Prof. Roman Chlíbek: Role of Multivalent Pneumococcal Conjugate Vaccines in Healthy and Premature Children
Children are frequent carriers of pneumococci, which can cause both common non-invasive and more severe, life-threatening invasive pneumococcal diseases, especially in children under 1 year of age and in people over 65 years old. Almost a year ago, a pediatric indication for a 15-valent pneumococcal vaccine was approved, which is enriched with 2 new serotypes and, according to study results, appears to be potentially more effective even in protecting against serotype 3. So what are the vaccination options for healthy immunocompetent children, and what benefits does this vaccine offer for premature infants? Professor Roman Chlíbek, chair of the Czech Vaccinology Society ČLS JEP, answered these questions in his presentation at the June Interdisciplinary Conference of PLDD.
Introduction
In nearly 60% of children, pneumococcal colonies can be found in the nasopharynx. These children are asymptomatic but act as carriers of pneumococci to more vulnerable older individuals in the family and surroundings. From the nasopharynx, pneumococcus can spread to the middle ear (80% of pneumococcal infections in children manifest as otitis media), paranasal sinuses, or lungs; invasive pneumococcal diseases (IPDs) include bacteremia, invasive pneumonia, and meningitis. Pneumococcal vaccines reduce not only life-threatening IPDs but also highly prevalent otitis, sinusitis, and non-bacteremic pneumonia.
Benefits of Pneumococcal Vaccination
Even a completely healthy full-term newborn has immature B lymphocytes, and this is even more true for premature individuals. Pneumococcal vaccines help bridge the immature immune system by utilizing T-cell-dependent antigens. Vaccination also leads to the formation of memory cells, providing long-term protection (thus far without the need for revaccination). Ideally, vaccination should begin at 6 weeks of age, with benefits for at-risk children regardless of age.
The reasons for vaccination include reducing life-threatening IPDs, as well as pneumonia and acute otitis, and also nasopharyngeal carriage. Thanks to vaccinating children, the occurrence of pneumococcal diseases also decreases in the unvaccinated population (indirect effect), primarily among seniors. In the Czech Republic, the vaccination rate against pneumococci among seniors is very low, at most up to 25%, while the incidence of IPDs in the 65+ age group is higher than in children under 1 year of age.
Incidence and Epidemiology of IPDs
According to European and Czech data, the incidence of IPDs in children is highest in the first year of life. From 2018 to 2020, the incidence of IPDs in children under 1 year of age in the Czech Republic was 2-3 times higher than in children aged 1-4 years.
The most frequent long-term serotypes causing IPDs across age categories include serotype 3 due to its strong polysaccharide capsule. The proportion of IPD cases caused by this serotype has been steadily increasing since 2011 (2011: 44/334 cases; 2019: 85/483 cases). Other common serotypes circulating in children under 5 years old include 19A, 22F, 10A, and others (data from 2018 and 2019). Serotypes 22F and 33F are not included in the 13-valent vaccine (PCV13), yet 22F is responsible for up to 5% of global IPD cases in children under 5, and 33F accounts for 4.5% of IPD cases in children.
15-valent Pneumococcal Conjugate Vaccine and Its Results
Currently, in addition to the 10-valent and 13-valent pneumococcal vaccines, a 15-valent vaccine (PCV15) is registered and indicated for infants, children, and adolescents. PCV15 contains, in addition to the 13-valent vaccine serotypes, the additional serotypes 22F and 33F. The Czech Vaccinology Society ČLS JEP recommends vaccinating immunocompetent children with a 2+1 schedule, or a 3+1 schedule for premature infants. Vaccination is covered by public health insurance when all doses of the primary series are administered by the 7th month of age, with subsequent revaccination by the 15th month also being covered.
The randomized double-blind controlled phase III study PNEU-PED-EU1 (protocol 025) evaluated the safety, tolerability, and immunogenicity of PCV15 in a 3-dose schedule (2+1) for full-term infants and a 4-dose schedule (3+1) for premature infants. The study results demonstrated non-inferiority of PCV15 compared to PCV13 for the 13 common serotypes and superiority for the 2 unique serotypes 22F and 33F. PCV15 induced the production of functional antibodies capable of eliminating pneumococcal bacteria. In the PNEU-PED study (protocol 029) with a 4-dose schedule (3+1), PCV15 superiority was proven both for the unique serotypes 22F and 33F and for serotype 3.
Co-administration of PCV15 with Routinely Administered Vaccines and Interchangeability
For infants and children aged 6 weeks to < 2 years, PCV15 can be administered concurrently with many vaccines, including live vaccines (against diphtheria, tetanus, whooping cough, poliomyelitis – serotype 1, 2, and 3, hepatitis A and B, Haemophilus influenzae type b, measles, mumps, rubella, chickenpox, rotaviruses) in monovalent or combined forms.
Infants and children who started immunization with another pneumococcal conjugate vaccine can switch to PCV15 anytime during the schedule.
Safety and Immunogenicity of PCV15 in Premature Infants
Premature infants are not a negligible group. This is confirmed by data from the Czech Statistical Office, according to which the proportion of premature infants has been approximately 7% from 2011 to 2020. In absolute terms, this is more than 7,000 newborns (in 2020), so it is important to have vaccine clinical trial data for this group.
Premature infants are vulnerable concerning IPDs. Doubling the insufficient immune system performance results in approximately 5 times higher risk of IPDs compared to full-term infants. The proportion of responders, i.e., children achieving at least a minimum level of IgG antibodies against the 13 shared serotypes (≥ 0.35 µg/ml 30 days after the 3rd dose), was comparable in premature infants receiving PCV15 and PCV13. The proportion of children with sufficient IgG levels against serotypes 22F and 33F was, of course, higher with PCV15. In terms of safety, PCV15 is well tolerated even in premature infants (before the completion of the 37th gestation week), with results consistent with data in the general population of healthy children.
Conclusion
Multivalent PCV15 induces a robust immune response for the 13 serotypes included in PCV13. For serotype 3, it demonstrated a superior immune response compared to PCV13 (protocol 029, 3+1 schedule) and additionally for the newly added serotypes 22F and 33F (protocols 025 and 029). PCV15 can be administered concurrently with other pediatric vaccines and can switch from PCV13 to PCV15 anytime in the vaccination schedule while maintaining a comparable immune response to the 13 serotypes included in both vaccines. The 15-valent conjugate vaccine has demonstrated a consistent safety profile and immunogenicity even in premature infants.
(lexi)
Source: Chlíbek R. Role of Multivalent Pneumococcal Vaccines in Vaccination of Healthy and Premature Infants. Interdisciplinary Conference of PLDD, Prague, June 9, 2023.
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