This page has only limited features, please log in for full access.

Dr. Deborah Fuller
Department of Microbiology, University of Washington, PO Box 35807, 750 Republican Street, Seattle, WA 98109, USA

Basic Info


Research Keywords & Expertise

0 HBV
0 HIV
0 Influenza
0 ZIKV
0 Cellular immunity, mucosal immunity

Fingerprints

HIV
Influenza
HBV
ZIKV
Nonhuman primate models for infectious disease

Honors and Awards

The user has no records in this section


Career Timeline

The user has no records in this section.


Short Biography

The user biography is not available.
Following
Followers
Co Authors
The list of users this user is following is empty.
Following: 0 users

Feed

Journal article
Published: 14 August 2021 in Viruses
Reads 0
Downloads 0

Selection of a pre-clinical non-human primate (NHP) model is essential when evaluating therapeutic vaccine and treatment strategies for HIV. SIV and SHIV-infected NHPs exhibit a range of viral burdens, pathologies, and responses to combinatorial antiretroviral therapy (cART) regimens and the choice of the NHP model for AIDS could influence outcomes in studies investigating interventions. Previously, in rhesus macaques (RMs) we showed that maintenance of mucosal Th17/Treg homeostasis during SIV infection correlated with a better virological response to cART. Here, in RMs we compared viral kinetics and dysregulation of gut homeostasis, defined by T cell subset disruption, during highly pathogenic SIVΔB670 compared to SHIV-1157ipd3N4 infection. SHIV infection resulted in lower acute viremia and less disruption to gut CD4 T-cell homeostasis. Additionally, 24/24 SHIV-infected versus 10/19 SIV-infected animals had sustained viral suppression <100 copies/mL of plasma after 5 months of cART. Significantly, the more profound viral suppression during cART in a subset of SIV and all SHIV-infected RMs corresponded with less gut immune dysregulation during acute SIV/SHIV infection, defined by maintenance of the Th17/Treg ratio. These results highlight significant differences in viral control during cART and gut dysregulation in NHP AIDS models and suggest that selection of a model may impact the evaluation of candidate therapeutic interventions for HIV treatment and cure strategies.

ACS Style

Megan A. O’Connor; Paul V. Munson; Sandra E. Dross; Hillary C. Tunggal; Thomas B. Lewis; Jessica Osborn; Christopher W. Peterson; Meei-Li W. Huang; Cassandra Moats; Jeremy Smedley; Keith R. Jerome; Hans-Peter Kiem; Kenneth C. Bagley; James I. Mullins; Deborah Heydenburg Fuller. A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART. Viruses 2021, 13, 1609 .

AMA Style

Megan A. O’Connor, Paul V. Munson, Sandra E. Dross, Hillary C. Tunggal, Thomas B. Lewis, Jessica Osborn, Christopher W. Peterson, Meei-Li W. Huang, Cassandra Moats, Jeremy Smedley, Keith R. Jerome, Hans-Peter Kiem, Kenneth C. Bagley, James I. Mullins, Deborah Heydenburg Fuller. A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART. Viruses. 2021; 13 (8):1609.

Chicago/Turabian Style

Megan A. O’Connor; Paul V. Munson; Sandra E. Dross; Hillary C. Tunggal; Thomas B. Lewis; Jessica Osborn; Christopher W. Peterson; Meei-Li W. Huang; Cassandra Moats; Jeremy Smedley; Keith R. Jerome; Hans-Peter Kiem; Kenneth C. Bagley; James I. Mullins; Deborah Heydenburg Fuller. 2021. "A Gut Reaction to SIV and SHIV Infection: Lower Dysregulation of Mucosal T Cells during Acute Infection Is Associated with Greater Viral Suppression during cART." Viruses 13, no. 8: 1609.

Immunology
Published: 17 June 2021 in PLoS ONE
Reads 0
Downloads 0

A therapeutic vaccine that induces lasting control of HIV infection could eliminate the need for lifelong adherence to antiretroviral therapy. This study investigated a therapeutic DNA vaccine delivered with a single adjuvant or a novel combination of adjuvants to augment T cell immunity in the blood and gut-associated lymphoid tissue in SIV-infected rhesus macaques. Animals that received DNA vaccines expressing SIV proteins, combined with plasmids expressing adjuvants designed to increase peripheral and mucosal T cell responses, including the catalytic subunit of the E. coli heat-labile enterotoxin, IL-12, IL-33, retinaldehyde dehydrogenase 2, soluble PD-1 and soluble CD80, were compared to mock-vaccinated controls. Following treatment interruption, macaques exhibited variable levels of viral rebound, with four animals from the vaccinated groups and one animal from the control group controlling virus at median levels of 103 RNA copies/ml or lower (controllers) and nine animals, among all groups, exhibiting immediate viral rebound and median viral loads greater than 103 RNA copies/ml (non-controllers). Although there was no significant difference between the vaccinated and control groups in protection from viral rebound, the variable virological outcomes during treatment interruption enabled an examination of immune correlates of viral replication in controllers versus non-controllers regardless of vaccination status. Lower viral burden in controllers correlated with increased polyfunctional SIV-specific CD8+ T cells in mesenteric lymph nodes and blood prior to and during treatment interruption. Notably, higher frequencies of colonic CD4+ T cells and lower Th17/Treg ratios prior to infection in controllers correlated with improved responses to ART and control of viral rebound. These results indicate that mucosal immune responses, present prior to infection, can influence efficacy of antiretroviral therapy and the outcome of immunotherapeutic vaccination, suggesting that therapies capable of modulating host mucosal responses may be needed to achieve HIV cure.

ACS Style

Hillary Claire Tunggal; Paul Veness Munson; Megan Ashley O’Connor; Nika Hajari; Sandra Elizabeth Dross; Debra Bratt; James Thomas Fuller; Kenneth Bagley; Deborah Heydenburg Fuller. Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs. PLoS ONE 2021, 16, e0253265 .

AMA Style

Hillary Claire Tunggal, Paul Veness Munson, Megan Ashley O’Connor, Nika Hajari, Sandra Elizabeth Dross, Debra Bratt, James Thomas Fuller, Kenneth Bagley, Deborah Heydenburg Fuller. Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs. PLoS ONE. 2021; 16 (6):e0253265.

Chicago/Turabian Style

Hillary Claire Tunggal; Paul Veness Munson; Megan Ashley O’Connor; Nika Hajari; Sandra Elizabeth Dross; Debra Bratt; James Thomas Fuller; Kenneth Bagley; Deborah Heydenburg Fuller. 2021. "Effects of therapeutic vaccination on the control of SIV in rhesus macaques with variable responsiveness to antiretroviral drugs." PLoS ONE 16, no. 6: e0253265.

