biomolecules Review Vaccine Adjuvants Derived from Marine Organisms Nina Sanina Department of Biochemistry, Microbiology and Biotechnology, School of Natural Sciences, Far Eastern, Federal University, Sukhanov Str., 8, Vladivostok 690091, Russia; [email protected]; Tel.: +7-423-265-2429 Received: 10 July 2019; Accepted: 1 August 2019; Published: 3 August 2019 Abstract: Vaccine adjuvants help to enhance the immunogenicity of weak antigens. The adjuvant effect of certain substances was noted long ago (the 40s of the last century), and since then a large number of adjuvants belonging to different groups of chemicals have been studied. This review presents research data on the nonspecific action of substances originated from marine organisms, their derivatives and complexes, united by the name ‘adjuvants’. There are covered the mechanisms of their action, safety, as well as the practical use of adjuvants derived from marine hydrobionts in medical immunology and veterinary medicine to create modern vaccines that should be non-toxic and efficient. The present review is intended to briefly describe some important achievements in the use of marine resources to solve this important problem. Keywords: squalene; cucumariosides; chitosan; fucoidans; carrageenans; laminarin; alginate 1. Introduction The oil-in-water-based complete Freund’s adjuvant developed by Jules Freund and Katherine McDermott in 40s of last century is the first vaccine adjuvant. The basis of immune stimulation and provide immunologists with a way to stimulate the production of antibodies and cellular immune responses to weak antigens. This elaboration allowed to establish the basis of immune stimulation and provide immunologists with an instrument to stimulate the production of antibody and cellular immune responses to weak antigens. Today, adjuvants are of primary importance in vaccination strategies. Throughout its history, mankind has fought with infectious diseases and made different scientific discoveries in the field of studying pathogens and the mechanisms of their effects on the host organism. These efforts resulted in the emergence of vaccinology based on the achievements of immunology, microbiology, biochemistry, and other sciences. Due to vaccination, most acute socially significant infectious diseases—such as smallpox, polio, tetanus, measles, diphtheria, and rabies—are practically eliminated or controlled [1]. That is perhaps one of the outstanding medical achievements [2]. Vaccines allow to save millions of people from illness, disability, and death each year. The World Health Organization (WHO) evaluates vaccination as one of the most cost-effective method of fighting for the preservation of human and animal health in many countries around the world [3]. Most vaccines that are successfully used today are based on inactivated (killed) or live attenuated (weakened) whole pathogens (viruses or bacteria). However, these empirically designed vaccines may exhibit undesirable side effects [4]. For example, the so-called killed vaccine may not be sufficiently inactivated, and weakened vaccines may reverse to a wild strain or cause a related disease in people with immunodeficiency or impaired health. When vaccines are inactivated, epitopes important for a protective response can be destroyed. Moreover, microorganisms may contain antigens that can cause such an undesirable response as the formation of blocking antibodies, which prevent the binding of functional, bactericidal antibodies [5]. Finally, traditional approaches to vaccination were unsuccessful against many important pathogens [6]. Biomolecules 2019, 9, 340; doi:10.3390/biom9080340 www.mdpi.com/journal/biomolecules Biomolecules 2019, 9, x FOR PEER REVIEW 2 of 18 which prevent the binding of functional, bactericidal antibodies [5]. Finally, traditional approaches Biomoleculesto vaccination2019, 9were, 340 unsuccessful against many important pathogens [6]. 2 of 16 Developing safer vaccines is needed an approach based on current knowledge of the mechanismsDeveloping involved safer vaccines in protective is needed immune an approach responses based [7]. on The current most knowledge promising of trend the mechanisms in rational involveddesign is inthe protective creation of immune subunit responses vaccines [ which,7]. The unlike most promising traditional trend ones in based rational on designthe whole is the pathogen, creation ofcontain subunit microbial vaccines antigen/s which, unlike determining traditional the development ones based on of the a protective whole pathogen, immune contain response microbial in the antigenmacroorganism/s determining [8]. the development of a protective immune response in the macroorganism [8]. However,However, individualindividual antigens antigens usually usually induce