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The example of maternal pertussis vaccination

Pertussis, or whooping cough, is a bacterial infection of the respiratory tract. After the introduction of mass vaccination in the 1950s, the bacteria seemed to have disappeared, but in the 1990s pertussis re-emerged despite the high vaccination coverage rates, mostly affecting very young infants who are not yet (fully) vaccinated (Figure 1).[1,2] In an effort to address this problem, Tdap (tetanus, diphtheria and acellular pertussis) vaccination for pregnant women, also called the maternal pertussis vaccination, was introduced in the USA in 2011 and in England a year later.[3] Many European countries followed soon after that. By inducing the transfer of antibodies from mother to child through the placenta, the vaccine provides protection of the new-born child until it gets its first vaccination.[3] The resurge of pertussis also happened in the Netherlands. Tdap vaccination for pregnant women was introduced following an advice by the national health council in 2015, but it was not free of charge and the vaccine has not always been available. In December 2019, maternal pertussis vaccination will be added to the Dutch national immunisation programme (NIP). The safety and effectiveness of all vaccinations in the Netherlands, including maternal pertussis vaccination, is monitored by the Centre for Infectious Disease Control (CIb, part of the National Institute of Health and the Environment (RIVM)) together with the pharmacovigilance centre Lareb. Surveillance of diseases included in the NIP consists of mandatory notifications and monitoring of laboratory and hospital admission data. Other ‘pillars’ include vaccination uptake, adverse events surveillance, pathogen surveillance and immunosurveillance (Figure 2).[4,5] Here we illustrate these five pillars with the example of maternal pertussis vaccination.

Vaccination uptake

Vaccination coverage is assessed yearly and reported in the annual vaccination coverage report, using the individually based vaccination registration system Praeventis. [6] After a small decrease in the period 2012-15, full vaccination coverage of 2-year old children stabilized at around 90%. With the implementation of maternal pertussis vaccination, a new target group has been added to the NIP: all pregnant women are eligible and those who are actually vaccinated under the pregnant women (the enumerator) are registered in the NIP register of Praeventis. All pregnant women who deliver in a certain year in the Netherlands (the denominator) are registered in a special perinatal register called Perined. [7]

Acceptance of vaccination is periodically assessed through qualitative studies. [4] A recent study (unpublished), carried out in 2018-19 among pregnant women and mothers of children below the age of two, assessed knowledge about maternal pertussis vaccination and willingness to vaccinate. It showed that 70% of the women had heard or read about maternal pertussis vaccination, and 60% of pregnant women had the intention to get vaccinated. The most common reason among women who had already given birth to refrain from vaccination was lack of information: when they were pregnant they did not know that this was an option. Most pregnant women interviewed indicated a high level of trust in the information provided by their midwives, consultation centres and RIVM (78%, 70% and 79%, respectively).

Safety surveillance

Safety surveillance is important to assess the nature and frequency of adverse events in order to ensure the population does not mistrust the NIP. This pillar relies on a passive reporting system of adverse events following immunisation (AEFI), in place at the centre for pharmacovigilance in the Netherlands, Lareb. Both professionals and the general public can report AEFIs. It is important to bear in mind that reported events do not necessarily have a (proven) causal link to vaccination. The influence of media attention on such reporting should not be underestimated. When notable signals are observed, Lareb performs a causality assessment and decides what is more likely: a causal relation with the vaccination or a coincidental signal. Regarding maternal pertussis vaccination, safety studies and reviews show that maternal pertussis vaccination is safe. No adverse pregnancy outcomes, such as stillbirth or neonatal death were reported. [3,8-10] After implementation of maternal pertussis vaccination, safety monitoring will also be performed in the Netherlands to provide relevant information to the public.

Disease surveillance

Besides monitoring of hospital admissions and mortality attributed to vaccine-preventable diseases, disease surveillance involves mandatory notifications. WHO also requires notification (annually), and there is an exchange of information on the occurrence of several diseases (e.g. diphtheria, tetanus, poliomyelitis, pertussis, mumps, measles, rubella, hepatitis B, and meningococcal disease) with other European countries through the European Surveillance System (TESSy) of the European Centre for Disease Control (ECDC). [11] Differences in incidence between countries, considering their vaccination programme and history, are evaluated to optimize vaccination impact and better identify high-risk groups.

The maternal pertussis vaccination will be implemented in the Netherlands because of the high incidence of pertussis in new-born children (Figure 1) combined with a good vaccine effectiveness. Vaccine effectiveness (VE) in the Netherlands is usually assessed through a screening method developed by Farrington. [12] For the calculation of the VE of maternal pertussis vaccination, the coverage of a certain age cohort and the difference in pertussis incidence between vaccinated and unvaccinated children below 3 months of age is needed.

Pathogen surveillance

RIVM studies the possible adaptation of the Bordetella pertussis bacteria based on samples provided by medical microbiology laboratories. It involves antigen expression validation assays to determine pertussis antigens: pertussis toxin (Ptx), pertactin (Prn), and filamentous hemagglutinin (FHA). A high frequency of pathogens that are deficient in one of these genes could predict vaccine evasion, which might lead to a pertussis outbreak. [4] Recently, whole genome sequencing was introduced, which can detect even smaller strain differences and changes. A change in the pertussis strains due to the maternal pertussis vaccination is not expected, as the vaccination protects against the same strains as the vaccination during childhood.

