GlaxoSmithKline (Belgium)

Data on human papillomavirus (HPV) type distribution in invasive and pre-invasive cervical cancer is essential to predict the future impact of HPV16/18 vaccines and HPV-based screening tests. A meta-analyses of HPV type distribution in invasive cervical cancer (ICC) and high-grade squamous intraepithelial lesions (HSIL) identified a total of 14,595 and 7,094 cases, respectively. In ICC, HPV16 was the most common, and HPV18 the second most common, type in all continents. Combined HPV16/18 prevalence among ICC cases was slightly higher in Europe, North America and Australia (74-77%) than in Africa, Asia and South/Central America (65-70%). The next most common HPV types were the same in each continent, namely HPV31, 33, 35, 45, 52 and 58, although their relative importance differed somewhat by region. HPV18 was significantly more prevalent in adeno/adenosquamous carcinoma than in squamous cell carcinoma, with the reverse being true for HPV16, 31, 33, 52 and 58. Among HSIL cases, HPV16/18 prevalence was 52%. However, HPV 16, 18 and 45 were significantly under-represented, and other high-risk HPV types significantly over-represented in HSIL compared to ICC, suggesting differences in type-specific risks for progression. Data on HPV-typed ICC and HSIL cases were particularly scarce from large regions of Africa and Central Asia.

BACKGROUND: In previous phase 1-2 clinical trials involving older adults, a subunit vaccine containing varicella-zoster virus glycoprotein E and the AS01B adjuvant system (called HZ/su) had a clinically acceptable safety profile and elicited a robust immune response. METHODS: We conducted a randomized, placebo-controlled, phase 3 study in 18 countries to evaluate the efficacy and safety of HZ/su in older adults (≥50 years of age), stratified according to age group (50 to 59, 60 to 69, and ≥70 years). Participants received two intramuscular doses of the vaccine or placebo 2 months apart. The primary objective was to assess the efficacy of the vaccine, as compared with placebo, in reducing the risk of herpes zoster in older adults. RESULTS: A total of 15,411 participants who could be evaluated received either the vaccine (7698 participants) or placebo (7713 participants). During a mean follow-up of 3.2 years, herpes zoster was confirmed in 6 participants in the vaccine group and in 210 participants in the placebo group (incidence rate, 0.3 vs. 9.1 per 1000 person-years) in the modified vaccinated cohort. Overall vaccine efficacy against herpes zoster was 97.2% (95% confidence interval [CI], 93.7 to 99.0; P<0.001). Vaccine efficacy was between 96.6% and 97.9% for all age groups. Solicited reports of injection-site and systemic reactions within 7 days after vaccination were more frequent in the vaccine group. There were solicited or unsolicited reports of grade 3 symptoms in 17.0% of vaccine recipients and 3.2% of placebo recipients. The proportions of participants who had serious adverse events or potential immune-mediated diseases or who died were similar in the two groups. CONCLUSIONS: The HZ/su vaccine significantly reduced the risk of herpes zoster in adults who were 50 years of age or older. Vaccine efficacy in adults who were 70 years of age or older was similar to that in the other two age groups. (Funded by GlaxoSmithKline Biologicals; ZOE-50 ClinicalTrials.gov number, NCT01165177.).

In low-income countries, infectious diseases still account for a large proportion of deaths, highlighting health inequities largely caused by economic differences. Vaccination can cut health-care costs and reduce these inequities. Disease control, elimination or eradication can save billions of US dollars for communities and countries. Vaccines have lowered the incidence of hepatocellular carcinoma and will control cervical cancer. Travellers can be protected against "exotic" diseases by appropriate vaccination. Vaccines are considered indispensable against bioterrorism. They can combat resistance to antibiotics in some pathogens. Noncommunicable diseases, such as ischaemic heart disease, could also be reduced by influenza vaccination. Immunization programmes have improved the primary care infrastructure in developing countries, lowered mortality in childhood and empowered women to better plan their families, with consequent health, social and economic benefits. Vaccination helps economic growth everywhere, because of lower morbidity and mortality. The annual return on investment in vaccination has been calculated to be between 12% and 18%. Vaccination leads to increased life expectancy. Long healthy lives are now recognized as a prerequisite for wealth, and wealth promotes health. Vaccines are thus efficient tools to reduce disparities in wealth and inequities in health.

Induction of broadly cross-reactive neutralizing antibodies is a high priority for AIDS vaccine development but one that has proven difficult to be achieved. While most immunogens generate antibodies that neutralize a subset of T-cell-line-adapted strains of human immunodeficiency virus type 1 (HIV-1), none so far have generated a potent, broadly cross-reactive response against primary isolates of the virus. Even small increments in immunogen improvement leading to increases in neutralizing antibody titers and cross-neutralizing activity would accelerate vaccine development; however, a lack of uniformity in target strains used by different investigators to assess cross-neutralization has made the comparison of vaccine-induced antibody responses difficult. Thus, there is an urgent need to establish standard panels of HIV-1 reference strains for wide distribution. To facilitate this, full-length gp160 genes were cloned from acute and early subtype B infections and characterized for use as reference reagents to assess neutralizing antibodies against clade B HIV-1. Individual gp160 clones were screened for infectivity as Env-pseudotyped viruses in a luciferase reporter gene assay in JC53-BL (TZM-bl) cells. Functional env clones were sequenced and their neutralization phenotypes characterized by using soluble CD4, monoclonal antibodies, and serum samples from infected individuals and noninfected recipients of a recombinant gp120 vaccine. Env clones from 12 R5 primary HIV-1 isolates were selected that were not unusually sensitive or resistant to neutralization and comprised a wide spectrum of genetic, antigenic, and geographic diversity. These reference reagents will facilitate proficiency testing and other validation efforts aimed at improving assay performance across laboratories and can be used for standardized assessments of vaccine-elicited neutralizing antibodies.