induce a weaka weak immune immune response, response, insu insufficientfficient to protect to protect the organism.the organism. To enhance To enhance immunogenicity, immunogenicity, antigens antige must bens presentedmust be topresented the immune to systemthe immune appropriately. system Variousappropriately. adjuvants Various can be adjuvants used for thiscan be purpose. used for Adjuvants this purpose. (from Adjuvants the latin ‘ adjuvare(from the’, which latin ‘adjuvare means ‘to’, help’)which aremeans substances ‘to help’) of di ffareerent substances origin and of composition different origin that improvesand composition the effectiveness that improves of vaccines the througheffectiveness their of eff vaccinesect on the through innate their immune effect system.on the innate In turn, immune these system. nonspecific In turn, responses these nonspecific influence theresponses adaptive influence immune the response, adaptive enhancing immune response, and modulating enhancing the and specific modulating immune the response specific to immune vaccine antigenresponse [9 to]. vaccine antigen [9]. OceansOceans areare thethe habitathabitat ofof organismsorganisms characterizedcharacterized byby greatgreat diversity.diversity. MarineMarine hydrobiontshydrobionts areare abundantabundant inin didifferentfferent biomedicalbiomedical activeactive substancessubstances ofof didifferentfferentchemical chemicalstructures structures [ [10].10]. SomeSome ofof themthem possesspossess adjuvantadjuvant properties.properties. TheThe presentpresent reviewreview summarizessummarizes thethe mostmost importantimportant achievementsachievements inin thethe developmentdevelopment ofof vaccinevaccine adjuvantsadjuvants basedbased onon substancessubstances isolatedisolated fromfrom marinemarine organisms.organisms. 2.2. Adjuvant Familiesfamilies 2.1.2.1. Squalene SqualeneSqualene (2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene,(2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene, CC3030H5050)) is unsaturatedunsaturated triterpene,triterpene, consistingconsisting ofof sixsix isopreneisoprene groupsgroups (Figure(Figure1 )[1) 11[11].]. FigureFigure 1.1. Structural formula ofof squalene.squalene. Initially,Initially, squalenesqualene hashas beenbeen widelywidely usedused inin cosmeticscosmetics duedue toto itsits emollient,emollient, moisturizing,moisturizing, andand antioxidantantioxidant eeffectsffects onon thethe skin.skin. Then,Then, squalenesqualene hashas alsoalso beenbeen usedused asas anan adjuvantadjuvant inin vaccinesvaccines againstagainst somesome virusvirus diseases.diseases. The Japanese scientist MitsumaroMitsumaro Tsujimoto was thethe firstfirst toto discoverdiscover squalenesqualene whichwhich waswas isolated from the liver of of the the shark shark DeaniaDeania hystricosa in in 1906 1906 [ 12[12].]. The The obtainedobtained substancesubstance waswas calledcalled "squalene""squalene" duedue toto thethe namename ofof aa familyfamily ofof sharkssharks Squalidae.Squalidae. In 1936,1936, thethe studystudy waswas continuedcontinued byby NobelNobel laureate Paul Karrer, whowho described in detail the molecular structure of squalene. TheThe discoverydiscovery ofof aa naturallynaturally occurringoccurring substance—squalenesubstance—squalene waswas aa newnew stagestage ofof creatingcreating nonspecificnonspecific stimulators.stimulators. Squalene Squalene used used in in vaccines vaccines is is obtained from fish fish oil, and inin particularparticular sharkshark liverliver oiloil followingfollowing additionaladditional purification,purification, due to the highhigh levellevel ofof squalenesqualene inin sharkssharks comparedcompared withwith otherother sources.sources. The The concentration concentration of of pure pure squalene squalene in in shark shark liver liver can can reach reach about about 80%. 80%. The The main main source source of ofcommercially commercially obtained obtained squalene squalene is the isthe most most abunda abundantnt species species of shark of shark known known as the as thespiny spiny dog dogfish fishSqualusSqualus acanthias acanthias. Alternative. Alternative sources sources of squalene, of squalene, including including olives olives are areknown known [13], [13 while], while they they are arenot notestablished established for forcommercial commercial production. production. Marine Marine yeast yeast strains strains JCC207 JCC207 and and SD301 SD301 belonging belonging to toPseudozymaPseudozyma speciesspecies also also produce produce large large amount amount of squalene. Therefore, Therefore, these these novel strains areare consideredconsidered asas thethe bestbest candidatecandidate forfor thethe commercializationcommercialization ofof microbialmicrobial squalenesqualene [ 14[14,15].,15].