Safety, tolerability and immunogenicity of a novel 24-valent pneumococcal vaccine in toddlers: A phase 1 randomized controlled trial.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) significantly reduced pneumococcal disease burden. Nevertheless, alternative approaches for controlling more serotypes are needed. Here, the safety, tolerability, and immunogenicity of a 24-valent (1/2/3/4/5/6A/6B/7F/8/9N/9V/10A/11A/12F/14/15B/17F/18C/19A/19F/20B/22F/23F/33F) pneumococcal vaccine based on Multiple Antigen-Presenting System (MAPS) technology (Pn-MAPS24v) was assessed in toddlers. METHODS: In this phase 1, blinded, dose-escalation, active-controlled multicenter study conducted in the United States (September/2020-April/2022), 12-15-month-old toddlers primed with three doses of 13-valent PCV (PCV13) were randomized 3:2 to receive a single dose of one of three Pn-MAPS24v dose levels (1 µg/2 µg/5 µg per polysaccharide) or PCV13 intramuscularly. Reactogenicity (within 7 days), treatment-emergent adverse events (TEAEs, within 180 days), serious/medically attended adverse events (SAEs/MAAEs, within 180 days), and immunogenicity (serotype-specific anti-capsular polysaccharide immunoglobulin G [IgG] and opsonophagocytic activity [OPA] responses at 30 days post-vaccination) were assessed. RESULTS: Of 75 toddlers enrolled, 74 completed the study (Pn-MAPS24v 1 µg/2 µg/5 µg: 15/14/16, PCV13: 29). Frequencies of local (60 %/67 %/31 %) and systemic events (67 %/67 %/75 %) in the Pn-MAPS24v 1 µg/2 µg/5 µg and the PCV13 (55 %, 79 %) groups were in similar ranges. TEAEs were reported by 47 %/40 %/63 % of Pn-MAPS24v 1 µg/2 µg/5 µg recipients and 52 % of PCV13 recipients. No vaccine-related SAE was reported. At 30 days post-vaccination, for each of the 13 common serotypes, ≥93 % of participants in each group had IgG concentrations ≥0.35 µg/mL; >92 % had OPA titers ≥lower limit of quantitation (LLOQ), except for serotype 1 (79 %). For 7/11 unique serotypes (2/8/9N/11A/17F/22F/33F), at all dose levels, ≥78 % of Pn-MAPS24v recipients in each group had IgG concentrations ≥0.35 µg/mL and 80 %-100 % had OPA titers ≥LLOQ. CONCLUSIONS: In 12-15-month-old toddlers, a single dose of Pn-MAPS24v showed an acceptable safety profile, regardless of dose level; AEs were reported at similar frequencies by Pn-MAPS24v and PCV13 recipients. Pn-MAPS24v elicited IgG and OPA responses to all common and most unique serotypes. These results support further clinical evaluation in infants.

Phase 1/2 study of a novel 24-valent pneumococcal vaccine in healthy adults aged 18 to 64 years and in older adults aged 65 to 85 years.

BACKGROUND: Pneumococcal diseases remain prevalent despite available polysaccharide and conjugate vaccines. This phase 1/2 study evaluated safety/tolerability and immunogenicity of a novel 24-valent pneumococcal vaccine (ASP3772) based on high-affinity complexing of proteins and polysaccharides. METHODS: Pneumococcal vaccine-naïve adults aged 18-85 years were randomized to receive either ASP3772 or PCV13 (13-valent conjugate vaccine). Participants received a single intramuscular injection of ASP3772 (1-, 2-, or 5-µg dose per polysaccharide) or PCV13. A separate, nonrandomized group of PCV13-vaccinated participants (65-85 years) received PPSV23 (23-valent polysaccharide vaccine). Assessments were obtained through Day 7 for reactogenicity, through Day 30 for safety and tolerability, and through Month 6 for serious adverse events. Immunogenicity was measured at Day 30 using assays for functional opsonophagocytic activity (OPA) and pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G for each serotype. RESULTS: In both age cohorts, the most frequently reported local reactions were self-limited tenderness and pain after ASP3772 at all dose levels or after PCV13, occurring within 2-3 days. Fatigue, headache, and myalgia were the most frequently reported systemic reactions following either vaccine. Robust OPA responses for all serotypes were observed across all ASP3772 dose groups in both age cohorts. Older adults (aged 65-85 years) who received ASP3772 had significantly higher immune responses to several PCV13 serotypes and all non-PCV13 serotypes than participants who received PCV13. OPA responses to the ASP3772 5-µg dose were significantly higher for several serotypes in naïve participants than in older adults with prior exposure to PCV13 who were administered PPSV23 in this study. CONCLUSIONS: These results demonstrate that ASP3772 is well tolerated, highly immunogenic, and in adults may offer significantly broader protection than existing pneumococcal vaccines. CLINICALTRIALS: gov: NCT03803202.

