Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease

Background

Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2 × 20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng).

Methods

An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18–75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg + 3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2 × 20 mcg rHBsAg + 500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year.

Results

Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs ≥ 10 mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs ≥ 100 mIU/mL in theHBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1 mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5 mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response toHBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng.

Conclusion

In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng.     

Hepatitis B vaccine immunogenicity among adults vaccinated during an outbreak response in an assisted living facility—Virginia, 2010

Background

Failure to adhere to infection control guidelines, especially during assisted monitoring of blood glucose, has caused multiple hepatitis B outbreaks in assisted living facilities (ALFs). In conjunction with the response to such an outbreak at an ALF (“Facility X”) where most residents had neuropsychiatric disorders, we evaluated seroprotection rates conferred by hepatitis B vaccine and assessed the influence of demographic factors on vaccine response.

Methods

Residents were screened for hepatitis B and C infection, and those susceptible were vaccinated against hepatitis A and hepatitis B with one dose of TWINRIX™ (GSK) given at 0, 1, and 7 months. Blood samples were collected 1–2 months after receipt of the third vaccine dose to test for antibody to hepatitis B surface antigen (anti-HBs).

Results

Of the 27 residents who had post-vaccination blood specimens collected, 22 (81%) achieved anti-HBs concentrations ≥10 mIU/mL. Neither age nor neuropsychiatric comorbidity was a significant determinant of seroprotection. Geometric mean concentration was lower among residents aged 60–74 years (74.3 mIU/mL) than among residents aged 46–59 years (105.3 mIU/mL) but highest among residents aged ≥75 years (122.5 mIU/mL). The effect of diabetes on vaccination response could not be examined because 16/17 (94%) diabetic residents had HBV infection by the time of investigation.

Conclusions

Adult vaccine recipients of all ages, even those over 60 years of age, demonstrated a robust capacity for achieving hepatitis B seroprotection in response to the combined hepatitis A/hepatitis B vaccine. The role for vaccination in interrupting HBV transmission during an outbreak remains unclear, but concerns about age-related response to hepatitis B vaccine may be insufficient to justify foregoing vaccination of susceptible residents of ALFs.     

Immune response after one or two doses of pandemic influenza A (H1N1) monovalent,AS03-adjuvanted vaccine in HIV infected adults

Introduction

Continued research is needed to evaluate and improve the immunogenicity of influenza vaccines in HIV infected patients. We aimed to determine the antibody responses after one or two doses of the AS03-adjuvanted pandemic influenza A (H1N1) vaccine in HIV infected patients.

Method

Following the influenza season 2009/2010, 219 HIV infected patients were included and divided into three groups depending on whether they received none (n = 60), one (n = 31) or two (n = 128) doses of pandemic influenza A (H1N1) vaccine. At inclusion, antibody titers for all patients were analyzed and compared to pre-pandemic antibody titers analyzed from serum samples in a local storage facility.

Results

4–9 months after a single immunization, we found a seroprotection rate of 77.4% and seroconversion rate of 67.7%. After two immunizations the rates increased significantly to seroprotection rate of 97.7% and seroconversion rate of 86.7%.

Conclusion

A single dose of AS03-adjuvanted pandemic influenza A (H1N1) vaccine created an adequate immune response in HIV infected patients lasting as long as 4–9 months. Two doses improved the immunogenicity further.     

Hepatitis B virus vaccine in chronic kidney disease: Improved immunogenicity by adjuvants? A meta-analysis of randomized trials

Background

Patients with chronic kidney disease typically show an impaired immune response to hepatitis B virus vaccine compared with healthy individuals. A variety of inherited or acquired factors have been implicated in this diminished response. Some authors suggested a benefit with adjuvantation to improve the immunogenicity of existing HBV vaccines.

Aim

To evaluate the efficacy and safety of adjuvantation for hepatitis B virus vaccine in patients with chronic kidney disease.

Methods

Only prospective, randomized clinical trials (RCTs) were included. We used the random effects model of DerSimonian and Laird with heterogeneity and subgroups analyses. The primary end-point of interest was the seroprotection rate after HBV vaccination with recombinant vaccine plus adjuvants (study group) versus recombinant vaccine alone (control group).

