Patients with chronic kidney disease (CKD) respond poorly to hepatitis B virus (HBV) vaccines, and a 2018 randomized trial (da Silva et al., PLoS ONE) showed that a four-dose 40 µg schedule improves seroconversion in pre-dialysis CKD yet fails to restore the normal activation of CXCR3+CCR6- circulating T follicular helper cells (cTFH) seen in healthy controls. The trial, together with an earlier TLR9-agonist-adjuvanted vaccine trial in CKD (Janssen et al., 2013), leaves a precisely defined open problem: identify the cellular mechanism by which CKD impairs vaccine-elicited seroconversion, determine by what mechanism augmented dosing or TLR9-agonist adjuvantation improves it, and establish whether any schedule, adjuvant, or formulation can restore normal vaccine-elicited cTFH activation in CKD.

Background

Chronic kidney disease (CKD) is the progressive loss of kidney function, staged by estimated glomerular filtration rate; patients approaching kidney failure (end-stage kidney disease, ESKD) require dialysis or transplantation. Because dialysis requires repeated vascular access and, historically, blood transfusions, HBV infection has long been an occupational and clinical hazard in this population, and vaccination against HBV is standard of care. Protection is measured by the serum level of antibody to hepatitis B surface antigen (anti-HBs, expressed in mIU/mL): seroconversion (seroprotection) is conventionally defined as an anti-HBs titer of at least 10 mIU/mL, and titers above 100 mIU/mL are considered preferable in CKD because they are associated with longer-lasting protection.

CKD patients mount suboptimal responses to HBV vaccination: seroconversion rates are lower than in healthy adults, protective titers decay faster, and older age, diabetes, and advancing CKD worsen the defect. The immunological basis is only partly understood. CKD is associated with broad immune dysfunction — reduced numbers and impaired function of B cells and T cells, chronic low-grade inflammation, and T-cell exhaustion — attributed in part to the uremic milieu (the accumulation of metabolites and toxins that failing kidneys no longer clear), with proposed contributors including decreased cytokine clearance, increased gut permeability, oxidative stress, and accumulation of protein-bound uremic retention solutes such as indoxyl sulfate and p-cresyl sulfate, none of which has been causally tied to any specific vaccine-response defect.

High-affinity antibody responses depend on germinal centers, the specialized microanatomical sites in lymph nodes where B cells proliferate, mutate their immunoglobulin genes, and are selected for antigen affinity. This process is driven by T follicular helper (TFH) cells, a CD4+ T-cell subset characterized by expression of the chemokine receptor CXCR5, the co-receptor PD-1 (a marker of recent T-cell activation), and the co-stimulatory molecule ICOS, and by secretion of IL-21. Because germinal centers are inaccessible in living humans, research uses circulating TFH (cTFH) cells — the memory CXCR5+ CD4+ T cells in blood that share functional properties with germinal-center TFH. cTFH can be subdivided by the chemokine receptors CXCR3 and CCR6 into functional subsets (CXCR3+CCR6- roughly Th1-like, CXCR3-CCR6+ Th17-like); in healthy people, the CXCR3+CCR6- cTFH subset transiently upregulates PD-1 and ICOS about seven days after vaccination (e.g., influenza or HBV), and the magnitude of this activation correlates with the subsequent antibody response. The cellular events underlying antibody responses can also be glimpsed through plasmablasts (short-lived antibody-secreting cells) that transiently appear in blood about a week after vaccination.

Against this background, da Silva, Baker, Alshekaili, Karpe and Cook (PLOS ONE 2018, DOI 10.1371/journal.pone.0204477) reported a randomized trial in pre-dialysis CKD patients comparing four doses of 20 µg versus four doses of 40 µg of recombinant hepatitis B surface antigen (HBsAg) vaccine (Engerix-B), with age-matched healthy controls receiving a standard 20 µg schedule. They showed for the first time that the four-dose 40 µg schedule is superior in both rate and magnitude of seroconversion in CKD. Mechanistically, they found that CKD patients were selectively deficient at baseline in the CXCR3+CCR6- cTFH subset (most pronounced in serological non-responders), and that HBV vaccination elicited PD-1 upregulation on CXCR3+CCR6- cTFH in healthy controls but not in CKD patients — in either dose arm — whereas influenza vaccination activated this subset in both groups. Their longitudinal follow-up (only 7 CKD and 4 healthy initial responders) showed a significant decline of anti-HBs titer in CKD over roughly 4.5 years.

The authors also pointed to an adjacent result: an investigational recombinant HBsAg vaccine adjuvanted with a Toll-like receptor 9 (TLR9) agonist — a CpG dinucleotide oligodeoxynucleotide that activates innate immunity through TLR9 (HBsAg-1018, the basis of the later-licensed two-dose HepB-CpG vaccine HEPLISAV-B) — had improved seroconversion in CKD patients (Janssen et al., Vaccine 2013, DOI 10.1016/j.vaccine.2013.05.067), but, as they stated verbatim, "the cellular mechanism to account for this response remains to be determined". The trial itself had acknowledged limitations: CKD participants were not blinded (the augmented dose required two injections), there was no 40 µg healthy-control group, and failure to reach the pre-planned enrollment increased the risk of type II error. The unresolved questions that survive form the problem stated below.

Problem Statement

The overarching open problem, as left by da Silva et al. (2018) and the earlier TLR9-agonist trial of Janssen et al. (2013), is to determine the cellular basis of impaired hepatitis B vaccine responses in chronic kidney disease and to use that understanding to optimize vaccination in this population. Its linked, source-faithful components are:

  1. Cellular mechanism of impaired seroconversion. By what cellular mechanism does CKD impair seroconversion to HBV vaccination? In particular, is the deficiency and defective vaccine-elicited activation (PD-1 upregulation) of the CXCR3+CCR6- subset of circulating T follicular helper cells causally responsible for poor antibody responses, or a correlate of an upstream defect?

  2. Mechanism of rescue by dose or adjuvant, and restorability of cTFH activation. By what cellular mechanism does an augmented (40 µg four-dose) schedule improve seroconversion in CKD — the source trial having shown that it overcomes the serological defect in many CKD patients "although this does not restore the peripheral cellular events to normality" — and by what cellular mechanism does a TLR9-agonist (CpG)-adjuvanted recombinant HBsAg vaccine improve seroconversion in CKD, the mechanism the source paper states verbatim "remains to be determined"? Can any schedule, adjuvant, or formulation restore the normal vaccine-elicited activation of CXCR3+CCR6- cTFH in CKD to the pattern seen in healthy controls?

  3. Cause of the cTFH defect. Which uremia-related metabolic and inflammatory mediators (e.g., altered cytokine clearance, increased gut permeability, protein-bound uremic retention solutes, oxidative stress), if any, cause the depletion or dysfunctional activation of the CXCR3+CCR6- cTFH subset in CKD, and by what pathway?

Components 1-3 constitute the mechanistic core left open by the source papers, whose stated forward direction is to "test the cellular basis of this finding, in order to optimize vaccine responses in patients with CKD". The restorability question in component 2 is open in both directions: the source trial itself observed that the augmented 40 µg schedule improved seroconversion without restoring the peripheral cellular events to normality.

References

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