Non-responder Children Research Articles

Effect of Revaccination with Recombinant Hepatitis B Virus Vaccine Containing Higher Antigen Concentration in Non-responder Children

BACKGROUND: Hepatitis B is a global health problem carrying significant morbidity and mortality. Vaccination against hepatitis B virus (HBV) has been implemented with good effectiveness, but a small proportion of children do not respond well after complete routine vaccination. They are called non-responders and are at higher risk for HBV infection.
 AIM: The objective of the study was to determine the effect of revaccination with recombinant HBV vaccine containing higher antigen concentration in non-responder children.
 METHODS: A prospective study was conducted from January 2018 until December 2019. Inclusion criteria were children aged 9–15 months and had three doses of recombinant HBV at 0, 1, and 6 months old. Exclusion criteria were the presence of acute or chronic hepatitis B and conditions which alter immune function and immunosuppressant medications consumption. Demographic and clinical characteristics were gathered from each subject along with serum HBsAb titer examination. Subjects with serum anti-hepatitis B surface antigen (HBsAb) titer of <10 IU/L were classified into non-responders and underwent revaccination with 3 doses of vaccine containing 20 μg HBsAg. The revaccination series was repeated until all subjects showed seroconversion. After each series, repeated serum HBsAb titer measurements were conducted.
 RESULTS: A total of 400 children were enrolled in this study with a mean age of 12.1 (SD 2.64) months. Subjects were dominated with females (54.0) and normal nutritional status (79.0). The rate of non-responsiveness was 9.0%. Of all non-responders, 88.9% experienced seroconversion after the first revaccination series. After the third revaccination series, all subjects had serum HBsAb titer at the protective level.
 CONCLUSION: Revaccination with recombinant HBV vaccine containing higher antigen concentration in non-responder children is effective.

Viral evolution in the cell-associated HIV-1 DNA during early ART can lead to drug resistance and virological failure in children.

Using cell-associated DNA and cell-free RNA of human immunodeficiency virus type-1 (HIV-1), we investigated the role of drug-resistant viral variants that emerged during early antiretroviral therapy (ART) in determining virological outcome. This case-control study compared virologic nonresponder children (two viral loads [VLs] ≥ 200 copies/mL within 2 years of ART) and responder children (two VLs < 200 copies/mL after six months of ART) infected with HIV-1 initiated on nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART. The partial reverse-transcriptase gene of HIV-1 in cell-associated DNA was genotyped using next-generation sequencing (NGS; Illumina; threshold 0.5%; at baseline and month six of ART) and in cell-free RNA (concurrently and at virological failure; VL > 1000 copies/mL at ≥ 12 months of ART) using the Sanger method. Among 30 nonresponders and 37 responders, baseline differences were insignificant while adherence, VL, and drug resistance mutations (DRMs) observed at month six differed significantly ( P ≥ 0.05). At month six, NGS estimated a higher number of DRMs compared with Sanger (50% vs 33%; P = 0.001). Among the nonresponders carrying a resistant virus (86.6%) at virological failure, 26% harbored clinically relevant low-frequency DRMs in the cell-associated DNA at month six (0.5%-20%; K103N, G190A, Y181C, and M184I). Plasma VL of > 3 log 10 copies/mL (AOR, 30.4; 95% CI, 3.3-281; P = 0.003) and treatment-relevant DRMs detected in the cell-associated DNA at month six (AOR, 24.2; 95% CI, 2.6-221; P = 0.005) were independently associated with increased risk for early virological failure. Our findings suggest that treatment-relevant DRMs acquired in cell-associated DNA during the first six months of ART can predict virological failure in children initiated on NNRTI-based ART.

Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer's Disease.

The ketogenic diet, originally developed for the treatment of epilepsy in non-responder children, is spreading to be used in the treatment of many diseases, including Alzheimer’s disease. The main activity of the ketogenic diet has been related to improved mitochondrial function and decreased oxidative stress. B-Hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species (ROS), improving mitochondrial respiration: it stimulates the cellular endogenous antioxidant system with the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), it modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) and it increases the efficiency of electron transport chain through the expression of uncoupling proteins. Furthermore, the ketogenic diet performs anti-inflammatory activity by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome as well as inhibiting histone deacetylases (HDACs), improving memory encoding. The underlying mechanisms and the perspectives for the treatment of Alzheimer’s disease are discussed.

