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Biomedical subjects

C A Siegrist

Publications and source records attributed to C A Siegrist.

At least 37 records · Page 2Linked to original sources
PubMed2000

Detection of enteroviruses in the cerebrospinal fluid by polymerase chain reaction: prospective study of impact on the management of hospitalized children.

A polymerase chain reaction kit (AMPLICOR EV) for the detection of enteroviruses (EV-PCR) in the cerebrospinal fluid (CSF) was evaluated in clinical conditions in a prospective blinded-intention study. Forty-three children (mean age 2.7 years) hospitalized for suspected meningitis or fever of unclear etiology were enrolled. EV-PCR was performed on a daily basis. Results were available in less than 2 days in 72% of cases. EV-PCR was positive in nine (21%) children, including three infants without CSF pleocytosis. Knowing their EV-PCR result would have allowed a saving of 18 hospital days and 12 days of antibiotic therapy. The EV-PCR in the CSF can thus be practically useful for children hospitalized for meningitis or fever if available on-site on a daily basis.

Adolescent↗
PubMed2000

Vaccination in the neonatal period and early infancy.

Immune maturation is responsible for a progressive increase in antibody responses that can be elicited during the first year of life, such that neonatal immunization may currently not be expected to induce strong antibody responses. In contrast, B and T cell priming can be induced very early in life, without interference of maternal immunity. Strong IL-5 and IL-13 responses in young mice, and limited IL-12 and IFN-gamma release capacity by early life APC and T cells both in young mice and infants, could contribute to the severity of infections with intracellular pathogens in early life. It calls for evaluation of novel delivery systems, adjuvants and/or prime-boost immunization strategies capable to meet the challenge of both strong neonatal immunogenicity and acceptable reactogenicity. The extent to which early life murine immunization models may be useful for preclinical evaluation of infant responses is outlined in this review.

Animals↗
PubMed1999

Combined vaccination of Haemophilus influenzae type b conjugate and diphtheria-tetanus-pertussis containing acellular pertussis.

After the introduction of effective Haemophilus influenzae type b (Hib) conjugate vaccines, clinical practice has driven the development of combination vaccines comprising Hib conjugates with the infant diphtheria-tetanus-pertussis (DTP) vaccines. However, when such combinations contain an acellular pertussis component (Pa), the antibody response to Hib is lower than that with separate injections and doubts have been raised about their efficacy. We believe that such concerns are unwarranted, since the serological correlates of efficacy previously applied for Hib polysaccharide vaccines seem inappropriate for Hib conjugates. Furthermore, our own studies have shown that the lower antibody responses are not associated with impaired function of the antibodies induced, nor, and possibly more importantly, with the induction of immune memory against Hib. Therefore, with the proviso that careful clinical surveillance of Hib disease is maintained, we encourage the introduction of DTPa-Hib combinations to facilitate the inclusion of Hib into the already crowded childhood immunisation schedule.

Bacterial Capsules↗
PubMed1999

CpG oligodeoxynucleotides can circumvent the Th2 polarization of neonatal responses to vaccines but may fail to fully redirect Th2 responses established by neonatal priming.

Neonatal murine responses to a panel of conventional vaccines differ qualitatively from adult responses by a particular polarization toward a Th2 pattern and a frequent limitation of the Th1 and CTL responses required for protection against intracellular microorganisms. In contrast, DNA vaccines induce adult-like Th1/CTL neonatal responses against the same vaccine Ags. In this report, we show that this can be related to their content in unmethylated CpG motifs. Oligodeoxynucleotides (ODN) containing CpG motifs activate neonatal APCs to produce IL-12 in vitro and induce adult-like Th1 responses to tetanus toxoid and measles Ags in vivo, with production of IgG2a-specific Abs and adult-like secretion of IFN-gamma and IL-5 by Ag-specific T cells. However, in spite of their capacity to trigger neonatal B cell proliferation in vitro, CpG-ODN only partially enhanced early life Ab responses. Finally, using Th1-driving CpG-ODN with the boosting dose of a protein vaccine was sufficient to redirect adult but not neonatally primed Th2 responses. These observations could be important for the development of novel vaccines that will have to be effective early in life.

Animals↗
PubMed1999

Combining DNA and protein vaccines for early life immunization against respiratory syncytial virus in mice.

