader community from pneumococcal diseases.^48,49

Table 1.

Details of pneumococcal vaccines, stereotypes, and their indications for active immunization for the prevention of pneumonia caused by S. pneumonia serotypes.

	PPSV2315,38	PCV1339,40	PCV1541,42	PCV2041,43	PCV2141,44	PCV2445
Serotypes	23 (1, 2, 3, 4, 5, 6B, 7 F, 8, 9 N, 9 V, 10A, 11A, 12 F, 14, 15B, 17 F, 18C, 19 F, 19A, 20, 22 F, 23 F, and 33 F)	13 (1, 3, 4, 5, 6A, 6B, 7 F, 9 V, 14, 18C, 19A, 19 F, and 23 F)	15 (1, 3, 4, 5, 6A, 6B, 7 F, 9 V, 14, 18C, 19A, 19 F, 22 F, 23 F, and 33 F)	20 (1, 3, 4, 5, 6A, 6B, 7 F, 8, 9 V, 10A, 11A, 12 F, 14, 15B, 18C, 19A, 19 F, 22 F, 23 F, and 33 F)	21 (3, 6A, 7 F, 8, 9 N, 10A, 11A, 12 F, 15A, 15C, 16 F, 17 F, 19A, 20A, 22 F, 23A, 23B, 24 F, 31, 33 F, and 35B)	24 (1, 2, 3, 4, 5, 6A, 6B, 7 F, 8, 9 N, 9 V, 10A, 11A, 12 F, 14, 15B, 17 F, 18C, 19A, 19 F, 20, 22 F, 23 F, and 33 F)
Launch date in the Chinese Mainland	1996	2016	NA	NA	NA	NA
Indications (Chinese Mainland)	For prevention of pneumococcal disease- persons 50 years of age or older; persons aged ≥2 years who are at increased risk for pneumococcal disease	For prevention of invasive pneumococcal disease-children aged 6 weeks through 5 years.	NA	NA	NA	NA
Recommendedvaccination schedule in the Chinese Mainland	Single dose	Three to Four doses	NA	NA	NA	NA
Indications (FDA)	For prevention of pneumococcal disease- persons 50 years of age or older; persons aged ≥2 years who are at increased risk for pneumococcal disease	For prevention of invasive pneumococcal disease-children aged 6 weeks through 5 years. For prevention of invasive pneumococcal disease- children aged 6 years through 17 years. For prevention of pneumonia and invasive pneumococcal disease- adults aged 18 years of age and older.	For prevention of invasive pneumococcal disease- individuals aged 6 weeks of age and older.	For prevention of invasive pneumococcal disease- individuals aged 6 weeks of age and older For prevention of invasive pneumococcal disease- individuals aged 6 weeks thorough 5 years age For prevention of pneumonia pneumococcal disease- individuals aged 18 years and older	For prevention of pneumonia and invasive pneumococcal disease- individuals aged 18 years of age and above	NA

Note: Abbreviation: NA: not available

Early pneumococcal vaccines against pneumococci contained purified polysaccharide capsules as antigens. These were 4-valent PPVs containing serotypes 1, 2, 5, and 7 and were protective against the pneumococcal disease caused by the same serotypes.^20,50 Much later in 1968, 6-valent and 13-valent pneumococcal polysaccharide vaccines were shown to be safe. Different 6 PCVs include the number of serotypes against which they impart immunity.. Of all the PCVs presently available, only PCV13 has been introduced in China. Pooled analysis on the prevalence showed that 19 F was reported highest with 27.29% followed by 19A (13.66%), 6B (12.10%), 14 (11.42%), 6A (8.05%), and 23 F (3.13%). The regional analysis on prevalence of serotypes reported that serotype 19A and 19 F were most predominant types in Northern and Southern China, respectively.⁵¹

A PPSV23 was developed in 1983 to provide protection against 80% to 90% of the disease caused by pneumococcal capsular serotypes. In 1977, the Food and Drug Administration (FDA) licensed a 14-valent PPV (PPV14), which contained capsular polysaccharide serotypes 1, 3, 4, 6A, 6B, 7 F, 8, 9 N, 12 F, 14, 18C, 19 F, 20, and 23 F. In 1983, the FDA licensed PPSV23, which contained 10 additional serotypes (2, 5, 9 V, 10A, 11A, 15B, 17 F, 19A, 22 F, and 33 F, but not 6A). This vaccine covered 65% to 91% of the isolates from adult IPD cases worldwide. At present, PPSV23 is licensed in more than 75 countries worldwide for those aged ≥2 years. PPSV23 was approved in 1996 in China, used to prevent pneumococcal disease with a coverage of 3.7% in urban followed by 3.34% in rural and 2.16% in suburban areas. The PPSV23 vaccine is administered as a single dose of 0.5 mL and currently being produced by four manufacturers: MSD, Chengdu Institute of Biological Products, Yuxi Walvax Biotechnology Company, and Beijing Minhai Biotechnology.^20,52,53

Proper understanding on the serotype distribution of Streptococcus pneumoniae is crucial for effective implementation of pneumococcal vaccines. In China, the most common serotypes identified in children <14 years includes 19 F, 19A, 23 F, 14, 6B, and 6A1. Variation in the coverage rates for different vaccines was observed especially with PCV13 covering about 74.77% of these serotypes.⁵¹ Ongoing surveillance is essential to ensure that vaccines remain effective against the prevalent serotypes and to guide the development of new vaccines that can cover a broader range of serotypes.⁵¹

Pneumococcal Vaccine Coverage

Vaccination schedules vary significantly between countries due to different reasons such as economic and countries’ medical capabilities, commitment to vaccination and local epidemic situation. In such scenarios, recommendations from the World Health Organization (WHO), play a major role in properly implementing these decisions. The WHO has provided a detailed recommendations on pneumococcal vaccines in their position papers from 2019 and 2021. The 2019 position paper emphasized on the use of PCVs in both infants and children <5 years of age whereas the 2021 focused on the use of these vaccines in elder adults and in community outbreak settings.^54,55

Pneumococcal vaccination coverage in Western countries (USA and England) is as high as 60% in elderly patients.⁵⁶ Beijing, Shanghai, and Shenzhen implemented policies to provide free vaccination to local elderly residents. However, data from local areas show that the rate of pneumococcal vaccination coverage in elderly population is very low.⁶ Children aged between 2–5 years was considered as main age for vaccination.⁵² Children aged ≤14 years showed higher vaccination coverage in urban area (42.93%) followed by rural (29.81%) and suburban (20.16%) areas.⁵² Additionally, the vaccination coverage was higher in children aged ≤5 years with vaccination coverage rate of approx. 40–54%.⁵² Elderly patients showed vaccination rates of only 2.1% in Chaoyang district of Beijing in 2010.⁵⁷ A cross-sectional study conducted in residents aged >2 years of Hangzhou city of China vaccinated during 2006–2017 showed a PPSV23 vaccination coverage of 2.98%. More than 379,000 elderly individuals aged >65 years received pneumococcal vaccination, accounting for approximately 34% of the concerned age group. The vaccination coverage among elderly (aged ≥60 years) was higher, with a high rate in urban areas (3.70%) compared with rural areas (3.34%).⁵² The coverage of pneumococcal vaccine was suboptimal in elderly patients aged ≥65 years in Hong Kong especially in community-living elder patients.⁵⁸ In October 2021, the Advisory Committee on Immunization Practices recommended single dose of pneumococcal vaccines either alone or in serial immunizations for elderly patients with high-risk conditions.⁵⁹ Further in another cross-sectional study in Hong Kong, approx. 53.4% of clinicians recommended pneumococcal vaccination to elderly patients.⁶⁰

On the contrary, Chengdu region in China demonstrated a pneumococcal vaccination rate of 42.1% in a survey of 1200 randomly selected elderly residents in 2015 due to free vaccination to older adults.⁶¹ A detailed analysis of the effectiveness of PPSV23 vaccination in Chinese population is essential in order to implement pneumococcal vaccination subsidy program across the provinces of China.

Effectiveness of PPSV23 in Elderly Individuals

Although PPSV23 has been used for almost three decades in China since 1996, uncertainties still remain, especially for older adults.²⁰ Some studies suggest that PPSV23 protects against IPD but not against NIPD; however, contradictory results have been observed in other studies showing a lack of efficacy required for preventing either invasive or noninvasive disease^62,63 or for reducing mortality.^64,65 Reasons for such conflicting results may be under-representative of specific outcome assessment, leading to a small number of events in studies, difficulties in accurately diagnosing NBPP, and the use of non-validated diagnostic tests, thereby causing false-positive results that ultimately result in the reduction of vaccine efficacy.⁶⁶

Vaccination of PPSV23 in older adults has not shown convincing results to prevent all-cause CAP, and its effectiveness in preventing laboratory-confirmed NBPP has varied based on study design and execution.²⁰ However, studies evaluating the efficacy of PPSV23 against NBPP in Chinese elderly population are still lacking. Despite favorable evidences, PPSV-23 vaccination coverage among the elderly across several regions in China was reported to be less than 3.7% in 2019.³⁴ In comparison, the vaccination rates for pneumococcal disease in Western countries (USA and England) were as high as 60% among elderly patients. Recent studies have demonstrated the effectiveness of PPSV-23 vaccine in preventing pneumonia in adults aged ≥ 65 years old.^67–69 In a study conducted in China, PPSV-23 vaccination in elderly patients was associated with a 69.7% and 65.9% reduction in the incidence of lower respiratory tract infection and hospitalization, respectively.⁷⁰ A recent systematic review reported the effectiveness of pneumococcal vaccines for older adults.⁷¹ All the reported studies were from high-income countries. For the PPSV23 vaccine, the follow-up period ranged from 1 to 9 years, mostly between 2 to 5 years. For the PCV13 vaccine, the follow-up was about 4 years in one major trial and 1 to 5 years in other studies.⁷²

Several studies have shown the efficacy of PPSV23 ranging from 9.34%(95%CI: 2.05-16.62%) to 57.7%(95%CI: 20.7-77.5%) in elderly individuals.^73–76 A systematic review and meta-analysis showed that the vaccine effectiveness (VE) of PPSV23 in preventing IPD and all-cause CAP in the general population of 50 years of age and older was 50% to 54% and 4% to 17%, respectively. PPSV23 can minimize the severity of CAP among hospitalized patients and reduce the burden of other pneumococcal diseases.⁷⁷ A matched, test-negative, case-control study was conducted in Shanghai, China, on elderly individuals aged >60 years. PPSV23 was effective against pneumococcal diseases, with VE of 24% (95% CI: 2%-40%) for the whole population and 44% (95% CI: 6%-67%) for women. The effectiveness was statistically significant even after adjusting for multiple variables, with VE of 25% (95% CI: 3%-42%) for the whole population and 49% (95% CI: 11%-71%) for women.⁷³

Serologic immunity against S pneumoniae significantly influences the incidence of IPD and pneumococcal pneumonia. This immunity can be acquired through infection or vaccination and is serotype specific. Pneumococcal vaccines are active vaccines composed of the pneumococcal capsular polysaccharide, thereby preventing pneumococcal diseases.²⁶ By preventing severe disease, pneumococcal vaccination also imparts cardioprotective effects, and these effects reduce the risk of myocardial infarction and mortality.⁷⁸To evaluate the effectiveness of PPSV23 vaccine in elderly adults aged ≥75 years in Taiwan, data were analyzed from the Taiwan National Health Insurance Research Database (NHIRD), the cause-of-death registration database, and the IPD notification database of Taiwan’s Ministry of Health and Welfare. It was observed that the percentages of elderly adults with a ≥2-fold increase in antibody concentration decreased 1 month after PPV vaccination (76%-87%) compared with 1 year after vaccination (55%-73%).⁶⁷ Similar results were observed in another study conducted on elderly individuals aged >60 years against CAP in Shanghai, China. The incidence density of CAP in the vaccinated group (0.848/100 person-years [PYs]) was lower than that of the control group (1.452/100 PYs), with a statistically significant vaccine protection rate of 41.6% (P < .001). Age-wise stratification showed the vaccine protective rates of 36.7%, 21.6%, and 26.0%, respectively, in the 60- to 69-year-old group, the 70- to 79-year-old group, and the ≥80-year-old group, but only the 60- to 69-year-old group showed a statistical difference (P = .045).⁷⁴

A prospective cohort study evaluated 1200 elderly individuals aged ≥75 years in Minhang District, Shanghai, for clinical symptoms and the incidence of respiratory tract infectious diseases as well as the acute onset of chronic respiratory diseases in vaccinated and unvaccinated groups. Development of clinical symptoms was much lesser in the inoculated group as compared with the uninoculated group (relative risk [RR]: 0.894; 95% CI: 0.804–0.994). Immunization with the PPSV23 protected 57.7% of elderly individuals aged ≥75 years from respiratory tract infections.⁷⁵ Thus, revaccination with PPSV23 should be considered in order to prolong protection against pneumococcal disease, especially in elderly patients. At present, both the Advisory committee on immunization and the Japanese Association for Infectious Diseases recommend PPSV23 revaccination at least 5 years after the most recent dose of PPSV23 for adults aged ≥65 years.⁷⁹ However, there are no such studies documented on Chinese population (Table 2).

Table 2.

Effectiveness of PPSV23 in Chinese Elderly Adults.

Vaccines	Regions	Age	Key findings	Ref
PPSV23	Shanghai	≥60 years	Significant VE of 24%(95%CI: 2%, 40%) for whole population and 44%(95%CI: 6%, 67%) for women	73
PPSV23	Kaifeng City	≥60 years	PPSV23 vaccine group patients showed was non-inferiority to the commercial vaccine group for all 23 serotypes.	76
PPSV23	Shanghai	≥60 years	Lower CAP density in the vaccinated group (0.848/100 person-years) than the control group (1.452/100 person-years), and the vaccine protection rate was 41.6% for the elderly aged 60 years old, with a statistically significant difference [RR (95%CI)= 0.584 (0.428-0.790), P<0.001].	74
PPSV23	Shanghai	≥75 years	Lesser clinical symptoms developed in the vaccinated group as compared with the uninoculated group (RR: 0.894; 95% CI: 0.804–0.994), with 57.7% (95%CI: 20.7%, 77.5%) protection rate from respiratory tract infections	75

Note: Abbreviations: CAP, community-acquired pneumonia; CI, confidence interval; PPSV23, 23-valent pneumococcal polysaccharide vaccine; RR: Risk ratio; Ref: Reference; VE, vaccine effectiveness.

Effectiveness of PPSV23 in Patients with Comorbidities

PPSV23 vaccination is essential for patients with comorbidities, as conditions such as acquired immunodeficiency syndrome (AIDS), diabetes, cancer, and pulmonary, cardiovascular, liver, and kidney diseases put these individuals at a higher risk as compared with healthy individuals. Administration of PPSV23 has been proven to be beneficial by reducing treatments or hospitalizations in patients with comorbidities in several previous studies (Table 3).

Table 3.

Effectiveness of PPSV23 in Chinese Elderly Adults with Comorbidities.

Vaccines	Regions	Study population		Key findings	Ref
		Age	Comorbidities
PPSV23	Shanxi Province and Shandong Province	≥60 years	COPD	Reduced 1.12 ± 2.51 treatments due to acute exacerbation, including 0.28 ± 2.09 outpatient treatments and 0.85 ± 1.15 hospitalizations	80
PPSV23	Taiwan	≥75 years	Cancer	A lower incidence rate of pneumonia-related hospitalization (73.66/1000 PYs) as compared with unvaccinated patients (117.82/1000 PYs)	81
PPSV23	Taiwan	≥75 years	Cancer	A lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% vs 42.3%; P < .001) as compared with unvaccinated patients	82
PPSV23	Lanshan county	≥18 years	HIV infection	VE of 81.79% with an infection rate of 9.17% in the unvaccinated group as compared with 1.67% in the vaccinated group 1 year after vaccination, and no adverse events were reported	83

Note: Abbreviations: COPD, chronic obstructive pulmonary disease; HIV, human immunodeficiency virus; PPSV23, 23-valent pneumococcal polysaccharide vaccine; PY, person-year; Ref: References; VE, vaccine effectiveness.

As reported in a case-control study, PPSV23 was effective against pneumococcal diseases in adults aged 60 years or older in China which is higher in women (44%).⁷³ In comorbidities such as chronic respiratory diseases, cardiovascular diseases, diabetes mellitus, chronic liver diseases, chronic kidney diseases, immunocompromising conditions, and asplenia or splenic dysfunction, the reported cutoff age was 18–64 years.^73,84 For instance, in another cross-sectional survey which was conducted in ten provinces in China, PPSV23 vaccination rates were higher in older adults with chronic diseases (8.87%) compared to adults without chronic diseases (3.29%).⁸⁴

Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a major risk factor for CAP, and smoking – which is one of the major causes for the occurrence of COPD – has been reported as an important risk factor for IPD. As patients with COPD belong to the high-risk category for pneumococcal infections, pneumococcal vaccination is recommended for these patients according to the major COPD guidelines.⁸⁵ PPSV23 vaccination in Chinese patients with COPD was also beneficial in terms of their quality of life. These patients benefitted post-vaccination with a reduction in 1.12 ± 2.51 treatments due to acute exacerbation, including 0.28 ± 2.09 outpatient treatments and 0.85 ± 1.15 hospitalizations.⁸⁰ Future research on pneumococcal vaccination in patients with COPD should consider potential confounding by systemic inflammation and their frequent use of systemic corticosteroids.

Cancer

The risk of pneumonia in patients with cancer is much more than those with other comorbidities. Since immunity is highly compromised in patients with cancer, the disease rates can be >20 times than those without high-risk medical conditions as patients are prone to pulmonary infections. Administration of PPSV23 can help patients with cancer in the better management of pulmonary infections.⁸¹ PPSV23 vaccination in 30,249 patients with cancer in Taiwan showed a significantly lower incidence rate of pneumonia hospitalization (73.66/1000 PYs) as compared with unvaccinated patients (117.82/1000 PYs). PPSV23 vaccination was beneficial with a reduced prevalence of pneumonia hospitalization with a frequency of >0 to 1 (6.63% vs 9.28%), >1 to 2 (1.86% vs 2.52%), >2 to 3 (0.80% vs 1.59%), and >3 (0.27% vs 0.53%) times per PY as compared with those without vaccination.⁷³ A 7-year follow-up study conducted on patients with prostate cancer showed a significantly lower incidence density of pneumonia in vaccinated patients (142.8/1000 PYs) as compared with unvaccinated patients (162.0/1000 PYs). PPSV23-vaccinated patients also showed a lower cumulative incidence for the first occurrence of pneumonia-related hospitalization (34.49% vs 36.36%; P = .178) and higher overall survival (47.5% vs 42.3%; P < .001) as compared with unvaccinated control patients. Thus, PPSV23 vaccination in elderly patients with prostate cancer was associated with decreased risk of pneumonia and prolonged overall survival.⁸²

