AS03B-adjuvanted H5N1 influenza vaccine in children 6 months through 17 years of age: a phase 2/3 randomized, placebo-controlled, observer-blinded trial.

BACKGROUND: This phase 2/3, randomized, placebo-controlled, observer-blinded study assessed the immunogenicity, reactogenicity, and safety of an inactivated, split-virion H5N1 influenza vaccine (A/Indonesia/5/2005) in children aged 6 months through 17 years. METHODS: Children received 2 influenza vaccine doses 21 days apart, each containing 1.9 µg of hemagglutinin and AS03B adjuvant (5.93 mg of α-tocopherol). The randomization ratio was 8:3 for vaccine to placebo, with equal allocation between 3 age strata (6-35 months, 3-8 years, and 9-17 years). Immunogenicity against the vaccine strain was assessed 21 days after the first and second vaccine doses for all vaccinees, at day 182 for half, and at day 385 for the remaining half. Reactogenicity after each dose and safety up to 1 year after vaccination were evaluated. RESULTS: Within each age stratum, the lower limit of the 98.3% confidence interval for the day 42 seroprotection rate was ≥70%, thus fulfilling the US and European licensure criteria. The immune responses elicited by vaccine persisted well above baseline levels for 1 year. The vaccine was more reactogenic than placebo, but no major safety concerns were identified. CONCLUSIONS: AS03B-adjuvanted H5N1 influenza vaccine was immunogenic and showed an acceptable safety profile in all age groups studied. Clinical Trials Registration: NCT01310413.

Heterologous prime-boost vaccination using an AS03B-adjuvanted influenza A(H5N1) vaccine in infants and children<3 years of age.

BACKGROUND: Protecting young children from pandemic influenza should also reduce transmission to susceptible adults, including pregnant women. METHODS: An open study assessed immunogenicity and reactogenicity of a heterologous booster dose of A/turkey/Turkey/1/2005(H5N1)-AS03B (AS03B is an Adjuvant System containing α-tocopherol and squalene in an oil-in-water emulsion [5.93 mg tocopherol]) in infants and children aged 6 to <36 months that was given 6 months following 2-dose primary vaccination with A/Indonesia/05/2005(H5N1)-AS03B. Vaccines contained 1.9 µg of hemagglutinin antigen and AS03B. Hemagglutinin inhibition (HI) responses, microneutralization titers, and antineuraminidase antibody levels were assessed for 6 months following the booster vaccination. RESULTS: For each age stratum (defined on the basis of the subject's age at first vaccination as 6 to <12 months, 12 to <24 months, and 24 to <36 months) and overall (n=113), European influenza vaccine licensure criteria were fulfilled for responses to A/turkey/Turkey/1/2005(H5N1) 10 days following the booster vaccination. Local pain and fever increased with consecutive doses. Anamnestic immune responses were demonstrated for HI, neutralizing, and antineuraminidase antibodies against vaccine-homologous/heterologous strains. Antibody responses to vaccine-homologous/heterologous strains persisted in all children 6 months following the booster vaccination. CONCLUSIONS: Prevaccination of young children with a clade 2 strain influenza A(H5N1) AS03-adjuvanted vaccine followed by heterologous booster vaccination boosted immune responses to the homologous strain and a related clade, with persistence for at least 6 months. The results support a prime-boost vaccination approach in young children for pandemic influenza preparedness. CLINICAL TRIALS REGISTRATION: NCT01323946.

Exploring the evidence behind the comparable impact of the pneumococcal conjugate vaccines PHiD-CV and PCV13 on overall pneumococcal disease.

The worldwide implementation of pneumococcal conjugate vaccines (PCVs) in children has reduced the overall pneumococcal disease burden. Two PCVs are widely available for infant vaccination: the pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) and the 13-valent PCV (PCV13). While these PCVs differ in serotype composition (PCV13 includes polysaccharides of serotypes 3, 6A and 19A; PHiD-CV does not), their impact on the overall pneumococcal disease burden in children is comparable. This commentary summarizes the evidence of comparability between PHiD-CV and PCV13 and explores why differences in serotype composition may not necessarily translate into a differential clinical impact. Both vaccines confer similarly high protection against disease caused by vaccine serotypes and lead to a partial replacement by non-vaccine serotypes. PHiD-CV does not protect against serotype 3 disease (not included in the vaccine) and PCV13's effect on this serotype has been inconsistent. PHiD-CV provides some cross-protection against disease caused by vaccine-related serotype 19A but neither vaccine has fully controlled 19A disease. While protection against 19A is higher for PCV13 than PHiD-CV, replacement by non-PCV13 serotypes in settings with a PCV13 program appears to compensate for this difference. This results in a similar residual overall disease burden with both vaccines.

