Responses In Vaccinated Patients Research Articles

Children Unresponsive to Hepatitis B Virus Vaccination Also Need Celiac Disease Testing

To the Editor: We read with great interest the new ESPGHAN guidelines for the diagnosis of celiac disease (CD) (1). Regarding the categories at increased CD risk requiring specific antibodies testing, we believe that individuals with (selective) unresponsiveness to hepatitis B virus (HBV) vaccination should also be included. There are several reports that, after HBV vaccination, naïve patients with CD on a gluten-containing diet have low titers of hepatitis B surface antibodies (HBsAb) and percentages of protective (>10 U/L) values lower than those in controls (2–5). The HBsAb response after an IM (3–7) or ID (8) booster normalizes after starting a proper gluten-free diet (GFD) (Table 1).TABLE 1: Response to HBV vaccination (HBsAb > 10 IU/L) in pediatric patients with celiac disease compared with age-matched controlsThe HBsAb response seems to be associated with immunogenetic factors: multiple candidate genes have been implicated, including human leukocyte antigen phenotype DQ2, strongly linked to CD (4,9–11). The amount of gluten intake at vaccination has also been implicated (3). The still worrying high prevalence of HBV infection in some industrialized and most developing countries requires pediatric gastroenterologists’ alertness to the relevance of poor HBV vaccine response in patients with CD. In fact, the latter could signal undiagnosed CD, requiring investigation of patients by specific antibody testing and/or duodenal biopsy and possible correction by an appropriate booster program during a strict GFD. On the contrary, every new diagnosis of CD in a previously HBV-vaccinated individual should trigger the evaluation of HBsAb titers to take appropriate action in case of nonresponse and to alert patients to their possible lack of full protection against HBV.

Durable immune response to inactivated H1N1 vaccine is less likely in children with sickle cell anemia receiving chronic transfusions

Defects in the immune system may affect vaccine responsiveness. Because of the splenic hypofunction and abnormal opsonic activity, it was unknown whether patients with sickle cell disease (SCD) would respond appropriately to H1N1 vaccination. The objective of this study was to assess seroprotective post-vaccine H1N1 antibody response in children with SCD. Serum antibody titers were measured by hemagglutination inhibition and microneutralization (MN) assays. Correlations were established between clinical and treatment parameters and immune response. Twenty-nine of 38 (76.3%) subjects (mean age 11 ± 5.4 years) had durable protective antibody titers 8 ± 1.6 months (range 5-12 months) post-vaccination. Lessened immune response was not associated with time interval from vaccination, splenectomy, or hydroxyurea treatment. Lack of antibody response was associated with age less than 3 years and treatment with chronic transfusions. Of the nine non-responders, seven were on chronic transfusions (39% unresponsiveness rate in the transfused group). The difference in the number of patients with seropositivity between the non-transfused and the transfused groups was statistically significant (P = 0.039). Most subjects were able to mount an influenza-specific antibody response against the inactivated H1N1 vaccine. Similar to the general population, children less than 3 years were less likely to respond. In addition, patients on chronic transfusions were less likely to respond when compared to non-transfused children. Clinicians should be aware of the possibility of decreased vaccine response in patients with SCD on chronic transfusions. We postulate that transfusion-related immunomodulation (TRIM) may be related to decreased response.

Impact of synthetic and biologic disease-modifying antirheumatic drugs on antibody responses to the AS03-adjuvanted pandemic influenza vaccine: A prospective, open-label, parallel-cohort, single-center study

To identify the determinants of antibody responses to adjuvanted split influenza A (H1N1) vaccines in patients with inflammatory rheumatic diseases. One hundred seventy-three patients (82 with rheumatoid arthritis, 45 with spondylarthritis, and 46 with other inflammatory rheumatic diseases) and 138 control subjects were enrolled in this prospective single-center study. Controls received 1 dose of adjuvanted influenza A/09/H1N1 vaccine, and patients received 2 doses of the vaccine. Antibody responses were measured by hemagglutination inhibition assay before and 3-4 weeks after each dose. Geometric mean titers (GMTs) and rates of seroprotection (GMT≥40) were calculated. A comprehensive medical questionnaire was used to identify the determinants of vaccine responses and adverse events. Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the GMT and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P<0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease-modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor α antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity. DMARDs exert distinct influences on influenza vaccine responses in patients with inflammatory rheumatic diseases. Two doses of adjuvanted vaccine were necessary and sufficient to elicit responses in patients similar to those achieved with 1 dose in healthy controls.

