Humoral immunity is an essential component to clear infections and robust, long-lasting B cell-mediated memory is a correlate of protection for many vaccines. However, numerous factors related to both host and pathogen can influence the quality of humoral memory upon infection and vaccination. Studying the origin, maturation and evolutionary barriers of functionally active B cell clones provides valuable information on the natural history of effective and abherrant B cell reponses and a platform for the rational selection of immunogen designs.

The mission of the Translational Immunobiology Unit is to extend the basic understanding of B cell selection, clonal expansion and maturation into memory responses; to gather information from the natural evolution of B cell responses to inform effective immunogen designs, and to identify prophylactic and therapeutic antibody-based countermeasures. Studies will encompass primarily human and non-human primate specimens, as well as murine models, and will use multiple virus models, including HIV, flaviviruses, influenza virus, herpesviruses and betacoronaviruses.

Dr. Bonsignori received his M.D. and M.S. in clinical microbiology and virology from the University of Insubria Medical School in Varese, Italy. He conducted postdoctoral research in the Department of Immunology at St. Jude Children’s Research Hospital in Memphis, Tennessee before being appointed research associate at the Duke Human Vaccine Institute, Duke University School of Medicine in Durham, North Carolina, where his activity focused primarily on HIV vaccine development. In 2009, he established the Laboratory of B-cell Repertoire Analysis and ultimately attained the position of associate professor of medicine. In the HIV field, Dr. Bonsignori isolated multiple broadly neutralizing antibody B cell lineages from chronically HIV-1 infected individuals and characterized antibody/virus co-evolution to rationally select immunogen candidates for sequential vaccination schemes. Dr. Bonsignori developed a high-throughput memory B cell culture system for the functional screening of memory B cells at the single-cell level and conceptualized a novel framework for steering the immune response through immunogen design based on the probability of individual mutations and their effect on antibody effector functions. He later applied some of the technologies and workflows to study B cell responses to P. falciparum and Zika virus. Before NIAID, Dr. Bonsignori supported the Duke University student COVID-19 surveillance program by establishing a high-throughput workflow for the rapid accessioning, pooling and storage of nasal swab samples that sustained the screening of up to 20,000 samples per week.  Dr. Bonsignori joined the Laboratory of Infectious Diseases in March 2021.

SM, Zhang R, Montefiori DC, Henderson R, Nie X, Kelsoe G, Moody MA, Chen X, Joyce MG, Kwong PD, Connors M, Mascola JR, McGuire AT, Stamatatos L, Medina-Ramírez M, Sanders RW, Saunders KO, Kepler TB, Haynes BF. Inference of the HIV-1 VRC01 Antibody Lineage Unmutated Common Ancestor Reveals Alternative Pathways to Overcome a Key Glycan Barrier. Immunity. 2018 Dec;49(6):1162-1174.e8.

Bonsignori M, Kreider EF, Fera D, Meyerhoff RR, Bradley T, Wiehe K, Alam SM, Aussedat B, Walkowicz WE, Hwang KK, Saunders KO, Zhang R, Gladden MA, Monroe A, Kumar A, Xia SM, Cooper M, Louder MK, McKee K, Bailer RT, Pier BW, Jette CA, Kelsoe G, Williams WB, Morris L, Kappes J, Wagh K, Kamanga G, Cohen MS, Hraber PT, Montefiori DC, Trama A, Liao HX, Kepler TB, Moody MA, Gao F, Danishefsky SJ, Mascola JR, Shaw GM, Hahn BH, Harrison SC, Korber BT, Haynes BF. Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies. Sci Transl Med. 2017 Mar;9(381):eaai7514.