Microbiology
Published: 07 May 2021 in PLOS Pathogens
Reads 0
Downloads 0

HIV-infected infants are at an increased risk of progressing rapidly to AIDS in the first weeks of life. Here, we evaluated immunological and virological parameters in 25 SIV-infected infant rhesus macaques to understand the factors influencing a rapid disease outcome. Infant macaques were infected with SIVmac251 and monitored for 10 to 17 weeks post-infection. SIV-infected infants were divided into either typical (TypP) or rapid (RP) progressor groups based on levels of plasma anti-SIV antibody and viral load, with RP infants having low SIV-specific antibodies and high viral loads. Following SIV infection, 11 out of 25 infant macaques exhibited an RP phenotype. Interestingly, TypP had lower levels of total CD4 T cells, similar reductions in CD4/CD8 ratios and elevated activation of CD8 T cells, as measured by the levels of HLA-DR, compared to RP. Differences between the two groups were identified in other immune cell populations, including a failure to expand activated memory (CD21-CD27+) B cells in peripheral blood in RP infant macaques, as well as reduced levels of germinal center (GC) B cells and T follicular helper (Tfh) cells in spleens (4- and 10-weeks post-SIV). Reduced B cell proliferation in splenic germinal GCs was associated with increased SIV+ cell density and follicular type 1 interferon (IFN)-induced immune activation. Further analyses determined that at 2-weeks post SIV infection TypP infants exhibited elevated levels of the GC-inducing chemokine CXCL13 in plasma, as well as significantly lower levels of viral envelope diversity compared to RP infants. Our findings provide evidence that early viral and immunologic events following SIV infection contributes to impairment of B cells, Tfh cells and germinal center formation, ultimately impeding the development of SIV-specific antibody responses in rapidly progressing infant macaques.

ACS Style

Matthew P. Wood; Chloe I. Jones; Adriana Lippy; Brian G. Oliver; Brynn Walund; Katherine A. Fancher; Bridget S. Fisher; Piper J. Wright; James T. Fuller; Patience Murapa; Jakob Habib; Maud Mavigner; Ann Chahroudi; D. Noah Sather; Deborah H. Fuller; Donald L. Sodora. Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques. PLOS Pathogens 2021, 17, e1009575 .

AMA Style

Matthew P. Wood, Chloe I. Jones, Adriana Lippy, Brian G. Oliver, Brynn Walund, Katherine A. Fancher, Bridget S. Fisher, Piper J. Wright, James T. Fuller, Patience Murapa, Jakob Habib, Maud Mavigner, Ann Chahroudi, D. Noah Sather, Deborah H. Fuller, Donald L. Sodora. Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques. PLOS Pathogens. 2021; 17 (5):e1009575.

Chicago/Turabian Style

Matthew P. Wood; Chloe I. Jones; Adriana Lippy; Brian G. Oliver; Brynn Walund; Katherine A. Fancher; Bridget S. Fisher; Piper J. Wright; James T. Fuller; Patience Murapa; Jakob Habib; Maud Mavigner; Ann Chahroudi; D. Noah Sather; Deborah H. Fuller; Donald L. Sodora. 2021. "Rapid progression is associated with lymphoid follicle dysfunction in SIV-infected infant rhesus macaques." PLOS Pathogens 17, no. 5: e1009575.

Journal article
Published: 23 February 2021 in AIDS Research and Human Retroviruses
Reads 0
Downloads 0

Coccidioidomycosis is a common fungal infection in people living with human immunodeficiency virus-1 (HIV-1), particularly in southwest regions of the United States where Coccidioides sp. is endemic, but rates of infection have significantly declined in the era of potent combination antiretroviral therapy (cART). Natural coccidioidomycosis also occurs in outdoor-housed macaques residing in the southwestern states that are utilized in biomedical research. Here, we report on a recrudescent case of previously treated, naturally occurring, coccidioidomycosis in a pigtail macaque that was experimentally infected with simian immunodeficiency virus (SIV) and virally suppressed on cART. Coccidioides IgG antibody titer became detectable prior to discontinuation of cART, but symptomatic coccidioidomycosis developed subsequent to cART withdrawal. This animal was screened and treated in accordance with the guidelines for the prevention and treatment of coccidioidomycosis, suggesting that macaques with a history of coccidioidomycosis should be excluded from enrollment in HIV studies. Continual monitoring for known endemic pathogens based on the colony of origin is also recommended for animals utilized for HIV/AIDS research.

ACS Style

Kathryn A. Guerriero; Robert D. Murnane; Thomas B. Lewis; Brieann Brown; Audrey Baldessari; Dean A. Jeffery; Ms. Carolyn M Malinowski; Deborah H. Fuller; Megan A. O'Connor. Recrudescence of Natural Coccidioidomycosis During Combination Antiretroviral Therapy in a Pigtail Macaque Experimentally Infected with Simian Immunodeficiency Virus. AIDS Research and Human Retroviruses 2021, 1 .

AMA Style

Kathryn A. Guerriero, Robert D. Murnane, Thomas B. Lewis, Brieann Brown, Audrey Baldessari, Dean A. Jeffery, Ms. Carolyn M Malinowski, Deborah H. Fuller, Megan A. O'Connor. Recrudescence of Natural Coccidioidomycosis During Combination Antiretroviral Therapy in a Pigtail Macaque Experimentally Infected with Simian Immunodeficiency Virus. AIDS Research and Human Retroviruses. 2021; ():1.

Chicago/Turabian Style

Kathryn A. Guerriero; Robert D. Murnane; Thomas B. Lewis; Brieann Brown; Audrey Baldessari; Dean A. Jeffery; Ms. Carolyn M Malinowski; Deborah H. Fuller; Megan A. O'Connor. 2021. "Recrudescence of Natural Coccidioidomycosis During Combination Antiretroviral Therapy in a Pigtail Macaque Experimentally Infected with Simian Immunodeficiency Virus." AIDS Research and Human Retroviruses , no. : 1.

Report
Published: 05 November 2020 in Science
Reads 0
Downloads 0

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo human angiotensin-converting enzyme 2 (hACE2) decoys to neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The best monovalent decoy, CTC-445.2, bound with low nanomolar affinity and high specificity to the receptor-binding domain (RBD) of the spike protein. Cryo–electron microscopy (cryo-EM) showed that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, showed ~10-fold improvement in binding. CTC-445.2d potently neutralized SARS-CoV-2 infection of cells in vitro, and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge.

