Johannes P. Kruppenbacher

Booster immunization of low- and non-responders after a standard three dose hepatitis B vaccine schedule—results of a post-marketing surveillance

Seventy-nine low-responders and 83 non-responders after a previous three-dose hepatitis B (HB) vaccine course at 0.1, and 6 months were enrolled to receive additional 20 micrograms recombinant HB vaccine doses every 2 months until all had anti-HBs levels > or = 100 mIU ml-1. After the first booster, 65.4% had anti-HBs levels > or = 100 mIU ml-1, 17.9% were low-responders (10-99 mIU ml-1), and 16.7% remained non-responders (< 10 mIU ml-1). All complying non-responders developed anti-HBs levels > or = 100 mIU ml-1 after the third booster at the latest, whereas all low-responders reached this level after the second booster. Although body mass index affected the response to the first hepatitis B booster, when full compliance to regular revaccination was ensured, all non- and low-responders eventually reached sufficient anti-HBs levels.

Analysis of sequence and pathogenic properties of two variants of encephalomyocarditis virus differing in a single amino acid in VP1.

The encephalomyocarditis (EMC) virus-induced diabetes-like syndrome in mouse inbred strains was used as a model to study the insulin-dependent diabetes mellitus (IDDM). Our investigations were performed with two EMC virus variants, PV2 and PV7. After infection of SJL mice with 10(5) PFU of PV2 about 70% of the animals developed a diabetes-like syndrome, whereas the PV7 infected mice appeared healthy. Histological examination and in situ experiments revealed that the islets of Langerhans are a main target of PV2, whereas PV7 infection leads to only modest changes of the islets. Sequence analysis of both variants revealed one amino acid exchange within the capsid protein VP1. Hence, we describe the first diabetogenic and non-diabetogenic EMCV variants differing in only one single amino acid.

Does the concurrent administration of an inactivated hepatitis A vaccine influence the immune response to other travelers vaccines

BACKGROUND Travelers seeking protection from hepatitis A also often need protection against other infections, prevalent at their destinations. METHODS A total of 396 volunteers received not only a hepatitis A vaccine but also either a vaccine against polio, hepatitis B, diphtheria, tetanus, yellow fever, Japanese encephalitis, typhoid fever or rabies according to their individual needs. We investigated the potential influence of the hepatitis A vaccination on the immune response to the other travelers vaccines that were administered concurrently. RESULTS With seroprotection rates of 100% for yellow fever, Japanese encephalitis and rabies immunization and tetanus boosters our data demonstrate that the concurrent administration of hepatitis A vaccine does not compromise the immune response of these vaccines. Also for oral typhoid, hepatitis B and diphtheria vaccination we did not detect a negative influence of concurrent hepatitis A vaccine administration as compared with respective vaccinations when given alone. Prior to vaccination, more than one third of our subjects lacked protective antibody levels against diphtheria and only 44% of initially seronegative travelers seroconverted to an anti-diphtheria titer > or = 0.01 mIU/mL, supporting a need for an additional dose. Furthermore, only two thirds of the vaccinees tested prior to vaccination were protected against polio type 3, and the seroconversion rate following the administration of oral polio vaccine, was lower for viral type 3 (80%), as has been previously demonstrated in settings without concurrent other vaccinations. CONCLUSION No negative effect of concurrent travelers vaccinations on the immune response of a hepatitis A vaccine has been detected in a previous report, and, likewise our data suggest no impairment of the antibody response of these travelers vaccines by the concurrent administration of the hepatitis A vaccine.

Epidemiology of HIV and Hepatitis B Virus (HBV) in Selected African and Asian Populations

