Odile Launay

Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial

BACKGROUND Pathogenic avian influenza A virus H5N1 has caused outbreaks in poultry and migratory birds in Asia, Africa, and Europe, and caused disease and death in people. Although person-to-person spread of current H5N1 strains is unlikely, the virus is a potential source of a future influenza pandemic. Our aim was to assess the safety and immunogenicity of a vaccine against the H5N1 strain. METHODS We did a randomised, open-label, non-controlled phase I trial in 300 volunteers aged 18-40 years and assigned one of six inactivated split influenza A/Vietnam/1194/2004 (H5N1) influenza vaccine formulations, comprising 7.5 microg (with adjuvant n=50, without adjuvant n=49), 15 microg (n=50, n=50), or 30 microg (n=51, n=50) of haemagglutinin with or without aluminium hydroxide adjuvant. Individuals received two vaccinations (on days 0 and 21) and provided blood samples (on days 0, 21, and 42) for analysis by haemagglutination inhibition and microneutralisation. We recorded all adverse events. Analyses were descriptive. FINDINGS All formulations were well tolerated, with no serious adverse events, few severe reactions, and no oral temperatures of more than 38 degrees C. All formulations induced an immune response, and responses were detectable in some individuals after only one dose. The adjuvanted 30 microg formulation induced the greatest response (67% haemagglutinin-inhibition seroconversion rate after two vaccinations). Adjuvant did not improve the response to the lower doses. Two vaccinations of non-adjuvanted 7.5 microg, adjuvanted 15 microg, or non-adjuvanted 15 microg seroconverted more than 40% of participants (haemagglutinin-inhibition test only). Haemagglutinin inhibition and neutralising results were comparable. INTERPRETATION A two-dose regimen with an adjuvanted 30 microg inactivated H5N1 vaccine was safe and showed an immune response consistent with European regulatory requirements for licensure of seasonal influenza vaccine. We noted encouraging responses with lower doses of antigen that need further study to ascertain their relevance for the choice of the final pandemic vaccine.

Safety and Immunogenicity of 4 Intramuscular Double Doses and 4 Intradermal Low Doses vs Standard Hepatitis B Vaccine Regimen in Adults With HIV-1 A Randomized Controlled Trial

CONTEXT Alternative schedules more immunogenic than the standard hepatitis B vaccine regimen are needed in patients with human immunodeficiency virus 1 (HIV-1) infection. OBJECTIVE To compare the safety and immunogenicity of 4 intramuscular double-dose and 4 intradermal low-dose regimens vs the standard hepatitis B vaccine regimen. DESIGN, SETTING, AND PARTICIPANTS An open-label, multicenter, 1:1:1 parallel-group, randomized trial conducted between June 28, 2007, and October 23, 2008 (date of last patient visit, July 3, 2009) at 33 centers in France with patients enrolled in French National Agency for Research on AIDS and Viral Hepatitis trials in adults with HIV-1 infection who were hepatitis B virus (HBV) seronegative and having CD4 cell counts of more than 200 cells/μL. INTERVENTION Patients were randomly assigned to receive 3 intramuscular injections of the standard dose (20 μg) of recombinant HBV vaccine at weeks 0, 4, and 24 (IM20 × 3 group, n = 145); 4 intramuscular double doses (40 μg [2 injections of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (IM40 × 4 group, n = 148); or 4 intradermal injections of low doses (4 μg [1/5 of 20 μg]) of recombinant HBV vaccine at weeks 0, 4, 8, and 24 (ID4 × 4 group, n = 144). MAIN OUTCOME MEASURES Percentage of responders at week 28, defined as patients with hepatitis B surface antibody (anti-HBs) of at least 10 mIU/mL in patients who received at least 1 dose of vaccine. Patients with missing anti-HBs titer measurement at the final follow-up visit at week 28 were considered as nonresponders in the primary (efficacy) analysis. RESULTS A total of 437 patients were randomized to the 3 study groups, of whom 11 did not receive any vaccine. Of these, 396 had available anti-HBs titers at week 28. The percentage of responders at week 28 was 65% (95% confidence interval [CI], 56%-72%) in the IM20 × 3 group (n = 91), 82% (95% CI, 77%-88%) in the IM40 × 4 group (n = 119) (P < .001 vs IM20 × 3 group), and 77% (95% CI, 69%-84%) in the ID4 × 4 group (n = 108) (P = .02 vs IM20 × 3 group). No safety signal and no effect on CD4 cell count or viral load were observed. CONCLUSION In adults with HIV-1, both the 4 intramuscular double-dose regimen and the 4 intradermal low-dose regimen improved serological response compared with the standard HBV vaccine regimen. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00480792.

