Vaccines and antivirals are the primary strategies used to combat viral infections in humans. HIV-1 and influenza pose significant challenges in that they are both highly variable viruses that rapidly evolve to evade host immunity and antiviral drugs. For HIV-1, infected individuals harbor a substantial array of HIV-1 variants, a situation that presents a daunting challenge for developing vaccines and therapies. Similarly, the worldwide variability in flu reservoirs makes it difficult to predict which flu strain might acquire the ability to infect the human population, and due to the narrow timeframe between detecting a human infection and the “predict and produce” method for generating the vaccine each season, current influenza vaccines will likely be inadequate for preventing the next flu pandemic. In an effort to address these issues, we are investigating new vaccine and antiviral concepts aimed at achieving broader, more universal protection against a wider range of highly variable viruses. Toward this goal, we have designed a therapeutic HIV DNA vaccine that when administered in combination with antiretroviral drugs to nonhuman primates infected with a primary isolate of SIV, induces profound control of viral replication that persists after antivirals are withdrawn. Viral control in this model correlated with strong mucosal CD8 responses localized in the gut, and this finding has more recently led us to investigate new DNA vaccine approaches that can more precisely focus CD8 against highly conserved epitopes and novel genetic adjuvants that can localize these responses to the gut, which is a primary source of residual virus. Similarly, using DNA vaccines and antivirals designed to precisely target highly conserved regions in influenza, we have shown significant protection against a wide range of influenza strains in mice, ferrets and nonhuman primates. These studies demonstrate the feasibility of these new platforms for achieving broad protection against HIV and influenza and other highly variable pathogens. Studies currently in progress in the Fuller lab aim to elucidate mechanisms of protection mediated by these strategies and investigate various approach including novel adjuvants, DNA vaccine delivery approaches and combinatorial regimens to further improve these outcomes. Results from our work has resulted in over a dozen patents and two start-up biotechnology companies.
Representative publications (within the last 5 years):
- O’Connor MA, Munson PV, Tunggal HC, Hajari N, Lewis TB, Bratt D, Moats C, Smedley J, Bagley KC, Mullins JI, Fuller DH (2019). Mucosal T helper 17 and T regulatory cell homeostasis correlates with acute SIV viremia and responsiveness to antiretroviral therapy in macaques. AIDS Research and Human Retroviruses; doi.org/10.1089/aid.2018.0184, PMID: 30398361
- O’Connor MA, Tisoncik-Go J, Lewis TB, Miller CJ, Bratt D, Moats CR, Smedley J, Klatt NR, Gale Jr, M, Fuller DH (2018). Zika viral persistence and tissue tropism in pigtail macaques is driven by early cellular innate immune responses. Nature Communications: 3371; doi: 10.1038/s41467-018-05826-w, PMID: 30135445
- Ramsingh AI, Gray SJ, Reilly A, Koday M, Bratt D, Koday MT, Murnane R, Smedley J, Hu Y, Munson PV, Messer A, Fuller DH (2018). Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation, PLoS One Jun 6;13(6):e0198154. doi: 10.1371/journal.pone.0198154. PMID: 29874260.
- Munson PV, Tunggal H, O’Connor M, Bratt D, May A, Wangari S, Agricola B, Smedley J, Fuller JT, Kulkarni V, Felber, BK, Pavlakis GN, Mullins JI, Fuller DH (2018). Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during chronic viral infection. Human Vaccines and Immunotherapy DOI: 10.1080/21645515.2018.1448328; PMID: 29648490
- Koday MT, Leonard J, Fuller JT, Bratt D, Koday M, Fuller DH (2017). Multivalent Influenza DNA Vaccine Induces Potent Antibodies and Broadly-Specific T Cell Responses in Non-human Primates, PLoS One https://doi.org/10.1371/journal.pone.0189780. PMID: 29267331
- Chevalier A, Silva D-A, Rocklin G-J, Hicks DR, Vergara R, Murapa P, Bernard SM, Zhang L, Lam K-H,Yao G, Bahl CD, Miyashita S-I, Inna G, Fuller JT, Koday MT, Jenkins C, Colvin T, Carter L, Bohn A, Bryan CM, Fernandez-Velasco DA, Stewart L, Dong M, Huang X, Jin R, Wilson IA, Fuller DH, Baker D (2017). Massively parallel de novo protein design for targeted therapeutics, Nature 550 (7674): 74-79; DOI: doi:10.1038/nature23912, PMID: 28953867.
