Pertussis resurgence: waning immunity and pathogen adaptation - two sides of the same coin.

Pertussis or whooping cough has persisted and resurged in the face of vaccination and has become one of the most prevalent vaccine-preventable diseases in Western countries. The high circulation rate of Bordetella pertussis poses a threat to infants that have not been (completely) vaccinated and for whom pertussis is a severe, life-threatening, disease. The increase in pertussis is mainly found in age groups in which immunity has waned and this has resulted in the perception that waning immunity is the main or exclusive cause for the resurgence of pertussis. However, significant changes in B. pertussis populations have been observed after the introduction of vaccinations, suggesting a role for pathogen adaptation in the persistence and resurgence of pertussis. These changes include antigenic divergence with vaccine strains and increased production of pertussis toxin. Antigenic divergence will affect both memory recall and the efficacy of antibodies, while higher levels of pertussis toxin may increase suppression of the innate and acquired immune system. We propose these adaptations of B. pertussis have decreased the period in which pertussis vaccines are effective and thus enhanced the waning of immunity. We plead for a more integrated approach to the pertussis problem which includes the characteristics of the vaccines, the B. pertussis populations and the interaction between the two.

A literature review and evidence-based evaluation of the Dutch national immunisation schedule yield possibilities for improvements.

National Immunisation Programmes (NIPs) develop historically. Its performance (disease incidences, vaccination coverage) is monitored. Reviewing the schedule as a whole could inform on further optimisation of the programme, i.e., providing maximal protection with the lowest number of doses. We systematically evaluated the performance and strategies of the Dutch pathogen-specific NIP schedules through literature review, assessment of surveillance data and expert opinions. Pathogen-specific vaccinations were categorised according to their strategy of protection: I) elimination or eradication, II) herd immunity or III) 'only' individual protection. The schedule of each vaccine-component was evaluated based on fixed criteria: 1. Is the achieved protection adequate? 2. Is the intended protection achieved? 3. Does the programme include too many or too few doses? 4. Is the timing optimal or acceptable? and 5. Are there drawbacks of the NIP for (part of) the population? Identified issues were explored using surveillance data and literature. Using fixed criteria facilitated comparison between pathogens and revealed opportunities to optimise the Dutch NIP by: i. Reducing the number of polio and tetanus vaccinations; ii. prolonging the interval between diphtheria, pertussis, tetanus, polio, hepatitis B, and Hib vaccine doses for improved effectiveness; iii. Expedite the second measles vaccination from 9 to 2-4 years of age to offer unvaccinated children and primary vaccine failures an earlier chance to be protected; and iv. Delaying the second mumps vaccination to enhance protection in adolescents/young adults. No schedule adaptations were deemed necessary for the vaccines against HPV, rubella, pneumococcal disease, and meningococcal disease. Based on this evaluation the NITAG advised to move the DTaP-IPV-HBV-Hib-booster from age 11 to 12 months, the second MMR-dose from 9 to 2-4 years, replace the Tdap-IPV at 4 years with a Tdap at 5-6 years and move the dt-IPV from 9 to 14 years. Implementation of these changes is planned for 2025.

Incidence of multiple sclerosis in the general population in the Netherlands, 1996-2008.

BACKGROUND: We estimated the multiple sclerosis (MS) incidence in the Netherlands for better active monitoring of potential vaccine safety signals. METHODS: A retrospective cohort study (1996-2008) was conducted using a population-based general practice research database containing electronic medical records. Additional information was collected to validate incident probable cases. RESULTS: In the source population (648,656 persons), 146 incident probable MS cases were identified. Overall incidence rate was 6.3/100,000 person years (py; 95% CI, 5.2-7.2). In the subgroup in which MS could be fully validated, the incidence increased from 4/100,000 py (95% CI, 3-5) in 1996-2004 to 9/100,000 py in 2007/8 (95% CI, 6-16). This increase was highest among women, but not statistically significantly different by gender. The median lag time between first recorded symptoms and MS diagnosis decreased from 32 months (<1998) to 2 months (>2005). CONCLUSIONS: MS is rare in the Netherlands. In recent years, there was a slight increase in the incidence especially among women during the fertile age. This increase coincided with a decrease in lag time between symptoms and diagnosis, both for men and women. This trend should be taken into account in the interpretation of MS cases occurring in a population where new vaccinations will be introduced shortly.

[Introduction of pertussis vaccination during pregnancy]. / Invoering van een kinkhoestvaccinatie voor zwangeren.

