Persistence of protection through 33 months of age provided by immunization in infancy with two three-component acellular pertussis vaccines. Stage II Working Group.

A large, randomized, placebo-controlled clinical trial in Italy on two three-component pertussis vaccines, given as DTaP in infancy, one manufactured by SmithKline and Beecham (SB) and one by Chiron Biocine (CB), found each vaccine to be 84% efficacious through the average age of 24 months. The cohort of children enrolled in the trial was followed with unmodified case ascertainment procedures for nine additional calendar months, during which partial unblinding occurred, for the unvaccinated randomized group. For the DTaP groups, the specific vaccine assignment remained double-blinded throughout the entire additional observation period. Pertussis was defined as paroxysmal cough lasting at least 21 days and confirmed by culture or serology. In the additional 9 months the observed absolute efficacy was 78% (95% CI, 62-87%) for SB DTaP vaccine and 89% (95% CI, 79-94%) for CB DTaP. The relative risk of developing pertussis in SB DTaP recipients compared to CB DTaP vaccinees was 1.99 (95% CI, 1.13-3.51). By combining observations from the initial and additional follow-up periods, the overall observed vaccine efficacy through an average age of 33 months of SB DTaP was 80% and of CB DTaP, 85%.

Antibody responses and persistence in the two years after immunization with two acellular vaccines and one whole-cell vaccine against pertussis.

OBJECTIVE: To evaluate the persistence of specific antibodies induced by primary immunization with three doses of two three-component acellular vaccines against pertussis with an observed efficacy of 84%, and one whole-cell vaccine with an observed efficacy of 36%. STUDY DESIGN: Serum samples were collected from a subsample of 1572 children from the Italian double-blind, placebo-controlled, randomized trial of vaccines used in 15,601 children at three time points: before administration of the first dose of vaccine, and 1 month and approximately 15 months after administration of the third dose. Further evaluation included pooled cross-sectional analysis of serum specimens associated with episodes of cough (which were not laboratory confirmed as pertussis infection) occurring among the entire population enrolled in the trial. RESULTS: With both acellular vaccines there was a fast and steep decrease in geometric mean antibody titers to pertussis toxin, filamentous hemagglutinin, and pertactin after vaccination. Mean titers were close to the limit of detection 15 months after primary immunization. The immunogenicity of the whole-cell study vaccine was poor 1 month after the third dose, and no antibody was detected in nearly all children 15 months after whole-cell vaccination. CONCLUSIONS: Although the study acellular pertussis vaccines induced a strong primary specific antibody response in almost all recipients, the duration of the response was limited. Sustained high-level production of antibody to the antigens tested does not account for the observed efficacy of acellular pertussis vaccines.

Predictors of adverse events after the administration of acellular and whole-cell diphtheria-tetanus-pertussis vaccines.

Recurrence of adverse events, the effect of site of injection, and concurrent administration of oral polio vaccine (OPV) and hepatitis B vaccine (HBV) on reactogenicity were assessed in recipients of two acellular pertussis vaccines given in combination with diphtheria and tetanus toxoids (DTaP), one whole-cell DTP vaccine (DTPwc) and one DT vaccine during a double blind, randomized, controlled clinical trial. Local and systemic side reactions were more likely to recur after the administration of DTaP and DT compared with DTPwc. In all vaccine groups, injection in the buttock was associated with a lower rate of common adverse events compared with injection in the thigh, while simultaneous administration of OPV and/or HBV did not increase the risk of onset of side reactions.

Outbreak of paralytic poliomyelitis in Albania, 1996: high attack rate among adults and apparent interruption of transmission following nationwide mass vaccination.