PLAIN LANGUAGE SUMMARYWhat is the context?The pneumococcus bacterium can cause infections of the meninges, blood, lung, middle ear and sinuses.Two vaccins, Synflorix (GSK) and Prevnar 13 (Pfizer Inc.), are widely used to protect young children against these infections.The vaccines' compositions differ: Synflorix includes antigens from 10 pneumococcus strains (or "serotypes") and Prevnar 13 from 13 serotypes.However, both have a similar effect on the total pneumococcal disease burden in children.What does this commentary highlight?This commentary summarizes the evidence beihnd the two vaccines' comparable impact on pneumococcal disase.It also looks at why the vaccines have a similar effect on the total pneumococcal disease burden despite their different compositions.What is the impact on current thinking?Given that Synflorix and Prevnar 13 have a comparable impact on pneumococcal disease, a country's choice between the two vaccines will depend on vaccine supply, cost, logistical factors (e.g., transport, storage, training requirements of health workers) and the local pneumococcal epidemiology.

Systematic review of the efficacy, effectiveness and impact of high-valency pneumococcal conjugate vaccines on otitis media.

Otitis media (OM) is a common disease of childhood and available pneumococcal conjugate vaccines (PCVs), with different compositions, could have different impact on OM reduction. This systematic literature review evaluated available data describing the efficacy, effectiveness, and impact of 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) and 13-valent PCV (PCV13) on OM outcomes. Statistically significant reductions in all-cause and complicated OM, tympanostomy tube placement and OM-related hospitalizations were consistently observed after the introduction of PHiD-CV and PCV13. Impact studies with data in children <2 years of age using PCV13 report 47-51% and PHiD-CV 34-43% reduction of all-cause OM (primary care, outpatient, ambulatory, emergency department visits) compared to periods before PCV introduction. When the impact of both vaccines is assessed in comparable settings, some studies suggest PHiD-CV may offer better protection against some OM outcomes. Well-designed, head-to-head comparisons are needed to better understand the differences and guide vaccination policies.

Plain Language SummaryWhat is the context?Pneumococcal vaccines are highly effective in preventing pneumonia and meningitis in children. The two main pneumococcal vaccines are PHiD-CV (Synflorix, GSK) and PCV13 (Prevenar 13, Pfizer). Both vaccines have been shown to provide protection against otitis media despite differing in their composition.However, it is currently unknown if both vaccines confer similar level of protection against otitis media.What is new?We conducted a literature review to evaluate the effects of PHiD-CV and PCV13 on otitis media.From 33 articles, we found that:‡Both vaccines were effective in reducing doctor visits for otitis media as well as the number of severe cases and cases requiring hospitalization.‡Four studies suggested a higher level of protection provided by PHiD-CV compared to PCV13, although more data is needed to confirm this finding. What is the impact?Available information shows that PHiD-CV and PCV13 are effective in preventing a proportion of otitis media during childhood.Given the remaining substantial burden associated with the disease and the related significant usage of antibiotics, the development of improved vaccines with higher impact on otitis media would be welcome.

Estimated public health impact of human rotavirus vaccine (HRV) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV) on child morbidity and mortality in Gavi-supported countries.

Vaccine impact models against rotavirus disease (RD) and pneumococcal disease (PD) in low- and middle-income countries assume vaccine coverage based on other vaccines. We propose to assess the impact on severe disease cases and deaths avoided based on vaccine doses delivered by one manufacturer to Gavi-supported countries. From the number of human rotavirus vaccine (HRV) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV) doses delivered, we estimated the averted burden of disease 1) in a specific year and 2) for all children vaccinated during the study period followed-up until 5 years (y) of age. Uncertainty of the estimated impact was assessed in a probabilistic sensitivity analysis using Monte-Carlo simulations to provide 95% confidence intervals. From 2009 to 2019, approximately 143 million children received HRV in 57 Gavi-supported countries, avoiding an estimated 18.7 million severe RD cases and 153,000, deaths. From 2011 to 2019, approximately 146 million children received PHiD-CV in 36 countries, avoiding an estimated 5.0 million severe PD cases and 587,000 deaths. The number of severe cases and deaths averted for all children vaccinated during the study period until 5 years of age were about 23.2 million and 190,000, respectively, for HRV, and 6.6 million and 749,000, respectively, for PHiD-CV. Models based on doses delivered help to assess the impact of vaccination, plan vaccination programs and understand public health benefits. In 2019, HRV and PHiD-CV doses delivered over a 5-y period may have, on average, averted nine severe disease cases every minute and one child death every 4 min.