Immunosurveillance

Protection against disease can be assessed by measuring antibody levels (seroprevalence). Seroprevalence studies enable the identification of susceptible population groups that are at risk of infection, and provide a standardized value to compare countries. Serosurveillance in the Netherlands, also called immunosurveillance, is done by the RIVM/CIb. They periodically collect blood samples and demographic data from a representative sample.

The immunologic effects of the maternal pertussis vaccination were measured in the Maternal Immunisation Pertussis (MIKI) study at the RIVM/CIb, which concluded that infants of women who obtained maternal pertussis vaccination could be vaccinated twice, at 3 and 5 months, instead of three times (at 2, 3 and 4 months). [13] The Premature Infants and Maternal Pertussis Immunisation (PIMPI) study, also conducted by RIVM/CIb, assesses the immunologic effects of maternal pertussis vaccination in premature infants, and the effect that timing of this vaccination has on antibody transmission from mother to child. Research on the immunologic effect of maternal pertussis vaccination in other countries has shown an increase in antibody levels during the first months of life in children whose mother had been vaccinated. Furthermore, several studies reported a lower immune response after the first dose of infant vaccination when the mother had been vaccinated during pregnancy. This is called ‘blunting’. [10,14] Recent research has shown no clinical relevance for the blunting effect, and confirmed that maternal pertussis vaccination offers protection against pertussis. [10,15]

Future perspective

Given the rapid development of new vaccines, the ever-changing epidemiology of vaccine preventable diseases, and new scientific evidence that has implications (e.g. for vaccination schedules), close monitoring of NIP performance is crucial. When a new vaccination is introduced, RIVM takes charge of the necessary surveillance. With the five pillars of the Dutch surveillance system in place, all elements of surveillance of vaccine preventable diseases are covered, safety and effectiveness are closely monitored, and cross-border communication and data-sharing is happening.

References

  1. Van der Maas NA, Mooi FR, de Greeff SC et al. Pertussis in the Netherlands, is the current vaccination strategy sufficient to reduce disease burden in young infants? Vaccine. 2013;31(41):4541-7.
  2. Mooi FR, Van Der Maas NA, De Melker HEJE. Infection. Pertussis resurgence: waning immunity and pathogen adaptation-two sides of the same coin. 2014;142(4):685-94.
  3. Gkentzi D, Katsakiori P, Marangos M et al. Maternal vaccination against pertussis: a systematic review of the recent literature. Arch Dis Child Fetal Neonatal Ed. 2017;102(5):F456-F63.
  4. RIVM. The National Immunisation Programme in the Netherlands: Surveillance and developments in 2016-2017. National Institute for Public Health and the Environment; 2017.
  5. Van der Maas NA. Vaccine-preventable diseases: evaluation of vaccination programmes and optimisation of surveillance. Zeist, The Netherlands 2018. 16-8 р.
  6. RIVM. Vaccinatiegraad en jaarverslag Rijksvaccinatieprogramma Nederland 2018. Rijksinstituut voor Volksgezondheid en Milieu; 2019.
  7. Perined. Perinatale Zorg in Nederland 2017. Utrecht: Perined; 2019.
  8. Donegan K, King B, Bryan PJB. Safety of pertussis vaccination in pregnant women in UK: observational study. BMJ 2014;349:84219.
  9. Munoz FM, Bond NH, Maccato M et al. Safety and immunogenicity of tetanus diphtheria and acellular pertussis (Tdap) immunization during pregnancy in mothers and infants: a randomized clinical trial. JAMA. 2014;311(17):1760-9.
  10. Campbell H, Gupta S, Dolan GP et al. Review of vaccination in pregnancy to prevent pertussis in early infancy. J Med Microbiol. 2018;67(10):1426-56.
  11. Surveillance atlas of infectious diseases ECDC: ECDC; 2017 [Available from: https://www.ecdc.europa.eu/en/surveillance-atlas-infectious-diseases.
  12. Farrington CP. Estimation of vaccine effectiveness using the screening method. Int J Epid. 1993;22(4):742-6.
  13. Barug D, Pronk I, van Houten MA et al. Maternal pertussis vaccination and its effects on the immune response of infants aged up to 12 months in the Netherlands: an open-label, parallel, randomised controlled trial. Lancet Infect Dis. 2019;19(4):392-401.
  14. Maertens K, Caboré RN, Huygen K et al. Pertussis vaccination during pregnancy in Belgium: results of a prospective controlled cohort study. Vaccine. 2016;34(1):142-50.
  15. Becker-Dreps S, Butler AM, McGrath LJ et al. Effectiveness of prenatal tetanus, diphtheria, acellular pertussis vaccination in the prevention of infant pertussis in the U.S. Am J Prev Med. 2018;55(2):159-66.