A five-year observation on efficacy of revaccination in children of non-response to hepatitis B vaccine

To evaluate the long-term efficacy of revaccination in non-responder children to primary hepatitis B (HB) vaccination and to compare the efficacy of low-dose intradermal inoculation to that of routine-dose intramuscular inoculation. 40 healthy non-responder children to primary HB vaccination identified by screening were given a three-dose revaccination randomly by intramuscular (n = 17, 10 microg per dose) or intradermal route (n = 23, 2 microg per dose) since September, 1999, and their blood specimens were collected regularly for testing for HB virus markers up to five years. Another 80 responder children to primary HB vaccination were also followed-up as controls without revaccination. By the end of five-year follow-up, HBsAg-specific lymphocyte response was investigated in vitro, and a booster dose (5 microg) was given to those with negative conversion of anti-HBs and their anamnestic responses were evaluated 12-14 days later. Serum anti-HBs did not reach 10 IU/L only in one of 40 non-responder children, who received intradermal revaccination. In the fifth year after revaccination, 50% of the non-responder children who received intramuscular revaccination still maintained anti-HBs of > or = 10 IU/L, though the rate was significantly lower than 85% in controls. Following the booster dose, a robust anamnestic response was developed in all of 8 intramuscular revaccinees and 11 controls but 16 of 18 intradermal revaccinees, who lost anti-HBs of > or = 10 IU/L over time, and geometric mean titers of anti-HBs climbed to 208, 105, and 549 IU/L, respectively. Secretions of HBsAg-specific interleukin-2 and -5 could be detected in peripheral blood mononuclear cell samples of more than 70% of non-responder children. Person-year infection rates of HB virus were 8.9% (8/89.9 person-years) for intradermal revaccinees, significantly higher than 3.6% (12/337.2 person-years) in controls, and 4.3% (3/70.2 person-years) for intramuscular revaccinees, approximating to that of controls, based on positive conversion of anti-HBc. Three-dose intramuscular revaccination did play an important immune protection for non-responder children to primary HB vaccination, but its efficacy could not reach the level of primary vaccination in responders. Low-dose intradermal inoculation was not as effective as route-dose intramuscular inoculation with the same doses in revaccination for non-responder children to primary HB vaccination.

Hepatitis B revaccination in healthy non-responder Chinese children: Five-year follow-up of immune response and immunologic memory

To assess persistence of anti-HBs and immunologic memory of non-responders after revaccination, 40 healthy non-responder children were given a three-dose recombinant hepatitis B vaccine revaccination randomly by intramuscular (10 μg per dose) or intradermal (2 μg per dose) route and followed up to five years. All 17 intramuscular and 22 of 23 intradermal children developed a seroprotective antibody response (anti-HBs ≥10 mIU/mL) after revaccination. Children of intramuscular group had significantly higher seroprotection rates and anti-HBs geometric mean titers than the intradermal group. At year 5, 50% of children in intramuscular group, but only 18.2% of intradermal group still maintained seroprotection ( P = 0.075). By the end of follow-up, a booster dose (5 μg) was given to those who had lost seroprotection. All the eight intramuscular children developed an anamnestic response with increase of anti-HBs level by 215 times, but two of the 18 intradermal children failed to produce seroprotective level. Three-routine-dose intramuscular revaccination was significantly more effective than low-dose intradermal revaccination with the same number of injections. No child seroconverted to HBsAg, and 11 had transient infections indicated by seroconversion to anti-HBc. These results demonstrated that non-responders could benefit from three doses intramuscular revaccination not only in high proportion of anti-HBs conversion but also in long-term persistence of seroprotection, and more importantly in preservation of the immunologic memory years after loss of protective anti-HBs.

No Evidence of Autoimmunity in 6-Year-Old Children Immunized at Birth With Recombinant Hepatitis B Vaccine