BACKGROUND: A trial involving adults 50 years of age or older (ZOE-50) showed that the herpes zoster subunit vaccine (HZ/su) containing recombinant varicella-zoster virus glycoprotein E and the AS01B adjuvant system was associated with a risk of herpes zoster that was 97.2% lower than that associated with placebo. A second trial was performed concurrently at the same sites and examined the safety and efficacy of HZ/su in adults 70 years of age or older (ZOE-70). METHODS: This randomized, placebo-controlled, phase 3 trial was conducted in 18 countries and involved adults 70 years of age or older. Participants received two doses of HZ/su or placebo (assigned in a 1:1 ratio) administered intramuscularly 2 months apart. Vaccine efficacy against herpes zoster and postherpetic neuralgia was assessed in participants from ZOE-70 and in participants pooled from ZOE-70 and ZOE-50. RESULTS: In ZOE-70, 13,900 participants who could be evaluated (mean age, 75.6 years) received either HZ/su (6950 participants) or placebo (6950 participants). During a mean follow-up period of 3.7 years, herpes zoster occurred in 23 HZ/su recipients and in 223 placebo recipients (0.9 vs. 9.2 per 1000 person-years). Vaccine efficacy against herpes zoster was 89.8% (95% confidence interval [CI], 84.2 to 93.7; P<0.001) and was similar in participants 70 to 79 years of age (90.0%) and participants 80 years of age or older (89.1%). In pooled analyses of data from participants 70 years of age or older in ZOE-50 and ZOE-70 (16,596 participants), vaccine efficacy against herpes zoster was 91.3% (95% CI, 86.8 to 94.5; P<0.001), and vaccine efficacy against postherpetic neuralgia was 88.8% (95% CI, 68.7 to 97.1; P<0.001). Solicited reports of injection-site and systemic reactions within 7 days after injection were more frequent among HZ/su recipients than among placebo recipients (79.0% vs. 29.5%). Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two study groups. CONCLUSIONS: In our trial, HZ/su was found to reduce the risks of herpes zoster and postherpetic neuralgia among adults 70 years of age or older. (Funded by GlaxoSmithKline Biologicals; ZOE-50 and ZOE-70 ClinicalTrials.gov numbers, NCT01165177 and NCT01165229 .).

While most people vaccinate according to the recommended schedule, this success is challenged by individuals and groups who delay or refuse vaccines. The aim of this article is to review studies on vaccine hesitancy among healthcare providers (HCPs), and the influences of their own vaccine confidence and vaccination behaviour on their vaccination recommendations to others. The search strategy was developed in Medline and then adapted across several multidisciplinary mainstream databases including Embase Classic & Embase, and PschInfo. All foreign language articles were included if the abstract was available in English. A total of 185 articles were included in the literature review. 66% studied the vaccine hesitancy among HCPs, 17% analysed concerns, attitudes and/or behaviour of HCPs towards vaccinating others, and 9% were about evaluating intervention(s). Overall, knowledge about particular vaccines, their efficacy and safety, helped to build HCPs own confidence in vaccines and their willingness to recommend vaccines to others. The importance of societal endorsement and support from colleagues was also reported. In the face of emerging vaccine hesitancy, HCPs still remain the most trusted advisor and influencer of vaccination decisions. The capacity and confidence of HCPs, though, are stretched as they are faced with time constraints, increased workload and limited resources, and often have inadequate information or training support to address parents' questions. Overall, HCPs need more support to manage the quickly evolving vaccine environment as well as changing public, especially those who are reluctant or refuse vaccination. Some recommended strategies included strengthening trust between HCPs, health authorities and policymakers, through more shared involvement in the establishment of vaccine recommendations.

