Aluminum and vaccines: Current state of knowledge.

French people have never been so wary about vaccines. The use of aluminum salts in vaccine adjuvants to enhance effectiveness is one of the major reasons for this lack of confidence. The direct toxicity of aluminum is often put forward. Direct toxicity of aluminum has long been known-especially with occupational exposure-to be associated with characteristic clinical manifestations and increased blood aluminum level. Intoxication related to the excessive amount of an element in the body, whether be it lead poisoning following exposure to lead or mercury poisoning for instance, is always associated with metal increase in biological media. To date no link has been established between the direct toxicity of aluminum and vaccines. Aluminum levels in biological media of vaccinated subjects are not different from those of unvaccinated subjects. This is consistent with the very small amount of aluminum contained in one dose of vaccine. Indirect toxicity of aluminum was suggested to explain macrophagic myofasciitis in humans in 2011, a disease that could be mediated by an autoimmune/autoinflammatory mechanism. This hypothesis has recently been refuted in a large pharmaco-epidemiological study proving that aluminum-containing adjuvants of vaccines are not responsible for this autoimmune/autoinflammatory syndrome.

Determination of rubella virus-specific humoral and cell-mediated immunity in pregnant women with negative or equivocal rubella-specific IgG in routine screening.

BACKGROUND: Immunity to rubella-virus (RV) is commonly determined by measuring specific IgG (RV-IgG). However, RV-IgG results may be different and even discordant, depending on the assay used. Cell-mediated immunity is not routinely investigated for diagnostic purposes. OBJECTIVES: Our aim was to investigate humoral and cellular immunity of women with negative or equivocal RV-IgG before, and after post-partum vaccination. STUDY DESIGN: A total of 186 pregnant women were included in the study. During pregnancy, humoral immunity was investigated with two RV-IgG immunoassays, an immunoblot and a T-cell mediated immunity test. In the post-partum vaccination period, measuring RV-IgM and RV-IgG avidity allowed us to determine whether women raised a primary or a secondary immune response. RESULTS: Before vaccination, 52.2% women, supposed to be susceptible, had positive anti-E1 RV-IgG indicating strong evidence of previous exposure to RV. All (100%) pregant women who had a positive immunoblot before immunization raised a secondary immune response to vaccination, and 96.8% who had a negative immunoblot before immunization, raised a primary immune response to vaccination. All women who raised a primary immune response after vaccination had negative anti-E1 RV-IgG and negative cell-mediated immunity. DISCUSSION: These results indicate that individuals can have evidence of protective immunity against rubella despite negative RV-IgG.

A 2-year study on cytomegalovirus infection during pregnancy in a French hospital.

OBJECTIVES: To evaluate the proportion of pregnant women agreeing to cytomegalovirus (CMV) serologic screening. To collect data on CMV infection during pregnancy. DESIGN: Prospective study. SETTING: During two years, all pregnant women were informed on CMV infection. If the patient agreed, serological testing was performed around 12 weeks of gestation (WG) and, if negative, redone around 36 WG. POPULATION: Four thousand two hundred and eighty-seven pregnant women followed from 12 weeks to delivery. METHODS: If the first CMV serologic test was negative, detailed hygiene information was given to the parents. Diagnosis of primary infection was based on the detection of CMV-G, CMV-M and low CMV-G avidity index. When maternal infection was confirmed, diagnosis of CMV congenital infection was done in the newborns by urine culture within the three days following birth. Crude infection-rate data consisted of the number of CMV infection cases and person-time units for both exposed to hygiene CMV information (12 to 36 WG) and unexposed pregnant women (first 12 WG). MAIN OUTCOME MEASURES: Rate of CMV seropositive and seronegative women. Rate of women agreeing for screening. Rate of primary infection. Rate of seroconversion. Number of CMV-infected newborns. RESULTS: Among the 4287 women followed, 3792 were either seronegative or with an unknown immune status. 96.7% out of them agreed for screening. 53.2% were initially CMV-specific IgG negative. Primary infection was detected in nine women between 0 and 12 WG (0.46%) and seroconversion was diagnosed in five women between 12 and 36 WG (0.26%) (mid P = 0.02, 95% CI [1.07-13.6]). CONCLUSIONS: If clear information on CMV infection during pregnancy is given, patients frequently agree to screening. The rate of seroconversion after information, observed in this study, is low after counselling.

