Utility of urinary cytokine levels as predictors of the immunogenicity and reactogenicity of AS01-adjuvanted hepatitis B vaccine in healthy adults.

Plasma cytokines are useful indicators of the inflammatory response to vaccination, and can serve as potential biomarkers of the systemic reactogenicity and immunogenicity of vaccines. Measurement of cytokines in urine may represent a non-invasive alternative to the blood-based markers. To evaluate whether urinary cytokine levels can help predict vaccine responses to an AS01B-adjuvanted vaccine, we measured concentrations of 24 cytokines in the urine from 30 hepatitis B virus (HBV)-naïve adults following administration of AS01B-adjuvanted HBV surface antigen vaccine (NCT01777295). Levels post-dose 2 were compared with the levels measured following a single placebo (saline) injection, which was administered 1 month before the first vaccination in the same participants. Urine was collected at eight timepoints before or up to 1 week following each treatment. Urinary concentrations were normalized to creatinine levels, and paired with previously reported, participant-matched plasma levels, local and systemic reactogenicity scores, and antibody response magnitudes. Of the urine cytokine panel, only few analytes were detectable: IL-8, IL-18 and IL-6 receptor, each showing no clear changes after vaccination as compared to placebo administration, and MCP-1 (CCL2) and IP-10 (CXCL10), which displayed in most participants transient surges post-vaccination. Urine levels did not correlate with the matched plasma levels. Interestingly, urinary IP-10 levels at 1 day post-second vaccination were significantly correlated (P = 0.023) with the concurrent intensity scores of systemic reactogenicity, though not with the local reactogenicity scores or peak antibody responses. No significant correlations were detected for MCP-1. Altogether, most urinary cytokines have limited utility as a proxy for plasma cytokines to help predict the inflammatory response, the immunogenicity or the reactogenicity of AS01B-adjuvanted vaccine, with the possible exception of IP-10. The utility of urinary IP-10 as a potential complementary biomarker of systemic vaccine reactogenicity needs substantiation in larger studies.

Association Between Immunogenicity and Reactogenicity: A Post Hoc Analysis of 2 Phase 3 Studies With the Adjuvanted Recombinant Zoster Vaccine.

A recurrent question is whether transient reactions to vaccines translate into better immune responses. Using clinical data from 2 large phase 3 studies of the recombinant zoster vaccine, we observed a small but statistically significant association between the intensity of a frequent side effect (pain) after vaccination and immune responses to vaccination. However, despite the statistical correlation, the impact on the immune response is so small, and the immune response in individuals without pain already sufficient, that pain cannot be a surrogate marker for an appropriate immune response. Reactogenicity cannot be used to predict immunity after vaccination.

An Analysis of Spontaneously Reported Data of Vesicular and Bullous Cutaneous Eruptions Occurring Following Vaccination with the Adjuvanted Recombinant Zoster Vaccine.

INTRODUCTION: With the approval of the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) in October 2017, GSK established enhanced safety surveillance measures to allow prompt identification of potential safety signals not observed during clinical development. In Germany, cases of vesicular and bullous cutaneous eruptions following RZV vaccination were reported. OBJECTIVE: Our objective was to search and analyse 2.5 years of worldwide spontaneously reported post-marketing data for vesicular and bullous cutaneous eruptions, represented by adverse events suggestive of (1) herpes zoster (HZ) and (2) non-HZ vesicular and bullous cutaneous eruptions, that occurred following RZV vaccination. METHODS: We conducted a descriptive analysis of all identified reports of HZ and non-HZ vesicular and bullous cutaneous eruptions following RZV vaccination and an observed versus expected (O/E) analysis of reports of HZ that met criteria of varicella zoster virus (VZV) reactivations following RZV vaccination (i.e., time to onset [TTO] of the event < 30 days or missing after any dose). RESULTS: Until the data lock point, 32,597,779 RZV doses had been distributed globally. There were 2423 reports of HZ (including complications) identified, of which 645 met the criteria of possible vaccination failure (i.e., TTO of the event ≥ 30 days or missing following a complete RZV vaccination schedule). The O/E analysis of 1928 reports assessed as possible VZV reactivations indicated that the observed number of cases was lower than that expected in the general population. Additionally, 810 reports of non-HZ vesicular and bullous cutaneous eruptions were identified, including injection site rashes attributed to the vaccine's reactogenicity. CONCLUSION: This review of spontaneously reported post-marketing data did not raise safety concerns regarding the occurrence of vesicular and bullous cutaneous eruptions following vaccination with RZV.