BACKGROUND: Rotavirus is the most common cause of severe gastroenteritis among young children worldwide. Data are needed to assess the efficacy of the rotavirus vaccine in African children. METHODS: We conducted a randomized, placebo-controlled, multicenter trial in South Africa (3166 infants; 64.1% of the total) and Malawi (1773 infants; 35.9% of the total) to evaluate the efficacy of a live, oral rotavirus vaccine in preventing severe rotavirus gastroenteritis. Healthy infants were randomly assigned in a 1:1:1 ratio to receive two doses of vaccine (in addition to one dose of placebo) or three doses of vaccine--the pooled vaccine group--or three doses of placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis caused by wild-type rotavirus during the first year of life were assessed through active follow-up surveillance and were graded with the use of the Vesikari scale. RESULTS: A total of 4939 infants were enrolled and randomly assigned to one of the three groups; 1647 infants received two doses of the vaccine, 1651 infants received three doses of the vaccine, and 1641 received placebo. Of the 4417 infants included in the per-protocol efficacy analysis, severe rotavirus gastroenteritis occurred in 4.9% of the infants in the placebo group and in 1.9% of those in the pooled vaccine group (vaccine efficacy, 61.2%; 95% confidence interval, 44.0 to 73.2). Vaccine efficacy was lower in Malawi than in South Africa (49.4% vs. 76.9%); however, the number of episodes of severe rotavirus gastroenteritis that were prevented was greater in Malawi than in South Africa (6.7 vs. 4.2 cases prevented per 100 infants vaccinated per year). Efficacy against all-cause severe gastroenteritis was 30.2%. At least one serious adverse event was reported in 9.7% of the infants in the pooled vaccine group and in 11.5% of the infants in the placebo group. CONCLUSIONS: Human rotavirus vaccine significantly reduced the incidence of severe rotavirus gastroenteritis among African infants during the first year of life. (ClinicalTrials.gov number, NCT00241644.)

BACKGROUND: An effective prophylactic vaccine would help control the spread of genital herpes. METHODS: We conducted two double-blind, randomized trials of a herpes simplex virus type 2 (HSV-2) glycoprotein-D-subunit vaccine with alum and 3-O-deacylated-monophosphoryl lipid A in subjects whose regular sexual partners had a history of genital herpes. In Study 1, subjects were seronegative for herpes simplex virus type 1 (HSV-1) and HSV-2; in Study 2, subjects were of any HSV serologic status. At months 0, 1, and 6, subjects received either vaccine or a control injection and were evaluated for 19 months. The primary end point was the occurrence of genital herpes disease in all subjects in Study 1 and in HSV-2-seronegative female subjects in Study 2. RESULTS: A total of 847 subjects who were seronegative for both HSV-1 and HSV-2 (268 of them women, in Study 1) and 1867 subjects who were seronegative for HSV-2 (710 of them women, in Study 2) underwent randomization and received injections. Vaccination was well tolerated and elicited humoral and cellular responses. Overall, the efficacy of the vaccine was 38 percent in Study 1 (95 percent confidence interval, -18 to 68 percent; 15 cases occurred in the vaccine group and 24 in the control group), and efficacy in female subjects was 42 percent in Study 2 (95 percent confidence interval, -31 to 74 percent; 9 cases occurred in the vaccine group and 16 in the control group). In both studies, further analysis showed that the vaccine was efficacious in women who were seronegative for both HSV-1 and HSV-2: efficacy in Study 1 was 73 percent (95 percent confidence interval, 19 to 91 percent; P=0.01), and efficacy in Study 2 was 74 percent (95 percent confidence interval, 9 to 93 percent; P=0.02). It was not efficacious in women who were seropositive for HSV-1 and seronegative for HSV-2 at base line or in men. CONCLUSIONS: These studies suggest that the glycoprotein D vaccine has efficacy against genital herpes in women who are seronegative for both HSV-1 and HSV-2 at base line but not in those who are seropositive for HSV-1 and seronegative for HSV-2. It had no efficacy in men, regardless of their HSV serologic status.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection. METHODS: -adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. RESULTS: A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups. CONCLUSIONS: A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.).

Adjuvant System 04 (AS04) combines the TLR4 agonist MPL (3-O-desacyl-4'-monophosphoryl lipid A) and aluminum salt. It is a new generation TLR-based adjuvant licensed for use in human vaccines. One of these vaccines, the human papillomavirus (HPV) vaccine Cervarix, is used in this study to elucidate the mechanism of action of AS04 in human cells and in mice. The adjuvant activity of AS04 was found to be strictly dependent on AS04 and the HPV Ags being injected at the same i.m. site within 24 h of each other. During this period, AS04 transiently induced local NF-kappaB activity and cytokine production. This led to an increased number of activated Ag-loaded dendritic cells and monocytes in the lymph node draining the injection site, which further increased the activation of Ag-specific T cells. AS04 was also found to directly stimulate those APCs in vitro but not directly stimulate CD4(+) T or B lymphocytes. These AS04-induced innate responses were primarily due to MPL. Aluminum salt appeared not to synergize with or inhibit MPL, but rather it prolonged the cytokine responses to MPL at the injection site. Altogether these results support a model in which the addition of MPL to aluminum salt enhances the vaccine response by rapidly triggering a local cytokine response leading to an optimal activation of APCs. The transient and confined nature of these responses provides further supporting evidence for the favorable safety profile of AS04 adjuvanted vaccines.

