PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: a first-in-human, randomised, double-blind, placebo-controlled study.

BACKGROUND: PRIMVAC is a VAR2CSA-derived placental malaria vaccine candidate aiming to prevent serious clinical outcomes of Plasmodium falciparum infection during pregnancy. We assessed the safety and immunogenicity of PRIMVAC adjuvanted with Alhydrogel or glucopyranosyl lipid adjuvant in stable emulsion (GLA-SE) in French and Burkinabe women who were not pregnant. METHODS: This first-in-human, randomised, double-blind, placebo-controlled, dose escalation trial was done in two staggered phases, a phase 1A trial in 18-35-year-old women who were malaria naive in a hospital in France and a subsequent phase 1B trial in women who were naturally exposed to P falciparum and nulligravid in the clinical site of a research centre in Burkina Faso. Volunteers were recruited into four sequential cohorts receiving PRIMVAC intramuscularly at day 0, 28, and 56: two cohorts in France receiving 20 µg or 50 µg of PRIMVAC and then two in Burkina Faso receiving 50 µg or 100 µg of PRIMVAC. Volunteers were randomly assigned (1:1) to two groups (PRIMVAC adjuvanted with either Alhydrogel or GLA-SE) in France and randomly assigned (2:2:1) to three groups (PRIMVAC adjuvanted with either Alhydrogel, GLA-SE, or placebo) in Burkina Faso. Randomisation was centralised, using stratification by cohort and blocks of variable size, and syringes were masked by opaque labels. The primary endpoint was the proportion of participants with any grade 3 or higher adverse reaction to vaccination up until day 35. Safety at later time points as well as humoral and cellular immunogenicity were assessed in secondary endpoints. This trial is registered with ClinicalTrials.gov, NCT02658253. FINDINGS: Between April 19, 2016, and July 13, 2017, 68 women (18 in France, 50 in Burkina Faso) of 101 assessed for eligibility were included. No serious adverse event related to the vaccine occurred. PRIMVAC antibody titres increased with each dose and seroconversion was observed in all women vaccinated with PRIMVAC (n=57). PRIMVAC antibody titres reached a peak (geometric mean 11 843·0, optical density [OD] 1·0, 95% CI 7559·8-18 552·9 with 100 µg dose and GLA-SE) 1 week after the third vaccination (day 63). Compared with Alhydrogel, GLA-SE tended to improve the PRIMVAC antibody response (geometric mean 2163·5, OD 1·0, 95% CI 1315·7-3557·7 with 100 µg dose and Alhydrogel at day 63). 1 year after the last vaccination, 20 (71%) of 28 women who were vaccinated with PRIMVAC/Alhydrogel and 26 (93%) of 28 women who were vaccinated with PRIMVAC/GLA-SE still had anti-PRIMVAC antibodies, although antibody magnitude was markedly lower (452·4, OD 1·0, 95% CI 321·8-636·1 with 100 µg dose and GLA-SE). These antibodies reacted with native homologous VAR2CSA expressed by NF54-CSA infected erythrocytes (fold change from baseline at day 63 with 100 µg dose and GLA-SE: 10·74, 95% CI 8·36-13·79). Limited cross-recognition, restricted to sera collected from women that received the 100 µg PRIMVAC dose, was observed against heterologous VAR2CSA variants expressed by FCR3-CSA (fold change from baseline at day 63: 1·49, 95% CI 1·19-1·88) and 7G8-CSA infected erythrocytes (1·2, 1·08-1·34). INTERPRETATION: PRIMVAC adjuvanted with Alhydrogel or GLA-SE had an acceptable safety profile, was immunogenic, and induced functional antibodies reacting with the homologous VAR2CSA variant expressed by NF54-CSA infected erythrocytes. Cross-reactivity against heterologous VAR2CSA variants was limited and only observed in the higher dose group. An alternate schedule of immunisation, antigen dose, and combinations with other VAR2CSA-based vaccines are envisaged to improve the cross-reactivity against heterologous VAR2CSA variants. FUNDING: Bundesministerium für Bildung und Forschung, through Kreditanstalt für Wiederaufbau, Germany; Inserm, and Institut National de Transfusion Sanguine, France; Irish Aid, Department of Foreign Affairs and Trade, Ireland.

