Seven-Valent Pneumococcal Conjugate Vaccine and Nasopharyngeal Microbiota in Healthy Children

Giske Biesbroek, Xinhui Wang1, Bart J.F. Keijser1, Rene M.J. Eijkemans, Krzysztof Trzciński, Nynke Y. Rots, Reinier H. Veenhoven2, Elisabeth A.M. Sanders, and Debby Bogaert

Author affiliations: University Medical Center Utrecht, Utrecht, the Netherlands (G. Biesbroek, X. Wang, K. Trzciński, E.A.M. Sanders. D. Bogaert); TNO, Zeist, the Netherlands (G. Biesbroek, B.J.F. Keijser); Julius Center for Health Sciences and Primary Care, Utrecht (R.M.J. Eijkemans); Netherlands Vaccine Institute, Bilthoven, the Netherlands (N.Y. Rots); Spaarne Hospital, Hoofddorp, the Netherlands (R.H. Veenhoven)

Abstract

Seven-valent pneumococcal conjugate vaccine (PCV-7) is effective against vaccine serotype disease and carriage. Nevertheless, shifts in colonization and disease toward nonvaccine serotypes and other potential pathogens have been described. To understand the extent of these shifts, we analyzed nasopharyngeal microbial profiles of 97 PCV-7–vaccinated infants and 103 control infants participating in a randomized controlled trial in the Netherlands. PCV-7 immunization resulted in a temporary shift in microbial community composition and increased bacterial diversity. Immunization also resulted in decreased presence of the pneumococcal vaccine serotype and an increase in the relative abundance and presence of nonpneumococcal streptococci and anaerobic bacteria. Furthermore, the abundance of Haemophilus and Staphylococcus bacteria in vaccinees was increased over that in controls. This study illustrates the much broader effect of vaccination with PCV-7 on the microbial community than currently assumed, and highlights the need for careful monitoring when implementing vaccines directed against common colonizers.

Vaccination is one of the most effective methods to prevent infectious diseases by direct protection of persons against a specific pathogen and by eradication of these specific pathogens from the population, leading to so called herd effects or indirect protection (1). Over the past decade, a 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in national immunization programs for newborns in most high-income countries, and the newer-generation 10-valent and 13-valent vaccines are being progressively introduced in developing countries (2).

The specific serotypes of the first licensed 7-valent pneumococcal vaccine are common colonizers of the upper respiratory tract of children during the first years of life, in which these serotypes generally reside as part of the nasopharyngeal microbiota (bacterial community) (3). However, these bacteria might occasionally spread beyond this niche and cause otitis media, pneumonia, sepsis, or meningitis (4). Vaccines show effectiveness against vaccine-serotype disease, nasopharyngeal acquisition of pneumococci, and pneumococcal transmission. However, nonvaccine pneumoccal serotypes fill the vacant nasopharyngeal niche, leaving overall pneumococcal carriage similar or only temporarily decreased (5,6) and lead to a gradual increase in nonvaccine serotype disease (7). In addition, several studies have raised awareness of the replacement of vaccine serotypes in the bacterial community with other potential pathogens, such as Haemophilus influenzae and Staphylococcus aureus in carriage or disease (8–11). This replacement is likely explained by the highly interactive nature of the microbiota in the natural habitat of the specific bacterium (12).

The recent availability of high-throughput, deep-sequencing techniques has made it possible to obtain more insight in the microbiota in humans, including the not yet cultivated fraction of bacteria. These techniques have elucidated that bacteria of the human microbiota outnumber human host cells by 10-fold, and microbiota composition varies greatly between body sites and persons. Colonization is a dynamic process of interactions among microbes and between microbes and the host and result in balanced bacterial ecosystems that benefit health. Perturbations of these interactive microbial structures (e.g., by environmental change or vaccinations) alter the bacterial network structures and may thereby influence the presence and containment of other microbiota members, and these alterations have effects on health and susceptibility to disease (13,14).

Given the changes in pneumococcal serotypes, as well as well as S. aureus and H. influenzaecarriage after vaccination with PCV-7 (7,8), we questioned whether the effects of PCV-7 could be even more extensive than initially believed. We therefore studied the effects of PCV-7 on the complete nasopharyngeal microbiota of healthy children in a randomized controlled trial by using deep-sequencing techniques. The study was initiated shortly before nationwide implementation of PCV-7 in the Netherlands, therefore before herd effects appeared, which enabled us to measure the direct effects of the vaccine (15).