Liposomes: from August Wassermann to vaccines against COVID-19




liposomal antigen delivery system, cardiolipin antigen, antilipid antibodies, Wassermann reaction, serodiagnosis of syphilis, lipid nanoparticle, mRNA vaccine
Graphical Abstract


Background and Purpose: The development of vaccines against the SARS-CoV-2 virus has become a big challenge for many countries in 2020-2022. mRNA vaccines were shown to be effective and safe and have been widely used worldwide in the fight against the COVID-19 pandemic. The fundamental factor in creating mRNA vaccines, which ensures effective delivery of mRNA to the host cells, is the composition of lipid nanoparticles, namely the presence of ionized charged lipids, which ensures the binding of mRNA molecules. However, the significant role of liposomes in the development of liposomal vaccines and identification of immunochemical reactions involving lipids should be assessed in the context of the development of the pioneering idea of August Wassermann about the use of liposomal antigens in the diagnosis and immunoprophylaxis of serious human diseases. Experimental Approach: The review is devoted to the use of liposomal antigens as antigen-delivery systems for diagnosis and immunoprophylaxis. Key  Results: Studies of cardiolipin antigen in serodiagnosis of syphilis became the foundation of antibodies in diagnosing various infectious diseases and pathological conditions, such as tuberculosis, lupus erythematosus, COVID-19, borreliosis, etc. Identification of antiphospholipid antibodies (mainly anticardiolipin) and today is the most important diagnostic tool for antiphospholipid syndrome. Conclusion: The liposomal system first proposed in 1906 for the diagnosis of syphilis evolved more than a century later into mRNA vaccines, which are used today in the fight against the COVID-19 pandemic.


Download data is not yet available.


U. Bulbake, S. Doppalapudi, N. Kommineni, W. Khan. Liposomal formulations in clinical use: an updated review. Pharmaceutics 9 (2017) 12.

V.I. Shvets, Yu.M. Krasnopolsky, G.M. Sorokoumova. Liposomal forms of drugs: technological features of production and use in the clinic. Remedium, Moscow, 2016, p. 200.

A. Wassermann, A. Neisser, C. Bruck. Eine serodiagnostische reaktion bei syphilis. Deutsche medicinische Wochenschrift 32 (1906) 745-746.

M.C. Pangborn. Isolation and purification of a serologically active phospholipid from beef heart. Journal of Biological Chemistry 143 (1942) 247-256.

M.C. Pangborn. The composition of cardiolipin. Journal of Biological Chemistry 168 (1947) 351-361.

G.L. Orlova, Yu.M. Krasnopolsky, I.I. Golbets. Method for obtaining highly purified cardiolipin. Chemistry and Technology of Organic Production 9 (1979) 86-91.

V.I. Shvets, G.A. Sennikov, I.I. Holbets. Production of purified lecithin. Pharmaceutical Journal 4 (1977) 79-81.

R.L. Kahn, E.B. McDermott. Kahn reactions with cardiolipin antigen compared with Kahn antigen, with a note on microflocculation procedure with cardiolipin antigen. University Hospital Bulletin 12 (1946) 81-84.

G.A. Sennikov, L.S. Reznikova, V.I. Shvets, I.I. Gol'bets, G.L. Orlova. Izuchenie optimal'nogo sostava kardiolipinovogo antigena dlia serodiagnostiki sifilisa Study of the optimal composition of cardiolipin antigen for serodiagnosis of syphilis. Vestnik Dermatologii i Venerologii 7 (1978) 48–52.

G.A. Sennikov, I.I. Golbets, Y.M. Krasnopolskyi, G.L. Orlova. Chemical criteria in the assessment of the quality of cardiolipin antigen used in the serodiagnosis of syphilis. Pharmaceutical Journal 3 (1977) 57-60.

V.T. Kung, Y.P. Vollmer, F.J. Martin. Large liposome agglutination technique for the serological detection of syphilis. Journal of Immunological Methods 90 (1986) 189-196.

