Surveillance during an era of rapidly changing poliovirus epidemiology in India: the role of one vs. two stool specimens in poliovirus detection, 2000-2010.

Since 2004, efforts to improve poliovirus detection have significantly increased the volume of specimen testing from acute flaccid paralysis (AFP) patients in India. One option to decrease collection and testing burden would be collecting only a single stool specimen instead of two. We investigated stool specimen sensitivity for poliovirus detection in India to estimate the contribution of the second specimen. We reviewed poliovirus isolation data for 303984 children aged <15 years with AFP during 2000-2010. Using maximum-likelihood estimation, we determined specimen sensitivity of each stool specimen, combined sensitivity of both specimens, and sensitivity added by the second specimen. Of 5184 AFP patients with poliovirus isolates, 382 (7.4%) were identified only by the second specimen. Sensitivity was 91.4% for the first specimen and 84.5% for the second specimen; the second specimen added 7.3% sensitivity, giving a combined sensitivity of 98.7%. Combined sensitivity declined, and added sensitivity increased, as the time from paralysis onset to stool collection increased (P = 0.032). The sensitivity added by the second specimen is important to detect the last chains of poliovirus transmission and to achieve certification of polio eradication. For sensitive surveillance, two stool specimens should continue to be collected from each AFP patient in India.

Preventing congenital rubella infection in the European Region of WHO: 2010 target.

The World Health Organisation (WHO) Regional Office for Europe has recently published a strategic plan and surveillance guidelines for measles and congenital rubella infection. The strategy prioritizes measles control activities but encourages the introduction of rubella vaccine when measles vaccine coverage has reached >90 %; although, many western European countries with suboptimal measles vaccine coverage are already using the combined measles, mumps and rubella (MMR) vaccine. Women in these countries may have an especially high risk of having an infant with congenital rubella syndrome. WHO is seeking to improve the surveillance for rubella and congenital rubella syndrome as a means to obtain better information on the burden of these diseases and engage policy decision makers in the need to support the WHO European Region's strategies for rubella.

Preventing congenital rubella infection in the European Region of WHO: 2010 target.

The World Health Organisation (WHO) Regional Office for Europe has recently published a strategic plan and surveillance guidelines for measles and congenital rubella infection. The strategy prioritises measles control activities but encourages the introduction of rubella vaccine when measles vaccine coverage has reached >90 %; although, many western European countries with suboptimal measles vaccine coverage are already using the combined measles, mumps and rubella (MMR) vaccine. Women in these countries may have an especially high risk of having an infant with congenital rubella syndrome. WHO is seeking to improve the surveillance for rubella and congenital rubella syndrome as a means to obtain better information on the burden of these diseases and engage policy decision makers in the need to support the WHO European Region's strategies for rubella.

Randomised study of the possible adjuvant effect of BCG vaccine on the immunogenicity of diphtheria-tetanus-acellular pertussis vaccine in Senegalese infants.

Following a study in Senegal (1990-1995) in which the relative efficacy of a diphtheria-tetanus-acellular pertussis vaccine (DTaP) was compared with that of a diphtheria-tetanus-whole-cell pertussis vaccine in children given a simultaneous injection of Bacille Calmette-Guérin (BCG) vaccine, this subsequent study was conducted to evaluate the possible adjuvant effect of the BCG vaccine on acellular pertussis vaccine components. A second objective was to compare the immunogenicity of these components when administered in accordance with a 2-4-6-month (spaced) schedule or an accelerated 2-3-4-month schedule. In all, 390 healthy Senegalese infants were randomly divided into three groups of 130 infants. Antibodies to acellular pertussis components were measured in serum samples obtained within 2 days of the first DTaP dose and 1 month after the third dose. BCG vaccine, given simultaneously with the DTaP vaccine, did not influence the immunogenicity of the acellular pertussis vaccine components when compared with separate administration of the two vaccines. Infants immunised according to a 2-4-6-month schedule had a significantly higher immune response than those immunised according to a 2-3-4-month schedule with respect to the response to pertussis toxoid assessed by seroneutralisation on Chinese hamster ovary cells (P<0.0001). These results suggest that BCG and DTaP vaccines can be given simultaneously without interference or enhancement and that more optimal immunogenicity is achieved with an extended than with an accelerated schedule.

Epidemiological factors in clinical trial design.

Randomised, double-blind, placebo-controlled clinical trials are human experiments in which the process of randomisation and blinded observation greatly simplify the interpretation of the results. However, epidemiological issues when properly addressed allow the optimal preparation of the study with anticipation of factors to be included in the analysis which are independent of the randomisation process but can affect the results, for example, the effect of age, dose, time since vaccination and exposure to other diseases. Alternative methods of estimating vaccine efficacy may be necessary in some settings, and such methods may have limitations which must be acknowledged in interpretation. This paper reviews some recently published studies of vaccine efficacy for the application of epidemiological principles in design and analysis.

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.

Certifying the elimination of poliomyelitis from Europe: advancing towards global eradication.