Trajectories of seasonal influenza vaccine uptake among French people with diabetes: a nationwide retrospective cohort study, 2006-2015.

BACKGROUND: Annual seasonal influenza vaccination (SIV) is recommended for people with diabetes, but their SIV rates remain far below public health targets. We aimed to identify temporal trajectories of SIV uptake over a 10-year period among French people with diabetes and describe their clinical characteristics. METHODS: We identified patients with diabetes in 2006 among a permanent, representative sample of beneficiaries of the French National Health Insurance Fund. We followed them up over 10 seasons (2005/06-2015/16), using SIV reimbursement claims and group-based trajectory modelling to identify SIV trajectories and to study sociodemographic, clinical, and healthcare utilization characteristics associated with the trajectories. RESULTS: We identified six trajectories. Of the 15,766 patients included in the model, 4344 (28%) belonged to the "continuously vaccinated" trajectory and 4728 (30%) to the "never vaccinated" one. Two other trajectories showed a "progressive decrease" (2832, 18%) or sharp "postpandemic decrease" (1627, 10%) in uptake. The last two trajectories (totalling 2235 patients, 14%) showed an early or delayed "increase" in uptake. Compared to "continuously vaccinated" patients, those in the "progressively decreasing" trajectory were older and those in all other trajectories were younger with fewer comorbidities at inclusion. Worsening diabetes and comorbidities during follow-up were associated with the "increasing" trajectories. CONCLUSIONS: Most patients with diabetes had been continuously vaccinated or never vaccinated and thus had stable SIV behaviours. Others adopted or abandoned SIV. These behaviour shifts might be due to increasing age, health events, or contextual factors (e.g., controversies about vaccine safety or efficacy). Healthcare professionals and stakeholders should develop tailored strategies that take each group's specificities into account.

Booster Vaccination With GVGH Shigella sonnei 1790GAHB GMMA Vaccine Compared to Single Vaccination in Unvaccinated Healthy European Adults: Results From a Phase 1 Clinical Trial.

The investigational Shigella sonnei vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-S. sonnei lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2-3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti-S. sonnei LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day [D]1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated.

Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination.

BACKGROUND: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes. METHODS: This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1. RESULTS: TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21. CONCLUSION: This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.

Trends in seasonal influenza vaccine coverage of target groups in France, 2006/07 to 2015/16: Impact of recommendations and 2009 influenza A(H1N1) pandemic.

Background and aimsSeasonal influenza vaccination (SIV) uptake (SIVU) rates in France are below target. We (i) describe trends in French SIVU over 10 consecutive seasons among different target groups and (ii) examine the effects of the 2009 influenza A(H1N1) pandemic and the publication of new SIV recommendations in 2011 and 2013.MethodsOur study was based on records of vaccines delivered in community pharmacies for a permanent, representative sample of 805,000 beneficiaries of the French National Health Insurance Fund. For the first objective, we analysed SIVU rate trends among ≥ 65 year olds as well as among < 65 year olds with each of the following conditions: diabetes, respiratory, cardiovascular, neuromuscular, or chronic liver disease. For the second goal, we computed segmented log-binomial regression analyses.ResultsAfter the 2009 pandemic, except for the target group with liver diseases, where the difference was not statistically significant, SIVU fell significantly in all groups during the 2010/11 season, remaining relatively stable until 2015/16 in groups not targeted by new recommendations. Crude SIVU rates in 2015/16 were 48% (43,950/91,794) for ≥ 65 year olds and between 16% (407/2,565) and 29% (873/3,056) for < 65 year olds depending on their condition. SIVU increased modestly after new recommendations were published, but only in patients newly eligible for a free vaccine voucher.ConclusionsOur results suggest: (i) a prolonged confidence crisis in SIV, initially impelled by the 2009 pandemic vaccination campaign; (ii) that new recommendations are ineffective without additional measures. Interventional research in this field is a priority.

