Co-Opting Host Receptors for Targeted Delivery of Bioconjugates-From Drugs to Bugs.

Bioconjugation has allowed scientists to combine multiple functional elements into one biological or biochemical unit. This assembly can result in the production of constructs that are targeted to a specific site or cell type in order to enhance the response to, or activity of, the conjugated moiety. In the case of cancer treatments, selectively targeting chemotherapies to the cells of interest limit harmful side effects and enhance efficacy. Targeting through conjugation is also advantageous in delivering treatments to difficult-to-reach tissues, such as the brain or infections deep in the lung. Bacterial infections can be more selectively treated by conjugating antibiotics to microbe-specific entities; helping to avoid antibiotic resistance across commensal bacterial species. In the case of vaccine development, conjugation is used to enhance efficacy without compromising safety. In this work, we will review the previously mentioned areas in which bioconjugation has created new possibilities and advanced treatments.

[Vaccination against Haemophilus influenzaetype b; why and how?] / Vaccinatie tegenHaemophilus influenzaetype b.

After a development period of around 13 years, in 1993 the vaccination against infections caused by Haemophilus influenzae type b (Hib) was introduced into the Dutch National Immunisation Programme. Before the introduction of the vaccination, the burden of disease was high; every year around 700 children acquired an invasive Hib infection, half of whom developed meningitis. Of those children with Hib-related meningitis, 2% died and more than 8% were left with severe residual symptoms. Furthermore, at least one-third of those who recovered developed learning and concentration problems. Hib also caused other infections such as epiglottitis, osteomyelitis and arthritis. Initially, the conjugated Hib vaccine PRP-T was given as a separate injection. From 2005 onwards PRP-T was included in the combination DTaP-IPV-Hib vaccine, and since 2011 PRP-T has been part of the DTaP-IPV-Hib-HepB vaccine. Although H. influenzae is still around, invasive Hib infections in children now occur only very rarely.

Epidemiology of pneumonia in the pre-pneumococcal conjugate vaccine era in children 2-59 months of age, in Ulaanbaatar, Mongolia, 2015-2016.

BACKGROUND: Respiratory diseases, including pneumonia, are the second largest cause of under-five mortality in Mongolia and the most common cause of childhood hospitalization. However information regarding the contribution of Streptococcus pneumoniae to pneumonia causation in Mongolia is limited. We aimed to describe the epidemiology of hospitalized children aged 2-59 months with pneumonia, enrolled into a surveillance program in the period prior to pneumococcal conjugate vaccine (PCV) introduction, in Mongolia. METHODS: An expanded pneumonia surveillance program enrolled children, who met the surveillance case definition, at participating hospitals, between April 2015 and May 2016. Cumulative incidence rates were calculated by district for all pneumonia endpoints using district specific denominators from the Mongolian Health Department census for 2016. Socio-economic and disease-associated factors were compared between districts using chi-squared tests. RESULTS: A total of 4318 eligible children with pneumonia were enrolled over the 14 month period. Overall the incidence for all-cause pneumonia in children aged 12-59 months was 31.8 per 1000 population; children aged 2-11 months had an almost four-fold higher incidence than children aged 12-59 months. Differences were found between districts with regards to housing type, fuel used for cooking, hospital admission practices and the proportions of severe and primary endpoint pneumonia. DISCUSSION: This study shows a high burden of pneumonia in children aged 2-59 months in Mongolia prior to PCV introduction. Rates differed somewhat by district and age group and were influenced by a number of socio-economic factors. It will be important to consider these differences and risk factors when assessing the impact of PCV introduction.

Fully liquid DTaP-IPV-Hib pediatric combination vaccine (Pediacel): a review of 18 years of clinical experience.

