Impact of adjuvants on CD4(+) T cell and B cell responses to a protein antigen vaccine: Results from a phase II, randomized, multicenter trial.

Immunogenicity and safety of different adjuvants combined with a model antigen (HBsAg) were compared. Healthy HBV-naïve adults were randomized to receive HBs adjuvanted with alum or Adjuvant Systems AS01B, AS01E, AS03A or AS04 at Days 0 and 30. Different frequencies of HBs-specific CD4+ T cells 14days post dose 2 but similar polyfunctionality profiles were induced by the different adjuvants with frequencies significantly higher in the AS01B and AS01E groups than in the other groups. Antibody concentrations 30days post-dose 2 were significantly higher in AS01B, AS01E and AS03A than in other groups. Limited correlations were observed between HBs-specific CD4+ T cell and antibody responses. Injection site pain was the most common solicited local symptom and was more frequent in AS groups than in alum group. Different adjuvants formulated with the same antigen induced different adaptive immune responses and reactogenicity patterns in healthy naïve adults. The results summary for this study (GSK study number 112115 - NCT# NCT00805389) is available on the GSK Clinical Study Register and can be accessed at www.gsk-clinicalstudyregister.com.

Long-Term Follow-up of HPV Infection Using Urine and Cervical Quantitative HPV DNA Testing.

The link between infection with high-risk human papillomavirus (hrHPV) and cervical cancer has been clearly demonstrated. Virological end-points showing the absence of persistent HPV infection are now accepted as a way of monitoring the impact of prophylactic vaccination programs and therapeutic vaccine trials. This study investigated the use of urine samples, which can be collected by self-sampling at home, instead of cervical samples for follow-up of an HPV intervention trial. Eighteen initially HPV DNA-positive women participating in an HPV therapeutic vaccine trial were monitored during a three-year follow-up period. A total of 172 urine samples and 85 cervical samples were collected. We obtained a paired urine sample for each of the 85 cervical samples by recovering urine samples from six monthly gynaecological examinations. We performed a small pilot study in which the participating women used a urine collection device at home and returned their urine sample to the laboratory by mail. All samples were analyzed using quantitative real-time HPV DNA PCR. A good association (κ value of 0.65) was found between the presence of HPV DNA in urine and a subsequent cervical sample. Comparisons of the number of HPV DNA copies in urine and paired cervical samples revealed a significant Spearman rho of 0.676. This correlation was superior in women with severe lesions. The HPV DNA results of the small pilot study based on self-collected urine samples at home are consistent with previous and subsequent urine and/or cervical results. We demonstrated that urine sampling may be a valid alternative to cervical samples for the follow-up of HPV intervention trials or programs. The potential clinical value of urine viral load monitoring should be further investigated.

GTL001, A Therapeutic Vaccine for Women Infected with Human Papillomavirus 16 or 18 and Normal Cervical Cytology: Results of a Phase I Clinical Trial.

PURPOSE: Women infected with human papillomavirus (HPV) with normal cytology to mild abnormalities currently have no treatment options other than watchful waiting or surgery if high-grade cervical lesions or cancer develop. A therapeutic vaccine would offer the possibility of preventing high-grade lesions in HPV-infected women. GTL001 is a therapeutic vaccine composed of recombinant HPV16 and HPV18 E7 proteins fused to catalytically inactive Bordetella pertussis CyaA. This study examined the tolerability and immunogenicity of GTL001 in women infected with HPV16 or HPV18 with normal cytology. EXPERIMENTAL DESIGN: This was a phase I trial (EudraCT No. 2010-018629-21). In an open-label part, subjects received two intradermal vaccinations 6 weeks apart of 100 or 600 µg GTL001 + topical 5% imiquimod cream at the injection site. In a double-blind part, subjects were randomized 2:1:1 to two vaccinations 6 weeks apart of 600 µg GTL001 + imiquimod, 600 µg GTL001 + placebo cream, or placebo + imiquimod. RESULTS: Forty-seven women were included. No dropouts, treatment-related serious adverse events, or dose-limiting toxicities occurred. Local reactions were transient and mostly mild or moderate. HPV16/18 viral load decreased the most in the 600 µg GTL001 + imiquimod group. In post hoc analyses, the 600 µg GTL001 + imiquimod group had the highest rates of initial and sustained HPV16/18 clearance. Imiquimod increased antigen-specific T-cell response rates but not rates of solicited reactions. All subjects seroconverted to CyaA. CONCLUSIONS: For women infected with HPV16 or HPV18 with normal cervical cytology, GTL001 was immunogenic and had acceptable safety profile. Clin Cancer Res; 22(13); 3238-48. ©2016 AACR.

Antibody Persistence and Booster Responses to Split-Virion H5N1 Avian Influenza Vaccine in Young and Elderly Adults.

Avian influenza continues to circulate and remains a global health threat not least because of the associated high mortality. In this study antibody persistence, booster vaccine response and cross-clade immune response between two influenza A(H5N1) vaccines were compared. Participants aged over 18-years who had previously been immunized with a clade 1, A/Vietnam vaccine were re-immunized at 6-months with 7.5 µg of the homologous strain or at 22-months with a clade 2, alum-adjuvanted, A/Indonesia vaccine. Blood sampled at 6, 15 and 22-months after the primary course was used to assess antibody persistence. Antibody concentrations 6-months after primary immunisation with either A/Vietnam vaccine 30 µg alum-adjuvanted vaccine or 7.5 µg dose vaccine were lower than 21-days after the primary course and waned further with time. Re-immunization with the clade 2, 30 µg alum-adjuvanted vaccine confirmed cross-clade reactogenicity. Antibody cross-reactivity between A(H5N1) clades suggests that in principle a prime-boost vaccination strategy may provide both early protection at the start of a pandemic and improved antibody responses to specific vaccination once available. TRIAL REGISTRATION: ClinicalTrials.gov NCT00415129.

