Evaluation of ready-to-use and multi-dose influenza vaccine formats in large clinic settings.

Large immunization clinics are commonly held to deliver influenza vaccine to seniors and others. Vaccine is typically dispensed from multi-dose vials but pre-filled syringes are now available, offering time savings for vaccinators. To determine if the higher purchase price of such syringes is offset by savings in time and injection supplies, we did a controlled comparison of syringe and vial formats in two large, concurrent, community-based influenza vaccination clinics. Vaccine preparation and immunization times were carefully documented along with costs for vaccine purchase, storage and injection supplies. Servicing 1,000 clients required 27 nurse hours using syringes and 36 hours using vials but the savings for personnel ($234) and supplies ($1,190) using syringes were exceeded by higher vaccine cost ($2,090 premium) and extra storage costs ($260) for bulkier packaging. Depending upon product and packaging style, programs using vials are cheaper by $709-$926 per 100 doses delivered compared to using pre-filled syringes.

Effect of reminder notices on the timeliness of early childhood immunizations.

OBJECTIVE: To determine whether reminder notices would improve the timeliness of toddler-age vaccinations. DESIGN: Prospective, randomized, controlled trial. POPULATION STUDIED: Two convenience cohorts of 320 children due to receive either measles-mumps-rubella (MMR) vaccine (at 12 months of age) or diphtheria-pertussis-tetanus (DPT)-inactivated polio (IPV)- Haemophilus influenzae type b (Hib) booster vaccine (at 18 months of age). SETTING: Suburban community. INTERVENTIONS: Parents of the identified children were randomly assigned either to a group to receive a reminder notice of pending vaccinations or a control group that did not receive a notice at a ratio of 1:1. Immunization uptake was assessed eights weeks after the initial due date for vaccination. RESULTS: Information was obtained for 224 children in the MMR group and 227 children in the DPT-IPV-Hib booster group. MMR uptake within eight weeks of the due date was about 90% in both the test and control groups, probably because of publicity surrounding a local college-based measles outbreak. In the DPT-IPV-Hib group, reminder notices had no effect; the uptake rates within eight weeks of the due date were 73.7% to 75.2%. Delays in immunization resulted mostly from parents' scheduling problems and provider-recommended delays. More than half of the parents whose child had delayed immunization did not recall receiving the reminder notice. CONCLUSIONS: Mailed reminders did not increase on-time immunization rates in the second year of a child's life. A telephone call or a more memorable reminder notice may be better suited to catch the attention of parents.

Comparative safety of tetanus-diphtheria toxoids booster immunization in students in Grades 6 and 9.

BACKGROUND: Tetanus-diphtheria toxoids (Td) booster immunization is generally recommended for Grade 9 students (14- to 16-year-olds) but targeting younger students may enhance vaccine uptake or facilitate simultaneous vaccinations. However, earlier vaccination might cause greater side effects. This study was undertaken to compare the safety of Td vaccinations in students in Grade 6 (11 to 12 years old) and Grade 9. METHODS: A controlled, sequential assessment of Td vaccine, adsorbed, was conducted in one urban school district, starting with Grade 9 students. Grade 6 students were given Td concurrently with Dose 3 of hepatitis B vaccine. Adverse effects were assessed during visits 2 days after vaccination. Participation criteria, immunization technique and assessment procedures were standardized. RESULTS: Of 410 students vaccinated, 204 in Grade 9 and 206 in Grade 6, 391 (95.4%) were assessed in person. Nineteen missed follow-up visits but telephone interviewers established that none missed school because of vaccine side effects. At follow-up Grade 6 students more often reported deltoid pain with arm movement (35.2% vs. 10.8%, P < 0.001). Injection site redness > or = 50 mm in diameter was present in 12.2% of Grade 6 and 3.6% of Grade 9 students (P < 0.001) whereas swelling > or = 50 mm diameter was present in 22.4 and 10.8%, respectively (P < 0.01). Fewer than 10% of subjects took analgesics for injection site pain. Only 5 students (1.3%) rated Td site morbidity as severe/unacceptable. Hepatitis B site morbidity was minimal in comparison. CONCLUSION: Td boosters were moderately reactogenic in adolescents. Younger students more often experienced injection site morbidity but considered it bearable. Booster immunizations can reasonably be offered within the age range of 11 to 16 years.

Assessment of parent education methods for infant immunization.