Multicenter evaluation of a rapid and convenient method for determination of cytomegalovirus immunoglobulin G avidity.

An easy, rapid, and reproducible test to distinguish residual cytomegalovirus (CMV) immunoglobulin M (IgM) antibodies from antibodies produced in primary infection could be useful, especially for pregnant women. The CMV avidity of IgG antibodies with the VIDAS automated enzyme-linked fluorescent assay and 6 M urea was evaluated in a multicenter study to differentiate between primary CMV infections and past infections or reactivations. A total of 416 serum specimens were tested: 159 specimens were from follow-up of primary infections, and 257 were from past infections. All of the specimens from primary infections collected within 4 months (17 weeks) after the onset of the infection had an avidity index lower than 0.8. An avidity index higher than 0.8 excludes a recent primary infection of less than 4 months. However, an avidity index higher than 0.8 cannot confirm all past infections, since 48 specimens (18%) from past infections had an avidity index lower than 0.8 (between 0.5 and 0.8). The exclusion capacity could be improved (96.9%) by using a cutoff of 0.7, but this index would decrease the specificity of the technique, since the avidity index was found to be between 0.7 and 0.8 in two patients with recent primary infection. All specimens from primary infections obtained more than 4 months after the onset of infection had an avidity index more than 0.2. In this study, an avidity index less than 0.2 confirms the presence of a recent primary infection of less than 4 months. The VIDAS CMV IgG avidity test is a rapid, reproducible test with very good performance.

Plasma levels of soluble tumor necrosis factor receptors p55 and p75 in patients with alcoholic liver disease of increasing severity.

BACKGROUND/AIMS: Correlations between serum levels of soluble tumor necrosis factor receptors p55 (TNFsRp55) and Child Pugh index have previously been reported in alcoholic patients with cirrhosis. We have undertaken this study to improve understanding of the role of tumor necrosis factor soluble receptors (TNFsRs) in alcoholic liver disease. METHODS: One hundred and two patients with alcoholic liver disease of various severity (23 pure steatosis, 22 fibrosis, seven acute alcoholic hepatitis without cirrhosis, 12 cirrhosis without acute alcoholic hepatitis, 14 cirrhosis with mild acute alcoholic hepatitis and 24 cirrhosis with severe acute alcoholic hepatitis) were studied. Blood was collected on EDTA and plasma was tested for TNFsR concentrations using ELISA assays. RESULTS: Plasma levels of TNFsRp55 and p75 increased progressively with the severity of liver disease, reaching a maximum in cirrhotic patients with severe acute alcoholic hepatitis. Plasma levels of TNFsRp55 in patients with fibrosis and of TNFsRp75 in patients with acute alcoholic hepatitis without cirrhosis were already higher than in healthy controls. In cirrhotic patients with or without acute alcoholic hepatitis TNFsRp55 and p75 were significantly increased compared with controls. In cirrhotic patients, plasma levels of TNFsRp55 correlated positively with all parameters of liver injury, whereas the TNFsRp75/ TNFsRp55 ratio correlated negatively. In cirrhotic patients with severe acute alcoholic hepatitis, the TNFsRp75/TNFsRp55 ratio was significantly lower than in all other groups. In cirrhotic patients with severe acute alcoholic hepatitis treated by prednisolone, the decrease in TNFsRp55 plasma levels between day 1 and day 15 was significantly more important in patients still alive at 2 months than in patients who died within 2 months. CONCLUSIONS: These results show that the expression of TNF-soluble receptors (TNFsRs) participates in the early phases of the alcoholic liver disease and that the TNFsRp75/TNFsRp55 ratio and plasma levels of TNFsRp55 may help to determine the diagnosis and the prognosis of severe acute alcoholic hepatitis in cirrhotics.

