Our findings demonstrate that healthy adults who develop an immune response to GBS CPS type Ia, III or V glycoconjugate vaccine retain robust in vitro
functional activity at least 18 to 24 months after immunization. The CPS-specific IgG levels at these time points have already been presented for these vaccines [5
]. The results of functional assays at intervals beyond 8 weeks post-immunization [5
] represent new data. Although the GMCs of CPS-specific IgG declined to 40 to 60% of peak concentrations at the latest interval, significant opsonophagocytic killing persisted, and suggests a possible correlate of protection.
Antibody to the capsular polysaccharide of GBS in a sufficient concentration was recognized as an immunologic correlate of protection against invasive GBS infection in the 1970’s [3
]. The specific concentration of maternal IgG required to protect neonates against invasive early-onset disease has been evaluated [14
]. Neonates whose mothers had levels of IgG to the CPS of type Ia GBS≥5 μg/mL had an 88% lower risk of developing early-onset disease caused by type Ia GBS compared with those whose mothers had levels <0.5 μg/mL [14
]. Neonates whose mothers had ≥10 μg/mL of IgG to the CPS of type III GBS had a 91% lower risk for early-onset disease compared with those whose mothers had levels of <2 μg/mL [15
]. Use of an opsonophagocytic assay as a functional correlate has been employed in prior studies of GBS vaccines [5
] but the assay has not previously been used to examine persistence of functional activity after immunization.
The importance of our observations is three-fold. First, it is probable that long-term protection after immunization against encapsulated bacteria is dependent upon persistence of functional antibodies and maintenance of B-cell memory [16
]. A functional assay that correlates with vaccine effectiveness is a particularly important surrogate of protection against a rapidly invasive pathogen such as GBS because immunological memory takes several days to activate after challenge by a pathogen, a response which may be too slow to prevent invasive infection. Second, a functional assay can be used as a correlate of protection over time after immunization. For example, serum bactericidal titers of at least 1:8, defined as a correlate of seroprotection for group C Neisseria meningitidis
, persisted for 5 years in 84.1% (95% confidence interval, 81.6% to 86.3%) of 987 participants immunized with a serogroup C meningococcal glycoconjugate vaccine at 6 to 15 years of age [17
]. In that cohort, geometric mean titers were significantly higher in those immunized at 10 years of age or older than among the younger children, suggesting that an adolescent immunization program could generate sustained protection against serogroup C meningococcal infection. Both opsonophagocytic activity and avidity have been shown to correlate better than antibody levels with in vivo
passive protection after immunization with pneumococcal polysaccharide vaccine, highlighting the importance of measuring functional activity [18
]. Finally, the finding that the functionality of CPS-specific IgG persists for at least 18 months to 2 years after GBS glycoconjugate immunization has implications for timing of immunization of women of childbearing age. Our results affirm the notion that women responding to GBS glycoconjugate vaccines administered early in pregnancy or prior to conception should have functionally active antibodies throughout pregnancy that theoretically could prevent early- or late-onset invasive infant infection.
Our findings are subject to several limitations. First, we studied vaccine recipients with very low pre-immunization concentrations of CPS-specific IgG to the immunizing GBS CPS type who responded with least a 1 μg/mL increase in CPS-specific IgG 4 weeks after immunization. It is likely that the kinetics of antibody function would differ, for example, among the 20% to 30% of individuals with moderate or high pre-immunization serum concentrations of CPS-specific IgG for whom immunization would be expected to boost existing immunity and potentially sustain functionality without decline for an even more prolonged interval after immunization [6
]. Colonization at the time of vaccination may also impact immune response. Studies of pneumococcal conjugate vaccines have found reduced response, using both qualitative and functional assays, among children who are colonized with vaccine serotypes at vaccine receipt [20
]. This potential correlation has not been assessed for recipients of GBS conjugate vaccines. Next, our data are limited to 2 years after immunization and evaluation of durability of function over a more extended interval of time would be required to direct vaccine platform constructs. Vaccination during adolescence would provide ample time for development of CPS-specific IgG before placental antibody transfer if pregnancy ensued quickly, but there are no data to date regarding durability of vaccine-induced antibodies or their function beyond 2 years. Finally, we evaluated persistence of function among adults 18–45 years of age. Aging reduces the functionality of anti-pneumococcal antibodies produced after natural exposure to the pathogen and in response to pneumococcal vaccine [21
]. A reduction in function in healthy elderly adults correlates with low IgG antibody avidity [18
]. Our evaluation of function of IgG elicited in response to a GBS conjugate in younger adults cannot be applied to durability in adults age 65 years or older who bear the highest attack rate and case-fatality ratio from invasive GBS infection among non-neonatal populations.
In conclusion, substantial functional activity, exceeding a 1 log10 reduction in GBS cfu/mL, was retained at 18 months to 2 years post-immunization among recipients of GBS Ia, III or V glycoconjugate vaccines. While additional long term assessment of vaccine-induced immunity should be undertaken, functional correlates should be considered in ongoing clinical trials of candidate GBS glycoconjugates to inform decisions regarding vaccine platforms and expected durability of vaccine-induced protection.