In a previous study, it was observed that children who were DTaP vaccine failures had a blunted antibody response to the nonvaccine antigen ACT, whereas unvaccinated children with pertussis had a vigorous antibody response to this antigen (4
). This observation led us to perform two retrospective studies of vaccine failure or primary infection in two Swedish vaccine efficacy trials (1
). Specifically, we have looked at and presented here the antibody responses to vaccine and nonvaccine antigens (FHA, PRN, and FIM 2/3) in vaccine failures and in unvaccinated children. The results of these two analyses led us to perform an additional retrospective study in Sweden and two retrospective studies of German children who participated in a DTaP vaccine efficacy trial (5
The results of the two retrospective analyses in Sweden indicated that children who were vaccine failures had brisk antibody responses to antigens present in the vaccines they had previously received, whereas their antibody responses to nonvaccine antigens were minimal. In the first Swedish trial, there was a suggestion that the antibody response to the nonvaccine antigen FHA in vaccine failures was lower than the response to the same antigen in nonvaccinated controls with pertussis. In the second Swedish trial, the antibody responses to the two nonvaccine antigens PRN and FIM 2/3 in vaccine failures were significantly lower than the responses to these antigens in the children with pertussis who were DT recipients (controls).
The blunted antibody response to nonvaccine antigens in the children with vaccine failure might be explained simply by the effect of priming versus nonpriming (11
). However, this does not explain the fact that the response to the nonvaccine antigens in the vaccine failures was lower than that which occurred in previously unvaccinated children with pertussis. There are perhaps two mechanisms which could explain the minimal response to the nonvaccine antigens in the children who were vaccine failures.
One explanation might be that illness in vaccine failures tends to be less severe, which might result in a lowered antibody response. To shed light on this hypothesis, we carried out the two analyses presented in Tables and . Although the findings in both data sets suggest that more severe illness is associated with a more vigorous antibody response, the differences overall are not striking.
A second hypothesis, which we favor, is that the findings can be explained by linked epitope suppression caused by preferential responses of memory B cells following secondary exposure to vaccine components (16
). Memory B cells and circulating antibodies are readily available to respond to additional exposures. They outcompete naïve B cells for access to the Bordetella
epitopes, as they are more numerous and their receptors exhibit a higher antigen affinity. Higher expression levels of cell surface major histocompatibility complex class II (MHC-II) and costimulatory molecules also allow memory B cells to preferentially interact with T helper cells required for further propagation of the immune response. Linked epitope suppression applies as the immune response to the new epitopes is suppressed by the strong response to the original vaccine components.
We believe that the blunted antibody response that we have demonstrated is an important consideration in the choice of DTaP vaccines for general use and for the development of new DTaP vaccines. For example, as data from our two previous studies (5
) of serologic correlates of immunity indicate, children who received only a PT toxoid or PT/FHA vaccine have enhanced and continued susceptibility to B. pertussis
infections compared to that of children immunized with multicomponent vaccines. As modest PRN antibody values are most important for exposed children, failure to include PRN in vaccines likely results in subsequent suppression of PRN responses. The original exposure essentially “locks in” the immune response to certain epitopes and inhibits the response to linked epitopes even following subsequent exposures. The only way to break this pattern is to expose the individual to new epitopes that are unlinked to the epitopes to which the individual had been exposed in prior encounters. Thus, if immunization against additional epitopes is desired, these epitopes have to be introduced separately in a vaccine to take effect, because in combination vaccines, the generation of antibodies against them is always suppressed due to the preferential response to previously introduced antigens.
Because the antibody responses to PRN and FIM 2/3 in primary infections in controls (DT recipients) were modest in the second study in Sweden, we performed the time-related-response study of the children in the German efficacy trial; we thought that the inferior responses in the controls might be due to the time of collection of the convalescent-phase serum samples. However, this does not appear to be the case (Fig. ). Of interest are the differences in the patterns of antibody response to PT in the vaccine failures and controls compared with the patterns of response to the other antigens. In the >50-day time period, the GMV response to PT in the control group was similar to or perhaps higher than that in the vaccine failures (106.3 versus 45.8 EU/ml, respectively [P
= 0.2]). In a study in Senegal, Simondon et al. (21
) noted similar findings with children who were vaccine failures or who were unvaccinated. In contrast, in our study of the >50-day period, the responses to FHA, PRN, and FIM-2 were significantly lower in the controls than in the vaccine failures.
The DTaP vaccine failure group has a memory response against specific Bordetella
antigens, while the DT group is considered naïve. Memory responses are characterized primarily as faster, not necessarily higher, at all time points (11
). Therefore, we expect the antibody responses to these Bordetella
antigens to initially be higher in the DTaP vaccine group than in the DT group but for the DT group's antibody values to eventually catch up. This result occurred with antibody to PT but not with antibody to FHA, PRN, or FIM-2. This difference in the response to PT compared with the responses to FHA, PRN, and FIM-2 might be explained by the uniqueness of PT. Specifically, PT is unique in nature, with no homologues, whereas the other antigens have many homologues in other bacterial species which infect children (14
Therefore, the DT group could have prior exposure to other bacteria that express FHA-, PRN-, and FIM-like proteins that could bias the immune response away from the B. pertussis
detectable form of each antigen. This again could be a manifestation of linked epitope suppression. Specifically, the children would have a major antibody response to the proteins like FHA, PRN, and FIM from other bacteria and a lower response to the B. pertussis
-specific proteins that our ELISAs detect. Since PT is soluble, it could be “seen” by the immune system as a nonlinked antigen (14
Upon subsequent exposure and infection, previous DTwP or DTaP vaccinees respond more vigorously to the antigens contained in the vaccines with which they were immunized than to other B. pertussis
proteins, as antibodies to more than one vaccine antigen correlate with protection. Our present findings as well as our previous serologic-correlate data suggest that DTaP vaccines should contain multiple antigens, rather than just PT or PT and FHA (5
). Since in five trials DTwP vaccines were more efficacious than DTaP vaccines (9
), we should reexamine the antibody responses of DTwP recipients to other antigens (such as lipopolysaccharide [LPS], BrkA, SphB1, Vag8, Bsp22, and TcfA) and explore whether one or more of these antigens as well as ACT should be added to DTaP vaccines.