Safe and effective combination pediatric vaccines are necessary to simplify complex immunization schedules and to improve coverage and protection for children worldwide. We provide an overview of the 18 years of clinical and worldwide experience with DTaP-IPV-Hib (Pediacel(®)), a unique fully liquid pentavalent vaccine (diphtheria [D], tetanus [T], acellular pertussis, inactivated poliovirus [IPV], Haemophilus influenzae type b [Hib]). Pediacel has demonstrated good and lasting immunogenicity in many populations, with differing primary series and booster schedules, and with a variety of coadministered vaccines. The acellular pertussis antigens have proven efficacy and real-world effectiveness. Clinical and post-marketing studies confirm the safety of Pediacel. Pediacel can be used for primary series and toddler booster doses, as well as in mixed pediatric vaccine schedules.

Pneumococcal vaccines for children: a global public health priority.

Pneumococcal conjugated vaccines have been recommended in children for over a decade in many countries worldwide. Here we review the development of pneumococcal vaccines with a focus on the two types currently available for children and their safety record. We discuss also the effect of vaccines, including the 13-valent pneumococcal conjugate vaccine, on invasive pneumococcal diseases in children, particularly bacteraemia, pneumonia and meningitis, as well as on mucosal disease and carriage. In regions where immunization was implemented in young children, the number of invasive pneumococcal diseases decreased significantly, not only in the target age group, but also in younger and much older subjects. Challenges and future perspectives regarding the development of new 'universal' vaccines, which could bypass the current problem of serotype-specific protection in a context of serotype replacement, are also discussed.

Meningococcal vaccine development--from glycoconjugates against MenACWY to proteins against MenB--potential for broad protection against meningococcal disease.

Novartis Vaccines has a long-standing research and development interest in the prevention of invasive meningococcal disease. From the initial licensure of the monovalent meningococcal C glycoconjugate vaccine, Menjugate(®), in response to the emergence of a virulent serogroup C ST-11 strain in the United Kingdom to the more recent development and licensure of a quadrivalent meningococcal ACWY glycoconjugate vaccine, Menveo(®), Novartis has a continuing commitment to the development of more effective tools for the control of meningococcal disease. Menveo is now licensed for use in adolescents and adults in over 50 countries and results from phase III studies have shown the vaccine to be well-tolerated and highly immunogenic in infants with vaccination beginning from 2 months of age. The 'holy grail' of meningococcal disease control is a broadly protective vaccine against serogroup B (MenB), preferably a vaccine that protects all age groups including infants. As the serogroup B capsule is poorly immunogenic, efforts over the past 40 years have focused on identifying conserved proteins expressed on the bacterial surface that elicit bactericidal antibodies. Novartis has approached this problem utilizing genomic tools to identify proteins meeting these criteria in a process now known as 'reverse vaccinology'[1]. This process has resulted in a novel multicomponent MenB vaccine (4CMenB) that consists of four major immunogenic components (three subcapsular MenB protein antigens plus outer membrane vesicles (OMVs) which themselves provide multiple subcapsular antigens, the immunodominant one being PorA). These all induce bactericidal antibodies against the antigens that are important in determining the survival, function, and virulence of the meningococci. Phase II studies of 4CMenB have been completed and have demonstrated that the vaccine is highly immunogenic against reference meningococcal strains selected to support licensure. Post-vaccination sera from clinical studies have also been tested against a diverse panel of serogroup B strains to support the development of the Meningococcal Antigen Typing System (MATS), a tool used to predict vaccine strain coverage [2] This overview is intended to give a broad summary of the key clinical data derived from the Menveo and 4CMenB clinical development programs.

Pneumococcal otitis media and pneumococcal vaccines, a historical perspective.

Although pneumococcal otitis media was recognized in the 19th century, the illness stimulated little interest in prophylaxis until recently. Whole cell vaccines of killed pneumococci, developed to prevent pneumonia, were replaced by vaccines of capsular polysaccharides following demonstration of their antigenicity in adults. Failure of the latter to stimulate antibodies in infants and young children and demonstration of the efficacy of capsular polysaccharide-protein conjugate vaccines in preventing infection with Hemophilus influenzae type b has led to the development of polyvalent pneumococcal polysaccharide-protein conjugate vaccines. Preliminary studies have shown them to be highly effective in preventing invasive pneumococcal disease in the first 2 years of life, and studies of their impact on otitis media are currently in progress.