The nanomedicines alliance: an industry perspective on nanomedicines.

The field of nanomedicines has expanded significantly in recent years in the breadth of compounds under development as well as in the types of technology that are being applied to generate nanomedicines. The pathway to licensure of new nanomedicines is sufficiently well defined by existing regulations and guidance. The future of nanomedicines requires collaboration between industry and regulatory agencies to ensure that safe and effective nanomedicines emerge from this field. FROM THE CLINICAL EDITOR: With the expansion of translational nanomedicine research, the "last steps" of translation, such as making sure all regulatory approvals are met, the availability of appropriate larger-scale production technologies, are becoming critically important. This review provides a perspective from the biomedical and pharmaceutical industry on the above issues.

Development of a nanoparticle-based influenza vaccine using the PRINT technology.

Historically it is known that presentation of vaccine antigens in particulate form, for a wide range of pathogens, has clear advantages over the presentation of soluble antigen alone [J.C. Aguilar, E.G. Rodriguez, Vaccine adjuvants revisited. Vaccine 25 (2007) 3752-3762, M. Singh, D. O'Hagan, Advances in vaccine adjuvants. Nature Biotechnology 17 (1999) 1075-1081]. Herein we describe a novel particle-based approach, which independently controls size, shape, and composition to control the delivery and presentation of vaccine antigen to the immune system. Highly uniform particles were produced using a particle molding technology called PRINT (Particle Replication in Non-wetting Templates) which is an off-shoot of imprint lithography [J Am Chem Soc 127 (2005) 10096-10100, J Am Chem Soc 126 (2004) 2322-2323, Chem Soc Rev 35 (2006) 1095-1104, J Am Chem Soc 130 (2008) 5008-5009, J Am Chem Soc 130 (2008) 5438-5439, Polymer Reviews 47 (2007) 321-327, Acc Chem Res 41 (2008) 1685-1695, Acc Chem Res 44 (10) (2011) 990-998]. Cylindrical (diameter [d]=80 nm, height [h]=320 nm) poly (lactide-co-glycolide) (PLGA) based PRINT particles were designed to electrostatically bind commercial trivalent injectable influenza vaccine. In a variety of blended PLGA formulations, these particles were safe and showed enhanced responses to influenza hemagglutinin in murine models. FROM THE CLINICAL EDITOR: Shape is one of the determining factors in interactions of nanoparticles with their biologic environment. PRINT technology is able to fabricate nearly uniform nanoparticles and this technology is tested here in murine models to effectively deliver influenza vaccine.

Evaluation of the Safety, Tolerability and Immunogenicity of ShigETEC, an Oral Live Attenuated Shigella-ETEC Vaccine in Placebo-Controlled Randomized Phase 1 Trial.

BACKGROUND: Shigella spp. and enterotoxigenic Escherichia coli (ETEC) cause high morbidity and mortality worldwide, yet no licensed vaccines are available to prevent corresponding infections. A live attenuated non-invasive Shigella vaccine strain lacking LPS O-antigen and expressing the ETEC toxoids, named ShigETEC was characterized previously in non-clinical studies. METHODS: ShigETEC was evaluated in a two-staged, randomized, double-blind and placebo-controlled Phase I clinical trial. A single dose of increasing amounts of the vaccine was given to determine the maximum tolerated dose and increasing number of immunizations were administered with an interval based on the duration of shedding observed. RESULTS: Oral immunization with ShigETEC was well tolerated and safe up to 4-time dosing with 5 × 1010 colony forming units. ShigETEC induced robust systemic immune responses against the Shigella vaccine strain, with IgA serum antibody dominance, as well as mucosal antibody responses evidenced by specific IgA in stool samples and in ALS (Antibodies in Lymphocyte Supernatant). Anti- ETEC toxin responses were detected primarily in the 4-times immunized cohort and for the heat-labile toxin correlated with neutralizing capacity. CONCLUSION: ShigETEC is a promising vaccine candidate that is scheduled for further testing in controlled human challenge studies for efficacy as well as in children in endemic setting for safety and immunogenicity.

Characterization of ShigETEC, a Novel Live Attenuated Combined Vaccine against Shigellae and ETEC.

Background: Shigella spp. and enterotoxigenic Escherichia coli (ETEC) remain the two leading bacterial causes of diarrheal diseases worldwide. Attempts to develop preventive vaccines against Shigella and ETEC have not yet been successful. The major challenge for a broad Shigella vaccine is the serotype-specific immune response to the otherwise protective LPS O-antigen. ETEC vaccines mainly rely on the heat-labile enterotoxin (LT), while heat-stable toxin (ST) has also been shown to be an important virulence factor. Methods: We constructed a combined Shigella and ETEC vaccine (ShigETEC) based on a live attenuated Shigella strain rendered rough and non-invasive with heterologous expression of two ETEC antigens, LTB and a detoxified version of ST (STN12S). This new vaccine strain was characterized and tested for immunogenicity in relevant animal models. Results: Immunization with ShigETEC resulted in serotype independent protection in the mouse lung shigellosis model and induced high titer IgG and IgA antibodies against bacterial lysates, and anti-ETEC toxin antibodies with neutralizing capacity. Conclusions: ShigETEC is a promising oral vaccine candidate against Shigella and ETEC infections and currently in Phase 1 testing.