Bonsignori M, Zhou T, Sheng Z, Chen L, Gao F, Joyce MG, Ozorowski G, Chuang GY, Schramm CA, Wiehe K, Alam SM, Bradley T, Gladden MA, Hwang KK, Iyengar S, Kumar A, Lu X, Luo K, Mangiapani MC, Parks RJ, Song H, Acharya P, Bailer RT, Cao A, Druz A, Georgiev IS, Kwon YD, Louder MK, Zhang B, Zheng A, Hill BJ, Kong R, Soto C; NISC Comparative Sequencing Program, Mullikin JC, Douek DC, Montefiori DC, Moody MA, Shaw GM, Hahn BH, Kelsoe G, Hraber PT, Korber BT, Boyd SD, Fire AZ, Kepler TB, Shapiro L, Ward AB, Mascola JR, Liao HX, Kwong PD, Haynes BF. Maturation Pathway from Germline to Broad HIV-1 Neutralizer of a CD4-Mimic Antibody. Cell. 2016 Apr;165(2):449-63.

Gao F, Bonsignori M, Liao HX, Kumar A, Xia SM, Lu X, Cai F, Hwang KK, Song H, Zhou T, Lynch RM, Alam SM, Moody MA, Ferrari G, Berrong M, Kelsoe G, Shaw GM, Hahn BH, Montefiori DC, Kamanga G, Cohen MS, Hraber P, Kwong PD, Korber BT, Mascola JR, Kepler TB, Haynes BF. Cooperation of B cell lineages in induction of HIV-1-broadly neutralizing antibodies. Cell. 2014 Jul;158(3):481-91.

Bonsignori M, Wiehe K, Grimm SK, Lynch R, Yang G, Kozink DM, Perrin F, Cooper AJ, Hwang KK, Chen X, Liu M, McKee K, Parks RJ, Eudailey J, Wang M, Clowse M, Criscione-Schreiber LG, Moody MA, Ackerman ME, Boyd SD, Gao F, Kelsoe G, Verkoczy L, Tomaras GD, Liao HX, Kepler TB, Montefiori DC, Mascola JR, Haynes BF. An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1. J Clin Invest. 2014 Apr;124(4):1835-43.

Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, Marshall DJ, Crump JA, Kapiga SH, Sam NE, Sinangil F, Pancera M, Yongping Y, Zhang B, Zhu J, Kwong PD, O'Dell S, Mascola JR, Wu L, Nabel GJ, Phogat S, Seaman MS, Whitesides JF, Moody MA, Kelsoe G, Yang X, Sodroski J, Shaw GM, Montefiori DC, Kepler TB, Tomaras GD, Alam SM, Liao HX, Haynes BF. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol. 2011 Oct;85(19):9998-10009.

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We study the molecular virology, pathogenesis, and immune response of human respiratory pathogens, including RSV, HPIV serotypes 1, 2, and 3, and HMPV. These are enveloped, cytoplasmic viruses with single-stranded negative-sense RNA genomes of 13-19 kb. The laboratory investigates basic features of viral molecular biology, pathogenesis, and immunobiology of these viruses that provide an intellectual foundation for translational vaccine studies.

The pneumovirus RSV is a leading worldwide agent of respiratory tract disease, especially in young infants. The laboratory also studies several other major pediatric respiratory pathogens, namely HPIV1, 2, and 3 and HMPV. Other areas of interest include other pathogens of the paramyxoviridae and pneumoviridae families. The laboratory is using reverse genetics to design live, attenuated vaccines for RSV, HPIV3, and HMPV for intranasal administration to infants as pediatric vaccines. In studies supported in part by collaboration with industry, lead candidates for RSV and HPIV3 are in Phase I, and in some cases Phase II, clinical trials. The laboratory also is using paramyxoviruses and pneumoviruses as vaccine vectors to express protective antigens of emerging pathogens. In 2020, we expanded our program to include the development of vector vaccine candidates against SARS-CoV-2.

Dr. Buchholz received her Ph.D. in 1994 from the Free University of Berlin, Germany. She conducted postdoctoral studies at the Federal Research Center of Virus Diseases of Animals in Tuebingen, Germany, and became a tenured scientist at the Federal Research Center in 2000. In 2002, she joined Dr. Peter L. Collins’ section in the Laboratory of Infectious Diseases, and she became the Chief of the RNA Viruses Section in 2020.