UNLABELLED: Indigenous wild polioviruses have been virtually eliminated from the 51 countries of the European Region of the World Health Organization (WHO), an achievement that is of critical importance to the global initiative to eradicate poliomyelitis by the year 2000. An international commission has been established to certify the elimination of poliomyelitis from this region. European countries have recently been requested to establish National Certification Committees to review and submit the necessary documentation and surveillance data. In some Western European countries where polio has not been reported for many years, the challenge will be to produce robust evidence demonstrating both the current absence of wild poliovirus and the means to promptly detect and respond to possible importations of wild poliovirus for the next several years, up to global eradication and the cessation of polio vaccination. KEY MESSAGES: 1. laboratory-based surveillance with collection of faecal specimens is necessary to demonstrate the absence of indigenous wild poliovirus 2. certification can only occur after all countries have demonstrated the absence of indigenous wild polioviruses for at least 3 years and have the means to detect and respond to importations of wild poliovirus for several years into the future 3. any single case of poliomyelitis in Europe now requires an immediate public health response which includes virological investigation and prompt notification to the World Health Organization.

A randomized double-blind trial comparing a two-component acellular to a whole-cell pertussis vaccine in Senegal.

A randomized, double-blind trial comparing a diphtheria-tetanus-acellular pertussis vaccine (DTaP) (pertussis toxoid and filamentous hemagglutinin) with a whole-cell vaccine (DTwP) was conducted. A case-contact study was nested in the trial to estimate absolute efficacy. From 1990 through 1994, 4181 children were randomized to receive one of the vaccines at 2, 4, and 6 months. Severe adverse events were monitored weekly during two visits after vaccination. Fewer serious adverse events were observed after DTaP. Surveillance for cough illnesses persisting more than 7 days, in children under 15 years of age, was made by weekly home visits. Examining physicians, blind to vaccination status, took samples for culture and serologic testing. Pertussis was defined as 21 or more days of cough confirmed by culture, serology, or contact with a culture-confirmed person. Beginning 28 days after the third vaccine dose, the overall ratio of pertussis incidence in the DTaP group relative to the DTwP group (RRac/wc) was 1.54 (95% CI, 1.23-1.93). In children younger than 18 months of age, RRac/wc was 1.16 (95% CI, 0.77-1.73) and 1.76 (95% CI, 1.33-2.33) in children older than 18 months, which suggests a shorter duration of protection with the acellular vaccine (P = 0.090). Absolute efficacy estimates derived from the case-contact study confirmed the lower protection afforded by the acellular vaccine compared with the whole-cell vaccine: 31% (95% CI, 7-49) versus 55% against the protocol case definition, and 85% (95% CI, 66-93) versus 96% for the more severe WHO case definition. Although vaccination with DTaP provided a lower degree of protection than the highly effective DTwP, this difference was less prominent before 18 months of age, the customary age for a fourth dose. The safer DTaP vaccine may prove a valuable substitute for whole-cell vaccines when used in a schedule that includes a booster-dose.

Risk of chronic arthropathy among women after rubella vaccination. Vaccine Safety Datalink Team.

CONTEXT: A review by the Institute of Medicine found a possible relationship between rubella vaccination and chronic arthritis among women. OBJECTIVE: To evaluate the risk of persistent joint and neurologic symptoms in rubella seronegative women subsequently vaccinated with RA 27/3 rubella vaccine. DESIGN: Retrospective cohort study based on computerized laboratory data and medical record review. Records were reviewed for symptoms occurring within 2 years before and after the date of serological testing and to identify vaccinees. Possible cases were evaluated by a rheumatologist blinded to serological findings and vaccination status. SETTING: Large health maintenance organization in northern California. PATIENTS: Women aged 15 to 59 years serotested for rubella during 1990 with continuous health plan membership for 2 years before and after the date of their serological test. Seronegative women immunized within 1 year of serotesting (n=971) were defined as exposed. Primary comparison groups included all unvaccinated, seronegative women (n=924) and randomly selected seropositive, unvaccinated women (n=2421) matched to exposed subjects on serological test date and age (+/-3 years). MAIN OUTCOME MEASURES: Prevalence and incidence of chronic joint and neurologic symptoms during 1-year follow-up period stratified by age and serological findings, immunization, and postpartum status. RESULTS: No significantly increased risk was associated with receipt of rubella vaccine for any outcome except for prevalence of carpal tunnel syndrome in vaccinated women at least 30 years old compared with seropositive, unvaccinated women (2.9% vs 1.4%; P=.03). A total of 34 women had onset of conditions within the 1-year follow-up period; 9 of these were in the group of seronegative, immunized women, of whom 6 had onset of symptoms within 6 weeks of vaccination. Among these 6 women, symptoms included transient arthritis or arthralgias (<6 weeks duration) in 4 women, arthralgia of indeterminate chronicity in 1 woman, and carpal tunnel syndrome in 1 woman. Postpartum women across all groups were less likely to be seen for nontraumatic arthropathies than nonpostpartum women (4.5% vs 7.2%, P=.08 in vaccinated women; 4.8% vs 8.1%, P=.09 in seronegative controls; and 4.8% vs 10.0%, P=.01 in seropositive controls). CONCLUSIONS: In this large retrospective cohort analysis there was no evidence of any increased risk of new onset chronic arthropathies or neurologic conditions in women receiving the RA 27/3 rubella vaccine. These data support the continued vaccination of rubella-susceptible women to reduce the risk of congenital rubella syndrome.

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.

Polio outbreak in Albania, 1996.

Between April and November 1996, a large outbreak of polio occurred in Albania, which had reported to be free of polio since 1985. Although Albania had not reported polio in that interval, the risk of introduction and circulation of wild poliovirus had in

Progress in Europe towards the goal of poliomyelitis eradication.

In 1988, the World Health Assembly set a target of global eradication of poliomyelitis due to wild poliovirus by the year 2000. The strategies of the campaign are: reach and maintain high levels of routine vaccination coverage throughout the population; p

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.