Human Papillomavirus vaccination: Immunological and epidemiological studies

This thesis has evaluated the immunological- and epidemiological aspects of human papillomavirus transmission dynamics and its effect on circumcision. Effective prophylactic vaccines are based on type-specific neutralizing antibodies. A major neutralizing epitope is defined by the monoclonal antibody H16.V5. To investigate the importance of this epitope for overall immunogenicity of HPV16, we engineered HPV16 virus-like particles devoid of the H16.V5 epitope by site-directed mutagenesis of 10 non-conserved, surface exposed residues. Removal of the V5-defined epitope had only marginal effect on antigenic reactivity with antibodies in sera from infected subjects, but affected immunogenicity in experimental immunization of mice, with reduced induction of both antibody responses and CTL responses. A serological survey of HPV16 antibody prevalence by age and sex in Sweden was performed and used it as a basis for modeling the optimal vaccination strategies in this population. By the year 2055, vaccination of females starting at age 12 in 2008 was most efficient, estimated to prevent 5.8 million cumulative HPV16 infections. Catch-up programs had a strong additional preventive effect. Vaccination also targeting males increased protective effect by about 4 percent, but had lower preventive effect per vaccination given. Addition of an HPV serosurvey to existing models and data has enabled us to estimate effect of different vaccination strategies, optimised to the HPV epidemiology in our population. The age-dependent seroprevalence of HPV6, 11, 16, 18, and 52 infection was investigated and further used to asses the transmission dynamics in a representative Swedish population. Analyses of age-specific prevalence revealed different patterns for high- and low-risk HPV infections between females and males. Circumcision has been reported to protect against infection with human papillomavirus in men, but results have been inconsistent. We followed males in a birth cohort born in Dunedin, New Zealand from age 3 to 32 years. Circumcision was not found to be protective, with the adjusted odds ratio (95% confidence interval) for HPV6/11/16/18 seropositivity among the circumcised compared with the uncircumcised being 1.4 (0.89-2.2)

EBF recommendation on practical management of critical reagents for antidrug antibody ligand-binding assays

Immunogenicity assays are required to measure antidrug antibodies that are generated against biotherapeutic modalities. As for any ligand-binding assays, critical reagents (CR) play a crucial role in immunogenicity assays, as the robustness and reliability of an assay are defined by the quality and long-term availability of these reagents. The current regulatory guidelines do not provide clear directions on how to implement and verify lot-to-lot changes of CR during an assay life cycle, or the acceptance criteria that should be used when implementing new lots of CR. These aspects were extensively discussed within the European Bioanalysis Forum community. In this paper, CR for immunogenicity assays are identified and the minimum requirements for introducing new lots of CR in immunogenicity assays are described

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Deletion of a major neutralizing epitope of human papillomavirus type 16 virus-like particles.

Human papillomavirus type 16 (HPV-16) is a major cause of human cancer. Effective prophylactic vaccines are based on type-specific neutralizing antibodies. A major neutralizing epitope has been defined by the monoclonal antibody H16.V5. To investigate the importance of this epitope for overall immunogenicity of HPV-16, HPV-16 virus-like particles devoid of the H16.V5 epitope were engineered by site-directed mutagenesis of ten non-conserved, surface-exposed residues. Removal of the H16.V5-defined epitope had only a marginal effect on antigenic reactivity with antibodies in sera from infected subjects, but affected immunogenicity in experimental immunization of mice, with reduced induction of both antibody responses and CTL responses

Seroepidemiology as basis for design of a human papillomavirus vaccination program.

We have performed a serological survey of HPV type 16-antibody prevalence by age and sex in Sweden and used it as a basis for modelling the optimal vaccination strategies in this population. Samples of 3317 subjects were tested for HPV16-specific antibodies. The observed age-specific seroprevalences along with sexual behaviour data were used to infer parameter values for a mathematical model representing Sweden and the preventive effect of possible strategies estimated. By the year 2055, vaccination of females starting at age 12 in 2008 was most efficient, estimated to prevent 5.8 million cumulative HPV16 infections. Catch-up programs had a strong additional preventive effect. Vaccination also targeting males increased protective effect by about 4%, but had lower preventive effect per vaccination given. Addition of an HPV serosurvey to existing models and data has enabled us to estimate effect of different vaccination strategies, optimized to the HPV epidemiology in our population

EBF Recommendation for stability testing of anti-drug antibodies; lessons learned from anti-vaccine antibody stability studies.

Long- and short-term stability testing of the analyte is one of the key parameters in bioanalytical method validation in support of pharmacokinetics. However, for immunogenicity testing the scientific rationale for long- and short-term stability testing on quality control (QC) samples most often spiked with polyclonal antibody raised in a different species should be questioned. Therefore, the European Bioanalysis Forum (EBF) formed a Topic Team (TT) to discuss the scientific rationale for stability testing of anti-drug antibodies (ADA). A review of EBF member companies’ experience on ADA stability and data from vaccine projects was the basis of this discussion. EBF recommends to perform short-term stability testing but not to perform long-term stability testing of ADAs in non-clinical and clinical studies

Male Circumcision and Serologically Determined Human Papillomavirus Infection in a Birth Cohort

Circumcision has been reported to protect against infection with human papillomavirus (HPV) in men, but results have been inconsistent. We followed males in a birth cohort born in Dunedin, New Zealand, in 1972 and 1973 from age 3 to 32 years. Seropositivity at age 32 years for the oncogenic types HPV-16 and 18, and the nononcogenic types 6 and 11, was studied in relation to maternal reports of circumcision status at age 3 for 450 men. Seropositivity to any of these types was associated with lifetime number of sexual partners (P = 0.03), and lower moral-religious emphasis of the family of origin (P < 0.001). Circumcision was not found to be protective, with the adjusted odds ratio (95% confidence interval) for HPV6/11/16/18 seropositivity among the circumcised compared with the uncircumcised being 1.4 (0.89-2.2)