Shingles is a disease caused by reactivation of the chickenpox virus. It mostly affects adults aged 50 years and older and patients of all ages who have an impaired immune system. Diagnosis of shingles is often based only on the presence of symptoms such as a typical rash and pain. However, rashes can have various other causes (e.g., allergies, autoimmune diseases, and infections). Consequently, rashes with other causes may be misdiagnosed as shingles. Adults at increased risk of shingles and/or aged 50 years and older may be vaccinated with Shingrix (GSK, Belgium) to protect them from shingles and its complications. Since Shingrix became available in Germany, blister-like skin rashes have been reported that occurred shortly after vaccination. We searched the GSK safety database for reports of blister-like skin rashes that occurred following vaccination with Shingrix and that were spontaneously reported from countries where Shingrix was first marketed. To analyse these reports of rashes, we described the reports that we retrieved, we performed a statistical analysis to quantify whether the number of events assessed as reactivations of the chickenpox virus following Shingrix vaccination was higher than the number of reactivations that would be expected in the general population, and we described possible explanations for the observed rashes and underlying disease mechanisms. Our analyses did not raise safety concerns related to the onset of these rashes after vaccination with Shingrix. This paper raises awareness about the varying causes of rashes since a shingles-like rash that onsets shortly after vaccination with Shingrix is not necessarily caused by vaccination. In conclusion, this analysis shows that caution is needed when evaluating rashes in older adults and that all potential contributing factors (e.g., pre-existing diseases, medication, vaccination) should be considered.

EVT-701 is a novel selective and safe mitochondrial complex 1 inhibitor with potent anti-tumor activity in models of solid cancers.

Targeting the first protein complex of the mitochondrial electron transport chain (MC1) in cancer has become an attractive therapeutic approach in the recent years, given the metabolic vulnerabilities of cancer cells. The anticancer effect exerted by the pleiotropic drug metformin and the associated reduction in hypoxia-inducible factor 1α (HIF-1α) levels putatively mediated by MC1 inhibition led to the development of HIF-1α inhibitors, such as BAY87-2243, with a more specific MC1 targeting. However, the development of BAY87-2243 was stopped early in phase 1 due to dose-independent emesis and thus there is still no clinical proof of concept for the approach. Given the importance of mitochondrial metabolism during cancer progression, there is still a strong therapeutic need to develop specific and safe MC1 inhibitors. We recently reported the synthesis of compounds with a novel chemotype and potent action on HIF-1α degradation and MC1 inhibition. We describe here the selectivity, safety profile and anti-cancer activity in solid tumors of lead compound EVT-701. In addition, using murine models of lung cancer and of Non-Hodgkin's B cell lymphoma we demonstrated that EVT-701 reduced tumor growth and lymph node invasion when used as a single agent therapy. LKB1 deficiency in lung cancer was identified as a potential indicator of accrued sensitivity to EVT-701, allowing stratification and selection of patients in clinical trials. Altogether these results support further evaluation of EVT-701 alone or in combination in preclinical models and eventually in patients.

Immunogenicity of the Adjuvanted Recombinant Zoster Vaccine: Persistence and Anamnestic Response to Additional Doses Administered 10 Years After Primary Vaccination.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) is highly immunogenic and efficacious in adults ≥50 years of age. We evaluated (1) long-term immunogenicity of an initial 2-dose RZV schedule, by following up adults vaccinated at ≥60 years of age and by modeling, and (2) immunogenicity of 2 additional doses administered 10 years after initial vaccination. METHODS: Persistence of humoral and cell-mediated immune (CMI) responses to 2 initial RZV doses was assessed through 10 years after initial vaccination, and modeled through 20 years using a Piecewise, Power law and Fraser model. The immunogenicity and safety of 2 additional RZV doses were also evaluated. RESULTS: Seventy adults were enrolled. Ten years after initial vaccination, humoral and CMI responses were approximately 6-fold and 3.5-fold, respectively, above those before the initial vaccination levels. Predicted immune persistence through 20 years after initial vaccination was similar across the 3 models. Sixty-two participants (mean age [standard deviation], 82.6 [4.4] years) received ≥1 additional RZV dose. Strong anamnestic humoral and CMI responses were elicited by 1 additional dose, without further increases after a second additional dose. CONCLUSIONS: Immune responses to an initial 2-dose RZV course persisted for many years in older adults. Strong anamnestic immune responses can be induced by additional dosing 10 years after the initial 2-dose course. CLINICAL TRIALS REGISTRATION: NCT02735915.

