Barton Haynes

Overview:

The Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.

Mucosal Immune Responses in Acute HIV Infection

The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.

The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.

The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.

Immunogen Design

To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.

Mucosal Immune Responses in TB and Influenza

The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.

Positions:

Frederic M. Hanes Distinguished Professor of Medicine

Medicine, Duke Human Vaccine Institute
School of Medicine

Professor of Medicine

Medicine, Duke Human Vaccine Institute
School of Medicine

Director of the Human Vaccine Institute in the Department of Medicine

Medicine
School of Medicine

Professor of Immunology

Immunology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of the Duke Human Vaccine Institute

Duke Human Vaccine Institute
School of Medicine

Education:

M.D. 1973

Baylor University

Publications:

Author Correction: Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.

Authors
Saunders, KO; Pardi, N; Parks, R; Santra, S; Mu, Z; Sutherland, L; Scearce, R; Barr, M; Eaton, A; Hernandez, G; Goodman, D; Hogan, MJ; Tombacz, I; Gordon, DN; Rountree, RW; Wang, Y; Lewis, MG; Pierson, TC; Barbosa, C; Tam, Y; Matyas, GR; Rao, M; Beck, Z; Shen, X; Ferrari, G; Tomaras, GD; Montefiori, DC; Weissman, D; Haynes, BF
MLA Citation
Saunders, Kevin O., et al. “Author Correction: Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.Npj Vaccines, vol. 6, no. 1, Nov. 2021, p. 136. Pubmed, doi:10.1038/s41541-021-00397-2.
URI
https://scholars.duke.edu/individual/pub1500441
PMID
34743171
Source
pubmed
Published In
Npj Vaccines
Volume
6
Published Date
Start Page
136
DOI
10.1038/s41541-021-00397-2

Strategies for eliciting multiple lineages of broadly neutralizing antibodies to HIV by vaccination.

A prophylactic vaccine would be a powerful tool in the fight against HIV. Passive immunization of animals with broadly neutralizing antibodies (bnAbs) affords protection against viral challenge, and recent data from the Antibody Mediated Prevention clinical trials support the concept of bnAbs providing protection against HIV in humans, albeit only at broad and potent neutralizing antibody titers. Moreover, it is now clear that a successful vaccine will also need to induce bnAbs against multiple neutralizing epitopes on the HIV envelope (Env) glycoprotein. Here, we review recent clinical trials evaluating bnAb-based vaccines, and discuss key issues in the development of an HIV vaccine capable of targeting multiple Env neutralizing epitopes.
Authors
Mu, Z; Haynes, BF; Cain, DW
MLA Citation
Mu, Zekun, et al. “Strategies for eliciting multiple lineages of broadly neutralizing antibodies to HIV by vaccination.Curr Opin Virol, vol. 51, Nov. 2021, pp. 172–78. Pubmed, doi:10.1016/j.coviro.2021.09.015.
URI
https://scholars.duke.edu/individual/pub1500601
PMID
34742037
Source
pubmed
Published In
Curr Opin Virol
Volume
51
Published Date
Start Page
172
End Page
178
DOI
10.1016/j.coviro.2021.09.015

Structural basis of glycan276-dependent recognition by HIV-1 broadly neutralizing antibodies.

