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Restoration of exhausted host immune system is critical to
the control and/or elimination of chronic infection. Theoretically,
therapeutic vaccines are promising to enhance
antigen-specific cytotoxic T cell response to eliminate
infected hepatocytes. Unfortunately, two recent clinical
trials showed unsatisfactory results. One trial used DNA
vaccine expressing preS2-S in combination with NAs for
48 weeks in patients receiving NAs for a median of
3 years. Virological reactivation developed in 97% of
vaccinated, not different from the control group. HBsAg
levels were around 2000 IU/ml before vaccination in both
groups and did not decline in either [21]. The other trial
applied recombinant yeast expressing HBsAg, core antigen,
and HBx in virally suppressed patients for 24 weeks.
Pre-trial median HBsAg levels were about 3.0–3.2 log IU/
ml. No significant difference was found in HBsAg declines
between NAs alone or NAs–vaccine combination at
24 weeks (- 0.019 for NA alone, - 0.020 to - 0.048 log
IU/ml for combined) [22]. In our pilot 48-week vaccine
trial, we found HBsAg-based conventional vaccine could
attain a significant HBsAg decline (- 0.27 log IU/ml) in a
selected group of low-HBsAg, with HBeAg-negative
patients with 73% participants continuously showing
decreasing levels even post-vaccination. The vaccine effect
on the HBsAg decrement in the participants was significantly
greater than a comparable group of CHB patients
with matched baseline HBsAg levels. The better response
in our trial may be related to several factors, including
younger age (mean 44 years in our trial, 49 and 47 years in
the other two trials, respectively), lower baseline HBsAg
levels, and more naı¨ve patients.
In the search for host factors in vaccine responders, we
identified significantly different mRNA expression levels
of HLA-DQ and DMB genes, indicating regulation of
adaptive immunity is crucial for treatment responses.
Further HLA genotyping revealed a higher frequency of
HLA-DRB1*04, HLA-DQB1*04, and HLA-B*40 in the
non-responders. Human leukocyte antigens play an essential
role in adaptive immunity against infection by
presenting microbe peptides to specific T cells. Different
HLA variants are associated with clinical outcome of HBV
infection. The most relevant HLA genetic polymorphisms
(SNPs, single nucleotide polymorphism) on viral clearance
or persistence are at HLA-DPA1 and -DPB1 regions in
Japanese, Thai, and Han Chinese and at HLA-DP and -DQ
regions in Argentineans [23–25]. HLA-DRB1*04:06 and
HLA-B*40:01 are related to natural recovery in Han Chinese
and Aborigines in Taiwan, respectively [26]. Whereas
HLA-DPB1 SNP (rs9277535 non-GG genotypes) is linked
to spontaneous HBsAg clearance in Taiwanese males [27].
HLA-DPA1 and -DPB1 SNPs C 2 A-alleles are associated
with the degree of HBsAg decline in lamivudine-treated
patients [28]. In PegIFN-treated patients, the degree of
HBsAg decline is related to G-alleles at HLA-DPA1 and
DPB1, and HBsAg loss, GG allele at HLA-DPB1 [29]. Our
finding that certain HLA genotypes (HLA-B*40,
DQB1*04, and DRB1*04) were associated with vaccine
responsiveness might be useful in future application (for
selection of potential responders). In the present study, if
the eight patients carrying C 1 poor response allele were
excluded, 11 of the remaining patients were responders.
Additionally, if the 4 patients carrying C 2 poor response
alleles were excluded, 14 of the 15 remaining patients were
responders.
In conclusion, in this pilot study applying conventional
HBsAg-based vaccine in low-level HBsAg CHB patients, a
significant decline of HBsAg serum levels could be
induced. For those experiencing a consistent on-treatment
and off-treatment HBsAg decline (responders), specific
HLA genotypes played a predictive role.
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发表于 2018-10-22 11:43
