Modeling specific antibody responses to natural immunization to predict a correlate of protection against infection before commencing a clinical vaccine trial

Abstract

Background: Clinical trials of vaccines for children to prevent acute otitis media (AOM) infections caused by the bacteria Streptococcus pneumonia (Spn) are in Phase I. The objective of this study was to use serum antibody measurements to pneumococcal purified protein candidate antigens that occurred after natural "immunization" to predict a correlate of protection response needed following an injectable vaccine against AOM in children.

Methods: 590 nasal and serum samples were collected from 129 healthy children at 6, 9, 12, 15, 18, 24 and 30-36 months of age and when the child developed AOM. Middle ear fluid to detect Spn was collected at every episode of AOM. Quantitative ELISA was used to determine serum IgG against 7 Spn vaccine antigens: PspA clade 3, PspA clade 5, PhtD, PhtE, LytB, PcpA and Ply. A correlate of protection (COP) was estimated by regressing AOM events against age adjusted antibody levels induced by nasopharyngeal colonization and AOM infections, using logistic regression and generalized estimating equation methods.

Results: A significant COP was found for Spn PhtD (p = 0.0015), PhtE (p = 0.00034), LytB (p = 0.004), PcpA (p = 0.002), and Ply (p = 0.007) between higher antibody levels and reduced frequency of AOM. We estimated that a 2-fold higher antibody level in a child than the mean antibody level induced by NP colonization (after adjusting for subject age) to PhtD, LytB, PcpA, PhtE or Ply reduced the risk of AOM by 14-21%, a 4-fold higher level reduced it by 25-38% and a 10-fold higher level reduced it by 39-54%.

Conclusion: We developed a model to predict the necessary level of serum antibody and fold higher above a threshold to PhtD, PhtE, LytB, PcpA and Ply that would correlate with a reduced likelihood of AOM in children age 6-24 months old if enrolled in a Phase III clinical efficacy trial.

Keywords: Streptococcus pneumoniae; antibody response; nasopharyngeal colonization.

Figure 1.

Plots of Spn antigen-specific antibody titers vs. age. The 4 colonization states are represented individually: dashed black line represents visits with no history of prior Spn colonization; solid black line represents visits where subjects experienced Spn colonization for the first time; dashed gray line represents visits where subjects had a history of prior colonization but were not currently colonized by Spn; solid gray line represents visits where subjects had a history of prior colonization and were currently colonized by Spn. P-values are given for the effect of colonization history on antigen-specific antibody titers.

Figure 2.

Estimated Spn AOM infection rates as a function of antibody concentration. The probability P-values, P(AOM), are given for dependence of AOM risk on specific antibody concentrations, log2 AB, adjusted by age of child.