Results

We identified ten studies involving 1228 unique patients with chronic kidney disease. Pooling of study results did not show a significant increase in seroprotection rate among study (HBV recombinant vaccine plus adjuvants) versus control (HBV recombinant alone) patients; the pooled odds ratio of seroprotection rate was 1.47 (95% CI: 0.88; 2.46, NS). The pooled OR for seroresponse rate after HBV vaccine (adjuvanted recombinant vaccine versus recombinant vaccine alone) did not change in the subgroup of studies based on novel adjuvant systems (i.e., HBV-AS04 or HBV-AS02), the pooled OR was 2.22 (95% CI, 0.72; 6.78), NS. Q-test for heterogeneity being 10.819 (P = 0.004).

Conclusions

Our meta-analysis showed that adjuvanted hepatitis B vaccine did not significantly improve the seroprotection rate in patients with renal insufficiency. These results do not support adjuvantation as an approach to increase the immunogenicity of existing recombinant vaccines towards HBV in this high-risk population.     

Seroprotection after recombinant hepatitis B vaccination among newborn infants: A review

Introduction

Hepatitis B vaccination starting at birth provides a safety net for infants exposed to hepatitis B virus (HBV) during delivery or in early life. Hepatitis B vaccine is recommended in the United States for infants prior to birthing facility discharge, and within the first 12 h of life for infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We performed a literature review and summarized the response to recombinant hepatitis B vaccine among infants.

Methods

Studies published between 1987 and 2011 assessing seroprotection from recombinant hepatitis B vaccine starting within the first 30 days of life were eligible. Seroprotection was defined using an antibody to hepatitis B surface antigen (anti-HBs) threshold of 10 mIU/mL at series completion. Infant seroprotection was compared in trial arms varying by maternal hepatitis B antigen status (e antigen [HBeAg], HBsAg), hepatitis B immune globulin (HBIG) administration, birth weight, vaccine dosage, schedule, and age at first dose.

Results

Forty-three studies were included. The median seroprotection proportion overall was 98% (range 52%, 100%). The final median seroprotection proportions did not vary appreciably by maternal HBsAg status, HBIG administration, or schedule. Higher compared to lower dosage resulted in earlier increases in anti-HBs but not in final seroprotection proportions. Infants with birth weights <2000 g compared to ≥2000 g had lower median seroprotection proportions (93% and 98%, respectively). Median seroprotection proportions were also lower when infants with birth weights <2000 g were vaccinated at 0–3 days of age compared to 1 month of age or older (68% versus 95%, respectively).

Conclusion

High levels of protection from recombinant hepatitis B vaccine are achieved in term infants vaccinated at birth, effectively preventing transmission of HBV and resultant morbidity and mortality. Implications, if any, for long-term protection are unknown for differences in responses among infants vaccinated at birth compared to ages older than 1 month.     

Comparable humoral response after two doses of adjuvanted influenza A/H1N1pdm2009 vaccine or natural infection in allogeneic stem cell transplant recipients

Background

The present study evaluated immunogenicity and tolerance of two-dose influenza A/H1N1pdm09 vaccination in allogeneic hematopoietic stem cell transplantation (HSCT) recipients, and compared the vaccine-induced humoral response to that triggered by natural infection in another group of HSCT patients.

Methods

Adult allogeneic HSCT recipients vaccinated with two doses of influenza A/H1N1pdm09 vaccine, separated by 3 weeks, and patients with proven influenza A/H1N1pdm09 infection were included. Antibody responses were measured by hemagglutination-inhibition assay 1) on days 0, 21, 42 and 6 months after the first vaccine injection in vaccinated patients and 2) before pandemic and after influenza A/H1N1pdm09 infection, in patients presented natural infection.

Results

At baseline, 3% of 59 recipients of adjuvanted vaccine and 0% of 20 infected patients were seroprotected (antibody titer ≥ 1/40). Seroprotection rate observed 42 days after vaccination was not different from that observed after natural infection (66% and 60% respectively, p = 0.78). In vaccinated patients, seroprotection rate increased significantly from 54% to 66% between day 21 and 42 (p = 0.015). Moreover, after 6 months, seroprotection rate in 21 vaccinated patients was similar to that observed in 10 infected patients evaluated at least 76 days after infection (D76–217) (60% and 81% respectively, p = 0.2). In multivariate analysis, no immunosuppressive treatment or chronic graft-versus-host disease (GVHD) and longer time between transplantation and vaccination/infection were associated with a stronger humoral response. The adjuvanted vaccine was safe with low rate of GVHD worsening.

