The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A

Abstract

The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 dramatically reduced the incidence of invasive pneumococcal disease (IPD) caused by the seven serotypes covered by the vaccine. Following the introduction of PCV7, which contains a serotype 6B conjugate, some decrease in IPD due to serotype 6A was noted suggesting that the serotype 6B conjugate provided some partial cross-protection against serotype 6A. However, no effect on serotype 6C was observed. In 2010, a pneumococcal conjugate vaccine with expanded serotype coverage (PCV13) was introduced that expanded the serotype coverage to 13 serotypes including serotype 6A. To assess whether the 6A conjugate in PCV13 could potentially induce functional anti-6C antibody responses, an opsonophagocytic assay (OPA) for serotype 6C was developed. Randomly chosen subsets of immune sera collected from infants receiving three doses of PCV7 or PCV13 were tested in OPA assays for serotype 6A, 6B and 6C. PCV7 immune sera demonstrated strong OPA responses, defined as percentage of subjects having an OPA titer ≥1:8, to serotype 6B (100% responders), partial responses to serotype 6A (70% responders) but only minimal responses to serotype 6C (22% responders). In contrast, PCV13 immune sera showed strong OPA responses to serotypes 6A (100% responders), 6B (100% responders) and 6C (96% responders). Furthermore, during pre-clinical work it was observed that serotype 7F (included in PCV13) and serotype 7A (not included in PCV13) shared serogroup-specific epitopes. To determine whether such epitopes also may be eliciting cross-functional antibody, PCV13 immune sera were also tested in serotype 7A and 7F OPA assays. All PCV13 immune sera demonstrated OPA responses to both of these serotypes. Taken together these results suggest that immunization with PCV13 has the potential to induce cross-protective responses to related serotypes not directly covered by the vaccine.

Figure 1

Comparison of polysaccharide structures: A. Serotypes 6A, 6B, 6C and 6D. B. Serotypes 7F and 7A.

Figure 2

OPA responses to pneumococcal serotypes 6A, 6B and 6C elicited by PCV7 or PCV13 immunization. A subset of post-immunization infant sera from PCV7 and PCV13 cohorts were assessed for functional antibody in serotypes 6A, 6B and 6C OPA assays. A. The percent of samples determined to be OPA positive (titer ≥1:8) are indicated above each group; bars indicate the geometric mean titer. B. Correlation plots of PCV13 OPA titers between Serotype 6A and 6C; 6B and 6C with Pearson correlation indicated.

Figure 2

OPA responses to pneumococcal serotypes 6A, 6B and 6C elicited by PCV7 or PCV13 immunization. A subset of post-immunization infant sera from PCV7 and PCV13 cohorts were assessed for functional antibody in serotypes 6A, 6B and 6C OPA assays. A. The percent of samples determined to be OPA positive (titer ≥1:8) are indicated above each group; bars indicate the geometric mean titer. B. Correlation plots of PCV13 OPA titers between Serotype 6A and 6C; 6B and 6C with Pearson correlation indicated.

Figure 3

Cross-functional OPA responses within serogroup 7. A subset of post-immunization infant sera from the PCV13 cohort positive for serotype 7F OPA responses, were assessed for OPA responses against the serotype 7A target strain. The percent of samples determined to be OPA positive are indicated above each group; bars indicate the geometric mean titer. B. Correlation plot of PCV13 OPA titers between Serotype 7F and 7A with Pearson correlation indicated.

Figure 3

Cross-functional OPA responses within serogroup 7. A subset of post-immunization infant sera from the PCV13 cohort positive for serotype 7F OPA responses, were assessed for OPA responses against the serotype 7A target strain. The percent of samples determined to be OPA positive are indicated above each group; bars indicate the geometric mean titer. B. Correlation plot of PCV13 OPA titers between Serotype 7F and 7A with Pearson correlation indicated.