- Strauch EM, Bernard SM, Bohn AJ, Lee PS, Anderson, CE, Nieusma T, Holstein CA, La D, Garcia NK, Hooper KA, Ravichandran R, Nelson J, Sheffler W, Bloom JD, Lee KK, Ward AB, Yager P, Fuller DH, Wilson IA, Baker D (2017). Design of trimeric influenza neutralizing proteins targeting the hemagglutinin receptor binding site. Nature Biotechnology 35(7): 667-71. DOI:10.1038/nbt.3907. PMID: 28604661.
- Dross SE, Munson P, Kim, SE, Bratt, D, Gervassi, A, Fuller DH, Horton, H (2016). Kinetics of myeloid derived suppressor cell frequency and function during SIV infection and combination antiretroviral therapy. J Immunol. 198(2): 757-766; DOI: 10.4049/jimmunol.1600759; PMID: 27974456.
- Smedley, J, Macalister R, Wangari S, Gathuka M, Ahrens J, Iwayama N, May D, Bratt D, Munson P, Lifson J, Fuller DH (2016). Laparoscopic Technique for Serial Collection of Para-Colonic, Left Colic, and Inferior Mesenteric Lymph Nodes in Macaques. PLoS One 11(6): e0157535. doi:10.1371/journal.pone.0157535. PMID: 27309717, PMCID: PMC 4911112.
- McBurney SP, Sunshing JE, Huynh GS, Sutton WF, Fuller DH, Haigwood NL, Messer WB (2016). Evaluation of protection induced by a dengue virus serotype 2 envelope domain III protein scaffold/DNA vaccine in non-human primates. Vaccine 24;34(30):3500-7. doi: 10.1016/j.vaccine.2016.03.108. PMID: 27085173.
- Koday MT, Nelson J, Chevalier A, Koday M, Kalinoski H, Stewart L, Carter L, Nieusma T, Lee PS, Ward AB, Wilson IA, Dagley A, Smee DF, Baker D, Fuller DH (2016). A Computationally Designed Hemagglutini Stem-Binding Protein Provides In Vivo Prorection from Influenza Independent of a Host Immune Response. PLoS Pathog: doi: 10.1371/journal.ppat.1005409. PubMed PMID: 26845438; PMCID: PMC4742065.
- Fuller DH, Richert-Spuhler L, Klatt NA (2014). HIV Vaccine Trial Exploits a Dual and Central Role for Innate Immunity. J. Virol. 88(20):11640-3 PMID 25122775.
- Palermo RE, Fuller DH (2013). ‘Omics Investigations of HIV and SIV Pathogenesis and Innate Immunity. Curr Top Microbiol Immunol (2013);363:87-116. PMID:22923094.
- Fuller DH, Rajakumar P, Che JW, Nyaundi J, Narendran A, Yager E, Stagnar C, Wahlberg B, Michael H, Taber R, Haynes JR, Cook F, Ertl P, Tite J, Amedee, A, Murphey-Corb M (2012). Therapeutic DNA vaccine in Combination with a Mucosal Adjuvant Induces Broad T Cell Responses in the Gut and Sustained Protection from Viral Rebound and AIDS in SIV-Infected Rhesus Macaques. PLoS One 7(3): e33715. doi:10.1371/journal.pone.0033715 PMID 22442716.
Extended list of publications: