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Biomedical subjects

S A Halperin

Publications and source records attributed to S A Halperin.

At least 19 recordsLinked to original sources
PubMed2006

Immunogenicity and protective efficacy of a recombinant filamentous haemagglutinin from Bordetella pertussis.

Bordetella pertussis is the causative agent of whooping cough, a major childhood pathogen; acellular vaccines consisting of purified B. pertussis antigens such as filamentous haemagglutinin (FHA) are commonly used to prevent pertussis. Despite the importance of FHA in B. pertussis pathogenesis and its inclusion in most acellular vaccines, the functional importance of individual domains in the induction of protective immunity is largely unknown. In this study, we have purified a recombinant FHA protein from Escherichia coli consisting of a 42 kDa maltose binding domain of E. coli and the 43 kDa type I immunodominant domain of FHA. The fusion protein (Mal85) was purified from E. coli cell lysates via affinity chromatography with an amylose column. Mal85 was then delivered to BALB/c mice intranasally encapsulated in liposomes, formulated with Protollin(TM) or in conjunction with an immunostimulatory CpG oligonucleotide. Mice were also vaccinated intraperitoneally with alum-adsorbed Mal85. Sera from all treatment groups showed strong IgG responses to Mal85 and recognized native FHA. Specific salivary IgA was induced in mice vaccinated with Mal85 in liposomes, Protollin(TM) and delivered with CpG. Vaccination with Mal85 encapsulated in liposomes or formulated with Protollin(TM) provided protection against aerosol challenge with B. pertussis in BALB/c mice. These data indicate that the type I domain of FHA is a protective antigen in mice and may serve as a candidate for inclusion in new acellular pertussis vaccines.

Adhesins, Bacterial↗
PubMed2006

Expression of a pertussis toxin S1 fragment by inducible promoters in oral Streptococcus and the induction of immune responses during oral colonization in mice.

Previous work aimed at developing a live oral vaccine expressing pertussis toxin S1 fragment on the surface of the bacterium Streptococcus gordonii elicited a lower than expected antibody response, perhaps because of low antigen expression. In this study, in-frame promoter fusions were constructed to investigate whether an increase in antigen production by the streptococcal vaccine strain results in a better antibody response. The promoters tested were (i) the Streptococcus mutans sucrose-inducible fructosyltransferase (ftf) promoter and (ii) the Bacillus subtilis/Escherichia coli chimeric tetracycline-inducible xyl/tetO promoter. Each of these two promoters was placed upstream of the spaP/s1 fusion gene to drive its expression. The constructs were introduced into S. gordonii DL1 and S. mutans 834. The inducibility of the promoters was confirmed through the determination of SpaP/S1 production via Western blottings. Induced production of SpaP/S1 was observed in S. gordonii and S. mutans with each of the promoters, but the level of expression was the highest in S. mutans, using the xyl/tetO promoter. Thus, S. mutans carrying the xyl/tetO/spaP/s1 construct (S. mutans PM14) was used in oral colonization studies in BALB/c mice. Streptococccus mutans PM14 was able to colonize the animals for the 14-week duration of experimentation. A mucosal IgA response was observed in all the treatment groups but was highest in mice receiving tetracycline induction. In the mouse model of Bordetella pertussis respiratory infection, animals colonized with S. mutans PM14 showed a decreased in B. pertussis lung colony count (P = 0.03) on day 3 compared with control mice colonized by the parent S. mutans 834.

Administration, Oral↗
PubMed2005

Safety and immunogenicity of a pentavalent combination vaccine (diphtheria, tetanus, acellular pertussis, polio, and haemophilus influenzae type B conjugate) when administered as a fourth dose at 15 to 18 months of age.