Should we routinely screen for cytomegalovirus antibody during pregnancy?

In order to evaluate the usefulness of cytomegalovirus (CMV) antibody screening during pregnancy, women attending for antenatal care at the Antoine Béclère Hospital (Clamart, France) were prospectively studied during 22 months (1995-1996). Forty-five percent of these women were CMV-seropositive. Twenty suspected or confirmed CMV primary infections were detected. Nine infected infants were born to these women. All infected infants are now between 10 months and 2.5 years old. They all are asymptomatic even those who initially presented abnormal biological parameters or slightly abnormal ultrasound scans during fetal life. Presently, screening for CMV antibody cannot be recommended because it induces economic, psychological and ethical problems. Furthermore, there is no efficient and safe treatment available so far. However, we do think that large studies must be performed to increase our knowledge about the natural history of intrauterine CMV infection. This is also important for an improved assessment of the value of ultrasound examination results as well as the biological parameters measured in fetal blood samples.

Interleukin-1 receptor antagonist plasma concentration is specifically increased by alpha-2A-interferon treatment.

BACKGROUND/AIMS: The mechanism of action of recombinant interferon-alpha (rIFN alpha) treatment in chronic hepatitis C is not fully understood, and may include modulation of the immune system as well as a direct antiviral effect. We have therefore evaluated the plasma concentrations of pro- and anti-inflammatory cytokines in patients with chronic hepatitis C before and during treatment with rIFN alpha. METHODS: Twenty-three patients were studied. Plasma concentrations of IL-1 beta, IL-6, TNF, IL-1 receptor antagonist (IL-1RA) and soluble TNF receptors (sTNFRs) type I and type II were determined twice before rIFN alpha treatment (on day -11 and day 1), and on days 11, 32 and 120 of treatment. RESULTS: IL-1 beta, IL-6 and TNF plasma concentrations were rarely increased before treatment (in one, six and seven patients, respectively), and usually declined during treatment. sTNFRs I and II plasma concentrations were not increased either before or during treatment. This was not the case for IL-1RA. In untreated patients, the plasma concentration of IL-1RA was higher than normal in 16 out of 23 patients. When rIFN alpha treatment was initiated, there was a constant and dramatic increase in IL-1RA levels, which reached 8 times the upper limit of the normal range (p < 0.001 as compared to pretreatment values). This increase was sustained up to day 120. CONCLUSIONS: These results indicate that induction of an anti-inflammatory status through modulation of the IL-1/IL-1RA balance may be a key mechanism of action of rIFN alpha treatment in chronic hepatitis C.

Evaluation of a new enzyme immunoassay based on recombinant Rubella virus-like particles for detection of immunoglobulin M antibodies to Rubella virus.

A new enzyme immunoassay for the detection of specific antibodies to rubella virus was evaluated at two different sites. This assay, the Roche Cobas Core Rubella IgM EIA recomb, uses a recombinant rubella virus-like particle and is based upon the immunoglobulin M (IgM) capture principle. It was compared to the Abbott IMx Rubella IgM test and to the Sorin ETI-RUBEK-M reverse test. The relative clinical specificities were 99.30% for the Roche test, 98.26% for the Abbott test, and 100% for the Sorin test. The relative clinical sensitivities were 100, 93.87, and 82.65%, respectively. In the case of most primary infections, IgM antibodies could be detected immediately at the onset of the disease and for up to 7 weeks. In the case of vaccinations, they could be detected between 3 and 12 weeks after vaccination.

In vivo role of IL-6 on the viral load and on immunological abnormalities of HIV-infected patients.