Impact of Reactogenicity After Two Doses of Recombinant Zoster Vaccine Upon Physical Functioning and Quality of Life: An Open Phase III Trial in Older Adults.

BACKGROUND: Herpes zoster may significantly impact quality of life (QoL) in older adults. The recombinant zoster vaccine (RZV) is efficacious in adults aged ≥50 and older and is associated with increased reactogenicity compared to placebo. We report here on the impact of reactogenicity of the second RZV dose on the QoL and physical functioning (PF) of vaccine recipients, and summarize findings following both doses. METHOD: In this single-arm study, 401 adults aged ≥50 and older were enrolled to receive two RZV doses 2 months apart. Change in mean Short Form Survey-36 (SF-36) PF and EuroQol-5 Dimension (EQ-5D) scores, reactogenicity, safety, productivity loss, and healthcare resource utilization were evaluated. RESULTS: In total, 391 (97.5%) participants received dose 2. Post-dose 2, the most common solicited local symptoms were injection site pain (75.1%), erythema (22.4%), and swelling (13.9%), and the most common systemic symptoms were fatigue (46.3%), headache (37.5%), and myalgia (32.9%). Grade 3 solicited (local and systemic) adverse events were reported by 61 (15.6%) participants and were associated with a transient clinically significant decrease in SF-36 PF score on Days 1-2 post-dose 2 that recovered by Day 3. Overall, no clinically important reduction in mean SF-36 PF scores was observed from baseline to post-dose 2 (mean change -0.4), and no quality-adjusted-life-year loss was recorded. CONCLUSIONS: Overall, QoL and PF of RZV vaccinees were not affected by vaccine-related reactogenicity. A transient reduction was observed in the first 2 days after RZV vaccination in individuals with Grade 3 adverse events. No safety concerns were identified.

Efficacy and serious adverse events profile of the adjuvanted recombinant zoster vaccine in adults with pre-existing potential immune-mediated diseases: a pooled post hoc analysis on two parallel randomized trials.

ABSTRACT OBJECTIVE: In the ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229) phase 3 clinical trials, the adjuvanted recombinant zoster vaccine (RZV) demonstrated ≥90% efficacy in preventing herpes zoster (HZ) in all age groups ≥50 years. Given the increased HZ risk associated with certain underlying autoimmune diseases or their treatment regimes, we conducted a post hoc analysis of RZV's efficacy against HZ and safety profile [specifically, the occurrence of serious adverse events (SAEs)] in ZOE-50/70 participants who reported pre-existing potential immune-mediated diseases (pIMDs) at enrolment and were not on immunosuppressive therapies. METHODS: Adults aged ≥50 (ZOE-50) and ≥70 (ZOE-70) years were randomized to receive two doses of RZV or placebo 2 months apart. In this subgroup analysis of participants with at least one pIMD at enrolment, the efficacy was calculated for two-dose recipients who did not develop confirmed HZ before 30 days post-dose 2. SAE occurrence was evaluated for all participants who received at least one dose. RESULTS: Of the 14 645 RZV and 14 660 placebo recipients from the ZOE-50/70 studies, 983 and 960, respectively, reported at least one pre-existing pIMD at enrolment and were included in these analyses. The most frequent pre-existing conditions were psoriasis, spondyloarthropathy and RA. Efficacy against HZ was 90.5% (95% CI: 73.5, 97.5%) overall with the lowest being 84.4% (95% CI: 30.8, 98.3%) in the 70-79-year-old age group. SAEs and fatal SAEs were similar between RZV and placebo recipients. CONCLUSION: In ZOE-50/70 participants with pre-existing pIMDs, RZV was highly efficacious against HZ and SAE incidence was similar between RZV and placebo recipients. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT01165177 (ZOE-50), NCT01165229 (ZOE-70).