Early life responses to respiratory syncytial virus (RSV)-F DNA and RSV-F protein immunization were studied in murine models of neonatal immunization. RSV-F DNA induced similar antibody (Ab) responses, antigen-specific IFN-gamma production and cytotoxic T lymphocyte (CTL) responses in 1-week-old and adult BALB / c mice. In contrast, RSV-F protein induced much higher IL-5 responses in early life. Both vaccines elicited Ab and CTL responses in spite of maternal Ab, but with distinctive kinetics. Sequential RSV-F DNA priming / protein boosting primed 1-week-old mice for RSV-F-specific CTL responses, reduced IL-5 production and enhanced Ab responses. In contrast, IL-5 exceeded IFN-gamma responses when young mice were primed with protein and boosted with DNA. Last, when protein and DNA immunization were combined, a single vaccine dose induced early Ab responses, preferential IL-5 responses but strong CTL responses. Sequential or combined DNA / protein immunization thus represent interesting strategies for early life immunization.

Animals↗
PubMed1999

Protective efficacy against respiratory syncytial virus following murine neonatal immunization with BBG2Na vaccine: influence of adjuvants and maternal antibodies.

Alum-adsorbed BBG2Na, a recombinant vaccine derived in part from the respiratory syncytial virus (RSV) subgroup A G protein, induced moderate antibody titers after 1 immunization in 1-week-old mice but conferred complete lung protection upon RSV challenge. The anti-BBG2Na IgG1-IgG2a neonatal isotype profile was suggestive of dominant Th2 responses compared with those in adults. Formulation of BBG2Na with a Th1-driving adjuvant efficiently shifted neonatal responses toward a more balanced and adultlike IgG1-IgG2a profile without compromising its protective efficacy. BBG2Na-induced protective immunity was maintained even after early life immunization in the presence of high titers of maternal antibodies. Under these conditions, the protective efficacy (86%-100%) reflected the high capacity of the nonglycosylated G2Na immunogen to escape inhibition by RSV-A-induced maternal antibodies. Thus, immunization with BBG2Na protected against viral challenge despite neonatal immunologic immaturity and the presence of maternal antibodies, two major obstacles to neonatal RSV vaccine development.

Adjuvants, Immunologic↗
PubMed1998

CpG DNA can induce strong Th1 humoral and cell-mediated immune responses against hepatitis B surface antigen in young mice.

Successful neonatal immunization of humans has proven difficult. We have evaluated CpG-containing oligonucleotides as an adjuvant for immunization of young mice (1-14 days old) against hepatitis B virus surface antigen. The protein-alum-CpG formulation, like the DNA vaccine, produced seroconversion of the majority of mice immunized at 3 or 7 days of age, compared with 0-10% with the protein-alum or protein-CpG formulations. All animals, from neonates to adults, immunized with the protein-alum vaccine exhibited strong T helper (Th)2-like responses [predominantly IgG1, weak or absent cytotoxic T lymphocytes (CTL)]. Th2-type responses also were induced in young mice with protein-CpG (in 1-, 3-, and 7-day-old mice) and protein-alum-CpG (in 1- and 3-day-old mice) but immunization carried out at older ages gave mixed Th1/Th2 (Th0) responses. DNA vaccines gave Th0-like responses when administered at 1 and 7 days of age and Th1-like (predominantly IgG2a and CTL) responses with 14-day-old or adult mice. Surprisingly, the protein-alum-CpG formulation was better than the DNA vaccine for percentage of seroconversion, speed of appearance, and peak titer of the antibody response, as well as prevalence and strength of CTL. These findings may have important implications for immunization of human infants.

Aging↗
PubMed1998

Prevention of vertical HIV transmission: additive protective effect of elective Cesarean section and zidovudine prophylaxis. Swiss Neonatal HIV Study Group.

OBJECTIVE: To study the effect of elective Cesarean section and zidovudine prophylaxis on vertical HIV transmission. DESIGN: Prospective study. SETTING: Obstetric and paediatric clinics in Switzerland. PARTICIPANTS: Children of mothers with HIV infection identified before or at delivery. INTERVENTIONS: Routine use of elective Cesarean section for HIV-infected parturients by some Swiss centres since 1985. National recommendation for zidovudine prophylaxis in mid-1994. MAIN OUTCOME MEASURE: HIV infection status of children. RESULTS: In a cohort of 494 children born at least 6 months before the analysis date, 67 out of 414 children with known infection status were found to be infected, giving an overall transmission rate of 16.2% [95% confidence interval (CI), 13.0-18.51. Elective Cesarean section with intact membranes and without previous labour was associated with a lower transmission rate of 6% [odds ratio (OR), 0.29; 95% CI, 0.12-0.70; P = 0.006 versus other delivery modes]. Transmission rate was intermediate after spontaneous delivery or non-elective Cesarean section (18%), and higher after obstetric interventions (27%; test for trend, P < 0.001). Since mid-1994, 78% of all women with registered pregnancies have received some form of zidovudine prophylaxis. Transmission rate was reduced from 17 to 7% after any zidovudine exposure (OR, 0.4; 95% CI, 0.11-1.41). Combined use of elective Cesarean section and zidovudine resulted in a 0% transmission rate (none out of 31), compared with 8% (seven out of 86) after elective Cesarean section without zidovudine, 17% (four out of 24) after zidovudine alone, and 20% (55 out of 271) after no intervention. CONCLUSIONS: Elective Cesarean section and zidovudine prophylaxis appear to have an additive effect in the prevention of vertical HIV transmission.

