{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:31:51Z","timestamp":1790015511569,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2017,5,21]],"date-time":"2017-05-21T00:00:00Z","timestamp":1495324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more efficacious alternative, we tested whether vaccinations with influenza recombinant hemagglutinin (HA) mixed with a novel vegetable oil in water emulsion adjuvant (Natural Immune-enhancing Delivery System, NIDS), based on the immune-enhancing synergy of vitamins A and E and a catechin, could protect against intra-nasal challenge with live influenza virus. Vaccinations of inbred Brag Albino strain c (BALB\/c) mice, with HA mixed with NIDS compared to other adjuvants, i.e., a squalene oil in water emulsion (Sq. oil), and the Toll Like Receptor 3 (TLR3) agonist Poly (I:C), induced significantly lower select innate pro-inflammatory responses in serum, but induced significantly higher adaptive antibody and splenic T Helper 1 (TH1) or TH2, but not TH17, responses. Vaccinations with NIDS protected against infection, as measured by clinical scores, lung viral loads, and serum hemagglutination inhibition titers. The NIDS exhibited a strong dose sparing effect and the adjuvant action of NIDS was intact in the outbred CD1 mice. Importantly, vaccinations with the Sq. oil, but not NIDS, induced a significantly higher Serum Amyloid P component, an acute phase reactant secreted by hepatocytes, and total serum IgE. Thus, the NIDS may be used as a clinically safer and more efficacious vaccine adjuvant against influenza, and potentially other infectious diseases.<\/jats:p>","DOI":"10.3390\/nu9050516","type":"journal-article","created":{"date-parts":[[2017,5,23]],"date-time":"2017-05-23T01:47:33Z","timestamp":1495504053000},"page":"516","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Comparative Safety and Efficacy Profile of a Novel Oil in Water Vaccine Adjuvant Comprising Vitamins A and E and a Catechin in Protective Anti-Influenza Immunity"],"prefix":"10.3390","volume":"9","author":[{"given":"Sapna","family":"Patel","sequence":"first","affiliation":[{"name":"EpitoGenesis, Inc., 933 Hartford Turnpike Vernon, Hartford, CT 06066, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasser","family":"Faraj","sequence":"additional","affiliation":[{"name":"EpitoGenesis, Inc., 933 Hartford Turnpike Vernon, Hartford, CT 06066, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debra","family":"Duso","sequence":"additional","affiliation":[{"name":"TICRO at Trudeau Institute, 154 Algonquin Ave, Saranac Lake, NY 12983, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Reiley","sequence":"additional","affiliation":[{"name":"TICRO at Trudeau Institute, 154 Algonquin Ave, Saranac Lake, NY 12983, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6004-5671","authenticated-orcid":false,"given":"Erik","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stacey","family":"Schultz-Cherry","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Vajdy","sequence":"additional","affiliation":[{"name":"EpitoGenesis, Inc., 933 Hartford Turnpike Vernon, Hartford, CT 06066, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,5,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1111\/j.1440-1711.2004.01288.x","article-title":"Mucosal adjuvants and delivery systems for protein-, DNA- and RNA-based vaccines","volume":"82","author":"Vajdy","year":"2004","journal-title":"Immunol. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/978-1-4684-5712-4_6","article-title":"The immune response of humans to live and inactivated influenza vaccines","volume":"257","author":"Ghendon","year":"1989","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1001\/jama.1983.03330470029026","article-title":"Influenza vaccination","volume":"249","author":"Riddiough","year":"1983","journal-title":"JAMA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1097\/01.inf.0000143643.44463.b1","article-title":"Live attenuated influenza vaccine induces cross-reactive antibody responses in children against an a\/Fujian\/411\/2002-like H3N2 antigenic variant strain","volume":"23","author":"Mendelman","year":"2004","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_5","unstructured":"Levine, M.M., Woodrow, G.C., Kaper, J.B., and Cobon, G.S. (1997). New and improved vaccines against influenza. New Generation Vaccines, Marcel Dekker, Inc.. [2nd ed.]."