The Adjuvanted Recombinant Zoster Vaccine in Adults Aged ≥65 Years Previously Vaccinated With a Live-Attenuated Herpes Zoster Vaccine.

BACKGROUND: Efficacy of the live-attenuated herpes zoster (HZ) vaccine (ZVL) wanes substantially over time. We evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) in previous ZVL recipients. METHODS: Adults aged ≥65 years who were previously vaccinated with ZVL ≥5 years earlier (n = 215) were group-matched with ZVL-naive individuals (n = 215) and vaccinated with RZV. Glycoprotein E (gE)-specific humoral and cell-mediated immune responses and the correlation between them, polyfunctional gE-specific CD4 T-cell responses, safety, and confirmed HZ cases were assessed. RESULTS: Through 12 months after dose 2, anti-gE antibody concentrations, gE-specific CD4 T-cell frequencies, and activation marker profiles were similar between groups. Safety outcomes were also similar. No HZ episodes were confirmed. CONCLUSIONS: RZV induced strong humoral and polyfunctional cell-mediated immune responses that persisted above prevaccination levels through 1 year after dose 2 in adults aged ≥65 years irrespective of previous ZVL vaccination. The RZV safety profile was not affected. CLINICAL TRIALS REGISTRATION: NCT02581410.

Safety of the adjuvanted recombinant zoster vaccine in adults aged 50 years or older. A phase IIIB, non-randomized, multinational, open-label study in previous ZOE-50 and ZOE-70 placebo recipients.

BACKGROUND: Efficacy of the adjuvanted recombinant zoster vaccine (RZV) against herpes zoster (HZ) was demonstrated in pivotal trials ZOE-50 (NCT01165177) and ZOE-70 (NCT01165229). This study was designed to offer RZV to placebo recipients of these parent studies. METHODS: Vaccine safety and suspected HZ episode occurrence were assessed for 12 months following vaccination. RESULTS: Of the 14,550 eligible participants, 8687 received RZV and 97.8% completed the 2-dose schedule. During the 30-day post-vaccination period, 5175 (59.6%) participants experienced ≥ 1 unsolicited adverse event (AE), 4422 (50.9%) were vaccination-related. The most common AEs were injection-site reactions, pyrexia, and headache. During the study, 734 (8.4%) participants reported ≥ 1 serious AE (SAE) and 62 (0.7%) reported ≥ 1 potential immune-mediated disease (pIMD); 2 of each were assessed as vaccination-related. Suspected HZ episodes were reported by 30 participants (0.3%). CONCLUSIONS: Nature and incidence of AEs, SAEs, and pIMDs were as expected and in line with the parent studies.

Post hoc analysis of reactogenicity trends between dose 1 and dose 2 of the adjuvanted recombinant zoster vaccine in two parallel randomized trials.

In two large clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]), two doses of the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster in adults ≥50 years of age. Solicited adverse events (AEs) were collected for 7 days post-each dose in a study sub-cohort. The incidence of reported solicited AEs was higher for RZV compared to placebo recipients. Since reactogenicity may contribute to a person's willingness to be vaccinated, knowing about expected reactogenicity might help keep high compliance with the second dose. This post hoc analysis assessed the intensity of solicited AEs post-dose 2 reported to the same event's intensity post-dose 1. Intensity was graded from 0 to 3, grade 3 indicating the highest severity. Of the vaccinees who did not experience a specific AE post-dose 1, 72.6-91.7% did not experience the same event after dose 2. Although the frequency of grade 3 AEs post-dose 2 was the highest in participants reporting the same AEs at grade 3 post-dose 1, 65.8-89.3% of vaccinees with grade 3 specific AEs post-dose 1 reported the same AEs at lower intensity post-dose 2. These data can help inform health-care professionals about the frequency and intensity of AEs post-dose 2 with respect to post-dose 1.

