Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis.

BACKGROUND: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. METHODS: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. RESULTS: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). CONCLUSION: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.

The changing epidemiology of diphtheria in the vaccine era.

The epidemic of diphtheria in the Newly Independent States (NIS) of the former Soviet Union has drawn attention to our incomplete understanding of the epidemiology of diphtheria. Many unanswered questions remain concerning the reasons for a resurgence of diphtheria and for the shift in the age of patients and concerning the mechanisms for acquisition of immunity in adults through natural infection under unfavorable living conditions. Other unanswered questions relate to the precise role of socioeconomic factors and hygiene conditions in the initiation, buildup, and spread of the epidemic. Important characteristics of the NIS epidemic can be used to help predict the spread of future diphtheria epidemics. These characteristics include a high proportion of infected adults, a progressive spread of disease from urban centers to rural areas, and transition from initial amplification of disease in groups with high rates of close contacts in focalized, well-distinguished outbreaks to a more generalized epidemic.

Successful control of epidemic diphtheria in the states of the Former Union of Soviet Socialist Republics: lessons learned.

Epidemic diphtheria reemerged in the Russian Federation in 1990 and spread to all Newly Independent States (NIS) and Baltic States by the end of 1994. Factors contributing to the epidemic included increased susceptibility of both children and adults, socioeconomic instability, population movement, deteriorating health infrastructure, initial shortages of vaccine, and delays in implementing control measures. In 1995, aggressive control strategies were implemented, and since then, all affected countries have reported decreases of diphtheria; however, continued efforts by national health authorities and international assistance are still needed. The legacy of this epidemic includes a reexamination of the global diphtheria control strategy, new laboratory techniques for diphtheria diagnosis and analysis, and a model for future public health emergencies in the successful collaboration of multiple international partners. The reemergence of diphtheria warns of an immediate threat of other epidemics in the NIS and Baltic States and a longer-term potential for the reemergence of vaccine-preventable diseases elsewhere. Continued investment in improved vaccines, control strategies, training, and laboratory techniques is needed.

Implications of the diphtheria epidemic in the Former Soviet Union for immunization programs.

The massive diphtheria epidemic in the former Soviet Union provides important lessons for all diphtheria immunization programs: It is important to achieve a high level of childhood immunization, maintain immunity against diphtheria in older age groups, and use anti-epidemic measures, including immunization, to control epidemics in the early phase. The immunization coverage among children should be at least 90%. Further studies are needed to elaborate the most effective strategy to maintain immunity against diphtheria in adults (periodic booster doses, immunization of selected age groups in health care settings, use of Td [tetanus-diphtheria toxoids with reduced diphtheria toxoid content] vaccine instead of monovalent tetanus toxoid whenever tetanus toxoid is indicated [e.g., in treatment of wounds or in school-based immunization programs]). Efforts should be undertaken to monitor diphtheria immunity in different groups by conducting age-specific serologic studies.

Mumps and mumps vaccine: a global review.

Mumps is an acute infectious disease caused by a paramyxovirus. Although the disease is usually mild, up to 10% of patients can develop aseptic meningitis; a less common but more serious complication is encephalitis, which can result in death or disability. Permanent deafness, orchitis, and pancreatitis are other untoward effects of mumps. Based on data reported to WHO up to April 1998, mumps vaccine is routinely used by national immunization programmes in 82 countries/areas: 23 (92%) of 25 developed countries, 19 (86%) of 22 countries with economies in transition (mainly the Newly Independent States of the former Soviet Union), and 40 (24%) of 168 developing countries. Countries that have achieved high coverage have shown a rapid decline in mumps morbidity. Furthermore, in many of these countries, mumps-associated encephalitis and deafness have nearly vanished. This review considers the disease burden due to mumps; summarizes studies on the immunogenicity, efficacy, and safety of different strains of mumps vaccine; and highlights lessons learned about implementing mumps immunization in different countries. Countries already using mumps vaccine should monitor immunization coverage and establish routine mumps surveillance with investigation of outbreaks. Where mumps is targeted for elimination, countries need to add a second dose of mumps vaccine for children, keeping in mind that the disease may still occur in susceptible adults.

