Streptococcus pneumoniae is the most common bacterial cause of pneumonia, sinusitis, and acute otitis media (AOM). It also causes invasive pneumococcal disease (IPD), such as bacteremia and meningitis, and it is the leading cause of vaccine-preventable death in children younger than 5 years of age. Pneumococcal conjugate vaccines (PCVs) are effective in infants and young children against IPD, non-IPD, and the acquisition of vaccine serotype nasopharyngeal carriage (contagion). PCV7 was licensed and introduced in 2000 on a schedule that matched the schedule of other routine infant immunizations of three primary doses at 2, 4, and 6 months, and a booster at 12-15 months. Later in 2010, PCV13 was licensed on that same “3+1” schedule. Different pneumococcal vaccination schedules are recommended across Europe and other countries, after consideration of the epidemiology, disease burden, immunogenicity of the vaccine, its compatibility with other vaccines, and its cost. The World Health Organization recently updated its PCV policy to support the use of three doses on either 3+0 or 2+1 schedules. Most European countries have adopted the 2+1 schedule used for routine infant immunizations.
In light of the escalating costs of providing current vaccines, and the anticipated need for additional vaccines, the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) has convened a working group to evaluate the transition from a 3+1 to a 2+1 schedule for PCV administration to infants and children. This is not a trivial decision. In the United States, cost must be considered in the context of an additional focus on non-IPD disease prevention, especially AOM, where serotypes and immune protection levels differ from IPD. A 2+1 schedule may be effective to prevent IPD, compared with a 3+1 schedule, but its impact on non-IPD may be compromised, especially for AOM, for some serotypes of pneumococci, and for control of nasopharyngeal carriage.
Dr. Michael E. Pichichero
Immunogenicity studies show that antibody responses from a vaccine regimen consisting of two doses in the primary series are less immunogenic, compared with those for a three-dose regimen, yet both regimens are effective for the prevention of IPD. Immunogenicity data that support the use of reduced-dose schedules for most, but not all, vaccine serotypes, were based on IPD. The degree to which higher antibody concentrations are important for protecting against nonbacteremic pneumonia, sinusitis, and AOM, and for preventing nasopharyngeal carriage, is not established.
However, clinical outcomes since the introduction of PCVs indicate that the true threshold will vary by serotype and host and disease condition, with higher concentrations required for certain serotypes, in immunologically less mature hosts, and in mucosal infections like nonbacteremic pneumonia, sinusitis, and AOM, compared with IPD. Also, higher IgG levels clearly are important in protecting against nasopharyngeal colonization, thereby conferring herd immunity, prolonging individual protection, and possibly correlating at the individual level with disease protection. Studies that evaluated the correlation of antibody concentration and protection against nasopharyngeal colonization have shown that a greater than 10-fold higher antibody concentration is needed, compared with levels in blood, to protect against IPD. Similarly protection against AOM require higher levels of antibody than are needed to protect against IPD, as evidenced by the lower efficacy of PCVs against AOM, compared with IPD.
Epidemiology and risk factors differ among countries of the world. Therefore, even among developed countries, there is a need for caution in accepting that what works in one country will work as well in another. For example, attendance at day care is the highest risk factor for both IPD and non-IPD. In the United States, we have many types of day care, including relatively large day care centers, and many infants enter day care at 2 months of age. In other developed countries, the size of day care centers is much smaller, and children may not enter day care until 1 or even 2 years of age. Those differences may have implications for protective efficacy with a reduced-dose vaccine schedule.
Siblings under the age of 8 years are also at significant risk. Again, the family size may differ among developed countries. Breastfeeding is protective for pneumococcal infections. Breastfeeding duration may differ among countries. The theme of this concern is apparent: Even evidence of adequate protection with a reduced-dose schedule in Finland, France, Germany, the United Kingdom, or elsewhere should not be interpreted to be completely applicable to the United States.
Whether reduced-dose schedules can provide equivalent protection against vaccine type IPD equivalent to a 3+1 schedule for all serotypes and for non-IPD when introduced into a national immunization program is unclear. Do we have enough data to inform the decision process, and specifically do we have a clear understanding of the full impact of reduced-dose schedules on non-IPD relative to 3+1? How would you vote?