The self-controlled case series method was developed to investigate associations between acute outcomes and transient exposures, using only data on cases, that is, on individuals who have experienced the outcome of interest. Inference is within individuals, and hence fixed covariates effects are implicitly controlled for within a proportional incidence framework. We describe the origins, assumptions, limitations, and uses of the method. The rationale for the model and the derivation of the likelihood are explained in detail using a worked example on vaccine safety. Code for fitting the model in the statistical package STATA is described. Two further vaccine safety data sets are used to illustrate a range of modelling issues and extensions of the basic model. Some brief pointers on the design of case series studies are provided. The data sets, STATA code, and further implementation details in SAS, GENSTAT and GLIM are available from an associated website.

The concept of stimulating the body's immune response is the basis underlying vaccination. Vaccines act by initiating the innate immune response and activating antigen presenting cells (APCs), thereby inducing a protective adaptive immune response to a pathogen antigen. Adjuvants are substances added to vaccines to enhance the immunogenicity of highly purified antigens that have insufficient immunostimulatory capabilities, and have been used in human vaccines for more than 90 years. While early adjuvants (aluminum, oil-in-water emulsions) were used empirically, rapidly increasing knowledge on how the immune system interacts with pathogens means that there is increased understanding of the role of adjuvants and how the formulation of modern vaccines can be better tailored towards the desired clinical benefit. Continuing safety evaluation of licensed vaccines containing adjuvants/adjuvant systems suggests that their individual benefit-risk profile remains favorable. Adjuvants contribute to the initiation of the innate immune response induced by antigens; exemplified by inflammatory responses at the injection site, with mostly localized and short-lived effects. Activated effectors (such as APCs) then move to draining lymph nodes where they direct the type, magnitude and quality of the adaptive immune response. Thus, the right match of antigens and adjuvants can potentiate downstream adaptive immune responses, enabling the development of new efficacious vaccines. Many infectious diseases of worldwide significance are not currently preventable by vaccination. Adjuvants are the most advanced new technology in the search for new vaccines against challenging pathogens and for vulnerable populations that respond poorly to traditional vaccines.

After decades of slow progress, the last years have seen a rapid acceleration of the development of adjuvanted vaccines which have lately been approved for human use. These adjuvants consist of different components, e.g. aluminium salts, emulsions such as MF59 and AS03, Toll-like receptor (TLR) agonists (CpG ormonophosphoryl lipid A (MPL) adsorbed on aluminium salts as in AS04) or combination of immunopotentiators (QS-21 and MPL in AS01). Despite their distinctive features, most of these adjuvants share some key characteristics. For example, they induce early activation (although at different levels) of innate immunity which then translates into higher antibody and cellular responses to the vaccine antigens. In addition, most of these adjuvants (e.g. MF59, AS03, AS04) clearly induce a wider breadth of adaptive responses able to confer protection against, for example, heterovariants of the influenza viruses (MF59, AS03) or against human papillomavirus strains not contained in the vaccine (AS04). Finally, the use of some of these adjuvants has contributed to significantly enhance the immune response and the efficacy and effectiveness of vaccines in the elderly who experience a waning of the immune responsiveness to infection and vaccination, as shown for MF59- or AS03-adjuvanted influenza vaccines and AS01-adjuvanted herpes zoster vaccine. These results, together with the track record of acceptable safety profiles of the adjuvanted vaccines, pave the way for the development of novel vaccines at the extremes of age and against infections with a high toll of morbidity and mortality. Here, we review the mechanisms associated with the performance of those adjuvanted vaccines in animal models and in humans through recent advances in systems vaccinology and biomarker discovery. We also provide some perspectives on remaining knowledge gaps but also on opportunities that could accelerate the development of new vaccines.

Background Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. Methods From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon- release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. Results A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. Conclusions Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598. opens in new tab.)v

BACKGROUND: Hepatitis E virus (HEV) is an important cause of viral hepatitis. We evaluated the safety and efficacy of an HEV recombinant protein (rHEV) vaccine in a phase 2, randomized, double-blind, placebo-controlled trial. METHODS: In Nepal, we studied 2000 healthy adults susceptible to HEV infection who were randomly assigned to receive three doses of either the rHEV vaccine or placebo at months 0, 1, and 6. Active (including hospital) surveillance was used to identify acute hepatitis and adverse events. The primary end point was the development of hepatitis E after three vaccine doses. RESULTS: A total of 1794 subjects (898 in the vaccine group and 896 in the placebo group) received three vaccine doses; the total vaccinated cohort was followed for a median of 804 days. After three vaccine doses, hepatitis E developed in 69 subjects, of whom 66 were in the placebo group. The vaccine efficacy was 95.5% (95% confidence interval [CI], 85.6 to 98.6). In an intention-to-treat analysis that included all 87 subjects in whom hepatitis E developed after the first vaccine dose, 9 subjects were in the vaccine group, with a vaccine efficacy of 88.5% (95% CI, 77.1 to 94.2). Among subjects in a subgroup randomly selected for analysis of injection-site findings and general symptoms (reactogenicity subgroup) during the 8-day period after the administration of any dose, the proportion of subjects with adverse events was similar in the two study groups, except that injection-site pain was increased in the vaccine group (P=0.03). CONCLUSIONS: In a high-risk population, the rHEV vaccine was effective in the prevention of hepatitis E. (ClinicalTrials.gov number, NCT00287469 [ClinicalTrials.gov].).

