Reversible encephalopathy complicating post-streptococcal glomerulonephritis

We describe a 15-year-old boy with acute transient encephalopathy complicating poststreptococcal glomerulonephritis. Based on advanced magnetic resonance imaging, cerebral alterations were related to cerebrovascular autoregulatory dysfunction (ie, a vasogenic edema) and vasculitis was excluded. These insights into the pathophysiology improve patient management and argue against the therapeutic immunosuppression postulated by some authors.

Efficacy of a strategy to prevent neonatal early-onset group B streptococcal (GBS) sepsis

BACKGROUND: Existing guidelines recommend different strategies to prevent early-onset neonatal GBS sepsis. In 1997, using our own data on incidence and risk factors, we established a new prevention strategy which includes GBS screening at 36 weeks' gestation and intrapartum antibiotic prophylaxis (IAP) in women with positive or unknown GBS colonization with at least one risk factor. The present study evaluates the efficacy of the new prevention strategy. METHODS: Retrospective study of the incidence of early-onset GBS sepsis among all live births at the University Women's Hospital Basel between 1997 and 2002. Additional analysis of delivery and post partum period of all GBS sepsis cases, including GBS screening, risk factors during labor (prematurity, rupture of membranes (ROM) <12 h, intrapartum signs of infection), and IAP. Comparison of this group's characteristics G2 (9,385 live births, using the new strategy) with the previous group, G1 (1984-1993, 16,126 live births, without GBS screening or routine IAP) was performed. RESULTS: The incidence of early-onset GBS sepsis was reduced from 1/1000 (G1) to 0.53/1000 (G2). We observed a significant reduction of overall intrapartum risk factors in cases of GBS sepsis. CONCLUSION: This study suggests that our new prevention strategy is effective in reducing the incidence of early-onset GBS sepsis in neonates. In comparison, implementation of the CDC's prevention strategy might have prevented 2 additional cases in 9385 live births. However, this would have required treating a much larger number of pregnant women with IAP with consequential increasing costs, side effects and complications.

Biological safety concepts of genetically modified live bacterial vaccines

Live vaccines possess the advantage of having access to induce cell-mediated and antibody-mediated immunity; thus in certain cases they are able to prevent infection, and not only disease. Furthermore, live vaccines, particularly bacterial live vaccines, are relatively cheap to produce and easy to apply. Hence they are suitable to immunize large communities or herds. The induction of both cell-mediated immunity as well as antibody-mediated immunity, which is particularly beneficial in inducing mucosal immune responses, is obtained by the vaccine-strain's ability to colonize and multiply in the host without causing disease. For this reason, live vaccines require attenuation of virulence of the bacterium to which immunity must be induced. Traditionally attenuation was achieved simply by multiple passages of the microorganism on growth medium, in animals, eggs or cell cultures or by chemical or physical mutagenesis, which resulted in random mutations that lead to attenuation. In contrast, novel molecular methods enable the development of genetically modified organisms (GMOs) targeted to specific genes that are particularly suited to induce attenuation or to reduce undesirable effects in the tissue in which the vaccine strains can multiply and survive. Since live vaccine strains (attenuated by natural selection or genetic engineering) are potentially released into the environment by the vaccinees, safety issues concerning the medical as well as environmental aspects must be considered. These involve (i) changes in cell, tissue and host tropism, (ii) virulence of the carrier through the incorporation of foreign genes, (iii) reversion to virulence by acquisition of complementation genes, (iv) exchange of genetic information with other vaccine or wild-type strains of the carrier organism and (v) spread of undesired genes such as antibiotic resistance genes. Before live vaccines are applied, the safety issues must be thoroughly evaluated case-by-case. Safety assessment includes knowledge of the precise function and genetic location of the genes to be mutated, their genetic stability, potential reversion mechanisms, possible recombination events with dormant genes, gene transfer to other organisms as well as gene acquisition from other organisms by phage transduction, transposition or plasmid transfer and cis- or trans-complementation. For this, GMOs that are constructed with modern techniques of genetic engineering display a significant advantage over random mutagenesis derived live organisms. The selection of suitable GMO candidate strains can be made under in vitro conditions using basic knowledge on molecular mechanisms of pathogenicity of the corresponding bacterial species rather than by in vivo testing of large numbers of random mutants. This leads to a more targeted safety testing on volunteers and to a reduction in the use of animal experimentation.