OBJECTIVE: To assess whether a video about infant immunization could inform parents as well as human counselling (oral presentation). METHODS: Core information for parents about infant immunization was identified and packaged in an instructional video and a scripted oral presentation. Volunteer prenatal classes were randomly assigned a video or oral presentation. Participants completed pre- and post-test questionnaires covering the same 16 items. Scores were compared for each question and as a group means, using Fisher's exact test, 2-sided. RESULTS: 227 subjects participated, including 102 men and 124 women. Groups were similar in terms of gender mix, parenting experience and recent reading about immunization. Pre-test knowledge scores were similarly low between groups. Post-test scores were much higher but did not differ significantly between groups. CONCLUSIONS: In a prenatal classroom setting, video and oral presentations were equally effective in conveying key information about infant immunization.

Safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate) administered concurrently or combined with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine to healthy infants at two, four and six months of age.

The safety and immunogenicity of Haemophilus influenzae vaccine (tetanus toxoid conjugate (PRP-T) administered concurrently in separate sites or mixed in the same syringe with diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine were assessed in 439 infants at 2, 4 and 6 months of age. The proportions with local redness, tenderness and swelling in the separate and combined groups were 18% vs. 11% (P < 0.001), 27% vs. 24% and 15% vs. 13%, respectively. Systemic reactions occurred at similar rates in both groups. The combined vaccine induced tetanus and diphtheria antitoxin titers > or = 0.01 IU/ml in 99.5 and 99.1% of infants, pertussis agglutinin titers > or = 64 in 92.4%, anti-polyribosylribitol phosphate titers > or = 0.15 microgram/ml in 93.8% and > or = 1.0 microgram/ml in 75% and polio-neutralizing titers > or = 8 in > 98% of infants. However, antibody concentrations to PRP-T, some pertussis antigens and tetanus toxoid were significantly lower after combined than after separate injections of DPT/diphtheria and tetanus toxoids, pertussis vaccine and inactivated poliomyelitis vaccine and PRP-T. The clinical significance of these differences is not known, but the interactions observed among the components of the pentavalent vaccine may be of concern because they might influence antibody persistence until the fourth dose is administered.

Role of whole-cell pertussis vaccine in severe local reactions to the preschool (fifth) dose of diphtheria-pertussis-tetanus vaccine.

OBJECTIVE: To estimate the contribution of whole-cell pertussis vaccine to severe local reactions after the preschool (fifth) dose of adsorbed diphtheria toxoid-pertussis vaccine-tetanus toxoid (DPT) vaccine. DESIGN: Double-blind randomized controlled trial. SETTING: Urban community. PARTICIPANTS: Volunteer sample of 200 healthy children 4 to 6 years old who were eligible for the fifth dose of DPT vaccine. INTERVENTIONS: Children received, in both arms, either diphtheria toxoid-tetanus toxoid (DT) and monovalent pertussis vaccines (group A, 99 children) or DPT and meningococcal vaccines (group B, 101 children). All were licensed products from single lots. The children were assessed 24 hours later by a trained observer. Serum samples obtained before vaccination were tested for antibodies to tetanus and diphtheria toxins and five pertussis antigens by means of enzyme-linked immunosorbent assay. MAIN OUTCOME MEASURES: Rates of severe local reactions (an area of redness or swelling or both of 50 mm or greater) 24 hours after vaccination. Relation between serum antibody levels before vaccination and rates of severe local reactions to corresponding vaccines. RESULTS: All of the subjects were followed up 24 hours after vaccination. Severe redness was present in 38% given DPT vaccine, 29% given intramuscular pertussis vaccine and 9% given DT vaccine (p < or = 0.002, three-way comparison). Severe swelling was common after vaccination with all three products. After intramuscular pertussis vaccination a relation was evident between the prevaccination levels of antibody to whole-cell pertussis bacteria and the rates of redness (p < 0.02) but not between the prevaccination subcellular antibody levels and the rates of redness. CONCLUSION: That pertussis vaccine resembled the DPT vaccine in causing severe redness suggests that it is the principal cause of such reactions after DPT vaccination. The DT vaccine was also reactogenic; thus, cumulative sensitization to one or more of its constituents may be a factor.

What do parents learn by reading a DPT vaccine information form?