V.T. Rung, F.V. Martin, Y.P. Volmer, (Cooper Lipotech Inc.). Large-liposome agglutination reagent and method. US 4605630 A (1980).

Yu.M. Krasnopol'skii, I.I. Gol'bets, G.A. Sennikov, V.I. Shvets. Immunology of lipids (survey). Pharmaceutical Chemistry Journal 15 (1981) 455–465.

I.A. Vasylenko, V.V. Chupin, Yu.M. Krasnopolsky. Relationship between the structure and properties of the cardiolipin antigen. Chemical Pharmaceutical Journal 15 (1981) 14-18.

I.A. Vasilenko, V.V. Chupin, Yu.M. Krasnopol'skii, I.I. Gol'bets, G.A. Sennikov, V.I. Shvets, R.P. Evstigneeva. Interrelationship of the structure and properties of the cardiolipin antigen. Pharmaceutical Chemistry Journal 15 (1981) 71–74.

Yu.M. Krasnopolsky, I.I. Golbets, G.L. Orlova, Influence of fatty acid composition and degree of lipid oxidation on the immunochemical activity of cardiolipin antigen. Vestnik Dermatologii i Venerologii 8 (1986). 51-56.

I.I. Golbets, Yu.M. Krasnopolsky, G.L. Orlova. On the chemical composition of industrial lipid cardiolipin antigens. Chemistry and Technology of Organic Production 7 (1977) 24-26.

T. Takashi, K. Inoue, S. Nojima. Immune reactions of liposomes containing cardiolipin and their relation to membrane fluidity. Journal of Biochemistry 87 (1980) 679-685.

O. Orum, J.R. Nielsen, A. Birch-Andersen. The effect of cholesterol on the morphology and reactivity of the mixture of lipids used in syphilis serology. APMIS 98 (1990) 9-18.

K. Gao, X. Shen, Y. Lin, X.Z. Zhu, L.R. Lin, M.L. Tong, Y. Xiao, H.L. Zhang, X.M. Liang, J.J. Niu, L.L. Liu, T.C. Yang. Origin of nontreponemal antibodies during Treponema pallidum infection: evidence from a rabbit model. Journal of Infectious Diseases 218 (2018) 835-843.

D.R. Schultz. Antiphospholipid antibodies: basic immunology and assays. Seminars in Arthritis and Rheumatism 26 (1997) 724–739.

R.C. Johnson, B.P. Livermore, H.M. Jenkin, L. Eggebraten. Lipids of Treponema pallidum Kazan 5. Infection and Immunity 2 (1970) 606-609.

H.M. Matthews, T.K. Yang, H.M. Jenkin. Unique lipid composition of Treponema pallidum (Nichols virulent strain Infection and Immunity 24 (1979) 713-719.

V.I. Shvets, Yu.M. Krasnopolsky. The main directions of lipid immunochemistry. Ukrainian Biochemical Journal 56 (1984) 254-263.

Q.L. Li, Q.Y. Xu, K. Gao, H.L. Zhang, L.L. Liu, L.R. Lin, J.J. Niu, T.C. Yang. Membrane location of cardiolipin antigen in Treponema pallidum: further study on the origin of nontreponemal antibodies. Future Microbiology 17 (2022) 873-886.

A. Luchini, D. Cavasso, A. Radulescu, G. D'Errico, L. Paduano, G. Vitiello. Structural organization of cardiolipin-containing vesicles as models of the bacterial cytoplasmic membrane. Langmuir 37 (2021) 8508-8516.

M. Guarnieri. Reaction of cardiolipin and phosphatidylinositol antisera with phospholipid antigens. Lipids 9 (1974) 692-695.

A.J. DeSiervo. Anti-cardiolipin and anti-phosphatidylglycerol antibodies prepared against bacterial phospholipids. Infection and immunity 9 (1974) 835-838.

Yu.M. Krasnopolsky, G.L. Orlova, I.I. Golbets. To the question of the immunogenicity of lipids. Chemistry and Technology of Organic Production 1X (1979) 80-85.