Vaccination response to protein and carbohydrate antigens in patients with rheumatoid arthritis after rituximab treatment

IntroductionRheumatoid arthritis (RA) is frequently complicated with infections. The aim of our study was to evaluate vaccination response in patients with RA after B-cell depletion by using rituximab.MethodsInfluenza (Afluria) and pneumococcal polysaccharides (Pneumo23) vaccines were given 6 months after rituximab (post-RTX group, n = 11) or 6 days before rituximab treatment (pre-RTX group; n = 8). RA patients never exposed to RTX composed the control group (n = 10). Vaccine-specific cellular responses were evaluated on day 6 after vaccination, and vaccine-specific humoral responses, on day 21.ResultsOn day 6 after vaccination, formation of influenza-specific B cells was lower in post-RTX group as compared with the pre-RTX group and controls (P = 0.04). Polysaccharide-specific B cells were found in 27% to 50%, being equally distributed between the groups. On day 21, the impairment of humoral responses was more pronounced with respect to influenza as compared with the pneumococcal vaccine and affected both IgG and light-chain production. Total absence of influenza-specific IgG production was observed in 55% of the post-RTX group.ConclusionsRTX compromises cellular and humoral vaccine responses in RA patients. However, repeated RTX treatment or previous anti-tumor necrosis factor (anti-TNF) treatment did not accentuate these defects.

Poor antibody response after tetanus and pneumococcal vaccination in immunocompromised, HIV-infected patients

Ten patients with symptomatic HIV infection (six with ARC, four with AIDS) received tetanus and 23-valent pneumococcal vaccination. Anti-tetanus IgG and IgM, and anti-pneumococcal IgG against all 23 capsular types of the vaccine were measured on days 0, 11, 17, 30, and 90. Anti-pneumococcal IgG were simultaneously determined in two plasma pools of 100 healthy unimmunized blood donors and of 112 healthy adults who had previously received a 14-valent pneumococcal vaccination. Peak IgG responses to both vaccines were observed on day 17; thereafter, the antibody levels gradually fell again. Anti-tetanus IgG rose from 0.6 U/ml (geometric mean) to 2.0 U/ml on day 17. Anti-tetanus IgM remained unchanged. Anti-pneumococcal IgG increased only by 1.14-fold compared with pre-vaccination levels (geometric mean of IgG rises against all 23 polysaccharides in 10 patients), and exceeded the upper 95% limit of unvaccinated blood donors in only 30 out of 230 specimens. Pre-vaccination levels for pneumococcal type-specific IgG were significantly higher in HIV-infected patients compared with the pool of unimmunized healthy controls, possibly indicating a higher rate of previous pneumococcal infections in HIV-seropositive subjects. However, post-pneumococcal vaccination levels were significantly lower in HIV-infected patients than in the pool of healthy controls. The increase in anti-tetanus IgG significantly correlated with the level of CD4 lymphocytes and with in vitro lymphocyte proliferation by pokeweed mitogen (5 micrograms/ml) and phytohaemagglutinin (2.5 micrograms/ml), confirming a particularly low vaccination response in patients who were severely immunocompromised.

Vaccine responses in patients with rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease that is associated with immunologic alterations in T cells and B cells. Moreover, many of the agents used in RA patients are potentially immunosuppressive. Thus, the underlying disease and treatment may both increase the susceptibility to infections and decrease vaccine responses. With the growing use of aggressive therapies for RA, including anti-tumor necrosis factor agents and newer biologic therapies such as rituximab and abatacept, an increasing concern will be that patients may not respond to conventional vaccination. Further prospective studies on response to vaccination are needed to answer this important public health question. Nevertheless, it is already clear that vaccination does induce response in many patients. Unfortunately, vaccination is underutilized in RA patients and needs to be aggressively promoted.

An overview of vaccinations in HIV.

Prevention is an important aspect of HIV care in the era of highly active antiretroviral therapy. Vaccines provide an excellent opportunity to avert certain infectious diseases for which patients with HIV infection are at increased risk due to immunosuppression. However, the state of immunosuppression reduces the efficacy of vaccines and increases the risk associated with certain vaccines. The study of vaccine responses in patients with HIV infection has greatly advanced the understanding of the underlying immune deficits, particularly with regards to reduced CD4 cell number and function and the level of immune activation associated with chronic viremia. This research has also solidified the safety and utility of vaccines for this population. Continued research of vaccine responses will further our understanding of the immune system and optimize the utilization of routine immunizations.