Abortion, Induced↗
PubMed1998

Influence of maternal antibodies on vaccine responses: inhibition of antibody but not T cell responses allows successful early prime-boost strategies in mice.

The transfer of maternal antibodies to the offspring and their inhibitory effects on active infant immunization is an important factor hampering the use of certain vaccines, such as measles or respiratory syncytial virus vaccine, in early infancy. The resulting delay in protection by conventional or novel vaccines may have significant public health consequences. To define immunization approaches which may circumvent this phenomenon, experiments were set up to further elucidate its immunological bases. The influence of maternal antibodies on antibody and T cell responses to measles hemagglutinin (MV-HA) were analyzed following MV-HA immunization of pups born to immune or control BALB/c mothers using four different antigen delivery systems: live or inactivated conventional measles vaccine, a live recombinant canarypox vector and a DNA vaccine. High levels (> 5 log10) of maternal anti-HA antibodies totally inhibited antibody responses to each of the vaccine constructs, whereas normal antibody responses were elicited in presence of lower titers of maternal antibodies. However, even high titers of maternal antibodies affected neither the induction of vaccine-specific Th1/Th2 responses, as assessed by proliferation and levels of IFN-gamma and IL-5 production, nor CTL responses in infant mice. On the basis of these unaltered T cell responses, very early priming and boosting (at 1 and 3 weeks of age, respectively) with live measles vaccine allowed to circumvent maternal antibody inhibition of antibody responses in pups of immune mothers. This was confirmed in another immunization model (tetanus toxoid). It suggests that effective vaccine responses may be obtained earlier in presence of maternal antibodies through the use of appropriate immunization strategies using conventional or novel vaccines for early priming.

Animals↗
PubMed1998

[Vaccination against hepatitis B].

Three comparable vaccines against hepatitis B, consisting of recombinant HBsAg, are registered in Switzerland. After intramuscular administration (deltoid, thigh), they induce seroconversion in 95% of subjects following a 0, 1, 6 or 0, 1, 2 and 12 months schedule. The determination of antibody titers is thus not required in healthy subjects in absence of an increased risk of exposure (healthcare workers). Vaccine induced protection is extended beyond the disappearance of specific antibodies, through the persistence of immunological memory, which reactivates immune defense mechanisms upon viral exposure. A booster immunization is thus not necessary after a full immunization course, even if given in the first year of life or in newborns of HBsAg positive mothers. The excellent safety profile of these vaccines (local pain 3-29%, fever 1-6%) allows their universal administration. Two combined vaccines are already available, and new vaccines may yet facilitate prevention of hepatitis B in the future by allowing a reduction in the number of doses required for protection.

Adult↗
PubMed1998

Optimization of vaccine responses in early life: the role of delivery systems and immunomodulators.

Infant immunization is a particularly important field with multiple challenges for vaccine research and development. There is, together with a high susceptibility to infections, a lower efficacy of most vaccinations in newborns and young infants, compared to those performed later in life. In the present review, the authors focus on problems arising from the attempt to vaccinate against pathogens very early in life, and on the role of selective adjuvants (i.e. antigen delivery systems or immunomodulators) that could be used to: (i) rapidly induce strong antibody responses of the appropriate isotypes; (ii) elicit sustained antibody responses extending beyond infancy; (iii) induce efficient Th1 and CTL responses in spite of the preferential Th2 polarization of early life responses; (iv) escape from maternal antibody mediated inhibition of vaccine responses; (v) show acceptable reactogenicity in early life; and (vi) allow incorporation of several vaccine antigens into a single formulation so as to reduce the number of required injections. How such objectives might be achieved by several of the vaccine formulations currently in development is illustrated by reviewing data from experimental models and clinical studies, when available.

Adjuvants, Immunologic↗
PubMed1998

Influenza immunization: improving compliance of healthcare workers.