V.I. Shvets, G.A. Sennikov, I.I. Golbets, Yu.M. Krasnpolsky. Immunochemical structural study of syphilitic reagins. Voprosy Meditsinskoi Khimii 26 (1980) 55-58.

R. Dadhich, S. Kapoor. Various facets of pathogenic lipids in infectious diseases: exploring virulent lipid-host interactome and their druggability. Journal of Membrane Biology 253 (2020) 399-423.

P.J. Gwynne, L.H. Clendenen, S.P. Turk, A.R. Marques, L.T. Hu. Antiphospholipid autoantibodies in Lyme disease arise after scavenging of host phospholipids by Borrelia burgdorferi. Journal of Clinical Investigation 132 (2022) e152506.

J. Ngeh-Ngwainbi, S.S. Kuan, F. Steinman, G.G. Guilbault. The cardiolipin antigen: chemistry and composition. Biotechnology and Applied Biochemistry 8 (1986) 553-563.

E.M.N. Do Egito, A.G. Silva-Júnior, R.P.S. Lucena, M.D.L. Oliveira, C.A.S. Andrade. Electrochemical platform for anti-cardiolipin antibody detection in human syphilitic serum. Current Research in Biotech¬nology 104 (2022) 58-65.

T.M. Dhason, E.L. Jairaj, R. Sankaralingam, B. Mahendren, B. Chilukuri, S. Vengudusamy, M. Seetharaman. Role of anticardiolipin antibodies in bad obstetric history detected by ELISA test in a tertiary care centre. Journal of Immunology and Clinical Microbiology 2 (2017) 43-47.

Yu.M. Krasnopolsky, I.I. Golbets, G.A. Sennikov. Antigenic activity of phospholipids of mycobacteria. Problems of Tuberculosis 11 (1985) 55-58.

C. Ordoñez, H.P. Savage, M. Tarajia, R. Rivera, C. Weeks-Galindo, D. Sambrano, L. Riley, P.L. Fernandez, N. Baumgarth, A. Goodridge. Both B-1a and B-1b cells exposed to Mycobacterium tuberculosis lipids differentiate into IgM antibody-secreting cells. Immunology 154 (2018) 613–623.

A.S. Sanoff, M.J. Ostro, M.J. Weiner, G. Weissmann, J.R. Seibold, (The Lipodome Company, Inc.), Liposome composition for lupus assay, US 4564599A, (1983).

A. Hollerbach, N. Müller-Calleja, D. Pedrosa, A. Canisius, M.F. Sprinzl, T. Falter, H. Rossmann, M. Bodenstein, C. Werner, I. Sagoschen, T. Münzel, O. Schreiner, V. Sivanathan, M. Reuter, J. Niermann, P.R. Galle, L. Teyton, W. Ruf, K.J. Lackner. Pathogenic lipid-binding antiphospholipid antibodies are associated with severity of COVID-19. Journal of Thrombosis and Haemostasis 19 (2021) 2335-2347.

S. Hörkkö, E. Miller, D.W. Branch, W. Palinski, J.L. Witztum. The epitopes for some antiphospholipid antibodies are adducts of oxidized phospholipid and beta2 glycoprotein 1 (and other proteins). Proceedings of the National Academy of Sciences of the United States of America 94 (1997) 10356-10361.

C. Landa-Saldívar, A. Reséndiz-Mora, S. Sánchez-Barbosa, A. Sotelo-Rodríguez, G. Barrera-Aveleida, I. Nevárez-Lechuga, I. Galarce-Sosa, K. Taniguchi-Ponciano, O.D.R. Cruz-Guzmán, I. Wong-Baeza, A. Escobar-Gutiérrez, I. Baeza, C. Wong-Baeza. Liposomes bearing non-bilayer phospholipid arrangements induce specific IgG anti-lipid antibodies by activating NK1.1+, CD4+ T cells in mice. Membranes (Basel) 12 (2022) 643.