Conclusion

In HSCT recipients, two doses of influenza A/H1N1pdm09 adjuvanted vaccine were safe and induced a humoral response comparable to that triggered by natural infection in these patients.     

Vaccine induced Hepatitis A and B protection in children at risk for cystic fibrosis associated liver disease

Objectives

Hepatitis A (HAV) and Hepatitis B (HBV) infections can cause serious morbidity in patients with liver disease, including cystic fibrosis associated liver disease (CFALD). HAV and HBV vaccinations are recommended in CFALD, and maintenance of detectable antibody levels is also recommended with chronic liver disease. A better understanding of factors predicting low HAV and HBV antibodies may help physicians improve protection from these viruses in CFALD patients.

Methods

We examined HAV and HBV vaccine protection in children at risk for CFALD. Clinical and vaccine histories were reviewed, and HAV and HBV antibody titers measured. Those with no vaccination history or low HAV or HBV titers received primary or booster vaccinations, and responses were measured.

Results

Thirty-four of 308 children were at risk for CFALD per project criteria. Ten had previous HAV vaccination, of which 90% had positive anti-HAV antibodies. Thirty-three of 34 had previously received primary HBV vaccination (most in infancy), but only 12 (35%) had adequate anti-HBs levels (≥10 mIU/mL). Children with adequate anti-HBs levels were older at first HBV vaccine (median 2.3 vs. 0.1 years, p < 0.01), and at final HBV vaccine (median 4.0 vs. 0.8 years, p = 0.01). Fourteen of 19 (74%) responded to HBV boosters. Z-scores for BMI at HBV booster were significantly lower in booster non-responders (p = 0.04).

Conclusions

Children at increased risk of CFALD have inadequate HAV and HBV antibody levels, and HBV antibody protection can be enhanced through vaccine boosters. HBV antibody titers should be assessed in CFALD patients with a history of vaccination, particularly in those who received HBV vaccines in infancy or who are malnourished.     

Knowledge,attitudes and vaccination coverage of healthcare workers regarding occupational vaccinations

Objectives

Immunization of healthcare workers (HCWs) is a major issue for infection control in healthcare facilities. The aim of this study was to evaluate knowledge regarding occupational vaccinations, HBV, varicella and influenza vaccination rates and attitudes towards influenza vaccine among HCWs.

Design and setting

A cross-sectional survey was conducted in two wards (Medicine and Paediatrics) of a 1182-bed teaching hospital in Paris, France.

Methods

A standardized, anonymous, self-administered questionnaire was used.

Results

Of 580 HCWs, 395 (68%) completed the questionnaire. Knowledge about the occupational vaccinations of HCWs was low. HBV (69%), tuberculosis (54%) and influenza (52%) were the most cited vaccinations. Paediatric staff was more aware of influenza and pertussis immunizations (p < .05). HBV vaccination rate was 93%, among whom 65% were aware of their immune status. Influenza vaccination rate for 2006–2007 was 30% overall, ranging from 50% among physicians to 20% among paramedical staff (p < .05). Physicians based their refusal on doubts about vaccine efficacy, although paramedics feared side effects. Influenza vaccination was associated with knowledge of vaccine recommendations [OR = 1.75, 95% CI: 1.13–2.57] and contact with patients [OR = 3.05, 95% CI: 1.50–5.91].

Conclusions

Knowledge of recommended occupational vaccinations is insufficient in HCWs, except for HBV and influenza. Although the HBV vaccine coverage of HCWs is satisfactory, a large proportion of them is unaware of immune status. Influenza vaccine coverage remains low, especially among paramedical staff because of fear of side effects. As vaccine coverage is associated with knowledge, educational campaigns should be strengthened to increase the adhesion of HCWs to vaccinations.     

