Michael Bröker

Chemistry of a new investigational quadrivalent meningococcal conjugate vaccine that is immunogenic at all ages

Meningococcal disease is a serious medical condition that can prove fatal within hours in otherwise healthy individuals. Disease incidence is highest in infants, yet there is no broadly protective quadrivalent vaccine that covers this age group. A new investigational quadrivalent meningococcal glycoconjugate vaccine against meningococcal serogroups A, C, W-135, and Y (MenACWY-CRM, Novartis Vaccines, Siena, Italy), has been developed to meet this medical need. This article discusses the vaccine technology behind MenACWY-CRM, focusing on the heritage of CRM(197), the conjugation chemistry, the sizing of the oligosaccharides, and the advantages that these may confer on the vaccine. We highlight the differences between available vaccines and look at the clinical experience with vaccines against other diseases, demonstrating the importance of each component to the immunogenicity of conjugate vaccines. The specific technological approach, including conjugation of meningococcal oligosaccharides of defined length to the CRM(197) protein, has led to a vaccine that has the potential to provide broad meningococcal protection against serogroups A, C, W-135, and Y for all ages.

Biochemical and biological characteristics of cross-reacting material 197 (CRM197), a non-toxic mutant of diphtheria toxin: Use as a conjugation protein in vaccines and other potential clinical applications

The biochemical and biological characteristics of CRM(197) are reviewed. Polysaccharide protein conjugate vaccines represent an important technological advancement that allowed for protection against dangerous diseases in vulnerable populations such as infants. The first carrier proteins, diphtheria and tetanus toxoids, were chosen in the context of an extensive body of information describing their immunogenicity and safety profiles in clinical use. These carriers perform well, and they require detoxification. A non-toxic mutant of diphtheria toxin, cross-reacting material 197 (CRM(197)), is a useful carrier protein with several manufacturing and other potential advantages over toxoids. For over a decade, several important and widely used routine childhood glycoconjugate vaccines against serious illnesses, including Haemophilus influenzae type b and pneumococcal disease, have employed CRM(197) as carrier protein. Additional clinical applications of CRM(197), as in chemotherapy, also exist.

Tick-borne encephalitis vaccines: past and present.

Vaccines to protect against tick-borne encephalitis (TBE) are produced by two manufacturers and are widely used in European and Asian countries, where TBE virus is endemic. General trends in vaccine development during recent decades and extensive postmarketing experience resulted in several modifications to their formulations and practical implications for use. Modifications were made to the production process, such as the change of the virus master bank from mouse brain to primary cells; to the excipients, especially the stabilizers and preservative; and to include formulations for children. Additionally, a rapid vaccination schedule has been developed for persons who require a fast onset of protection. Recent data from clinical studies and postmarketing surveillance indicate that both vaccines are safe, efficacious and interchangeable. Further (major) changes to formulation or alternative targets for vaccine development are not anticipated in the next 5 years. Recent serologic studies indicate that the persistence of protective immunity was longer than expected. Thus, recommendations for prolongation of TBE booster intervals have been made in several European countries, and a harmonization for booster recommendations is predicted within the European Union. Based on epidemiologic trends, the use of TBE vaccines will continue to increase in all age groups, including children.

After a tick bite in a tick-borne encephalitis virus endemic area: current positions about post-exposure treatment.

If a person suffers a tick bite in tick-borne encephalitis (TBE) endemic areas, there is uncertainty on post-exposure treatment of naïve (non-immune) persons in order to protect the patient against TBE. Particularly, there are no distinct positions on the use of TBE active immunization as post-exposure treatment. Of special concern is the possibility of antibody-dependent enhancement of infection and exacerbation of disease in case of post-exposure vaccination. Such phenomena have been reported for other flavivirus infections. In the past, immune globulin treatment was recommended, but these preparations are no longer available. Active immunization by using the current immunization schedules after a tick bite will not result in appropriate neutralizing antibody concentrations within due time. Based on the assumptions that vaccination is not quick acting enough after a tick bite and that the theoretical risk of antibody-dependent enhancement cannot be excluded, no vaccination or other specific measure is currently recommended after a tick bite in non-vaccinated patients, leaving the patient in a completely dissatisfactory position. A risk/benefit analysis has been re-assessed for persons with a history with at least one vaccine injection, certain patient groups and in relation to the vaccination schedule which has been used and to the geographic area where the tick bite has occurred. In order to evaluate the value of the vaccine for post-exposure immunization, new immunization schedules have to be evaluated with respect to their capacity to induce antibodies more quickly.

Meningococcal serogroup Y emergence in Europe: update 2011.

Neisseria meningitidis is differentiated into 12 distinct serogroups, of which A, B, C, W-135, X, and Y are medically most important and represent an important health problem in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Recent epidemiological surveillance has indicated an increase of serogroup Y invasive meningococcal disease in some parts of Europe as shown in the epidemiological data for 2010 from various European countries previously published in this journal.1 Here, data is reported indicating that the emergence of serogroup Y continued in 2011 in various regions of Europe. The average age of persons affected by N. meningitidis serogroup Y seems to have decreased in some countries in comparison to the previous decade.

Protection against tick-borne encephalitis with a new vaccine formulation free of protein-derived stabilizers.