Chikungunya Virus Infection: Why Should U.S. Geriatricians Be Aware of It?

Chikungunya virus (CHIKV) was until recently perceived only as a tropical disease. Since the first report of a case in Saint Martin Island in 2013, it has spread to South, Central, and North America. The first local transmission in the continental United States was reported in Florida in July 2014. CHIV infection is known to cause debilitating rheumatologic disease. Older adults are particularly susceptible to severe and chronic infection. Without an effective vaccine and antiviral therapy to prevent and control CHIKV, U.S. geriatricians could soon be confronted with major clinical, functional, and therapeutic challenges. After a general overview of CHIKV infection, this review will examine reasons why it has become such a threat to the United States and consider factors that contribute to the greater burden and effect of this disease in elderly adults. Consideration will be given to how aging and immunosenescence may contribute to CHIKV's atypical and more-severe clinical features in older adults. This review concludes with possible therapeutic approaches that best fit the unique needs of older adults, especially with regard to multimorbidity and polypharmacy.

Safety Profile and Immunologic Responses of a Novel Vaccine Against Shigella sonnei Administered Intramuscularly, Intradermally and Intranasally: Results From Two Parallel Randomized Phase 1 Clinical Studies in Healthy Adult Volunteers in Europe.

BACKGROUND: Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults. METHODS: To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France ("study 1") and the United Kingdom ("study 2") between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18-45years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100µg of OAg/µg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10µg ID, 0.29/5, 1.2/20, 4.8/80µg IN and 0.29/5µg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei. FINDINGS: Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥1.5/25µg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody. INTERPRETATION: Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100µg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines.

Association of the HLA-B*53:01 Allele With Drug Reaction With Eosinophilia and Systemic Symptoms (DRESS) Syndrome During Treatment of HIV Infection With Raltegravir.

Background: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare, severe adverse event during treatment with raltegravir. The occurrence of DRESS syndrome during treatment with other drugs is strongly associated with particular HLA alleles. Methods: We performed HLA testing in 3 of the 5 patients previously reported to have developed raltegravir-induced DRESS syndrome and in 1 previously unreported patient. We then used virtual modeling to visualize interactions between raltegravir and the imputed HLA molecule. Results: Five of the 6 patients who developed raltegravir-induced DRESS syndrome were African, and 1 was Hispanic. HLA typing was performed in 4 patients, all of whom carried both the HLA-B*53 allele and the HLA-C*04 allele to which it is commonly haplotypic. No other HLA alleles were shared by all of the tested patients. Given the approximate prevalence of HLA-B*53 carriage in African (20%) and Hispanic (6%) populations, the probability of all 4 patients being HLA-B*53 carriers, and 2 of 3 African patients being homozygous for HLA-B*53:01, is approximately 0.00002. Conclusions: These data implicate the prevalent African allele HLA-B*53:01 in the immunopathogenesis of raltegravir-induced DRESS syndrome. Although the immunopathogenic mechanisms are currently unknown, virtual modeling suggests that raltegravir may bind within the antigen binding cleft of the HLA-B*53:01 molecule, but not within the closely related HLA-B*35:01 molecule. Further studies are necessary to confirm the strength of the association between carriage of the HLA-B*53:01 allele and raltegravir-induced DRESS syndrome, and the potential utility of HLA screening before raltegravir treatment.

Vaccination recommendations for the adult immunosuppressed patient: A systematic review and comprehensive field synopsis.