Evaluation of hepatitis B vaccine immunogenicity among older adults during an outbreak response in assisted living facilities

Background

During the past decade, in the United States, an increasing number of hepatitis B outbreaks have been reported in assisted living facilities (ALFs) as a result of breaches in infection control practices. We evaluated the seroprotection rates conferred by hepatitis B vaccine among older adults during a response to an outbreak that occurred in multiple ALFs and assessed the influence of demographic and clinical factors on vaccine response.

Methods

Residents were screened for hepatitis B and C infection prior to vaccination and susceptible residents were vaccinated against hepatitis B with one dose of 20 μg Engerix-B™ (GSK) given at 0, 1, and 4 months. Blood samples were collected 80-90 days after the third vaccine dose to test for anti-HBs levels.

Results

Of the 48 residents who had post-vaccination blood specimens collected after the third vaccine dose, 16 (33.3%) achieved anti-HBs concentration ≥10 mIU/mL. Age was a significant determinant of seroprotection with rates decreasing from 88% among persons aged ≤60 years to 12% among persons aged ≥90 years (p = 0.001). Geometric mean concentrations were higher among non-diabetic than diabetic residents, however, the difference was not statistically significant (5.1 vs. 3.8 mIU/mL, p = 0.7).

Conclusions

These findings highlight that hepatitis B vaccination is of limited effectiveness when administered to older adults. Improvements in infection control and vaccination at earlier ages might be necessary to prevent spread of infection in ALFs.     

Effect of two injections of non-adjuvanted influenza A H1N1pdm2009 vaccine in renal transplant recipients: INSERM C09-32 TRANSFLUVAC trial

Background

Enhancing vaccine immunogenicity in kidney transplant recipients, particularly against influenza, is required since the immunosuppression used to prevent graft rejection limits vaccine immunogenicity. We therefore investigated the immunogenicity and safety of a double dose non-adjuvanted vaccination regimen against influenza H1N1pdm2009 in kidney transplant adult recipients.

Methods

A prospective single-arm study was conducted including 121 renal transplant recipients under triple immunosuppressive regimen. Patients received 2 injections (day 0, day 21) of an inactivated, non-adjuvanted H1N1pdm2009 vaccine. Immunogenicity (hemagglutination-inhibition [HI] antibodies and anti-hemagglutin [HA] specific T cells) was evaluated after one and two injections (day 21, day 42) and at 6 months (day 182).

Results

The seroprotection rate (HI antibody titer ≥ 1/40) was 19% at day 0 (n = 119), 53% at day 21 (n = 118), 60% at day 42 (n = 116) (p = 0.013; day 42 vs. day 21) and 56% at day 182 (n = 113). The seroconversion rate was 24% and 32%, the geometric mean fold rise was 3.7 and 4.6 after the first and second injections, respectively. T-cell immunity to the H1N1pdm2009 vaccine showed a two-fold increase from baseline, though not statistically significant, in H1N1pdm2009-HA-specific CD4+ and CD8+ T cells in 34% and 48% of cases, respectively. No rejection episodes related to vaccination were observed while the donor-specific antibodies and creatinine clearance remained unchanged throughout the study.

Conclusion

Administration of two doses of the non-adjuvanted influenza H1N1pdm2009 vaccine in renal transplant patients is safe and induces a significant seroprotection, not strong enough yet to meet European or US requirements for adults below 60 years, but comparable to seroprotection levels usually observed in the non immunosuppressed elderly population or conferred by a single dose of adjuvanted vaccine in solid organ transplant recipients. These results provide useful indications for future strategies required to improve immunogenicity of vaccines against influenza in transplanted patients.     

Effects of hepatitis B immunization on prevention of mother-to-infant transmission of hepatitis B virus and on the immune response of infants towards hepatitis B vaccine

Background

Combined immunization with hepatitis B immunoglobulin (HBIG) plus hepatitis B vaccine (HB vaccine) can effectively prevent perinatal transmission of hepatitis B virus (HBV). With the universal administration of HB vaccine, anti-HBs conferred by HB vaccine can be found increasingly in pregnant women, and maternal anti-HBs can be passed through the placenta. This study was designed to evaluate the effect of hepatitis B immunization on preventing mother-to-infant transmission of HBV and on the immune response of infants towards HB vaccine.