Pertussis is an endemic disease in the Netherlands. In order to protect infants under 6 months of age, women can be vaccinated during pregnancy with a DTaP(-IPV) booster vaccine. After this so-called maternal vaccination, pertussis antibodies are passed through the placenta to the unborn child, who will be protected after birth. The vaccine is offered as a part of the national vaccination programme (Rijksvaccinatieprogramma, RVP) since 16 December 2019. Children of maternally vaccinated women will follow a different vaccination schedule, namely the 3-5-11-months schedule. This schedule change applies to the DTaP-IPV-HiB-HepB combination vaccine and the 10-valent pneumococcal (PCV10) vaccine. High-risk groups and children of unvaccinated mothers will follow the 2-3-5-11 months schedule. Maternal vaccination is offered from 22 weeks of gestation in the Netherlands. This timing is logistically feasible. We have seen that women already got themselves actively vaccinated during pregnancy before the inclusion of the vaccine in the RVP.

No evidence found for an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls.

INTRODUCTION: In 2013, the Netherlands Pharmacovigilance Center Lareb published an overview of reports of long-lasting fatigue following bivalent HPV-vaccination (2vHPV). After an update of this overview in 2015, concerns regarding the safety of 2vHPV was picked up by the media, which led to further reports of long-lasting fatigue. Therefore, the Dutch National Institute for Public Health and the Environment (RIVM) investigated a possible association between HPV-vaccination and long-term fatigue. METHODS: In this retrospective cohort study conducted in the Integrated Primary Care Information database, we investigated the occurrence of chronic fatigue syndrome (CFS), fatigue ≥6 months and 3-6 months in all girls born in 1991-2000 during the follow-up period January 1st 2007-December 31st 2014 (2007-2008 pre-vaccination and 2009-2014 post-vaccination). Patients with certain fatigue ≥6 m were asked for consent to link their primary care information with vaccination data. Incidence rates per 10,000 person years (PY) for 12-16-year-old girls were compared between pre- and post-HPV-vaccine era. A self-controlled case series (SCCS) analysis was performed using consenting vaccinated cases. A primary high-risk period of 12 months after each dose was defined. RESULTS: The cohort consisted of 69,429 12-16-year-old girls accounting for 2758 PY pre-vaccination and 57,214 PY post-vaccination. Differences between pre- and post-vaccination incidences (CFS: 3.6 (95% CI 0.5-25.7)/10,000 PY and 0.9 (0.4-2.1); certain fatigue ≥6 m: 7.3 (1.8-29.0) and 19.4 (16.1-23.4); certain fatigue 3-6 m: 0.0 and 16.6 (13.6-20.3), respectively) were not statistically significant. SCCS analyses in 16 consenting vaccinated cases resulted in an age-adjusted RR of 0.62 (95%CI 0.07-5.49). CONCLUSIONS: Fatigue ≥6 m and 3-6 m was frequently found among adolescent girls, but CFS was rarely diagnosed. No statistically significant increased incidence rates were found post-vaccination compared to similar age groups of girls pre-vaccination. The SCCS analysis included a low number of cases but revealed no elevated risk of certain fatigue ≥6 m in the high-risk period.

[Safety surveillance in the National Vaccination Programme; fewer adverse events with the DTP-IPV-Hib vaccine after the transition to an acellular pertussis component in 2005]. / Veiligheidsbewaking van Rijksvaccinatieprogramma; minder bijwerkingen van DKTP-Hib-combinatievaccin sinds overgang in 2005 naar vaccin met acellulaire kinkhoestcomponent.

OBJECTIVE: To determine the adverse reactions to the combined vaccine against diptheria, acellular pertussis, tetanus, poliomyelitis and Haemophilus Infuenzae type B (DTP-IPV-Hib) before and after the introduction of an acellular pertussis component. DESIGN: Descriptive. METHOD: Safety surveillance of the Dutch National Vaccination Programme is performed by the National Institute for Public Health and Environment (RIVM). It is based on an enhanced passive reporting system and complemented by targeted survey-based studies. The data obtained were analysed. RESULTS: The passive surveillance system showed a large increase in reports in 2004, probably linked to increased media attention on the efficacy and safety of the whole-cell DTP-IPV-Hib vaccine. The Health Council recommended transitioning to the use of a DTP-IPV-Hib vaccine with an acellular pertussis component, which was implemented in January 2005. The number of reports dropped sharply in 2005 to a level below that of 2002-2003. Results of a survey study on adverse events following DTP-IPV-Hib vaccination that began in late 2003 and continued in 2005 confirmed the wide coverage ofthe enhanced passive surveillance system and revealed low rates of underreporting of rare adverse events, such as collapse and convulsions. CONCLUSION: This study confirms the data from the passive surveillance system, which show that the newly introduced acellular DTP-IPV-Hib vaccine is associated with fewer adverse events than the whole-cell vaccine that was used previously.

Severe underestimation of pertussis related hospitalizations and deaths in the Netherlands: A capture-recapture analysis.

OJECTIVE: Despite vaccination, pertussis has remained endemic, sometimes leading to severe disease. We aimed to quantify the completeness of reporting (CoR) of pertussis hospitalizations and deaths in the Netherlands. STUDY DESIGN: CoR was estimated using capture-recapture analyses. Hospitalizations (2007-2014) from the National Registration Hospital Care (hospital data) were matched to the notifiable Infectious Disease case registry (notifications) providing (month and) year of birth, gender and postal code. Deaths (1996-2014) from Statistics Netherlands (death registry) were matched to notifications using gender, age, year of death and notification date. Cases <2years (y) and ≥2y were analysed separately. Chao's estimator estimated the total population, which was used to calculate CoR. RESULTS: Using strict matching criteria, we found 461 matches among 876 (hospital data) and 757 (notifications) hospitalizations <2y. The population estimate of hospitalized infants was 1446, resulting in CoR between 52% and 61%. For hospitalizations ≥2y (246; hospital data and 264; notifications) 43 matches were found, with a population estimate of 1512 and CoR between 16.5% and 22%. Among thirteen (death registry) and eight (notifications) deaths <2y, seven cases overlapped. The population estimate was 16. CoR of the two sources was 50-81%. With two (death registry) and eight (notifications) deaths ≥2y without overlap, the population estimate was 26 and CoR 8-31%. CONCLUSION: Results showed substantial underestimation of pertussis hospitalizations and deaths. This has to be taken into account in evaluation of current and future immunization programs.

Tolerability of 2 doses of pandemic influenza vaccine (Focetria®) and of a prior dose of seasonal 2009-2010 influenza vaccination in the Netherlands.

In the Netherlands, people indicated for seasonal influenza vaccination are divided in 3 risk groups, i.e. those less than 60 y (y) with comorbidity and those 60 y and over with and without comorbidity. Those risk groups were also eligible for pandemic vaccination during the 2009 influenza A(H1N1) pandemic. We assessed tolerability of seasonal influenza vaccination and 2 doses of pandemic influenza A(H1N1) vaccine, adjuvanted with MF-59, administered 2 and 5 weeks after seasonal 2009-2010 vaccination among adults. Vaccinees were asked to return questionnaires on local and systemic adverse events (AEs) after each of 3 consecutive vaccinations given at the office of their General Practitioner. Sex- and risk group-specific AE-frequencies were calculated. Generalized Linear Mixed Model with seasonal vaccination as reference was used to calculate odds ratios (ORs) for AEs of the 2 pandemic doses. 5553 questionnaires (3251 vaccinees) were returned. Vaccinees reported any local AE after seasonal vaccination and both pandemic doses in 34%, 23%, and 18%, respectively. These percentages were 29%, 25%, and 16% for any systemic AE. Men reported fewer local and systemic AEs then women (p<0.0001). The risk of local (OR range 0.34-0.63) and systemic (OR range 0.39-0.99) AEs (overall, stratified by risk group and by sex) was lower after both pandemic doses compared to seasonal vaccination. This decreased risk was more pronounced after the second pandemic dose than after the first. Therefore, we conclude that MF59-adjuvanted pandemic vaccine given after seasonal vaccination was well tolerated.

[Infection prevention in newborns through maternal vaccination: current insights and developments]. / Infectiepreventie bij zuigelingen door maternale vaccinatie.

- In the first few months of life, newborns are vulnerable to infections.- Vaccination of the pregnant mother leads to transplacental antibody transfer, resulting in the best possible protection of the newborn.- Maternal vaccination has long been given for the prevention of tetanus in developing countries, and for the prevention of pertussis and influenza in developed countries, such as the United States, England and Belgium. These vaccinations give newborns good protection and, to date, no adverse effects are known for the foetus or the pregnancy.- Currently, phase 3 trials during pregnancy are ongoing following maternal vaccination against group B streptococci and respiratory syncytial virus. Here, again, no risks to mother or child have been reported.- Recently, the Dutch Health Council advised that all pregnant women in the Netherlands be vaccinated against pertussis in a vaccination programme.- This paper gives an overview of effectiveness, safety and practicalities of maternal vaccination.

Reported adverse events in girls aged 13-16 years after vaccination with the human papillomavirus (HPV)-16/18 vaccine in the Netherlands.