What is the context?The WHO added the pneumococcal conjugate vaccine and the rotavirus vaccine in the recommended vaccination schedule of all countries in 2007 and 2009, respectively.Previous studies estimated the public health benefit of these vaccines by approximating the number of children who received them.What is new?We used an alternative approach to estimate the benefit based on actual number of doses of the vaccines, human rotavirus vaccine (HRV; Rotarix) and pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix) delivered to each country considered.The study analyzed data from children under 5 years of age in 60 Gavi-supported countries by identifying the number of vaccine doses delivered, estimating the number of children fully covered, applying the country-specific disease epidemiology, estimating the number of severe disease cases and deaths avoided.From 2009 to 2019, approximately 143 million children were vaccinated with HRV avoiding an estimated 18.7 million severe rotavirus disease cases and 153,000 deaths.From 2011 to 2019, about 146 million children were vaccinated with pneumococcal vaccine avoiding an estimated 5.0 million severe pneumococcal disease cases and 587,000 deaths.What is the impact? The benefit of HRV and PHiD-CV in Gavi-supported countries is often estimated based on assumptions of vaccine coverage rates.A modeling approach based on doses delivered by the vaccine manufacturer can provide an additional view on the potential vaccine benefits and improve planning, contribution, and sustainability of the immunization programs at a country level.In 2019, HRV and PHiD-CV together averted nine cases of severe disease each minute and one child death every 4 minutes.

CIRCULATING CLONAL COMPLEXES AND SEQUENCE TYPES OF STREPTOCOCCUS PNEUMONIAE SEROTYPE 19A WORLDWIDE: THE IMPORTANCE OF MULTIDRUG RESISTANCE: A SYSTEMATIC LITERATURE REVIEW.

INTRODUCTION: Streptococcus pneumoniae is a major cause of morbidity and mortality, especially amongst young children and the elderly. Childhood implementation of pneumococcal conjugate vaccines (PCVs) significantly reduced the incidence of invasive pneumococcal disease (IPD), while several nonvaccine serotypes remained substantial. Although there is evidence of the impact of higher-valent PCVs on serotype 19A, 19A IPD burden and antibiotic resistance remain a major concern post-vaccination. AREAS COVERED: We performed a systematic literature review to analyze the frequency and clonal distribution of serotype 19A isolates in the pre- and post-PCV era worldwide providing a scientific background on the factors that influence multidrug resistance in pneumococcal isolates. EXPERT COMMENTARY: Serotype 19A IPD incidence increased in all regions following the introduction of the 7-valent PCV. The higher-valent PCVs have reduced the rates of 19A IPD isolates, but several circulating strains with diverse antibiotic resistance prevailed. Heterogeneous clonal distribution in serotype 19A was observed within countries and regions, irrespective of higher-valent PCV used. An increase of 19A isolates from pre- to post-vaccination periods were associated with frequently occurring serotype switching events and with the prevalence of multidrug resistant strains. Rational antibiotic policies must be implemented to control the emergence of resistance.Plain Language SummaryWhat is the context?Streptococcus pneumoniae is a major cause of pneumococcal diseases especially amongst young children and the elderly. Vaccination with pneumococcal conjugate vaccines has significantly reduced the incidence of invasive pneumococcal disease worldwide. However, the invasive pneumococcal disease remains an important health problem due to the increase of nonvaccine serotypes. Serotype 19A is predominant in many countries worldwide. Factors contributing to its prevalence include serotype replacement, the emergence of clones with multidrug resistance due to antibiotic overuse, and potential bacteria adaptation in response to the vaccine.What is new?We performed a systematic literature review to 1) analyze the incidence and clonal distribution of serotype 19A isolates pre- and post-vaccination worldwide, and to collect data evaluating antimicrobial resistance patterns displayed by the clones of serotype 19A. We found that 1) clonal distribution in serotype 19A was heterogeneous within countries and regions, irrespective of the vaccine used; 2) the diversity of 19A isolates increased after vaccination. It was associated with frequent serotype switching events and with the prevalence of multidrug resistant strains.What is the impact?Implementation of policies to educate on sustainable antibiotic use and infectious prevention measures may help control the emergence of antibiotic resistance. High-quality active surveillance and future molecular epidemiology studies are needed to understand rapid genetic changes.