BACKGROUND: To further increase the efficacy of malaria vaccine RTS,S/AS02A, we tested the RTS,S antigen formulated using the AS01B Adjuvant System (GlaxoSmithKline Biologicals). METHODS: In a double-blind, randomized trial, 102 healthy volunteers were evenly allocated to receive RTS,S/AS01B or RTS,S/AS02A vaccine at months 0, 1, and 2 of the study, followed by malaria challenge. Protected vaccine recipients were rechallenged 5 months later. RESULTS: RTS,S/AS01B and RTS,S/AS02A were well tolerated and were safe. The efficacy of RTS,S/AS01B and RTS,S/AS02A was 50% (95% confidence interval [CI], 32.9%-67.1%) and 32% (95% CI, 17.6%-47.6%), respectively. At the time of initial challenge, the RTS,S/AS01B group had greater circumsporozoite protein (CSP)-specific immune responses, including higher immunoglobulin (Ig) G titers, higher numbers of CSP-specific CD4(+) T cells expressing 2 activation markers (interleukin-2, interferon [IFN]-gamma, tumor necrosis factor-alpha, or CD40L), and more ex vivo IFN-gamma enzyme-linked immunospots (ELISPOTs) than did the RTS,S/AS02A group. Protected vaccine recipients had a higher CSP-specific IgG titer (geometric mean titer, 188 vs 73 mug/mL; P < .001), higher numbers of CSP-specific CD4(+) T cells per 10(6) CD4(+) T cells (median, 963 vs 308 CSP-specific CD4(+) T cells/10(6) CD4(+) T cells; P < .001), and higher numbers of ex vivo IFN-gamma ELISPOTs (mean, 212 vs 96 spots/million cells; P < .001). At rechallenge, 4 of 9 vaccine recipients in each group were still completely protected. CONCLUSIONS: The RTS,S/AS01B malaria vaccine warrants comparative field trials with RTS,S/AS02A to determine the best formulation for the protection of children and infants. The association between complete protection and immune responses is a potential tool for further optimization of protection. Trial registration. ClinicalTrials.gov identifier NCT00075049.

Reactogenicity represents the physical manifestation of the inflammatory response to vaccination, and can include injection-site pain, redness, swelling or induration at the injection site, as well as systemic symptoms, such as fever, myalgia, or headache. The experience of symptoms following vaccination can lead to needle fear, long-term negative attitudes and non-compliant behaviours, which undermine the public health impact of vaccination. This review presents current knowledge on the potential causes of reactogenicity, and how host characteristics, vaccine administration and composition factors can influence the development and perception of reactogenicity. The intent is to provide an overview of reactogenicity after vaccination to help the vaccine community, including healthcare professionals, in maintaining confidence in vaccines by promoting vaccination, setting expectations for vaccinees about what might occur after vaccination and reducing anxiety by managing the vaccination setting.

Introduction: Adjuvants are used to improve vaccine immunogenicity and efficacy by enhancing antigen presentation to antigen-specific immune cells with the aim to confer long-term protection against targeted pathogens. Adjuvants have been used in vaccines for more than 90 years. Combinations of immunostimulatory molecules, such as in the Adjuvant System AS01, have opened the way to the development of new or improved vaccines.Areas covered: AS01 is a liposome-based vaccine adjuvant system containing two immunostimulants: 3-O-desacyl-4ʹ-monophosphoryl lipid A (MPL) and the saponin QS-21. Here we describe studies investigating the mode of action of AS01, and consider the role of AS01 in enhancing specific immune responses to the antigen for selected candidate vaccines targeting malaria and herpes zoster. The effects of AS01 are rapid and transient, being localized to the injected muscle and draining lymph node. AS01 is efficient at promoting CD4+ T cell-mediated immune responses and is an appropriate candidate adjuvant for inclusion in vaccines targeting viruses or intracellular pathogens.Expert commentary: AS01 activity to enhance adaptive responses depends on synergistic activities of QS-21 and MPL. AS01 adjuvantation shows good prospects for use in new vaccines targeted to populations with challenging immune statuses and against diseases caused by complex pathogens.

An estimated 350 million persons worldwide and 1.25 million in the United States are infected with hepatitis B virus (HBV). Hepatitis B carriers are at risk for development of cirrhosis and hepatocellular carcinoma (HCC). The natural history of chronic HBV infection is variable. Persons with chronic HBV infection need lifelong monitoring to determine if and when intervention with antiviral therapy is needed and to observe for serious sequelae. These guidelines were developed under the auspices of, and approved by, the Practice Guidelines Committee of the American Association for the Study of Liver Diseases. The original guidelines were published in HEPATOLOGY 2001;34:1225–1241.1 In light of recent progress, particularly in the treatment of chronic hepatitis B, these guidelines were updated in September of 2003. A complete version of the updated guidelines, including a review of recently published literature, can be found at the AASLD web site, www.aasld.org. Following is a summary of the updated recommendations for treatment of chronic hepatitis B. The recommendations were graded as I (randomized controlled trials), II-1 (controlled trials without randomization), II-2 (cohort or case-control analytic studies), II-3 (multiple time series, dramatic uncontrolled experiments), and III (opinions of respected authorities, descriptive epidemiology). HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HBeAg, hepatitis B e antigen; ALT, alanine aminotransferase; IFN-α, interferon alfa; HBsAg, hepatitis B surface antigen. In a controlled trial that involved 286 children aged 2 to 17 years, randomized to lamivudine (3 mg/kg/d up to 100 mg/d) or placebo, hepatitis B e antigen (HBeAg) seroconversion was observed in 22% lamivudine-treated children versus 13% placebo controls (P = .06), while HBeAg loss was observed in 26% and 15%, respectively (P = 0.03).2 HBeAg seroconversion rate was higher among children with elevated alanine aminotransferase (ALT) levels. Lamivudine-resistant mutation was detected in 19% of treated children during the 1-year period. Among patients who experienced HBeAg seroconversion during lamivudine treatment, the durability of response after cessation of therapy has ranged from 38% to 77%.3-5 The 3-year cumulative relapse rate varied from 36% to 54%, with most of the relapses occurring during the first year posttreatment. The risk of developing lamivudine resistance increases with the duration of therapy. In a study from Asia, genotypic resistance increased from 14% in year 1 to 38%, 49%, 66%, and 69% after 2, 3, 4, and 5 years, respectively, of treatment.6 Long-term follow-up studies showed that over time, the initial benefit is negated in patients with lamivudine-resistant mutants. In one study that compared liver histology in 63 patients prior to and after 3 years of lamivudine treatment, necroinflammatory scores were improved in 77% and worsened in 5% of patients without lamivudine-resistant mutants, but improved in only 45% and worsened in 14% of those with lamivudine-resistant mutants.7 For patients with confirmed lamivudine-resistance, the options include continuing lamivudine treatment as long as benefit to the patient (based on clinical assessment, ALT, and HBV DNA levels) is maintained; discontinuing treatment and monitoring for hepatitis flares; or switching to other antiviral agents such as adefovir, which are effective in suppressing lamivudine-resistant HBV. Two recent reports from Asia suggest that discontinuation of lamivudine in patients with resistant mutants is not associated with increased frequency of hepatitis flares or decompensation, compared with those who continued to receive lamivudine.8, 9 Thus, stopping lamivudine is a reasonable option for immunocompetent patients without cirrhosis, as long as they are closely monitored; but patients with underlying cirrhosis or immunosuppression should be switched to adefovir before stopping lamivudine. Adefovir dipivoxil is an orally bioavailable prodrug of adefovir, a nucleotide analog of adenosine monophosphate that inhibits both HBV reverse transcriptase and DNA polymerase activity. Adefovir has been shown to be effective in suppressing not only wild-type HBV but also lamivudine-resistant HBV mutants. In a randomized trial of 515 patients with HBeAg-positive chronic hepatitis B treated with 30-mg or 10-mg doses of adefovir or placebo for 48 weeks, a significantly higher proportion of adefovir-treated patients had histologic response, HBeAg loss, normalization of ALT levels, and reduction of HBV DNA, compared with those who received placebo (all P < .001).10 HBeAg seroconversion was observed in 12% of the adefovir and 6% of the placebo groups (P = .049). In a trial of 184 patients with HBeAg-negative chronic hepatitis B who were randomized to receive adefovir 10 mg or placebo for 48 weeks, histologic response, normalization of ALT, and undetectable serum HBV DNA by polymerase chain reaction assay were observed significantly more frequently in the treatment group (all P < .001).11 During year 2, the proportion of patients with undetectable serum HBV DNA and normal ALT levels increased from 46% at week 48 to 51% at week 96 among those who continued treatment, and decreased from 59% to 3% among those in whom therapy was stopped.12 In a compassionate-use study involving 128 patients with decompensated cirrhosis and 196 patients with recurrent hepatitis B after liver transplant, with lamivudine resistance, addition of adefovir was associated with a 3–4 log10 reduction in serum HBV DNA levels, which was sustained throughout the course of treatment.13 Virologic response was accompanied by stable or decreased ALT and Child-Pugh score. A pilot study in 58 patients with compensated chronic hepatitis B and lamivudine resistance found that adefovir alone had similar efficacy as combination treatment of lamivudine and adefovir in suppressing replication of lamivudine-resistant HBV.14 Adefovir has not been evaluated in children. Nephrotoxiciy (increase in serum creatinine by ≥0.5 mg/dL above baseline values on two consecutive occasions) was observed in 8% of patients who received adefovir 30 mg for 1 year and in none of the patients with compensated liver disease who received adefovir 10 mg for 1 year. However, nephrotoxicity has been reported in 2.5% of patients with compensated liver disease who received 2 years of adefovir 10 mg, and in 12% of transplant recipients and 28% of patients with decompensated cirrhosis who received 1 year of adefovir 10 mg.13, 15 The recommended dose of adefovir for adults with normal renal function is 10 mg daily orally. Dosing interval should be increased in patients with renal insufficiency. The optimal duration of adefovir treatment is unclear. Data on the durability of HBeAg seroconversion after adefovir is discontinued have not been presented. Preliminary data indicate that patients with HBeAg negative chronic hepatitis will require long-term treatment as most patients will relapse when adefovir is withdrawn after 1 year.14 Based on experience with lamivudine, consideration should be given to treating patients in whom HBeAg seroconversion has occurred for an additional 3 to 6 months after HBeAg seroconversion is confirmed (two occasions at least 2 months apart) to reduce post-treatment relapse. Long-term treatment will also be required for patients with lamivudine-resistant mutants, particularly those with decompensated cirrhosis or recurrent hepatitis B posttransplant. A major advantage of adefovir is the lack of resistance after the first year of therapy, but drug-resistant mutation, asparagine to threonine (rtN236T), downstream of the YMDD motif, has been reported in 2 of 79 (2.5%) patients with HBeAg-negative chronic hepatitis B during the second year of therapy.16In vitro studies confirmed that this mutation confers resistance to adefovir, but the resistant mutant appears to be susceptible to lamivudine and entecavir. Reactivation of HBV replication with hepatitis flares and rarely hepatic decompensation have been reported to occur in 20% to 50% of hepatitis B carriers undergoing immunosuppressive or cancer chemotherapies, especially when corticosteroids are included.17, 18 Administration of lamivudine has been reported to reduce the frequency and severity of the hepatitis flares, and to improve survival compared to historical controls.17, 19 HBeAg-positive patients with elevated ALT levels and compensated liver disease should be observed for 3 to 6 months for spontaneous seroconversion from HBeAg to HBe antibody prior to initiation of treatment (III). Patients who meet the criteria for chronic hepatitis B (serum HBV DNA >105 copies/mL and persistent or intermittent elevation in aminotransferase levels) should be evaluated further with a liver biopsy (III). Patients in the inactive hepatitis B surface antigen (HBsAg) carrier state should be monitored with periodic liver chemistries every 6 to 12 months, as liver disease may become active even after many years of quiescence (III). Patients with HBeAg-positive chronic hepatitis B: A. ALT greater than 2 times normal, or moderate/severe hepatitis on biopsy. These patients should be considered for treatment. Treatment should be delayed for 3 to 6 months in persons with compensated liver disease to determine whether spontaneous HBeAg seroconversion occurs. Treatment may result in virologic, biochemical, and histologic response (I) and also appear to improve clinical outcome (II-3). Treatment may be initiated with IFN-α, lamivudine or adefovir as the 3 treatments have similar efficacy. B. ALT persistently normal or minimally elevated (<2 times normal). These patients should not be initiated on treatment (I). Liver biopsy may be considered in patients with fluctuating or minimally elevated ALT levels and treatment initiated if there is moderate or severe necroinflammation. C. Children with elevated ALT greater than 2 times normal. These patients should be considered for treatment if ALT levels remain elevated at this level for longer than 6 months (I). Both IFN-α and lamivudine are approved treatments for children with chronic hepatitis B. Patients with HBeAg-negative chronic hepatitis B (serum HBV DNA >105 copies/mL, elevated ALT >2 times normal or moderate/severe hepatitis on biopsy) should be considered for treatment (I). Treatment may be initiated with IFN-α, lamivudine, or adefovir (I for adefovir and II-1 for IFNα and lamivudine). In view of the need for long-term treatment, IFNα or adefovir is preferred. Patients who failed to respond to prior IFN-α therapy may be retreated with lamivudine or adefovir if they fulfill the criteria listed above (I). Persons who develop breakthrough infection while on lamivudine should be treated with adefovir if there is worsening of liver disease, if they had decompensated cirrhosis or recurrent hepatitis B after liver transplant, or if they require concomitant immunosuppressive therapy (II-2). Patients with compensated cirrhosis are best treated with lamivudine or adefovir because of the risk of hepatic decompensation associated with IFN-α related flares of hepatitis. Patients with decompensated cirrhosis should be considered for lamivudine treatment (III-3). Adefovir may be used as an alternative to lamivudine, although it has not been evaluated as a primary treatment in these patients. If adefovir is used, close monitoring of renal function with testing of blood urea nitrogen and creatinine every 1 to 3 months should be performed. Treatment should be coordinated with transplant centers. IFN-α should not be used in patients with decompensated cirrhosis (II-3). For patients with an inactive HBsAg carrier state, antiviral treatment is not indicated. IFN-α is administered as subcutaneous injections. The recommended IFN-α dose for adults is 5 million units (MU) daily or 10 MU thrice weekly (I). The recommended IFN-α dose for children is 6 MU/m2thrice weekly with a maximum of 10 MU (I). The recommended treatment duration for HBeAg-positive chronic hepatitis B is 16 weeks (I). The recommended treatment duration for HBeAg-negative chronic hepatitis B is 12 months (II-3). Lamivudine is administered orally. The recommended lamivudine dose for adults with normal renal function and no HIV coinfection is 100 mg daily (I). The recommended lamivudine dose for children is 3 mg/kg/d with a maximum of 100 mg/d (I). The recommended treatment duration for HBeAg-positive chronic hepatitis B is a minimum of 1 year (I). Patients in whom HBeAg seroconversion has occurred should be maintained on treatment for 3 to 6 months after HBeAg seroconversion is confirmed (two occasions at least 2 months apart) to reduce posttreatment relapse. Treatment may be continued in patients who have not developed HBeAg seroconversion. Treatment may be continued in patients who have breakthrough infection due to lamivudine-resistant mutants as long as benefit to the patient (based on clinical assessment, ALT level, and HBV DNA level) is maintained. The recommended treatment duration for HBeAg-negative chronic hepatitis B is longer than 1 year, but the optimal duration has not been established (II-3). The recommended dose of lamivudine for persons coinfected with HIV is 150 mg twice daily, along with other antiretroviral medications (I). Adefovir is administered orally. The recommended adefovir dose for adults with normal renal function is 10 mg daily (I). The recommended treatment duration for HBeAg-positive chronic hepatitis B is a minimum of 1 year. The benefits versus risks of longer duration of treatment are unknown (I). The recommended treatment duration for HBeAg-negative chronic hepatitis B is longer than 1 year. Longer duration of treatment is likely necessary for sustained response, but the optimal duration of treatment and the benefits versus risks of longer duration of treatment remain to be determined (I). The recommended treatment duration for patients with lamivudine-resistant mutants has not been determined. Long-term treatment is required particularly for patients with decompensated cirrhosis or allograft infection. For patients with compensated liver disease, there appears to be no advantage to continuing lamivudine therapy in patients switched to adefovir but an overlap period of 2–3 months is advisable to minimize the risk of hepatitis flares during the transition (III). HBsAg testing should be performed in persons who have high risk of HBV infection, prior to initiation of chemotherapy or immunosuppressive therapy (III). Prophylactic antiviral therapy with lamivudine is recommended for HBV carriers at the onset of cancer chemotherapy or of a finite course of immunosuppressive therapy, and maintained for 6 months after completion of chemotherapy or immunosuppressive therapy (III). This guideline was approved by the American Association for the Study of Liver Diseases (AASLD) and represents the position of the Association. It was produced in collaboration with the AASLD Practice Guidelines Committee. Members of the AASLD Practice Guidelines Committee included: K. Rajender Reddy, M.D. (Chair), Bruce R. Bacon, M.D., David E. Bernstein, M.D., Thomas D. Boyer, M.D., Henry C. Bodenheimer, M.D., Robert L. Carithers, M.D., Gary L. Davis, M.D., James E. Everhart, M.D., Thomas W. Faust, M.D., Stuart C. Gordon, M.D., Elizabeth Hospenheide, R.N., B.S.N., F. Blaine Hollinger, M.D., Donald M. Jensen, M.D., Maureen Jonas, M.D., Jacob Korula, M.D., Michael R. Lucey, M.D., Timothy M. McCashland, M.D., Jan M. Novak, M.D., Melissa Palmer, M.D., F. Fred Poordad, M.D., Robert Reindollar, M.D., Eve A. Roberts, M.D., Thomas Shaw-Stiffel, M.D., Margaret C. Shuhart, M.D., James R. Spivey, M.D., Brent A. Tetri, M.D., and Zobair M. Younossi, M.D.

BACKGROUND: The RTS,S/AS01 vaccine targets the circumsporozoite protein of Plasmodium falciparum and has partial protective efficacy against clinical and severe malaria disease in infants and children. We investigated whether the vaccine efficacy was specific to certain parasite genotypes at the circumsporozoite protein locus. METHODS: We used polymerase chain reaction-based next-generation sequencing of DNA extracted from samples from 4985 participants to survey circumsporozoite protein polymorphisms. We evaluated the effect that polymorphic positions and haplotypic regions within the circumsporozoite protein had on vaccine efficacy against first episodes of clinical malaria within 1 year after vaccination. RESULTS: In the per-protocol group of 4577 RTS,S/AS01-vaccinated participants and 2335 control-vaccinated participants who were 5 to 17 months of age, the 1-year cumulative vaccine efficacy was 50.3% (95% confidence interval [CI], 34.6 to 62.3) against clinical malaria in which parasites matched the vaccine in the entire circumsporozoite protein C-terminal (139 infections), as compared with 33.4% (95% CI, 29.3 to 37.2) against mismatched malaria (1951 infections) (P=0.04 for differential vaccine efficacy). The vaccine efficacy based on the hazard ratio was 62.7% (95% CI, 51.6 to 71.3) against matched infections versus 54.2% (95% CI, 49.9 to 58.1) against mismatched infections (P=0.06). In the group of infants 6 to 12 weeks of age, there was no evidence of differential allele-specific vaccine efficacy. CONCLUSIONS: These results suggest that among children 5 to 17 months of age, the RTS,S vaccine has greater activity against malaria parasites with the matched circumsporozoite protein allele than against mismatched malaria. The overall vaccine efficacy in this age category will depend on the proportion of matched alleles in the local parasite population; in this trial, less than 10% of parasites had matched alleles. (Funded by the National Institutes of Health and others.).