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Recent Advances of Vaccine Adjuvants for Infectious Diseases http://dx.doi.org/10.4110/in.2015.15.2.51 REVIEW ARTICLE pISSN 1598-2629 eISSN 2092-6685 Recent Advances of Vaccine Adjuvants for Infectious Diseases Sujin Lee1,2* and Minh Trang Nguyen1,2 1Department of Pediatrics, Emory University, School of Medicine, 2Children's Healthcare of Atlanta, Atlanta, Georgia 30322, USA Vaccines are the most effective and cost-efficient method for VACCINES preventing diseases caused by infectious pathogens. Despite the great success of vaccines, development of safe Infectious diseases remain the second leading cause of death and strong vaccines is still required for emerging new patho- worldwide after cardiovascular disease, but the leading cause gens, re-emerging old pathogens, and in order to improve the of death in infants and children (1). Vaccination is the most inadequate protection conferred by existing vaccines. One of efficient tool for preventing a variety of infectious diseases. the most important strategies for the development of effec- The ultimate goal of vaccination is to generate a patho- tive new vaccines is the selection and usage of a suitable adjuvant. Immunologic adjuvants are essential for enhancing gen-specific immune response providing long-lasting pro- vaccine potency by improvement of the humoral and/or tection against infection (2). Despite the significant success cell-mediated immune response to vaccine antigens. Thus, of vaccines, development of safe and strong vaccines is still formulation of vaccines with appropriate adjuvants is an at- required due to the emergence of new pathogens, re-emer- tractive approach towards eliciting protective and long-last- gence of old pathogens and suboptimal protection conferred ing immunity in humans. However, only a limited number of by existing vaccines. Recent important emerging or re-emerg- adjuvants is licensed for human vaccines due to concerns ing diseases were severe acute respiratory syndrome (SARS) about safety and toxicity. We summarize current knowledge in 2003, the 2009 H1N1 influenza pandemic, and Ebola virus about the potential benefits of adjuvants, the characteristics in 2014 (3). Last year, the most widespread epidemic of Ebola of adjuvants and the mechanisms of adjuvants in human virus caused significant mortality in several West African vaccines. Adjuvants have diverse modes of action and should countries (4). As a result, we are aware of pursuing a new be selected for use on the basis of the type of immune re- approach towards the rapid development of vaccines against sponse that is desired for a particular vaccine. Better under- standing of current adjuvants will help exploring new ad- emerging diseases. juvant formulations and facilitate rational design of vaccines Three different types of vaccine are currently used in hu- against infectious diseases. mans: live-attenuated vaccines, inactivated vaccines and sub- [Immune Network 2015;15(2):51-57] unit vaccines (5). Many of the most effective vaccines in use are live-attenuated vaccines. As an attenuated vaccine is com- Keywords: Vaccine, Adjuvant, Infectious disease, Innate im- posed of a virus or bacterium that can replicate within the munity, Adaptive immunity host, this type of vaccine elicits robust humoral and cell-medi- ated immunity (CMI). Examples of live-attenuated vaccine in- clude MMR (Measles, Mumps, Rubella), chicken pox, oral po- lio (Sabin), influenza (the seasonal flu nasal spray and the Received on February 10, 2015. Revised on March 28, 2015. Accepted on April 2, 2015. CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribu- tion, and reproduction in any medium, provided the original work is properly cited. *Corresponding Author. Sujin Lee, Department of Pediatrics, Emory Children’s Center, Emory University, 2015 Uppergate Dr. NE Rm 512, Atlanta, GA 30322, United States of America. Tel: 404-712-1637; Fax: 404-727-9223; E-mail: [email protected] Abbreviations: CMI, cell-mediated immunity; DC, dendritic cell; IRIV, immunopotentiating reconstituted influenza viro- somes; PRR, pattern recognition receptors; ODN, oligodeoxynucleotides; poly I:C, polyriboinosinic acid-polyribocytidylic acid; ISCOM, immune stimulating complexes IMMUNE NETWORK Vol. 15, No. 2: 51-57, April, 2015 51 Recent Advances of Vaccine Adjuvants for Infectious Diseases Sujin Lee and Minh Trang Nguyen 2009 H1N1 nasal spray), rotavirus and yellow fever vaccine. because it is a poor inducer of T cell responses. The use of Inactivated (killed) vaccines (e.g. inactivated polio - Salk, appropriate adjuvants will allow for vaccine formulations that Hepatitis A) are either heat-inactivated or chemically in- selectively trigger innate immunity and/or adaptive