Monitoring of community-acquired pneumonia hospitalisations before the introduction of pneumococcal conjugate vaccine into Polish National Immunisation Programme (2009-2016): A nationwide retrospective database analysis.

PURPOSE: Community-acquired pneumonia (CAP) is a common infection with significant morbidity and mortality. In January 2017, Poland introduced pneumococcal conjugate vaccine (PCV) into their national immunisation programme to protect children against invasive pneumococcal disease. This study was designed to investigate pneumonia-related hospitalisation rates and trends from 2009 to 2016 prior to the introduction of nationally funded PCV vaccination. METHODS: Using national public statistic data available from the National Institute of Public Health - National Institute of Hygiene, annual hospitalisation rates for pneumonia were analysed, categorised by aetiology and age (<2, 2-3, 4-5, 6-19, 20-59, 60+ years). Trends over time were assessed, as well as in-hospital mortality. RESULTS: The overall hospitalisation rate due to pneumonia varied between 325.9 and 372.2/100,000 population. Higher rates of hospitalisation were seen in older adults and children ≤5 years. Trends were observed when analysing hospitalisations by pneumonia aetiology within age groups: between 2009 and 2016, Streptococcus pneumoniae hospitalisations significantly increased for children aged <2, 2-3, and 4-5 years, from 5.3 to 12.4, 5.2 to 8.2, and 1.9 to 4.6/100,000 population respectively. Whereas hospitalisations due to Haemophilus influenzae pneumonia decreased significantly from 7.8 to 1.8 and 4.8 to 1.9/100,000 children aged <2 and 2-3 years respectively. The numbers of in-hospital deaths increased from 5578 in 2009 to 8149 in 2016, with >85% of deaths in the 60+ age group. CONCLUSIONS: This is the first national study of pneumonia hospitalisations in Poland, providing the baseline data from which to investigate the impact of the change in vaccination policy on pneumonia hospitalisations in Poland.

Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials.

A pooled analysis of the safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine Cervarix (GlaxoSmithKline) was performed in a cohort of almost 30,000 girls and women aged > or =10 years, 16,142 who received at least one dose of the HPV-16/18 vaccine and 13,811 who received one of three controls [Al(OH)(3) or hepatitis A vaccine (720 or 360 EU)]. Data are available for a total of 45,988 vaccine doses. Solicited local and general symptoms were recorded for seven days after each dose. Serious adverse events (SAEs), pregnancies, medically significant conditions (MSCs) and new onset of chronic diseases (NOCDs), including new onset of autoimmune diseases (NOADs), were proactively monitored. Data were analyzed by vaccine group according to age (10-14, 15-25 and >25 years) and reporting period (months 0-7, months 7-12 and >month 12). Rates of solicited local and general symptoms were higher in the HPV-16/18 vaccine group than in the control groups. However, compliance with the three-dose schedule was high and did not differ between groups (93.4% for HPV-16/18 vaccine group versus 92.5% for pooled controls). No clinically relevant differences were seen between the HPV-16/18 vaccine and pooled control groups in rates of SAEs (2.8% versus 3.1%), MSCs (19.4% versus 21.4%), NOCDs (1.7% in both groups) or NOADs (0.4% versus 0.3%). Similarly, no differences in pregnancy outcomes or rates of withdrawals due to AEs or SAEs were observed between groups. In conclusion, analysis of this large database shows the HPV-16/18 AS04-adjuvanted cervical cancer vaccine to have a favorable safety profile in women of all ages.

A systematic literature review and network meta-analysis feasibility study to assess the comparative efficacy and comparative effectiveness of pneumococcal conjugate vaccines.

Background: No head-to-head studies are currently available comparing pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) with 13-valent pneumococcal conjugate vaccine (PCV-13). This study explored the feasibility of using network meta-analysis (NMA) to conduct an indirect comparison of the relative efficacy or effectiveness of the two vaccines.Methods: A systematic literature search was conducted for published randomized controlled trials (RCTs) and non-RCT studies reporting data on vaccine efficacy or effectiveness against invasive pneumococcal disease in children aged <5 years receiving 7-valent pneumococcal conjugate vaccine (PCV-7), PHiD-CV or PCV-13. Study quality was evaluated using published scales. NMA feasibility was assessed by considering whether a connected network could be constructed by examining published studies for differences in study or patient characteristics that could act as potential treatment effect modifiers or confounding variables.Results: A total of 26 publications were included; 2 RCTs (4 publications), 7 indirect cohort studies, and 14 case-control studies (15 publications). Study quality was generally good. The RCTs could not be connected in a network as there was no common comparator. The studies differed considerably in design, dose number, administration schedules, and subgroups analyzed. Reporting of exposure status and subject characteristics was inconsistent.Conclusion: NMA to compare the relative efficacy or effectiveness of PHiD-CV and PCV-13 is not feasible on the current evidence base, due to the absence of a connected network across the two RCTs and major heterogeneity between studies. NMA may be possible in future if sufficient RCTs become available to construct a connected network.

