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The increased incidence of whooping cough worldwide suggests that current vaccination against Bordetella pertussis infection has limitations in quality and duration of protection. The resurgence of infection has been linked to the introduction of acellular vaccines (aP), which have an improved safety profile compared with the previously used whole-cell (wP) vaccines. To determine immunological differences between aP and wP priming in infancy, we performed a systems approach of the immune response to booster vaccination. Transcriptomic, proteomic, cytometric, and serologic profiling revealed multiple shared immune responses with different kinetics across cohorts, including an increase of blood monocyte frequencies and strong antigen-specific IgG responses. Additionally, we found a prominent subset of aP-primed individuals (30%) with a strong differential signature, including higher levels of expression for CCL3, NFKBIA, and ICAM1. Contrary to the wP individuals, this subset displayed increased PT-specific IgE responses after boost and higher antigen-specific IgG4 and IgG3 antibodies against FHA and FIM2/3 at baseline and after boost. Overall, the results show that, while broad immune response patterns to Tdap boost overlap between aP- and wP-primed individuals, a subset of aP-primed individuals present a divergent response. These findings provide candidate targets to study the causes and correlates of waning immunity after aP vaccination.

Whole-cell inactivated vaccine against Bordetella pertussis (wP) was substituted in many countries by an acellular subunit vaccine (aP) to reduce side effects. Recent epidemiological studies have shown that aP vaccination in infancy induces less durable immunity than wP vaccination. To determine immunological differences associated with aP vs. wP priming, we performed system-level profiling of the immune response in adults primed with aP vs. wP vaccine in infancy following the Tdap booster vaccination as a surrogate to antigen encounter in vivo. Shared immune responses across cohorts were identified, including an increase of the blood monocyte frequency on day 1, and strong antigen-specific IgG response seven days after boost. Comparing aP and wP primed individuals, we found a subset of aP-primed individuals with higher levels of expression for several genes including CCL3 on day 3 and NFKBIA and ICAM1 on day 7 post immunization. These observations were supported by increased CCL3 concentrations in plasma of aP primed individuals. Contrary to the wP individuals, the CCL3-high aP subset presented boosted PT-specific IgE responses. Furthermore, higher antigen specific IgG4 and IgG3 antibodies against specific vaccine antigens at baseline and post boost of aP individuals was observed, suggesting a long term maintained difference in the IgG subtype response. Overall our findings demonstrate that, while broad immune response patterns to Tdap boost overlap between aP and wP primed individuals, a subset of aP primed individuals present a divergent response. These findings provide candidate targets to study the causes and correlates of waning immunity after aP vaccination.

In the mid-1990s, whole-cell pertussis (wP) vaccines were associated with local and systemic adverse events that prompted their replacement with acellular pertussis (aP) vaccines in many high-income countries. In the past decade, rates of pertussis disease have increased in children receiving only aP vaccines. We compared the immune responses to aP boosters in individuals who received their initial doses with either wP or aP vaccines using activation-induced marker (AIM) assays. Specifically, we examined pertussis-specific memory CD4+ T cell responses ex vivo, highlighting a type 2/Th2 versus type 1/Th1 and Th17 differential polarization as a function of childhood vaccination. Remarkably, after a contemporary aP booster, cells from donors originally primed with aP were (a) associated with increased IL-4, IL-5, IL-13, IL-9, and TGF-β and decreased IFN-γ and IL-17 production, (b) defective in their ex vivo capacity to expand memory cells, and (c) less capable of proliferating in vitro. These differences appeared to be T cell specific, since equivalent increases of antibody titers and plasmablasts after aP boost were seen in both groups. In conclusion, our data suggest that there are long-lasting effects and differences in polarization and proliferation of T cell responses in adults originally vaccinated with aP compared with those that initially received wP, despite repeated acellular boosters.

