Assessing the Safety of Adjuvanted Vaccines

Abstract

Despite the very low risk-to-benefit ratio of vaccines, fear of negative side effects has discouraged many people from getting vaccinated, resulting in reemergence of previously controlled diseases such as measles, pertussis, and diphtheria. Part of this fear stems from the lack of public awareness of the many preclinical and clinical safety evaluations that vaccines must undergo before they are available to the general public, as well as from misperceptions of what adjuvants are or why they are used in vaccines. The resultant "black box" leads to a preoccupation with rare side effects (such as autoimmune diseases) that are speculated, but not proven, to be linked to some vaccinations. The focus of this review article is to open this black box and provide a conceptual framework for how vaccine safety is traditionally assessed. We discuss the strengths and shortcomings of tools that can be and are used preclinically (in animal studies), translationally (in biomarker studies with human sera or cells), statistically (for disease epidemiology), and clinically (in the design of human trials) to help ascertain the risk of the infrequent and delayed adverse events that arise in relation to adjuvanted vaccine administration.

Distinct TLR adjuvants differentially stimulate systemic and local innate immune responses in nonhuman primates

“…Despite their clear benefits and widespread use in vaccines, until recently, the only adjuvant licensed worldwide for clinical use was alum. 10 More recently, MF-59, an oil-in-water solution based on squalene, has been licensed as a vaccine adjuvant for influenza vaccines. 11 Furthermore, a derivative of lipopolysaccharide (LPS), the monophosphoryl lipid-A (MPL), has been approved recently for use as one of the components of the AS04 adjuvant (alum ϩ MPL) used in Cervarix, 12,13 the vaccine against cervical cancer.…”

“…1,3 TLR ligands (TLR-Ls) represent an emerging new class of molecules with great potential as vaccine adjuvants. [3][4][5]8,10 Several TLR-dependent compounds are in advanced preclinical and clinical trials (eg, cytosine-phosphate-guanine oligodeoxynucleotide [CpG-ODN], 10 poly I-C/L-C, 10 and glucopyranosyl lipid adjuvant 14 ) and some have already been licensed for clinical use as adjuvants (eg, MPL-AS04 13 ) or therapeutics (eg, imidazoquilines 15 ). TLRs sense a wide range of pathogen-associated molecular patterns from bacteria, viruses, and parasites (reviewed in Kawai and Akira 16 and in Takeuchi and Akira 17 ).…”

Synthetic Toll-Like Receptor 4 (TLR4) and TLR7 Ligands as Influenza Virus Vaccine Adjuvants Induce Rapid, Sustained, and Broadly Protective Responses

“…The combined adjuvant was highly effective in all cases. While various adjuvants under development exhibit efficacy in preclinical models, U.S. regulators have considerable safety concerns regarding adjuvants and vaccine reactogenicity that must be addressed (12,13,(25)(26)(27). 1Z105 and 1V270 demonstrate little in vitro toxicity (14,19).…”

Influenza immunization during pregnancy: Benefits for mother and infant

“…35,36 AS03 is a combination of a-tocopherol (vitamin E) and squalene in an oil-inwater emulsion and was extensively used in European global immunization campaigns during the 2009 pandemic with an estimated 380,000 pregnant women receiving this vaccine. [37][38][39][40] While one retrospective study in pregnant women suggested a trend to increased gestational diabetes and eclampsia in those that received MF59-adjuvanted influenza vaccine, 41 other studies have not reported similar effects during pregnancy. [42][43][44][45] A randomized controlled clinical trial comparing MF59-adjuvanted vaccine (Focetria Ò ) in pregnant and non-pregnant women found that a non-significant trend to a lower antibody response in pregnant women; 72% of the women reported adverse reactions, with 64% experiencing local reactions and 26% systemic reactions with malaise as the most common symptom.…”