Summary401 sera from patients of a rural hospital in Zimbabwe (1987), 211 South African sera (1982/83), as well as 460 sera from four Katmandu hospitals (1985) were tested for HIV-1 antibodies. The sera from Zimbabwe and Nepal were additionally tested for anti-HIV-2 using a panel of different tests, for hepatitis B markers, and partially for antibodies against other viral, bacterial, and protozoal antigens. Detailed clinical and sociodemographic data were taken from the Zimbabwe and Katmandu patients. The prevalence of HIV-1 antibodies in the Zimbabwe study population was 3.2%. All infections were found in the age group 17 to 30 years (n=254). The epidemiological situation was entirely different from that of HBV (hepatitis B virus). No serum could be confirmed to be anti-HIV-2-positive, but a definite diagnosis is still difficult to establish. Regular town contacts may be considered a possible risk factor. Antibodies against HIV-1 could not be detected in the South African and Asian sera. The seropositivity for anti-HBc in Katmandu (14%) and the prevalence of HBsAg (1.1%) was much lower than reported from other Asian countries.Zusammenfassung401 Seren von Patienten eines ländlichen Hospitals in Zimbabwe (1987), 211 Seren von Südafrikanern (1982/83) und 460 Seren aus vier Krankenhäusern in Katmandu (1985) wurden auf HIV-1-Antikörper untersucht. Die Seren aus Zimbabwe und Nepal wurden darüber hinaus vergleichend mit mehreren Tests auf HIV-2-Antikörper, Hepatitis B-Marker und zum Teil auf Antikörper gegen andere Viren, Bakterien und Protozoen untersucht. Ausführliche klinische und soziodemographische Daten wurden bei den Patienten in Zimbabwe und Katmandu erhoben. 3,2% der Seren aus Zimbabwe waren anti-HIV-1-positiv. Alle Infizierten gehörten der Altersgruppe zwischen 17 und 30 Jahren (n=254) an. Damit unterschied sich die epidemiologische Situation deutlich von der bei Hepatitis B. Antikörper gegen HIV-2 konnten in keinem Serum gefunden werden, aber eine definitive Diagnose ist z. Zt. noch schwierig. Regelmäßige Stadtkontakte stellen möglicherweise einen Risikofaktor dar. Weder in den Seren aus Südafrika noch in denen aus Nepal konnten HIV-1-Antikörper gefunden werden. Das Vorkommen von anti-HBc (14%) und vor allem HBsAg (1,1%) in Katmandu war wesentlich seltener als für andere asiatische Länder angegeben.

Encephalomyocarditis Virus and Diabetes Mellitus: Studies on Virus Mutants in Susceptible and Non-susceptible Mice

The so-called M-variant (especially subtype D) of encephalomyocarditis virus (EMCV) induces a diabetes-like syndrome in certain mouse strains which may serve as a model of insulin-dependent diabetes mellitus (IDDM) in man. The development and course of diabetes was influenced by a number of virus and host factors, among these being virus strain, virus dose, mouse strain, age, sex, and the hosts immunological status. In a D-variant stock of EMCV, we found a virus plaque variant (PV 2) diabetogenic for DBA/2 mice, and at least one variant (PV 7) that did not affect carbohydrate metabolism. Although the diabetogenicity of PV 2 proved to be a genetically stable characteristic after further passages in vivo and in vitro, the incidence of diabetes varied somewhat (mean value 65% in 10-week-old DBA/2 mice infected with 10(5) p.f.u.). Both lower (10(1) or 10(3) p.f.u.) and higher (10(7) or 10(8) p.f.u.) virus doses led to a diminished incidence and severity of diabetes. In younger animals (5 weeks) transient hyperglycaemia often appeared, whereas in older animals (20 weeks) there was a higher rate of mortality. Histological examination of the islets of Langerhans in diabetes-susceptible (DBA/2) and resistant (C57BL/6) mice revealed that EMCV-induced hyperglycaemia appeared to develop in parallel to islet cell damage. Even in diabetic animals, some unaffected islets were regularly found. This study demonstrates that EMCV mutants may have completely different biological effects and produce diabetes only in special circumstances. Host factors play a significant role in the development of diabetes.

Problems of live virus vaccine-associated poliomyelitis a paralytic case with isolation of all three poliovirus types.

The case of a 4-month-old girl is described who developed a paralytic polio-like syndrome 3 weeks after oral polio vaccination (OPV). All three poliovirus types could be isolated (9 days after onset of disease polio type 2, and 33 days after onset of disease types 1 and 3, respectively).In order to classify these isolates as Sabin (vaccine)-like (SL) or non-Sabin-like (non-SL), several markers were tested in three laboratories [intratypic serodifferentiation, reproductive capacity at supraoptimal temperature (RTC), A1(OH)3 gel elution assay, and oligonucleotide mapping]. The results of the marker determinations were not uniform, but — summarizing all data — it seems plausible to associate the disease with the OPV. The significance of marker determinations in proving a vaccine-induced poliomyelitis is discussed in the light of this clinical case. Some comments are made on poliovirus vaccination policy in developed countries.