S.G. Barreno-Rocha, S. Guzmán-Silahua, S.D. Rodríguez-Dávila, G.E. Gavilanez-Chávez, E.G. Cardona-Muñoz, C. Riebeling-Navarro, B. Rubio-Jurado, A.H. Nava-Zavala. Antiphospholipid antibodies and lipids in hematological malignancies. International Journal of Molecular Sciences 23 (2022) 4151.

D. Tiwari, S. Haque, R.P. Tiwari, A. Jawed, T. Govender, H.G. Kruger. Fast and efficient detection of tuberculosis antigens using liposome encapsulated secretory proteins of Mycobacterium tuberculosis. J Microbiol Immunol Infect 50 (2017) 189-198.

K.J. Bednar, L. Hardy, J. Smeekens, D. Raghuwanshi, S. Duan, M.D. Kulis, M.S. Macauley. Antigenic Liposomes for Generation of Disease-specific Antibodies. Journal of visualized experiments 140 (2018) 58285.

D. Green. Pathophysiology of antiphospholipid syndrome. Thrombosis and Haemostasis 122 (2022) 1085-1095.

A. Radu, S.C. Dudu, A. Ciobanu, G. Peltecu, G. Iancu, R. Botezatu, N. Gica, A.M. Panaitescu. Pregnancy Management in Women with Antiphospholidic Syndrome. Maedica (Bucur) 14 (2019) 148-160.

A.D. Bangham, R.W. Horne. Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope. Journal of Molecular Biology 8 (1964) 660-668.

N. Dusgunes, G. Gregoriadis. Introduction: The origins of liposomes: Alec Bangham at Babraham. Methods in Enzymology 391 (2005). 1-3.

D. Guimarães, A. Cavaco-Paulo, E. Nogueira. Design of liposomes as drug delivery system for therapeutic applications. International Journal of Pharmaceutics 601 (2021) 120571.

T.M. Allen, P.R. Cullis. Liposomal drug delivery systems: from concept to clinical applications. Advanced Drug Delivery Reviews 65 (2013) 36-48.

E. Beltrán-Gracia, A. López-Camacho, I. Higuera-Ciapara, J.B Velázquez-Fernández, A.A. Vallejo-Cardona. Nanomedicine review: clinical developments in liposomal applications. Cancer Nano 10 (2019) 11.

M. Alavi, M. Hamidi. Passive and active targeting in cancer therapy by liposomes and lipid nanoparticles. Drug Metabolism and Personalized Therapy 34 (2019).

M.A. Mohamed, E. Alaaeldin, A.K. Hussein, H.A. Sarhan. Liposomes and PEGylated liposomes as drug delivery system. Journal of Advanced Biomedical and Pharmaceutical Sciences 3 (2020) 80-88.

I.M. Mikheytseva, G.S. Grygorieva, N.V. Pasyechnikova, S.G. Kolomiichuk, T.I. Siroshtanenko, N.F. Konakhovych. Ocular hypotensive efficacy of a new liposomal latanoprost formulation administered by different routes for experimental ocular hypertension. Journal of Ophthalmology 505 (2022) 37-41.

M.D. Buschmann, M.J. Carrasco, S. Alishetty, M. Paige, M.G. Alameh, D. Weissman. Nanomaterial delivery systems for mRNA vaccines. Vaccines (Basel) 9 (2021) 65.

N. Pardi, M.J. Hogan, D. Weissman. Recent advances in mRNA vaccine technology. Current Opinion in Immunology 65 (2020) 14-20.

D.K. Lvov, S.V. Alkhovsky Source of the COVID-19 pandemic: ecology and genetics of coronaviruses (Betacoronavirus: Coronaviridae) SARS-CoV, SARS-CoV-2 (subgenus Sarbecovirus), and MERS-CoV (subgenus Merbecovirus). Problems of Virology 65 (2020) 62-70.