PIP: Mumps is an acute infectious disease caused by a paramyxovirus. While the disease is usually mild, up to 10% of patients can develop aseptic meningitis. A less common but more serious complication is encephalitis, which can result in death or disability. Permanent deafness, orchitis, and pancreatitis are other adverse effects of mumps. Based upon data reported to the World Health Organization (WHO) up to April 1998, mumps vaccine is routinely used by national immunization programs in 82 countries/areas: 23 of 25 developed countries, 19 of 22 countries with economies in transition, and 40 of 168 developing countries. Countries which have achieved high vaccine coverage have realized a rapid decline in mumps morbidity. Also in many such countries, mumps-associated encephalitis and deafness have almost vanished. The authors consider the disease burden due to mumps; summarize studies on the immunogenicity, efficacy, and safety of different strains of mumps vaccine; and note lessons learned about implementing mumps immunization in different countries. Countries already using mumps vaccine should monitor immunization coverage and establish routine mumps surveillance with investigation of outbreaks. Where mumps is targeted to be eliminated, countries need to add a second dose of mumps vaccine for children.

Surveillance of foodborne botulism in Poland: 1960-1998.

Human foodborne botulism, in contrast to the other two forms of botulism (wound and infant botulism), is an intoxication that results when preformed botulinum toxin is ingested. Sporadic cases and family and general outbreaks occur when food products are

Impact of anti-vaccine movements on pertussis control: the untold story.

To assess the impact of anti-vaccine movements that targeted pertussis whole-cell vaccines, we compared pertussis incidence in countries where high coverage with diphtheria-tetanus-pertussis vaccines (DTP) was maintained (Hungary, the former East Germany, Poland, and the USA) with countries where immunisation was disrupted by anti-vaccine movements (Sweden, Japan, UK, The Russian Federation, Ireland, Italy, the former West Germany, and Australia). Pertussis incidence was 10 to 100 times lower in countries where high vaccine coverage was maintained than in countries where immunisation programs were compromised by anti-vaccine movements. Comparisons of neighbouring countries with high and low vaccine coverage further underscore the efficacy of these vaccines. Given the safety and cost-effectiveness of whole-cell pertussis vaccines, our study shows that, far from being obsolete, these vaccines continue to have an important role in global immunisation.

[Controlled release antigen from the injection site--new model for a single-shot vaccination?]. / Kontrolowane uwalnianie antygenu z miejsca wstrzykniecia szczepionki--nowy model jednodawkowej szczepionki?

Continuously increasing number of available vaccines and a wide use of mass vaccination campaigns lead to the development of simpler methods of vaccine delivery. There is the WHO-sponsored project, including several scientific groups, which aims to reduce the number of repeated administrations of vaccines required for long-term protection and to obviate the need for booster immunization. Such a task may be achieved by the use of controlled-release parenteral systems. One such delivery system comprises microspheres constructed from biodegradable, biocompatible polymers based on poly lactic/glycolic acid. Recent developments of a single-shot tetanus toxoid, encapsulated in the biodegradable polymeric microspheres or microcapsules are reviewed. There are promising advances in the WHO-sponsored project. However, further efforts are needed to elaborate an affective late release of antigen and to obtain a strong booster effect in vaccinated animals.

[Wide spread inflammation of the parotid glands (mumps): underestimated disease. I. Epidemiology of the mumps and its medical meaning in Poland]. / Nagminne zapalenie przyusznic (swinka)--niedoceniona choroba. I. Epidemiologia swinki i jej zdrowotne znaczenie w Polsce.

Mumps is commonly considered a "mild" infectious disease in children because death due to mumps is very rare. However, mumps causes a high rate of complications in young adults, and its burden should not be underestimated. Before the introduction of vaccine, mumps was a common infectious disease with high incidence rates which exceeded 100 per 100,000 population in most countries. Poland continues to belong to the group of countries, which do not use mumps vaccine. In Poland, the number of reported mumps cases per year ranges from 40,000 to 220,000, yielding an annual incidence rates of 110 and 570 per 100,000 population. It is estimated that each year in Poland, mumps causes 1000 cases of aseptic meningitis (range 400 to 2,200), 100 cases of encephalitis, 250 to 1375 cases of epidymo-orchitis in post-pubertal men, 50-275 cases of oophoritis in women. The age distribution of mumps cases is characteristic for a country that does not use mumps vaccine. For more that 20 years, the highest mumps incidence has occurred in children aged 5-9 years. In many countries the number of reported cases has declined significantly following the introduction of mumps vaccine, and in several countries the incidence has fallen to less than 1 per 100,000 population. Several countries using mumps vaccine have reported a shift in the age distribution of mumps cases, with an increased incidence in older children and young adults. Countries with high levels of coverage with measles-mumps-rubella (MMR) vaccine have nearly eliminated encephalitis associated with these diseases. A few countries using mumps vaccine have experienced relative resurgence of the disease, either due to incomplete vaccine coverage of certain age groups (USA) or problems with the long-term immunogenicity of mumps vaccine based on the Rubini strain (Portugal, Switzerland).

