Peter Wutzler

Oil-in-Water Emulsion Adjuvant with Influenza Vaccine in Young Children

BACKGROUND The efficacy of inactivated influenza vaccines is known to be poor in infants and young children. METHODS We studied the effect of the adjuvant MF59, an oil-in-water emulsion, on the efficacy of trivalent inactivated influenza vaccine (TIV) in 4707 healthy children 6 to less than 72 months of age who had not previously been vaccinated against influenza. The children were randomly assigned to three study groups, each of which received the assigned vaccines in two doses, 28 days apart, during two consecutive influenza seasons. Two of the groups were given age-appropriate doses of TIV either with or without the MF59 adjuvant, and the third group was given control (noninfluenza) vaccines to assess their absolute and relative efficacy against influenza-like illness, as confirmed by means of polymerase-chain-reaction (PCR) assay. RESULTS Attack rates of influenza-like illness across both influenza seasons were 0.7%, 2.8%, and 4.7% in the adjuvant, nonadjuvant, and control vaccine groups, respectively. The absolute vaccine efficacy rates against all influenza strains (94 of 110 cases were due to vaccine-matched H3N2 viruses) were 86% (95% confidence interval [CI], 74 to 93) for the MF59-adjuvant vaccine (ATIV) and 43% (95% CI, 15 to 61) for the vaccine without the adjuvant (TIV); the relative vaccine efficacy rate for ATIV versus TIV was 75% (95% CI, 55 to 87). The efficacy rates for ATIV were 79% (95% CI, 55 to 90) in children 6 to less than 36 months of age and 92% (95% CI, 77 to 97) in those 36 to less than 72 months of age, as compared with 40% (95% CI, -6 to 66) and 45% (95% CI, 6 to 68), respectively, for TIV. Antibody responses were higher with ATIV and remained so through day 181. The rates of systemic and local reactions to the influenza vaccines with and without the adjuvant were similar in the younger age group (relative risk, 1.04; 95% CI, 0.98 to 1.09), but systemic events in the older age group were more frequent after administration of ATIV (63%) than after administration of TIV (44%) or the control vaccine (50%). Serious adverse events were distributed evenly across the three vaccine groups. CONCLUSIONS Influenza vaccine with the MF59 adjuvant is efficacious against PCR-confirmed influenza in infants and young children. (Funded by Novartis Vaccines and Diagnostics; ClinicalTrials.gov number, NCT00644059.).

Seroprevalence of varicella-zoster virus in the German population

The present study was conducted to generate data on the epidemiology of varicella-zoster virus (VZV) infections in Germany as a basis for health economic evaluations of varicella vaccination strategies. The survey was designed as a cross-sectional, age-stratified study of the VZV seroprevalence in the German population. The status of immunity of 4602 individuals a aged 0 to >70 years was investigated by means of an indirect enzyme immunoassay and the fluorescent antibody to membrane assay. After waning of maternal antibodies over the period of 6-9 months seropositivity rates remained low by the end of the 1st year of life. By the age of 4-5 years 62.5% (95% CI; 56.0-68.5) of the pre-school children had already been infected with VZV and at the age of 10-11 years 94.2% (95% CI; 91.0-96.0) of children were positive for anti-VZV antibodies. Among the age-group of >40 years old, only few individuals were susceptible for VZV. The median antibody levels to VZV did not significantly decline with increasing age. In comparison with figures of previous studies the age-specific seroprevalence data presented here do not provide evidence for an upward shift in the age distribution of varicella in Germany. Since the majority of VZV infections occurs during the early childhood, the best option to reduce the circulation of wild-type VZV in the population would be the immunization of young children.

Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 1: Herpes simplex virus infections

Varicella during pregnancy can be associated with severe illnesses for both the mother and her neonate. Varicella pneumonia must be regarded as a medical emergency, since pregnant women are at risk of life-threatening ventilatory compromise and death. After maternal chickenpox in the first and second trimesters, congenital varicella syndrome may occur in nearly 2% of the cases. The characteristic symptoms consist of skin lesions in dermatomal distribution, neurological defects, eye diseases and skeletal anomalies. If the mother develops varicella rashes between day 4 (5) antepartum and day 2 postpartum, generalized neonatal varicella leading to death in about 20% of the cases has to be expected. Normal zoster has not been shown to be associated with maternal pneumonia, birth defects or problems in the perinatal period. On the basis of the clinical consequences of varicella-zoster virus infections during pregnancy, the present paper summarizes the currently available concepts of prevention, diagnosis and therapy.