L.A. Brito, S. Kommareddy, D. Maione, Y. Uematsu, C. Giovani, F. Berlanda Scorza, G.R. Otten, D. Yu, C.W. Mandl, P.W. Mason, P.R. Dormitzer, J.B. Ulmer, A.J. Geall. Self-amplifying mRNA vaccines. Advances in Genetics 89 (2015) 179-233.

N. Pardi, D. Weissman. Nucleoside modified mRNA vaccines for infectious diseases. Methods in Molecular Biology (Clifton, N.J.) 1499 (2017) 109-121.

N. Pardi, M.J. Hogan, M.S. Naradikian, K. Parkhouse, D.W. Cain, L. Jones, M.A. Moody, H.P. Verkerke, A. Myles, E. Willis, C.C. LaBranche, D.C. Montefiori, J.L. Lobby, K.O. Saunders, H.X. Liao, B.T. Korber, L.L. Sutherland, R.M. Scearce, P.T. Hraber, I. Tombácz, H. Muramatsu, H. Ni, D.A. Balikov, C. Li, B.L. Mui, Y.K. Tam, F. Krammer, K. Karikó, P. Polacino, L.C. Eisenlohr, T.D. Madden, M.J. Hope, M.G. Lewis, K.K. Lee, S.L. Hu, S.E. Hensley, M.P. Cancro, B.F. Haynes, D. Weissman. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. Journal of Experimental Medicine 215 (2018) 1571-1588.

D. Davis, G. Gregoriadis Liposomes as immunological adjuvants in vaccines: studies with entrapped and surface-linked antigen. Biochemical Society Transactions 6 (1986) 1036-1037.

Gregoriadis G. Liposomes and mRNA: Two technologies together create a COVID-19 vaccine. Medicine in Drug Discovery 12 (2021) 100104.

Y. Huang, C. Yang, X.F. Xu, W. Xu, S.W. Liu. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacologica Sinica 41 (2020) 1141-1149.

L. Schoenmaker, D. Witzigmann, J.A. Kulkarni, R. Verbeke, G. Kersten, W. Jiskoot, D.J.A. Crommelin. mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability. International Journal of Pharmaceutics 601 (2021) 120586.

X. Hou, T. Zaks, R. Langer, Y. Dong. Lipid nanoparticles for mRNA delivery. Nature Reviews Materials 6 (2021) 1078–1094.

Y. Krasnopolsky, D. Pylypenko. Licensed liposomal vaccines and adjuvants in the antigen delivery system. BioTechnologia (Pozn) 103 (2022) 409-423.

K.J. Hassett, K.E. Benenato, E. Jacquinet, A. Lee, A. Woods, O. Yuzhakov, S. Himansu, J. Deterling, B.M. Geilich, T. Ketova, C. Mihai, A. Lynn, I. McFadyen, M.J. Moore, J.J. Senn, M.G. Stanton, Ö. Almarsson, G. Ciaramella, L.A. Brito. Optimization of Lipid Nanoparticles for Intramuscular Administration of mRNA Vaccines. Molecular Therapy. Nucleic Acids 15 (2019) 1-11.

L.A. Jackson, E.J. Anderson, N.G. Rouphael, P.C. Roberts, M. Makhene, et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. New England journal of medicine 383 (2020) 1920-1931.

H.C. Hong, K.S. Kim, S.A. Park, M.J. Chun, E.Y. Hong, S.W. Chung, H.J. Kim, B.G. Shin, A. Braka, J. Thanappan, S. Jang, s. Wu, Y.J. Cho, S.H. Kim. An mRNA vaccine against SARS-CoV-2: Lyophilized, liposome-based vaccine candidate EG-COVID induces high levels of virus neutralizing antibodies. bioRxiv preprint (2021)



30-06-2023 — Updated on 30-06-2023

How to Cite

Grygorieva, G., Pylypenko, D., & Krasnopolsky, Y. (2023). Liposomes: from August Wassermann to vaccines against COVID-19. ADMET and DMPK, 11(4), 487–497.