After >10 years without detection of any cases of wild virus-associated poliomyelitis, a large outbreak of poliomyelitis occurred in Albania in 1996. A total of 138 paralytic cases occurred, of which 16 (12%) were fatal. The outbreak was due to wild poliovirus type 1, isolated from 69 cases. An attack rate of 10 per 100,000 population was observed among adults aged 19-25 years who were born during a time of declining wild poliovirus circulation and had been vaccinated with two doses of monovalent oral poliovirus vaccines (OPVs) that may have been exposed to ambient temperatures for prolonged periods. Control of the epidemic was achieved by two rounds of mass vaccination with trivalent oral poliovirus vaccine targeted to persons aged 0-50 years. This outbreak underscores the ongoing threat of importation of wild poliovirus into European countries, the importance of delivering potent vaccine through an adequate cold chain, and the effectiveness of national OPV mass vaccination campaigns for outbreak control.

Vaccine Safety Datalink project: a new tool for improving vaccine safety monitoring in the United States. The Vaccine Safety Datalink Team.

OBJECTIVE: To fill the large "gaps and limitations" in current scientific knowledge of rare vaccine adverse events identified in recent reviews of the Institute of Medicine. METHODS: Computerized information on immunization, medical outcomes, and potential confounders on more than 500 000 children 0 to 6 years of age is linked annually at several health maintenance organizations to create a large cohort for multiple epidemiologic studies of vaccine safety. RESULTS: Analysis of 3 years of follow-up data shows that 549 488 doses of diphtheria-tetanus-pertussis (DTP) and 310 618 doses of measles-mumps-rubella (MMR) vaccines have been administered to children in the study cohort. Analyses for associations between vaccines and 34 medical outcomes are underway. Screening of automated data shows that seizures are associated with receipt of DTP on the same day (relative risk [RR], 2.1; 95% confidence interval [CI], 1.1 to 4.0) and 8 to 14 days after receipt of MMR (RR, 3.0; 95% CI, 2.1 to 4.2). The diversity of vaccination exposures in this large cohort permits us to show that an apparent association of seizures 8 to 14 days after Haemophilus influenzae type b vaccine (RR, 1.6; 95% CI, 1.2 to 2.1) was attributable to confounding by simultaneous MMR vaccination; the association disappears with appropriate adjustment (RR, 1.0; 95% CI, 0.7 to 1.4). CONCLUSION: Preliminary design, data collection, and analytic capability of the Vaccine Safety Datalink project has been validated by replication of previous known associations between seizures and DTP and MMR vaccines. The diversity in vaccine administration schedules permits potential disentangling of effects of simultaneous and combined vaccinations. The project provides a model of public health-managed care collaborations in addition to an excellent infrastructure for safety and other studies of vaccines.

Incidence of invasive Haemophilus influenzae type b disease in Italian children.

To estimate the incidence of Haemophilus influenzae type b (Hib) invasive disease in Italian infants we performed a prospective study in a cohort of newborns enrolled for a randomized trial on safety and efficacy of three pertussis vaccines and followed for onset of serious disease or pertussis. The overall cumulative incidence observed in 15,601 children was 51.3/100,000 for all invasive Hib infections and 38.4/100,000 for Hib meningitis, over 27 months of observation. The incidence density of all invasive Hib disease was 28.7/100,000 person-years, while meningitis occurred with an incidence of 21.5/100,000 person-years. Among the eight cases detected, six were meningitis, one sepsis, and one cellulitis. The child with sepsis died. The incidence and epidemiology of invasive Hib disease in Italy are comparable to those reported from other European countries. Cost-benefit analyses are needed for planning Italian vaccination policy.

Differences by antigen in seroconversion: sensitivity, specificity and bias in the serological confirmation of pertussis.

Vaccine efficacy of the most efficacious acellular pertussis vaccines in the three recent placebo-controlled clinical trials, when estimated using the primary clinical case criterion, does not change substantially with the inclusion of serological confirmation in addition to culture confirmation. In the Italy trial, because of relatively high anti-PT antibody levels at the time of the acute-phase specimen in episodes of 21 or more days of paroxysmal cough, significant increases in antibody to PT are less likely to be seen in the acellular vaccine groups when evaluating children with bacterial isolation. However, the effect of this decreased sensitivity appears to be compensated by significant antibody increases in the FHA assay. When projecting a maximally sensitive criterion for serological assessment using the observed decreases in IgG antibody to PT over time following primary vaccination stratified by vaccine group, and comparing the expected antibody level with the observed level in the convalescent-phase specimen, the effect on estimated vaccine efficacy is minimal.