OBJECTIVE: In spite of yearly recalls, influenza immunization rates of healthcare workers (HCWs) remained low (10%) at the University Hospitals of Geneva. This study was conducted to identify HCWs' reasons for rejection of immunization, to design specific intervention methods based on these reasons, and to evaluate the impact of such interventions. METHODS: Three departments with high-risk patients (geriatrics, obstetrics, and pediatrics) were selected as main targets. Questionnaires were distributed in these units. Based on HCWs' perceptions, different intervention methods were designed and used either in these departments only (educational conferences, on-site availability of a vaccination nurse) or in the whole institution (posters, personal letters). Immunization rates were collected throughout the institution. RESULTS: 797 completed questionnaires from 1,092 HCWs (73%) were returned. Major reasons for immunization rejection were confidence that their bodies' self-defense mechanisms would ward off infection (32%), perception of low exposure risk (23%), and doubts concerning vaccine efficacy (19%). The use of intervention methods designed to address these factors increased influenza immunization rates in the three targeted departments from 13% (95% confidence interval [CI95], 11.4-15.6) in 1995 and 1996 to 37% (CI95, 34.5-40.3) in the following season (P<.001). In all other departments, immunization rates rose from 9% (CI95, 8.5-10.3) to 23% (CI95, 21.6-24.1; P<.001). Nurses were, and remained, more reluctant to be immunized compared to other HCWs. CONCLUSIONS: Influenza immunization rates can be increased significantly by specific interventions based on local concerns of HCWs, among which educational conferences and the on-site availability of a vaccination nurse appeared important.

Cross Infection↗
PubMed1998

Procalcitonin is a marker of severity of renal lesions in pyelonephritis.

OBJECTIVE: In an attempt to differentiate acute pyelonephritis from lower urinary tract infection (UTI), we measured serum procalcitonin levels, a recently described marker of infection. We compared it with other commonly used inflammatory markers and evaluated its ability to predict renal involvement as assessed by dimercaptosuccinic acid (DMSA) scintigraphy. METHODS: Serum C-reactive protein, leukocyte counts, and procalcitonin levels were measured in 80 children, 1 month to 16 years of age, admitted for suspected pyelonephritis. Renal involvement was assessed by 99mTe-DMSA scintigraphy in the first 5 days after admission. The examination was repeated at least 3 months later if the first result was abnormal. RESULTS: In lower UTI, the mean procalcitonin (PCT) was 0.38 micrograms/L +/- 0.19 compared with 5.37 micrograms/L +/- 1.9 in pyelonephritis. In these two groups, respectively, leukocyte counts were 10939/mm3 +/- 834 and 17429/mm3 +/- 994, and C-reactive protein (CRP) levels were 30.3 mg/L +/- 7.6 and 120.8 mg/L +/- 8.9. When inflammatory markers were correlated to the severity of the renal lesion as ranked by DMSA scintigraphy, we found a highly significant correlation with plasma levels of PCT, but borderline significance with CRP and none with leukocyte counts. Patients without vesicoureteral reflux had a mean PCT of 5.16 micrograms/L +/- 2.33, which was not significantly different from that in patients with reflux who had a mean PCT of 5.76 micrograms/L +/- 3.49. For the prediction of renal lesions at admission, CRP had a sensitivity of 100% and a specificity of 26.1%. The sensitivity and specificity of PCT were 70.3% and 82.6%, respectively. CONCLUSION: We conclude that serum PCT levels were increased significantly in children with febrile UTI when renal parenchymal involvement (assessed by DMSA scintigraphy) was present and allowed for prediction of patients at risk of severe renal lesions.

Calcitonin↗
PubMed1998

Maternal immunity and infant responses to immunization: factors influencing infant responses.

The presence of maternally-derived antibodies at the time of immunization is known to interfere frequently with active immunization, with variable levels of clinical significance. Deciphering the rules as the basis of such inhibitory effects on infant vaccine responses would certainly contribute to the development of vaccination strategies for early life. These questions were addressed in murine neonatal or early life immunization models using various antigens (measles, tetanus, RSV) and antigen-presentation systems (peptides, proteins, live attenuated vaccines, live recombinant vectors or DNA plasmids) in the absence or presence of maternal antibodies. Factors identified as crucial determinants of maternal antibody-mediated effects on both live and non-live vaccines include the relative amount of maternal antibodies and of vaccine antigens present at immunization, antigenic conformation, epitope specificity and the distinct influence on B-cell and T-cell vaccine responses.

Animals↗