Taking into account that genetic predisposition, marked by human leukocyte antigen (HLA) class I and II genes, augments the probability of developing an autoimmune disorder after a triggering vaccination, as largely debated, we investigated the frequency of autoantibody production after recombinant hepatitis B vaccine (rHBv) in 6-year-old children immunized at birth to evaluate an association between autoimmune disorders and hepatitis B virus vaccination. We investigated the presence of autoantibodies in 210 6-year-old children who were immunized at birth with rHBv: 200 showed anti-hepatitis B surface antigen concentrations > or =10 mUI/mL at seroconversion (responders), and 10 were nonresponders. Data were compared with those obtained in 109 unvaccinated children. All participants were screened for the presence of antinuclear antibodies (ANAs), anti-DNA, antimitochondrial, anti-liver/kidney microsomal, antireticulin, anti-smooth muscle (SMA), and antiribosomal antibodies. All participants were also screened for the presence of antithyroid antibodies, such as antithyroglobulin and antiperoxidase, and for antibodies found in type 1 diabetes, such as tyrosine phosphatase (IA-2A) and glutamic acid decarboxylase (GADA). HLA typing was extended to all 10 nonresponders. Autoantibodies were found in 16 of the 200 responders: ANAs were found in 12 (6%), smooth muscle antibodies were found in 4 (2.0%), and antireticulin antibodies and endomysial antibodies were found in 1 girl with ANAs. Antithyroid antibodies, IA-2A, and GADA were not present in any of the participants. No significant difference was found in the frequency of autoantibodies between vaccinated and control children. Three of the 10 nonresponder children were SMA-positive (30% vs 2% of responders); they also carried the supratype HLA-C4AQ0,DRB1*0301,DQB1*02. A family history for autoimmune disorders was present in 3 (18%; 95% confidence interval [CI]: 4.0%-45.6%) of the 16 responder infants with autoantibodies, in 15 (8.4%; 95% CI: 4.6%-13.1%) of responder children without autoantibodies, and in 1 (10%) of the 10 nonsreponder children. From our data, vaccination with rHBv given during the neonatal period does not seem to increase autoantibody production in a 6-year-old children. Autoantibodies, referred to as natural autoantibodies, can be found in healthy participants, but their significance is unclear. These autoantibodies often cross-react with bacteria or tumor antigens, suggesting their importance in innate immunity. It has been demonstrated in an animal model that self-antigen can promote B-cell accumulation, and that a significant proportion of natural autoantibodies is the product of this self-antigen- dependent process. Consequently, it has been speculated that self-antigens play a positive role in recruiting B cells as a part of innate immunity, but this process carries a potential risk for unregulated growth. Spreading of the immune response is a common theme in organ-specific and systemis autoimmune diseases, and this could be initiated by exogenous agents, in genetically susceptible hosts, owing to molecular mimicry of natural antigen. Moreover, 3 (18%) of the 16 children who had autoantibodies had a family history of autoimmume diseases. Thus, it is apparent that susceptibility to autoimmunity is determined by genetic factors rather than by vaccine challenge. Among all the children considered, only 1 girl (0.5%) developed celiac disease, reflecting the prevalence described in the literature. GADA and IA-2A were not found in our children; this observation is in agreement with data showing that type 1 diabetes risk may not be altered by vaccinations administered during childhood. On the contrary, a high frequency (30%) of autoantibodies, in particular SMA, was observed in the nonresponder children. The 3 SMA-positive children carried the HLA-C4Q0,DRB1*0301,DQB1*02 haplotype, a well-known predisposing factor for autoimmune disorders. On the other hand, the presence of autoantibodies to smooth muscle is known to be common in hepatitis B infection, and, it has been shown that cross-reactive immunity targeting homologous self-protein may partly account for autoantibody production. Although hepatitis B vaccination given during the neonatal period does not increase autoantibody production in 6-year-old immunized children, we deem useful a more prolonged follow-up for these nonresponder children carrying certain HLA haplotypes (such as C4AQ0,DRB1*0301,DQB1*02), particularly because most autoimmune diseases do not develop until later in life.

Varicella vaccination in children with steroid-sensitive nephrotic syndrome.

We have studied serological and clinical response to live, attenuated varicella zoster virus (VZV) vaccine (Varilrix, SmithKline Beecham) in 20 patients with steroid-sensitive nephrotic syndrome (SSNS) in remission and 22 normal controls who had no history of varicella and no detectable antibody to VZV. Nephrotic patients included 15 boys and 5 girls, with a mean age of 4.7 years (range 2-11.4 years). The controls were healthy age-matched children (13 girls and 9 boys). Seventeen patients with SSNS (85%) and 19 healthy controls (86%) seroconverted 8 weeks after vaccination. One patient with SSNS had a relapse 20 days after vaccination, and 1 child in the control group had a rash. Two years after vaccination, antibodies to VZV were detected in 12 of 17 responders, 2 of 3 non-responders, and 13 of 22 controls. Within 2 years of vaccination, 3 of the vaccine responder children with SSNS had a mild varicella infection. Two responder and 1 non-responder nephrotic children and 9 controls were lost to long-term follow-up. Our results show that immunization with a single dose of VZV vaccine is safe and effective in children with SSNS in remission.