OBJECTIVE: Information forms are commonly used to inform parents about childhood vaccination. This study assessed the knowledge of mothers about pertussis and pertussis vaccine before and after reading a form about diphtheria-pertussis-tetanus (dpt) vaccine. DESIGN: A test was administered to mothers before and after the first vaccination of their infant. By random allocation, one-half of the mothers received the form (study group) in addition to the routine counselling by a public health nurse given to the others (control group). SETTING: Public health immunization clinics in suburban Vancouver, British Columbia. SUBJECTS: One hundred and fifty-one mothers who were scheduled to bring their infant for the first dpt immunization were recruited, of whom 145 (96%) completed the study. INTERVENTIONS: A test consisting of 20 true/false questions was administered by telephone two weeks before and two weeks after the first dpt vaccination. Additional data about sources of vaccine information, maternal education, number of children and maternal age were obtained. OUTCOME MEASURES: Mean scores and mean change in scores on test. RESULTS: The mean changes in scores between tests 1 and 2 in study and control groups were +22.2% and +6.9%, respectively, on the disease-related questions (P<0.001) and +14.6% and +10.7%, respectively, on the vaccine-related questions (P=0.16). The forms were considered to be very useful by the mothers and clearly enabled them to score higher on a test of their knowledge of pertussis and pertussis vaccine. CONCLUSIONS: Reading a dpt vaccine form enabled mothers to improve their knowledge of pertussis and pertussis vaccine.

Evaluation of Haemophilus influenzae type b conjugate vaccine (meningococcal protein conjugate) in Canadian infants.

OBJECTIVE: To assess adverse effects and immune responses with a three-dose series of Haemophilus influenzae type b meningococcal protein conjugate (PedvaxHIB or Hib.OMP) vaccine, including any immunological response alterations from concurrent administration with routine vaccines for infants. DESIGN: Randomized, controlled trial with treatment group crossover for dose 3. SETTING: Two public health units near Vancouver. PARTICIPANTS: One hundred and ten healthy infants eight to 14 weeks old were enrolled; 105 completed the study (95%). INTERVENTIONS: All participants received two doses of diphtheria-pertussis-tetanus (dpt) vaccine (at two and four months of age) and one dose of measles-mumps-rubella (mmr) vaccine at 12 months. In each instance, Hib.OMP was given either concurrently in another limb or after a delay of two weeks (after dpt) or four weeks (after mmr). MAIN OUTCOME MEASURES: Adverse effects, particularly fever and local erythema, were monitored by parents for 72 h after each dose of Hib.OMP vaccine. Five blood samples were taken at prescribed intervals to assess responses to each dose of Hib.OMP and to selected other vaccine antigens. MAIN RESULTS: Follow-up was obtained after all 322 doses of Hib.OMP. Local adverse effects were infrequent and mild: 13% had redness, 17% tenderness. Systemic effects in those given Hib.OMP alone included fever in 8%, irritability in 29%. Anti-polyribose-ribitol phosphate (prp) responses to Hib.OMP were not impaired by coadministration with dpt or mmr vaccines, nor were tetanus or diphtheria antitoxin levels or rubella or measles response rates affected. After two doses of Hib.OMP, 92% were seropositive and 64% had greater than 1.0 µg/mL of anti-prp. After three doses, 100% were seropositive and 82% exceeded 1.0 µg/mL. CONCLUSION: Hib.OMP vaccine was well tolerated, immunogenic and compatible with vaccines routinely given to infants in Canada.

Evaluation of inactivated hepatitis A vaccine in Canadians 40 years of age or more.

OBJECTIVE: To assess the side effects and immune responses after three serial doses of a new inactivated hepatitis A vaccine in people 40 years of age or more. DESIGN: Open, noncomparative trial. SETTING: A hospital, a regional laboratory and public health units in British Columbia. PARTICIPANTS: A volunteer sample of 64 healthy adults aged 40 to 61 years who were seronegative for hepatitis A virus (HAV). All were staff or associates of the health facilities. Exclusion criteria included elevated serum alanine and aspartate aminotransferase levels, a history of liver disease and recent travel to areas of high risk for HAV infection. INTERVENTION: A formalin-inactivated, alum-adsorbed vaccine containing 720 ELISA (enzyme-linked immunosorbent assay) units of antigen from HAV strain HM175 per 1.0-mL dose was injected intramuscularly into the delgoid area. The second and third doses were given 1 and 6 months later respectively. MAIN OUTCOME MEASURES: A detailed diary of any adverse effects for 3 days after each dose. HAV antibody levels in blood samples taken before and 30 days after each dose. RESULTS: All subjects completed the planned series of vaccinations and blood tests; symptom diaries were returned after 190 (99%) of 192 vaccinations. Local symptoms, most often soreness, were reported after 46% of the vaccinations but were mild and usually resolved within 24 hours. A temperature of more than 38.0 degrees C was never reported. Seroconversion occurred in all cases after the two primary doses, and the subjects were still seropositive at 6 months. After the booster dose the geometric mean titre was 2380 mIU/mL, all values being 200 mIU/mL or greater. CONCLUSION: In healthy adults 40 years of age or more the HAV vaccine was well tolerated and highly immunogenic. Final antibody levels were much higher than reported in people passively immunized against HAV with immune serum globulin.