Knowledge, attitudes and vaccination coverage of healthcare workers regarding occupational vaccinations

OBJECTIVES Immunization of healthcare workers (HCWs) is a major issue for infection control in healthcare facilities. The aim of this study was to evaluate knowledge regarding occupational vaccinations, HBV, varicella and influenza vaccination rates and attitudes towards influenza vaccine among HCWs. DESIGN AND SETTING A cross-sectional survey was conducted in two wards (Medicine and Paediatrics) of a 1182-bed teaching hospital in Paris, France. METHODS A standardized, anonymous, self-administered questionnaire was used. RESULTS Of 580 HCWs, 395 (68%) completed the questionnaire. Knowledge about the occupational vaccinations of HCWs was low. HBV (69%), tuberculosis (54%) and influenza (52%) were the most cited vaccinations. Paediatric staff was more aware of influenza and pertussis immunizations (p<.05). HBV vaccination rate was 93%, among whom 65% were aware of their immune status. Influenza vaccination rate for 2006-2007 was 30% overall, ranging from 50% among physicians to 20% among paramedical staff (p<.05). Physicians based their refusal on doubts about vaccine efficacy, although paramedics feared side effects. Influenza vaccination was associated with knowledge of vaccine recommendations [OR=1.75, 95% CI: 1.13-2.57] and contact with patients [OR=3.05, 95% CI: 1.50-5.91]. CONCLUSIONS Knowledge of recommended occupational vaccinations is insufficient in HCWs, except for HBV and influenza. Although the HBV vaccine coverage of HCWs is satisfactory, a large proportion of them is unaware of immune status. Influenza vaccine coverage remains low, especially among paramedical staff because of fear of side effects. As vaccine coverage is associated with knowledge, educational campaigns should be strengthened to increase the adhesion of HCWs to vaccinations.

Gag Mutations Strongly Contribute to HIV-1 Resistance to Protease Inhibitors in Highly Drug-Experienced Patients besides Compensating for Fitness Loss

Human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors (PI) results from mutations in the viral protease (PR) that reduce PI binding but also decrease viral replicative capacity (RC). Additional mutations compensating for the RC loss subsequently accumulate within PR and in Gag substrate cleavage sites. We examined the respective contribution of mutations in PR and Gag to PI resistance and RC and their interdependence using a panel of HIV-1 molecular clones carrying different sequences from six patients who had failed multiple lines of treatment. Mutations in Gag strongly and directly contributed to PI resistance besides compensating for fitness loss. This effect was essentially carried by the C-terminal region of Gag (containing NC-SP2-p6) with little or no contribution from MA, CA, and SP1. The effect of Gag on resistance depended on the presence of cleavage site mutations A431V or I437V in NC-SP2-p6 and correlated with processing of the NC/SP2 cleavage site. By contrast, reverting the A431V or I437V mutation in these highly evolved sequences had little effect on RC. Mutations in the NC-SP2-p6 region of Gag can be dually selected as compensatory and as direct PI resistance mutations, with cleavage at the NC-SP2 site behaving as a rate-limiting step in PI resistance. Further compensatory mutations render viral RC independent of the A431V or I437V mutations while their effect on resistance persists.

Respiratory Syncytial Virus and Other Respiratory Viral Infections in Older Adults With Moderate to Severe Influenza-like Illness