Public health impact of pneumococcal conjugate vaccine infant immunization programs: assessment of invasive pneumococcal disease burden and serotype distribution.

INTRODUCTION: Pneumococcal conjugate vaccine (PCV) impact studies have reported substantial reductions in the incidence of invasive pneumococcal disease (IPD) after implementation of childhood PCV programs. Heterogeneity in surveillance systems, local epidemiology and PCV programs hampers comparisons between studies. We aimed to better understand the impact of childhood PCV programs on overall IPD and serotype distribution. AREAS COVERED: We analyzed the impact of PCV programs on the incidence of overall IPD, and the distribution of vaccine serotypes (VT) and non-vaccine serotypes (NVT) in children <5 years and adults ≥65 years old. We retrieved datasets from observational post-marketing studies and surveillance reports from countries with high-quality surveillance data available for at least 2 years before PCV program initiation and 3 years after higher-valent PCV implementation. We harmonized pre- and post-PCV analysis periods and assessment methods. EXPERT COMMENTARY: After introduction of pediatric PCV programs, the residual overall IPD burden in children was low and in a narrow range across countries with high vaccination coverage, irrespective of differences in PCV programs and pneumococcal epidemiology. Effects on overall IPD were more variable in the elderly. Whereas IPD was mainly due to VTs before PCV introduction, NVTs are the major contributor today in children and adults.

Assessment of Prime-boost Vaccination Using an AS03B-adjuvanted Influenza A (H5N1) Vaccine: A Randomized Trial in Children of Three to Less Than Eighteen Years of Age.

BACKGROUND: Heterologous prime-boost vaccination is a pandemic response strategy utilizing subtype-matched vaccine at pandemic onset followed by strain-matched vaccine once available. Persistence of immune response and safety of influenza A (H5N1) vaccine adjuvanted with adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion (AS03B) were evaluated. METHODS: An open phase 3 active-controlled study (www.clinicaltrials.gov NCT01379937) assessed immunogenicity and reactogenicity of a heterologous booster dose of A/turkey/Turkey/1/2005-H5N1-AS03B in children 3 to <18 years of age, given 6 months after 2-dose priming with A/Indonesia/05/2005-H5N1-AS03B (H5N1(2) -H5N1 group) compared with a single dose of A/turkey/Turkey/1/2005-H5N1-AS03B in unprimed subjects (hepatitis A vaccine (HAV)-H5N1 group). Hemagglutinin inhibition responses and microneutralization antibodies were assessed to 6 months after booster vaccination. RESULTS: Hemagglutinin inhibition antibody responses against A/turkey/Turkey/1/2005-H5N1 were superior in the H5N1(2)-H5N1 versus the hepatitis A vaccine-H5N1 group overall and in each age strata (3 to <10 and 10 to <18 years). Anamnestic immune responses were demonstrated against vaccine-homologous/heterologous strains in the H5N1(2)-H5N1 group. Injection site pain and fever increased with consecutive doses for children <6 years (H5N1(2)-H5N1). Immune responses to vaccine-homologous/heterologous strains persisted to 6 months after booster vaccination in the H5N1(2)-H5N1 group. CONCLUSIONS: Heterologous H5N1-AS03B-adjuvanted booster vaccination in children/adolescents was immunogenic for vaccine-homologous and heterologous strains following 2-dose priming, with immune persistence for at least 6 months. Prime-boost strategies using H5N1-AS03 could be effectively employed in this age group.

Immunogenicity and safety of AS03A-adjuvanted H5N1 influenza vaccine prepared from bulk antigen after stockpiling for 4 years.