ACS Style

Thomas W. Linsky; Renan Vergara; Nuria Codina; Jorgen W. Nelson; Matthew J. Walker; Wen Su; Christopher O. Barnes; Tien-Ying Hsiang; Katharina Esser-Nobis; Kevin Yu; Z. Beau Reneer; Yixuan J. Hou; Tanu Priya; Masaya Mitsumoto; Avery Pong; Uland Y. Lau; Marsha L. Mason; Jerry Chen; Alex Chen; Tania Berrocal; Hong Peng; Nicole S. Clairmont; Javier Castellanos; Yu-Ru Lin; Anna Josephson-Day; Ralph S. Baric; Deborah H. Fuller; Carl D. Walkey; Ted M. Ross; Ryan Swanson; Pamela J. Bjorkman; Michael Gale; Luis M. Blancas-Mejia; Hui-Ling Yen; Daniel-Adriano Silva. De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2. Science 2020, 370, 1208 -1214.

AMA Style

Thomas W. Linsky, Renan Vergara, Nuria Codina, Jorgen W. Nelson, Matthew J. Walker, Wen Su, Christopher O. Barnes, Tien-Ying Hsiang, Katharina Esser-Nobis, Kevin Yu, Z. Beau Reneer, Yixuan J. Hou, Tanu Priya, Masaya Mitsumoto, Avery Pong, Uland Y. Lau, Marsha L. Mason, Jerry Chen, Alex Chen, Tania Berrocal, Hong Peng, Nicole S. Clairmont, Javier Castellanos, Yu-Ru Lin, Anna Josephson-Day, Ralph S. Baric, Deborah H. Fuller, Carl D. Walkey, Ted M. Ross, Ryan Swanson, Pamela J. Bjorkman, Michael Gale, Luis M. Blancas-Mejia, Hui-Ling Yen, Daniel-Adriano Silva. De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2. Science. 2020; 370 (6521):1208-1214.

Chicago/Turabian Style

Thomas W. Linsky; Renan Vergara; Nuria Codina; Jorgen W. Nelson; Matthew J. Walker; Wen Su; Christopher O. Barnes; Tien-Ying Hsiang; Katharina Esser-Nobis; Kevin Yu; Z. Beau Reneer; Yixuan J. Hou; Tanu Priya; Masaya Mitsumoto; Avery Pong; Uland Y. Lau; Marsha L. Mason; Jerry Chen; Alex Chen; Tania Berrocal; Hong Peng; Nicole S. Clairmont; Javier Castellanos; Yu-Ru Lin; Anna Josephson-Day; Ralph S. Baric; Deborah H. Fuller; Carl D. Walkey; Ted M. Ross; Ryan Swanson; Pamela J. Bjorkman; Michael Gale; Luis M. Blancas-Mejia; Hui-Ling Yen; Daniel-Adriano Silva. 2020. "De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2." Science 370, no. 6521: 1208-1214.

Journal article
Published: 17 August 2020 in Journal of Virology
Reads 0
Downloads 0

The only HIV vaccine trial for which protective efficacy was detected correlated this efficacy with V2-specific Abs that were effectively nonneutralizing. This result has fueled a decade of HIV vaccine research focused on designing an HIV vaccine capable of eliciting V2-focused, polyfunctional Abs that effectively bind HIV and trigger various leukocytes to kill the virus and restrict viral spread. From the numerous vaccine candidates designed and tested as part of our V2-focused preclinical vaccine program, we have identified immunogens and a vaccine regimen that induces a highly durable and polyfunctional V2-focused Ab response in rhesus macaques, described herein.

ACS Style

Rebecca L. Powell; Svenja Weiss; Alisa Fox; Xiaomei Liu; Vincenza Itri; Xunqing Jiang; Christina C. Luo; David A. Spencer; Shilpi Pandey; Tracy Cheever; Deborah H. Fuller; Maxim Totrov; Ann J. Hessell; Nancy L. Haigwood; Xiang-Peng Kong; Susan Zolla-Pazner. An HIV Vaccine Targeting the V2 Region of the HIV Envelope Induces a Highly Durable Polyfunctional Fc-Mediated Antibody Response in Rhesus Macaques. Journal of Virology 2020, 94, 1 .

AMA Style

Rebecca L. Powell, Svenja Weiss, Alisa Fox, Xiaomei Liu, Vincenza Itri, Xunqing Jiang, Christina C. Luo, David A. Spencer, Shilpi Pandey, Tracy Cheever, Deborah H. Fuller, Maxim Totrov, Ann J. Hessell, Nancy L. Haigwood, Xiang-Peng Kong, Susan Zolla-Pazner. An HIV Vaccine Targeting the V2 Region of the HIV Envelope Induces a Highly Durable Polyfunctional Fc-Mediated Antibody Response in Rhesus Macaques. Journal of Virology. 2020; 94 (17):1.

Chicago/Turabian Style

Rebecca L. Powell; Svenja Weiss; Alisa Fox; Xiaomei Liu; Vincenza Itri; Xunqing Jiang; Christina C. Luo; David A. Spencer; Shilpi Pandey; Tracy Cheever; Deborah H. Fuller; Maxim Totrov; Ann J. Hessell; Nancy L. Haigwood; Xiang-Peng Kong; Susan Zolla-Pazner. 2020. "An HIV Vaccine Targeting the V2 Region of the HIV Envelope Induces a Highly Durable Polyfunctional Fc-Mediated Antibody Response in Rhesus Macaques." Journal of Virology 94, no. 17: 1.

Preprint content
Published: 12 August 2020
Reads 0
Downloads 0

SUMMARY A safe, effective, and scalable vaccine is urgently needed to halt the ongoing SARS-CoV-2 pandemic. Here, we describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 copies of the SARS-CoV-2 spike (S) glycoprotein receptor-binding domain (RBD) in a highly immunogenic array and induce neutralizing antibody titers roughly ten-fold higher than the prefusion-stabilized S ectodomain trimer despite a more than five-fold lower dose. Antibodies elicited by the nanoparticle immunogens target multiple distinct epitopes on the RBD, suggesting that they may not be easily susceptible to escape mutations, and exhibit a significantly lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. The high yield and stability of the protein components and assembled nanoparticles, especially compared to the SARS-CoV-2 prefusion-stabilized S trimer, suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms for inducing potent neutralizing antibody responses and have launched cGMP manufacturing efforts to advance the lead RBD nanoparticle vaccine into the clinic.