A novel active respiratory syncytial virus surveillance system in the United States: variability in the local and regional incidence of infection.

BACKGROUND: To characterize the onset, peak, and duration of the RSV season in major metropolitan areas in the United States as determined from laboratory test data collected by a novel RSV surveillance program (RSV Alert), including regional and national trends. METHODS: We prospectively analyzed results of more than 600,000 tests collected weekly during 3 seasons (2004/2005-2006/2007) by the RSV Alert program. More than 200 institutions participated in the first 2 seasons of the program, and more than 600 sites in the third. Data were analyzed for trends in season onset, offset, and duration at the local, regional, and national levels. RESULTS: Considerable variability in season onset and duration was noted between metropolitan areas located geographically within the same region. Seasonal outbreaks of RSV consistently peaked first, concluded earliest, and were of longest duration in the Southern region. The onset of the RSV season occurred latest and peaked last in the Midwest region each season. CONCLUSIONS: The variable nature of outbreaks observed between metropolitan areas located geographically within the same regions of the country is highlighted through data collected for 3 consecutive seasons. The RSV Alert program is a valuable reporting system that provides real-time surveillance data at a city/local level nationwide and has potential to aid clinicians in decisions regarding RSV management.

Post-marketing effectiveness of Prevnar [pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein)] and implications for adult immunization.

Pneumococcal pneumonia is a significant health concern for pediatric, healthy adult, and elderly populations. The newly licensed pneumococcal 7-valent conjugate (diphtheria CRM197 protein) vaccine, Prevnar, and a second generation experimental 9-valent product have demonstrated, for the first time, a clear and significant impact on pneumococcal pneumonia in children. The potential for saccharide-conjugate vaccines to help prevent pneumococcal pneumonia in adult and elderly populations and potential barriers to the introduction of a conjugate vaccine in adults are discussed.

US Military contributions to the global response to pandemic chikungunya.

Chikungunya virus, transmitted by mosquitoes to man, causes an acute illness characterized by fever, rash and striking joint symptoms. US Military investigators developed, manufactured at The Salk Institute-Government Services Division (TSI-GSD), and tested the live, attenuated Chikungunya Vaccine TSI-GSD-218. The manufacturing facility stopped production in 1994. The Chikungunya Vaccine TSI-GSD-218 development effort was terminated in 1998, and materials were archived. In 2005, an alarming outbreak of chikungunya disease began in Africa and spread to islands in the Indian Ocean and throughout much of Asia. Abrupt epidemics with high attack rates and serious, even fatal, complications were reported, and travelers carried the virus to Europe and the Americas. In response to urgent requests, the US Military offered assistance by providing non-exclusive access to the previously stored vaccine production seed materials, bulk vaccine, regulatory documentation, and reports of previous clinical trials. Five companies requested technology transfers. This experience provides lessons about epidemiological unpredictability, preparedness, vaccine manufacturing, the potential global importance of vaccine seed materials and the advisability of a global strategic plan. Consideration should be given to banking of vaccine production seeds, cell substrates, and manufacturing instructions. In view of the manufacturability, attenuation, and immunogenicity of Chikungunya Vaccine TSI-GSD-218, authorities may wish to consider this product as a possible candidate itself, as a comparator vaccine to improve upon, as a seed for inactivated vaccine, or as a source of virus or antigen for neutralization assays or immunoassays.

Efficacy of live attenuated influenza vaccine in children: A meta-analysis of nine randomized clinical trials.

Nine randomized clinical trials, including approximately 25,000 children aged 6-71 months and 2000 children aged 6-17 years, have evaluated the efficacy of live attenuated influenza vaccine (LAIV) against culture-confirmed influenza as compared to placebo or trivalent inactivated vaccine (TIV). We conducted meta-analyses, based on Mantel-Haenszel relative risks from fixed effect models, to provide an estimate of vaccine efficacy (VE). Relative to placebo, year 1 VE for two doses in vaccine-naïve young children was 77% (95% CI: 72%, 80%; P<0.001) against antigenically similar strains and 72% against strains regardless of antigenic similarity. Efficacy was 85%, 76%, and 73% against antigenically similar A/H1N1, A/H3N2, and B, respectively. Year 1 VE of one dose against antigenically similar strains in vaccine-naive children was 60%; efficacy of one dose in previously vaccinated children in year 2 of the various studies was 87%. In head-to-head trials comparing two doses of TIV and LAIV, vaccine-naïve children who received two doses of LAIV experienced 46% fewer cases of influenza illness caused by antigenically similar strains. Similarly, for studies including older children who had been previously vaccinated, those receiving one LAIV dose experienced 35% fewer cases of influenza illness than those receiving one TIV dose. LAIV showed high VE versus placebo with no evidence of difference by age or by circulating subtype. In these studies, LAIV was more effective than TIV.