In 2009, human papillomavirus (HPV) vaccination was offered to girls born in 1993-1996 in a catch-up campaign, followed in 2010 by the implementation of the vaccination in the National Immunization Programme (NIP) for girls born in 1997. To monitor the tolerability of the 2009 catch-up campaign, we investigated the occurrence of adverse events within 7 days after vaccination with the bivalent HPV vaccine. A total of 6000 girls were asked to participate, including 1500 from each birth cohort from 1993 to 1996. One week after each of the required three successive doses, the participants received by e-mail a Web-based questionnaire focused on local reactions and systemic events. One or more questionnaires were returned by 4248 girls. Any local reaction was reported by 92.1% of the girls after the first dose, 79.4% after the second dose, and 83.3% after the third dose, and 91.7%, 78.7%, and 78.4% reported any systemic event after the three doses, respectively. Pain in the arm was the most frequently reported local reaction, of which 24.0%, 11.7%, and 14.7% was classified as pronounced. Myalgia was the most often reported systemic event. The proportion of local reactions and most systemic events was significantly lower after the second and third dose compared with the first dose (Odds ratio [OR], 0.33-0.76). Older girls reported a higher proportion of adverse events than younger girls. After vaccination with the bivalent HPV vaccine, girls 13-16 years of age reported a high proportion of short-term adverse events. These are maximum estimates and not necessarily caused by the vaccination itself. Although, girls experienced HPV vaccination as painful, no serious or unexpected adverse events were reported. The results of this survey are being communicated to health care workers and the public.

Acute cerebellar ataxia in the Netherlands: a study on the association with vaccinations and varicella zoster infection.

AIM: Acute cerebellar ataxia (ACA, sudden onset of truncal ataxia and gait disturbances) usually follows a benign illness (25% varicella). It is also described after vaccination, like MMR and varicella zoster virus (VZV). We will establish incidence rates of (varicella related) ACA and assess the attributable risk of vaccination to ACA in the Netherlands. METHOD: Data on ACA in children, following infections, like varicella, and vaccinations, obtained from prospective, active pediatric surveillance and passive surveillance on adverse events following immunizations (AEFI) were compared with hospitalization data for ataxia. Capture-recapture (CRC) method was used to estimate the burden of ACA in the Netherlands. RESULTS: 45 children with ACA were included (44 and 1 reported by pediatric and AEFI surveillance respectively, 30 were hospitalized). Chickenpox preceded ACA in 15 cases, one case followed MMR. Of the hospitalization reports, 13 fulfilled the criteria for ACA. Using CRC the estimated number of hospitalized ACA cases was 42. For varicella related ACA, this estimate was 10, resulting in an incidence rate of 0.7:100,000 (95%CI 0.52-0.94, all cases) and 0.17:100,000 (95%CI 0.09-0.31, varicella related cases) for children under 15 years of age. CONCLUSION: The incidence rates were comparable with other studies. We found no association with MMR, but chickenpox was clearly related to ACA. According to age-specific seroprevalence data the incidence rate of ACA was 5:100,000 VZV infections for children up to 5 years, compared to an ACA-reporting rate of 0.15:100,000 doses VZV-vaccine. Therefore, uptake of VZV-vaccine in the immunization programme will diminish the incidence rate of ACA.

Assessing the introduction of universal rotavirus vaccination in the Netherlands.

Rotarix and RotaTeq are both prophylactic vaccines against rotavirus (RV) gastroenteritis. In 2006, these vaccines obtained a European license and because RV infections are widespread among Dutch children inclusion of these vaccines in the Dutch National Immunization Program (NIP) should be considered. Using an evaluation model for introducing a new vaccine, we assessed the introduction of universal RV vaccination in the Netherlands. Although post-marketing surveillance will be essential, both RV vaccines have proven to be safe and effective. Furthermore, the vaccines will prevent most of the RV-related hospitalizations and deaths. However, for the Netherlands with the current vaccine prices, universal RV vaccination is not expected to be cost-effective.

Adverse events following booster doses of diphtheria-tetanus-inactivated poliovirus and acellular pertussis vaccines for 4-year-old children in The Netherlands.

The aim of the study was to assess the incidence and severity of local reactions and systemic events among 4-year-old children receiving a fifth dose of diphtheria-tetanus-inactivated poliovirus (dT-IPV) and acellular pertussis (aP) vaccines. Of 810 children, 483 had no adverse events following immunization. Of the reported local reactions of 281 children, pain was the most frequent (n=246). Eighty-one children developed redness, and 54, swelling. Pain, reduced use of the arm, redness, and swelling occurred significantly more often at the dT-IPV injection site than at the aP injection site (p<0.05). Local reactions were mainly mild and transient. Among the 104 reported systemic events, fever was the most frequent (n=42). In general, the vaccinations for the 4-year-olds are well tolerated.