A DTaP-IPV//PRP-T combination vaccine (Pentacel) has been universally used in Canada to provide immunization against diphtheria, tetanus, pertussis, polio, and Haemophilus influenzae type b with single injections at 2, 4, 6 and 18 months of age. This randomized, multicenter study was conducted to evaluate administration of a fourth dose of DTaP-IPV//PRP-T at 15 to 18 months of age, similar to the US immunization schedule. Participants who had received three doses of DTaP-IPV//PRP-T by 8 months of age were enrolled at 12 months and randomized to receive a fourth dose at 15, 16, 17 or 18 months. Antibody levels for each vaccine antigen were measured prior to and four weeks following booster vaccination. Overall, 1782 subjects were immunized and monitored for adverse events, and 735 were evaluated for immune responses. Preimmunization antibody levels differed minimally by age, for all antigens. The immune responses elicited by DTaP-IPV//PRP-T were comparable between participants vaccinated at 15 or 16 months and those vaccinated at 17 or 18 months, as demonstrated by specific antibody geometric mean titers, seroprotection/seroresponse rates, and reverse cumulative distribution curves. The fourth dose was well tolerated in all age groups. Toddlers at 15, 16, 17 or 18 months of age are equally suitable recipients for booster immunization with the DTaP-IPV//PRP-T vaccine.

Age Distribution↗
PubMed2005

Infection of newborn piglets with Bordetella pertussis: a new model for pertussis.

Bordetella pertussis is the causative agent of pertussis or whooping cough. This bacterium is a human pathogen that under experimental conditions also infects selected rodents and primates. Here, we show for the first time that newborn piglets can be infected with B. pertussis when it is delivered intrapulmonarily. Infected piglets displayed fever and respiratory symptoms, such as nasal discharge, nonparoxysmal coughing, and breathing difficulties. Eventually, all infected animals developed severe bronchopneumonia, which in some cases was combined with a fibrinous pleuritits. Immunohistochemical staining revealed the presence of large numbers of B. pertussis cells within airways, adhering to the epithelial lining or phagocytosed by macrophages and neutrophils. Viable bacteria were reisolated from bronchoalveolar lavages and lung lesions for more than 10 days postinfection. The systemic presence of pertussis toxin was shown by hypoglycemia, lymphocytosis, and induction of a clustered pattern of CHO cells by serum and bronchoalveolar lavage samples. Thus, a large-animal model for pertussis was developed, which should complement existing rodent models for identifying the immune responses relevant to the design of new vaccines. In particular, this model should help researchers analyze the roles of both maternal and mucosal immunity in disease protection against pertussis and should ultimately assist in the design of new vaccines for early life protection.

Animals↗
PubMed2005

Expression of diphtheria toxin in Streptococcus mutans and induction of toxin-neutralizing antisera.

The nontoxic full-length diphtheria toxin (DTX), fragment A (DTA), and fragment B (DTB) were each genetically fused to the major surface protein antigen P1 (SpaP) of Streptococcus mutans. Repeated attempts to express the recombinant DTX and DTB in the live oral vaccine candidate Streptococcus gordonii were unsuccessful, whereas DTA could be readily expressed in this bacterium. However, the recombinant DTX, DTB, and DTA could be expressed in the related oral bacterium S. mutans. Western blotting and enzyme-linked immunosorbant assay (ELISA) using anti-DTX and anti-P1 antibodies demonstrated the expression of the three fusion proteins in S. mutans. Mouse antisera raised against the recombinant S. mutans recognized the native DTX in Western immunoblotting. The antibodies raised against S. mutans expressing the recombinant DTX and DTA neutralized the cytotoxicity of the native toxin in a Vero cell assay, but the neutralization titers were relatively low. The potential of using S. gordonii as a live vaccine against diphtheria faces major challenges in the expression of DTX in this organism and in the induction of high-titer toxin-neutralizing antibodies.

Animals↗
PubMed2002

Oral colonization and immune responses to Streptococcus gordonii expressing a pertussis toxin S1 fragment in mice.