Abstract Background. Few studies have prospectively assessed viral etiologies of acute respiratory infections in community-based elderly individuals. We assessed viral respiratory pathogens in individuals ≥65 years with influenza-like illness (ILI). Methods. Multiplex reverse-transcriptase polymerase chain reaction identified viral pathogens in nasal/throat swabs from 556 episodes of moderate-to-severe ILI, defined as ILI with pneumonia, hospitalization, or maximum daily influenza symptom severity score (ISS) >2. Cases were selected from a randomized trial of an adjuvanted vs nonadjuvanted influenza vaccine conducted in elderly adults from 15 countries. Results. Respiratory syncytial virus (RSV) was detected in 7.4% (41/556) moderate-to-severe ILI episodes in elderly adults. Most (39/41) were single infections. There was a significant association between country and RSV detection (P = .004). RSV prevalence was 7.1% (2/28) in ILI with pneumonia, 12.5% (8/64) in ILI with hospitalization, and 6.7% (32/480) in ILI with maximum ISS > 2. Any virus was detected in 320/556 (57.6%) ILI episodes: influenza A (104/556, 18.7%), rhinovirus/enterovirus (82/556, 14.7%), coronavirus and human metapneumovirus (each 32/556, 5.6%). Conclusions. This first global study providing data on RSV disease in ≥65 year-olds confirms that RSV is an important respiratory pathogen in the elderly. Preventative measures such as vaccination could decrease severe respiratory illnesses and complications in the elderly.

AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial

BACKGROUND We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. METHODS We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65-74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. FINDINGS We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12-1·43] of 21 573 vs 310 [1·44%, 1·29-1·61] of 21 482; relative efficacy 12·11%, 95% CI -3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91-1·18] vs 270 [1·26, 1·11-1·41]; relative efficacy 17·53%, 95% CI 1·55-30·92) and influenza A H3N2 (170 [0·79, 0·67-0·92] vs 205 [0·95, 0·83-1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68-35·49). INTERPRETATION AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. FUNDING GlaxoSmithKline Biologicals SA.

Patient perspective on herpes zoster and its complications: an observational prospective study in patients aged over 50 years in general practice.

Summary Despite early diagnosis and treatment with antiviral agents, many herpes zoster patients report persistent pain and marked long‐term reduction in health‐related quality of life. Abstract Understanding the effect of herpes zoster and zoster‐related pain should inform care to improve health‐related quality of life in elderly patients. A 12‐month, longitudinal, prospective, multicenter observational study conducted in primary care in France enrolled patients aged ⩾50 years with acute eruptive herpes zoster. Patient‐reported zoster‐related pain was assessed by validated questionnaires (Douleur Neuropathique en 4 Questions [DN4], Zoster Brief Pain Inventory [ZBPI], and Neuropathic Pain Symptom Inventory [NPSI]) on days 0 and 15, and at months 1, 3, 6, 9, and 12. Health‐related quality of life was assessed by the 12‐item short‐form health survey (SF‐12) and the Hospital Anxiety and Depression scale on day 0 and at months 3, 6, and 12. Of 1358 patients included, 1032 completed follow‐up. Mean ± standard deviation age was 67.7 ± 10.7 (range, 50–95) years; 62.2% were women. Most patients (94.1%) were prescribed antiviral drugs. The prevalence of zoster‐related pain on day 0 and at months 3, 6, 9, and 12 was 79.6%, 11.6%, 8.5%, 7.4%, and 6.0%, respectively. Patients with persistent pain had lower scores on the physical and mental component summaries of the SF‐12 and the ZBPI interference score than those without pain. By logistic regression analysis, main predictive factors on day 0 for postherpetic neuralgia at month 3 were age, male sex, ZBPI interference score, Physical Component Summary score of the SF‐12, and neuropathic quality of pain (DN4 score ⩾4). Despite early diagnosis and treatment with antiviral agents, many patients with herpes zoster experience persistent pain and marked long‐term reduction in health‐related quality of life.

Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients

Objective: To characterise major infectious complications and analyse potential risk factors in patients with Wegener granulomatosis (WG). Methods: Data from 113 patients with WG (69 male) followed at least once between January 1984 and March 2006 in our internal medicine department, were analysed retrospectively. Results: A total of 35 patients (mean (SD) age at WG diagnosis: 50.2 (13.05) years) developed 53 major infections. Infections were: bronchopneumonias (n = 19), herpes zoster recurrences (n = 9), cellulitis (n = 4), prostatitis (n = 4), spondylodiscitis and septic arthritis (n = 3), digestive tract infections (n = 2), Enterococcus faecalis or Staphylococcus aureus septicaemia (n = 2), viral hepatitis B reactivations (n = 2), post transfusion HIV infection with fatal cerebral toxoplasmosis, oesophageal candidiasis, disseminated herpes simplex and cytomegalovirus infection, cytomegalovirus retinitis, herpetic keratitis, herpetic stomatitis, Serratia sp. node suppuration and fever resolving under broad spectrum antibiotics (n = 1 each). Half of the major infectious episodes occurred within 3 years after WG diagnosis. Eight (7%) patients died, with two (2%) infection-related deaths. Patients diagnosed with WG before 1996 had a significantly higher rate of infection than those diagnosed later (48% vs 24%, p = 0.02). Cyclophosphamide and corticosteroids were independently associated with significantly higher risk of major infection (p<0.05 and <0.001, respectively). All patients treated since 1993 received antipneumocystosis prophylaxis. Conclusion: Cyclophosphamide and corticosteroids were associated with higher risk of infection. Despite systematic cotrimoxazole prophylaxis, major infections, mostly bronchopneumonias and herpes zoster recurrences, were still common in the course of WG.