Review of the initial post-marketing safety surveillance for the recombinant zoster vaccine.

BACKGROUND: The adjuvanted recombinant zoster vaccine (RZV) received its first marketing authorization in October 2017, for prevention of herpes zoster in individuals aged ≥50 years. METHODS: We summarized safety information, following RZV administration, received by GSK via spontaneous adverse event (AE) reports submitted by healthcare providers, vaccine recipients and other reporters. Observed-to-expected (O/E) analyses were performed for selected outcomes: reports of death, Guillain-Barré syndrome and Bell's palsy. Standard case definitions were used to assess individual case reports. Data mining, using proportional reporting ratio and time-to-onset signal detection methods, was employed to identify RZV-AE pairs with disproportionate reporting or unexpected time-to-onset distribution. RESULTS: Between October 13, 2017 and February 10, 2019, an estimated 9.3 million doses were distributed and GSK received 15,638 spontaneous AE reports involving RZV. Most reports were classified as non-serious (95.3%) and originated from the United States (81.7%), where the majority of doses were distributed. Among reports with age or sex reported, individuals were mainly 50-69-year-olds (62.1%) and female (66.7%). Of all reports, 3,579 (22.9%) described vaccination errors, of which 82.7% were without associated symptoms. Of all vaccination error reports, most described errors of vaccine preparation and reconstitution (29.7%), inappropriate schedule or incomplete course of administration (26.7%), incorrect route of administration (16.4%), and storage errors (12.9%). The most commonly reported symptoms were consistent with the known RZV reactogenicity profile observed in clinical trials, including injection site reactions, pyrexia, chills, fatigue, headache. O/E analyses for selected outcomes and data mining analyses for all reported AEs did not identify any unexpected patterns. CONCLUSIONS: Review of the initial data from the post-marketing safety surveillance showed that the safety profile of RZV is consistent with that previously observed in pre-licensure clinical trials. Other studies are ongoing and planned, to continue generating real-world safety data and further characterize RZV.

The how's and what's of vaccine reactogenicity.

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.

Adjuvant Systems for vaccines: 13 years of post-licensure experience in diverse populations have progressed the way adjuvanted vaccine safety is investigated and understood.

Adjuvant Systems (AS) are combinations of immune stimulants that enhance the immune response to vaccine antigens. The first vaccine containing an AS (AS04) was licensed in 2005. As of 2018, several vaccines containing AS04, AS03 or AS01 have been licensed or approved by regulatory authorities in some countries, and included in vaccination programs. These vaccines target diverse viral and parasitic diseases (hepatitis B, human papillomavirus, malaria, herpes zoster, and (pre)pandemic influenza), and were developed for widely different target populations (e.g. individuals with renal impairment, girls and young women, infants and children living in Africa, adults 50 years of age and older, and the general population). Clearly, the safety profile of one vaccine in one target population cannot be extrapolated to another vaccine or to another target population, even for vaccines containing the same adjuvant. Therefore, the assessment of adjuvant safety poses specific challenges. In this review we provide a historical perspective on how AS were developed from the angle of the challenges encountered on safety evaluation during clinical development and after licensure, and illustrate how these challenges have been met to date. Methods to evaluate safety of adjuvants have evolved based on the availability of new technologies allowing a better understanding of their mode of action, and new ways of collecting and assessing safety information. Since 2005, safety experience with AS has accumulated with their use in diverse vaccines and in markedly different populations, in national immunization programs, and in a pandemic setting. Thirteen years of experience using antigens combined with AS attest to their acceptable safety profile. Methods developed to assess the safety of vaccines containing AS have progressed the way we understand and investigate vaccine safety, and have helped set new standards that will guide and support new candidate vaccine development, particularly those using new adjuvants. FOCUS ON THE PATIENT: What is the context? Adjuvants are immunostimulants used to modulate and enhance the immune response induced by vaccination. Since the 1990s, adjuvantation has moved toward combining several immunostimulants in the form of Adjuvant System(s) (AS), rather than relying on a single immunostimulant. AS have enabled the development of new vaccines targeting diseases and/or populations with special challenges that were previously not feasible using classical vaccine technology. What is new? In the last 13 years, several AS-containing vaccines have been studied targeting different diseases and populations. Over this period, overall vaccine safety has been monitored and real-life safety profiles have been assessed following routine use in the general population in many countries. Moreover, new methods for safety assessment, such as a better determination of the mode of action, have been implemented in order to help understand the safety characteristics of AS-containing vaccines. What is the impact? New standards and safety experience accumulated over the last decade can guide and help support the safety assessment of new candidate vaccines during development.