ACS Style

Alexandra C. Walls; Brooke Fiala; Alexandra Schaefer; Samuel Wrenn; Minh N. Pham; Michael Murphy; Longping V. Tse; Laila Shehata; Megan A. O'Connor; Chengbo Chen; Mary Jane Navarro; Marcos C. Miranda; Deleah Pettie; Rashmi Ravichandran; John C. Kraft; Cassandra Ogohara; Anne Palser; Sara Chalk; E-Chiang Lee; Elizabeth Kepl; Cameron M. Chow; Claire Sydeman; Edgar A. Hodge; Brieann Brown; Jim T. Fuller; Kenneth H. Dinnon; Lisa E. Gralinski; Sarah R. Leist; Kendra L. Gully; Thomas B. Lewis; Miklos Guttman; Helen Y. Chu; Kelly K. Lee; Deborah H. Fuller; Ralph S. Baric; Paul Kellam; Lauren Carter; Marion Pepper; Timothy P. Sheahan; David Veesler; Neil P. King. Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. 2020, 1 .

AMA Style

Alexandra C. Walls, Brooke Fiala, Alexandra Schaefer, Samuel Wrenn, Minh N. Pham, Michael Murphy, Longping V. Tse, Laila Shehata, Megan A. O'Connor, Chengbo Chen, Mary Jane Navarro, Marcos C. Miranda, Deleah Pettie, Rashmi Ravichandran, John C. Kraft, Cassandra Ogohara, Anne Palser, Sara Chalk, E-Chiang Lee, Elizabeth Kepl, Cameron M. Chow, Claire Sydeman, Edgar A. Hodge, Brieann Brown, Jim T. Fuller, Kenneth H. Dinnon, Lisa E. Gralinski, Sarah R. Leist, Kendra L. Gully, Thomas B. Lewis, Miklos Guttman, Helen Y. Chu, Kelly K. Lee, Deborah H. Fuller, Ralph S. Baric, Paul Kellam, Lauren Carter, Marion Pepper, Timothy P. Sheahan, David Veesler, Neil P. King. Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2. . 2020; ():1.

Chicago/Turabian Style

Alexandra C. Walls; Brooke Fiala; Alexandra Schaefer; Samuel Wrenn; Minh N. Pham; Michael Murphy; Longping V. Tse; Laila Shehata; Megan A. O'Connor; Chengbo Chen; Mary Jane Navarro; Marcos C. Miranda; Deleah Pettie; Rashmi Ravichandran; John C. Kraft; Cassandra Ogohara; Anne Palser; Sara Chalk; E-Chiang Lee; Elizabeth Kepl; Cameron M. Chow; Claire Sydeman; Edgar A. Hodge; Brieann Brown; Jim T. Fuller; Kenneth H. Dinnon; Lisa E. Gralinski; Sarah R. Leist; Kendra L. Gully; Thomas B. Lewis; Miklos Guttman; Helen Y. Chu; Kelly K. Lee; Deborah H. Fuller; Ralph S. Baric; Paul Kellam; Lauren Carter; Marion Pepper; Timothy P. Sheahan; David Veesler; Neil P. King. 2020. "Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2." , no. : 1.

Research article
Published: 20 July 2020 in Science Translational Medicine
Reads 0
Downloads 0

The coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is having a deleterious impact on health services and the global economy, highlighting the urgent need for an effective vaccine. Such a vaccine would need to rapidly confer protection after one or two doses and would need to be manufactured using components suitable for scale up. Here, we developed an Alphavirus-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with lipid inorganic nanoparticles (LIONs) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti–SARS-CoV-2 S protein IgG antibody isotypes indicative of a type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in the lung and spleen. Prime-only immunization of aged (17 months old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. In nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in five intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.

ACS Style

Jesse H. Erasmus; Amit P. Khandhar; Megan A. O’Connor; Alexandra C. Walls; Emily A. Hemann; Patience Murapa; Jacob Archer; Shanna Leventhal; James T. Fuller; Thomas B. Lewis; Kevin E. Draves; Samantha Randall; Kathryn A. Guerriero; Malcolm S. Duthie; Darrick Carter; Steven G. Reed; David W. Hawman; Heinz Feldmann; Michael Gale; David Veesler; Peter Berglund; Deborah Heydenburg Fuller. An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates. Science Translational Medicine 2020, 12, eabc9396 .

AMA Style

Jesse H. Erasmus, Amit P. Khandhar, Megan A. O’Connor, Alexandra C. Walls, Emily A. Hemann, Patience Murapa, Jacob Archer, Shanna Leventhal, James T. Fuller, Thomas B. Lewis, Kevin E. Draves, Samantha Randall, Kathryn A. Guerriero, Malcolm S. Duthie, Darrick Carter, Steven G. Reed, David W. Hawman, Heinz Feldmann, Michael Gale, David Veesler, Peter Berglund, Deborah Heydenburg Fuller. An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates. Science Translational Medicine. 2020; 12 (555):eabc9396.

Chicago/Turabian Style

Jesse H. Erasmus; Amit P. Khandhar; Megan A. O’Connor; Alexandra C. Walls; Emily A. Hemann; Patience Murapa; Jacob Archer; Shanna Leventhal; James T. Fuller; Thomas B. Lewis; Kevin E. Draves; Samantha Randall; Kathryn A. Guerriero; Malcolm S. Duthie; Darrick Carter; Steven G. Reed; David W. Hawman; Heinz Feldmann; Michael Gale; David Veesler; Peter Berglund; Deborah Heydenburg Fuller. 2020. "An Alphavirus-derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates." Science Translational Medicine 12, no. 555: eabc9396.

Journal article
Published: 01 July 2020 in Molecular Therapy
Reads 0
Downloads 0
ACS Style

Jesse H. Erasmus; Deborah Heydenburg Fuller. Preparing for Pandemics: RNA Vaccines at the Forefront. Molecular Therapy 2020, 28, 1559 -1560.

AMA Style

Jesse H. Erasmus, Deborah Heydenburg Fuller. Preparing for Pandemics: RNA Vaccines at the Forefront. Molecular Therapy. 2020; 28 (7):1559-1560.

Chicago/Turabian Style

Jesse H. Erasmus; Deborah Heydenburg Fuller. 2020. "Preparing for Pandemics: RNA Vaccines at the Forefront." Molecular Therapy 28, no. 7: 1559-1560.

Review article
Published: 18 June 2020 in New England Journal of Medicine
Reads 0
Downloads 0

Clinical Implications of Basic Research from The New England Journal of Medicine — Amplifying RNA Vaccine Development

ACS Style

Deborah Fuller; Peter Berglund. Amplifying RNA Vaccine Development. New England Journal of Medicine 2020, 382, 2469 -2471.