Pharmacotherapy, vaccines and malaria advice for HIV-infected travellers

Since the introduction of effective antiretroviral therapy (ART), HIV-infected individuals are travelling more frequently and international travel has become much safer. Specific concerns include the safety of ART during travel, drug adherence and interaction considerations, and effects of immunosuppression. This review describes potentially important infections, vaccine effectiveness, safety and special approaches for their use, and HIV-related issues regarding predeparture counselling. With advanced immunosuppression (CD4+ T-cell count < 200/microl or < 14%), the immunogenicity of several vaccines is reduced, complications could occur after live attenuated vaccines and certain infections acquired during travel may be more frequent or severe. Challenges include the best options for malaria chemoprophylaxis, standby treatment and medical follow-up of the increasing number of HIV-infected long-term travellers.

Expression of proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta in the brain during experimental group B streptococcal meningitis

We performed mRNA in situ hybridization for TNF-alpha and IL-1beta from infant rats with group B streptococcal meningitis. Induction of both cytokines was seen in the ependyma and the meninges at 4 h. Both cytokines were expressed in the brain parenchyma at 12 h. Induction of IL-1beta mRNA was seen in vessels within the brain cortex. Neutrophilic infiltrate at all time points examined was minimal and could not account for the observed cytokine expression.

Tumor necrosis factor-alpha contributes to apoptosis in hippocampal neurons during experimental group B streptococcal meningitis

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) in neuronal injury in experimental group B streptococcal meningitis, infected neonatal rats were treated with a monoclonal antibody against TNF-alpha (20 mg/kg intraperitoneally) or saline given at the time of infection. Histopathology after 24 h showed necrosis in the cortex and apoptosis in the hippocampal dentate gyrus. Treated animals had significantly less hippocampal injury than did controls (P < .001) but had similar cortical injury and cerebrospinal fluid (CSF) inflammation. The antibody was then administered directly intracisternally (170 microg) to test whether higher CSF concentrations reduced inflammation or cortical injury. Again, hippocampal apoptosis was significantly reduced (P < .01), while cortical injury and inflammation were not. Thus, TNF-alpha played a critical role in neuronal apoptosis in the hippocampus, while it was not essential for the development of inflammation and cortical injury in this model.

Effect of thrombocytopenia on the early course of streptococcal endocarditis

Although platelets are a major factor in the pathogenesis of endocarditis, it is unclear if these cells promote or limit disease progression. To address this issue, the effects of thrombocytopenia on the early course of endovascular infection were examined. Aortic valve endocarditis was produced in rabbits by using Streptococcus sanguis M99. Thrombocytopenia was induced by intravenous administration of antiplatelet serum. Compared with controls (infected rabbits given nonimmune serum), thrombocytopenic rabbits had higher densities of streptococci within vegetations (mean log10 cfu/g, 9.78 vs. 8.11, P < .002) and a higher total number of bacteria per valve (mean log10 total cfu/valve, 8.96 vs. 7.43, P < .004). When tested for its interactions with platelets in vitro, strain M99 bound, activated, and aggregated rabbit platelets extensively and was rapidly killed by platelet microbicidal protein. These results indicate that platelets can limit disease progression in endocarditis. The host defense properties of platelets may in part be mediated by platelet microbicidal protein.