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S0140-6736(79)90468-9","article-title":"Assessment of inactivated influenza-A vaccine after three outbreaks of influenza A at Christ\u2019s Hospital","volume":"313","author":"Hoskins","year":"1979","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1001\/jama.1985.03350320060017","article-title":"Efficacy of influenza vaccine in nursing homes. Reduction in illness and complications during an influenza A (H3N2) epidemic","volume":"253","author":"Patriarca","year":"1985","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1016\/j.vaccine.2011.01.024","article-title":"A novel retinoic acid, catechin hydrate and mustard oil-based emulsion for enhanced cytokine and antibody responses against multiple strains of HIV-1 following mucosal and systemic vaccinations","volume":"29","author":"Yu","year":"2011","journal-title":"Vaccine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1111\/imm.12614","article-title":"Vitamin A or E and a catechin synergize as vaccine adjuvant to enhance immune responses in mice through induction of early IL-15 but not IL-1\u03b2","volume":"148","author":"Patel","year":"2016","journal-title":"Immunology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1517\/14712598.2011.623695","article-title":"Immunomodulatory properties of vitamins, flavonoids and plant oils and their potential as vaccine adjuvants and delivery systems","volume":"11","author":"Vajdy","year":"2011","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1517\/14712598.2015.1066331","article-title":"Induction of cellular and molecular immunomodulatory pathways by vitamin A and flavonoids","volume":"15","author":"Patel","year":"2015","journal-title":"Expert Opin. Biol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"953461","DOI":"10.5402\/2012\/953461","article-title":"Acute Phase Reactants as Novel Predictors of Cardiovascular Disease","volume":"2012","author":"Ahmed","year":"2012","journal-title":"ISRN Inflamm."},{"key":"ref_13","first-page":"355","article-title":"Differences in the acute phase responses of serum amyloid P-component (SAP) and C3 to injections of casein or bovine serum albumin in amyloid-susceptible and -resistant mouse strains","volume":"39","author":"Baltz","year":"1980","journal-title":"Clin. Exp. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"885","DOI":"10.4049\/jimmunol.130.2.885","article-title":"Acute-phase reactants of mice. II. Strain dependence of serum amyloid P-component (SAP) levels and response to inflammation","volume":"130","author":"Mortensen","year":"1983","journal-title":"J. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"239","DOI":"10.7150\/ijms.8.239","article-title":"Long term persistence of IgE anti-influenza virus antibodies in pediatric and adult serum post vaccination with influenza virus vaccine","volume":"8","author":"Wong","year":"2011","journal-title":"Int. J. Med. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1111\/j.0818-9641.2004.01286.x","article-title":"Aluminium compounds for use in vaccines","volume":"82","author":"Lindblad","year":"2004","journal-title":"Immunol. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1006\/viro.1996.0259","article-title":"When two strands are better than one: The mediators and modulators of the cellular responses to doublestranded RNA","volume":"219","author":"Jacobs","year":"1996","journal-title":"Virology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1016\/S1074-7613(01)00126-1","article-title":"Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo","volume":"14","author":"Schiavoni","year":"2001","journal-title":"Immunity"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2490","DOI":"10.1128\/JVI.02105-08","article-title":"Targeted delivery of small interfering RNA to human dendritic cells to suppress dengue virus infection and associated proinflammatory cytokine production","volume":"84","author":"Subramanya","year":"2010","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"McKenna, J.J., Bramley, A.M., Skarbinski, J., Fry, A.M., Finelli, L., and Jain, S. (2013). Asthma in patients hospitalized with pandemic influenza A(H1N1)pdm09 virus infection-United States, 2009. BMC Infect. Dis., 13.","DOI":"10.1186\/1471-2334-13-57"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1111\/j.1348-0421.2012.00489.x","article-title":"Cytokine and chemokine responses in pediatric patients with severe pneumonia associated with pandemic A\/H1N1\/2009 influenza virus","volume":"56","author":"Matsumoto","year":"2012","journal-title":"Microbiol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Van den Wijngaard, C.C., van Asten, L., Koopmans, M.P.G., van Pelt, W., Nagelkerke, N.J.D., Wielders, C.C.H., van Lier, A., van der Hoek, W., Meijer, A., and Donker, G.A. (2012). Comparing pandemic to seasonal influenza mortality: Moderate impact overall but high mortality in young children. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0031197"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"66","DOI":"10.3201\/eid1201.051147","article-title":"Vaccines for pandemic influenza","volume":"12","author":"Luke","year":"2006","journal-title":"Emerg. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.immuni.2005.12.005","article-title":"Development of effective vaccines against pandemic influenza","volume":"24","author":"Subbarao","year":"2006","journal-title":"Immunity"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Suguitan, A.L., McAuliffe, J., Mills, K.L., Jin, H., Duke, G., Lu, B., Luke, C.J., Murphy, B., Swayne, D., and Kemble, G. (2006). Live, attenuated influenza A H5N1 candidate vaccines provide broad cross-protection in mice and ferrets. PLoS Med., 3.","DOI":"10.1371\/journal.pmed.0030360"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Baras, B., Stittelaar, K.J., Simon, J.H., Thoolen, R.J.M.M., Mossman, S.P., Pistoor, F.H.M., van Amerongen, G., Wettendorff, M.A., Hanon, E., and Osterhaus, A.D.M.E. (2008). Cross-protection against lethal H5N1 challenge in ferrets with an adjuvanted pandemic influenza vaccine. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0001401"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1016\/S0140-6736(07)61297-5","article-title":"Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: A randomised controlled trial","volume":"370","author":"Borkowski","year":"2007","journal-title":"Lancet"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/S0140-6736(06)69294-5","article-title":"Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: A phase I randomised controlled trial","volume":"368","author":"Lin","year":"2006","journal-title":"Lancet"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1128\/JVI.01928-07","article-title":"Vaccination of macaques with adjuvanted formalin-inactivated influenza A virus (H5N1) vaccines: Protection against H5N1 challenge without disease enhancement","volume":"82","author":"Ruat","year":"2008","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1084\/jem.20130376","article-title":"BET bromodomain inhibition suppresses TH17-mediated pathology","volume":"210","author":"Mele","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2234","DOI":"10.1172\/JCI73411","article-title":"CaMK4-dependent activation of AKT\/mTOR and CREM-a underlies autoimmunity-associated Th17 imbalance","volume":"124","author":"Koga","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.cyto.2007.11.022","article-title":"IL-23 and IL-17 in tuberculosis","volume":"41","author":"Khader","year":"2008","journal-title":"Cytokine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"510","DOI":"10.4161\/hv.5.8.8879","article-title":"Manipulation of TH17 responses in pulmonary immunity and disease through vaccination","volume":"5","author":"Sonnenberg","year":"2014","journal-title":"Hum. Vaccin."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1084\/jem.20061551","article-title":"Identification of an IL-17-producing NK1.1(neg) iNKT cell population involved in airway neutrophilia","volume":"204","author":"Michel","year":"2007","journal-title":"J. Exp. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"129","DOI":"10.3389\/fimmu.2012.00129","article-title":"TH17 cells in autoimmunity and immunodeficiency: Protective or pathogenic?","volume":"3","author":"Marwaha","year":"2012","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5968","DOI":"10.1016\/j.vaccine.2016.09.057","article-title":"Role of antibodies and IL17-mediated immunity in protection against pneumococcal otitis media","volume":"34","author":"Habets","year":"2016","journal-title":"Vaccine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.2174\/092986706778521760","article-title":"Generation and maintenance of mucosal memory B cell responses?","volume":"13","author":"Vajdy","year":"2006","journal-title":"Curr. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.imlet.2011.03.003","article-title":"Maintenance of long-term immunological memory by Ig+CD45R+ non-plasma B cells following mucosal immunizations","volume":"138","author":"Yu","year":"2011","journal-title":"Immunol. Lett."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1016\/j.vaccine.2007.11.083","article-title":"Dynamics of acute and memory mucosal and systemic immune responses against HIV-1 envelope following immunizations through single or combinations of mucosal and systemic routes","volume":"26","author":"Srivastava","year":"2008","journal-title":"Vaccine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1016\/j.vaccine.2003.10.018","article-title":"Maintenance of long-term immunological memory by low avidity IgM-secreting cells in bone marrow after mucosal immunizations with cholera toxin adjuvant","volume":"22","author":"Soenawan","year":"2004","journal-title":"Vaccine"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/9\/5\/516\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:36:33Z","timestamp":1760207793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/9\/5\/516"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,5,21]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2017,5]]}},"alternative-id":["nu9050516"],"URL":"https:\/\/doi.org\/10.3390\/nu9050516","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,5,21]]}}}