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Efficiency of some papillomavirus vaccines is reduced in the presence of thimerosal



Figure: Structure of thimerosal 
EVISA reported frequently about thimerosal (also called thiomersal),  an organomercury compound known for its antiseptic and antifungal properties and used as an antibacterial agent in pharmaceutical products, including vaccines and other injectable biological products (see the EVISA News related to thimerosal below). While thimerosal is a strong neurotoxin, its use as an adjuvant in vaccines is considered by the WHO  to be safe and the Organization continues to recommend the use of vaccines containing thimerosal for global immunization programmes because "the benefits of using such products far outweigh any theoretical risk of toxicity".

While often regarded as an "additive" (adjuvant), researchers from the University of Münster (with participation of EVISA director Michael Sperling) already in 2009 demonstrated that thimerosal reacts with proteins (namely human serum albumin, HSA)  in the human blood to form adducts. Later it was shown, that thimerosal not only reacts with HSA but also other proteins containing thiol-functions. More recently, researchers from Münster also showed that thimerosal is reacting with the protein in influenza vaccine, being the active part of the vaccine (see Strohmidel et al. 2018). That finding raised the question, whether adding thimerosal to a vaccine has an influence on the immunization efficiency, since the molecular structure of the target protein is changed by the adduct formation.

The new study:
A group of researchers from China now studied the influence of the adjuvant thimerosal on the activity of thiol-containing immunogens. HEV p239 and four types of HPV VLPs were used in this experiment. HEV causes epidemic hepatitis and HPV is the primary cause of genital warts and cervical cancer. Mice were immunized with formulations that contained different amounts of thimerosal via i.m.. Serum samples were collected weekly to measure the immunogenicity. 

In each of the four HPV VLPs, a substantial portion lost all binding activity to antibodies due to the addition of thimerosal. For the most affected HPV18 VLP, the binding titre of the high dose thimerosal group (0.05 %) decreased by an average of 25-fold compared with that of the control. Using cryo-electron microscopy for 3D reconstruction, structural alterations were observed in HPV19 VLPs as a result of thimerosal treatment. The authors concluded from their results, that "the choice of vaccine preservatives should be carefully considered, particularly if the antigen contains thiol, in vaccine research and development where the addition of a preservative is deemed necessary".

The cited study:

Siyi Chen, Xiaofen Huang, Yike Li, Xin Wang, Huirong Pan, Zhijie Lin, Qingbing Zheng, Shaowei Li, Jun Zhang, Ningshao Xia, Qinjian Zhao, Altered antigenicity and immunogenicity of human papillomavirus virus-like particles in the presence of thimerosal, Eur. J. Pharmaceut. Biopharmaceut., 141 (2019) 221–231. DOI: 10.1016/j.ejpb.2019.05.027

Related studies (newest first)

Philipp Strohmidel, Michael Sperling, Uwe Karst, Investigations on the binding of ethylmercury from thiomersal to proteins in influenza vaccines, J. Trace Elem. Med. Biol., 50 (2018) 100-104. DOI: /10.1016/j.jtemb.2018.06.011

J.C.N. Santos, I.M. da Silva, T.C. Braga, A. de Fatima, I.M. Figueireda, J. C. Caldas Santos, Thimerosal changes protein conformation and increase the rate of fibrillation in physiological conditions: Spectroscopic studies using bovine serum albumin (BSA), Int. J. Biol. Macromol., 113 (2018) 1032-1040. DOI: 10.1016/j.ijbiomac.2018.02.116

J. Hogeback, M. Schwarzer, C.A. Wehe, M. Sperling, U. Karst, Investigating the adduct formation of organic mercury species with carbonic anhydrase and hemoglobin from human red blood cell hemolysate by means of LC/ESI-TOF-MS and LC/ICP-MS, Metallomics 8 (2016) 101–107. DOI: 10.1039/C5MT00186B.

S. Trümpler, B. Meermann, S. Nowak, W. Buscher, U. Karst, M. Sperling, In vitro study of thimerosal reactions in human whole blood and plasma surrogate samples, J. Trace Elem. Med. Biol. 28 (2014) 125–130. DOI: 10.1016/j.jtemb.2014.01.006.

R. Janzen, M. Schwarzer, M. Sperling, M. Vogel, T. Schwerdtle, U. Karst, Adduct formation of thimerosal with human and rat hemoglobin: a study using liquid chromatography coupled to electrospray time-of-flight mass spectrometry (LC/ESITOF-MS), Metallomics 3 (2011) 847–852. DOI: 10.1039/c1mt00043h.

S. Trümpler, W. Lohmann, B. Meermann, W. Buscher, M. Sperling, U. Karst, Interaction of thimerosal with proteins—ethylmercury adduct formation of human serum albumin and β-lactoglobulin A, Metallomics 1 (2009) 87–91. DOI: 10.1039/B815978E.

E.M. Krupp, B.F. Milne, A. Mestrot, A.A. Meharg, J. Feldmann, Investigation into mercury bound to biothiols: structural identification using ESI–ion-trap MS and introduction of a method for their HPLC separation with simultaneous detection by ICP-MS and ESI-MS, Anal. Bioanal. Chem. 390 (2008) 1753–1764. DOI: 10.1007/s00216-008-1927-x.

Related EVISA News

November 12, 2017: Mercury and Autism: Is there a Link ?
February 15, 2017: Toxicity of organomercury compounds
May 5, 2014: Global policy on the use of mercury as a preservative in vaccine called discriminatory
September 12, 2013: Scientists reveal how organic mercury can interfer with vision

June 19, 2012: Vaccine ingredient causes brain damage; some nutrients prevent it
October 28, 2011: WHO worries mercury treaty could affect costs and availability of vaccines 
August 8, 2011: UNEP Global Mercury Treaty May Include Ban on Mercury in Medicine
March 17, 2011: Researchers Urge the Removal of Mercury From Flu Shots
August 16, 2010: Methylmercury: What have we learned from Minamata Bay?
March 31, 2010: Researcher Behind CDC Vaccine Safety Claims Disappears with $2M
September 24, 2009: Huge field experiment for assessing human ethylmercury risk starting in october
July 15, 2009: New Study Finds: Thimerosal Induces Autism-like Neurotoxicity
March 24, 2006: American lawmakers initiate mercury probe for vaccines
April 4, 2005: New results about toxicity of thimerosal
February 11, 2005: New findings about Thimerosal Neurotoxicity

last time modified: June 11, 2019

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