Genetic risks of antiviral nucleoside analogues - a survey

The available informations on the genotoxic effects in experimental systems of the antiherpesvirus nucleosides aciclovir, penciclovir, ganciclovir, brivudine and cidofovir as well as of the antiretrovirals zidovudine (AZT), lamivudine, zalcitabine (ddC), didanosine and stavudine are reviewed. Furthermore, data on carcinogenic activity of these drugs in laboratory rodents are compiled. Most nucleoside analogue antivirals induce chromosomal aberrations but are inactive in gene mutation assays. Carcinogenicity findings in mice and rats are variable but clearly positive for AZT and ddC. The possible mechanisms by which these agents may cause damage in the genetic information are still largely hypothetical, and experimental findings do not permit relevant extrapolations to the situation in man. There is no conclusive evidence that any of the drugs caused tumours in humans. The use of nucleoside analogues in antiviral therapy remains a pragmatic option that seems justified by risk/benefit assessment.

Seroprevalence of herpes simplex virus type 1 and type 2 in selected German populations—relevance for the incidence of genital herpes

This study was carried out to determine the prevalence of antibodies to herpes simplex virus types 1 (HSV‐1) and 2 (HSV‐2) in selected German populations, such as blood donors, hospital patients, and human immunodeficiency virus (HIV)‐seropositive individuals. Serum samples collected between 1996 and 1998 were tested by enzyme immunoassays using monoclonal antibody‐selected native gG1 and gG2 as antigens and an immunoblot using type‐specific recombinant glycoproteins. Equivocal results were resolved by an “in‐house” Western blot assay. The prevalence of HSV‐1 antibodies increased steadily with age and reached high levels of ≥88% among subjects 40 years of age or older. In the sample of patients and blood donors, the HSV‐2 seroprevalence was 12.8% (95% CI = 11.9–13.8%). About 81% of the HSV‐2 seropositive subjects were coinfected with HSV‐1. When adjusted for age, there was no difference in the HSV‐2 seroprevalence between hospital patients and blood donors. The HSV‐2 seroprevalence was significantly higher among women (15%) than among men (10.5%), yielding a female : male odds ratio of 1.5 for hospital patients and of 1.67 for blood donors. Among the HIV‐infected population, 91.1% were seropositive for HSV‐1 and 47.9% for HSV‐2. HIV‐infected women have a significantly higher risk of HSV‐2 infection than men (odds ratio [OR] = 3.22; 95% confidence ratio [CI] 1.99–5.20). In conclusion, although the rate of infections with HSV‐2 is relatively low in the German population, attention should be given to the further development in adolescents, especially in view of a possible decrease of HSV‐1 seroprevalence in childhood. J. Med. Virol. 61:201–207, 2000.

Varicella vaccination in children after bone marrow transplantation

Herpes zoster (HZ) is one of the most common complications after bone marrow transplantation (BMT) in children. Apart from treatment with antiviral drugs, effective prevention by active immunization with varicella-zoster virus (VZV) appears to be possible. In this study 15 patients were vaccinated with a live attenuated VZV vaccine (Varilrix) 12–23 months after BMT. The vaccine was well tolerated without adverse reactions. Chickenpox or HZ were not observed for up to 2 years after immunization. Eight out of nine seronegative patients seroconverted and in six virus-specific IgG could still be demonstrated 2 years later. The incidence of VZV diseases in 133 non-immunized children after BMT was 26.3%. Infections usually occurred within 18 months after BMT.