BACKGROUND: Immunosuppressed patients are at risk of severe viral infections-related complications. National and international vaccination guidelines have been developed to decrease the mortality risk associated with these infections. However, a summary of these guidelines and the value of immunisation in this population is missing. OBJECTIVES: To summarize specific guidelines regarding vaccination in immunosuppressed patients. METHODS: We performed a literature search based on last update vaccine guidelines in immunosuppressed adult patients published between 1/1/2005-1/31/2016 in English or French language using PubMed, Cochrane and Embase, as well as relevant medical society websites. RESULTS: Of the 389 citations identified, 12 guidelines were selected Three additional guidelines were selected by searching on the websites from medical societies of each specialty. 15 guidelines were included, involving 19 medical societies issued from the US (n = 6), international collaboration (n = 3), UK (n = 2), Canada (n = 1), Australia (n = 1), France (n = 1), and Germany (n = 1). These guidelines provide recommendations on vaccination in asplenic patients (n = 5), cancer patients (n = 4), HIV patients (n = 5), hematopoietic stem cell recipients (n = 4), inflammatory bowel diseases patients (n = 5), psoriasis patients (n = 4), primary immunocompromised patients (n = 3), inflammatory rheumatic diseases patients (n = 6), and solid organ transplant recipients (n = 5). All guidelines recommended pneumococcal and injectable influenza vaccines. Other inactivated vaccines were recommended only in high risk patients. Live vaccines were usually contraindicated in patients under immunosuppressive therapy and/or in HIV patients with a CD4 count under 200/mm3. CONCLUSION: Pneumococcal and injectable influenza are the two essential vaccines recommended in all immunocompromised patients. Other inactivated vaccines are only indicated in high risk patients. Live vaccines are usually contraindicated.

Safety of raltegravir-based antiretroviral therapy in HIV-infected patients receiving multi-kinase inhibitors.

Background The risk of pharmacokinetic interaction is important in HIV-infected cancer patients receiving concomitantly highly active antiretroviral therapy (HAART) and anti-cancer systemic treatments. We aimed to evaluate the safety profile of raltegravir-based HAART in cancer patients receiving multi-kinase inhibitors (MKIs). Patients and Methods We conducted a retrospective medical record review of adult, HIV-infected cancer patients treated in our institutions from January 2010 to December 2015. Patients eligible for the present analysis were those receiving a raltegravir-based HAART at the time of the initiation of a MKI for the treatment of advanced solid tumors. Treatment-related toxicity, virological outcomes and pharmacokinetic profile of MKIs were examined. Results Twelve patients (7 males, median age 55 years) were identified. Seven had sarcoma/GIST, 3 had hepatocellular carcinoma, one had pancreatic neuroendocrine tumor, and one had NSCLC. Patients received the following MKIs: imatinib (n = 3), sorafenib (n = 3), pazopanib (n = 3), sunitinib (n = 2) and erlotinib (n = 1). The mean CD4+ count at baseline was 929 cells/mm3, and 860 cells/mm3 after completion of MKI treatment. In all patients, HIV viral loads remained below the limit of detection (40 copies/ mm3) during the whole MKI treatment. No virological failure occurred. No unexpected or serious adverse event related either to raltegravir-based HAART or to MKIs was observed. The trough plasma concentrations of MKIs were assessed in 8 patients, and were found normal in all but one case (not related to raltegravir-based HAART). Conclusions The present data represent the first documentation of the concomitant use of raltegravir-containing HAART and MKIs in HIV-infected adult patients with advanced non-AIDS defining malignancies, with a reassuring safety profile.

Neutropenia as an Adverse Event following Vaccination: Results from Randomized Clinical Trials in Healthy Adults and Systematic Review.

