Vaccines with the MF59 Adjuvant Do Not Stimulate Antibody Responses against Squalene

Abstract

Squalene is a naturally occurring oil which has been used in the development of vaccine adjuvants, such as the oil-in-water emulsion MF59. In past years, by use of noncontrolled and nonvalidated assays, a claim was made that antisqualene antibodies were detectable in the sera of individuals with the so-called Gulf War syndrome. Using a validated enzyme-linked immunosorbent assay for the quantitation of immunoglobulin G (IgG) and IgM antibodies against squalene, we demonstrated that antisqualene antibodies are frequently detectable at very low titers in the sera of subjects who were never immunized with vaccines containing squalene. More importantly, vaccination with a subunit influenza vaccine with the MF59 adjuvant neither induced antisqualene antibodies nor enhanced preexisting antisqualene antibody titers. In conclusion, antisqualene antibodies are not increased by immunization with vaccines with the MF59 adjuvant. These data extend the safety profile of the MF59 emulsion adjuvant.Squalene is a triterpenoid hydrocarbon oil (C 30 H 50 ) produced by plants and is present in many foods. Squalene is also produced abundantly by human beings, for whom it serves as a precursor of cholesterol and steroid hormones (8) It is synthesized in the liver and the skin, transported in the blood by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), and secreted in large amounts by sebaceous glands (10,17).Since it is a natural component of the human body and is biodegradable, squalene has been used as a component of vaccine adjuvants. One of these adjuvants is MF59, an oil-inwater emulsion developed by Chiron (14). MF59 has been shown in various preclinical and clinical studies to significantly enhance the immune response to a wide variety of vaccine antigens (15). MF59 is a part of an influenza subunit vaccine which has been licensed in various European countries since 1997. More than 20 million doses of this vaccine have been given, and it has been shown to have an excellent safety profile. The safety of vaccines with the MF59 adjuvant has also been shown by various investigational clinical studies using recombinant antigens from hepatitis B virus, hepatitis C virus, cytomegalovirus, herpes simplex virus, human immunodeficiency virus, uropathogenic Escherichia coli, etc., with various age groups, including 1-to 3-day-old newborns (16).In 2000, antisqualene antibodies were reported to be present in the sera of veterans returning from the first Persian Gulf War with a series of symptoms diagnosed by the authors of the report as representing the so-called Gulf War syndrome (4). The conclusions of this work, based on Western blot assays, were severely criticized on technical grounds (1) and were considered inconclusive by the Institute of Medicine (7).Despite the fact that vaccines given to veterans returning with Gulf War syndrome did not contain squalene (6) and despite that fact that symptoms similar to those of the so-called Gulf War syndrome have been reported after several wars, including the American...

Anti-vakcinalni pokreti i naučna medicina

“…Najpoznatiji primer su teze o pogubnim efektima skvalena i timerosala (etil-žive) koji se nalaze u pojedinim vakcinama u svojstvu adjuvansa, odnosno konzervansa. Iako nam raspoloživ prostor ovog rada ne dozvoljava zadovoljavajuće potpunu analizu bezbednosti ovih komponenti, uputno je pomenuti da je skvalen fiziološki metabolit koji se u ljudskom telu dnevno stvara u većoj količini od one koja se može naći u bilo kojoj vakcini [13], te da antitela na skvalen nisu nađena u većoj meri kod osoba koje su primile skvalen u svojstvu adjuvansa u odnosu na kontrolne osobe [14]; količina žive u jednoj dozi vakcine koja sadrži timerosal, pak, grubo odgovara količini u jednom obroku ribe ulovljene u prosečno zagađenom području 1 [15]. Iz naučnih studija koje su do sada tragale za dokazima toksičnosti skvalena i timerosala ne može se izvući zaključak da merljiv štetni efekat postoji [16], premda je, u skladu sa principom predostrožnosti, u mnogim zemljama, naročito u SAD, prisutna težnja da se prednost dâ vakcinama bez ovih sastojaka.…”

Cross-protection against drifted influenza viruses

“…51 As previously pointed out, squalene is a biodegradable and biocompatible compound; in humans, it is precursor of cholesterol and play an important role in the synthesis of steroid hormones and Vitamin D; moreover, it has been demonstrated that the administration of MF59 TM -adjuvanted subunit influenza vaccines did not elicit a specific humoral response against squalene. [52][53][54] In 1997, the first MF59™ adjuvanted vaccine has been licensed for human use and registered in Europe for use in adults ≥ 65 y old for seasonal influenza vaccine and furthermore, consistent preclinical, clinical and post-marketing experience on the use of MF59 TM adjuvanted pandemic vaccine has been accumulated in the last decade both against avian A(H5N1) and A(H1N1) pdm 09.…”

Selection of Adjuvants for Enhanced Vaccine Potency

“…However, the species-and antigen-dependent variation in immunogenicity enhancement by MF59 appears to be a deficiency of this adjuvant system [15,138]. MF59 does not seem to induce significant side effects compared with vaccines without MF59 in healthy adults [137,139]. Recent studies show that MF59 is associated with more reports of injection site pain and tenderness (local reactogenicity) relative to a non-adjuvanted flu vaccine in children and young adults [140,141].…”

“…CEL-1000 (18-mer) is an analogue of peptide G (a peptide from human MHCII beta chain, aa [135][136][137][138][139][140][141][142][143][144][145][146][147][148][149], which is known to enhance immune responses of other immunogenic peptides. They can be conjugated to HIV (HGP-30) and malaria peptides as potential vaccines.…”