In the mid-1990s vaccine-related side effects prompted the replacement of the whole Pertussis (wP) by a new acellular Pertussis vaccine (aP). Unexpectedly, whooping cough cases have recently increased, and the switch to the aP vaccine suspected to underlie this rise in morbidity, despite the use of routine boosters. Here we compared the immune responses to aP boosters in children who received their initial doses with either wP or aP vaccines. The use of ex vivo AIM assays highlighted a Th2 vs Th1/Th17 differential polarization of PT-specific memory CD4+ T cells as a function of childhood vaccination. The nature of the differences was further investigated for memory subset composition, activation, exhaustion marker expression, and transcriptomic profiles. Remarkably, donors originally primed with aP were defective in their ex vivo capacity to expand memory cells following a booster aP immunization and less capable to proliferate in vitro in response to PT epitopes. By contrast antibody responses are boosted in both aP and wP cohorts following IgG subclass distribution. Most recently, we have assessed early immune responses followed aP boosting for the aP and wP cohorts using longitudinal transcriptomics data from PBMC. We have identified several modules of genes that are co-expressed; using cell frequency data from CyTOF we infer modules correlated with specific cell types. Furthermore, we identified certain modules that show differential expression profiles between the two cohorts and are mostly enriched in immune related functions. In conclusion, our data suggest that the original priming after birth with aP and wP vaccines induce different T cell phenotypes associated with long-term T cell polarization.

Background The use of hamstring autografts less than 8.0mmin size to reconstruct anterior cruciate ligament (ACL) injuries is associated with a higher risk of graft failure. A hybrid graft consisting of hamstring autograft tendons supplemented by allograft tendon to create a more robust graft has been proposed as an alternative treatment option in patients with small hamstring graft size. Multiple studies have shown inconsistent results for ACL reconstructions with hybrid grafts. This meta-analysis was designed to examine the rates of graft failure and clinical outcome measures for hybrid grafts in primary ACL reconstructions. Methods A search was performed of PubMed, MEDLINE and Google Scholar using the terms “Anterior Cruciate Ligament” OR “ACL” combined with “reconstruction” and “hybrid.” Two authors reviewed the papers, and outcomes were subdivided into autograft and hybrid graft. Chi Square with Yates Correction was used to determine the correlation between failure and type of graft for all patients, as well as for the subanalysis done for patients less than 18 years old and patients greater than 18 years old. Chi Square with Yates Correction and unpaired t-test were used to compare the demographic characteristics of the two groups. Unpaired t-test was used to evaluate for differences in subjective outcome scores. Results A total of 9 studies met the inclusion criteria. Only one study included a comparison of hybrid grafts with autografts and allografts, and as such, the allograft data was excluded from the analysis. Overall a total of 506 patients were treated with autografts with an average age of 26.7 +/- 10.8 years; and a total of 453 patients were treated with hybrid grafts with an average age of 28.33 +/-10.4 years. All patients had minimum follow up of 2 years with average follow up of 38.2 months. There was no significant difference in sex between the two groups (p = 0.07). There were significantly more females in the hybrid group compared to the autograft group (48% versus 42%, respectively p = 0.02). There was no significant difference in failure rates for the autograft or hybrid graft subgroups (p = 0.92). International Knee Documentation (IKDC) scores and Lysholm scores were significantly higher in the autograft group than the hybrid graft group (p = 0.02 and p < 0.01, respectively). There was no significant difference in Tegner Activity scores (p =0.68). On further subgroup analysis, there was no difference in failure rates for autografts vs hybrid grafts with subgroup analysis for both patients under 18 years of age and patients over 18 years of age (p = 0.78 and p = 0.24, respectively). Conclusions Supplementation of hamstring autograft with allograft tissue to form a “hybrid graft” did not alter the graft failure rate. But, the use of hybrid graft was associated with worse subjective outcome scores as measured by IKDC and Lysholm scores. Level of Evidence Level IV (A meta-analysis of Level II, III, and IV studies)