Premature infants and maternal perfussis immunization

Re-emergence of pertussis despite high vaccination coverage in western countries, results in increased risk for severe and even fatal pertussis among newborns. For this reason, late 2015 the Dutch Health Council (HC) advised to offer 3rd trimester pertussis vaccination to pregnant women. At the start of the maternal pertussis programme late 2019, the maternal Tdap was advised from 22w of gestation onwards.

Preterms, accounting for 8% of newborns in the Netherlands, are at highest risk for severe pertussis leading to prolonged hospital and intensive care admissions and sometimes death. Recently, it has become evident that despite 3rd trimester vaccination, preterms remain at high risk because the vaccination is likely given too late for sufficient antibody transfer. For this vulnerable group 2nd trimester vaccination may offer better protection because of extended time for antibody transfer.

To date, most countries recommend 3rd trimester vaccination to protect young, not yet (fully) vaccinated infants. Data from England show 91% effectiveness against infant pertussis after maternal Tetanus- diphtheria
-acellular Pertussis (Tdap) vaccination in the 3rd trimester.

Studies focussing on preterms and protection after maternal vaccination are scarce. Two observational studies reported on effectiveness and antibody levels in cord blood of 2nd trimester vaccination in term infants. While one study showed significantly higher antibody levels after 2nd trimester vaccination (13-25 gestational weeks; GW), another study showed decreased effectiveness of 2nd trimester (<27 GW) vaccination. Only one study concerned antibody transfer in preterms and reported higher antibody levels after 2nd (n=37) than after 3rd (n=48) trimester vaccination.

Aiming to contribute to setting optimal vaccine strategy of maternal pertussis vaccination in the Netherlands and elsewhere and particular for the most vulnerable group of preterms, we propose a study that compares pertussis antibody levels in preterms and terms after 2nd trimester maternal vaccination. We can compare these to data we have on 3rd trimester Tdap in terms. In addition to adequate antibody levels, success of 2nd trimester vaccination depends on acceptance of this strategy by pregnant women and professionals.

Our primary endpoint is IgG anti-pertussis toxin (Pt) antibody concentration in preterms and terms at 2m of age,

Pt is considered the most relevant antibody for protection against clinical pertussis. Secondary endpoints are e.g. pertussis specific antibody concentrations in preterms and terms in cord blood and in women at delivery. Determinants of acceptance of 2nd trimester maternal vaccination are also a secondary endpoint.

Antibody concentrations will be assessed in serum, using a fluorescent bead-based multiplex immunoassay, with required blood volume of minimal 100µl.

For the survey on acceptance, we aim to have 4 groups of 100 women each, i.e. women who are pregnant for the 1st time, women who already gave birth and in both groups women with and without a known increased risk of preterm delivery. For the immunogenicity part, we aim to have at least 60 preterms and 60 terms, as this is, according to experts, the minimum number to enable good comparisons.

Pregnant women will be offered 2nd trimester pertussis vaccination. Both among acceptors and non-acceptors acceptance of 2nd trimester vaccination will be assessed.
Women are first asked to participate in the acceptance part after the 1st antenatal visit to a midwife or obstetrician. They fill in a questionnaire to assess behavioral determinants and beliefs that underlie acceptance of 2nd trimester maternal vaccination. Only after this consent, women will be asked to participate in the immunogenicity part. Hereby, women will receive Tdap after they have the 20w standard anomaly ultrasound scan (20-24 GW). Vaccinated women will be followed until delivery. All preterms and a random selection of 60 terms, all of vaccinated mothers, will be followed until 2m of age, i.e. just before start of the NIP. By including both women in primary and secondary antenatal care, we aim to enrich our study population with women who are at increased risk for preterm delivery, as these women are usually seen by an obstetrician.

Data from our study will determine whether 2nd trimester Tdap leads to sufficient Pt antibodiy concentration in terms and preterms compared to 3rd trimester vaccination. Furthermore, we will have knowledge about obstacles for acceptance and can tailor information for all pregnant women to overcome these. Finally, given that in near future besides pertussis other maternal vaccines are likely to become available for prevention of severe disease in newborns (RSV, GBS), in particular in preterms, this study generates essential knowledge for future vaccine policy of maternal vaccines.