Method

From 2008 to 2013, a prospective study was conducted in 15 centers in China. HBsAg-positive pregnant women and their infants aged 8–12 months who completed immunoprophylaxis were enrolled in the study and tested for HBV markers (HBsAg, anti-HBs, HBeAg, anti-HBe and anti-HBc). Antepartum administration of HBIG to HBsAg-positive women was based on individual preference. HBsAg-negative pregnant women and their infants of 7–24 months old who received HB vaccines series were enrolled and tests of their HBV markers were performed.

Results

1202 HBsAg-positive mothers and their infants aged 8–12 months were studied and 40 infants were found to be HBsAg positive with the immunoprophylaxis failure rate of 3.3%. Infants with immunoprophylaxis failure were all born to HBeAg-positive mothers of HBV-DNA ≥ 6 log₁₀ copies/ml. Among infants of HBeAg-positive mothers, immunoprophylaxis failure rate in vaccine plus HBIG group, 7.9% (29/367), was significantly lower than the vaccine-only group, 16.9% (11/65), p = 0.021; there was no significant difference in the immunoprophylaxis failure rate whether or not antepartum HBIG was given to the pregnant woman, 10.3% (10/97) vs 9.0% (30/335), p = 0.685. Anti-HBs positive rate was 56.3% (3883/6899) among HBsAg-negative pregnant women and anti-HBs positive rate was 94.2% in cord blood of anti-HBs-positive mothers. After completing the HB vaccine series, anti-HBs positive rate among infants with maternal anti-HBs titers of <10 IU/L, 10–500 IU/L and ≥500 IU/L was 90.3% (168/186), 90.5% (219/242) and 80.2% (89/111) respectively, p = 0.011. Median titers of anti-HBs (IU/L) among infants in the three groups was 344.2, 231.9 and 161.1 respectively, p = 0.020.

Conclusions

HBIG plus HB vaccine can effectively prevent mother-to-infant transmission of HBV, but no HBV breakthrough infection was observed in infants born to HBeAg-negative mothers who received HB vaccine with or without HBIG after birth. Antepartum injection of HBIG has no effect on preventing HBV mother-to-infant transmission. High maternal titer of anti-HBs can transplacentally impair immune response of infants towards HB vaccine.     

Safety and immunogenicity of adjuvanted inactivated split-virion and whole-virion influenza A (H5N1) vaccines in children: A phase I–II randomized trial

Objective

Highly pathogenic avian influenza A virus H5N1 has the potential to cause a pandemic. Many prototype pandemic influenza A (H5N1) vaccines had been developed and well evaluated in adults in recent years. However, data in children are limited. Herein we evaluate the safety and immunogenicity of adjuvanted split-virion and whole-virion H5N1 vaccines in children.

Methods

An open-labelled phase I trial was conducted in children aged 3–11 years to receive aluminum-adjuvated, split-virion H5N1 vaccine (5–30 μg) and in children aged 12–17 years to receive aluminum-adjuvated, whole-virion H5N1 vaccine (5–15 μg). Safety of the two formulations was assessed. Then a randomized phase II trial was conducted, in which 141 children aged 3–11 years received the split-virion vaccine (10 or 15 μg) and 280 children aged 12–17 years received the split-virion vaccine (10–30 μg) or the whole-virion vaccine (5 μg). Serum samples were collected for hemagglutination-inhibition (HI) assays.

Findings

5–15 μg adjuvated split-virion vaccines were well tolerated in children aged 3–11 years and 5–30 μg adjuvated split-virion vaccines and 5 μg adjuvated whole-virion vaccine were well tolerated in children aged 12–17 years. Most local and systemic reactions were mild or moderate. Before vaccination, all participants were immunologically naïve to H5N1 virus. Immune responses were induced after the first dose and significantly boosted after the second dose. In 3–11 years children, the 10 and 15 μg split-virion vaccine induced similar responses with 55% seroconversion and seroprotection (HI titer ≥1:40) rates. In 12–17 years children, the 30 μg split-virion vaccine induced the highest immune response with 71% seroconversion and seroprotection rates. The 5 μg whole-virion vaccine induced higher response than the 10 μg split-virion vaccine did.

Interpretation

The aluminum-adjuvanted, split-virion prototype pandemic influenza A (H5N1) vaccine showed good safety and immunogenicity in children and 30 μg dose induced immune response complying with European Union licensure criteria. [ClinicalTrials.gov identifiers: NCT00900588 and NCT00900991].     