Pilot interferon-beta trial in children with chronic hepatitis B who had previously not responded to interferon-alpha therapy.

Recombinant interferon alpha (IFN-alpha) treatment is useful in 40% of children with chronic hepatitis B. However, nonresponder children continue to have viral replication and a progressive disease. To administer natural IFN-beta to hepatitis B virus chronic carrier children who had not responded to a previous IFN-alpha cycle. Twenty-two children with chronic hepatitis B, nonresponders to a previous IFN-alpha cycle, were retreated with 5 MU/m2 of body surface of natural IFN-beta, administered intramuscularly, three times per week for 24 weeks. At the end of treatment, 9 (41%) of 22 children became hepatitis B virus DNA negative. Hepatitis B e antibodies (anti-HBe) developed in 5 of these children, and 6 had normal alanine aminotransferase values. At the end of the posttreatment follow-up (21 months from the beginning of the study), 10 (45%) of 22 children were viral DNA negative, 7 (32%) of 22 were anti-HBe positive (none of them had viral DNA in serum), and 11 (50%) of 22 had normal alanine aminotransferase levels (10 without detectable viral DNA and 7 anti-HBe positive). IFN-beta seems to be an effective retreatment therapy for children with chronic hepatitis B who are nonresponders to a first IFN-alpha cycle; however, a controlled study should be performed to confirm these results.

Effect of chemotherapy on immune response to egg antigens of Schistosoma mansoni in chronically infected children from areas of low transmission.

In an attempt to identify antigenic molecules from Schistosoma mansoni eggs, a serological study was performed on children of a Venezuelan town (Caraballeda) in which the transmission of schistosomiasis had been interrupted two years prior to sera sampling. Infected children received treatment with Praziquantel and, based on the disappearance of eggs in the stools plus negativization of the circumoval precipitin test (COPT) one year after treatment, they were classified as either responders or non-responders to chemotherapy. Western blots of soluble egg antigen (SEA) with a very sensitive chemiluminescent substrate were performed. Sera from responder children recognized a 25 kDa band of SEA which diminished significantly after treatment. This was less frequent in non-responder children. When the sera of responder and non-responder children were compared before treatment, we found that the recognition of the 40 and 41 kDa proteins could be predictive of response to chemotherapy. All these antigens, used in ELISA-type techniques, might be of importance in the evaluation and follow-up of large scale schistosome control programmes.

Beta interferon therapy in alpha interferon non-responder children with chronic hepatitis B

Beta interferon therapy in alpha interferon non-responder children with chronic hepatitis B

Long term growth hormone (GH)-releasing hormone and biosynthetic GH therapy in GH-deficient children: comparison of therapeutic effectiveness

Twenty-five GH-deficient children were treated with GHRH (1-44), once daily sc for 6-24 months. At the 6th month of therapy, 40% of our patients showed a catch-up growth (responders), while the remaining 60% did not (nonresponders). No differences in auxological and biological variables at inclusion were found between the two groups. However, integrated GH secretion elicited by iv GHRH at inclusion was significantly (p less than 0.025) higher in responders than in non responders. During GHRH therapy, no significant increase in IGF 1/SmC was found in both groups. In all patients treatment was discontinued after 6-24 months, when its effect on growth rate failed. After a wash-out period of at least 6 months, patients were submitted to biosynthetic GH therapy. After 6 months of GH treatment a significant catch-up growth was found in both responder and non-responder children. Although the majority of GH-deficient children have hypothalamic rather than pituitary dysfunction, GHRH therapy is found to be less effective than GH treatment. Other methods of GHRH administration are worth investigating.

Average evoked responses in normal and minimally brain dysfunctioned children treated with amphetamine.

Visual and auditory average evoked responses (AERs) were studied in 24 minimally brain dysfunctioned (MBD) children and 24 age- and sex-matched normal controls. MBD children showed AERs characteristic of relatively younger normal children. MBD children who showed clinical improvement on amphetamine tended to show these immature patterns of AER response off drug to a greater extent than MBD amphetamine nonresponders. Pretreatment AER was successfully used to predict drug response; responders could be separated from normal children with 64% accuracy. Amphetamine-related AER changes were also in opposite directions in responder and nonresponder MBD children. The data support the concept of a neurophysiological maturational lag in MBD children.