A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. Progetto Pertosse Working Group.

BACKGROUND: Concern about both safety and efficacy has made the use of whole-cell pertussis vaccines controversial. In some European countries, including Italy, the rate of vaccination against pertussis is low. METHODS: We conducted a double-blind trial in Italy in which infants were randomly assigned to vaccination at two, four, and six months of age with an acellular pertussis vaccine together with diphtheria and tetanus toxoids (DTP); a DTP vaccine containing whole-cell pertussis (manufactured by Connaught Laboratories); or diphtheria and tetanus toxoids without pertussis (DT). The acellular DTP vaccine was either one containing filamentous hemagglutinin, pertactin, and pertussis toxin inactivated with formalin and glutaraldehyde (SmithKline Beecham) or one with filamentous hemagglutinin, pertactin, and genetically detoxified pertussis toxin (Chiron Biocine). Pertussis was defined as 21 days or more of paroxysmal cough, with infection confirmed by culture or serologic testing. RESULTS: The efficacy of each vaccine, given in three doses, against pertussis was determined for 14,751 children over an average of 17 months, with cases included in the analysis if cough began 30 days or more after the completion of immunization. For both of the acellular DTP vaccines, the efficacy was 84 percent (95 percent confidence intervals, 76 to 89 percent for Biocine DTP and 76 to 90 percent for SmithKline DTP), whereas the efficacy of the whole-cell DTP vaccine was only 36 percent (95 percent confidence interval, 14 to 52 percent). The antibody responses were greater to the acellular vaccines than to the whole-cell vaccine. Local and systemic adverse events were significantly more frequent after the administration of the whole-cell vaccine. For the acellular vaccines, the frequency of adverse events was similar to that in the control (DT) group. CONCLUSIONS: The two acellular DTP vaccines we studied were safe, immunogenic, and efficacious against pertussis, whereas the efficacy of the whole-cell DTP vaccine was unexpectedly low.

The Vaccine Adverse Event Reporting System (VAERS).

Immunizations against most vaccine-preventable diseases will be needed indefinitely unless the disease is eradicated. Public acceptance of immunizations may be threatened as vaccine coverage increases and disease decreases, however, due to the increase in both causally and coincidentally related vaccine adverse events. The post-marketing surveillance for such events in the USA in response to the mandatory reporting requirements of the National Childhood Injury Act of 1986. While VAERS has many methodological limitations intrinsic to such systems, it can play an important role in helping to monitor vaccine safety and maintain public confidence in immunizations.

Risk of serious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine. A population-based case-control study.

OBJECTIVE: To evaluate the association between serious acute neurological illness and receipt of whole-cell pertussis vaccine, given as diphtheria-tetanus-pertussis (DTP) vaccine. DESIGN: Population-based case-control study. SETTING: Outpatient and inpatient hospital settings, physician practices, and the general population in Washington and Oregon states. SUBJECTS: A total of 424 confirmed cases of neurological illness were identified prospectively during a 12-month period by statewide active surveillance from the population of 218,000 children 1 to 24 months of age living in Washington and Oregon (estimated 368,000 DTP immunizations given). Each case child was matched to two population control children by birth date (+/- 5 days), gender, and county of birth. Written immunization records were used to determine whether illness occurred within 7 days of immunization in case children, or within 7 days of the same reference date in control children, thus qualifying as exposed. MAIN OUTCOME MEASURES: Outpatient and inpatient cases of complex febrile seizures, seizures without fever, infantile spasms, and acute encephalitis/encephalopathy confirmed by an expert panel masked to immunization history. RESULTS: The estimated odds ratio (OR) for onset of serious acute neurological illness within 7 days for young children exposed to DTP vaccine was 1.1 (95% confidence interval [CI], 0.6 to 2.0). When the analysis was restricted to children with encephalopathy or complicated seizures and adjusted for factors possibly affecting vaccine administration, the OR was 3.6 (95% CI, 0.8 to 15.2). Odds ratios for specific study diagnoses varied, but all CIs included 1. No elevated risk was observed for the largest group of illnesses studied, nonfebrile seizures (OR, 0.5; 95% CI, 0.2 to 1.5). CONCLUSIONS: This study did not find any statistically significant increased risk of onset of serious acute neurological illness in the 7 days after DTP vaccine exposure for young children.