Effectiveness of influenza vaccination in elderly diabetic patients: A retrospective cohort study

Purpose

Studies regarding the clinical benefits of influenza vaccination in diabetic patients are limited. This study evaluated if the elderly diabetic patients who have had influenza vaccination would have benefits such as reduced medical care and mortality.

Methods

We used the universal insurance claims data from 2001 to 2009 in Taiwan to identify annual elderly patients with diabetes cohorts with (N = 4454) and without (N = 4571) influenza vaccination. The risk of developing pneumonia or influenza, respiratory failure, intensive care, hospitalization, and mortality were measured and compared between cohorts within one year of follow-up.

Results

The vaccine cohort had lower incidences of pneumonia or influenza and respiratory failure compared with the non-vaccine cohort. More importantly, the vaccine cohort had a hospitalization rate that was 11% less than the non-vaccine cohort (29.6 vs. 33.1 per 100 person-years) with an adjusted hazard ratio (HR) of 0.88 (95% CI 0.81–0.96). The vaccine cohort was also less likely to be admitted to the intensive care unit (ICU) [0.58 vs. 2.05 per 100 person-year; adjusted HR 0.30 (95% CI 0.19–0.47)] and less likely to expire [3.13 vs. 7.96 per 100 person-year; adjusted HR 0.44 (95% CI 0.36–0.54)]. Influenza vaccination reduced the hospitalization cost by 1282.6 USD, compared with patients without influenza vaccination (95% CI −2210.3, −354.8).

Conclusion

Influenza vaccination is associated with a reduced risk of morbidity, hospitalization, ICU admissions, and mortality. In addition, the hospitalization cost is reduced.     

Enhanced and persistent antibody response against homologous and heterologous strains elicited by a MF59®-adjuvanted influenza vaccine in infants and young children

Background

Non-adjuvanted seasonal influenza vaccines show only modest efficacy in young children. This study compared the immunogenicity, reactogenicity and safety of the MF59^®-adjuvanted trivalent subunit vaccine (aTIV) with two non-adjuvanted trivalent vaccines, TIV-1, the non-adjuvanted version of aTIV, and TIV-2, a split virion vaccine.

Methods

6078 children received two doses of aTIV (n = 3125), TIV-1 (n = 1479), or TIV-2 (n = 1474) four weeks apart (Days 1 and 29). Children aged 6 to <36 months and 36 to <72 months received 0.25 mL and 0.50 mL doses, respectively. Immunogenicity was assessed by hemagglutination inhibition (HI) assay (n = 2435) on Days 1, 29, 50 and 209. Safety was assessed up to Day 394.

Results

After the second vaccination (Day 50), the aTIV group showed significantly higher geometric mean HI titers and seroconversion rates than the TIV-1 or TIV-2 groups against all homologous and heterologous strains. The difference was enhanced at HI titers ≥110. aTIV elicited a faster, more persistent antibody response, with significantly higher titers in the aTIV group after one vaccination (Day 29) and after six months (Day 209) than in either TIV group. aTIV was more reactogenic than were TIV-1 and TIV-2 but rates of severe adverse events were very low for all three vaccines.

Conclusion

In infants and young children, the MF59-adjuvanted vaccine induced substantially faster (after one dose), higher, persistent HI titers than the non-adjuvanted vaccines, with consistently higher seroprotection rates at increased threshold HI titers.This trial is registered at clinicaltrials.gov: NCT01346592.     

Barriers to influenza vaccination among pregnant women

Objective

Despite pregnant women's increased morbidity and mortality from influenza, vaccination rates remain low. This study intended to evaluate barriers to pregnant women's uptake of influenza vaccine.

Study design

A survey was designed that assessed participant demographics, knowledge, beliefs, attitudes, and general experiences with seasonal and 2009 novel H1N1 influenza. Associations between patient characteristics and vaccine uptake were then assessed.

Results

88 women completed the survey. Women who correctly answered >75% of knowledge questions regarding influenza were significantly more likely to accept the influenza vaccine (seasonal: p = 0.04, H1N1: p < 0.01). Conversely, patients who declined the vaccine were more likely to hold false beliefs, such as perceiving that the vaccine was not protective (seasonal: p < 0.01, H1N1: p < .01) and that they were not at risk for influenza (seasonal: p <  0.01).

