Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.

Oil-in-water adjuvants have been shown to improve immune responses against pandemic influenza vaccines as well as reduce the effective vaccine dose, increasing the number of doses available to meet global vaccine demand. Here, we use genome fragment phage display libraries and surface plasmon resonance to elucidate the effects of MF59 on the quantity, diversity, specificity, and affinity maturation of human antibody responses to the swine-origin H1N1 vaccine in different age groups. In adults and children, MF59 selectively enhanced antibody responses to the hemagglutinin 1 (HA1) globular head relative to the more conserved HA2 domain in terms of increased antibody titers as well as a more diverse antibody epitope repertoire. Antibody affinity, as inferred by greatly diminished (≥10-fold) off-rate constants, was significantly increased in toddlers and children who received the MF59-adjuvanted vaccine. Moreover, MF59 also improved antibody affinity maturation after each sequential vaccination against avian H5N1 in adults. For both pandemic influenza vaccines, there was a close correlation between serum antibody affinity and virus-neutralizing capacity. Thus, MF59 quantitatively and qualitatively enhances functional antibody responses to HA-based vaccines by improving both epitope breadth and binding affinity, demonstrating the added value of such adjuvants for influenza vaccines.

NCT00630331.

CCIV was well tolerated and highly immunogenic in adults 18 years of age or older. Cell culture may offer greater flexibility of supply during periods of high demand for both seasonal and pandemic vaccines.

Erythromycin resistance rates were found to be increased, from 7.1 in 1993 to 32.8% in 1997, among community-acquired Streptococcus pneumoniae isolates from the Siena area of central Italy. Most of the erythromycin-resistant isolates carried ermAM determinants and were also resistant to josamycin and clindamycin, whereas a minority (5.8%) carried mefA determinants and remained susceptible to the latter drugs.

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Susceptibility to macrolides and lincosamides was investigated with 299 consecutive nonduplicate Streptococcus pyogenes clinical isolates collected over a 6-year period (1992 to 1997) from an area of central Italy. During this period, macrolide resistance rates steadily increased (from 9% in 1992 to 53% in 1997; P < 0.001). The increase was caused by isolates with a macrolide-lincosamide-streptogramin B resistance phenotype, carrying mostly erm(B) but also erm(TR) genes, that were not detected in the first 2 years and were detected with increasing prevalence (8, 5, 26, and 37%, respectively) during the following 4 years. During the same period, the prevalence of isolates with a macrolide resistance phenotype, carrying mef(A) determinants, did not vary significantly; on average it was 13%, with modest rate fluctuations in different years and no definite trend. Molecular typing revealed a remarkable clonal diversity among susceptible and resistant isolates and a notable heterogeneity of the genetic environment of the resistance genes. The analysis of clonal diversity in relation with resistance phenotypes and genotypes revealed that increased macrolide resistance rates were due to a complex interplay of different mechanisms, with a relevant contribution played by an "epidemic" spread of genetic elements carrying the erm(B) gene among the circulating streptococcal population.Streptococcus pyogenes (group A streptococcus) remains one of the leading bacterial pathogens worldwide. Superficial infections caused by group A streptococci, such as pharyngitis and impetigo, are usually mild and self-limiting but ubiquitous and extremely common. On the other hand, the occurrence of severe invasive infections and of nonsuppurative sequelae, although less common, make of S. pyogenes a major public health concern (see reference 3 and references therein).Macrolide antibiotics are among the preferred drugs for the treatment of group A streptococcal pharyngitis and are largely used in community medicine for empirical chemotherapy of respiratory tract infections, due to their clinical efficacy, good compliance, and low toxicity (34). Resistance to macrolides in S. pyogenes can be caused by two different mechanisms: (i) active drug efflux via a transmembrane pump encoded by horizontally acquired mef genes (7, 35) and (ii) modification of the 23S rRNA target by rRNA adenine methylases encoded by horizontally acquired erm genes (see references 19 and 38 and references therein). The Mef efflux system operates only with 14-and 15-membered ring macrolides (M resistance phenotype) (7), while ribosomal modification by Erm methylases prevents the binding of macrolides, lincosamides, and streptogramins B, leading to resistance to all these compounds (MLS resistance phenotype) (19 (19,38,39).Since the first report in the 1950s (20), a large number of epidemiological surveys on macrolide resistance in S. pyogenes have been carried out. Results of these studies overall revealed a remarkable variability of resistance rates at different times and...