HIV Infection

Pneumonia is one of the most serious complications of AIDS caused due to HIV infection with 35- to 100-fold high morbidity rates in HIV-infected individuals as compared with those without HIV infection.^86,87 PPSV23 vaccination showed good antibody responses, thereby proving to be beneficial in HIV-infected patients in Chinese population. A study conducted on 60 HIV-infected adults in Lanshan County, China, showed serologic responses in 76.67% of patients after 1 year of vaccination. VE was observed to be 81.79% with an infection rate of 9.17% in the unvaccinated group as compared with 1.67% in the vaccinated group after 1 year of vaccination, and no adverse events were reported.⁸³

Diabetes

Diabetes is an immunocompromising condition associated with increased risk of pneumonia. However, due to the influence of diabetes on immune dysfunction, which may influence the efficacy of PPSV23.^88,89 For instances, impaired immune system in patients with diabetes combined age-factor (both in pediatric and elderly patients). Limited data on the effectiveness of PPSV23 in both patients with diabetes was reported. Despite these limitations, PPSV23 vaccination was proven beneficial in prevention of pneumococcal diseases in both children and elderly patients with diabetes.^90–93

Cost effectiveness of PPSV23 vaccine

The rate of vaccination coverage is significantly influenced by the cost-effectiveness of vaccine. A few published studies have evaluated the cost-effectiveness of PPSV23 vaccination. In a study conducted on elderly Chinese patients, the incremental cost-effectiveness ratio of PPSV23 vaccine was $16,699/quality-adjusted life years gained compared with no vaccination. Similarly, a study in Shanghai reported that compared with no vaccination cost, PPSV23 costed US $19.62 million more and received an additional 10,321.3 quality-adjusted life-year (QALY). Additionally, PPSV23 was associated with an ICER of $190.1 per QALY gained.⁹⁴ COPD patients vaccinated with PPSV23 within 1-year resulted in reduced treatment cost due to acute exacerbation.⁹⁵ A cost-benefit ratio was also observed in patients affected with HIV.⁸³ A significant statistical difference was observed between the vaccinated group and the non-vaccinated group in terms of outpatient costs, medicine costs and disease related indirect costs within one year of vaccination.⁸³

Coadministration of PPSV23 With Other Non-PCV Vaccines

Coadministration of pneumococcal vaccines with other vaccines might result in slight cross-interference, thereby hampering the effectiveness of both the vaccines and, hence, the effectiveness needs to be evaluated. This cross-interference has been observed especially in case of influenza vaccines. However, favorable results have been observed in case of coadministration of PPSV23 and trivalent inactivated influenza vaccine (IIV3), or quadrivalent inactivated influenza vaccine (IIV4) yielded no worsening of antibody responses and no increased adverse reactions.⁹⁶ In a retrospective cohort study conducted on elderly persons in Shenzhen, China, effectiveness was evaluated for influenza and PPSV23 dual-vaccination program. Administration of both IIV3 and PPSV23 vaccines was associated with a 41% lower risk of all-cause hospitalization and a 51% lower risk of acute respiratory hospitalization.⁹⁷ Additive vaccination with influenza and pneumococcal vaccines observed a significant reduction in lower all-cause mortality (RR: 0.74; 95% CI: 0.57–0.96), hospitalization for pneumonia, influenza, COPD, respiratory diseases, and congestive heart disease (RR: 0.77; 95% CI: 0.67–0.90) and a 13% reduction (95% CI: 0.81–0.94) in inpatient expenditures as compared with individuals receiving influenza vaccine alone. Thus, vaccination of elderly individuals with pneumococcal vaccine and influenza vaccine had substantial beneficial effects.⁹⁸