The ability of a recombinant Streptococcus gordonii RJM4 expressing the N-terminal 179-amino acid fragment of S1 subunit of pertussis toxin (PT) as a SpaP/S1 fusion protein was tested for oral colonization and immunogenicity in BALB/c mice. Following two consecutive oral inoculations, 100% of the mice were colonized by the recombinant strains for up to 9 weeks and >60% of the animals still retained the strains after 19 weeks. RJM4 recovered from the animals continued to express the SpaP/S1 fusion protein indicating the stability of the fusion gene in vivo. Secretory (S) IgA antibody against PT could be detected in saliva from RJM4-colonized mice but not from the control groups of mice. SIgA against SpaP was also detected in saliva from the RJM4-inoculated and the S. gordonii SL3 (control)-inoculated mice. Serum antibodies against PT and SpaP were not detected in these animals. In conclusion, long-term oral colonization of BALB/c mice with our recombinant S. gordonii was established and the colonization elicited mucosal antibodies against PT and SpaP.

Animals↗
PubMed2001

Assessment of injection site reactions to an acellular pertussis-based combination vaccine, including novel use of skin tests with vaccine antigens.

Recent reports indicate that children receiving a fifth consecutive dose of DTPa vaccine have a moderate likelihood of developing a large injection site reaction, the etiology of which remains unknown. We assessed the frequency, severity and outcome of local reactions in 205 children who had participated in earlier studies of DTPa-based vaccines and were due for a fifth dose at 4-6 years. DTPa.IPV vaccine was given intramuscularly in the deltoid. To explore the role of cell-mediated immunity in local reactions we applied epicutaneous (patch) tests at the same visit, using code-labeled solutions of DTPa.IPV, DT, Pa, IPV, alum solution and saline, leaving them in place for 48 h. Subjects were assessed by research staff on the following day. Injection site redness or swelling >/=50 mm diameter was present in 24.4 and 20.5%, respectively, but none of the subjects had fever or persistent limitation of arm movement. Large local reactions were more common in bigger children (P<0.01) but not in those with allergy/atopy. Large reactions resolved within 14 days. Positive skin tests (erythema) occurred at 85 test sites in 51 of 187 evaluable children, principally with DTPa.IPV, IPV and alum solutions. However, only DT and Pa solutions caused positive tests significantly more often in children with injection site redness > or =50 mm than in non-reactors (P < 0.05, odds ratios 5.2 and 6.1, respectively). Presence of alum in most test solutions might have confounded the results as it caused non-specific inflammation when applied alone. We conclude that local reactions to a fifth dose of DTPa-type vaccine are frequent and sometimes extensive but not incapacitating and that concurrent skin testing has potential to identify the vaccine antigens and immune mechanism contributing to local reactions with more refinement of the method.

Adjuvants, Immunologic↗
PubMed2001

Pertussis is a frequent cause of prolonged cough illness in adults and adolescents.

Although pertussis is increasingly recognized as a cause of prolonged cough illness in adolescents and adults, its prevalence is not well established. We evaluated pertussis infection in 442 adolescents and adults > or = 12 years old (mean age, 41.3 years) who had a cough-related illness of 7--56 days' duration. For 4 patients (0.9%), results of nasopharyngeal culture or PCR were positive for Bordetella pertussis; for 10 patients (2.3%), either results of culture or PCR were positive or pertussis antibody titers increased 4-fold. Eighty-eight patients (19.9%) had either laboratory-confirmed pertussis or laboratory evidence of pertussis. These patients had significantly longer duration of cough than did patients without laboratory evidence of pertussis (56 days vs. 46 days), and more of them had vomiting with cough (45.5% vs. 28.5%, respectively). Pertussis is a common cause of prolonged cough illness in adolescents and adults and is frequently associated with other symptoms of whooping cough.

Adolescent↗
PubMed2001

Effectiveness of a single dose of acellular pertussis vaccine to prevent pertussis in children primed with pertussis whole cell vaccine.

We estimated the protection given by one booster dose of acellular pertussis vaccine (aP) given at 18 months or before school entry to children already primed with whole cell vaccine (wP). Case-control studies were conducted in these two age groups. In children who received or were eligible to receive their 18 months booster, the risk of pertussis was 1.4 and 3.6 times higher for those with 4 and 3 wP, respectively, compared to those with 3 wP + 1 aP. In 5 and 6 yr old children, the risk of pertussis among the subjects with 5 and 4 wP, was 1.4 and 2.1 times higher respectively than in those who received 4 wP + 1 aP. A single dose of aP increased the protection against pertussis and this protection was greater than that obtained with a wP booster.

