Investigations into the emergence of pertactin-deficient Bordetella pertussis isolates in six European countries, 1996 to 2012.

Pathogen adaptation has been proposed to contribute to the resurgence of pertussis. A striking recent example is the emergence of isolates deficient in the vaccine component pertactin (Prn). This study explores the emergence of such Prn-deficient isolates in six European countries. During 2007 to 2009, 0/83 isolates from the Netherlands, 0/18 from the United Kingdom, 0/17 Finland, 0/23 Denmark, 4/99 Sweden and 5/20 from Norway of the isolates collected were Prn-deficient. In the Netherlands and Sweden, respectively 4/146 and 1/8 were observed in a later period (2010­12). The Prn-deficient isolates were genetically diverse and different mutations were found to inactivate the prn gene. These are indications that Prn-deficiency is subject to positive selective pressure. We hypothesise that the switch from whole cell to acellular pertussis vaccines has affected the balance between 'costs and benefits' of Prn production by Bordetella pertussis to the extent that isolates that do not produce Prn are able to expand. The absence of Prn-deficient isolates in some countries may point to ways to prevent or delay the spread of Prn-deficient strains. In order to substantiate this hypothesis, trends in the European B. pertussis population should be monitored continuously.

A review of the evidence to inform pneumococcal vaccine recommendations for risk groups aged 2 years and older.

For decades, vaccination with the 23-valent polysaccharide pneumococcal vaccine (PPV23) has been available for risk groups aged ⩾2 years to prevent invasive pneumococcal disease (IPD). Recently, a 13-valent pneumococcal conjugated vaccine (PCV13) has been licensed for use in all age groups. PCV13 may induce better protection than PPV23 because of different immunogenic properties. This called for a revision of vaccine recommendations for risk groups. We therefore reviewed literature on risk groups for IPD, and effectiveness and safety of pneumococcal vaccines and supplemented that with information from public health institutes, expert consultations and data on IPD epidemiology. We included 187 articles. We discuss the implications of the heterogenic vulnerability for IPD within and between risk groups, large indirect effects of childhood immunization, and limited knowledge on additional clinical benefits of PCV13 in combination with PPV23 for the Norwegian recommendations. These are now step-wise and consider the need for vaccination, choice of pneumococcal vaccines, and re-vaccination interval by risk group.

Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A.

BACKGROUND: From October 2009 to January 2010, approximately 470,000 children and adolescents in Norway ages 4-19 years were vaccinated with Pandemrix® against influenza A (H1N1 subtype). The vaccination coverage in this age cohort was approximately 50%. OBJECTIVES: Our study was performed to evaluate the possible association between Pandemrix® vaccination and narcolepsy in Norway. METHODS: Children and adolescents with sudden onset of excessive daytime sleepiness (EDS) and cataplexy occurring after the 2009-2010 vaccination period were registered by the National Institute of Public Health in cooperation with the Norwegian Resource Center for AD/HD, Tourette Syndrome, and Narcolepsy. RESULTS: Fifty-eight vaccinated children and adolescents (35 girls, 23 boys) ages 4-19 years (mean age, 10.5 years) were diagnosed as new cases of confirmed narcolepsy and were included in our study during 2010 and 2011. Forty-two children had onset of symptoms within 6 months after vaccination, with 12 of them having symptoms within the first 6 weeks. All had EDS, 46 had documented cataplexy, 47 had mean sleep latency less than 8 min, and 43 had two or more sleep-onset rapid eye movement sleep (SOREM) periods in multiple sleep latency tests (MSLT). Cerebrospinal fluid (CSF) hypocretin levels were measured in 41 patients, with low levels in all. Thirty seven patients that were analyzed had tissue type HLADQB1*0602. During the same period, 10 unvaccinated cases were reported (mean age, 12.5 years). CONCLUSION: The data collected during 3 years following vaccination showed a significantly increased risk for narcolepsy with cataplexy (P<.0001) and reduced CSF hypocretin levels in vaccinated children ages 4-19 years the first year after Pandemrix® vaccination, with a minimum incidence of 10 of 100,000 individuals per year. The second year after vaccination, the incidence was 1.1 of 100,000 individuals per year, which was not significantly different from the incidence of 0.5-1 of 100,000 per year in unvaccinated children during the same period.

Calibrated serological techniques demonstrate significant different serum response rates to an oral killed cholera vaccine between Swedish and Nicaraguan children.

Serum responses to oral cholera vaccines were assessed in three paediatric vaccine trials, two in León, Nicaragua and one in Stockholm, Sweden. A calibrated anti-cholera toxin B subunit (CTB) IgA ELISA was used together with an assay for vibriocidal antibodies. Swedish children had lower pre-vaccination levels of antibody, but serum responses were more pronounced in Swedish children than in Nicaraguan children. Post-vaccination levels of anti-toxin antibody were generally above those found after natural infections with enterotoxigenic Escherichia coli, that cross-reacts serologically with Vibrio cholerae. Adverse events seen after vaccination were generally mild and of little clinical significance.