French experience of 2009 A/H1N1v influenza in pregnant women.

Background The first reports on the pandemic influenza 2009 A/H1N1v from the USA, Mexico, and Australia indicated that this disease was associated with a high mortality in pregnant women. The aim of this study was to describe and compare the characteristics of severe critically ill and non-severe pregnant women with 2009 A/H1N1v-related illness in France. Methodology/Principal Findings A national registry was created to screen pregnant women with laboratory-confirmed 2009 A/H1N1v influenza. Three hundred and fifteen patients from 46 French hospitals were included: 40 patients were admitted to intensive care units (severe outcomes), 111 were hospitalized in obstetric or medical wards (moderate outcomes), and 164 were outpatients (mild outcomes). The 2009 A/H1N1v influenza illness occurred during all pregnancy trimesters, but most women (54%), notably the severe patients (70%), were in the third trimester. Among the severe patients, twenty (50%) underwent mechanical ventilation, and eleven (28%) were treated with extracorporeal membrane oxygenation. Three women died from A/H1N1v influenza. We found a strong association between the development of a severe outcome and both co-existing illnesses (adjusted odds ratio [OR], 5.1; 95% confidence interval [CI], 2.2–11.8) and a delay in oseltamivir treatment after the onset of symptoms (>3 or 5 days) (adjusted OR, 4.8; 95% CI, 1.9–12.1 and 61.2, 95% CI; 14.4–261.3, respectively). Among the 140 deliveries after 22 weeks of gestation known to date, 19 neonates (14%) were admitted to a neonatal intensive care unit, mainly for preterm delivery, and two neonates died. None of these neonates developed 2009 A/H1N1v infection. Conclusions This series confirms the high incidence of complications in pregnant women infected with pandemic A/H1N1v observed in other countries but depicts a lower overall maternal and neonatal mortality and morbidity than indicated in the USA or Australia. Moreover, our data demonstrate the benefit of early oseltamivir treatment in this specific population.

Cryptococcal Neuroradiological Lesions Correlate with Severity during Cryptococcal Meningoencephalitis in HIV-Positive Patients in the HAART Era

Cryptococcal meningoencephalitis has an overall global mortality rate of 20% in AIDS patients despite antifungals. There is a need for additional means of precise assessment of disease severity. We thus studied the radiological brain images available from 62 HIV-positive patients with cryptococcocal meningoencephalitis to analyse the brain lesions associated with cryptococcosis in relationship with disease severity, and the respective diagnostic contribution of magnetic resonance (MR) versus computed tomography (CT). In this retrospective multicenter analysis, two neuroradiologists blindly reviewed the brain imaging. Prospectively acquired clinical and mycological data were available at baseline and during follow-up. Baseline images were abnormal on 92% of the MR scans contrasting with 53% of the CT scans. MR/CT cryptococcosis-related lesions included mass(es) (21%/9%), dilated perivascular spaces (46%/5%) and pseudocysts (8%/4%). The presence compared to absence of cryptococcosis-related lesions was significantly associated with high serum (78% vs. 42%, p = 0.008) and CSF (81% vs. 50%, p = 0.024) antigen titers, independently of neurological abnormalities. MR detected significantly more cryptococcosis-related lesions than CT for 17 patients who had had both investigations (76% vs. 24%, p = 0.005). In conclusion, MR appears more effective than CT for the evaluation of AIDS-associated cerebral cryptococcosis. Furthermore, brain imaging is an effective tool to assess the initial disease severity in this setting. Given this, we suggest that investigation for cryptococcosis-related lesions is merited, even in the absence of neurological abnormality, if a high fungal burden is suspected on the basis of high serum and/or CSF antigen titers.