AMA Style

Deborah Fuller, Peter Berglund. Amplifying RNA Vaccine Development. New England Journal of Medicine. 2020; 382 (25):2469-2471.

Chicago/Turabian Style

Deborah Fuller; Peter Berglund. 2020. "Amplifying RNA Vaccine Development." New England Journal of Medicine 382, no. 25: 2469-2471.

Research article
Published: 12 March 2020 in PLOS Pathogens
Reads 0
Downloads 0

The recombinant Canarypox ALVAC-HIV/gp120/alum vaccine regimen was the first to significantly decrease the risk of HIV acquisition in humans, with equal effectiveness in both males and females. Similarly, an equivalent SIV-based ALVAC vaccine regimen decreased the risk of virus acquisition in Indian rhesus macaques of both sexes following intrarectal exposure to low doses of SIVmac251. Here, we demonstrate that the ALVAC-SIV/gp120/alum vaccine is also efficacious in female Chinese rhesus macaques following intravaginal exposure to low doses of SIVmac251 and we confirm that CD14+ classical monocytes are a strong correlate of decreased risk of virus acquisition. Furthermore, we demonstrate that the frequency of CD14+ cells and/or their gene expression correlates with blood Type 1 CD4+ T helper cells, α4β7+ plasmablasts, and vaginal cytocidal NKG2A+ cells. To better understand the correlate of protection, we contrasted the ALVAC-SIV vaccine with a NYVAC-based SIV/gp120 regimen that used the identical immunogen. We found that NYVAC-SIV induced higher immune activation via CD4+Ki67+CD38+ and CD4+Ki67+α4β7+ T cells, higher SIV envelope-specific IFN-γ producing cells, equivalent ADCC, and did not decrease the risk of SIVmac251 acquisition. Using the systems biology approach, we demonstrate that specific expression profiles of plasmablasts, NKG2A+ cells, and monocytes elicited by the ALVAC-based regimen correlated with decreased risk of virus acquisition.

ACS Style

Giacomo Gorini; Slim Fourati; Monica Vaccari; Mohammad Arif Rahman; Shari N. Gordon; Dallas R. Brown; Lynn Law; Jean Chang; Richard Green; Fredrik Barrenäs; Namal P. M. Liyanage; Melvin N. Doster; Luca Schifanella; Massimiliano Bissa; Isabela Silva de Castro; Robyn Washington-Parks; Veronica Galli; Deborah H. Fuller; Sampa Santra; Michael Agy; Ranajit Pal; Robert E. Palermo; Georgia D. Tomaras; Xiaoying Shen; Celia C. Labranche; David C. Montefiori; David J. Venzon; Hung V. Trinh; Mangala Rao; Michael Gale; Rafick P. Sekaly; Genoveffa Franchini. Engagement of monocytes, NK cells, and CD4+ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 vaginal acquisition. PLOS Pathogens 2020, 16, e1008377 .

AMA Style

Giacomo Gorini, Slim Fourati, Monica Vaccari, Mohammad Arif Rahman, Shari N. Gordon, Dallas R. Brown, Lynn Law, Jean Chang, Richard Green, Fredrik Barrenäs, Namal P. M. Liyanage, Melvin N. Doster, Luca Schifanella, Massimiliano Bissa, Isabela Silva de Castro, Robyn Washington-Parks, Veronica Galli, Deborah H. Fuller, Sampa Santra, Michael Agy, Ranajit Pal, Robert E. Palermo, Georgia D. Tomaras, Xiaoying Shen, Celia C. Labranche, David C. Montefiori, David J. Venzon, Hung V. Trinh, Mangala Rao, Michael Gale, Rafick P. Sekaly, Genoveffa Franchini. Engagement of monocytes, NK cells, and CD4+ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 vaginal acquisition. PLOS Pathogens. 2020; 16 (3):e1008377.

Chicago/Turabian Style

Giacomo Gorini; Slim Fourati; Monica Vaccari; Mohammad Arif Rahman; Shari N. Gordon; Dallas R. Brown; Lynn Law; Jean Chang; Richard Green; Fredrik Barrenäs; Namal P. M. Liyanage; Melvin N. Doster; Luca Schifanella; Massimiliano Bissa; Isabela Silva de Castro; Robyn Washington-Parks; Veronica Galli; Deborah H. Fuller; Sampa Santra; Michael Agy; Ranajit Pal; Robert E. Palermo; Georgia D. Tomaras; Xiaoying Shen; Celia C. Labranche; David C. Montefiori; David J. Venzon; Hung V. Trinh; Mangala Rao; Michael Gale; Rafick P. Sekaly; Genoveffa Franchini. 2020. "Engagement of monocytes, NK cells, and CD4+ Th1 cells by ALVAC-SIV vaccination results in a decreased risk of SIVmac251 vaginal acquisition." PLOS Pathogens 16, no. 3: e1008377.

Journal article
Published: 15 September 2019 in Journal of Virology
Reads 0
Downloads 0

The development of chimeric SHIVs has been instrumental in advancing our understanding of HIV-host interactions and allowing for in vivo testing of novel treatments. However, many of the currently available SHIVs have distinct drawbacks and are unable to fully reflect the features characteristic of primary SIV and HIV strains. Here, we utilize rhesus macaques to define the immunopathogenesis of the recently developed SHIV.CH505, which was designed without many of the limitations of previous SHIVs. We observed that infection with SHIV.CH505 leads to peripheral viral kinetics and mucosal immunopathogenesis comparable with those caused by pathogenic SIV and HIV. Overall, these data provide evidence of the value of SHIV.CH505 as an effective model of SIV/HIV infection and an important tool that can be used in future studies, including preclinical testing of new therapies or prevention strategies.

ACS Style

Katharine J. Bar; Ernesto Coronado; Tiffany Hensley-McBain; Megan A. O’Connor; Jessica M. Osborn; Charlene Miller; Toni M. Gott; Solomon Wangari; Naoto Iwayama; Chul Y. Ahrens; Jeremy Smedley; Cassie Moats; Rebecca M. Lynch; Elias K. Haddad; Nancy Haigwood; Deborah Fuller; George M. Shaw; Nichole R. Klatt; Jennifer A. Manuzak. Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology. Journal of Virology 2019, 93, 1 .