Long-term antibody persistence in children after vaccination with the pediatric formulation of an aluminum-free virosomal hepatitis A vaccine.

BACKGROUND: The pediatric dose of the virosomal hepatitis A vaccine Epaxal, Epaxal Junior, is safe and immunogenic in children from 1 to 17 years of age. The present study investigated the long-term immunogenicity of Epaxal Junior. The standard doses of Epaxal and aluminum-adsorbed hepatitis A vaccine (Havrix Junior) were used as comparators. METHODS: A total of 271 children who had completed a 0/6-month immunization schedule (priming and booster dose) participated in this follow-up study. Anti-hepatitis A virus (HAV) antibody levels were measured using a microparticle enzyme immunoassay (HAVAB 2.0 Quantitative; Abbott Diagnostics, Wiesbaden, Germany) starting at 18 months following the second dose, and then yearly until 66 months (ie, 5.5 years) after the second dose. RESULTS: All subjects tested at Month 66 still had protective anti-HAV antibodies (≥10 mIU/mL). Antibody titers were generally lower in subjects 1-7 years old than in subjects 8-17 years old and higher in females 11-17 years old than in males 11-17 years old. In addition, an age-dependent decay was observed, that is, antibody decreased more rapidly in younger than in older children. CONCLUSIONS: Vaccination of children with two doses of Epaxal Junior confers a real-time protection of at least 5.5 years. This protection is estimated to last approximately 25 years. Younger children showed lower antibody titers and a faster antibody decline than older children. Additional follow-up studies are needed beyond 5.5 years to further assess the long-term immunogenicity of Epaxal Junior.

Exploring the impact of exposure to primary varicella in children on varicella-zoster virus immunity of parents.

Varicella-zoster virus (VZV) causes both primary varicella, and through reactivation of the virus, herpes zoster. It is hypothesized that VZV-immune adults may reduce the probability of developing herpes zoster through exposure to varicella. In this study we examine the existence of immunological boosting in VZV-immune adults after close contact with primary varicella. We followed-up 18 parents with household exposure to primary varicella for 1 y. Fifteen age-matched healthy and 20 older volunteers served as control groups. Cellular (IFN-γ ELISPOT) and humoral responses were measured. Data analyses were performed by t-tests and linear mixed models. The young control group only showed higher cellular responses than the older control group and the exposed group 1 mo after exposure. The exposed group had a strong tendency toward higher cellular responses compared to the older control group, reaching significance 1 y post-exposure. The best fitting linear mixed model predicts a decline in cellular response of 50% between 1 wk and 1 mo post-exposure, followed by an increase to attain an 80% higher level at 1 y compared to the first week post-exposure. No significant results emerged based on the humoral response of the individual parents in the exposed group, despite a general tendency toward higher antibody concentrations in the exposed versus the control groups. No significant difference in humoral immunity was found between the control groups. One year after initial re-exposure to VZV, VZV-immune adults showed a rise in cellular response as assessed by IFN-γ ELISPOT, and steady-state levels for the humoral response.

Safety and immunogenicity of an inactivated whole virus Vero cell-derived Ross River virus vaccine: a randomized trial.

BACKGROUND: Ross River virus (RRV) is endemic in Australia and several South Pacific Islands. Approximately 5000 cases of RRV disease, which is characterized by debilitating polyarthritis, are recorded each year in Australia. This study describes the first clinical trial of a candidate RRV vaccine. METHODS: An inactivated whole-virus Vero cell-derived RRV vaccine was tested in 382 healthy, RRV-naïve adults in a phase 1/2 dose-escalation study at ten sites in Austria, Belgium and The Netherlands. Subjects were equally randomized to receive 1.25 µg, 2.5 µg, 5 µg, or 10 µg aluminum hydroxide-adjuvanted or non-adjuvanted RRV vaccine, with a second dose after three weeks and a booster at six months. Vaccine immunogenicity was determined by measurements of serum IgG and neutralizing antibody titers. Vaccine tolerability and safety were monitored over the entire study period. RESULTS: The optimal vaccine formulation was the adjuvanted 2.5 µg dose, as calculated using a repeated mixed model analysis of covariance comparing log-transformed RRV-specific IgG titers between different dose groups. Geometric means of RRV-specific serum antibodies measured 21 days after the third vaccination with the 2.5 µg adjuvanted formulation were 520.9 (90% CI 377.2-719.4) as determined by IgG ELISA and 119.9 (82.6-173.9) as determined by virus neutralization assay, resulting in seropositivity rates of 92.9% (82.6-98.0) and 92.7% (82.2-98.0), respectively. All vaccine formulations and doses were well tolerated after the first, second and third vaccination. CONCLUSIONS: The adjuvanted, inactivated whole-virus Vero cell-derived Ross River virus vaccine is highly immunogenic in RRV-naïve adults and well tolerated at all dose levels.