Conclusion

The reasons for influenza vaccine declination in pregnant patients include lower levels of knowledge and unfavorable attitudes regarding the safety and efficacy of the vaccine, and suggest the importance of education as a tool to improve vaccination uptake     

Comparison of the safety and immunogenicity of an MF59-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects

Aim

Adjuvanted influenza vaccines can overcome the poor antibody response of conventional non-adjuvanted vaccines in the elderly. We evaluated the immunogenicity, safety and clinical effectiveness of an MF59^®-adjuvanted trivalent influenza vaccine (aTIV) compared with a non-adjuvanted vaccine (TIV) in subjects ≥65 years old, with or without co-morbidities.

Methods

In 2010–2011, subjects (N = 7082) were randomized to receive one dose of aTIV or TIV. Co-primary objectives were to assess lot-to-lot consistency of aTIV, non-inferiority, superiority and immunogenicity 22 days after vaccination. Clinical effectiveness, reactogenicity and serious adverse events were monitored up to Day 366.

Results

The immunological equivalence of three lots of aTIV was demonstrated. aTIV was not only non-inferior to TIV but also elicited significantly higher antibody responses at Day 22 than TIV against all homologous and heterologous strains, even in subjects with co-morbidities. Superiority was not established. Reactogenicity was higher in the aTIV group, but reactions were mild to moderate and transient.

Conclusions

aTIV elicited a significantly higher antibody response than TIV, especially against A/H3N2 strains, although superiority by pre-defined criteria was not formally met. The study demonstrates potential immunological benefits of MF59-adjuvanted influenza vaccines for the elderly.This trial was registered with www.clinicaltrials.gov (NCT01162122).     

Evaluation of immune responses to combined hepatitis A and B vaccine in HIV-infected children and children on immunosuppressive medication

Objective

A phase IV interventional study with a combined hepatitis A and B vaccine was conducted in HIV-infected children and children receiving immunosuppressive medication for treatment of rheumatic diseases to evaluate immune responses.

Methods

Both groups (1–16 years of age) received combined (inactivated) HAV and (rDNA) HBV vaccine Ambirix^® at months 0 and 6. Serum samples were taken at four time points and tested for anti-HAV and anti-HBs antibodies. Anti-HAV concentrations ≥20 mIU/mL or anti-HBs concentrations ≥10 mIU/mL were considered protective. Seropositivity percentages were calculated and geometric mean concentrations (GMCs) were compared by nonparametric Mann–Whitney U-test or Kruskal–Wallis one-way-analysis-of-variance.

Results

Of 80 HIV-infected children who completed the study, 67 were HAV-susceptible and 68 HBV-susceptible at enrolment. Of 80 children with rheumatic diseases who completed the study, 65 were HAV-susceptible and 74 HBV-susceptible at enrolment. Immune responses to HAV after first dose of vaccine in both study groups were low: 71% and 55% respectively, whereas immune responses after the second dose were 99% and 100% respectively. Immune response to HBV after first dose of vaccine in both groups was also low: 27% and 17% respectively. Immune responses after the second dose were 97% and 93%, respectively. A larger proportion of children on combination antiretroviral therapy (cART) and of children with viral load <50 copies/mL responded to HBV, and also showed a significantly higher GMC.

Conclusions

Although immune response after full series of combined HAV and HBV vaccine in both groups was excellent and comparable to healthy children, a substantial proportion of both groups was not protected for HAV after first dose of vaccine. This protection gap is especially important for HAV in travel health and postexposure prophylactic treatment: both groups of children should be serologically tested for anti-HAV prior to travel to ensure protection if there is no time to await second dose of vaccine.     

Mannose-binding lectin and ficolin-2 do not influence humoral immune response to hepatitis B vaccine

Background

Host genetics appear to be an important factor in the failure to generate a protective immune response after hepatitis B (HBV) vaccination. Mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway of complement, influence the clinical outcome of HBV, and MBL deficiency has been shown to augment the humoral response to HBV vaccination in several experimental models. Here, we investigated the association of MBL and FCN2 with the humoral response to HBV vaccination in a candidate gene and functional study.