PURIFICATION AND EFFECTIVENESS OF VACCINES AND ANTIVIRAL COMPOUNDS

Viral infections account for over 13 million deaths per year. Antiviral drugs and vaccines are the most effective method to treat viral diseases. Antiviral compounds have revolutionized the treatment of AIDS, and reduced the mortality rate. However, this disease still causes a large number of deaths in developing countries that lack these types of drugs. Vaccination is the most effective method to treat viral disease; vaccines prevent around 2.5 million deaths per year. Vaccines are not able to offer full coverage due to high operational costs in the manufacturing processes. Although vaccines have saved millions of lives, conventional vaccines often offer reactogenic effects. New technologies have been created to eliminate the undesired side effects. However, new vaccines are less immunogenic and adjuvants such as vaccine delivery vehicles are required. This work focuses on the discovery of new natural antivirals that can reduce the high cost and side effects of synthetic drugs. We discovered that two osmolytes, trimethylamine N-oxide (TMAO) and glycine reduce the infectivity of a model virus, porcine parvovirus (PPV), by 4 LRV (99.99%), likely by disruption of capsid assembly. These osmolytes have the potential to be used as drugs, since they showed antiviral activity after 20 h. We have also focused on improving current vaccine manufacturing processes that will allow fast, effective and economical vaccines to be produced worldwide. We propose virus flocculation in osmolytes followed by microfiltration as an economical alternative for vaccine manufacturing. Osmolytes are able to specifically flocculate hydrophobic virus particles by depleting a hydration layer around the particles and subsequently cause virus aggregation. The osmolyte mannitol was able to flocculate virus particles, and demonstrate a high virus removal, 81% for PPV and 98.1% for Sindbis virus (SVHR). Virus flocculation with mannitol, followed by microfiltration could be used as a platform process for virus purification. Finally, we perform biocompatibility studies on soft-templated mesoporous carbon materials with the aim of using these materials as vaccine delivery vehicles. We discovered that these materials are biocompatible, and the degree of biocompatibility is within the range of other biomaterials currently employed in biomedical applications.

Randomized, double-blind comparative trial of subunit and virosomal influenza vaccines for immunocompromised patients

BACKGROUND: To our knowledge, no study to date has compared the effects of a subunit influenza vaccine with those of a virosomal influenza vaccine on immunocompromised patients. METHODS: A prospective, double-blind, randomized study was conducted to compare the immunogenicity and reactogenicity of subunit and virosomal influenza vaccines for adult patients who had an immunosuppressive disease or who were immunocompromised as a result of treatment. RESULTS: There were 304 patients enrolled in our study: 131 with human immunodeficiency virus (HIV) infection, 47 with a chronic rheumatologic disease, 74 who underwent a renal transplant, 47 who received long-term hemodialysis, and 5 who had some other nephrologic disease. There were 151 patients who received the subunit vaccine and 153 patients who received the virosomal vaccine. A slightly higher percentage of patients from the subunit vaccine group were protected against all 3 influenza vaccine strains after being vaccinated, compared with patients from the virosomal vaccine group (41% vs. 30% of patients; P = .03). Among HIV-infected patients, the level of HIV RNA, but not the CD4 cell count, was an independent predictor of vaccine response. Among renal transplant patients, treatment with mycophenolate significantly reduced the immune response to vaccination. The 2 vaccines were comparable with regard to the frequency and severity of local and systemic reactions within 7 days after vaccination. Disease-specific scores for the activity of rheumatologic diseases did not indicate flare-ups 4-6 weeks after vaccination. CONCLUSIONS: For immunosuppressed patients, the subunit vaccine was slightly more immunogenic than the virosomal vaccine. The 2 vaccines were comparable with regard to reactogenicity. Vaccine response decreased with increasing degree of immune suppression. Among HIV-infected patients, the viral load, rather than the CD4 cell count, predicted the protective immune response to the vaccine. CLINICAL TRIALS REGISTRATION: NCT00783380 .

Bacterial phenotype variants in group B streptococcal toxic shock syndrome

We conducted genetic and functional analyses of isolates from a patient with group B streptococcal (GBS) necrotizing fasciitis and toxic shock syndrome. Tissue cultures simultaneously showed colonies with high hemolysis (HH) and low hemolysis (LH). Conversely, the HH and LH variants exhibited low capsule (LC) and high capsule (HC) expression, respectively. Molecular analysis demonstrated that the 2 GBS variants were of the same clonal origin. Genetic analysis found a 3-bp deletion in the covR gene of the HH/LC variant. Functionally, this isolate was associated with an increased growth rate in vitro and with higher interleukin-8 induction. However, in whole blood, opsonophagocytic and intracellular killing assays, the LH/HC phenotype demonstrated higher resistance to host phagocytic killing. In a murine model, LH/HC resulted in higher levels of bacteremia and increased host mortality rate. These findings demonstrate differences in GBS isolates of the same clonal origin but varying phenotypes.