Controlled trial of Haemophilus influenzae type B diphtheria toxoid conjugate combined with diphtheria, tetanus and pertussis vaccines, in 18-month-old children, including comparison of arm versus thigh injection.

A randomized, controlled comparison was made in 175 healthy 18-month-old children given either diphtheria and tetanus toxoids and pertussis vaccine, adsorbed (DTP) and haemophilus b diphtheria toxoid conjugate vaccine (PRP/D) concurrently at separate sites (66 children) or a new vaccine combining these products (109 children). Rates of local or systemic adverse effects postimmunization and antibody responses to each component did not differ significantly between groups. DTP-containing vaccines were better tolerated when given in the thigh than in the arm. The combination DTP-PRP/D vaccine performed satisfactorily at 18 months of age, avoiding the inconvenience of two injections.

Comparison of adverse reactions to whole-virion and split-virion influenza vaccines in hospital personnel.

OBJECTIVE: To compare the adverse effects, particularly generalized aching, of a trivalent, inactivated whole-virion vaccine (WVV) and split-virion vaccine (SVV) for influenza in hospital personnel. DESIGN: Recipient-blinded study; first-time vaccinees were randomly assigned to receive either of the vaccines from one manufacturer in the 1989-90 influenza season. Subjects were asked to complete a symptom questionnaire during the 48 hours after immunization. SETTING: Annual influenza program for staff of a tertiary care children's hospital. PARTICIPANTS: Volunteers were sought among approximately 2200 members of the hospital staff. Of the 358 vaccinated for the first time, 333 (93%) returned the questionnaire. RESULTS: During the 48 hours after vaccination 13% of the SVV recipients reported generalized aching, as compared with 26% of the WVV recipients (p less than 0.01). Also, the SVV group reported fewer visible local reactions and more transient arm soreness, but the actual differences between the two groups were small. The occurrence of mild symptoms was equally common in the two groups (local reactions in at least 70% of cases, systemic reactions in at least 33%). In each group 1% of the subjects reported missing work because of the vaccination. CONCLUSIONS: The use of SVV reduces the rate of the most objectionable of the common adverse effects of influenza vaccination. Therefore, as with children, it might be more acceptable to health care workers than the current use of WVV.

Amino acid sequence of a deltalike toxin from Staphylococcus epidermidis.

A deltalike toxin produced by a clinical isolate of Staphylococcus epidermidis was purified, and the amino acid sequence was determined. The toxin molecule consisted of 25 amino acid residues and shared a high degree of molecular homology with delta toxin purified from a Staphylococcus aureus human isolate.

Evaluation of adverse events after influenza vaccination in hospital personnel.

Reactogenicity of trivalent influenza vaccine prepared for the 1988-89 season was assessed as part of a first-time voluntary influenza prevention program among hospital staff. Of approximately 500 full-time workers in areas with the highest concentrations of patients at high risk for influenza complications offered the vaccine 288 accepted. Of these, 266 (92%) returned a questionnaire regarding any symptoms experienced within 48 hours after vaccination; 238 (90%) of the respondents reported adverse effects. Soreness at the injection site was described by 229 subjects, 58 (25%) of whom had constant aching and 123 (54%) soreness with arm movement. Symptoms resolved in 1 to 2 days, and only 21 (9%) of those who reported symptoms said they took analgesic medication. Systemic adverse effects were described by 130 subjects (49%). Intercurrent illness accounted for some of these complaints, but 65 people (24%) described at least two of the following symptoms: generalized aching, tiredness, nausea, chills or onset of fever within 12 hours after vaccination (a symptom complex previously attributed to influenza vaccine). Systemic symptoms resolved within 0.5 to 2 days. Thirteen subjects (5%) reported missing work because of arm soreness (1 subject) or systemic symptoms (12). Adverse effects were encountered more often than expected, probably because most of the workers were young and lacked immunity to influenza. Acceptability of the program could likely be improved by using a split-virus vaccine.