Abrogation of potent humoral vaccine responses in patients on long-term anti-CD25 therapy (B196)

Abstract Daclizumab, a monoclonal antibody that binds CD25, has been effective in the treatment of a number of autoimmune diseases. Despite continuous IL-2 receptor blockade for extended periods in these patients, there have been no instances of opportunistic infection and the rate of community-acquired infections is no greater than that of the general populace. This suggests that daclizumab dosing is balanced between prevention of autoimmunity and susceptibility to infection. To test this hypothesis, as a surrogate for infection we measured hepatitis vaccine responses in five patients with autoimmune uveitis who had been on daclizumab therapy for as long as 92 months. Surprisingly, only one equivocal vaccine response was observed. Given the high frequency of seroconversion (&amp;gt;95%) induced by these vaccines in healthy adults, this study is sufficiently powered to demonstrate statistically significant differences from the expected hepatitis vaccine response rate (p=0.0005). These results show that daclizumab can block the response to a potent immunogen in vivo. Given that alum based vaccine responses are highly dependent on IL-4, the known inhibition of Th2 cytokine production by daclizumab is likely to have contributed to the vaccine failures we observed. Our results indicate that, where possible, antibiotic/antiviral drug prophylaxis may be preferable to vaccination in patients on daclizumab therapy.

Response to Immunizations Following Allogeneic HCT with Adjuvant Rituximab Therapy.

Use of anti-CD20 monoclonal antibody after allogeneic HCT for the treatment EBV lymphoma or viremia, autoimmune cytopenias, and the prevention or treatment of recurrent NHL has become more frequent. There is limited data on the effect of this therapy on specific antibody production following allogeneic HCT. We therefore examined the response to standard childhood immunizations of 30 patients, including 20 adults (>18 years of age) who received rituximab following a T cell depleted (n=26) or unmodified (n=4) HCT at our institution. T cell function was assessed in vitro by proliferative response to PHA and B cell reconstitution was confirmed by recovery of CD19+ and CD20+ circulating lymphocytes. Patients received a median (range) of 4 (1–12) doses of rituximab, with 15 patients receiving 4–6 doses. The median age of the patient population was 28.5 years with a range of 0.8–63.0 years. Children (median age: 8.5 yrs) received a transplant from an unrelated (n=7), HLA mismatched related (n=2), or HLA matched related (n=1) donor and adults (median age: 42.5 yrs), received a transplant from an unrelated (n=7), HLA mismatched related (n=2), or HLA-matched related (n=11) donor. Patients were vaccinated when their PHA response was at least 75% of the lower limit of normal and CD20+ cells were >100/ul. Vaccination was initiated at a median of 270 and 525 days following the last dose of rituximab in children and adults, respectively. A two to 3-fold rise in titers following a series of 3 tetanus and IPV vaccinations occurred in 19 of 21 and 19 of 19 evaluable patients, respectively. Although 8 of 9 children responded to the H flu conjugate vaccine, only 5 of 13 adults mounted an adequate response. Eighteen patients received the recombinant Hepatitis B vaccine. Nine responded following the initial series (5/7 children, 4/11 adults). Two of three patients who failed initial Hepatitis B vaccination, responded to a second series (1 child, 1 adult). Response to pneumococcal vaccination was the least consistent. None of 11 adults who received the unconjugated 23-valent pneumococcal vaccine developed an adequate response. In view of this observation, children given rituximab were immunized with the conjugated pneumococcal vaccine. Four of eight children responded to the initial series, and two additional children responded following a second series. These preliminary data suggest that both adult and pediatric patients given rituximab following an allogeneic HCT can mount successful antibody responses to standard T-helper cell dependent vaccines. However, B cell responses to T cell independent vaccines may be particularly impaired. Larger prospective trials, stratified by age, comparing vaccine responses in patients following allogeneic transplant in the presence or absence of post transplant rituximab therapy are warranted.

Haemophilus Influenzae Type b (Hib) Antibody Concentrations and Vaccination Responses in Patients with Chronic Lymphocytic Leukaemia: Predicting Factors for Response

We have recently demonstrated a moderate vaccination response rate of 43% against Haemophilus influenzae type b (Hib) conjugate vaccine among adult and elderly patients with chronic lymphocytic leukaemia (CLL). We now investigated demographic and immunological factors predicting the favourable response and protective antibody concentrations for Hib conjugate vaccine in CLL. Lower age was associated with protective pre- and post-vaccination antibody concentrations. High IgG1 and IgA concentrations were also associated with the protective efficacy. High IgM, in turn, was the best predictor of a significant vaccination response. Again, lower age seemed to be involved in this outcome. Judging from these findings, it would seem beneficial to vaccinate all CLL patients with conjugate vaccines at the presentation of the disease. Investigations of a new pneumococcal conjugate vaccine in CLL are warranted.

Preretinal hemorrhages. Their mechanism of production and significance.

<h3>Objectives</h3> To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response. <h3>Methods</h3> We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response. <h3>Results</h3> Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC. <h3>Conclusions</h3> Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.