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.

Summary report of PQRI Workshop on Nanomaterial in Drug Products: current experience and management of potential risks.

At the Product Quality Research Institute (PQRI) Workshop held last January 14-15, 2014, participants from academia, industry, and governmental agencies involved in the development and regulation of nanomedicines discussed the current state of characterization, formulation development, manufacturing, and nonclinical safety evaluation of nanomaterial-containing drug products for human use. The workshop discussions identified areas where additional understanding of material attributes, absorption, biodistribution, cellular and tissue uptake, and disposition of nanosized particles would continue to inform their safe use in drug products. Analytical techniques and methods used for in vitro characterization and stability testing of formulations containing nanomaterials were discussed, along with their advantages and limitations. Areas where additional regulatory guidance and material characterization standards would help in the development and approval of nanomedicines were explored. Representatives from the US Food and Drug Administration (USFDA), Health Canada, and European Medicines Agency (EMA) presented information about the diversity of nanomaterials in approved and newly developed drug products. USFDA, Health Canada, and EMA regulators discussed the applicability of current regulatory policies in presentations and open discussion. Information contained in several of the recent EMA reflection papers was discussed in detail, along with their scope and intent to enhance scientific understanding about disposition, efficacy, and safety of nanomaterials introduced in vivo and regulatory requirements for testing and market authorization. Opportunities for interaction with regulatory agencies during the lifecycle of nanomedicines were also addressed at the meeting. This is a summary of the workshop presentations and discussions, including considerations for future regulatory guidance on drug products containing nanomaterials.

Engineered PRINT(®) nanoparticles for controlled delivery of antigens and immunostimulants.

Particle replication in non-wetting templates (PRINT) is a novel nanoparticle platform that provides compositional flexibility with the ability to specify size and shape in formulating vaccines. The PRINT platform also offers manufacturing and cost advantages over traditional particle technologies. Across multiple antigen and adjuvant formulations, robust antibody and cellular responses have been achieved using PRINT particles in mouse models. Preclinical studies applying PRINT technology in the disease areas of influenza, malaria, and pneumonia are described in this commentary. The proof of principle studies pave the way toward significant cost-effective solutions to global vaccine supply needs.

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.

Parenteral nutrition prescribing pattern: a medical chart review of 191 preterm infants.

BACKGROUND: In 2005, the European Society for Clinical Nutrition and Metabolism released guidelines for the use of pediatric parenteral nutrition (PN). The purpose of this study was to compare PN prescribing patterns in preterm infants with current guideline recommendations. MATERIALS AND METHODS: Six neonatologists in Germany conducted observational, retrospective medical chart reviews on preterm infants <28 days postnatal, hospitalized from October 2009 to April 2011. Infants with a complete medical record who received PN for a minimum of 4 days were enrolled. Patient weight and the change in daily amino acids and intravenous fat emulsion (IVFE) doses administered for the first 7 days of life were abstracted. Median data were used to determine quartiles to compare study results with the current guidelines. RESULTS: Only 30% of patients met current guidelines that recommend all preterm infants receive amino acids on the first day of life. When amino acids were given, the dose was lower than recommended in the current guidelines. The start of IVFE by day 3 of life was given only to 34% of patients despite the guideline recommendation of 100%. CONCLUSION: This study identified several gaps between the current guidelines and patient care that should be explored further.

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.

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.

Influenza vaccination with a live attenuated vaccine.

Influenza is a highly contagious, acute respiratory illness with a long history of outbreaks dating back several centuries. Although immunization is an effective means of protection against influenza, vaccination rates have been suboptimal, especially among certain high-risk groups, including children and health care personnel. This article reviews basic information about influenza and immunization, discusses the relevance of children as vectors of disease, and highlights current information on FluMist, an intranasally administered, live attenuated influenza vaccine, including studies of its use compared with trivalent inactivated vaccine and in children.

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.

Correlation between respiratory syncytial virus (RSV) test data and hospitalization of children for RSV lower respiratory tract illness in Florida.

