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

Vaccination During Pregnancy

Information on the safety of several vaccines during human pregnancy can be found in public literature. Most data available concern the use of unadjuvanted seasonal influenza vaccines because vaccination against seasonal influenza during pregnancy is recommended in several countries. No study to date has demonstrated an increased risk of either maternal complications or adverse fetal outcomes associated with inactivated, unadjuvanted (seasonal) influenza vaccination.^{[4,6,110,111]} Therefore, vaccination against seasonal influenza is considered safe.

There are also data available from the WHO/UNICEF program against maternal and neonatal tetanus. Many pregnant women have received an alum-adsorbed tetanus toxoid vaccine in this program and thus far no association with fetal malformations has been demonstrated.^[112] Although reports are scarce, it is likely that adverse effects by tetanus toxoid vaccines would have been reported when observed. Therefore, it is generally assumed that tetanus vaccination is not associated with major birth defects or severe adverse pregnancy outcome. Reports on the safety of other vaccines, including smallpox,^[113] polio,^[114] yellow fever,^[115] pertussis^[7,8] and even anthrax^[116] during pregnancy are reassuring and show a lack of association between maternal vaccination (including first-trimester exposure) and preterm delivery or major malformations. However, the studies generally focus on major malformations and most are not sufficiently powered to detect a moderate increased risk of birth defects. Therefore, more subtle effects such as early pregnancy loss, abortion, preeclampsia or reduced fetal growth may have been missed as potential adverse effects caused by vaccination during early pregnancy. Overall, for the unadjuvanted seasonal influenza vaccines and tetanus toxoid vaccines, routine vaccination during pregnancy may be considered safe, while currently, for other vaccines, the limited data do not show side effects of the vaccination.

However, these observations may not be extended to all vaccines. Since it is the modulation of the maternal immune system that may affect pregnancy outcome, differences in the immune response to vaccines may have varying effects on pregnancy. Unadjuvanted seasonal influenza vaccines are relatively poorly immunogenic and only mildly activate the immune system when compared with adjuvanted influenza vaccines.^[117,118] Therefore, the relevance of the safety data obtained with unadjuvanted (seasonal) vaccines in the assessment of the safety of adjuvanted (pandemic) influenza vaccines is very limited. In addition, the data obtained from the alum-adjuvanted tetanus vaccine are of limited relevance to the safety of the more recent oil-in-water adjuvant emulsions such as AS03 and MF59, which were used in the pandemic influenza vaccines, because of the differences in the immunomodulatory actions of these adjuvants.

There are a few publications of the pregnancy registries of the MPL/alum-adjuvanted HPV vaccine Cervarix.^{[119,120,201]} Preliminary results of the analysis of these registries do not indicate that there is a significant effect of vaccination on fetal malformations or spontaneous abortions. However, the majority of uncertainty surrounds the effect of vaccination in women becoming pregnant within 30 days of vaccination, because of the limited amount of data.^[120,121]

There is only one publication on exposure to MF59-adjuvanted influenza vaccine during pregnancy.^[9] A retrospective analysis of inadvertent pregnancies occurring in clinical trials by Novartis revealed that pregnancy outcomes in subjects exposed to MF59-adjuvanted influenza vaccine (n = 43) were similar to those exposed to unadjuvanted influenza vaccines (n = 60) at any time during pregnancy and also when exposure occurred in early pregnancy. These data are too limited to draw any conclusions on the safety of oil-in-water adjuvants during pregnancy. Therefore, data obtained in animal reproductive toxicity studies on the new adjuvanted vaccines are needed for the assessment of their safety.

Regulatory Requests for Reproduction Toxicity Testing of Vaccines

The 2005 EMA guidelines on adjuvants^[202] only provide guidance on when to perform reproductive toxicity studies, but specific guidance on the study design is missing. In the US FDA Guidelines Considerations for Developmental Toxicity Studies for Preventive and Therapeutic Vaccines for Infectious Disease Indications^[203] it is recommended to optimize maternal antibody titers throughout the embryonic, fetal and early post-natal period, to ensure a peak antibody response during the critical phases of pregnancy (i.e., organogenesis) and to administer one or several doses during organogenesis. These recommendations are based upon the hypothesis that the risk of vaccination is associated with the increase of antibodies against the relevant antigens or with potential direct embryotoxic effects of the vaccine formulation. As a result of these recommendations, many vaccine reproductive toxicity studies encompass one or several vaccinations prior to mating (to ensure the high antibody titers during pregnancy) and several vaccinations after implantation, during organogenesis. However, it is clear that in humans, antibodies are rarely transferred to the embryo and not at all in the first trimester because of the absence of neonatal Fc receptors.^[122] It is only during the second trimester that there is an increase in placental transfer of antibodies, with a steady rise to maternal levels at the end of pregnancy.^[123] The same is true for several animal species that have been used as models for vaccine testing.^[122] Therefore, the risk to the fetus of high antibody levels during the first trimester (implantation and organogenesis) appears almost negligible.