In vitro experiments have suggested that interleukin (IL)-6 may contribute to human immunodeficiency virus (HIV) burden and to immunological abnormalities in HIV-infected patients. We had the opportunity to directly address this question in vivo through the virological and immunological monitoring of HIV-infected patients treated with an anti-IL-6 monoclonal antibody (mAb) for a lymphoma (ANRS 018 trial). Sixteen courses of anti-IL-6 mAb administration, performed in 11 patients, were studied. All patients were at a late stage of HIV infection. The HIV load and the immunological status were determined at the initiation of each course and at its end, 21 days later. The mAb induced no significant change of HIV load, as evaluated by p24 antigenemia, plasma viremia, and quantification of circulating HIV RNA by reverse transcriptase-polymerase chain reaction and branched DNA techniques. The anti-IL-6 mAb also did not affect CD4+, CD8+, and CD19+ circulating cell counts, nor the serum concentrations of sIL-2R and of sCD8. In contrast, the mAb completely abrogated acute-phase reaction, as demonstrated by the normalization of C-reactive protein and fibrinogen circulating levels (p = 0.013 and p = 0.008, respectively). It increased serum albumin concentration. The latter effect was restricted to patients with a spontaneously low albuminemia (p = 0.01). It decreased B-lymphocyte hyperactivity, as reflected by decreased IgG and IgA serum levels (p = 0.008 and p < 0.001, respectively), and by a decreased production of IgG in vitro (p = 0.017). In contrast, the IgM hyperproduction was not affected by the mAb. Therefore, increased IL-6 production in HIV-infected patients at a late stage of the infection may not stimulate HIV replication in vivo, but it may represent a key mechanism contributing to the metabolic and immunological dysbalance of the disease.

Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension.

Primary pulmonary hypertension (PPH) is characterized by the proliferation of smooth-muscle cells, fibroblasts, and endothelial cells in the walls of small pulmonary arteries. In order to evaluate a role for proinflammatory cytokines in this process, we studied the concentration of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the serum of 29 patients with severe PPH referred to our center for lung transplantation. Results were compared with those obtained in 15 normal controls and nine patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD-PH). TNF alpha serum levels were within the normal range in each group. This contrasted with increased IL-1 beta serum levels in severe PPH (118 +/- 36 pg/ml, mean +/- SEM) as compared with controls (3 +/- 1 pg/ml, p < 0.001) or COPD-PH patients (3 +/- 1 pg/ml, p < 0.001). IL-6 serum concentrations were also higher in severe PPH (66 +/- 20 pg/ml) than in controls (14 +/- 6 pg/ml, p < 0.01). This study demonstrates increased serum levels of IL-1 beta and IL-6 in severe PPH, and suggests a role for proinflammatory cytokines in PPH.

Rapid and constant detection of HIV antibody response in saliva of HIV-infected patients; selective distribution of anti-HIV activity in the IgG isotype.

Anti-HIV antibodies can be specifically detected with a sensitivity and a specificity of 100% in the saliva of all HIV-infected patients. A saliva collection device facilitates the sampling procedure, and if a rapid test is used, the diagnosis of infection can be established in as little as 10 min. The analysis of a group of CDC stage IV AIDS patients showed a decrease in lactoferrin (produced by the oral mucosa) in comparison with HIV-negative controls, associated with an increase in albumin (filtering from plasma), indicating an alteration of the mucosal barrier. The salivary anti-HIV-gp160 activity was largely carried by the IgG isotype whereas the salivary antibacterial activity (anti-Streptococcus sobrinus; anti-LPS from Escherichia coli) remained located in the IgA isotype as usually observed with all infectious agents. Salivary IgG carried a specific anti-gp160 activity 25-fold higher than that of serum IgG. Thus, significant local synthesis of specific IgG by oral mucosa was revealed as a characteristic of HIV infection.