Patients and methods

A post hoc analysis of a prospective, interventional HBV vaccination study among human immunodeficiency virus type 1 (HIV-1) uninfected individuals in Kenya was conducted. Serum levels and polymorphisms of MBL and FCN2 were analysed in relation to the immune response to HBV vaccination.

Results

Protective hepatitis B surface antibody levels (≥10 mIU/mL) were evident in 251/293 (85.7%) individuals. Median MBL and FCN2 levels were similar in responders vs. non-responders with a weak trend towards lower median MBL levels in non-responders (1.0 vs. 1.6 μg/mL, p = 0.1). Similarly, there was no difference in four MBL and six FCN2 polymorphisms analysed in the two groups with the exception of an increased frequency of a homozygous MBL codon 57 mutation in non-responders (4 (9.5%) vs. 8 (3.2%), p = 0.05) corresponding to lower MBL levels. Results were similar after adjusting for age and sex.

Conclusions

Our study does not support a prominent role of the lectin pathway of complement in general and MBL and FCN2 in particular in the humoral immune response to HBV vaccination in African adults.     

DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial

Background

We have developed a Trivalent DNA vaccine for influenza consisting of three plasmids expressing haemagglutinin from different seasonal influenza virus strains delivered using PMED™ (particle mediated epidermal delivery). We set out to determine whether this vaccine (with and without a molecular adjuvant DNA Encoded Immunostimulator-Labile Toxin (DEI-LT)) could protect subjects from a controlled influenza virus challenge.

Methods

Healthy adult subjects were screened for susceptibility to infection with influenza A/H3 Panama/2007/99 then vaccinated with 4 μg Trivalent influenza DNA vaccine, 2 μg Trivalent influenza DNA vaccine plus DEI-LT or placebo. Safety and serological responses to vaccination were assessed and on Day 56 subjects were challenged with A/H3 Panama/2007/99 virus.

Results

Vaccination with 4 μg Trivalent or 2 μg Trivalent/DEI-LT was well tolerated and induced antibody responses to two of the three influenza virus vaccine strains. Post challenge, subjects in the 4 μg Trivalent group (N = 27) showed reductions in disease symptoms and viral shedding compared to placebo (N = 27), with an overall vaccine efficacy of 41% (95% confidence interval (CI) = −1.5, 67.7) for ‘Any illness with or without fever’ and 53% for ‘Upper respiratory tract infection’ (95% CI = 8.0, 77.7).

Conclusion

It was concluded that PMED vaccination with 4 μg Trivalent influenza DNA vaccine was safe and elicited immunological responses that protected human subjects from influenza; this is the first report of protection of human subjects from disease by DNA vaccination.     

High expression of MAGE-A4 and MHC class I antigens in tumor cells and induction of MAGE-A4 immune responses are prognostic markers of CHP-MAGE-A4 cancer vaccine

Purpose

We conducted a cancer vaccine clinical trial with MAGE-A4 protein. Safety, clinical response, and antigen-specific immune responses were analyzed and the prognostic factors by vaccination were investigated.

Experimental design

Twenty patients with advanced esophageal, stomach or lung cancer were administered MAGE-A4 vaccine containing 300 μg protein subcutaneously once every 2 weeks in six doses. Primary endpoints of this study were safety and MAGE-A4 immune responses.

Results

The vaccine was well tolerated. Fifteen of 20 patients completed one cycle of vaccination and two patients showed SD. A MAGE-A4-specific humoral immune response was observed in four patients who had high expression of MAGE-A4 and MHC class I on tumor cells. These four patients showed significantly longer overall survival than patients without an antibody response after vaccination (p = 0.009). Patients with tumor cells expressing high MAGE-A4 or MHC class I antigen showed significantly longer overall survival than those with low expression. Induction of CD4 and CD8T cell responses was observed in three and six patients, respectively, and patients with induction of MAGE-A4-specific IFNγ-producing CD8T cells, but not CD4T cells, lived longer than those without induction.

Conclusions

The CHP-MAGE-A4 vaccine was safe. Expression of MAGE-A4 and MHC class I in tumor tissue and the induction of a MAGE-A4-specific immune response after vaccination would be feasible prognostic markers for patients vaccinated with MAGE-A4.