尽管西方国家疫苗接种覆盖率较高，但百日咳的再次流行导致新生儿患严重甚至致命百日咳的风险增加。鉴于此，荷兰卫生委员会（HC）于2015年底建议对孕妇提供孕晚期百日咳疫苗接种。2019年底启动孕产妇百日咳接种计划之初，建议从妊娠22周开始接种孕产妇Tdap疫苗。

早产儿占荷兰新生儿的8%，他们患严重百日咳的风险最高，可能导致长时间的住院和重症监护，有时甚至死亡。最近，尽管进行了孕晚期疫苗接种，但早产儿仍然处于高风险状态，因为疫苗接种可能过于延迟，无法实现足够的抗体转移。对于这一脆弱群体，孕中期疫苗接种可能提供更好的保护，因为抗体转移的时间更长。

截至目前，大多数国家建议在孕晚期接种疫苗以保护尚未（完全）接种疫苗的婴幼儿。来自英格兰的数据显示，在孕晚期接受孕产妇破伤风-白喉-无细胞百日咳（Tdap）疫苗接种后，对婴幼儿百日咳的有效性为91%。

针对早产儿和母体疫苗接种后的保护作用的研究较少。有两项观察性研究报告了关于孕中期疫苗接种在足月儿中的有效性和脐带血中的抗体水平。虽然一项研究显示孕中期疫苗接种（13-25周妊娠；GW）后抗体水平显著升高，但另一项研究显示孕中期（<27 GW）疫苗接种的有效性降低。只有一项研究关注早产儿的抗体转移，并报告称，与孕晚期（n=48）相比，孕中期（n=37）疫苗接种后的抗体水平更高。

为了为荷兰以及其他国家制定母体百日咳疫苗接种的最佳策略做出贡献，尤其是为最脆弱的早产儿群体，我们提议一项研究，比较孕中期母体疫苗接种后早产儿和足月儿的百日咳抗体水平。我们可以将这些数据与我们关于足月儿孕晚期Tdap的数据进行比较。除了足够的抗体水平外，孕中期疫苗接种的成功还取决于孕妇和专业人士对该策略的接受程度。

我们的主要终点是2个月大时早产儿和足月儿的IgG抗百日咳毒素（Pt）抗体浓度，Pt被认为是预防临床百日咳的最相关抗体。次要终点包括例如早产儿和足月儿的脐带血和分娩时妇女的百日咳特异性抗体浓度。接受孕中期母体疫苗接种的决定因素也是一项次要终点。

抗体浓度将通过荧光微球多重免疫测定法在血清中进行评估，所需血液量为至少100µl。

对于接受度调查，我们旨在拥有4组各100名妇女，即首次怀孕的妇女、已生育的妇女，以及两组中均有和没有已知早产风险增加的妇女。在免疫原性部分，我们旨在至少拥有60名早产儿和60名足月儿，因为专家认为这是进行良好比较的最低数量。

孕妇将被提供孕中期百日咳疫苗接种。在接受者和非接受者中，都将评估对孕中期疫苗接种的接受程度。

妇女首先在首次进行助产士或产科医生的产前检查后参与接受度部分。她们填写问卷以评估支持孕中期母体疫苗接种的行为决定因素和信念。仅在获得此同意后，妇女才会被要求参与免疫原性部分。因此，妇女将在进行20周标准异常超声扫描（20-24 GW）后接受Tdap疫苗。接种疫苗的妇女将一直随访到分娩。所有早产儿和60名足月儿的随机选择，所有接种疫苗的母亲，都将随访到2个月大，即NIP开始之前。通过包括初级和二级产前护理中的妇女，我们旨在使我们的研究人群丰富化，包括那些有早产风险增加的妇女，因为这些妇女通常由产科医生接诊。

我们研究的数据将确定孕晚期Tdap是否会导致与孕晚期疫苗接种相比，在足月儿和早产儿中产生足够的Pt抗体浓度。此外，我们将了解接受度障碍，并能够为所有孕妇量身定制信息以克服这些障碍。最后，鉴于未来除了百日咳外，其他母体疫苗（如RSV、GBS）也可能可用于预防新生儿严重疾病（特别是早产儿），这项研究为未来母体疫苗政策提供了关键知识。