BACKGROUND: In the context of early vaccine trials aimed at evaluating the safety profile of novel vaccines, abnormal haematological values, such as neutropenia, are often reported. It is therefore important to evaluate how these trials should be planned not to miss potentially important safety signals, but also to understand the implications and the clinical relevance. METHODOLOGY: We report and discuss the results from five clinical trials (two with a new Shigella vaccine in the early stage of clinical development and three with licensed vaccines) where the absolute neutrophil counts (ANC) were evaluated before and after vaccination. Additionally, we have performed a systematic review of the literature on cases of neutropenia reported during vaccine trials to discuss our results in a more general context. PRINCIPAL FINDINGS: Both in our clinical trials and in the literature review, several cases of neutropenia have been reported, in the first two weeks after vaccination. However, neutropenia was generally transient and had a benign clinical outcome, after vaccination with either multiple novel candidates or well-known licensed vaccines. Additionally, the vaccine recipients with neutropenia frequently had lower baseline ANC than non-neutropenic vaccinees. In many instances neutropenia occurred in subjects of African descent, known to have lower ANC compared to western populations. CONCLUSIONS: It is important to include ANC and other haematological tests in early vaccine trials to identify potential safety signals. Post-vaccination neutropenia is not uncommon, generally transient and clinically benign, but many vaccine trials do not have a sampling schedule that allows its detection. Given ethnic variability in the level of circulating neutrophils, normal ranges taking into account ethnicity should be used for determination of trial inclusion/exclusion criteria and classification of neutropenia related adverse events. TRIAL REGISTRATION: ClinicalTrials.gov NCT02017899, NCT02034500, NCT01771367, NCT01765413, NCT02523287.

Seasonal influenza vaccination of high-risk adults.

INTRODUCTION: Adults at a high risk of severe influenza, because of their age and/or underlying health disorders, should receive seasonal influenza vaccination in order to reduce the incidence of severe illness and premature death. However, because current influenza vaccines are perceived to have suboptimal efficacy, vaccine coverage is below the recommended level in this population. Areas covered: This review examines, for each high-risk group, available data on influenza infection, vaccine efficacy and safety, and vaccine coverage. We conducted a literature search in the PubMed database to identify randomized controlled trials, observational studies and reviews published from 2000 through 2015 on both seasonal and pandemic influenza. Only studies published in English were considered. While the topic of this review is seasonal influenza, data on pandemics are included when relevant. Expert Commentary: Current seasonal influenza vaccines are only moderately protective, and vaccines eliciting broader and more durable immunity are therefore needed. Research on the use of higher doses, adjuvants, and a universal influenza vaccine is ongoing. Influenza vaccine coverage needs to be increased. Vaccination of contacts of high-risk individuals, including healthcare workers, should be encouraged.

Factors associated with poor outcomes among adults hospitalized for influenza in France: A three-year prospective multicenter study.

BACKGROUND: Influenza is an important cause of serious illness and death, particularly in elderly and high-risk groups. OBJECTIVES: Aim of this study was to identify factors associated with poor outcomes among adults hospitalized in France for laboratory-confirmed seasonal influenza. STUDY DESIGN: Patients hospitalized for influenza were identified in a prospective, multicenter study carried out in French hospitals during three consecutive influenza seasons (2012-2015). Influenza virus infection was confirmed by reverse transcription polymerase chain reaction. Sociodemographic and clinical variables were compared according to the virus type and subtype. Risk factors for complications, intensive care unit (ICU) admission and death were analyzed by backward stepwise logistic regression. RESULTS: The study population consisted of 566 patients, of whom 56% were older than 65 years and 82% had underlying chronic illnesses. Type A influenza viruses infected 422 patients (75%), including subtype H3N2 in 239 patients (57%). The prior vaccine coverage rate was 38%. Complications occurred in 255 patients (45%), consisting mainly of pneumonia (n=143, 30%) and respiratory failure (n=116, 20%). Eighty-three patients (15%) were admitted to an ICU, and the in-hospital mortality rate was 4% (n=21). Sixty-six patients (12%) received oseltamivir. Age over 65 years was the only identified risk factor for complications. Risk factors for ICU admission were an absence of vaccination, no oseltamivir administration before admission, pre-existing chronic respiratory disease, and current smoking. Age over 65 years and ICU admission were risk factors for death. CONCLUSIONS: Older individuals and patients with underlying conditions are most at risk of influenza complications. Vaccination and early oseltamivir administration, both of which are recommended for these patients, appear to reduce ICU admissions.