Current limitations & Future Directions

PPSV23 vaccination elicits good antibody responses, limited toxicity, and encouraging protection against pneumococcal diseases. However, in most low- and middle-income countries, there are availability issues with respect to PPSV23 vaccination program. Thus, an increase in awareness of pneumococcal disease and the need for its prevention are required in all countries.²⁰ The period for immunogenicity and efficacy of PPSV23 against pneumococcal diseases in healthy individuals or those with comorbidities is still uncertain. There are a lot of gaps in the current vaccination strategies, which need to be rectified. Vaccine strategies should be revised with the need for revaccination intervals as well as increasing the dose levels in case of elderly and immune-compromised individuals. Most of the epidemiologic data for pneumococcal disease in China come from large cities, with a small sample size and with no continuous monitoring. There is a need to have regular surveillance with respect to serotype distribution for the better management of pneumococcal disease in China via the development of newer vaccines specific for prevalent serotypes.

Although promising, there are no reported epidemiological surveillance data for invasive pneumococcal disease in China or data on pneumococcal pneumonia diagnosis at hospital discharge. Thus, prior to developing a suitable vaccination program, a robust surveillance system is necessary for assessing the magnitude of problem which could aid in differentiating regions based on vaccination coverage.

After a single-dose PPSV23 vaccination, declining antibody response is observed in elderly persons aged ≥65 years for the first 5 years after vaccination. Considering higher incidence rate of IPD in these individuals, revaccination could be considered every 5 years.⁹⁹ Since both PCV13 and PPSV23 are not included in Chinese NIP, Chinese individuals have to bear the expenses for pneumococcal vaccination themselves.

PPSV23 has been observed to be beneficial in elderly population due to its high serotype coverage and cost-effectiveness in China.^100,101 Further, dual vaccination with PCV-13 and PPSV23 is more effective in the short term, but PPSV23 alone should be considered compared with PCV-13 for the management of pneumococcal diseases in healthy individuals. The incidence of pneumococcal serotypes against which PCVs and PPSV23 vaccines imparts immunity has been decreasing. Instead of these serotypes, there is an increase in occurrence of pneumococcal diseases caused due to nonvaccine serotypes, which is known as serotype replacement. To combat pneumococcal diseases related to nonvaccine serotypes, novel strategies for the development of newer vaccines will be required. Current evidence suggests that utilization of PCV in Chinese children has significantly altered the serotype distribution of Streptococcus pneumoniae. Mounting evidences have shown that while vaccine-type serotypes have decreased, there has been a substantial increase in non-vaccine serotypes, indicating serotype replacement.¹⁰² This change underlines the need for ongoing surveillance to monitor these changes and inform public health strategies. Proper understanding on the ong-term impacts of serotype replacement will be critical for optimizing vaccination programs and reducing pneumonia-related morbidity.^103,104

The effectiveness of PPSV23 in adults aged >60 years remains debatable due to differences in the results from many meta-analyses which often arise due to differences in study designs, populations, and endpoints considered. Despite this, there exists a substantial evidence indicating that both polysaccharide (PPSV23) and conjugate vaccines (PCV13) provide reasonable protection against invasive pneumococcal disease (IPD) in older adults.^105,106 For instance, a study conducted in Japan reported an adjusted effectiveness of 42.2% for PPSV23 against IPD adults.¹⁰⁵ Additionally, the CDC notes that PPSV23 can prevent pneumococcal disease, including pneumonia, meningitis, and bacteremia.¹⁰⁶