[Wide-spread inflammation of the parotid glands (mumps): an underestimated disease. II. Development, use, efficacy and safety of mumps vaccines]. / Nagminne zapalenie przyusznic (swinka)--niedoceniona choroba. II. Stosowanie, skutecznosc i bezpieczenstwo szczepionki przeciw swince.

Effective attenuated live virus mumps vaccines have been available for more than 30 years. Vaccine strains have been developed on various cell culture systems; the attenuated mumps virus strain most commonly used is the Jeryl Lynn strain. Various vaccines differ in their immunogenicity, efficacy and associated adverse events. It is estimated that the immunization coverage needed to block the transmission of mumps virus is at least 70%. Models indicate that low to moderate levels of mumps vaccine coverage may actually increase the number of susceptibles and the number of cases in older age groups. Benefit-cost analyses in a number of countries have found that the introduction of mumps vaccine is economically justifiable, as vaccination can avert the considerable medical and economic costs associated with mumps morbidity. Countries that do not immunize against mumps continue to register high mumps morbidity, and pay a high toll from neurological and other complications of mumps. Poland, which already has a high level of measles vaccine coverage, should make efforts to replace monovalent measles vaccine with trivalent measles-mumps-rubella (MMR) vaccine.

[The 50th anniversary of the World Health Organization]. / 50 lat swiatowej Organizacji Zdrowia.

In the 1998, the World Health Organization celebrates its 50th anniversary. The creation of the WHO in 1948 has terminated long-lasting efforts in the development of the international organization which can promote, support and coordinate improvement in the international health. In the paper, the history of the WHO, its present structure and functions, budget, main areas of activity, achievements and problems are discussed. The WHO's contribution in the improvements in the world's public health and especially in the control of infectious diseases is essential. However, to meet new challenges of the coming XXI century, and to catalyse, encourage and support needed reforms, the WHO itself has to reorganize its structure and to discuss its strategical concepts.

Recombinant human interferon-beta in the treatment of condylomata acuminata.

The number of clinic consultations for condylomata acuminata (genital warts) has increased substantially during the last 30 years. Most infections produce benign lesions but a few types may be associated with cervical and penile cancers. Interferons (IFN) have shown antiviral properties to these infections and IFN-beta in particular has demonstrated a specific cytopathic effect in humans. A total of 124 patients with condylomata acuminata, the majority of whom had failed previous therapy, were treated intralesionally with either recombinant human interferon-beta la (r-hIFN-beta-1a) or placebo. Up to 6 lesions were treated in each patient, and injections were made 3 times per week for a total of 9 injections. The patients were then followed up for 3 months. Efficacy assessments at all time points (day 19, week 6 and month 3) showed a clear advantage for the r-hIFN-beta-1a interferon-beta treatment. Patients receiving r-hIFN-beta-1a showed a greater proportion of treatment success in terms of the complete or partial reduction (at least 50%) of the total area of the treated lesions. The treatment was also well tolerated. Headache, flu-like symptoms and asthenia were more common in patients receiving r-hIFN-beta-1a, but these adverse events were generally mild in severity and rarely led to patient withdrawal. It was concluded that r-hIFN-beta-1a has good efficacy in condylomata acuminata, and therefore presents a useful therapeutic alternative in this hard-to-treat condition.

Why do adults contract diphtheria?

When diphtheria was a common disease, it most commonly affected children. Typically, at least 40% of diphtheria cases were children under 5 years of age, and some 70% of cases were children under 15 years of age. This classical pattern of diphtheria cases

Changes in age specific immunity to diphtheria in Poland in the past 40 years.

In recent years people in Poland have acquired diphtheria from eastern neighbours. It was considered important therefore to study the age specific immunity against diphtheria and to compare it with the results of seroepidemiological studies conducted in t