Addressing vaccine supply challenges in Europe: Expert industry perspective and recommendations.

Shortages of medicines are an increasing concern worldwide. In the European Union (EU), several initiatives have been launched by authorities to address this important public health issue. To contribute in finding solutions, Vaccines Europe (VE), representing 14 vaccine companies operating in Europe, conducted an analysis of the main root causes of vaccine shortages in Europe. Vaccines Europe has identified six main causes of vaccine shortages. Finding solutions will require a concerted effort and dialogue with the involvement of all key stakeholders. In this publication, Vaccines Europe is making a series of recommendations aiming at improving vaccine availability for Europe and beyond.

Immunogenicity, reactogenicity and safety of two-dose versus three-dose (standard care) hepatitis B immunisation of healthy adolescents aged 11-15 years: a randomised controlled trial.

This trial assessed the immunogenicity, safety and reactogenicity of a two-dose hepatitis B immunisation regimen (thiomersal-free Engerix-B 20 microg HBsAg doses 6 months apart) compared to the standard three-dose vaccination regimen (preservative-free Engerix-B 10 microg HBsAg doses, 0, 1, 6 month dose schedule) in healthy adolescents aged 11-15 years. Subjects were randomly assigned (2:1 ratio) to one of the two regimens (258 to the two-dose [20 microg] and 126 to the three-dose [10 microg] regimen) (Study ID 103860/280). One month after the final vaccine dose, the seroprotection (anti-HBs >or=10mIU/ml) rate in the two-dose (20 microg) group (233/241 individuals -96.7% seroprotected) was non-inferior to the seroprotection rate in the three-dose (10 microg) group (111/113 individuals -98.2% seroprotected). Both regimens were shown to be safe and well tolerated. Two doses of Engerix-B (20 microg HBsAg) could be considered as an alternative to standard three-dose Engerix-B (10 microg HBsAg) immunisation for adolescents aged 11-15 years.

Antibody persistence and immune memory elicited by combined hepatitis A and B vaccination in older adults.

Response to hepatitis A and B vaccines has been reported to decline with age. This open, prospective, single-site study examined the long-term response to the combined hepatitis A/B vaccine Twinrix in 98 primary responders aged 45-67 years. Levels of antibody against hepatitis A virus (HAV) and hepatitis B surface antigen (HBs) were tested 30 months after initial vaccination. At this stage, all participants remained seropositive for anti-HAV and 70% for anti-HBs. A booster vaccination was offered to those who had responded to the first vaccination but then lost protective levels of anti-HBs. An anamnestic response was observed in all cases.

Immunogenicity and safety of an experimental adjuvanted hepatitis B candidate vaccine in liver transplant patients.

Patients with chronic liver disease are at higher risk of hepatitis B (HB) virus infection before and after liver transplantation, and they commonly have a suboptimal immune response to HB vaccines. In this randomized trial, we compared the immunogenicity of primary vaccination with 2 doses of an experimental adjuvanted HB vaccine (adjuvant system 04 containing aluminium and monophosphoryl lipid A [HB-AS04]) to that of 3 double doses of a licensed HB vaccine in 93 liver transplant candidates. Depending on the waiting list for liver transplantation, a booster dose of HB-AS04 or double booster dose of the licensed HB vaccine was given before or after surgery, at 6 to 12 months after initiation of the vaccination course. The percentage of subjects with seroprotective anti-HB surface antibody concentrations 1 month after booster was twice as high in the HB-AS04 group (60.0%), vs. patients in the comparator group (32.0%) (P = 0.035). In subjects who did not undergo liver transplantation before administration of the booster, better immunogenicity results were obtained: 80% of subjects were seroprotected after HB-AS04 vaccination vs. 60% with the comparator (P = 0.2302). Despite a slightly higher reactogenicity, the safety profile of the HB-AS04 vaccine was clinically acceptable. In conclusion, an improved antibody response was observed in liver transplant candidates with 3 doses of HB-AS04, as compared to 4 double doses of a comparator. Liver transplant candidates could benefit from the use of this experimental adjuvanted HB vaccine to further increase their protection against HB infection.

Immunogenicity and safety of an adjuvanted hepatitis B vaccine in pre-hemodialysis and hemodialysis patients.

BACKGROUND: Due to their impaired immune system, patients with renal insufficiency have a suboptimal response to hepatitis B (HB) vaccination and frequent boosters are needed to maintain protection. GlaxoSmithKline Biologicals has developed a HB vaccine containing a new adjuvant system AS04 for use in this immunocompromised patient population. METHODS: In an open, randomized clinical trial conducted in pre-hemodialysis (documented creatinine clearance < or =30 mL/min) and hemodialysis patients, over 15 years of age and naïve for HB, the immunogenicity and safety of single doses of HB-AS04 (Fendrix, GlaxoSmithKline Biologicals) were compared to double doses of commercially available HB vaccine (Engerix, GlaxoSmithKline Biologicals) administered at 0, 1, 2, and 6 months, and followed-up for 36 months. RESULTS: The HB-AS04 vaccine elicited a more rapid onset of protection than the currently licensed vaccine for this particular population, with 74% versus 52% of subjects seroprotected at month 3. After the vaccination course, seroprotection rates increased to 91% versus 84% in the HB-AS04 and standard vaccine groups, respectively. Differences persisted up to 36 months post-vaccination (73% vs. 52%, respectively). Antibody concentrations were higher following the HB-AS04 vaccine at all post-vaccination time points. During the follow-up, significantly fewer subjects primed with the HB-AS04 vaccine needed a booster dose as a consequence of anti-HBs loss below seroprotective levels (11/62 subjects in the HB-AS04 group vs. 22/57 subjects in the standard vaccine group, respectively, P = 0.014). The HB-AS04 was more locally reactogenic than the standard immunization regimen, with pain at the injection site occurring with 41% of HB-AS04 doses versus 19% of standard vaccine doses. The occurrence of grade 3 pain was less than 1% in both groups and all events resolved within the 4-day follow-up period. CONCLUSION: The improved immunogenicity profile and clinically acceptable reactogenicity of HB-AS04 vaccine are of key importance to provide a more rapid, enhanced, and longer seroprotection to these immunocompromised patients at risk for HB infection.