Recent guidelines have recommended the use of a single dose of PCV20 instead of sequential vaccination schedules such as PCV13 followed by PPSV23. This change aims to simplify the vaccination process while providing broad protection against pneumococcal disease.¹⁰⁷ The Advisory Committee on Immunization Practices (ACIP) now recommends PCV20 for all adults aged ≥65 years, as well as for adults aged 18–64 years with certain underlying medical conditions.¹⁰⁸ Another newly licensed vaccine by FDA, PCV21 was approved in in July 2024 for its use in US adults ≥ 18 years old.¹⁰⁹ PCV21 showed better results in individuals with immunocompromised complications including cancer and HIV, as it offers improved protection against serious infections like pneumonia, meningitis, and sepsis. For patients undergoing chemotherapy, PCV21 significantly reduces the risk of infections that can impede treatment and recovery.¹¹⁰ Recent progress in PCV21 include successful clinical trials confirming its safety and efficacy in pneumococcal diseases, leading to its regulatory approval.^44,111

Funding pneumococcal vaccination programs presents significant challenges, especially in countries like China with large and diverse populations. In China, national immunization program (NIP) vaccines benefit from robust financial support and have achieved high coverage. Although over 14 cities are currently providing free pneumococcal vaccination PPSV23 for people over 60 years of age. However, non-NIP vaccines, including pneumococcal vaccines, rely on fragmented funding sources, primarily out-of-pocket payments, which leads to sub-optimal and inequitable coverage.¹⁴ High out-of-pocket costs remain a significant barrier to equitable vaccine uptake, particularly in underdeveloped regions.¹¹²

Efforts to secure sustainable financing for non-NIP vaccines are crucial. Local funding support for free vaccination programs faces challenges related to sustainability and regional disparity, though governmental commitment to vaccination is growing.¹⁴ Centralized procurement organized by the government has helped lower vaccine prices and reduce the financial burden on individuals. Despite these efforts, ensuring universal access to pneumococcal vaccines requires a concerted and synergistic approach to secure sufficient, sustainable resources and enhance public financial management.¹⁴

Conclusions

Although the 23-valent pneumococcal polysaccharide vaccine has been widely used to impart immunity against pneumococcal diseases for many years, there are challenges in terms of its effectiveness, especially among elderly individuals and patients with comorbidities in China. PPSV23 was protective in elderly patients with effectiveness outcomes within the range of 9.34%(95%CI: 2.05%, 16.62%) to 57.7%(95%CI: 20.7%, 77.5%) in elderly individuals. However, the antibody concentration gradually reduced within the first 5 years after vaccination. Administration of PPSV23 vaccine has been proven to be beneficial by reducing treatments or hospitalizations in elderly patients or those with comorbidities. Considering the existing data on the effectiveness of pneumococcal vaccines in national and international levels, further research is essential to refine vaccination strategies, in identifying additional risk-groups and optimize the timing and vaccine combinations. Further, there is a need for improving monitoring of morbidity and mortality due to pneumococcal diseases, pneumococcal serotypes, and strengthening the supervision on antibacterial resistance.

Disclosure statement

Peng Bai is employee of MSD China. All the other authors have no conflict of interest to declare.

Funding

Medical writing support was funded by MSD China.

Author contributions

Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: Bai Peng, Weiyan Zhang, Weijun Hu

Drafting the work or reviewing it critically for important intellectual content: Bai Peng, Weiyan Zhang, Weijun Hu

Final approval of the version to be published: Bai Peng, Weiyan Zhang, Weijun Hu

Agreement to be accountable for all aspects of the work: Bai Peng, Weiyan Zhang, Weijun Hu.

All authors attest they meet the ICMJE criteria for authorship

Weijun Hu, director of the Immunization Planning Institute of the Shaanxi Provincial Center for Disease Control and Prevention, is mainly responsible for vaccine control of infectious diseases and vaccine clinical evaluation. Member/Secretary of the Northwest Immunization Program Coordination Committee, standing member of the Hepatitis Prevention and Control Branch of the China Vaccine Industry Association, deputy chairman of the Vaccine and Immunization Branch of the China Elderly Care Association, director of the Shaanxi Preventive Medicine Society, and expert on basic public health services in Shaanxi Province. Master tutor of Shaanxi University of Traditional Chinese Medicine, and off-campus practical instructor of Jilin University.