Francisco Noya

Humoral immunity 10 years after booster immunization with an adolescent and adult formulation combined tetanus, diphtheria, and 5-component acellular pertussis vaccine

Persistence of antibodies after a single dose of Tdap vaccine (tetanus, diphtheria, and 5-component acellular pertussis vaccine) was evaluated in a follow-up study of adolescents (N=324) and adults (N=644) who had received Tdap in earlier clinical trials. Outcome measures were seroprotection (tetanus and diphtheria) or seropositivity (pertussis) and geometric mean concentrations. Humoral immune responses to all antigens were robust 1 month after initial immunization, decreased at subsequent measurements, but continued to exceed pre-immunization levels 1, 3, 5, and 10 years later. Protective levels of diphtheria and tetanus antitoxin persisted in 99.3% of adolescents 10 years after a booster dose of Tdap. Seropositivity to 1 or more pertussis antigens also persisted in most adolescents for 10 years. Although tetanus antitoxin responses were similar in adults to those observed in adolescents, diphtheria antitoxin titers were lower, reflecting the fact that a smaller proportion of adults had received diphtheria toxoid in the previous 10 years compared to adolescents. These data will contribute to the selection of the optimal interval for repeat doses of Tdap.

Immune responses in adults to revaccination with a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine 10 years after a previous dose.

BACKGROUND Although decennial adult boosters of tetanus and diphtheria toxoids are recommended in Canada and the United States, a second dose of pertussis vaccine during adulthood is not currently recommended. METHODS This open-label, multicenter study compared the safety and immunogenicity of a first dose of an adult formulation of tetanus, diphtheria, and acelluar pertussis vaccine (Tdap) with a repeat dose of Tdap in adults who had received Tdap 10 years previously. RESULTS A total of 769 participants ranging in age from 20 to 72 years took part in this study; 92.3% of naïve and 92.7% of repeat-dose participants had at least one solicited adverse event. Injection-site pain (84.4% and 87.8%), erythema (29.7% and 23.1%), and swelling (23.3% and 20.5%), and myalgia (53.5% and 60.1%), headache (37.6% and 40.6%), malaise (29.0% and 29.4%), and fever (4.9% and 4.2%) were the most common solicited adverse events reported in the naïve and repeat-dose groups, respectively. Postvaccination antibody levels ≥0.1 IU/mL were achieved by 99.7% of the naïve-group participants and all of the repeat-dose participants for tetanus and 96.1% of the naïve group and 98.5% of the repeat-dose group for diphtheria, both meeting the predefined noninferiority criteria. For pertussis antibodies, anti-PT (89.2 EU/mL vs. 116 EU/mL) was higher in the repeat-dose group, anti-FHA (249 vs. 214) and anti-PRN (216 vs. 266) were similar, and anti-FIM (1015 vs. 779) was higher in the naïve group. Noninferiority criteria were met for all antigens except for anti-FIM. CONCLUSION A repeat dose of Tdap vaccine 10 years after the first dose was well tolerated and immunogenic in adults (ClinicalTrials.gov identifier: NCT00712959).

Biochemical mediators of meningeal inflammatory response to group B streptococcus in the newborn piglet model

ABSTRACT: The meningeal inflammatory response to a heat-killed mutant unencapsulated strain of type III group B Streptococcus (GBS) was studied in a newborn piglet model. GBS (109 colony-forming unit equivalents) or saline (control) was inoculated intraventricularly. Serial cerebrospinal fluid measurements were done at baseline and over the course of the next 24 h for cytochemical changes and production of tumor necrosis factor (TNF) and prostaglandins. In separate experiments, we defined the time course of early changes during the first 6 h and dose response relationship over a range of inocula 106 to 109 colony-forming unit equivalents. The intraventricular inoculation of the heat-killed unencapsulated GBS induced marked leukocytosis and increased protein by 6 h. These changes were preceded by a several hundredfold increase in TNF (maximum at 2 h) and prostaglandins (maximum at 2–4 h). The early and sharp rise in TNF suggests its pivotal role in initiating the inflammatory cascade. The magnitude of the inflammatory response increased with increasing bacterial dose over the range studied. To study the effect of encapsulation of GBS in the induction of meningeal inflammation, we compared the response to the unencapsulated mutant strain with that to the encapsulated parent strain. The encapsulated strain produced much smaller inflammatory changes, and only with high doses of bacteria. The GBS cell wall appeared to be the primary bacterial product triggering inflammation. Intraventricular injection of the heat-killed unencapsulated GBS with exposed cell wall can serve as a valid model for studying neonatal meningitis.

Tolerability and antibody response in adolescents and adults revaccinated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap) 4-5 years after a previous dose.

