Patrick Olin

A Controlled Trial of a Two-Component Acellular, a Five-Component Acellular, and a Whole-Cell Pertussis Vaccine

BACKGROUND Because of concern about safety and efficacy, no pertussis vaccine has been included in the vaccination program in Sweden since 1979. To provide data that might permit the reintroduction of a pertussis vaccine, we conducted a placebo-controlled trial of two acellular and one whole-cell pertussis vaccines. METHODS After informed consent was obtained, 9829 children born in 1992 were randomly assigned to receive one of four vaccines: a two-component acellular diphtheria-tetanus-pertussis (DTP) vaccine (2566 children), a five-component acellular DTP vaccine (2587 children), a whole-cell DTP vaccine licensed in the United States (2102 children), or (as a control) a vaccine containing diphtheria and tetanus toxoids (DT) alone (2574 children). The vaccines were given at 2, 4, and 6 months of age, and the children were then followed for signs of pertussis for an additional 2 years (to a mean age of 21/2 years). RESULTS The whole-cell vaccine was associated with significantly higher rates of protracted crying, cyanosis, fever, and local reactions than the other three vaccines. The rates of adverse events were similar for the acellular vaccines and the control DT vaccine. After three doses, the efficacy of the vaccines with respect to pertussis linked to a laboratory-confirmed case of pertussis or contact with an infected household member with paroxysmal cough for > or = 21 days was 58.9 percent for the two-component vaccine (95 percent confidence interval, 50.9 to 65.9 percent), 85.2 percent for the five-component vaccine (95 percent confidence interval, 80.6 to 88.8 percent), and 48.3 percent for the whole-cell vaccine (95 percent confidence interval, 37.0 to 57.6 percent). CONCLUSIONS The five-component acellular pertussis vaccine we evaluated can be recommended for general use, since it has a favorable safety profile and confers sustained protection against pertussis. The two-component acellular vaccine and the whole-cell vaccine were less efficacious.

Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis

Vaccine efficacies against typical pertussis after household exposure to Bordetella pertussis were estimated to be 75.4% for an acellular five-component vaccine, 42.4% for an acellular two-component vaccine, and 28.5%, for a licensed US whole cell vaccine, compared to placebo. Logistic regression analyses demonstrated statistically significant correlations between clinical protection and the presence of IgG antibodies against pertactin, fimbriae 2/3 and pertussis toxin in pre-exposure sera. Multicomponent pertussis vaccines of proven high efficacy in recent Swedish NIAID-sponsored efficacy trials induced higher antibody levels against pertactin and fimbriae 2/3 than less efficacious vaccines. Anti-pertactin, anti-fimbriae 2/3, and anti-PT may be used as surrogate markers of protection for multicomponent acellular and whole-cell vaccines against pertussis.

Randomised controlled trial of two-component, three-component, and five-component acellular pertussis vaccines compared with whole-cell pertussis vaccine

Summary Background Trials in Italy and Sweden showed high efficacy for three-component and five-component pertussis vaccines, and poor efficacy for a whole-cell vaccine licensed in the USA and a two-component vaccine. We compared the efficacy of three acellular vaccines with a UK whole-cell vaccine. Methods We enrolled 82892 babies aged 2–3 months. Babies were vaccinated at age 3 months, 5 months, and 12 months, or age 2 months, 4 months, and 6 months. They were randomly assigned a two-component acellular diphtheria-tetanus-pertussis (DTP) vaccine (n=20697), a three-component acellular DTP vaccine (n=20728), a five-component acellular DTP vaccine (n=20747), or a UK whole-cell DTP vaccine (n=20720). We collected data for all reported cases of culture-confirmed pertussis during 3 years of follow-up. The treatment status of the two-component-vaccine group had to be made known midway through the trial for boosting because of poor efficacy. We included data for the two-component vaccine in the analysis of safety and immunogenicity, and data up its unmasking in secondary analyses of relative efficacy. Analyses were by intention to treat. Findings During follow-up from the third dose (mean 22 months), in the 3 months, 5 months, 12 months schedule, there were 15 cases of culture-confirmed pertussis with at least 21 days of paroxysmal cough in the whole-cell group, relative risk 1·00, compared with 13 in the five-component group (0·85 [95% Cl 0·41–1·79]), and 21 in the three-component group (1·38 [0·71–2·69]). For culture-confirmed pertussis, with or without cough, there were 19 cases in the whole-cell group (1·00), 27 in the five-component group (1·40 [0·78–2·52]), and 49 in the three-component group (2·55 [1·50–4·33]). In the intention-to-treat analyses, from the first dose in the 3 months, 5 months, 12 months schedule the whole-cell vaccine was significantly more protective than the three-component vaccine against typical pertussis. Between the second and the third doses, culture-confirmed pertussis with any cough and with at least 21 days of paroxysmal cough was significantly more frequent in the two-component group than in the three-component group, and in the three-component group than in the five-component and the whole-cell groups, respectively. The serological response of the acellular vaccines in the 2 months, 4 months, 6 months schedule were similar to those previously reported. The whole-cell vaccine was highly immunogenic for fimbriae, pertactin, and filamentous haemagglutinin, but had a low antipertussis toxin response. Hypotonic hyporesponsiveness occurred significantly more frequently in the whole-cell group (p Interpretations The efficacy of the UK whole-cell vaccine and the five-component and three-component vaccines was similar against culture-confirmed pertussis with at least 21 days of paroxysmal cough. The lower efficacy of the three-component vaccine against mild disease suggests that fimbriae have a role in protection against infection. The efficacy of acellular vaccines depends on the number of components, and different whole-cell vaccines have variable efficacies.