immunity activated particles of the pathogen. Although these vaccines to obtain a desired type of antigen-specific immune are safe and non-infectious, they stimulate only weak, responses. We also describe the practical and functional rea- short-lived and often insufficient immunity. Thus, large and sons for why adjuvants are needed as a component in vac- multiple doses of inactivated vaccine are required to confer cines in Table I. protective immunity (6). In contrast to live-attenuated vac- cines, inactivated vaccines elicit mainly humoral immunity, ADJUVANTS APPROVED FOR HUMAN VACCINES with little to no induction of CMI. Purified or recombinant subunit vaccines derived from Licensed adjuvants in use for human vaccines are listed in non-living vaccine antigens are poorly immunogenic and re- Table II. quire the addition of some components to help stimulate pro- tective immunity. In some cases, these vaccines utilize epito- Aluminium Salts (Alum) pes recognized and bound by antibodies or T-cells. Because In 1926, Glenny et al. reported the adjuvant activity of alumi- subunit vaccines contain only an essential part of the antigen nium compounds utilizing a suspension of alum-precipitated instead of the entire microbe, the chances of adverse re- diphtheria toxoid (DT) (8). Aluminium salts are the most actions to the vaccine are relatively low (7). Subunit vaccines widely used adjuvants in human vaccines. These adjuvants have been made for hepatitis B virus (HBV), influenza virus have been used in practical vaccination for more than 80 (injection) and pertussis (part of DTaP combined immuniza- years and are generally considered stimulators of Th2 im- tion). Recently developed subunit vaccines are less immuno- munity (9,10). Until 2009 aluminium salt (referred to as genic and reactogenic than traditional vaccines such as live-at- “alum”) adjuvants were the only ones contained in vaccines tenuated, and inactivated vaccines. Thus, repeated boost im- licensed for human use in the United States. Alum is a com- munizations or the addition of adjuvant are necessary to en- ponent of licensed human vaccines such as Hepatitis A virus hance the efficacy of subunit vaccines. (HAV), Hepatitis B virus (HBV), human papilloma virus (HPV), diphtheria, tetanus, Haemophilus Influenzae Type b NEED FOR ADJUVANTS (Hib) and meningococcal. Although there are a number of adjuvants more potent than alum, they have not been used The word “adjuvant” is derived from the Latin adjuvare, for human vaccine formulations due to high levels of toxicity. meaning “to help” or “to aid”. Adjuvants have been defined Surprisingly, despite the wide use of alum adjuvants in li- as agents added to vaccine formulations that enhance the im- censed human vaccines, the mechanisms of action are not munogenicity of antigens and induce protection against well characterized. The most well-known mechanism of ac- infection. Vaccines made from live-attenuated or inactivated tion of alum is the “depot effect”, first proposed by Glenny pathogens can elicit robust protective immune responses be- in 1925, whereby depot formation was cited to facilitate con- cause those vaccines contain naturally occurring adjuvants. In contrast, protein-based vaccines in most cases have limited Table I. The benefits of adjuvants immunogenicity although they have some advantages in terms of safety and cost-effectiveness. Thus, adjuvants are 1. Decrease the dose of antigen needed (dose sparing) necessary to help these proteins become effective vaccines 2. Decrease the number of vaccine doses needed by inducing strong and long-lasting protective immune 3. Enhance vaccine efficacy in infants, the elderly and immunocompromised people responses. Indeed, some protein-based vaccines have been 4. Increase functional antibody titer successfully developed in use for human vaccines by mixing 5. Induce more rapid and long-lasting immune responses with aluminium salts (alum). However, new vaccine targets 6. Induce robust cell-mediated immunity will require not only strong antibody responses but also ro- 7. Provide broad protection (cross-reactivity) bust CMI including T helper (Th) cells and cytotoxic T lym- 8. Facilitate mucosal immunity phocytes (CTL). Alum alone will be insufficient for such cases 9. Overcome antigen competition in combination vaccines 52 IMMUNE NETWORK Vol. 15, No. 2: 51-57, April, 2015 Recent Advances of Vaccine Adjuvants for Infectious Diseases Sujin Lee and Minh Trang Nguyen Table II. Licensed vaccine adjuvants Adjuvant name Class Manufacturer Description References (year licensed) Alum (1926) Mineral Salt Various Improves humoral immune responses and antigen stability. (44, 45) Antigens are adsorbed to the surface. The adjuvant
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