Medical conditions at enrollment do not impact efficacy and safety of the adjuvanted recombinant zoster vaccine: a pooled post-hoc analysis of two parallel randomized trials.

In two pivotal efficacy studies (ZOE-50; ZOE-70), the adjuvanted recombinant zoster vaccine (RZV) demonstrated >90% efficacy against herpes zoster (HZ).Adults aged ≥50 or ≥70 years (ZOE-50 [NCT01165177]; ZOE-70 [NCT01165229]) were randomized to receive 2 doses of RZV or placebo 2 months apart. Vaccine efficacy and safety were evaluated post-hoc in the pooled (ZOE-50/70) population according to the number and type of selected medical conditions present at enrollment.At enrollment, 82.3% of RZV and 82.7% of placebo recipients reported ≥1 of the 15 selected medical conditions. Efficacy against HZ ranged from 84.5% (95% Confidence Interval [CI]: 46.4-97.1) in participants with respiratory disorders to 97.0% (95%CI: 82.3-99.9) in those with coronary heart disease. Moreover, efficacy remained >90% irrespective of the number of selected medical conditions reported by a participant.As indicated by the similarity of the point estimates, this post-hoc analysis suggests that RZV efficacy remains high in all selected medical conditions, as well as with increasing number of medical conditions. No safety concern was identified by the type or number of medical conditions present at enrollment.

Inflammatory parameters associated with systemic reactogenicity following vaccination with adjuvanted hepatitis B vaccines in humans.

BACKGROUND: Adjuvants like AS01B increase the immunogenicity of vaccines and generally cause increased transient reactogenicity compared with Alum. A phase II randomized trial was conducted to characterize the response to AS01B and Alum adjuvanted vaccines. A post-hoc analysis was performed to examine the associations between reactogenicity and innate immune parameters. METHODS: The trial involved 60 hepatitis B-naïve adults aged 18-45 years randomized 1:1 to receive either two doses of HBsAg-AS01B on Day (D)0 and D30, or three doses of HBsAg-Alum on D0, D30, D180. Prior to vaccination, all subjects received placebo injection in order to differentiate the impact of injection process and the vaccination. Main outcomes included reactogenicity symptoms, vital signs, blood cytokines, biochemical and hematological parameters after vaccination. Associations were explored using linear regression. FINDINGS: The vaccine with AS01B induced higher HBsAg-specific antibody levels than Alum. Local and systemic symptoms were more frequent in individuals who received HBsAg AS01B/Alum vaccine or placebo, but were mild and short-lived. Blood levels of C-reactive protein (CRP), bilirubin, leukocyte, monocyte and neutrophil counts increased rapidly and transiently after AS01B but not after Alum or placebo. Lymphocyte counts decreased in the AS01B group and lactate dehydrogenase levels decreased after Alum. Modelling revealed associations between systemic symptoms and increased levels of CRP and IL-6 after the first HBsAg-AS01B or HBsAg-Alum immunization. Following the second vaccine dose, CRP, IL-6, IP-10, IFN-γ, MIP-1ß and MCP-2 were identified as key parameters associated with systemic symptoms. These observations were confirmed using an independent data set extracted from a previous study of the immune response to HBsAg-adjuvanted vaccines (NCT00805389). CONCLUSIONS: IL-6 and IFN-γ signals were associated with systemic reactogenicity following administration of AS01B-adjuvanted vaccine. These signals were similar to those previously associated with antibody and T-cell responses induced by HBsAg-adjuvanted vaccines, suggesting that similar innate immune signals may underlie adjuvant reactogenicity and immunogenicity. TRIAL REGISTRATION: www.clinicaltrials.gov NCT01777295.

