Development and Pediatric Use of the 20-Valent Pneumococcal Conjugate Vaccine

The Center for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) recommends pneumococcal vaccination for all children younger than 5 years, for people aged 5 to 64 years with high-risk conditions (see Table 1), and for all adults 65 years or older. In 2021 ACIP approved a 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20]) for use in adults aged 19 to 64 years with high-risk conditions, and all adults 65 years or older. In June 2023, ACIP expanded their recommendation for use of PCV20 (as an optional alternative to 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance]) for routine vaccination of children younger than 5 years and children between ages 2 and 18 years with high-risk conditions. This guidance also expanded high-risk conditions to include moderate persistent and severe persistent asthma, chronic liver disease, and chronic kidney diseases beyond nephrotic syndrome and maintenance dialysis.The discovery of Streptococcus pneumoniae, a gram-positive, aerobic diplococcus, dates back to 1881, when Louis Pasteur first isolated it from a patient with rabies. S. pneumoniae spreads through respiratory droplets and asymptomatically colonizes the upper respiratory tract of more than 50% of children younger than 5 years, decreasing to colonization rates of 5% to 10% in adults. Children younger than 5 years and adults 65 years or older have the highest risk for pneumococcal disease. S. pneumoniae causes a spectrum of illness from noninvasive diseases, including otitis media, sinusitis, and community-acquired pneumonia, to invasive pneumococcal diseases (IPD) including meningitis, bacteremia, osteomyelitis, and pneumonia with bacteremia. In the United States, S. pneumoniae is the most common bacterial cause of community-acquired pneumonia in children younger than age 5 years (second to Mycoplasma pneumoniae in older children) and the most common cause of bacterial meningitis in children ages 2 months to 11 years. There are over 100 S. pneumoniae serotypes. Most serotypes have a polysaccharide capsule, which helps them evade some human immune defenses. Differences in the capsule polysaccharide are often the basis for serotype classification and primarily influence the virulence of the serotype.Efforts to develop a pneumococcal vaccine started more than 100 years ago when British physician Sir Almroth Wright developed a whole-cell vaccine to prevent pneumococcal pneumonia in South African gold miners. By the 1940s, 2 pneumococcal vaccines were commercially available. However, with the discovery of penicillin, the interest and investment in a pneumococcal vaccine waned and it was deemed obsolete in the antibiotic age, and the pneumococcal vaccines were removed from the market. Despite the use of penicillin, case-fatality rates from S. pneumoniae remained high. Hence, a group of researchers, motivated by a desire to decrease IPD, developed the 14-valent polysaccharide vaccine, which was licensed in the United States in 1977. In 1983, the 23-valent polysaccharide vaccine (PPSV23) replaced the 14-valent vaccine and was recommended only for patients aged 2 years and older with specific high-risk conditions. While effective in older children and adults, unconjugated vaccines such as PPSV23, which rely on a T-cell independent immune response, are ineffective in children younger than 2 years due to lack of immune system maturity. Given that children younger than 2 years are at highest risk for pneumococcal disease, researchers continued to pursue a pneumococcal vaccine that would be effective across the age spectrum, from infants to adults. In 2000, the United States licensed the first conjugate pneumococcal vaccine, Prevnar 7 (PCV7).For conjugate pneumococcal vaccines, the pneumococcal polysaccharide of each included serotype is attached to an immunogenic protein—specifically, a genetically detoxified diphtheria toxin, which promotes both B lymphocyte and T lymphocyte enlistment. Conjugate vaccines produce a more robust and long-lasting immune response than unconjugated pneumococcal vaccines and are effective in children younger than 2 years. Prior to PCV7, there were approximately 17 000 pediatric cases of IPD and 200 deaths annually in the United States. After adoption of PCV7, nasopharyngeal colonization and noninvasive disease from PCV7 serotypes significantly decreased and cases of invasive disease from PCV7 serotypes declined by more than 80% among children younger than 5 years. Under pressure from broadening vaccine coverage, S. pneumoniae has adapted to evade the immune response through serotype replacement, in which serotypes not included in vaccines