BACKGROUND: Stockpiling vaccine for deployment in the event of an influenza pandemic is an important mitigation strategy. A necessary aspect of stockpiling is to determine the shelf-life of the stored vaccine. METHODS: In this Phase II, open-label study we assessed the immunogenicity and safety of H5N1 A/Indonesia/5/2005 vaccine adjuvanted with AS03A. The AS03A-H5N1 vaccine was prepared from bulk antigen that had been stored for 4 years, and adjuvant that had been stored for 2.5 years. Both the antigen and adjuvant were filled in separate multi-dose vials within 4 months of use, and on the day of vaccination, the contents of antigen and adjuvant vials were mixed. Seventy-eight adults aged 18-64 years were scheduled to receive two doses of hemagglutinin-antigen (3.75µg) given 21 days apart. Antibody responses were assessed by hemagglutination-inhibition (HI) assay according to age (18-30 years, 31-40 years, 41-50 years, and 51-64 years). Reactogenicity was assessed for 7 days after each vaccination, and safety was assessed for 385 days post-vaccination (NCT01416571). RESULTS: The vaccine was immunogenic. Twenty-one days after the second dose of vaccine in the overall population, the HI seroconversion rate and seroprotection rate (SPR; titer ≥1:40) was 96.0% and 98.7%, respectively. At Day 182 after vaccination, the SPR was 76.7% in the overall population. Injection site pain was the most frequent solicited adverse event (91.0%), and no safety concerns were raised. CONCLUSION: The immunogenicity and safety observed with AS03A-H5N1 vaccine formulated with bulk antigen which had been stockpiled before vialing and administration was consistent with that previously observed with newly manufactured AS03A-H5N1 vaccine. This suggests that stockpiling bulk antigen for 4 years does not compromise the immunogenicity or reactogenicity of the vaccine.

Immunogenicity and safety of an AS03-adjuvanted H5N1 pandemic influenza vaccine in Korean adults: a phase IV, randomized, open-label, controlled study.

BACKGROUND: AS03-adjuvanted H5N1 pandemic influenza vaccines have been assessed in an extensive clinical development program conducted in North America, Europe, and Asia including children from 6 months of age, adults, and elderly adults. We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age. METHODS: This Phase IV, randomized, study was conducted to assess the immunogenicity, reactogenicity, and safety of two doses (3.75µg of hemagglutinin antigen) of A/Indonesia/5/2005 (H5N1) adjuvanted with AS03 given 21 days apart in Korean adults. Antibody responses were assessed using hemagglutination-inhibition (HI) assays against the vaccine strain and a vaccine-heterologous strain (A/Vietnam/1194/2004) 21 days after the second dose. A control group (safety) received a licensed seasonal inactivated trivalent influenza vaccine (TIV). Reactogenicity was assessed for 7 days after each vaccination, and unsolicited adverse events were assessed for 182 days following vaccination in both study groups (NCT01730378). RESULTS: AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100% for the vaccine strain and 69.1% for the heterologous strain (N=81). HI antibody responses fulfilled the European licensure criteria for immunogenicity (primary endpoint). The incidence of local and systemic solicited adverse events (reactogenicity) was higher with AS03-H5N1 than TIV. There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups. CONCLUSION: The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine.

Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines.

Newly licensed vaccines against human papillomavirus (HPV) and hepatitis B (HBV), and several vaccines in development, including a vaccine against genital herpes simplex virus (HSV), contain a novel Adjuvant System, AS04, composed of 3-O-desacyl-4' monophosphoryl lipid A and aluminium salts. Given the background incidence of autoimmune disorders in some of the groups targeted for immunisation with these vaccines, it is likely that autoimmune events will be reported in temporal association with vaccination, even in the absence of a causal relationship. The objective of this integrated analysis was to assess safety of AS04 adjuvanted vaccines with regard to adverse events (AEs) of potential autoimmune aetiology, particularly in adolescents and young adults. All randomised, controlled trials of HPV-16/18, HSV and HBV vaccines were analysed in an integrated analysis of individual data (N = 68,512). A separate analysis of the HPV-16/18 vaccine trials alone was also undertaken (N = 39,160). All data were collected prospectively during the vaccine development programmes (mean follow-up of 21.4 months), and included in the analysis up to a pre-defined data lock point. Reporting rates of overall autoimmune events were around 0.5% and did not differ between the AS04 and control groups. The relative risk (AS04/control) of experiencing any autoimmune event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. Relative risks calculated overall, for disease category or for individual events were close to 1, and all confidence intervals around the relative risk included 1, indicating no statistically significant difference in event rates between the AS04 and control groups. This integrated analysis of over 68,000 participants who received AS04 adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04 adjuvanted vaccines.