Risk factors for delayed immunization in a random sample of 1163 children from Oregon and Washington.

Despite extensive study of vaccine safety and decades of effort to immunize infants and toddlers, little is known about the comprehensiveness of vaccine coverage in US children younger than 2 years of age. Provider and parent data from a population-based sample of 1163 children from two states were analyzed to assess coverage rates at three ages and to evaluate characteristics of children and their families that predict failure to immunize on schedule. Overall, 78% of the children had received their first dose of diphtheria and tetanus toxoids with pertussis vaccine (DTP) and their first dose of oral poliovirus (OPV) by 92 days of age. Similarly, 77% had received their third dose of DTP and their second dose of OPV by their first birthday. However, by their second birthday only 60% had received the full series of four doses of DTP, three doses of OPV, and one dose of the measles, mumps, and rubella vaccines. When considered singly, several variables including child birth order, family income, maternal education, and marital status significantly predicted failure to immunize on schedule. In multivariate logistic models, only birth order and maternal education consistently predicted vaccine status at each of the three ages. Compared with first-born children, those who were later-born were 1.7 times more likely to be incompletely immunized at 2 years of age (95% confidence interval: 1.2, 2.3). Children of more educated mothers were significantly less likely to be underimmunized at all ages.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of whole-cell pertussis vaccine in preschool children in the United States.

OBJECTIVE: To evaluate the efficacy of currently used whole-cell pertussis vaccines. DESIGN: Active surveillance to detect pertussis cases in Baltimore, Md, Denver, Colo, and Milwaukee, Wis, and investigation of secondary attack rates in 347 household contacts, aged 1 through 4 years, to estimate vaccine efficacy. OUTCOME MEASURE: Vaccine efficacy was estimated using different case definitions for pertussis. RESULTS: Vaccine efficacy was 64%, 81%, and 95% for case definitions of mild cough, paroxysmal cough, and severe clinical illness, respectively. Requiring laboratory confirmation increased efficacy to 95% to 98% for culture-positive children and to 77% to 95% for culture- or serology-confirmed cases, depending on disease severity. Vaccine efficacy for typical paroxysmal cough increased from 44% for one diphtheria, tetanus, and pertussis vaccine dose to 80% for four or more doses. CONCLUSIONS: The trend toward increasing vaccine efficacy with different case definitions may be due to improved efficacy in preventing severe illness and to case definitions that are more specific for pertussis. Whole-cell pertussis vaccine was highly effective in preventing pertussis in preschool children exposed to infection within their households. Direct side-by-side efficacy studies of whole-cell vaccine and the recently licensed acellular vaccine will be necessary to assure that comparable protection is afforded by the new vaccines if they are to be used for immunization of infants.

Epidemiological features of pertussis in the United States, 1980-1989.

From 1980 through 1989, 27,826 cases of pertussis were reported to the Centers for Disease Control, for an average annual crude incidence of 1.2 cases/100,000 population. The incidence of reported disease increased in all age groups during this period, but the increase was disproportionately large among adolescents and adults. Infants between 1 and 2 months of age were at highest risk for pertussis (average annual incidence, 62.8/100,000). Infants less than 2 months of age had the highest reported rates of pertussis-associated hospitalization (82%), pneumonia (25%), seizures (4%), encephalopathy (1%), and death (1%). Rates of complication were generally higher among unvaccinated children than among those who had received three or more doses of diphtheria-tetanus-pertussis vaccine; 64% of children 3 months to 4 years of age who had reported cases of pertussis had not been immunized appropriately for their age. Whereas control of pertussis in the United States may be further improved through increased levels of diphtheria-tetanus-pertussis vaccination among eligible infants and children, the use of acellular vaccines in adolescents and adults may also be needed to reduce the burden of pertussis in very young infants.