Antibody Response to Inactivated Viral Vaccines Administered to Calves at Weaning

Respiratory disease in beef calves has been associated with the stress of weaning. Management practices commonly delay vaccination of calves to this time, and weaning stress could potentially suppress the immune response. To reduce this stress we have been experimenting with a procedure termed “pasture weaning” in which the dams are removed and the calves remain on pasture. Observation suggests that calves weaned with this approach adapt to the weaned state much better than those held in drylot. Consequently, one would expect less stress-mediated effects including those on the immune system. Calves were weaned and assigned to groups that were pasture or drylot weaned, and calves within the groups were vaccinated with one of two inactivated virus vaccines by either the intramuscular or subcutaneous route. Weaning placement did not affect antibody responses to the viruses included in the vaccines. The route of administration did not influence responses with subcutaneous injection inducing responses equivalent to the intramuscular site. Utilization of this route for vaccination could be advantageous because it precludes the tissue damage and hidden abscessation that sometimes results from intramuscular injections. A distinct difference was noted in the immunogenicity of the vaccines with the Vira Shield product yielding significantly better responses to all viral entities.

Infectious Bovine Rhinotracheitis Virus Antibody Responses to Vaccines Used in Combination

The objective of this experimentation was to determine if circulating antibody titers to parainfluenza type-3 (PI-3) and infectious bovine rhinotracheitis (IBR) viruses could be enhanced by a combination of vaccines. The vaccines utilized were a modified live virus vaccine administered by the intranasal route and an inactivated virus vaccine injected intramuscularly. Virus neutralization tests were conducted on sera obtained at intervals before and following vaccination. Unfortunately, the calves were apparently exposed naturally to PI-3 virus, and the responses to that virus were inconclusive. However, antibody responses to IBR virus were dramatically enhanced by the combination of the two vaccines.

Antibody Responses of Young Calves to Inactivated Viral Vaccines

Three commercial inactivated virus vaccines were evaluated for immunogenicity in young calves with residual maternal antibodies. Groups of 30 calves were administered each of the vaccines at the start of the experimentation and were administered a second dose 32 days later. Serum was obtained from these calves and 30 calves in a nonvaccinated control group prior to vaccination and at 32, 61, 99 and 125 days thereafter. Antibody responses to viruses in two of the vaccines were extremely limited. The third vaccine overcame suppression by maternal antibodies and elicited responses clearly differentiated from antibody levels in the control group of calves.

Toward global prevention of sexually transmitted infections (STIs): The need for STI vaccines.

An estimated 499 million curable sexually transmitted infections (STIs; gonorrhea, chlamydia, syphilis, and trichomoniasis) occurred globally in 2008. In addition, well over 500 million people are estimated to have a viral STI such as herpes simplex virus type 2 (HSV-2) or human papillomavirus (HPV) at any point in time. STIs result in a large global burden of sexual, reproductive, and maternal-child health consequences, including genital symptoms, pregnancy complications, cancer, infertility, and enhanced HIV transmission, as well as important psychosocial consequences and financial costs. STI control strategies based primarily on behavioral primary prevention and STI case management have had clear successes, but gains have not been universal. Current STI control is hampered or threatened by several behavioral, biological, and implementation challenges, including a large proportion of asymptomatic infections, lack of feasible diagnostic tests globally, antimicrobial resistance, repeat infections, and barriers to intervention access, availability, and scale-up. Vaccines against HPV and hepatitis B virus offer a new paradigm for STI control. Challenges to existing STI prevention efforts provide important reasons for working toward additional STI vaccines. We summarize the global epidemiology of STIs and STI-associated complications, examine challenges to existing STI prevention efforts, and discuss the need for new STI vaccines for future prevention efforts.