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

The Use of Adjuvants in Vaccines

Initially, vaccines consisted of live-attenuated or inactivated whole-cell bacteria and whole viruses. However, as several of these vaccines were associated with side effects, a shift towards the use of highly purified proteins has been made to improve vaccine safety. As a consequence, the immunogenicity of some of these newly developed vaccines was reduced. This is assumed to be due to the absence of the pathogen's endogenous immune stimulators, since highly purified proteins are generally weak antigens.[87,88] To compensate for the reduced immunity, adjuvants can be added to the vaccine formulation.

An adjuvant can be defined as a substance that, when administered in combination with a specific antigen, enhances the immune response against the antigen when compared with the antigen alone. Adjuvants were first described in the 1920s[89,90] and have been used for decades to improve the immune response to vaccine antigens. Aluminium salts are the most widely accepted and used adjuvants.[88,91,92] Other types of adjuvants are emulsions (water-in-oil or oil-in-water), liposomes and substances containing pathogen-associated molecular patterns[87,93,94] such as MPL. For an overview of adjuvants that are constituent of EU-registered vaccines, see Table 1. Additive or even synergistic effects have also been obtained with combinations of different types of adjuvants (e.g., in the human papillomavirus [HPV] vaccine Cervarix® [GSK Biologicals, Rixensart, Belgium], the adjuvant MPL is combined with aluminium hydroxide).[201] In addition to the adjuvants that are part of a registered vaccine, there are also numerous other adjuvants under development; these include CpG motifs, immune-stimulating complexes (ISCOMs), microbial derivatives/Toll-like receptor (TLR) activators and several others.[87]

The molecular mechanism of the majority of adjuvants is still only partially characterized. Adjuvants are generally thought to act by nonspecific stimulation of the innate immune system through targeting of 'professional' antigen-presenting cells (APCs) such as DCs.[87,95–97] DCs can capture, process and present (foreign) antigen in their major histocompatibility complex (MHC) molecules, which together with the appropriate costimulatory molecules can lead to the activation of naive helper and cytotoxic T lymphocyte cells. This activation of the adaptive immune system is needed for the protective effect of vaccination.[97] The mechanism by which the APCs are activated is important in the understanding of the molecular mechanism of an adjuvant. For some adjuvants, specifically the pathogen-associated molecular pattern-containing adjuvants, specific receptors on the APC have been identified, for example, TLR9 for synthetic oligodeoxynucleotides containing unmethylated CpG motifs or TLR4 for MPL.[98,99] However, for other adjuvants, knowledge about the mechanism of action is still limited. Even for aluminium salts, there is still controversy on the mode of action and several mechanisms have been postulated (for a review, see[92]). Many years ago, it was suggested that aluminium salts induce an antigen depot effect; however, other mechanisms have recently been described, such as recruitment and activation of immune cells, enhancing of monocyte differentiation into DCs and augmentation of antigen uptake and migration of DCs into the draining lymph nodes.[92,100,101] Similar mechanisms have also been postulated for other adjuvants (e.g., the oil-in-water emulsion MF59 and ISCOM/ISCOMATRIX® [CSL Behring, King of Prussia, PA, USA]).[100–102]

In addition to enhancing the immune response towards an antigen, an adjuvant may also steer the immune response in a certain direction. Aluminium, for instance, is a well-known Th2-promoting adjuvant.[92] For CpG motifs, it is known that they stimulate human B cells and plasmacytoid DCs, thereby promoting the production of Th1 and proinflammatory cytokines and the maturation/activation of professional APCs.[103] In addition, the saponin-based adjuvants such as ISCOMATRIX are more prone to induce Th1-directed responses.[101,104] The data on the modulation of immune responses of oil-in-water emulsions such as the EU-licensed adjuvant MF59 are less clear and not fully consistent. For MF59, it has been shown that one dose of MF59 H5N1 vaccine induces the expansion of CD4+ T lymphocytes with a Th1-prone effector/memory phenotype,[105] while other results suggest that MF59 stimulates the Th2 response.[106–108] Based on studies of MF59 combined with other adjuvants, it was postulated that MF59 amplifies the ongoing immune response but does not change the Th1/Th2 balance.[109] Data on the effects of other EU-licensed adjuvants on the Th1/Th2 balance, such as AS03 and AF03, are scarce in this respect.

Thus, adjuvants are stimulators of the innate immune response. As the innate immune system is activated during pregnancy, it may be suggested that an adjuvant may elicit a different, for example a stronger, immune response in pregnant women as compared with nonpregnant women or males. Such a stronger immune response may interfere with the newly formed pregnancy-induced balance of the immune response and thus interfere with pregnancy. Adjuvants may also interfere with the Th1/Th2 balance. Although pregnancy can be considered a Th2-dependent process,[35,57–60] type 1 cytokines are also important for normal implantation and placentation. As adjuvants activate the immune response via different mechanisms and may steer the immune response towards Th1 or Th2 responses, it is currently not possible to predict which adjuvants can or cannot be safely used in pregnancy.

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