Long-term Follow-up of Swedish Children Vaccinated With Acellular Pertussis Vaccines at 3, 5, and 12 Months of Age Indicates the Need for a Booster Dose at 5 to 7 Years of Age

OBJECTIVES. The purpose of this work was to evaluate the long-term effectiveness of vaccination with acellular pertussis vaccines at 3, 5, and 12 months of age. METHODS. Clinical follow-up of reported culture- and polymerase chain reaction–confirmed cases of pertussis was initiated during October 1997 in most of Sweden (except Gothenburg and environs). The study population included 90% of Swedish children born during 1996 or later (ie, who received diphtheria-tetanus-acellular pertussis vaccines at 3, 5, and 12 months of age) and children who had participated in a large pertussis vaccine trial in 1993–1996. Age-specific incidences were estimated using reported culture- or polymerase chain reaction–confirmed pertussis from October 1997 to September 2004 in areas covered by enhanced surveillance. In addition, annual overall and age-specific incidences of pertussis throughout Sweden before and after introduction of acellular pertussis vaccines were estimated. RESULTS. The overall incidence of notified culture- and polymerase chain reaction–confirmed pertussis dropped from 113 to 150 per 100 000 during 1992–1995 to 11 to 16 per 100 000 during 2001–2004. In areas of enhanced surveillance, the incidence of pertussis was 31 per 100 000 person-years after 2 doses and 19 per 100 000 person-years after the third dose at 12 months of age. The age-specific incidence remained low for ∼5 years after the third dose but increased in children aged 6 to 8 years, becoming 32 and 48 per 100 000 person-years, respectively. The highest incidence occurred among infants who were unvaccinated or had received only 1 dose of diphtheria-tetanus-acellular pertussis vaccine. CONCLUSIONS. The increased incidence among 7- to 8-year-olds (ie, mainly acellular pertussis vaccine–vaccinated children) suggests waning of vaccine-induced protection from pertussis. Along with a concomitant increase in incidence among infants, most likely infected by older siblings, these data suggest a booster dose of acellular pertussis vaccine is warranted from 5 to 7 years of age.

Low levels of antipertussis antibodies plus lack of history of pertussis correlate with susceptibility after household exposure to Bordetella pertussis.

Prospectively collected data in a Swedish vaccine efficacy trial were used to investigate transmission of pertussis from small study infants to other household members. Forty one percent (258/627) of the exposed persons with paired serology had laboratory confirmed pertussis. The majority of those with laboratory confirmed pertussis had less than 14 days of cough and many were asymptomatic. High susceptibility to symptomatic pertussis was found among persons with low initial IgG antibody concentrations against pertussis toxin, especially those without previous history of pertussis vaccination or disease.

Bordetella pertussis, Bordetella parapertussis, Mycoplasma pneumoniae, Chlamydia pneumoniae and Persistent Cough in Children

Material collected during a prospective pertussis vaccine trial in 1992-95 was examined for Bordetella pertussis (culture and serology), Bordetella parapertussis (culture), Mycoplasma pneumoniae and Chlamydia pneumoniae (PCR). From 64% (99/155) of episodes with cough for less than 100 d, 115 aetiological agents were identified in one southern and one northern subset of DT-recipients. The most common single agent was B. pertussis, representing 56%(64/115), with a median cough period of 51 d, followed by M. pneumoniae 26%(30/115), 23 d, C. pneumoniae 17% (19/115), 26 d, and B. parapertussis 2% (2/115). For co-infections, the median duration of cough was about 60 d. Spasmodic cough for 21 d or more (clinical WHO criteria for pertussis) was present in 82% (41/50) of infections with B. pertussis as single agent, 38% (17/45) with B. parapertussis, 38% (5/13) with C. pneumoniae, 26% (5/19) with M. pneumoniae and 30%(17/56) in cases where no aetiology was found. In children with cough for more than 100 d (n = 78) using all vaccine arms, B. pertussis was responsible in 83% (65/78), in 21%(16/78) together with other agents. Acellular vaccines were more efficient against serious disease than whole cell vaccine. Antibiotic treatment was more common at the southern (34%) study site than at the northern one (12%). The findings indicate that diagnosis should rely on laboratory confirmation, both for rational treatment of an individual case and for monitoring outbreaks.