Age Factors↗
PubMed2000

Morbidity of pertussis in adolescents and adults.

The effect of age on the clinical presentation of pertussis was assessed in 664 adolescent and adult cases. Complications were more frequent in adults than in adolescents (28% vs. 16%). Pneumonia occurred in 2% of patients <30 years old but in 5%-9% of older patients. Urinary incontinence occurred in 34% of women >/=50 years old. Duration of cough, risk of sinusitis, and number of nights with disturbed sleep increased with smoking and asthma. The secondary attack rate in other household members >/=12 years was 11%. Pertussis in secondary case patients was less severe than in index case patients but presented with classic symptoms. The main source of infection in adolescents was schoolmates or friends; in adults it was workplace or their children. Teachers and health care workers had a greater risk of pertussis than did the general population. The burden of disease appears to increase with age, with smoking, and with asthma.

Adolescent↗
PubMed2000

An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults.

Pertussis is increasingly being recognized as an important cause of cough illness in adolescents and adults. To evaluate the safety and immunogenicity of an adult formulation of a five-component (pertussis toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular pertussis vaccine combined with diphtheria and tetanus toxoids, we randomly allocated 749 healthy adolescents and adults from 12-54 years of age recruited from five Canadian communities to receive either tetanus-diphtheria vaccine (Td), acellular pertussis vaccine (aP) or combined diphtheria-tetanus-acellular pertussis vaccine (TdaP). Subjects and personnel were unaware of the vaccine allocation. Antibody levels were measured before and one month postimmunization; adverse events were collected at 24 and 72 h and 8 to 10 days. Adverse events were reported in similar frequency amongst the three vaccine groups. Moderate pain at the injection site was reported less frequently in the aP group than the TdaP group (10.7% compared to 19.4%; relative risk 0.6, 95% confidence interval 0.3-0.9). Chills were reported less frequently after Td (5.3%) than after TdaP (12.5%; relative risk 0.4, 95% confidence interval 0.2-0.9). There were no statistically significant differences between recipients of Td and TdaP in tetanus and diphtheria antitoxin levels achieved. Antibody response against Bordetella pertussis antigens was vigorous in all groups although recipients of aP alone had higher levels of antibody levels against pertussis toxoid, fimbriae, and agglutinins and lower antibody levels against pertactin than did TdaP recipients. We conclude that this adult formulation 5-component acellular pertussis vaccine is safe and immunogenic in adolescents and adults and is a candidate vaccine for adolescent and adult immunization programs.

Adolescent↗
PubMed2000

Adult formulation of a five component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine is safe and immunogenic in adolescents and adults.

BACKGROUND: Pertussis is increasingly recognized as an important cause of cough illness in adolescents and adults. PURPOSE: To evaluate the safety and antibody response to a single dose of an adult formulation of a five component (pertussis toxoid, filamentous hemagglutinin, pertactin, fimbriae 2 and 3) acellular pertussis vaccine (aP) combined with diphtheria and tetanus toxoids (TdaP) and inactivated poliovirus vaccine (TdaP-IPV) in adolescents and adults and to assess the response to a second dose of the acellular pertussis vaccine in a subset of the adults. POPULATION AND SETTING: The study addressed 1207 healthy participants (736 adults and 466 adolescents) recruited in five Canadian communities. STUDY DESIGN: In a randomized, observer-blind, controlled clinical trial, adult participants received Td followed at a separate visit by aP, TdaP followed by IPV or TdaP-IPV; adolescents received Td-IPV followed at a separate visit by aP or TdaP-IPV. A subgroup of adults was given a booster of aP 1 month after TdaP. OUTCOME MEASURES: Antibody titers measured before and 1 month after each immunization; adverse events enumerated at 24 h, 72 h and 8 to 10 days. RESULTS: The aP vaccine given by itself was associated with adverse events less frequently than were Td, Td-IPV, TdaP or TdaP-IPV vaccines, but reaction rates did not differ significantly among the latter products. The antibody response against Bordetella pertussis antigens was vigorous in all groups, although adults given the TdaP-IPV vaccine had lower antibody titers against filamentous hemagglutinin, pertactin, diphtheria and tetanus antibodies than those given TdaP vaccine. Similarly adolescents given TdaP-IPV had lower antibody titers against pertussis toxin, filamentous hemagglutinin, fimbriae and agglutinins than those given Td-IPV and aP alone. A second dose of acellular pertussis vaccine was not associated with increased adverse events in adults but elicited increased antibody titers over that achieved by a single dose only against pertussis toxin. CONCLUSIONS: This adult formulation five component aP vaccine given as TdaP-IPV is safe and immunogenic in adolescents and adults and is a candidate vaccine for adolescent and adult immunization programs.