Memberships

• American Society for Virology
• American Society for Microbiology
• International RSV Society
• Pneumoviridae study group, International Committee on Taxonomy of Viruses

Laura Ahlers, Sharmin Afroz, Sonja Barbagallo, Bibha Dahal, Jaclyn Kaiser, Cyril Le Nouen, Xueqiao Liu, Cindy Luongo, Thomas McCarty, Shirin Munir, Hongsu Park, Celia Santos, Lijuan Yang, Jessica Chen, Megan Levy, Jana Liese

Karron RA, Luongo C, Mateo JS, Wanionek K, Collins PL, Buchholz UJ. Safety and Immunogenicity of the Respiratory Syncytial Virus Vaccine RSV/DeltaNS2/Delta1313/I1314L in RSV-Seronegative Children. J Infect Dis. 2020 Jun;222(1):82-91.

McFarland EJ, Karron RA, Muresan P, Cunningham CK, Libous J, Perlowski C, Thumar B, Gnanashanmugam D, Moye J, Schappell E, Barr E, Rexroad V, Fearn L, Spector SA, Aziz M, Cielo M, Beneri C, Wiznia A, Luongo C, Collins P, Buchholz UJ. Live Respiratory Syncytial Virus Attenuated by M2-2 Deletion and Stabilized Temperature Sensitivity Mutation 1030s Is a Promising Vaccine Candidate in Children. J Infect Dis. 2020 Feb;221(4):534-543.

Lingemann M, McCarty T, Liu X, Buchholz UJ, Surman S, Martin SE, Collins PL, Munir S. The alpha-1 subunit of the Na+,K+-ATPase (ATP1A1) is required for macropinocytic entry of respiratory syncytial virus (RSV) in human respiratory epithelial cells. PLoS Pathog. 2019 Aug;15(8):e1007963.

Le Nouën C, McCarty T, Brown M, Smith ML, Lleras R, Dolan MA, Mehedi M, Yang L, Luongo C, Liang B, Munir S, DiNapoli JM, Mueller S, Wimmer E, Collins PL, Buchholz UJ. Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure. Proc Natl Acad Sci USA. 2017 Jan;114(3):E386-E95.

Karron RA, Luongo C, Thumar B, Loehr KM, Englund JA, Collins PL, Buchholz UJ. A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children. Sci Transl Med. 2015 Nov;7(312):312ra175.

Le Nouën C, Hillyer P, Winter CC, McCarty T, Rabin RL, Collins PL, Buchholz UJ. Low CCR7-mediated migration of human monocyte derived dendritic cells in response to human respiratory syncytial virus and human metapneumovirus. PLoS Pathog. 2011 Jun;7(6):e1002105.

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Le Nouen C, Buchholz UJ, Collins PL, Mueller S, inventors; The United States of America as represented by the Secretary, Department of Health and Human Services and Codagenix, Inc., assignees. Vaccine candidates for human respiratory syncytial virus (RSV) having attenuated phenotypes. United States patent US 10,808,012. 20 Oct 2020.

Collins, PL, Luongo, C, Buchholz UJ, inventors; The United States of America as represented by the Secretary, Department of Health and Human Services, assignee. Recombinant Respiratory Syncytial Virus Strains with Mutations in the M2-2 ORF Providing a Range of Attenuation Phenotypes. United States Patent no. US 10,655,109. 19 May 2020.

Collins, PL, Liang, B, Munir, S, Schaap-Nutt, A, Buchholz UJ, Mackow, N, Kwong, P, Graham B, McLellan, J, inventors; The United States of America as represented by the Secretary, Department of Health and Human Services, assignee. Recombinant Bovine/Human Parainfluenza Virus 3 (B/HPIV3) Expressing a Chimeric RSV/BPIV3 F Protein and Uses Thereof. United States Patent no. US 10,654,898. 19 May 2020.

Collins, PL, Luongo, C, Buchholz UJ, Murphy, BR, inventors; The United States of America as represented by the Secretary, Department of Health and Human Services, assignee. Genetically stable live attenuated respiratory syncytial virus vaccine and its production. United States Patent no. US 10,307,476. 4 June 2019.