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.

[Should school children receive pertussis vaccine?]. / Bør skolebarn få kikhostevaksine?

BACKGROUND: A study comparing diphtheria immunity in Norwegian and Russian schoolchildren indicated low immunity against diphtheria in Norwegian children before the booster dose given at age 11 years. The pertussis epidemic in Norway 1997-98 demonstrated decreasing vaccine immunity from age 5-6 years. The possibility of improving immunity against both diseases by a booster dose during early school age is therefore under consideration. MATERIAL AND METHODS: Immune response and adverse events were studied after a combined vaccine against diphtheria, tetanus, pertussis (acellular) and poliomyelitis (DTPa-IPV) given at seven years of age, and a combined vaccine against diphtheria, tetanus and pertussis (acellular) (DTPa) at 11 years of age, in two parallel trials including 124 and 83 participants respectively. RESULTS: The trials confirmed that the diphtheria immunity is lower than it ideally should be in more than 40% of children before the booster dose at age 11. Pertussis immunity is difficult to assess because there is no clear relationship between antibody levels and protection. All study participants responded well to all vaccine components. The 11-year-old children reported higher occurrence of adverse events than the 7-year-olds. All adverse events were brief and none were serious. INTERPRETATION: The results indicate that a booster dose of DTPa-IPV in early school age would give better protection against diphtheria and pertussis in Norwegian schoolchildren, without unacceptable side effects.

Diphtheria antitoxin response to DTP vaccines used in Swedish pertussis vaccine trials, persistence and projection for timing of booster.

Data from two Swedish pertussis vaccine trials with various combination vaccines were used to compare anti-diphtheria antitoxin concentrations over time between different vaccines, vaccine lots and vaccine schedules. The immune responses were measured with a validated ELISA method.Results are given for 1326 children, born 1992, that were recruited to the placebo (DT)-controlled Trial I which used a 2, 4, 6 month schedule. Two DTP acellular and one DTP whole cell vaccine were used. No DT boosters were given until 5 years of age. Trial II recruited children born 1993-94 and compared three DTP acellular vaccines with one DTP whole cell vaccine. Results are given for 306 children in a 2, 4, 6 month schedule and for 531 children in a 3, 5, 12 month schedule. The latter schedule gave significantly higher diphtheria antitoxin concentrations post third dose. The various DTP acellular vaccines and an inefficacious DTP whole cell vaccine gave lower antitoxin concentrations than both an efficacious DTP whole cell vaccine and the DT vaccine. The larger differences in antigen response between vaccines was reduced in the course of time. Generally, an initial rapid decline of antitoxin concentration was followed by a slower decline; the change typically occurring when the antitoxin concentration reached 0.13-0.16 EU/ml. The time needed to reach this level was between 6 and 10 months based on the initial vaccine response.A "best-fit" combined exponential regression model was used to predict the optimal timing for booster vaccinations against diphtheria.Our data support a 3, 5, 12 month schedule followed by a fourth dose 4-5 years after the third dose, depending upon the vaccine used.

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.

Distinct T-cell subtypes induced with whole cell and acellular pertussis vaccines in children.

Recent clinical trials have demonstrated that new generation acellular pertussis vaccines can confer protection against whooping cough. However, the mechanism of protective immunity against Bordetella pertussis infection induced by vaccination remains to be defined. We have examined cellular immune responses in children immunized with a range of acellular and whole cell pertussis vaccines. Immunization of children with a potent whole-cell vaccine induced B. pertussis-specific T cells that secreted interferon-gamma (IFN-gamma), but not interleukin-5 (IL-5). In contrast, T cells from children immunized with acellular pertussis vaccines secreted IFN-gamma and/or IL-5 following stimulation with B. pertussis antigens in vitro. These observations suggest that protective immunity conferred by whole-cell vaccines, like natural immunity, is mediated by type 1 T cells, whereas the mechanism of immune protection generated with acellular vaccines may be more heterogeneous, involving T cells that secreted type 1 and type 2 cytokines.

Catch-up primary vaccination with acellular pertussis vaccines in 3-4-year-old children--reactogenicity and serological response.

In order to evaluate the optimum number of doses for catch-up primary vaccination against pertussis, 248 Swedish children 3-4 years of age were randomized to receive either two or three doses of a three-component or a five-component acellular pertussis vaccine. Adverse reactions were mild, but increased with increasing number of doses, especially in a subgroup of 17 children with serological signs of earlier pertussis. There were no clinically significant differences between the two vaccines. Antibody levels against pertussis were higher after two doses in this age group than after three doses in infancy. A primary vaccination program for older children can use two instead of three doses.