BACKGROUND Vaccination against tick-borne encephalitis (TBE) has been successfully employed for many years in TBE-endemic countries. Post-marketing experience gained from widespread use, however, prompted the development of improved TBE vaccines, the most modern versions of which do not contain the commonly used protein-derived stabilizers (human albumin or polygeline) of former vaccines. METHOD This article summarizes both the medical need for and clinical experience with a new TBE vaccine formulation (pediatric and adult versions). To this end, data from clinical trials and post-marketing experience are presented. The clinical database comprises immunogenicity and/or safety data of approximately 7,500 subjects ages 1 to 77 years who participated in eight clinical trials. The clinical trials were conducted at 69 centers in five European countries. Post-marketing experience includes safety data from passive pharmacovigilance systems in 18 countries where these vaccines have been licensed since 2001. RESULTS All subjects analyzed for immunogenicity achieved postimmunization levels of TBE antibodies that meet the definition of seroconversion or represent a fourfold increase. The pooled data of clinical trials revealed the expected rate of solicited local and systemic reactions. The majority of these transient postimmunization reactions were mild. Pharmacovigilance data confirm the high level of safety of these new TBE vaccines: only a common range of the side effects already noted for licensed TBE vaccines was reported. After the distribution of more than five million vaccine doses, no potential safety risk was noted. CONCLUSION Post-marketing experience supports results from clinical trials showing that these new TBE vaccines may safely be used for the vaccination of children, adolescents, and adults.

Are tick-borne encephalitis vaccines interchangeable?

Two tick-borne encephalitis vaccines produced by two vaccine manufacturers are available in most European countries. A question that is frequently asked regarding these two vaccines concerns their exchangeability, however, to date, no detailed assessment has been published. This review analyzes clinical studies investigating these two vaccines and describes possible approaches to boost or continue uncompleted primary immunization schedules, with either of the two tick-borne encephalitis vaccines.

Quadrivalent meningococcal vaccines: Hyporesponsiveness as an important consideration when choosing between the use of conjugate vaccine or polysaccharide vaccine

Regional variations in the incidence and the distribution of serogroups which are responsible of meningococcal disease necessitate multivalent vaccines to ensure broad coverage for travelers. For almost 30 years, this has been provided by quadrivalent polysaccharide vaccine to protect against serogroups A, C, W-135 and Y, but with the advent of quadrivalent conjugate vaccines is there still a case to use the polysaccharide? The well documented hyporesponsiveness induced by polysaccharide vaccines after repeated administration, most clearly observed against serogroup C, suggest that, where available, conjugate vaccines should always be considered ahead of polysaccharide vaccine.

Critical appraisal of a quadrivalent CRM(197) conjugate vaccine against meningococcal serogroups A, C W-135 and Y (Menveo) in the context of treatment and prevention of invasive disease.

Worldwide, invasive meningococcal disease affects about 500,000 people annually. Case fatality in developed countries averages 10%, and higher rates are reported in less prosperous regions. According to the World Health Organization, the most important pathogenic serogroups are A, B, C, W-135, X, and Y. Clinical features of invasive meningococcal disease make diagnosis and management difficult. Antibiotic measures are recommended for prophylaxis after exposure and for treatment of invasive meningococcal disease cases; however, resistant strains may be emerging. Vaccines are generally regarded as the best preventative measure for invasive meningococcal disease. Polysaccharide vaccines against serogroups A, C, W-135, and Y using protein conjugation technology have clear advantages over older plain polysaccharide formulations without a protein component. The first quadrivalent meningococcal conjugate vaccine (MenACWY-D) was licensed in the US in 2005. More recently, MenACWY-CRM (Menveo®) was licensed in Europe, the US, the Middle East, and Latin America. MenACWY-CRM uses cross-reactive material 197, a nontoxic mutant of diphtheria toxin, as the carrier protein. MenACWY-CRM offers robust immunogenicity in all age groups, with a tolerability profile similar to that of a plain polysaccharide vaccine. Given its potential for protecting persons from infancy to old age, MenACWY-CRM offers the opportunity to protect broad populations against invasive meningococcal disease. The most optimal strategy for use of the vaccine has to be assessed country by country on the basis of local epidemiology, individual health care systems, and need.

Meningococcal serogroup Y disease in Europe: Continuation of high importance in some European regions in 2013

Neisseria meningitidis or meningococcus is divided into 12 distinct serogroups of which A, B, C, W, X, and Y are medically most important and cause health problems in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Globally, serogoup A has been prevalent in the African “meningitis belt” whereas serogroup B and C have predominated in Europe. In a paper published earlier in this journal1, an increase in serogroup Y invasive meningococcal disease (IMD) in some European countries was reported based on the epidemiological data for 2010, 2011 and 2012. Here, we report additional data from 30 European countries indicating that high or increased serogroup Y disease levels have continued in 2013 in certain regions of Europe. In the Western and Central Europe, there were no major changes in the proportion of serogroup Y IMD cases in 2013 compared to 2012. In the Scandinavian countries, proportion of serogroup Y disease remained high, ranging from 26% to 51% in 2013. This was in contrast to Baltic, Eastern and most Southern European countries, where the proportion of serogroup Y IMD was low similarly to previous years. For the last 2 decades, the mean age of patients affected by serogroup Y was 41 y for 7 countries from which data was available and 50% of cases were in patients aged 45 to 88 y. The age distribution of serogroup Y was bimodal and did not change significantly despite the increase of the total number and the proportion of serogroup Y IMD in some European regions.