Adverse effects on neonatal development and/or pregnancy may also be caused by more secondary effects of vaccination, such as the activation of the maternal immune system. As described previously, it is clear that specific changes in the maternal immune system occur during pregnancy and are necessary for implantation, placentation and a healthy course of the pregnancy. Activation of the maternal immune system may interfere with the necessary changes of this system for the maintenance of a pregnancy and could therefore affect the course and outcome of a pregnancy. As described earlier, the issue of interference of adjuvanted vaccines with the immune response of pregnancy has not been addressed in the FDA's guideline on reproductive toxicity of vaccines, or in the WHO's 2005 Guideline on Preclinical Evaluation of Vaccines.^[204]

Reproductive Safety Testing of Adjuvants or Adjuvanted Vaccines

Publicly available data on nonclinical reproductive safety testing of adjuvants/adjuvanted vaccines are very limited. Most information can be found in the European public assessment reports (EPAR) of EU-registered vaccines that contain an adjuvant ( Table 1 ).

The EPAR of the MF59-adjuvanted influenza vaccine Focetria® (Novartis Vaccines and Diagnostics, Siena, Italy) shows that MF59 was tested for reproduction toxicity in two rabbit studies and one rat study, either as single agent or in conjunction with influenza proteins or other antigens.^[205] The two studies using rabbits investigated the effects of vaccination on either day 6 through to day 28 of gestation, or three times before mating and at days 7 and 20 of gestation. Information on the timing of dosing in the rat study was not described. In these studies, MF59-adjuvanted vaccines were well-tolerated, did not cause maternal or embryo–fetal toxicity, were not teratogenic and had no effects on post-natal development. It was concluded that there are no specific concerns for the use of this adjuvanted vaccine in pregnancy.

The AS03 adjuvant is present in two pandemic influenza vaccines, Pandemrix® (GSK Biologicals) and Arepanrix® (GSK Biologicals). The potential reproductive toxicity of this adjuvant was tested in rats, with and without influenza antigen.^[206,207] For both products, animals were dosed once before mating and at days 6, 8, 11 and 15 of gestation for Pandemrix and at days 7, 9, 12 and 16 for Arepanrix. The only potential treatment-related effect was a somewhat delayed air-righting reflex for some of the offspring of AS03-treated dams in the Pandemrix study.

Another pandemic influenza vaccine, Humenza® (Sanofi Pasteur, Lyon, France) contains the adjuvant AF03. Two studies in rats and rabbits have been reported using the adjuvant alone. Two rabbit studies using the AF03-adjuvanted A/California/07/2009 H1N1 influenza vaccine have been conducted with a similar schedule as for Pandemrix (days -21, -7, 6, 8, 11 and 27) and no embryo–fetal toxicity effects have been noted.^[208]

AS04 is another EU-registered adjuvant present in an HPV vaccine (Cervarix) as well as in a Hepatitis B vaccine (Fendrix® [GSK Biologicals]). For this adjuvant, no effect on any of the phases of reproduction or fetal development was seen in a reproductive toxicity study in rats.^[201] However, no data on the timing of vaccination during pregnancy were provided.

There are multiple registered vaccines that contain aluminium salts as adjuvants ( Table 1 ). Reproductive toxicity studies have not been performed with most of these vaccines, either because the ingredients and their concentrations are within ranges of already marketed or nationally registered vaccines or because the vaccine is not intended to be used in women of childbearing potential. For those vaccines that were tested (Gardasil® [Sanofi Pasteur MSD SNC, Lyon, France/Silgard® [Merck Sharp and Dohme Ltd., Hertfordshire, UK]), information on study design was lacking, but no adverse effects were reported.

A review of these studies confirms the observation that vaccine administration around the implantation phase of the embryos is generally not included in the study designs, while only booster vaccinations and not primary vaccinations are mostly given during pregnancy. These booster vaccinations are generally given at the time of implantation or after this. Thus, potential adverse effects due to vaccination early in pregnancy are not covered by the reproductive toxicity studies. According to the EPAR of Pandemrix, the marketing authorization holder has agreed to conduct a study in which the vaccine will be given to pregnant animals early in their pregnancy. The outcome of this study, when published, will be interesting in relation to this subject.

As noted earlier, low doses of proinflammatory components such as LPS, may have serious consequences during pregnancy, such as the development of preeclampsia at the end of pregnancy.^[80] It is not clear from the EPAR reports whether end points reflecting such effects have been included in the developmental and reproductive toxicology studies. Another apparent feature of the study designs is that the animals are often pretreated long before mating, while this is not a reflection of the clinical situation when a vaccine is administered for the first time during pregnancy. This may have some consequence for the interpretation of the results because the immune response during a booster immunization is likely to be different from the response after a first administration.^[105]

Several other studies in which pregnant animals have been vaccinated with adjuvanted vaccines can be found in the public literature.^[124–128] Adverse effects in these studies were not detected/reported, but the studies were generally small scale, aimed at detecting efficacy and not safety, and vaccination was usually performed in the second half of pregnancy. In one study, pregnant rats received a single intraperitoneal injection of either Bacillus Calmette–Guérin, Bordetella pertussis or Cryptosporidium parvum vaccine at the day of implantation. In this study, the bacterial adjuvants were not abortogenic. However, a nonsignificant trend towards a larger feto–placental interface compared with control was noted.^[129]

Taken together, even though the available animal data might be reassuring, several critical concerns, such as the safety of primary vaccination in the first trimester of pregnancy, have not been addressed during reproduction toxicity testing.

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

Cite this: New Adjuvanted Vaccines in Pregnancy: What is Known About Their Safety? - Medscape - Dec 01, 2010.