Bordetella pertussis respiratory infection in children is associated with preferential activation of type 1 T helper cells.

The mechanism of protective immunity against Bordetella pertussis generated following recovery from whooping cough in childhood has not yet been elucidated. Studies with a murine respiratory infection model have indicated that cellular immunity, mediated by Th1 cells, plays a role in the clearance of a primary infection with B. pertussis and in protection against subsequent challenge. In the present study, the induction of B. pertussis-specific Th cell subsets in children was examined. Peripheral blood mononuclear cells from B. pertussis-infected or convalescent children proliferated and secreted cytokines following antigen stimulation in vitro. In contrast, responses were weak or undetectable in the majority of children who had not been infected or vaccinated. In all cases, responding T cells produced interferon-gamma but low or undetectable interleukin-5. The findings suggest that Th1 cells may play a role in protective immunity generated following infection with B. pertussis in children.

Absolute efficacy of acellular pertussis vaccines in household settings.

Household studies in the two recently concluded Swedish pertussis vaccine efficacy trials demonstrated that one monocomponent and one five-component candidate acellular pertussis vaccine had reasonably good protective efficacy against clinically typical pertussis after household exposure. Another recently concluded German household study, led from Mainz, also demonstrated reasonably good efficacy for a three-component acellular pertussis vaccine. The methods of case ascertainment and duration of follow-up had a marked influence on the efficacy estimates of another candidate two-component acellular pertussis vaccine. This vaccine and a U.S. licensed commercial whole-cell vaccine had very low efficacy against pertussis infection after household exposure. Differences in methodology preclude direct comparisons between the efficacy estimates obtained in various household studies.

Bordetella pertussis-specific Th1/Th2 cells generated following respiratory infection or immunization with an acellular vaccine: comparison of the T cell cytokine profiles in infants and mice.

In an investigation of cell-mediated immunity against Bordetella pertussis, we found that B. pertussis infection in infants and in mice was associated with the induction of antigen-specific T cells that secrete IFN-g and IL-2, but not IL-4 or IL-5. This cytokine profile is characteristic of Th1 cells that mediate cellular immune responses against a range of intracellular pathogens. An examination of cytokine production following immunization with a three-component acellular vaccine, comprising inactive PT, FHA and pertactin adsorbed to alum, demonstrated that spleen cells from vaccinated mice produced high levels of IL-5, but no detectable IFN-g and low levels of IL-2. In contrast, peripheral blood mononuclear cells from vaccinated infants produced IL-2, IL-5 and IFN-g. These findings highlight significant differences in the immune responses generated by vaccination and natural infection with B. pertussis and demonstrate that the T-cell response induced with an acellular vaccine, although dominated by type 2 cytokines in mice, is more heterogeneous in infants with a Th0 or mixed Th1/Th2 cytokine profile.

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.

Pertussis antibodies, protection, and vaccine efficacy after household exposure.

During a randomized trial of a cellular pertussis vaccines, significantly fewer recipients of a two-component vaccine (Japanese National Institute of Health [JNIH]-6) were diagnosed as primary or coprimary cases in households than either placebo recipients or those who received a monocomponent pertussis toxoid vaccine (JNIH-7). After household exposure to a culture-confirmed primary case, efficacy for JNIH-6 was estimated to be 35% (95% confidence interval, -14% to 57%) against any culture-confirmed disease and 58% (95% confidence interval, -6% to 84%) against clinical disease with 21 days or more of coughing spasms. The corresponding efficacy estimates for JNIH-7 were 67% (95% confidence interval, 32% to 80%) and 82% (95% confidence interval, 41% to 96%). Differences between the JNIH-6 and JNIH-7 vaccines in efficacy after household exposure were not statistically significant. No association could be established between protection against pertussis after household exposure and serum levels of IgG antibody to pertussis toxin or filamentous hemagglutinin in vaccinated individuals, in either study children or other household members.

Relative efficacy of two acellular pertussis vaccines during three years of passive surveillance.

Prolonged unblinded passive surveillance of the trial cohort from the Swedish 1986-87 pertussis vaccine efficacy trial indicates that a two-component vaccine, containing pertussis toxoid and filamentous haemagglutinin, provided better long-term protection against pertussis than a monocomponent pertussis toxoid vaccine. The relative risk (RR) for culture-confirmed pertussis was 1.5 (95% confidence interval (CI) 1.0-2.4), and RR for pertussis according to parents' diagnoses was also 1.5 (95% CI 1.1-2.1), for the monocomponent vaccine compared with the two-component vaccine.