Immunogenicity and safety of the adjuvanted recombinant zoster vaccine co-administered with the 23-valent pneumococcal polysaccharide vaccine in adults ≥50 years of age: A randomized trial.

BACKGROUND: This study evaluated immunogenicity and safety of the adjuvanted recombinant zoster vaccine (RZV) when the first dose was co-administered with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in adults aged ≥50 years. METHODS: In this open label, multi-center study (NCT02045836), participants were randomized 1:1 to receive either the first dose of RZV and PPSV23, co-administered at Day 0 and the second dose of RZV at Month 2 (Co-Ad group), or PPSV23 at Day 0, the first dose of RZV at Month 2 and second dose of RZV at Month 4 (Control group). Co-primary objectives were the RZV vaccine response rate (VRR) in the Co-Ad group and the non-inferiority of the antibody responses to RZV and PPSV23 in the Co-Ad group compared to the Control group. Reactogenicity and safety were also assessed. RESULTS: 865 participants were vaccinated (Co-Ad: 432, Control: 433). VRRs to RZV were >98% in both groups. Humoral immune responses to co-administration of RZV and PPSV23 were non-inferior to sequential administration. All three co-primary immunogenicity objectives were met. Solicited local symptoms after the first RZV dose were reported by similar percentages of participants in both groups. Solicited general symptoms were more frequently reported when the first dose of RZV and PPSV23 were co-administered. No differences were apparent between groups after the second RZV dose. CONCLUSIONS: No immunologic interference was observed between RZV and PPSV23 when co-administered in adults ≥50 years. No safety concerns were raised.

Erratum: Author Correction: Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity.

[This corrects the article DOI: 10.1038/s41541-017-0027-3.].

Cellular and molecular synergy in AS01-adjuvanted vaccines results in an early IFNγ response promoting vaccine immunogenicity.

Combining immunostimulants in adjuvants can improve the quality of the immune response to vaccines. Here, we report a unique mechanism of molecular and cellular synergy between a TLR4 ligand, 3-O-desacyl-4'-monophosphoryl lipid A (MPL), and a saponin, QS-21, the constituents of the Adjuvant System AS01. AS01 is part of the malaria and herpes zoster vaccine candidates that have demonstrated efficacy in phase III studies. Hours after injection of AS01-adjuvanted vaccine, resident cells, such as NK cells and CD8+ T cells, release IFNγ in the lymph node draining the injection site. This effect results from MPL and QS-21 synergy and is controlled by macrophages, IL-12 and IL-18. Depletion strategies showed that this early IFNγ production was essential for the activation of dendritic cells and the development of Th1 immunity by AS01-adjuvanted vaccine. A similar activation was observed in the lymph node of AS01-injected macaques as well as in the blood of individuals receiving the malaria RTS,S vaccine. This mechanism, previously described for infections, illustrates how adjuvants trigger naturally occurring pathways to improve the efficacy of vaccines.

Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells.

In breast cancer, a key feature of peritumoral adipocytes is their loss of lipid content observed both in vitro and in human tumors. The free fatty acids (FFAs), released by adipocytes after lipolysis induced by tumor secretions, are transferred and stored in tumor cells as triglycerides in lipid droplets. In tumor cell lines, we demonstrate that FFAs can be released over time from lipid droplets through an adipose triglyceride lipase-dependent (ATGL-dependent) lipolytic pathway. In vivo, ATGL is expressed in human tumors where its expression correlates with tumor aggressiveness and is upregulated by contact with adipocytes. The released FFAs are then used for fatty acid ß-oxidation (FAO), an active process in cancer but not normal breast epithelial cells, and regulated by coculture with adipocytes. However, in cocultivated cells, FAO is uncoupled from ATP production, leading to AMPK/acetyl-CoA carboxylase activation, a circle that maintains this state of metabolic remodeling. The increased invasive capacities of tumor cells induced by coculture are completely abrogated by inhibition of the coupled ATGL-dependent lipolysis/FAO pathways. These results show a complex metabolic symbiosis between tumor-surrounding adipocytes and cancer cells that stimulate their invasiveness, highlighting ATGL as a potential therapeutic target to impede breast cancer progression.