Virological Examinations of Patients with AIDS‐Related Complex/Walter‐Reed 5 Enrolled in a Double‐Blind Placebo‐Controlled Study with Intravenous Gammaglobulin Administration.

Abstract. Thirty patients with AIDS‐related complex/Walter‐Reed 5 enrolled in a placebo‐controlled double‐blind study with high‐dose intravenous gammaglobulin administration were tested by quantitating HIV Western blot and other serological tests for viral antibodies. Furthermore, conventional virus isolation attempts were performed. Absence or loss of p24 antibodies during the study period was associated with progression to AIDS (p = 0.01) and thereby was an earlier prognostic parameter of a poor prognosis than T4 cell count. Neither changes in antibody patterns against other HIV polypeptides, HIV titers in the immunofluorescence test nor demonstration of HIV antigen were significantly associated with progression to AIDS. Cytomegalovirus (CMV) could be isolated from two duodenal biopsies of a patient who developed AIDS at the same time, but a concomitant serological diagnosis of CMV infection was not successful. Though signs in the serology of human herpesviruses (herpes simplex virus, CMV, Epstein‐Barr virus), possibly indicating a reactivation of latent infections, could be observed in some instances, a correlation with clinical symptoms or the clinical outcome was not feasible, perhaps also because of a poor standardization of some of the test kits used. All patients were positive for IgG antibodies against the three herpesviruses when entering the study. High prevalence of hepatitis B virus (HBV) markers was found (83% anti‐HBc positive), only 1 patient being chronically infected and highly infectious, as shown by HBV‐DNA hybridization. No significant difference between treatment and placebo group was observed with the parameters tested in this study.

Outbred mice infected by an encephalomyocarditis virus variant: a model for studying chronic viral heart disease.

Male 8 to 20-week-old NMRI mice (an outbred strain) infected with the encephalomyocarditis virus (EMCV) plaque variant (PV) 7 consistently develop a distinct myocarditis with a relatively low mortality (21%). Myocarditis occurs in essence independent of the virus dose applied, and other internal organs are not affected. Nevertheless, 3.5-week-old NMRI mice perished within 5 days of virus inoculation and exhibited disseminated myofibrillar degeneration (MFD); this obviously virus-induced myocardial damage was accompanied by scanty inflammatory infiltrates. EMCV PV7 infection of adult male C57B1/6 and DBA/2 mice causes myocarditis comparable to that seen in NMRI mice. In DBA/2 mice, however, the virus-induced myocardial necrosis is complicated by subtotal calcification. This strain has a genetically determined “spontaneous” calcification of the myocardium, as shown by the study of uninfected controls. EMCV PV7-infected NMRI mice appear a promising model for study of long-term effects of viral myocarditis, possibly including cardiomyopathy. Furthermore, this outbred mouse strain offers the possibility of examining the pathogenesis of direct viral cytolysis and its relation to MFD as well as immunologically mediated cell damage.

Perimyokarditis bei Influenza A Virus-Infektion

SummaryA 48-year old man was admitted with suspected acute myocardial infarction because of severe precordial pain and monophasic ST-elevations in the ECG. The patients history of an ongoing infection, the localization, extent, and course of the ECG changes as well as the development of a pericardial effusion suggested viral perimyocarditis. The diagnosis was supported by a significant rise of antibodies (seroconversion) against influenza A virus.

HPLC is an effective and fast method for analysis of viral proteins : a study of encephalomyocarditis virus mutants differing in pathogenicity

We investigated the use of HPLC in analysis of picornavirus variants by comparing structural polypeptides of three stable mutants of encephalomyocarditis virus (EMCV). The variants are known to differ in their pathogenicity for mice: plaque variant 2 (PV2) is diabetogenic, PV7 is non-diabetogenic and PV21 induces a generalized lethal infection. We first used HPLC to separate the structural proteins at high purity levels. Detailed analysis of these structural proteins by HPLC-peptide mapping revealed differences in all four viral proteins of PV21 as compared with mutants PV2 and PV7. A single amino acid exchange was found in viral protein 1 between PV2 and PV7. Altered peaks were identified by calculating retention times of tryptic peptides using sequence data and a computer program. Since peak alterations could be attributed to the observed amino acid exchanges, the results correlate well with cDNA sequencing data. Thus HPLC proved to be a useful and fast tool for primary or additional characterization of picornavirus variants at the level of whole virus proteins.