Delta toxin activity in coagulase-negative staphylococci from the bowels of neonates.

Coagulase-negative staphylococci are prominent in stools of neonates in some intensive care units and have been associated with necrotizing enterocolitis. A plausible mediator of bowel damage is delta-like toxin, which is produced in vitro by most coagulase-negative staphylococci, but factors influencing the expression of toxin in the bowel are unknown. We examined 105 coagulase-negative staphylococcus isolates from stools of neonates by using an enzyme-linked immunosorbent assay and detected delta toxin production by 92 isolates (88%). The amount present in 18-h broth cultures varied over 100-fold, from 933 to 125,000 ng/ml. All broths positive by enzyme-linked immunosorbent assay except one caused hemolysis of human erythrocytes. The threshold concentration for consistent cytotoxicity to fibroblasts was greater than or equal to 24,000 ng/ml. Only 56% of Staphylococcus epidermidis isolates were capable of producing this much toxin, and these were more often obtained from premature infants in intensive care than from healthy full-term infants (P = 0.003) and were more often resistant to multiple antibiotics (P less than 0.001). Cultures grown anaerobically seldom caused hemolysis (4 positive of 29 tested; P less than 0.001) because potency of the toxin was decreased (at least ninefold for S. epidermidis isolates). We conclude that only a portion of the fecal coagulase-negative staphylococci tested produced enough delta toxin in vitro to be cytotoxic, that such isolates have accumulated in our intensive care nursery, and that development of toxin-mediated bowel injury may also require a favorable redox potential within the host bowel.

Delta-like toxin produced by coagulase-negative staphylococci is associated with neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is a serious neonatal disorder of uncertain cause, although fecal bacteria have been implicated in some outbreaks. We examined coagulase-negative staphylococci (CONS) as possible etiologic agents. In our unit, CONS colonized the bowels of most infants studied, including 46% of 70 NEC cases (mean concentration, 10(9.1) CFU/g of stool). Over 90% of tested isolates produced a hemolysin resembling delta toxin of Staphylococcus aureus. Toxin purified from a NEC-associated isolate of Staphylococcus epidermidis resembled reference delta toxin from S. aureus in size, biologic properties, and antigenicity. This delta-like toxin was enteropathic, causing mucosal necrosis and hemorrhage in injected loops of the bowels of infant rats. Adjacent, nonexposed bowel remained normal, as did loops injected with lecithin-neutralized toxin. Using a new enzyme-linked immunosorbent assay (ELISA), we detected delta-like toxin in the stools of 11 of 35 infants colonized with CONS positive for delta-like toxin (Tox+). Positive tests were strongly associated with NEC. Of 18 cases with Tox+ CONS, 10 were positive (56%), whereas only 1 of 17 control infants so colonized was positive (6%, P = 0.002). In NEC patients, the mean fecal toxin concentration was 1,012 ng/g. Toxicity to fibroblasts was demonstrable in filtrates of each of six ELISA-positive samples tested but was absent in all five ELISA-negative samples tested. We conclude that delta-like toxin is elaborated in the bowels of some infants with Tox+ CONS, and its association with NEC suggests that such CONS are enteropathic. In our unit, this mechanism was apparent in 23% of 44 recent cases of endemic NEC.

Rapid postmortem gut autolysis in infant rats: a potential problem for investigators.

Experiments were designed to determine the rate and nature of postmortem autolysis in the gut of neonatal rats, as necessary baseline information for developing a model of human neonatal necrotizing enterocolitis. We studied 60 animals, including 33 Wistar rats, 18 Sprague-Dawley rats and nine CD-1 mice. The variables examined included age of the animals (2 or 14 days) and length of delay and holding temperature (20 degrees C or 37 degrees C) after sacrifice. At necropsy, bowel was rapidly removed and fixed for histopathological examination. In all instances, bowel removed immediately after sacrifice was normal whereas after delays as short as 30 minutes it was abnormal (P less than 0.001), becoming markedly so after 60 minutes. The prominent features were detachment and lysis of mucosal epithelial cells. The rate of autolysis was not altered in 14 day old animals or in carcasses held at 20 degrees C or 37 degrees C. Investigators of bowel injury syndromes in young rats should be aware that histopathological studies will be valid only if specimens held at room temperature are fixed within 15 minutes of death.