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

Discussion

Little is known about the safety of adjuvanted vaccines during pregnancy, particularly with regard to the recently introduced adjuvanted vaccines. It is slowly becoming recognized that exclusion of pregnant women from clinical trials withholds them from safe and effective treatment.[130] This is very true for vaccination during pregnancy, especially when using adjuvanted vaccines. The safety of adjuvanted vaccines in pregnant women has not been tested in clinical trials. A simple extrapolation of safety data of vaccines from the nonpregnant populations to the pregnant population is impossible owing to the changes occurring in the immune system during pregnancy. Proinflammatory stimuli that are present in vaccines, in particular in adjuvanted vaccines, may induce a stronger immune response in pregnant individuals, since pregnant individuals have been shown to be more sensitive to proinflammatory stimuli than nonpregnant individuals.[74–78] Moreover, vaccination may negatively affect the immune balance needed for a successful pregnancy in women. Consequently, vaccination may increase the risk of breaking immune tolerance against the fetus. This could theoretically result in pregnancy loss, restricted growth of the fetus and/or the placenta or in the development of preeclampsia.

Human data, thus far, suggest that there does not seem to be a particular concern with the use of vaccines during pregnancy. However, these data are mostly based on experience with unadjuvanted seasonal influenza vaccines and alum-adjuvanted tetanus vaccines, and their effects cannot simply be extrapolated to all vaccines. Human data on the safety of the more recently introduced adjuvants during pregnancy, that is, the oil-in-water emulsions MF59 and AS03 and the MPL/Alum combination of AS04, are limited. For oil-in-water adjuvanted vaccines, the limited human and animal data suggest that there are no direct teratogenic or other adverse effects when the vaccine is administered during the second and third trimester. The available safety data for the first trimester are too limited to draw any conclusions on the safety of the new adjuvanted vaccines in this period. In theory, a strong activation of the maternal immune system during this period, such as that induced by an adjuvanted vaccine, could have an impact on the implantation of the embryo and acceptance of the fetus.

In addition to the available human data, another important argument for claiming the safety of adjuvanted vaccines during pregnancy is that the immunological effects of adjuvants are local and that systemic effects are not expected. However, systemic effects such as malaise, myalgia and fever have been reported after administration of adjuvanted influenza vaccine.[131] This indicates that vaccination is more than a local reaction and that systemic effects are also induced. The cause of the systemic effects following vaccination is unknown, but it is probably due to triggering of cytokines of the innate immune system, such as IL-1, IL-6 and TNF-α, which can function as endogenous pyrogens.[132] While it may be unlikely that circulating maternal cytokines reach the fetal circulation and affect the fetus directly,[133,134] these cytokines may affect placentation[86] and may induce abortions[84,79] as seen, for example, in primates receiving human cytokines.[135] The effects of proinflammatory substances such as LPS on pregnancy may also relate to the induction of cytokine production and the effects of these cytokines on pregnancy.[83–85] Animal and human data addressing the proinflammatory effects of adjuvanted vaccines in pregnancy are thus far lacking.

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