Buchholz U, Collins PL, Murphy BR, Whitehead SS, Krempl CD, inventors; The United States of America as represented by the Secretary, Department of Health and Human Services, assignee. Production of attenuated, human-bovine chimeric respiratory syncytial virus vaccines. United States patent US 7,842,798. 30 Nov 2010.

Krempl CD, Collins PL, Murphy BR, Buchholz U, Whitehead SS, inventors; The United States of America as represented by the Department of Health and Human Services, assignee. Respiratory syncytial virus vaccines expressing protective antigens from promotor-proximal genes. United States patent US 7,744,902. 29 Jun 2010.

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Malaria parasites have a complex life cycle that takes place in between the human host and the mosquito vector. The parasite undergoes severe developmental bottlenecks during sexual reproduction in the mosquito midgut and during sporozoite infection of the human, making these two stages of the life cycle excellent targets for the development of new anti-malarial strategies. The research goals in the Molecular Parasitology and Entomology Unit are to study the biology of the malaria parasite during these vulnerable developmental bottlenecks by characterizing essential vector-parasite and host-parasite interactions. The long-term goal is to identify new targets that could be exploited for malaria interventions including chemotherapy, vaccine development, and transgenic mosquitoes. Two specific areas of study include

• The role of vector and host factors for sporozoite infectivity
• Molecular mechanisms required for Plasmodium sexual reproduction in the mosquito

To achieve these goals, our laboratory uses a combination of molecular, cellular, and entomological technologies including single-cell transcriptomics, proteomics, parasite and mosquito transgenesis, RNA interference, intravital confocal microscopy, and malaria transmission assays.

Inquiries about predoctoral and postdoctoral training, as well as Ph.D. studentships in the NIH Graduate Partnership Program, are welcome.

Dr. Joel Vega-Rodriguez received his Ph.D. in molecular biology in 2008 at the Rio Piedras Campus of the University of Puerto Rico in San Juan. In 2009 he joined the laboratory of Dr. Marcelo Jacobs-Lorena at the Johns Hopkins Malaria Research Institute, where he did his postdoctoral training and later became a research associate. In 2018, Dr. Vega-Rodriguez became a Stadtman tenure-track investigator in the Laboratory of Malaria and Vector Research.

Thiago Luiz Alves E Silva

Tales Vicari Pascini

Godman CD, Siregar JE, Mollard V, Vega-Rodríguez J, Syafruddin D, Matsuoka H, Matsuzaki M, Toyama T, Sturm A, Cozijnsen A, Jacobs-Lorena M, Kita K, Marzuki S, McFadden GI. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes. Science. 2016 Apr 15;352(6283):349-53.

Vega-Rodríguez J, Pastrana-Mena R, Crespo-Lladó KN, Ortiz JG, Ferrer-Rodríguez I, Serrano AE. Implications of glutathione levels in the Plasmodium berghei response to chloroquine and artemisinin. PLoS One. 2015 May 26;10(5):e0128212.

Vega-Rodriguez J, Perez-Barreto D, Ruiz-Reyes A, Jacobs-Lorena M. Targeting molecular interactions essential for Plasmodium sexual reproduction. Cell Microbiol. 2015 Nov;17(11):1594-604.

Vega-Rodríguez J, Ghosh AK, Kanzok SM, Dinglasan RR, Wang S, Bongio NJ, Kalume DE, Miura K, Long CA, Pandey A, Jacobs-Lorena M. Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut. Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):E492-500.

Fang W, Vega-Rodríguez J, Ghosh AK, Jacobs-Lorena M, Kang A, St Leger RJ. 2011. Development of transgenic fungi that kill human malaria parasites in mosquitoes. Science. 2011 Feb 25;331(6020):1074-7.

Vega-Rodríguez J, Franke-Fayard B, Dinglasan RR, Janse CJ, Coppens I, Pastrana-Mena R, Waters AP, Rodríguez-Orengo J, Jacobs-Lorena M, Serrano AE. The glutathione biosynthetic pathway of Plasmodium is essential for mosquito transmission. PLoS Pathog. 2009 Feb;5(2):e1000302.

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