become more prevalent, and by capsular switching, in which serotypes adapt their capsular types to nonvaccine capsules. Also, as pneumococcal vaccines decrease infection rates of covered serotypes, other uncovered serotypes become more prevalent, which has prompted vaccine developers to add new serotypes to pneumococcal vaccines. In 2010, PCV13 replaced PCV7; in 2022, PCV15 was approved for children; and in 2023, PCV20 became the newest pediatric pneumococcal vaccine. Once PCV20 was approved, the ACIP no longer recommended PCV13 for routine immunization, instead recommending either PCV15 or PCV20. When looking at IPD in US children younger than 5 years, researchers predict that PCV15 and PCV20 will protect against an additional 17% and 39% of cases, respectively, in comparison to PCV13.The ACIP used the Grading of Recommendations, Assessment, Development and Evaluation framework to evaluate PCV20 and determined that there was moderate evidence for approval both for efficacy and for safety. No published disease outcome studies were available to assess efficacy, so approval was based on immunogenicity studies. The immune response from PCV20 was slightly lower compared with PCV13 for the same 13 serotypes, but the clinical significance of this finding is unknown. Safety studies had limited sample sizes, but there were no vaccine-related serious side effects. PCV20 is contraindicated in anyone with a prior severe allergic reaction after a conjugate pneumococcal vaccine or to any vaccine containing diphtheria toxoid, or in anyone with a severe allergy to any component of PCV20.The ACIP recommends routine pneumococcal conjugate vaccination using either PCV15 or PCV20 for all children younger than 5 years: Routine schedule: Administer 4 doses of PCV15 or PCV20 to infants/toddlers at ages 2 months, 4 months, 6 months, and 12 through 15 months.Catch-up schedule: Administer PCV15 or PCV20 per CDC catch-up schedule to vaccinate children younger than 5 years who are unvaccinated or not fully vaccinated. The number of catch-up doses and dose schedule depend on the current age of the child and timing of any prior doses. Given the complex rules with pneumococcal vaccination, the CDC developed the PneumoRecs VaxAdvisor mobile app and website (https://www2a.cdc.gov/vaccines/m/pneumo/pneumo.html) to provide patient-specific guidance.Children aged between 2 and 18 years with certain high-risk conditions (Table 1) will need additional pneumococcal vaccine doses if their routine vaccinations did not include PCV20, and depending on whether they received PPSV23. Again, the PneumoRecs VaxAdvisor mobile application and website can provide patient-specific guidance.Despite the effectiveness of pneumococcal vaccination in preventing disease, there are substantial inequities in pneumococcal vaccination rates. Vaccination rates are below the national average for children younger than 2 years who live in poverty, have Medicaid or no insurance, or are Black, American Indian, or Alaskan Native. Providers may consider increased vaccine outreach in these groups. In addition, given that people with moderate persistent or severe persistent asthma are now considered high-risk for pneumococcal disease, it may be helpful for clinics to implement processes to identify these patients and target them for recommended PCV20 or PPSV23 immunization.Prior to the development of pneumococcal vaccines, many of my patients suffered morbidity from S. pneumoniae infections. Many health care visits involved treating infants/children with otitis media and community-acquired pneumonia, obtaining blood cultures to evaluate for potential S. pneumococcal bacteremia, and performing lumbar puncture procedures to evaluate for meningitis. I still remember many of the patients I cared for who suffered significant sequelae from S. pneumococcal infections: bacterial meningitis, neurological damage, permanent hearing loss, and even death. Yet what an amazing journey to witness the incredible benefit from continued research on pneumococcal vaccines and to observe how meningitis from this pathogen has become a much rarer event. I express gratitude to the many researchers who contributed to the development of pneumococcal vaccines, for their ongoing research efforts to continuously improve these vaccines, and now for the current benefit to patients across the life trajectory. When we look at the inequities of pneumococcal vaccine receipt, all of us as pediatricians must continue to advocate for equal access to these vaccines, minimize barriers to vaccine receipt, and strive to develop trust with parents to minimize and eliminate any vaccine hesitancy that may exist.Janet R. Serwint, MDAssociate Editor, In Brief