BACKGROUND: Florida experiences year-round outbreaks of respiratory syncytial virus (RSV), but it is unknown if there is a correlation between RSV virology data and disease-related hospitalizations. We analyzed RSV surveillance and hospitalization data for the state of Florida to determine if there is an association between seasonal virology data and the incidence of International Classification of Diseases, 9th revision, clinical modification (ICD-9-CM) coded hospitalizations for RSV lower respiratory tract illness. METHODS: We conducted a retrospective analysis for each of 5 regions of Florida for 4 years (2001-2004) of monthly RSV surveillance data presented on the Florida Department of Health website and hospitalization data provided by the Agency for Health Care Administration. RSV was considered present when > or =10% of laboratory tests were positive in a given month and the duration of seasons was determined by the number of consecutive months threshold values were exceeded. Hospitalizations in children 24 months of age and younger were defined as RSV related if any of the following RSV-specific ICD-9-CM codes appeared on the discharge summary: 079.6 RSV; 466.11 acute bronchiolitis caused by RSV; and 480.1 pneumonia caused by RSV. RESULTS: RSV circulated year-round statewide and seasons ranged from 7-8 months in the southwest, northwest, and north regions of Florida to 11-12 months in the central and southeast regions, respectively. More than 23,000 children younger than 24 months of age were hospitalized throughout the state for an RSV-related illness during the 4-year period, with almost 20,000 (86%) of the admissions in infants less than 12 months of age. There were 23 hospitalizations yearly per 1000 births and more than 90% of discharges occurred during the defined RSV seasons. CONCLUSIONS: To our knowledge, this is the first study to demonstrate a positive correlation between RSV test data and hospitalizations both statewide and for individual regions within Florida. It would be prudent for clinicians to obtain results of local RSV virology data to guide decisions on timing of prophylaxis to prevent RSV hospitalizations.

Respiratory syncytial virus: seasonal data for regions of Florida and implications for palivizumab.

BACKGROUND: The aims of this study are to define the length of the respiratory syncytial virus (RSV) season throughout Florida and evaluate the American Academy of Pediatrics (AAP) guidelines on the administration of palivizumab in light of the Florida data. METHODS: We retrospectively analyzed four seasons of monthly RSV surveillance data housed on the Florida Department of Health website for regional trends in RSV outbreaks. RESULTS: RSV circulated year round in Florida, with December being the peak month for RSV activity statewide. Regional virology data showed consistent patterns throughout the observation period, and all regions experienced widespread RSV activity for at least seven months of the year. The southeast region experienced the longest RSV seasons (10-12 mo), with year round outbreaks observed during 2000 to 2001 and 2001 to 2002. CONCLUSIONS: Local RSV surveillance provides meaningful data to guide decisions on the administration of palivizumab. Reliance on current AAP guidelines for RSV prophylaxis would result in under-protection of at-risk children in all regions within the state of Florida.

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.

Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants with human immunodeficiency virus type 1 infection.

OBJECTIVE: Heptavalent pneumococcal conjugate vaccine (PCV) has been shown to be safe and effective in healthy infants and children. However, little is known about its use in children who have human immunodeficiency virus (HIV) infection and are known to be at increased risk of developing pneumococcal infections. This study was conducted to evaluate the safety and immunogenicity of heptavalent PCV in infants with HIV infection. METHODS: The Pediatric AIDS Clinical Trials Group Study 292 Team randomized infants with HIV infection 2:1 to receive heptavalent PCV or placebo in a double-blinded manner. Infants were vaccinated with 3 doses at 2-month intervals, starting at ages 56 to 180 days. A booster dose was given at 15 months of age. Immunogenicity was evaluated after the third dose of vaccine, before and after the booster dose, and at 24 months of age. RESULTS: Thirty infants with HIV infection received PCV, and 15 received placebo. No differences in baseline characteristics were found across arms. Five severe acute reactions were experienced by 4 subjects: 3 in the PCV arm and 1 in the placebo arm; all occurred among subjects with symptomatic disease at study entry. No differences were found in the 2 arms with respect to the number or timing of new diagnoses through 24 months of age, including diagnoses of otitis media. However, when symptomatic subjects were examined separately, the first new diagnosis occurred more rapidly among PCV recipients. Three deaths, all judged to be unrelated to study vaccine, occurred during follow-up: 2 in the PCV arm and 1 in the placebo arm. The primary immunogenicity measures were based on composites of 4-fold changes in serotype-specific immunoglobulin G titers from preimmunization levels. We found a highly significant difference between the vaccine and placebo arms, with the PCV arm showing higher rates of response. Asymptomatic and symptomatic subjects who received PCV had similar immunologic responses for all serotypes. CONCLUSIONS: This study demonstrates that heptavalent PCV was well tolerated and not associated with vaccine-associated adverse reactions. Most important, this vaccine was immunogenic in the infant with HIV infection. However, additional studies of this vaccine (or others) must pay special attention to patients with symptomatic HIV disease, as they seem to be at higher risk for adverse events to any antigen.