AMA Style

Katharine J. Bar, Ernesto Coronado, Tiffany Hensley-McBain, Megan A. O’Connor, Jessica M. Osborn, Charlene Miller, Toni M. Gott, Solomon Wangari, Naoto Iwayama, Chul Y. Ahrens, Jeremy Smedley, Cassie Moats, Rebecca M. Lynch, Elias K. Haddad, Nancy Haigwood, Deborah Fuller, George M. Shaw, Nichole R. Klatt, Jennifer A. Manuzak. Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology. Journal of Virology. 2019; 93 (18):1.

Chicago/Turabian Style

Katharine J. Bar; Ernesto Coronado; Tiffany Hensley-McBain; Megan A. O’Connor; Jessica M. Osborn; Charlene Miller; Toni M. Gott; Solomon Wangari; Naoto Iwayama; Chul Y. Ahrens; Jeremy Smedley; Cassie Moats; Rebecca M. Lynch; Elias K. Haddad; Nancy Haigwood; Deborah Fuller; George M. Shaw; Nichole R. Klatt; Jennifer A. Manuzak. 2019. "Simian-Human Immunodeficiency Virus SHIV.CH505 Infection of Rhesus Macaques Results in Persistent Viral Replication and Induces Intestinal Immunopathology." Journal of Virology 93, no. 18: 1.

Journal article
Published: 01 July 2019 in Cell Reports
Reads 0
Downloads 0

Summary The V1V2 region of the HIV-1 envelope is the target of several broadly neutralizing antibodies (bNAbs). Antibodies to V1V2 elicited in the RV144 clinical trial correlated with a reduced risk of HIV infection, but these antibodies were without broad neutralizing activity. Antibodies targeting V1V2 also correlated with a reduced viral load in immunized macaques challenged with simian immunodeficiency virus (SIV) or simian/human immunodeficiency virus (SHIV). To focus immune responses on V1V2, we engrafted the native, glycosylated V1V2 domain onto five different multimeric scaffold proteins and conducted comparative immunogenicity studies in macaques. Vaccinated macaques developed high titers of plasma and mucosal antibodies that targeted structurally distinct V1V2 epitopes. Plasma antibodies displayed limited neutralizing activity but were functionally active for ADCC and phagocytosis, which was detectable 1–2 years after immunizations ended. This study demonstrates that multivalent, glycosylated V1V2-scaffold protein immunogens focus the antibody response on V1V2 and are differentially effective at inducing polyfunctional antibodies with characteristics associated with protection.

ACS Style

Ann J. Hessell; Rebecca Powell; Xunqing Jiang; Christina Luo; Svenja Weiss; Vincent Dussupt; Vincenza Itri; Alisa Fox; Mariya Shapiro; Shilpi Pandey; Tracy Cheever; Deborah Fuller; Byung Park; Shelly Krebs; Maxim Totrov; Nancy L. Haigwood; Xiang-Peng Kong; Susan Zolla-Pazner. Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses. Cell Reports 2019, 28, 877 -895.e6.

AMA Style

Ann J. Hessell, Rebecca Powell, Xunqing Jiang, Christina Luo, Svenja Weiss, Vincent Dussupt, Vincenza Itri, Alisa Fox, Mariya Shapiro, Shilpi Pandey, Tracy Cheever, Deborah Fuller, Byung Park, Shelly Krebs, Maxim Totrov, Nancy L. Haigwood, Xiang-Peng Kong, Susan Zolla-Pazner. Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses. Cell Reports. 2019; 28 (4):877-895.e6.

Chicago/Turabian Style

Ann J. Hessell; Rebecca Powell; Xunqing Jiang; Christina Luo; Svenja Weiss; Vincent Dussupt; Vincenza Itri; Alisa Fox; Mariya Shapiro; Shilpi Pandey; Tracy Cheever; Deborah Fuller; Byung Park; Shelly Krebs; Maxim Totrov; Nancy L. Haigwood; Xiang-Peng Kong; Susan Zolla-Pazner. 2019. "Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses." Cell Reports 28, no. 4: 877-895.e6.

Journal article
Published: 01 March 2019 in AIDS Research and Human Retroviruses
Reads 0
Downloads 0

Depletion of gut T helper 17 (Th17) cells during HIV infection leads to decreased mucosal integrity and increased disease progression. Conversely T regulatory (Treg) cells may inhibit antiviral responses or immune activation. In HIV elite controllers, a balanced Th17/Treg ratio is maintained in the blood, suggesting a role for these responses in controlling inflammation and viral replication. HIV-infected individuals exhibit a range in responsiveness to combination antiretroviral therapy (cART). Given the link between the Th17/Treg ratio and HIV disease, we reasoned these responses may play a role in cART responsiveness. Here, we investigated the relationship between the mucosal Th17/Treg ratio to acute SIV viremia and the response to cART. Nineteen rhesus macaques were infected with highly pathogenic SIVΔB670 virus and cART was initiated 6 weeks post-infection. Mucosal CD4 T-cell subsets were assessed by intracellular cytokine staining (ICS) in the colon and mesenteric lymph nodes. Higher baseline Th17/Treg ratios corresponded with increased acute SIV viremia. Th17/Treg ratios decreased during acute SIV infection and were not restored during cART, and this corresponded to increased gut immune activation (Ki67+), markers of microbial translocation (sCD14), and T-cell exhaustion (TIGIT+). Animals that maintained a more balanced mucosal Th17/Treg ratio at the time of cART initiation exhibited a better virological response to cART and maintained higher peripheral CD4 counts. These results suggest mucosal Th17 and Treg homeostasis influences acute viremia and the response to cART, a result that suggests therapeutic interventions that improve the Th17/Treg ratio before or during cART may improve treatment of HIV.

ACS Style

Megan A. O'connor; Paul V. Munson; Hillary C. Tunggal; Nika Hajari; Thomas B. Lewis; Debra Bratt; Cassie Moats; Jeremy Smedley; Kenneth C. Bagley; James I. Mullins; Deborah H. Fuller. Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques. AIDS Research and Human Retroviruses 2019, 35, 295 -305.

AMA Style

Megan A. O'connor, Paul V. Munson, Hillary C. Tunggal, Nika Hajari, Thomas B. Lewis, Debra Bratt, Cassie Moats, Jeremy Smedley, Kenneth C. Bagley, James I. Mullins, Deborah H. Fuller. Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques. AIDS Research and Human Retroviruses. 2019; 35 (3):295-305.

Chicago/Turabian Style

Megan A. O'connor; Paul V. Munson; Hillary C. Tunggal; Nika Hajari; Thomas B. Lewis; Debra Bratt; Cassie Moats; Jeremy Smedley; Kenneth C. Bagley; James I. Mullins; Deborah H. Fuller. 2019. "Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques." AIDS Research and Human Retroviruses 35, no. 3: 295-305.