Adolescent↗
PubMed2000

Lidocaine-prilocaine patch decreases the pain associated with the subcutaneous administration of measles-mumps-rubella vaccine but does not adversely affect the antibody response.

BACKGROUND: Topical lidocaine 2.5% and prilocaine 2.5% (EMLA) is effective in decreasing the pain associated with minor procedures including immunization, although the effect on the antibody response to vaccine constituents has not been assessed. OBJECTIVE: To measure the antibody response to measles-mumps-rubella (MMR) vaccine, as well as pain reduction associated with the use of the EMLA patch. PARTICIPANTS AND SETTING: One hundred sixty healthy infants at least 12 months old undergoing their first MM immunization in an ambulatory setting. DESIGN AND INTERVENTIONS: Randomized, double-blind, controlled trial of EMLA patch (5%-1 g) or placebo before MMR immunization. Blood sampling before and 28 to 35 days after immunization. OUTCOME MEASURES: The primary outcome measure was the antibody response to measles by plaque reduction neutralization and to mumps and rubella by enzyme immunoassay. The secondary outcomes were pain scores by the Modified Behavioral Pain Scale and drug- and vaccine-associated adverse events. RESULTS: There was no difference in the antibody response between the EMLA- and placebo-treated groups. The response rates in the EMLA group were 89.7%, 88.3%, and 92.3% to measles, mumps, and rubella, respectively, compared with rates of 91.1%, 94.9%, and 93.7% in the placebo group (P >.05 for all comparisons). EMLA recipients had less pain after immunization (mean Modified Behavioral Pain Scale score increase 3.1 compared with 3.8; P =.043) and less irritability (16% compared with 31%; P =.040) than did placebo recipients. CONCLUSIONS: The EMLA patch has no adverse effect on the antibody response to MMR vaccine and significantly reduces the pain associated with the subcutaneous administration of the vaccine.

Administration, Topical↗
PubMed1999

A single dose of an effective whole cell pertussis vaccine does not significantly increase protection in children primed with a less effective vaccine.

We evaluated if a single dose of a protective whole cell pertussis vaccine given before school entry to children primed with a less effective vaccine would increase their protection. A school cohort including 3876 students and a family cohort including 162 children were assessed. Although there was a trend toward increased protection. the better vaccine did not provide a significant improvement. These results suggest that a single dose of an effective vaccine given to children primed with a less effective one does not raise the protection to at level similar to that provided by three doses of the better vaccine.

Child, Preschool↗
PubMed1999

Extended follow-up of antibody levels and antigen responsiveness after 2 Haemophilus influenzae type b conjugate vaccines.