BACKGROUND Although decennial adult boosters of tetanus and diphtheria toxoids are recommended in Canada and the United States, a second dose of pertussis vaccine is not currently recommended for adults. METHODS This open-label, postmarketing, multicenter study evaluated the tolerability and immunogenicity of a second dose of an adult formulation of tetanus, diphtheria, and pertussis vaccine (Tdap) in adolescents and adults 5 years after a first dose. RESULTS A total of 545 participants from previous Tdap vaccine studies, ranging in age from 15 to 69 years, participated in this study. Of these participants, 94.2% had at least one solicited adverse event after the booster dose such as injection-site erythema (28.6%), swelling (25.6%), or pain (87.6%) or a systemic adverse event such as myalgia (61.0%), headache (53.2%), malaise (38.2%), or fever (6.5%). These adverse events were slightly more frequent than after the initial dose. Postvaccination, 100% of participants had a tetanus antibody level ≥0.10IU/mL and 95% had a diphtheria antibody level ≥0.10IU/mL. For pertussis, 82.1% (pertussis toxoid), 96.7% (filamentous hemagglutinin), 95.6% (pertactin), and 99.8% (fimbriae) had a postvaccination antibody threshold of ≥50EU/mL. CONCLUSION A second dose of Tdap vaccine 5 years after the initial dose was well tolerated and immunogenic in adolescents and adults.

Deregulation of cyclooxygenase and nitric oxide synthase gene expression in the inflammatory cascade triggered by experimental group B streptococcal meningitis in the newborn brain and cerebral microvessels

Group B Streptococcus (GBS) is the most common cause of neonatal sepsis and meningitis. Despite antibiotics, GBS in the newborn initiates a cascade of molecular and biological events leading to altered cerebral perfusion, blood-brain barrier disruption, cerebral edema, intracranial hypertension, neurological damage, and even death. Having previously shown that GBS infection impairs cerebral blood flow autoregulation and increases prostaglandin (PG) levels, we examined the regulation of some crucial inflammatory mediators (PGs, nitric oxide (NO), tumor necrosis factor-a) in the brain and cerebral microvessels (MVs) from newborn piglets. Cyclooxygenase (COX), the key enzyme in PG biosynthesis, exists in two isoforms, COX-1 and COX-2. Both may be directly induced by NO in a model of renal inflammation. Besides its neurotransmitter role, NO is a potent vasorelaxant whose production is catalyzed by at least three distinct nitric oxide synthases (NOS) (bNOS, ecNOS, iNOS). Western blot analyses showed that the newborn (4 day old) brain expressed lower levels of COX-1 (8-fold), COX-2 (20-fold), bNOS (12-fold), and ecNOS (5-fold) than in the 1 day old. MV showed approximately equal levels of COX-2, lower levels of COX-1 (4-fold), bNOS (5-fold), and higher levels of ecNOS (20-fold) in comparison to 4-day-old cerebral MV. A 4-day-old brain expressed lower levels of bNOS (5-fold), ecNOS (10-fold), and COX-1 (2-fold) than the 6-week-old pig. COX-2 protein was undetected in a 4-day-old pig brain, but present in great excess in MV. Purified MV showed lower ecNOS (14-fold), COX-1 (2-fold), and about equal levels of bNOS and COX-2 in comparison with MV from 6-week-old pigs. Reverse transcription polymerase chain reaction analyses confirmed these results. Treatment with noo-nitro-L-arginine (LNA), a NOS inhibitor, downregulated COX-1 expression in the newborn brain and both COX-1 and COX-2 cerebral MV expression. GBS infection (10(9) colony-forming units, 0.5 mL intracerebroventricular) of sedated newborn piglets induced the expression of tumor necrosis factor-alpha in the cerebrospinal fluid after 2 hours, upregulated bNOS expression in both brain and MVs, upregulated ecNOS in MVs, and downregulated COX-1, COX-2, and ecNOS in the brain. GBS did not trigger the expression of iNOS. Our data suggest that there is a net deficiency of NOS isoforms in the immature brain and microvasculature of the 4-day-old piglet and that the differences in expression lead to the immature control of NO and PG production, rendering newborns particularly susceptible to neurological damage because of the undeveloped nature of their response mechanisms. Moreover, the GBS-induced cascade deregulates the gene expression of interacting inflammatory mediators and may cause a net vasoconstrictor/vasodilator imbalance, leading to cerebral hypertension and edema in the early stages of infection. Pharmacological manipulations of the inflammatory cascade could lead to novel therapeutic approaches for the treatment of GBS meningitis.