Varicella vaccination in Europe – taking the practical approach

Varicella is a common viral disease affecting almost the entire birth cohort. Although usually self-limiting, some cases of varicella can be serious, with 2 to 6% of cases attending a general practice resulting in complications. The hospitalisation rate for varicella in Europe ranges from 1.3 to 4.5 per 100,000 population/year and up to 10.1% of hospitalised patients report permanent or possible permanent sequelae (for example, scarring or ataxia). However, in many countries the epidemiology of varicella remains largely unknown or incomplete.In countries where routine childhood vaccination against varicella has been implemented, it has had a positive effect on disease prevention and control. Furthermore, mathematical models indicate that this intervention strategy may provide economic benefits for the individual and society. Despite this evidence and recommendations for varicella vaccination by official bodies such as the World Health Organization, and scientific experts in the field, the majority of European countries (with the exception of Germany and Greece) have delayed decisions on implementation of routine childhood varicella vaccination, choosing instead to vaccinate high-risk groups or not to vaccinate at all.In this paper, members of the Working Against Varicella in Europe group consider the practicalities of introducing routine childhood varicella vaccination in Europe, discussing the benefits and challenges of different vaccination options (vaccination vs. no vaccination, routine vaccination of infants vs. vaccination of susceptible adolescents or adults, two doses vs. one dose of varicella vaccine, monovalent varicella vaccines vs. tetravalent measles, mumps, rubella and varicella vaccines, as well as the optimal interval between two doses of measles, mumps, rubella and varicella vaccines).Assessment of the epidemiology of varicella in Europe and evidence for the effectiveness of varicella vaccination provides support for routine childhood programmes in Europe. Although European countries are faced with challenges or uncertainties that may have delayed implementation of a childhood vaccination programme, many of these concerns remain hypothetical and with new opportunities offered by combined measles, mumps, rubella and varicella vaccines, reassessment may be timely.

Laboratory diagnosis of herpes zoster

Virological diagnosis of zoster should be rapid when effective antiviral chemotherapy is being considered. In the present study, vesicle specimens of 100 patients with zoster were analysed by detecting viral DNA using polymerase chain reaction (PCR). The findings were compared with those obtained by traditional virological and serological methods. PCR results confirmed the clinical diagnosis of zoster in 95%. Primers selected from varicella-zoster virus (VZV) gene 28 proved to be most sensitive. The sensitivity of virus culture was 20% (specificity 100%), of direct immunofluorescent VZV-specific antigen staining in vesicle samples 82% (specificity 76%), and in 48% there was a serological response to specific IgM and IgA antibodies within 4 days after the onset of rash. These findings suggest that PCR is the method of choice for rapid laboratory diagnosis of zoster.

Prevalence of hepatitis E virus-specific antibodies in humans with occupational exposure to pigs

Due to the increasing number of non-travel-associated hepatitis E virus (HEV) infections observed in several industrialised countries including Germany, there is a substantial interest in the characterisation of risk factors and transmission routes relevant to autochthonous HEV infections. Autochthonous cases are believed to be the result of a zoonotic HEV transmission from pigs, wild boars and deer. Recently, a high prevalence of HEV-specific antibodies in the German domestic pig population has been demonstrated. Thus, one may assume a higher prevalence of HEV-specific antibodies in humans with occupational exposure to pigs. In this study, sera obtained from 24 slaughterers, 14 meat inspectors, 46 pig farmers and 22 veterinarians were tested for the presence of HEV-specific antibodies using a line immunoassay. For comparison, sera obtained from 116 age- and gender-matched blood donors were also included. Twenty eight per cent (28.3%; 30/106) of the swine-exposed humans and 15.5% (18/116) of the blood donors without contact to pigs exhibited IgG-antibodies determined as reactive (i.e. borderline or positive) against HEV. Thus, an increased risk of HEV infection in humans occupationally exposed to pigs and particularly for slaughterers (41.7%; 10/24) was demonstrated.

Antiviral potential and molecular insight into neuraminidase inhibiting diarylheptanoids from Alpinia katsumadai.

At present, neuraminidase (NA) inhibitors are the mainstay of pharmacological strategies to fight against global pandemic influenza. In the search for new antiviral drug leads from nature, the seed extract of Alpinia katsumadai has been phytochemically investigated. Among the six isolated constituents, four diarylheptanoids showed in vitro NA inhibitory activities in low micromolar ranges against human influenza virus A/PR/8/34 of subtype H1N1. The most promising constituent, katsumadain A (4; IC(50) = 1.05 +/- 0.42 microM), also inhibited the NA of four H1N1 swine influenza viruses, with IC(50) values between 0.9 and 1.64 muM, and showed antiviral effects in plaque reduction assays. Considering the flexible loop regions of NA, extensive molecular dynamics (MD) simulations were performed to study the putative binding mechanism of the T-shaped diarylheptanoid 4. Docking results showed well-established interactions between the protein and the core of this novel NA-inhibiting natural scaffold, excellent surface complementarity to the simulated binding pocket, and concordance with experimentally derived SAR data.