Response to an experimental HBV vaccine permits withdrawal of HBIg prophylaxis in fulminant and selected chronic HBV-infected liver graft recipients.

Strategies using lamivudine and hepatitis B immunoglobulins (HBIg) for prevention of hepatitis B virus (HBV) reinfection after liver transplantation (LT) are expensive since life-long treatment is needed. We evaluated the possibility to obtain protective hepatitis B surface antigen (HBsAg) antibody (anti-HBs) titers after LT and to discontinue HBIg prophylaxis after a reinforced course of vaccination against HBV using an experimental adjuvant HBsAg / AS04 vaccine (GlaxoSmithKline Biologicals [GSK], Rixensart, Belgium) in patients transplanted for hepatitis B. Fifteen LT patients on stable low-level immunosuppression were vaccinated with a double dose of the vaccine at 0, 1, 2, 6, and 12 months: 5 patients were transplanted for nonviral diseases and 10 patients were transplanted for HBV on HBIg monotherapy. HBIg were continued during baseline vaccination (0, 1, and 2 months) and when anti-HBs titers determined every 6 weeks dropped below 150 IU/L. Overall follow-up was 18 months. Sustained long-term response to vaccination was defined as anti-HBs titers >500 IU/L without further need for HBIg administration during a follow-up period of at least 12 months. Overall sustained response to vaccination was 53% (8 / 15 patients); 80% (4 / 5 patients) in the nonviral disease group and 40% (4 / 10 patients) in the HBV group (2 /2 fulminant and 2/8 chronically infected patients) developed a sustained long-term response and were completely free of HBIg at the end of the 18-month follow-up. No HBV recurrence, rejection episodes, or side effects occurred during the follow-up. In conclusion, protective anti-HBs titers were obtained in a substantial number of LT patients following a reinforced course of HBV vaccination with vaccines containing new immunostimulating adjuvants. Vaccination seems well tolerated and safe and allows long-term discontinuation of HBIg.

Hepatitis A vaccine: indirect evidence of immune memory 12 years after the primary course.

Vaccine-induced hepatitis A antibodies persist up to 10 years in adults, with mathematical models estimating further persistence up to 20-25 years. Thirty-one adults received booster inoculations 12 years after their initial vaccination (Havrix 720 El.U at months 0, 1, 6). At the time of booster inoculation, all still had detectable antibodies. All but one subject met pre-defined criteria for anamnestic response 14 days after the booster, and all subjects did so after 30 days. The subjects' geometric mean titre (GMT) increased rapidly from 242 IU/L at baseline to 3,832 IU/L at day 14 and 5,282 IU/L at day 30. This study shows a substantial immune response to re-exposure to hepatitis A antigen after 12 years, which occurs rapidly to ensure protection within the average incubation period of hepatitis A virus.

Immunogenicity of Twinrix in older adults: a critical analysis.

Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) is the first combined vaccine to provide protection against both hepatitis A and B. This review presents a critical analysis of antibody responses stratified by age following vaccination with Twinrix in 264 adults aged above 40 years. A month after completion of a 0-, 1-, 6-month vaccination schedule with Twinrix, a good response was observed for both anti-HAV and anti-HBs serum antibodies, suggesting that is an effective vaccine in older adults.

Immune response of HLA DQ2 positive subjects, vaccinated with HBsAg/AS04, a hepatitis B vaccine with a novel adjuvant.

About 5-10% of the general adult population respond inadequately to hepatitis B vaccination. The histocompatibility leucocyte antigen (HLA) DQ2, DR3 and DR7 phenotypes have been linked with non-responsiveness to hepatitis B vaccination. A first part of our study determined the prevalence of the HLA DQ2 allele in a healthy population, aged 15-50 years. We found 35% of our study population (n=1008) positive for the HLA DQ2 allele. Positive subjects for HLA DQ2 were subsequently invited to participate in a trial and were to be given either the HBsAg/AS04 hepatitis B vaccine or a licensed hepatitis B vaccine (Engerix-B).(1) Both contained 20 microg of recombinant HBsAg. The HBsAg/AS04 vaccine was administered on a 0 and 6 months schedule whilst the comparator vaccine was given according to the standard 0, 1 and 6 months schedule. The experimental vaccine was formulated on a novel adjuvant containing 3' deacylated monophosphoryl lipid A (3D-MPL) and alum. A total of 230 subjects were enrolled into the vaccination study. At month 7, 99% of the subjects had a protective titre (>or=10mIU/ml) with a geometric mean titre (GMT) of 6613mIU/ml in the group receiving HBsAg/AS04 versus 97% seroprotected with a GMT of 2315mIU/ml in the other group. Both vaccines, with their respective schedule, give very high seroprotection rates (>96%). Our data suggest that HLA DQ2 positivity is not a good marker for non- or poor-responsiveness. The HBsAg/AS04 vaccine was more reactogenic mainly because of an increased local reactogenicity. Both vaccines, especially HBsAg/AS04, are highly immunogenic and well tolerated by the study subjects.