CEREBROVASCULAR PROSTANOID PRODUCTION IN NEONATAL GROUP B STREPTOCOCCAL MENINGITIS. † 1777

Group B Streptococcal (GBS) meningitis impairs cerebral blood flow (CBF) autoregulation in newborn piglets. We determined whether the early impairment could be related to increased prostaglandin (PG) production and if dexamethasone and ibuprofen alter PG production in the early phase (1st 6 hrs) of GBS meningitis. Net cerebrovascular PG production (calculated as total CBF× (sagittal-arterial plasma PG concentration) of 6-keto-PGF1α (stable metabolite of prostacyclin), TXB2(thromboxane B2) and PGE2 were measured in 4 groups of piglets given either 1) saline 0.5 ml intracerebroventrically (icv, control grp, n=9), 2) GBS alone (109 cfu/0.5 ml GBS icv, n=7), or 3) GBS icv plus dexamethasone (DEX) 1 mg/kg intraarterial, ia, n=8) or 4) GBS icv plus ibuprofen (IBU) 30 mg/kg ia,n=7) during periods of normotension (MABP= 50-90 mmHg), hypotension (MABP 90mmHg). MABP was randomly adjusted by balloon tipped catheters in the aortic root and descending aorta. CBF was measured by radioactive microsphere technique and PGs were measured by radioimmunoassay. Results show that within each treatment group there was a decrease in cerebrovascular production of 6 keto-PGF1α, TXB2 and PGE2 (p < 0.05) during hypotension possibly due to relative depletion in tissue oxygen for cyclo-oxygenation of arachidonate. However, between treatment groups (Control, GBS alone, GBS+DEX, and GBS+IBU) PG production did not change with BP adjustments except for increased PGE2 during cerebral hypertension(mean±SD, PGE2=250±25 ng/min/100 g brain tissue) compared to hypotension in GBS alone (PGE2=325±30 ng/min/100 g brain, p< 0.05). Irrespective of MABP, cerebral PG production is highest for PGE2, followed by 6-keto PGF1α with no production of TXB2. Since cerebral PG production is minimally influenced by GBS with or without DEX or IBU over a wide range of cerebral perfusion pressures, we suggest that vasoactive mediators other than PGs may mediate CBF impairment in early meningitis. Thus, treatment directed to PGs may not prevent CBF impairment in neonatal GBS meningitis.

Inflammatory Response and Dose-Responsive Prostaglandin E2 Production in Primary Cultures of Neonatal Cerebral Microvessels (CMVL) Infected with Group B Streptococcus (GBS). ♦ 320

Inflammatory Response and Dose-Responsive Prostaglandin E2 Production in Primary Cultures of Neonatal Cerebral Microvessels (CMVL) Infected with Group B Streptococcus (GBS). ♦ 320

Group B Streptococcal Meningitis (GBS) Increases Cyclic GMP Production with Cerebral Hypertension and Overexpression of Nitric Oxide Synthase (NOS) in Neonatal Procine Brain and Microvessels. † 1303

Group B Streptococcal Meningitis (GBS) Increases Cyclic GMP Production with Cerebral Hypertension and Overexpression of Nitric Oxide Synthase (NOS) in Neonatal Procine Brain and Microvessels. † 1303

NITRIC OXIDE (NO) MEDIATES CEREBRAL HYPEREMIA IN NEWBORN PIGLETS WITH GROUP B STREPTOCOCCAL (GBS) MENINGITIS. † 1072

NITRIC OXIDE (NO) MEDIATES CEREBRAL HYPEREMIA IN NEWBORN PIGLETS WITH GROUP B STREPTOCOCCAL (GBS) MENINGITIS. † 1072

IMPAIRED NEONATAL CEREBRAL BLOOD FLOW AUTOREGULATION IN GROUP B STREPTOCOCCAL MENINGITIS IS NOT MEDIATED BY TUMOR NECROSIS FACTOR (TNF|[alpha]|).|[bull]| 977

Group B streptococcal (GBS) meningitis impairs cerebral blood flow (CBF) autoregulation in newborn piglets probably via inflammatory mediators in response to GBS. We tested whether TNFα mediates early CBF impairment by GBS in 3 grps of awake sedated newborn piglets (0-5 days). Grp 1 (CTRL), n=8 had normal saline (0.5ml) via the lateral cerebral ventricle (icv), Grp 2(n=7) had heat killed unencapsulated GBS (109 cfu, 0.5ml icv) and Grp 3 had TNFα, 1,000 units icv, 0.5ml). CBF was measured over a range of mean arterial blood pressure (35-125 mmHg) induced by inflating balloon tipped catheters at the aortic root to produce cerebral hypotension or descending aorta for hypertension at 5 time points: 15 min pre (baseline) and post injection of either saline, GBS or TNFα), and during randome hypo-, normo-, and hypertension. RESULTS: 1) Grp 1, CBF and CPP (cerebral perfusion pressure) best fitted a 3rd order polynomial regression (R2=0.57,p=0.008) with constant CBF at 50-90 mmHg CPP. 2) Grp 2, GBS caused direct correlation in CBF and CPP (50-110 mmHg), r=0.52, p <0.05. Grp 3 (TNFα) had CBF constant at 50-110 mmHg, r=0.12, p=NS. Cerebrovascular resistance correlated with CPP(50-125 mmHg) in CTRL (r=0.458,p=0.009)and TNFα grps (r=0.60, p=0.002) but not in GBS grp (r=0.06, p=.8). Thus, TNFα did not mediate early impairment in neonatal CBF autoregulation in GBS meningitis and therapies directed to TNFα may not correct CBF changes.Figure