Recognition of N-linked glycan at residue N276 (glycan276) at the periphery of the CD4-binding site (CD4bs) on the HIV-envelope trimer is a formidable challenge for many CD4bs-directed antibodies. To understand how this glycan can be recognized, here we isolate two lineages of glycan276-dependent CD4bs antibodies. Antibody CH540-VRC40.01 (named for donor-lineage.clone) neutralizes 81% of a panel of 208 diverse strains, while antibody CH314-VRC33.01 neutralizes 45%. Cryo-electron microscopy (cryo-EM) structures of these two antibodies and 179NC75, a previously identified glycan276-dependent CD4bs antibody, in complex with HIV-envelope trimer reveal substantially different modes of glycan276 recognition. Despite these differences, binding of glycan276-dependent antibodies maintains a glycan276 conformation similar to that observed in the absence of glycan276-binding antibodies. By contrast, glycan276-independent CD4bs antibodies, such as VRC01, displace glycan276 upon binding. These results provide a foundation for understanding antibody recognition of glycan276 and suggest its presence may be crucial for priming immunogens seeking to initiate broad CD4bs recognition.
Authors
Cottrell, CA; Manne, K; Kong, R; Wang, S; Zhou, T; Chuang, G-Y; Edwards, RJ; Henderson, R; Janowska, K; Kopp, M; Lin, BC; Louder, MK; Olia, AS; Rawi, R; Shen, C-H; Taft, JD; Torres, JL; Wu, NR; Zhang, B; Doria-Rose, NA; Cohen, MS; Haynes, BF; Shapiro, L; Ward, AB; Acharya, P; Mascola, JR; Kwong, PD
MLA Citation
Cottrell, Christopher A., et al. “Structural basis of glycan276-dependent recognition by HIV-1 broadly neutralizing antibodies.Cell Rep, vol. 37, no. 5, Nov. 2021, p. 109922. Pubmed, doi:10.1016/j.celrep.2021.109922.
URI
https://scholars.duke.edu/individual/pub1500803
PMID
34731616
Source
pubmed
Published In
Cell Reports
Volume
37
Published Date
Start Page
109922
DOI
10.1016/j.celrep.2021.109922

The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.

Development of effective human immunodeficiency virus 1 (HIV-1) vaccines requires synergy between innate and adaptive immune cells. Here we show that induction of the transcription factor CREB1 and its target genes by the recombinant canarypox vector ALVAC + Alum augments immunogenicity in non-human primates (NHPs) and predicts reduced HIV-1 acquisition in the RV144 trial. These target genes include those encoding cytokines/chemokines associated with heightened protection from simian immunodeficiency virus challenge in NHPs. Expression of CREB1 target genes probably results from direct cGAMP (STING agonist)-modulated p-CREB1 activity that drives the recruitment of CD4+ T cells and B cells to the site of antigen presentation. Importantly, unlike NHPs immunized with ALVAC + Alum, those immunized with ALVAC + MF59, the regimen in the HVTN702 trial that showed no protection from HIV infection, exhibited significantly reduced CREB1 target gene expression. Our integrated systems biology approach has validated CREB1 as a critical driver of vaccine efficacy and highlights that adjuvants that trigger CREB1 signaling may be critical for efficacious HIV-1 vaccines.
Authors
Tomalka, JA; Pelletier, AN; Fourati, S; Latif, MB; Sharma, A; Furr, K; Carlson, K; Lifton, M; Gonzalez, A; Wilkinson, P; Franchini, G; Parks, R; Letvin, N; Yates, N; Seaton, K; Tomaras, G; Tartaglia, J; Robb, ML; Michael, NL; Koup, R; Haynes, B; Santra, S; Sekaly, RP
MLA Citation
Tomalka, Jeffrey Alan, et al. “The transcription factor CREB1 is a mechanistic driver of immunogenicity and reduced HIV-1 acquisition following ALVAC vaccination.Nat Immunol, vol. 22, no. 10, Oct. 2021, pp. 1294–305. Pubmed, doi:10.1038/s41590-021-01026-9.
URI
https://scholars.duke.edu/individual/pub1497341
PMID
34556879
Source
pubmed
Published In
Nat Immunol
Volume
22
Published Date
Start Page
1294
End Page
1305
DOI
10.1038/s41590-021-01026-9

SARS-CoV-2 and HIV-1 - a tale of two vaccines.

Authors
MLA Citation
Haynes, Barton F. “SARS-CoV-2 and HIV-1 - a tale of two vaccines.Nat Rev Immunol, vol. 21, no. 9, Sept. 2021, pp. 543–44. Pubmed, doi:10.1038/s41577-021-00589-w.
URI
https://scholars.duke.edu/individual/pub1488883
PMID
34272508
Source
pubmed
Published In
Nat Rev Immunol
Volume
21
Published Date
Start Page
543
End Page
544
DOI
10.1038/s41577-021-00589-w