Correction
Published: 01 November 2018 in PLOS ONE
Reads 0
Downloads 0

[This corrects the article DOI: 10.1371/journal.pone.0198154.].

ACS Style

Arlene I. Ramsingh; Steven J. Gray; Andrew Reilly; Michael Koday; Debbie Bratt; Merika Treants Koday; Paul Munson; Robert Murnane; Jeremy Smedley; Yuhui Hu; Anne Messer; Deborah Heydenburg Fuller. Correction: Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLOS ONE 2018, 13, e0207077 .

AMA Style

Arlene I. Ramsingh, Steven J. Gray, Andrew Reilly, Michael Koday, Debbie Bratt, Merika Treants Koday, Paul Munson, Robert Murnane, Jeremy Smedley, Yuhui Hu, Anne Messer, Deborah Heydenburg Fuller. Correction: Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLOS ONE. 2018; 13 (11):e0207077.

Chicago/Turabian Style

Arlene I. Ramsingh; Steven J. Gray; Andrew Reilly; Michael Koday; Debbie Bratt; Merika Treants Koday; Paul Munson; Robert Murnane; Jeremy Smedley; Yuhui Hu; Anne Messer; Deborah Heydenburg Fuller. 2018. "Correction: Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation." PLOS ONE 13, no. 11: e0207077.

Journal article
Published: 22 August 2018 in Nature Communications
Reads 0
Downloads 0

The immunological and virological events that contribute to the establishment of Zika virus (ZIKV) infection in humans are unclear. Here, we show that robust cellular innate immune responses arising early in the blood and tissues in response to ZIKV infection are significantly stronger in males and correlate with increased viral persistence. In particular, early peripheral blood recruitment of plasmacytoid dendritic cells and higher production of monocyte chemoattractant protein (MCP-1) correspond with greater viral persistence and tissue dissemination. We also identify non-classical monocytes as primary in vivo targets of ZIKV infection in the blood and peripheral lymph node. These results demonstrate the potential differences in ZIKV pathogenesis between males and females and a key role for early cellular innate immune responses in the blood in viral dissemination and ZIKV pathogenesis. The immune response to Zika virus is required to curtail the infection and avoid immunopathology, but may be involved in the associated pathophysiology. Here the authors show that viral persistence and tissue tropism is shaped by an early innate immune response in a pigtail macaque model of infection.

ACS Style

Megan A. O’Connor; Jennifer Tisoncik-Go; Thomas B. Lewis; Charlene J. Miller; Debra Bratt; Cassie R. Moats; Paul T. Edlefsen; Jeremy Smedley; Nichole R. Klatt; Michael Gale; Deborah Heydenburg Fuller. Early cellular innate immune responses drive Zika viral persistence and tissue tropism in pigtail macaques. Nature Communications 2018, 9, 1 -11.

AMA Style

Megan A. O’Connor, Jennifer Tisoncik-Go, Thomas B. Lewis, Charlene J. Miller, Debra Bratt, Cassie R. Moats, Paul T. Edlefsen, Jeremy Smedley, Nichole R. Klatt, Michael Gale, Deborah Heydenburg Fuller. Early cellular innate immune responses drive Zika viral persistence and tissue tropism in pigtail macaques. Nature Communications. 2018; 9 (1):1-11.

Chicago/Turabian Style

Megan A. O’Connor; Jennifer Tisoncik-Go; Thomas B. Lewis; Charlene J. Miller; Debra Bratt; Cassie R. Moats; Paul T. Edlefsen; Jeremy Smedley; Nichole R. Klatt; Michael Gale; Deborah Heydenburg Fuller. 2018. "Early cellular innate immune responses drive Zika viral persistence and tissue tropism in pigtail macaques." Nature Communications 9, no. 1: 1-11.

Research article
Published: 06 June 2018 in PLOS ONE
Reads 0
Downloads 0

A critical issue in transgene delivery studies is immune reactivity to the transgene- encoded protein and its impact on sustained gene expression. Here, we test the hypothesis that immunomodulation by rapamycin can decrease immune reactivity after intrathecal AAV9 delivery of a transgene (GFP) in non-human primates, resulting in sustained GFP expression in the CNS. We show that rapamycin treatment clearly reduced the overall immunogenicity of the AAV9/GFP vector by lowering GFP- and AAV9-specific antibody responses, and decreasing T cell responses including cytokine and cytolytic effector responses. Spinal cord GFP protein expression was sustained for twelve weeks, with no toxicity. Immune correlates of robust transgene expression include negligible GFP-specific CD4 and CD8 T cell responses, absence of GFP-specific IFN-γ producing T cells, and absence of GFP-specific cytotoxic T cells, which support the hypothesis that decreased T cell reactivity results in sustained transgene expression. These data strongly support the use of modest doses of rapamycin to modulate immune responses for intrathecal gene therapies, and potentially a much wider range of viral vector-based therapeutics.

ACS Style

Arlene I. Ramsingh; Steven J. Gray; Andrew Reilly; Michael Koday; Debbie Bratt; Merika Treants Koday; Robert Murnane; Jeremy Smedley; Yuhui Hu; Anne Messer; Deborah Heydenburg Fuller. Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLOS ONE 2018, 13, e0198154 .

AMA Style

Arlene I. Ramsingh, Steven J. Gray, Andrew Reilly, Michael Koday, Debbie Bratt, Merika Treants Koday, Robert Murnane, Jeremy Smedley, Yuhui Hu, Anne Messer, Deborah Heydenburg Fuller. Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation. PLOS ONE. 2018; 13 (6):e0198154.

Chicago/Turabian Style

Arlene I. Ramsingh; Steven J. Gray; Andrew Reilly; Michael Koday; Debbie Bratt; Merika Treants Koday; Robert Murnane; Jeremy Smedley; Yuhui Hu; Anne Messer; Deborah Heydenburg Fuller. 2018. "Sustained AAV9-mediated expression of a non-self protein in the CNS of non-human primates after immunomodulation." PLOS ONE 13, no. 6: e0198154.

