Vertically Transferred Immunity in Neonates (AQA 2020) PDF

REVIEW published: 31 March 2020...

REVIEW published: 31 March 2020 doi: 10.3389/fimmu.2020.00555 Vertically Transferred Immunity in Neonates: Mothers, Mechanisms and Mediators Marie Albrecht* and Petra Clara Arck* Laboratory for Experimental Feto-Maternal Medicine, Department of Gynecology and Obstetrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Over the last years, an increasing number of outbreaks of vaccine-preventable infectious diseases has been reported. Besides elderly and immunocompromised individuals, newborns and small infants are most susceptible to infections, as their immune system is still immature. This vulnerability during infancy can be mitigated by the transplacental transfer of pathogen-specific antibodies and other mediators of immunity from mother to the fetus during pregnancy, followed postnatally by breast milk-derived immunity. Edited by: Since this largely antibody-mediated passive immunity can prevent the newborn from Sarah Anne Robertson, infections, neonatal immunity depends strongly on the maternal concentration of The University of Adelaide, Australia respective specific antibodies during pregnancy. If titers are low or wane rapidly after Reviewed by: Gerard Chaouat, birth, the protection transferred to the child may not be sufficient to prevent disease. INSERM U976 Immunologie, Moreover, emerging concepts propose that mothers may transfer active immunity to the Dermatologie, Oncologie, France Guillermina Girardi, newborns via vertical transfer of pathogen-specific T cells. Overall, a promising strategy King’s College London, to augment and prolong neonatal immunity is to vaccinate the mother before or during United Kingdom pregnancy in order to boost maternal antibody concentrations or availability of specific *Correspondence: T cells. Hence, a large number of pre-and postconceptional vaccine trials have been Marie Albrecht [email protected] carried out to test and confirm this concept. We here highlight novel insights arising from Petra Clara Arck recent research endeavors on the influence of prenatal maternal vaccination against [email protected] pathogens that can pose a threat for newborns, such as measles, pertussis, rubella Specialty section: and influenza A. We delineate pathways involved in the transfer of specific maternal This article was submitted to antibodies. We also discuss the consequences for children’s health and long-term Immunological Tolerance and Regulation, immunity resulting from an adjustment of prenatal vaccination regimes. a section of the journal Keywords: maternal vaccination, measles, rubella, pertussis, influenza, FcRn, blunting, breastfeeding Frontiers in Immunology Received: 13 January 2020 Accepted: 11 March 2020 EARLY LIFE IMMUNITY AND TIME WINDOWS PERMITTING Published: 31 March 2020 PATHOGEN THREATS FOR NEONATES Citation: Albrecht M and Arck PC (2020) After birth and during their first months of life, human newborns are not yet equipped with a fully Vertically Transferred Immunity in Neonates: Mothers, Mechanisms matured immune system (1, 2). Hence, they are highly susceptible to infectious pathogens, such and Mediators. as measles, pertussis, rubella, and influenza. These pathogens can cause a severe course of disease Front. Immunol. 11:555. in neonates and infants, which may even be fatal (3–5). The availability of safe and immunogenic doi: 10.3389/fimmu.2020.00555 vaccines against infectious diseases, i.e., the combined measles-mumps and rubella vaccine, does Frontiers in Immunology | www.frontiersin.org 1 March 2020 | Volume 11 | Article 555 Albrecht and Arck Vertically Transferred Immunity in Neonates not mitigate this threat to neonatal health, as the vaccines reduced (18). Unfortunately, comparable achievements have not contain living pathogen components; hence, their use is not been made with regard to pertussis elimination. Outbreaks recommended to be administered to children under the age of of whooping cough have recently been occurring worldwide, 12 months. Similarly, the vaccination with the combined tetanus- exposing young infants to a particularly high risk of severe diphtheria-pertussis (Tdap) vaccine and the inactivated influenza infections. Thus, we here mainly discuss studies that focus on the vaccines (IIV) is not recommended until 2 or 6 months of age, outcome of pertussis vaccination in pregnant women. respectively (6, 7). These restrictions to vaccination leave a pivotal Amongst others, the authors of a recent study aimed to gap of neonatal immunity against these pathogens until routine evaluate the safety and immunogenicity of Tdap administration immunization can be administered (8). during pregnancy in mothers and their infants and to assess This gap in immunity is – at least in part – covered the possible interference of maternal antibodies with subsequent by the active, transplacental transfer of maternal pathogen- infant immunizations (19). Apart from mild and self-limiting specific antibodies. Mothers convey passive immunity to their local reactions at the vaccination site, no adverse events newborns through the transplacental transfer of antibodies, caused by the immunization with Tdap were reported in hereby providing a shield for the infant from pathogen- mothers and their infants. Anti-pertussis toxin (PT) antibodies, mediated diseases (1, 9). The amount of transferred antibodies which primarily mediate protection against Bordetella pertussis- can differ between individuals and is mainly dependent on induced disease (20), and anti-pertactin (PRN) antibodies, maternal antibody concentrations (10, 11). Based on this which convey protection by opsonization and subsequent natural immunity mediated by the mother, maternal vaccination phagocytosis of Bordetella pertussis (21), were significantly strategies during pregnancy are vividly discussed. Such strategies increased in mothers vaccinated with Tdap during pregnancy, could increase maternal antibody concentrations, enhance the compared to the placebo group. Accordingly, both anti-PT levels of transplacental antibody transfer and, in consequence, the and anti-PRN were significantly higher at birth in infants degree of passive immunity for the neonate (12). of vaccinated mothers. Irrespective of prenatal vaccination, In the light of the recent outbreaks of vaccine-preventable cord blood antibody titers exceeded maternal titers assessed diseases such as measles even in countries with high vaccine at delivery, indicating an active transplacental transport of coverage, the topic of immunization has received significant antibody. However, anti-PT and anti-PRN decreased quickly attention by medical professionals and the lay community. until the age of 2 months. Measles infection has caused more than 140,000 deaths The investigators also pointed out differences in anti-PRN globally in 2018, most of them among children under five and anti-PT seroresponses following routine infant vaccinations years of age (13). Promoting the immunity of newborns via at 2 and 4 months of age with a combined tetanus, diphtheria, maternal vaccination holds the potential to become an effective pertussis, polio and Hib vaccine (19). After vaccination, infants and low-cost approach to prevent neonatal morbidity and of placebo-receiving mothers showed a greater increase of anti- mortality caused by communicable diseases (14–16). In the PT levels compared to infants of Tdap-vaccinated mothers, present article, we comprehensively discuss recent research indicating an interference of maternal antibodies with the studies on maternal vaccination against common childhood child’s seroresponse to vaccination. Surprisingly, opposed to the infections such as pertussis, influenza, measles, and rubella. response to PT, an anti-PRN response was not mounted in We further highlight pathways involved in the transplacental these infants, irrespective of maternal Tdap vaccination. This transfer of antibodies as well as mechanisms through which is in contrast to a study focusing on infants’ response to Tdap neonatal immunity can be improved irrespective of maternal vaccination during early life, in which a significant seroresponse antibodies (Figure 1). to both PT and PRN was mounted (22). An explanation for the ambiguity between the vaccination responses observed in these two studies cannot be deduced from the respective articles, but may be due to different cohort sizes, variations in the procedure OBSERVATIONS FROM VACCINATION of specimen preparation or the different ELISA kits used to STUDIES AGAINST TETANUS, determine antibody concentrations. DIPHTHERIA AND PERTUSSIS DURING Another study focusing on the influence of maternal PREGNANCY vaccination with Tdap during the second trimester of pregnancy (23) revealed that anti-PT IgG could be detected in 92% of infants A number of recent studies confirm that vaccination with the born to vaccinated mothers, whilst anti-PT IgG was undetectable combined tetanus, diphtheria, and acellular pertussis vaccine in infants of unvaccinated mothers. Although this study has (Tdap) can be recommended during pregnancy, since vaccine some limitations, for example the lack of initial maternal anti- trials carried out on a large scale and in various countries have PT levels and the ELISA-based analysis allowing for detection generally demonstrated its safety and immunogenicity in mothers of antibody presence or absence only, but no concentrations, it and their infants (Table 1). The World Health Organization shows that maternal immunization with Tdap during the 2nd (WHO) reports a 96% reduction of death by neonatal tetanus trimester of pregnancy significantly increases the percentage of through implementation of recommended elimination practices seropositive newborns. from 1988 to 2015, including the vaccination of pregnant Not only immune responses of mother and child toward women (17). Similarly, the burden of diphtheria disease has been Tdap immunization during pregnancy have been investigated, Frontiers in Immunology | www.frontiersin.org 2 March 2020 | Volume 11 | Article 555 Albrecht and Arck Vertically Transferred Immunity in Neonates FIGURE 1 | Overview of maternal immunity and recommended vaccinations before, during and after pregnancy as well as consequences for maternal and children’s health. but also vaccine safety. By using information from different care from an obstetrician. Since pregnancy complications as national databases, Griffin et al. (24) identified a large well as mother and infant mortality are rather associated cohort of women who were eligible to receive governmental with lower socioeconomic status and non-caucasian ethnicity funded Tdap vaccination between gestational week 28 and (25–27), it is tempting to assume that higher rates for primary 38. Hospitalization for severe pregnancy complications was set and secondary outcomes observed in this study may be as the primary outcome and hospitalizations for less critical due to confounders. pregnancy complications as secondary outcomes. Key finding of Noteworthy, New Zealand had been facing a large pertussis this study was that the hazard ratio for primary or secondary epidemic from 2011 to 2013. However, only 11.9% of the outcomes did not increase when Tdap was administered during individuals eligible to receive Tdap in the study by Griffin et al. pregnancy. Intriguingly, the authors also report that Tdap have been vaccinated. This example shows the urgent need for vaccination during pregnancy significantly reduced the risk for further education of the population regarding the effectiveness of hospitalization due to severe pre-eclampsia, as well as the risk immunization against pertussis. for antenatal bleeding and preterm labor and delivery. Upon Whilst the evidence for safety and immunogenicity of Tdap inspection of the studied population, these risk reductions might is steadily increasing, Saul et al. also emphasized on the be biased by the demographic characteristics that distinguish effectiveness of maternal Tdap vaccination with regard to infant vaccinated and unvaccinated women. Vaccinated women tended hospitalization due to pertussis infection (28). The authors report to be European, have a higher income level and receive a 39% vaccine effectiveness (VE) to prevent pertussis infection Frontiers in Immunology | www.frontiersin.org 3 March 2020 | Volume 11 | Article 555 Albrecht and Arck Vertically Transferred Immunity in Neonates TABLE 1 | Overview of studies and trials assessing safety, effectiveness and outcome of vaccinations with Tdap, IIV, and MMR during child-bearing years, pregnancy or infancy in humans. Aim of study Study design N References Pathogens: C. tetani, C. diphtheriae, and B. pertussis Assessment of immunity against vaccine preventable diseases Prospective, observational study 194 (1) Safety and immunogenicity of Tdap matVac, interference of matAB Randomized double-blind controlled clinical trial 171 (19) Effect of 2 doses of pertussis vaccine before 2 months of age Randomized non-blinded clinical trial 76 (22) Assessment of B. pertussis titers in third trimester and newborns Observational, cross-sectional study 111 (23) Maternal outcome upon Tdap matVac Retrospective observational study 68,550 (24) Assess effectiveness of Tdap matVac Matched case-control study 234 (28) VE in protecting newborns from pertussis infection Matched case-control study 88 (29) Comparative analysis of Tdap matVac timepoint and AB yield in newborn Prospective study 81 (30) Determination of optimal GW for Tdap matVac in third trimester Prospective study 154 (31) Comparative analysis of Tdap matVac in second or third trimester Prospective observational study 335 (32) Effect of Tdap booster dose between two pregnancies Prospective study 144 (72) Comparative analysis of maternal and cord blood AB and proteins at term Observational study 16 (73) Analysis of neutralizing antibodies in infants after vaccination against Prospective study 44 (94) diphtheria Effect of matVac with Tdap and IIV on infant AB responses Prospective study 369 (95) Influence of Tdap booster dose during pregnancy on infant’s matAB levels Prospective controlled cohort study 99 (96) and immune responses Safety and immunogenicity of Tdap matVAc and effect on infant immune Randomized, double-blind, placebo-controlled trial 80 (97) responses Pathogen: Influenza A Assessment of safety and immunogenicity of seasonal trivalent IIV matVac Prospective, randomized, double-blind clinical trial 100 (40) Risk assessment for neonatal birth defects after first trimester IIV exposure Observational study 425,944 (41) Persistence of HAI titers and VE of IIV3 in subsequent influenza season in Double-blind, randomized, placebo-controlled trial 479 (43) women Duration of infant protection upon IIV matVac Substudy of randomized, double-blind, 322 (44) placebo-controlled clinical trial Clinical effectiveness of IIV matVac; safety and immunogenicity of Prospective, controlled, blinded, randomized study 340 (45) pneumococcal vaccines Risk assessment for infant hospitalization due to lower respiratory infection Secondary analysis of randomized controlled trial 52 (46) after IIV matVac Effect of IIV matVac on risk for influenza in infants < 6 months of age Non-randomized, prospective, observational cohort 1169 (47) study Influence of IIV matVac on subsequent B. pertussis infection rates in Retrospective testing of samples collected in 3125 (48) mothers randomized controlled trial Effect of vitamin A supplementation on immune response to IIV matVac Prospective study 112 (70) Investigation of sensitization to IIV antigens in utero Prospective observational study 126 (74) Effect of maternal influenza vaccination on influenza-specific IgA levels in Prospective, blinded, controlled trial 340 (80) breast milk Effect of cross-reactive cellular immunity on symptomatic influenza illness in Prospective study 342 (90) AB- naïve individuals Pathogens: Measles, Mumps, and Rubella Virus Repertoire of maternal anti-viral AB in newborns at birth Prospective study 78 (10) Assessment of safety of MMR vaccination in adults Retrospective observational study 3175 (51) Assessment of B cell impairment upon measles-associated Prospective observational study 29 (54) immunosuppression Identification of measles infection long- term effects on immune system Prospective study 196 (55) Association of maternal age and vaccination status with cord blood matAB Observational study 206 (57) MatAB transfer in vaccinated or naturally immune mothers to preterm/term Prospective study 195 (58) infants Quantification of AB against MMR and varicella zoster in mothers and Prospective observational study 138 (59) infants Duration of presence of matAB to measles in infants Prospective study 207 (60) (Continued) Frontiers in Immunology | www.frontiersin.org 4 March 2020 | Volume 11 | Article 555 Albrecht and Arck Vertically Transferred Immunity in Neonates TABLE 1 | Continued Aim of study Study design N References Seronegativity in infants < 6 months and serologic response to measles Cross-sectional study 203 (61) vaccine Prenatal fetal infection among women (re-) infected with rubella during Prospective observational study 40 (62) pregnancy Detection of rubella-specific IgM in subclinical rubella reinfection in Case report 8 (63) pregnancy Criteria for defining rubella reinfection Case report 5 (64) Fetal infection after maternal rubella reinfection during pregnancy Case report 1 (65) Seroepidemiology of anti-measles, -mumps and -rubella AB in pregnant Prospective study 353 (71) women