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:

Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses.

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)<sup>1-4</sup>. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID<sub>50</sub>) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.
Authors
Saunders, KO; Lee, E; Parks, R; Martinez, DR; Li, D; Chen, H; Edwards, RJ; Gobeil, S; Barr, M; Mansouri, K; Alam, SM; Sutherland, LL; Cai, F; Sanzone, AM; Berry, M; Manne, K; Bock, KW; Minai, M; Nagata, BM; Kapingidza, AB; Azoitei, M; Tse, LV; Scobey, TD; Spreng, RL; Rountree, RW; DeMarco, CT; Denny, TN; Woods, CW; Petzold, EW; Tang, J; Oguin, TH; Sempowski, GD; Gagne, M; Douek, DC; Tomai, MA; Fox, CB; Seder, R; Wiehe, K; Weissman, D; Pardi, N; Golding, H; Khurana, S; Acharya, P; Andersen, H; Lewis, MG; Moore, IN; Montefiori, DC; Baric, RS; Haynes, BF
MLA Citation
Saunders, Kevin O., et al. “Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses.Nature, vol. 594, no. 7864, June 2021, pp. 553–59. Epmc, doi:10.1038/s41586-021-03594-0.
URI
https://scholars.duke.edu/individual/pub1481809
PMID
33971664
Source
epmc
Published In
Nature
Volume
594
Published Date
Start Page
553
End Page
559
DOI
10.1038/s41586-021-03594-0

Structural and genetic convergence of HIV-1 neutralizing antibodies in vaccinated non-human primates.

A primary goal of HIV-1 vaccine development is the consistent elicitation of protective, neutralizing antibodies. While highly similar neutralizing antibodies (nAbs) have been isolated from multiple HIV-infected individuals, it is unclear whether vaccination can consistently elicit highly similar nAbs in genetically diverse primates. Here, we show in three outbred rhesus macaques that immunization with Env elicits a genotypically and phenotypically conserved nAb response. From these vaccinated macaques, we isolated four antibody lineages that had commonalities in immunoglobulin variable, diversity, and joining gene segment usage. Atomic-level structures of the antigen binding fragments of the two most similar antibodies showed nearly identical paratopes. The Env binding modes of each of the four vaccine-induced nAbs were distinct from previously known monoclonal HIV-1 neutralizing antibodies, but were nearly identical to each other. The similarities of these antibodies show that the immune system in outbred primates can respond to HIV-1 Env vaccination with a similar structural and genotypic solution for recognizing a particular neutralizing epitope. These results support rational vaccine design for HIV-1 that aims to reproducibly elicit, in genetically diverse primates, nAbs with specific paratope structures capable of binding conserved epitopes.
Authors
Cai, F; Chen, W-H; Wu, W; Jones, JA; Choe, M; Gohain, N; Shen, X; LaBranche, C; Eaton, A; Sutherland, L; Lee, EM; Hernandez, GE; Wu, NR; Scearce, R; Seaman, MS; Moody, MA; Santra, S; Wiehe, K; Tomaras, GD; Wagh, K; Korber, B; Bonsignori, M; Montefiori, DC; Haynes, BF; de Val, N; Joyce, MG; Saunders, KO
MLA Citation
Cai, Fangping, et al. “Structural and genetic convergence of HIV-1 neutralizing antibodies in vaccinated non-human primates.Plos Pathog, vol. 17, no. 6, June 2021, p. e1009624. Pubmed, doi:10.1371/journal.ppat.1009624.
URI
https://scholars.duke.edu/individual/pub1484408
PMID
34086838
Source
pubmed
Published In
Plos Pathog
Volume
17
Published Date
Start Page
e1009624
DOI
10.1371/journal.ppat.1009624

Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.

Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
Authors
Williams, WB; Meyerhoff, RR; Edwards, RJ; Li, H; Manne, K; Nicely, NI; Henderson, R; Zhou, Y; Janowska, K; Mansouri, K; Gobeil, S; Evangelous, T; Hora, B; Berry, M; Abuahmad, AY; Sprenz, J; Deyton, M; Stalls, V; Kopp, M; Hsu, AL; Borgnia, MJ; Stewart-Jones, GBE; Lee, MS; Bronkema, N; Moody, MA; Wiehe, K; Bradley, T; Alam, SM; Parks, RJ; Foulger, A; Oguin, T; Sempowski, GD; Bonsignori, M; LaBranche, CC; Montefiori, DC; Seaman, M; Santra, S; Perfect, J; Francica, JR; Lynn, GM; Aussedat, B; Walkowicz, WE; Laga, R; Kelsoe, G; Saunders, KO; Fera, D; Kwong, PD; Seder, RA; Bartesaghi, A; Shaw, GM; Acharya, P; Haynes, BF
MLA Citation
Williams, Wilton B., et al. “Fab-dimerized glycan-reactive antibodies are a structural category of natural antibodies.Cell, vol. 184, no. 11, May 2021, pp. 2955-2972.e25. Pubmed, doi:10.1016/j.cell.2021.04.042.
URI
https://scholars.duke.edu/individual/pub1482887
PMID
34019795
Source
pubmed
Published In
Cell
Volume
184
Published Date
Start Page
2955
End Page
2972.e25
DOI
10.1016/j.cell.2021.04.042

Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells.

Understanding and eliciting protective immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an urgent priority. To facilitate these objectives, we profile the repertoire of human leukocyte antigen class II (HLA-II)-bound peptides presented by HLA-DR diverse monocyte-derived dendritic cells pulsed with SARS-CoV-2 spike (S) protein. We identify 209 unique HLA-II-bound peptide sequences, many forming nested sets, which map to sites throughout S including glycosylated regions. Comparison of the glycosylation profile of the S protein to that of the HLA-II-bound S peptides reveals substantial trimming of glycan residues on the latter, likely induced during antigen processing. Our data also highlight the receptor-binding motif in S1 as a HLA-DR-binding peptide-rich region and identify S2-derived peptides with potential for targeting by cross-protective vaccine-elicited responses. Results from this study will aid analysis of CD4<sup>+</sup> T cell responses in infected individuals and vaccine recipients and have application in next-generation vaccine design.
Authors
Parker, R; Partridge, T; Wormald, C; Kawahara, R; Stalls, V; Aggelakopoulou, M; Parker, J; Powell Doherty, R; Ariosa Morejon, Y; Lee, E; Saunders, K; Haynes, BF; Acharya, P; Thaysen-Andersen, M; Borrow, P; Ternette, N
MLA Citation
Parker, Robert, et al. “Mapping the SARS-CoV-2 spike glycoprotein-derived peptidome presented by HLA class II on dendritic cells.Cell Reports, vol. 35, no. 8, May 2021, p. 109179. Epmc, doi:10.1016/j.celrep.2021.109179.
URI
https://scholars.duke.edu/individual/pub1483086
PMID
34004174
Source
epmc
Published In
Cell Reports
Volume
35
Published Date
Start Page
109179
DOI
10.1016/j.celrep.2021.109179

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