Research paper
Published: 12 April 2018 in Human Vaccines & Immunotherapeutics
Reads 0
Downloads 0

HIV-specific T-cell responses play a key role in controlling HIV infection, and therapeutic vaccines for HIV that aim to improve viral control will likely need to improve on the T-cell responses induced by infection. However, in the setting of chronic infection, an effective therapeutic vaccine must overcome the enormous viral genetic diversity and the presence of pre-existing T-cell responses that are biased toward immunodominant T-cell epitopes that can readily mutate to evade host immunity and thus potentially provide inferior protection. To address these issues, we investigated a novel, epidermally administered DNA vaccine expressing SIV capsid (p27Gag) homologues of highly conserved elements (CE) of the HIV proteome in macaques experiencing chronic but controlled SHIV infection. We assessed the ability to boost or induce de novo T-cell responses against the conserved but immunologically subdominant CE epitopes. Two groups of animals were immunized with either the CE DNA vaccine or a full-length SIV p57gag DNA vaccine. Prior to vaccination, CE responses were similar in both groups. The full-length p57gag DNA vaccine, which contains the CE, increased overall Gag-specific responses but did not increase CE responses in any animals (0/4). In contrast, the CE DNA vaccine increased CE responses in all (4/4) vaccinated macaques. In SIV infected but unvaccinated macaques, those that developed stronger CE-specific responses during acute infection exhibited lower viral loads. We conclude that CE DNA vaccination can re-direct the immunodominance hierarchy towards CE in the setting of attenuated chronic infection and that induction of these responses by therapeutic vaccination may improve immune control of HIV.

ACS Style

Paul Munson; Yi Liu; Debra Bratt; James T. Fuller; Xintao Hu; George N. Pavlakis; Barbara K. Felber; James I. Mullins; Deborah Fuller. Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during simian-human immunodeficiency virus infection. Human Vaccines & Immunotherapeutics 2018, 14, 1820 -1831.

AMA Style

Paul Munson, Yi Liu, Debra Bratt, James T. Fuller, Xintao Hu, George N. Pavlakis, Barbara K. Felber, James I. Mullins, Deborah Fuller. Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during simian-human immunodeficiency virus infection. Human Vaccines & Immunotherapeutics. 2018; 14 (7):1820-1831.

Chicago/Turabian Style

Paul Munson; Yi Liu; Debra Bratt; James T. Fuller; Xintao Hu; George N. Pavlakis; Barbara K. Felber; James I. Mullins; Deborah Fuller. 2018. "Therapeutic conserved elements (CE) DNA vaccine induces strong T-cell responses against highly conserved viral sequences during simian-human immunodeficiency virus infection." Human Vaccines & Immunotherapeutics 14, no. 7: 1820-1831.

Published erratum
Published: 02 January 2018 in PLoS ONE
Reads 0
Downloads 0
ACS Style

Jeremy Smedley; Rhonda MacAlister; Solomon Wangari; Mercy Gathuka; Joel Ahrens; Naoto Iwayama; Drew May; Debbie Bratt; Megan O’Connor; Paul Munson; Michael Koday; Deborah Heydenburg Fuller; Lifson. Correction: Laparoscopic Technique for Serial Collection of Para-Colonic, Left Colic, and Inferior Mesenteric Lymph Nodes in Macaques. PLoS ONE 2018, 13, e0190764 .

AMA Style

Jeremy Smedley, Rhonda MacAlister, Solomon Wangari, Mercy Gathuka, Joel Ahrens, Naoto Iwayama, Drew May, Debbie Bratt, Megan O’Connor, Paul Munson, Michael Koday, Deborah Heydenburg Fuller, Lifson. Correction: Laparoscopic Technique for Serial Collection of Para-Colonic, Left Colic, and Inferior Mesenteric Lymph Nodes in Macaques. PLoS ONE. 2018; 13 (1):e0190764.

Chicago/Turabian Style

Jeremy Smedley; Rhonda MacAlister; Solomon Wangari; Mercy Gathuka; Joel Ahrens; Naoto Iwayama; Drew May; Debbie Bratt; Megan O’Connor; Paul Munson; Michael Koday; Deborah Heydenburg Fuller; Lifson. 2018. "Correction: Laparoscopic Technique for Serial Collection of Para-Colonic, Left Colic, and Inferior Mesenteric Lymph Nodes in Macaques." PLoS ONE 13, no. 1: e0190764.

Research article
Published: 21 December 2017 in PLOS ONE
Reads 0
Downloads 0

Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemics. We investigated immunogenicity and protective efficacy of a multi-antigen (MA) universal influenza DNA vaccine consisting of HA, M2, and NP antigens in cynomolgus macaques. Following challenge with a heterologous pandemic H1N1 strain, vaccinated animals exhibited significantly lower viral loads and more rapid viral clearance when compared to unvaccinated controls. The MA DNA vaccine induced robust serum and mucosal antibody responses but these high antibody titers were not broadly neutralizing. In contrast, the vaccine induced broadly-reactive NP specific T cell responses that cross-reacted with the challenge virus and inversely correlated with lower viral loads and inflammation. These results demonstrate that a MA DNA vaccine that induces strong cross-reactive T cell responses can, independent of neutralizing antibody, mediate significant cross-protection in a nonhuman primate model and further supports development as an effective approach to induce broad protection against circulating and emerging influenza strains.

ACS Style

Merika T. Koday; Jolie A. Leonard; Paul Munson; Adriana Forero; Michael Koday; Debra L. Bratt; James T. Fuller; Robert Murnane; Shulin Qin; Todd A. Reinhart; Karen Duus; Ilhem Messaoudi; Amy L. Hartman; Kelly Stefano-Cole; Juliet Morrison; Michael G. Katze; Deborah Heydenburg Fuller. Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates. PLOS ONE 2017, 12, e0189780 .

AMA Style

Merika T. Koday, Jolie A. Leonard, Paul Munson, Adriana Forero, Michael Koday, Debra L. Bratt, James T. Fuller, Robert Murnane, Shulin Qin, Todd A. Reinhart, Karen Duus, Ilhem Messaoudi, Amy L. Hartman, Kelly Stefano-Cole, Juliet Morrison, Michael G. Katze, Deborah Heydenburg Fuller. Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates. PLOS ONE. 2017; 12 (12):e0189780.

Chicago/Turabian Style

Merika T. Koday; Jolie A. Leonard; Paul Munson; Adriana Forero; Michael Koday; Debra L. Bratt; James T. Fuller; Robert Murnane; Shulin Qin; Todd A. Reinhart; Karen Duus; Ilhem Messaoudi; Amy L. Hartman; Kelly Stefano-Cole; Juliet Morrison; Michael G. Katze; Deborah Heydenburg Fuller. 2017. "Multigenic DNA vaccine induces protective cross-reactive T cell responses against heterologous influenza virus in nonhuman primates." PLOS ONE 12, no. 12: e0189780.