and neonates Assessment of transplacental transport of IgG immune complexes Prospective study 152 (75) Immunogenicity of measles vaccine in infants < 12 months Cohort study 72 (92) Studies on breast milk immunity Assessment of gut microbiota bound by breast milk IgA Observational study 69 (81) Effects of infections during pregnancy on colostrum IgA levels Cross- sectional study 900 (82) matVac, maternal vaccination during pregnancy; Tdap, Tetanus, diphtheria, acellular pertussis vaccine; matAB, maternal antibody; VE, vaccine effectiveness; GW, gestational week; AB, antibody; IIV(3), (trivalent) inactivated influenza vaccine; MMR, measles, mumps, rubella vaccine; HAI, hemagglutination inhibition assay. for infants < 6 months and of 69% for infants younger than on higher cord blood anti-pertussis antibody concentrations 3 months of age; the overall VE against hospitalization due resulting from vaccination at this timepoint as compared to to severe pertussis infection was 94%. These results clearly later in gestation (32). Conversely, another study with a higher demonstrate that maternal Tdap vaccination is predominantly number of participants reports that maternal Tdap vaccination effective in preventing severe cases of pertussis disease, with between gestational week 13 and 25 results in higher cord blood maternal vaccination attenuating the intensity of the illness rather anti-pertussis antibody concentrations than immunization after than preventing it. Furthermore, the authors identified that 26 weeks of gestation (33). A longer period of time between breastfeeding may have a protective effect on pertussis infection vaccination and childbirth allows for a greater transfer window, of the infant. These findings are in line with a very similarly which may explain the observed higher cord blood titers. Re- set up of a study conducted in the same year (29). Here, the scheduling the recommended vaccination to an earlier timepoint authors found a 90.9% VE of maternal Tdap vaccination during during pregnancy might therefore be beneficial, not only for pregnancy in protecting infants < 3 months from laboratory preterm neonates (33). confirmed pertussis; yet, VE was calculated from a small Taken together, Tdap immunization should be recommended cohort. Also, apart from maternal vaccination, breastfeeding to each pregnant woman in every pregnancy, regardless of the was identified as the only other significant influence on infant previous vaccination status. This will yield to high maternal protection against pertussis. This effect could be observed not antibody concentrations toward the end of pregnancy, so that only in mothers vaccinated during pregnancy, where maternal antibodies can be transferred at greater extent to the fetus. Whilst IgA could be passed via the breast milk, but also in those who vaccination of the mother during the 2nd or 3rd trimester of had not been vaccinated against or in contact with pertussis pregnancy is safe and efficacious, the best strategy to ensure for the last 10 years. The authors suggest that this might be high neonatal anti-pertussis antibody concentrations seems to be attributed to other breast milk components which were not vaccination between gestational week 13 and 25. Besides maternal further specified. vaccination, passive protection of the neonate via reduction of There is still ambiguity with regard to vaccination timepoint pathogen exposure can result from a so-called cocooning effect, recommendation by national health services. The National achieved by vaccination of family members and caregivers of the Health Service (NHS) in the United Kingdom and the Advisory newborn (34, 35). By combining these protective techniques, the Committee on Immunization Practices (ACIP) in the US suggest risk for pertussis infection during the first months of life, until the two different vaccination schedules. While the NHS recommends neonate has mounted humoral and cellular immunity against this Tdap administration between 16 and 32 weeks of gestation pathogen, can be reduced. (30), the ACIP proposes that Tdap should be administered at a later timepoint between 27 and 36 weeks of gestation (6). Using cord blood concentrations of pertussis-specific IgG as a INSIGHTS FROM VACCINATION read out parameter, one study reports highest levels if mothers STUDIES AGAINST INFLUENZA DURING had been vaccinated with Tdap between 27 and