Although immunization programs with Haemophilus influenzae type b (Hib) conjugate vaccines have dramatically reduced disease incidence, few data are available regarding the duration of protection after vaccination. We measured serum anti-polyribosylribitol phosphate (PRP) levels in healthy 4- to 5- year-old children previously given 4 doses of PRP-T vaccine (at 2, 4, 6, and 18 months) or 1 dose of PRP-D vaccine (at 19 months) during clinical trials to assess antibody persistence. Concurrent with other preschool immunizations, half of the children were randomly assigned to receive a PRP-T booster immunization to assess responsiveness. Among 136 subjects who were primed with PRP-D, the baseline geometric mean concentration of antibody was 0.7 microg/mL (95% CI 0.5 to 0.9). Concentrations were <0.15 microg/mL in 24 (17.6%) subjects. Among 212 children who were primed with PRP-T, the geometric mean concentration was 2.2 microg/mL (95% CI 1.9 to 2.5) (P <.001). Only 2 (0.9%) had concentrations <0.15 microg/mL. Four weeks after PRP-T immunization, geometric mean concentrations had increased to 98.4 and 102.0 microg/mL, respectively. Responses were strong even in those with low or undetectable preimmunization antibody levels. Spontaneous increases in antibody levels were seen in 9 (5.2%) of 172 subjects not given additional PRP-T. We concluded that among 4- to 5-year-olds, anti-PRP levels remained above 0.15 microg/mL in nearly all children after PRP-T priming and in most after PRP-D priming, and that both groups were able to respond vigorously to restimulation, consistent with persistent immune memory.

Antibodies, Viral↗
PubMed1999

Safety and immunogenicity of Haemophilus influenzae-tetanus toxoid conjugate vaccine given separately or in combination with a three-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine for the first four doses.

The purpose of this randomized, controlled trial was to assess the safety and immunogenicity of a three-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids and inactivated poliovirus vaccine given either separately or combined as a single injection with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine. A total of 180 infants were immunized at 2, 4, and 6 months of age; 129 were given a booster dose at 16-19 months of age. Vaccine-associated adverse events were similar whether the vaccines were combined as a single injection or given separately. There were no differences in levels of antibodies to Bordetella pertussis antigens (pertussis toxoid, filamentous hemagglutinin, and pertactin), diphtheria toxoid, or the three poliovirus types. The tetanus antitoxin level after the primary three-dose series was higher in recipients of the combined vaccine (2.37 IU/mL) than in recipients of the separate injections (1.32 IU/mL; two-sided P = .0001). In contrast, combined vaccine recipients had lower levels of antibody to H. influenzae type b polysaccharide after the third dose (1.57 microg/mL) than did those given separate injections (3.22 microg/mL; two-sided P = .0026). The antibody levels were not significantly different before or 1 month after the booster dose (32.9 microg/mL vs. 47.8 microg/mL, respectively; two-sided P = .07). We conclude that the vaccines were immunogenic and well tolerated. Despite lower levels of antibody to the H. influenzae type b polysaccharide after the primary three-dose series, mixing of the vaccines in a single syringe likely induced immunologic priming, as suggested by the high antibody levels after the booster dose.

Antibodies, Bacterial↗
PubMed1999

Epidemiological features of pertussis in hospitalized patients in Canada, 1991-1997: report of the Immunization Monitoring Program--Active (IMPACT).

To assess the morbidity associated with the continued high levels of pertussis, we studied all children <2 years of age who were admitted to the 11 Immunization Monitoring Program--Active (IMPACT) centers, which constitute 85% of Canada's tertiary care pediatric beds. In the 7 years preceding implementation of acellular pertussis vaccine, a total of 1,082 pertussis cases were reported, of which 49.1% were culture-confirmed. The median age of the patients was 12.4 weeks; 78.9% of cases were in children <6 months of age. Complications of pertussis were common: pneumonia was reported in 9.4% of cases, new seizures in 2.3%, and encephalopathy in 0.5%. There were 10 deaths (0.9%), all in children < or =6 months of age. Duration of hospitalization was longer (9.3 days vs. 4.9 days; P = .001) and intensive care was required more frequently (19.2% vs. 4.9%; P = .001) in infants under <6 months of age than in those > or =6 months. Pertussis continues to cause significant morbidity and occasional mortality in Canada, particularly in young infants.

Canada↗