How to Make Sense of Pertussis Immunogenicity Data

Studies on serologic correlates to protection in pertussis were reviewed. Trials in the 1950s showed that agglutinogen titers correlated to protection of whole-cell vaccines, but postvaccination antibodies against pertussis toxin (PT) and against filamentous hemagglutinin did not in a later trial of acellular vaccines. However, in household studies nested in 2 recent trials, preexposure antibody levels against pertactin and against fimbriae correlated with protection against typical and mild pertussis, and anti-PT correlated only with protection against typical pertussis. These findings could be used by regulatory agencies to license pertussis vaccines. A reference laboratory for pertussis should distribute panels to control interlaboratory variation in recommended assays, and a minimal response should be set for each pertussis antigen. We conclude that 2 studies have shown correlates between measurable anti-pertactin, anti-fimbriae, and anti-PT antibody levels at exposure and individual protection against pertussis. We suggest that postvaccination response rates may be used as surrogate markers of protection.

Protective efficacy of a whole cell pertussis vaccine.

A trial of the efficacy of a plain whole cell pertussis vaccine was conducted in Sweden. In this non-blinded trial 525 infants aged 2 months who were born on days with an even number received three doses of vaccine one month apart and 615 infants of the same age who were born on days with an odd number were enrolled as controls. During the 18 months of follow up there were 55 cases of pertussis. The attack rate was 1·5% (8/525) among the vaccinated children and 7·6% (47/615) among the unvaccinated children (p<0·001). The estimated efficacy of the vaccine was 80% (95% confidence interval 58 to 90). The estimated efficacy of pertussis vaccine was similar to that observed in British trials over 30 years ago.

Screening for congenital hypothyroidism. I. Laboratory results of a pilot study based on dried blood samples collected for PKU screening.

ABSTRACT. Larsson, A., Ljunggren, J. G., Ekman, K., Nilsson, A. and Olin, P. (Departments of Paediatrics and Child Psychiatry, Karolinska Institute, St. Gorans Childrens Hospital; the Department of Medicine, St. Görans Hospital; and the PKU Section of the Department of Bacteriology, National Bacteriological Laboratory, Stockholm, Sweden). Screening for congenital hypothyroidism. I. Laboratory results of a pilot study based on dried blood samples collected for PKU screening. Acta Paediatr Scand, 70:141, 1981. – A pilot study was performed to establish optimal conditions for nation‐wide screening for congenital hypothyroidism in Sweden. The levels of T4 and TSH were determined by automated radioimmunoassay in the dried blood spots, routinely collected for PKU screening on the fifth postnatal day, from all 1979, 2 infants born in the Stockholm area during a 14‐month period. To identify safe minimum recall criteria for routine use, infants were recalled if the TSH level was more than 30 mU/l of plasma or–if they were not preterm–the T4 concentration was less than ‐2 S.D. of the mean. Altogether 160 infants were recalled. Seven newborns with congenital hypothyroidism were identified, 6 with primary and one with secondary hypothyroidism. Five infants had decreased levels of thyroxine‐binding globulin. The results of the follow‐up analyses from recalled infants showed that determination of the reverse‐T3 level may be of diagnostic value around the 23rd day of life. The results of the clinical investigation of recalled infants are reported in a subsequent paper and a programme for nation‐wide screening for congenital hypothyroidism is proposed.

Schedules and protection, simultaneous vaccination and safety: Experiences from recent controlled trials

Abstract Controlled clinical trials of pertussis vaccines are reviewed, and additional data are presented to elucidate the influence of simultaneous administration of other vaccines on early :symptoms after vaccination and the effect of number of doses, age, and dose-interval on observed efficacy. In a randomized placebo-controlled trial of a two-component acellular diphtheria, tetanus toxoids, pertussis (DTP) vaccine, a five-component acellular DTP, an American whole-cell DTP, and a DT vaccine, adverse events were documented by questionnaires 24 hours after vaccination in 9823 children 2 to 6 months of age. In another ongoing randomized double-blind trial, 82,892 children were enrolled in four DTP groups. An interim analysis of relative efficacy was done when one vaccine was unblinded, due to the low efficacy shown in the first trial. In the placebo-controlled trial, simultaneous administration of Haemophilus influenzae type b (Hib) vaccine increased the rate of systemic symptoms as compared to acellular DTP or DT alone. In the ongoing trial, the relative risk of culture-confirmed pertussis with cough for 1 or more days was 2.82 (2.06–3.88) after two doses of a two-component DTP vaccine compared to a three-component, a five-component, and a British whole-cell DTP vaccine, combined. Simultaneous Hib-vaccination is associated with increased rates of systemic symptoms compared to DT or acellular DTP alone. Two doses of multicomponent acellular vaccines and a British whole-cell vaccine seem to confer significant protection against mild and severe pertussis.