New Adjuvanted Vaccines in Pregnancy: What is Known About Their Safety?

Carla Herberts; Barbro Melgert; Jan Willem van der Laan; Marijke Faas

Disclosures

Expert Rev Vaccines. 2010;9(12):1411-1422. 

In This Article

Pregnancy & the Immune System

The maternal immune system during pregnancy is altered to actively tolerate the semiallogeneic fetus. These alterations include changes in local immune responses, that is, in the uterine mucosa (decidua),[10] and changes in peripheral immune responses.[11] After implantation, the uterine endometrium is rapidly infiltrated by fetal trophoblast cells; the endometrium will then develop into the decidua and ensure anchorage of the placenta and therefore proper fetal nutrition. However, this invasion needs to be properly regulated to protect the corporal integrity of the uterine wall of the mother. Both shallow- and over-invasion will lead to problematic pregnancies.[12,13] Local decidual immune cells, such as uterine natural killer (uNK) cells and macrophages, are important regulators of this balance between tolerance of fetal trophoblasts and limitation of their invasion.[14,15] When placental circulation is established, the peripheral blood also comes into close contact with fetal cells, specifically, villous trophoblasts. This may affect the peripheral maternal immune response.

Decidual Immune Responses

The decidua is an immunologically active tissue that is infiltrated by large numbers of maternal immune cells. The numbers of the different maternal immune cells change throughout the course of pregnancy.[10,16,17] The first trimester is dominated by uNK cells and alternatively activated macrophages.[16,18–20] The uNK cells are immunomodulatory but noncytotoxic in nature and, together with macrophages, have been suggested to be crucial for regulating trophoblast invasion and spiral artery remodeling.[21,22] Both uNK cells and macrophages decrease during the second trimester.[17] Although uNK cells and macrophages are the most dominant cells in the decidua, helper and cytotoxic T lymphocytes, as well as regulatory T cells, can also be found in the decidua.[17,23–28] They may also play an important immunoregulatory role. More recently, dendritic cells (DCs) have been shown to be present in the decidua.[29,30–34] The exact role of these cells in the decidua remains to be established, but they have been shown to promote a type 2 dominant state[34] and may be involved in immunotolerance induction.

Together these immune cells in the decidua play an important role in the acceptance of the semiallogeneic fetus, implantation and placentation. They do so by producing many factors, including cytokines and angiogenetic factors that are able to regulate implantation of the blastocyst and placentation. A critical balance in the number of immune cells, as well as in the factors they produce, is extremely important for pregnancy and it has been shown that interfering with these local immune responses may result in defective placentation or pregnancy loss.[35–37]

Changes in the Peripheral Immune Response During Pregnancy

During weeks 8–12, when placental circulation is established, the maternal peripheral blood is in close contact with semiallogeneic villous trophoblasts. These trophoblasts are able to produce and shed factors, such as IL-4[38] and syncytiotrophoblast microfragments[38] or fetal cells[39,40] into the maternal circulation. Such factors affect the immune system. The presence of proinflammatory factors in the plasma of pregnant women has been shown by Faas et al., who demonstrated that incubation of monocytes with plasma from pregnant women activated this cell type.[41] Moreover, the passage of maternal blood through the placenta activates inflammatory cells such as granulocytes and monocytes.[42] The most important changes in the immune response in the maternal circulation during human pregnancy will be described later.

Innate Immunity

It is generally accepted that the innate immune system is activated during pregnancy. The numbers of monocytes and granulocytes significantly increase during normal pregnancy[43–45] and these cells also show phenotypical and functional activation.[11,44,46,47] DC numbers, on the other hand, were found to be decreased during pregnancy[48–50] and, more recently, the functional properties of DCs have been studied. It was shown that expression of tolerance-inducing molecules, such as the costimulatory B7 complex[51] and indoleamine-2,3 dioxygenase, is increased in DCs during pregnancy.[52] Furthermore, the number of peripheral natural killer (NK) cells and their production of IFN-g is decreased in pregnant women as compared with nonpregnant women[35,53,54] and it was also shown that the ratio of NK1/NK2 cells is decreased.[55] Such changes in NK cell populations are important for normal pregnancy, as demonstrated when Beer et al. showed that in an in vitro fertilization population, no live infants were born when the percentage of maternal peripheral NK cells was above 18%.[56]

Specific T-cell-mediated Immunity

The concept that a healthy pregnancy is accompanied by a decreased Th1/Th2 balance proposed by Wegmann et al.[57] has been confirmed by many others.[35,58–60] However, it is now recognized that although the Th1/Th2 balance is important in pregnancy, the immunological paradox of pregnancy is much more complicated. Th17 cells and regulatory T cells have also been shown to be involved in the complex immune regulation seen during pregnancy.[61] Various studies have recently demonstrated that regulatory T cells are essential in pregnancy for promoting immune tolerance.[24,26,62] Indeed, in peripheral blood, regulatory T cells are increased during early pregnancy[24,63] and in mice they have been shown to be required for the maternal immune system to tolerate a fetal allograft.[62]

In addition, rather than having only deleterious effects on pregnancy, the type 1 cytokines were also found to be essential. It was shown that they are needed in triggering pregnancy-induced spiral artery remodeling.[64–68]

Consequences of the Adapted Immune Response for Pregnancy

Although the maternal immune response changes during pregnancy, most pregnant women experience a healthy pregnancy, suggesting that the immunological changes do not dramatically affect the integrity of the mother. However, it has been shown that pregnant women are more sensitive to certain infections. For instance, the risk of developing clinical disease after infection with poliovirus or hepatitis A virus is increased in pregnant women.[69] In addition, pregnancy has been shown to increase the infectivity of cytomegalovirus,[69] herpes simplex virus[70] and malaria.[71] The changes in maternal immune responses are also reflected by changes in autoimmune diseases: rheumatoid arthritis often ameliorates during pregnancy, while systemic lupus erythematosus can flare up.[72,73]

The altered immune responses seen during pregnancy are also apparent from the fact that pregnant animals are more sensitive to proinflammatory stimuli than nonpregnant animals.[74–78] This altered sensitivity may be particularly relevant for adjuvanted vaccines because adjuvants are usually potent proinflammatory stimulators. Pregnant animals are extremely sensitive to lipopolysaccharides (LPS), which is a potent stimulator of innate immune responses. In accordance with this, we have shown that infusion of an extremely low dose of LPS into pregnant rats induces hypertension and proteinuria,[79] which are symptoms of preeclampsia, whereas infusions into nonpregnant animals did not.[80] It may be important to note here that the adjuvant monophosphoryl lipid A (MPL; AS04) is a less toxic but still an immunoreactive derivate of the endotoxin LPS.[81,82] Adverse effects on pregnancy have also been described after infusion of other proinflammatory substances such as extracellular ATP,[83] poly I:C[84] and TNF-α,[85] as well as injection of type 1 cytokines.[86]

Taken together, the immune system significantly changes during pregnancy and these changes are essential for normal placentation and maintenance of a healthy pregnancy. Interfering with the maternal immune system could disturb the newly formed balance between tolerance and immunity during pregnancy and may affect placentation, the outcome and/or the course of pregnancy. This raises questions on the safety of vaccination during pregnancy, especially with vaccines that have a strong immune-stimulating/modulating ability, for example, adjuvanted vaccines.

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