The epidemiological situation of pertussis in the Federal Republic of Germany.

Whooping cough continues to be a major childhood disease in parts of West Germany. At age six, more than one third of the children in our area have had pertussis according to parental information, whereas only 12% received a specific vaccination. During a four-year period from 1984 to 1987, a total of 2,881 clinically diagnosed cases of whooping cough were investigated. The children had a mean age of 4.1 years, 11% of all patients were younger than one year and 6% of the patients were adults with a mean age of 35.8 years. No sex difference was observed in children (less than 20 years) with clinically overt whooping cough. The seasonal distribution showed that whooping cough was present throughout the year, peaking in early winter. In relation to clinical symptoms, the isolation rate of Bordetella pertussis or Bordetella parapertussis from nasopharyngeal swabs continuously decreased with the duration of paroxysms, starting with 56% positive swabs on day 1. Titers (greater than or equal to 1:100) of IgA-antibodies to B. pertussis antigens increased with the duration of paroxysmal coughing. B. pertussis, however, was also isolated from 152 of 964 patients without the clinical signs of whooping cough. IgA-antibodies were also found in 522 patients with non-typical respiratory symptoms, but not in healthy blood donors. Children with clinically diagnosed whooping cough were compared to a group of children showing the symptoms but without any clinical or laboratory signs of whooping cough. We can assume from our data that the incidence and duration of non-paroxysmal coughing, the nocturnal increase in coughing, fever, auscultatory findings and a contact anamnesis occurred with a similar frequency in the whooping cough group and the control group. Apart from the typical paroxysmal fits, whooping and vomiting were found significantly more often in the pertussis group. At least 19% of patients with a recent infection with B. pertussis, however, were not diagnosed by clinical symptoms. The leukocyte count differed only marginally between the three groups and was of no great diagnostic value. A relative lymphocytosis, however, was found significantly more often in whooping cough patients and in patients with laboratory-diagnosed infection with B. pertussis. Our study indicates that part of the symptomatology and some laboratory findings in whooping cough patients in endemic areas of West Germany may differ from the classical form of the disease. Furthermore, our data stress the importance of an accurate procedure in diagnosing B. pertussis infection, and this can be facilitated by a combination of bacteriological and serological tests.

Human serologic response to envelope-associated proteins and adenylate cyclase toxin of Bordetella pertussis.

The human serologic response to several envelope-associated proteins and adenylate cyclase toxin of Bordetella pertussis was examined using immunoblot techniques. Antigens recognized by sera from individuals with culture-confirmed pertussis and by sera from infants immunized with three doses of conventional whole-cell pertussis vaccine included a 63,000-Da protein that was shown to be antigenically related to a mycobacterial heat-shock protein. A 29,000-Da protein reacted with sera from convalescent individuals, whereas a 91,000-Da protein reacted with sera from vaccinated individuals. Antibodies to adenylate cyclase toxin were common in sera from individuals diagnosed with pertussis. B. pertussis lipooligosaccharide was also recognized by antibodies in some of these sera. These data suggest that some of these antigens may play a role in immunity to pertussis.

The health and economic burden of cigarette smoking in Georgia in 1985.

Using the estimated prevalence of current and former cigarette smoking among Georgians, death certificate data in 1985, and the available literature on smoking-related health risks, we estimated the health and economic impact of cigarette smoking in Georgia in a single year. We estimated, using relatively conservative assumptions, the mortality and years of life lost prematurely, as well as the costs of medical care for ill individuals, lost wages due to death, and lost wages due to illness attributable to smoking. In 1985, past or present smoking was the cause of death for more than 7,700 Georgians, accounting for over 120,000 years of expected life lost prematurely, and with an overall societal cost exceeding $1.5 billion dollars. Cardiovascular diseases were the major cause of all estimated deaths associated with smoking. The prevalence of current smokers is higher in Georgians than the national average; this approach to examining the risks may be useful in lowering that prevalence by influencing patient education in Georgia.