NEW PUBLICATION - Effects of human anti-spike protein receptor binding domain antibodies on SARS coronavirus neutralization escape and fitness
The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 has resulted in severe human respiratory disease with high death rates. Their zoonotic origins highlight the likelihood of reemergence or further evolution into novel human coronavirus pathogens. Broadly neutralizing antibodies (nAbs) that prevent infection of related viruses represent an important immunostrategy for combating coronavirus infections; however, for this strategy to succeed, it is essential to uncover nAb-mediated escape pathways and to pioneer strategies that prevent escape. Here, we used SARS-CoV as a research model and examined the escape pathways of broad nAbs that target the receptor binding domain (RBD) of the virus. We found that neither single nAbs nor two nAbs in combination blocked escape. Our results suggest that targeting conserved regions with less plasticity and more structural constraint rather than the SARS-CoV RBD-like region(s) should have broader utility for antibody-based immunotherapy
Sui J, Deming M, Rockx B, Liddington RC, Zhu QK, Baric RS, Marasco WA. Effects of human anti-spike protein receptor binding domain antibodies on severe acute respiratory syndrome coronavirus neutralization escape and fitness. J Virol. 2014 Dec;88(23):13769-80. doi: 10.1128/JVI.02232-14. Epub 2014 Sep 17. PMID: 25231316
June 26, 2014
NEW PUBLICATION - Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer
Topical microbicides are a leading strategy for prevention of HIV mucosal infection to women; however, numerous pharmacokinetic limitations associated with coitally related dosing strategy have contributed to their limited success. Here we test the hypothesis that adeno-associated virus (AAV) mediated delivery of the b12 human anti-HIV-1 gp120 minibody gene to the lower genital tract of female rhesus macaques (Rh) can provide prolonged expression of b12 minibodies in the cervical-vaginal secretions. Gene transfer studies demonstrated that, of various green fluorescent protein (GFP)-expressing AAV serotypes, AAV-6 most efficiently transduced freshly immortalized and primary genital epithelial cells (PGECs) of female Rh in vitro. In addition, AAV-6-b12 minibody transduction of Rh PGECs led to inhibition of SHIV162p4 transmigration and virus infectivity in vitro. AAV-6-GFP could also successfully transduce vaginal epithelial cells of Rh when applied intravaginally, including p63+ epithelial stem cells. Moreover, intravaginal application of AAV-6-b12 to female Rh resulted in prolonged minibody detection in their vaginal secretions throughout the 79-day study period. These data provide proof of principle that AAV-6-mediated delivery of anti-HIV broadly neutralizing antibody (BnAb) genes to the lower genital tract of female Rh results in persistent minibody detection for several months. This strategy offers promise that an anti-HIV-1 genetic microbicide strategy may be possible in which topical application of AAV vector, with periodic reapplication as needed, may provide sustained local BnAb expression and protection.
Abdel-Motal UM, Harbison C, Han T, Pudney J, Anderson DJ, Zhu Q, Westmoreland S, Marasco WA. Prolonged expression of an anti-HIV-1 gp120 minibody to the female rhesus macaque lower genital tract by AAV gene transfer. Gene Therapy. June 26, 2014; doi: 10.1038/gt.2014.56. pdf.
May 27-29, 2014
Endemic and Emerging Viral Diseases of Priority MENA (Middle East North Africa) Workshop in Doha, Qatar
Dr. Marasco will be speaking at the MENA workshop at the Four Seasons Hotel in Doha, Qatar on Wednesday, May 28. The workshops scientific focus will be on Flaviviruses (including Hepatitis C and Al-Khumra), Hepatitis E, HIV/AIDS and its co-morbidities, Coronaviruses (including Middle East Respiratory Syndrome), and other viral diseases important in the MENA region. The title of Dr. Marasco's talk is "Identification of Human Neutralizing Antibodies against MERS-CoV and Their Role in Virus Adaptive Evolution".
May 1, 2014
NEW PUBLICATION - Molecular Signatures of Hemagglutinin Stem-Directed Heterosubtypic Human Neutralizing Antibodies Against Influenza A Viruses
The quest for universal influenza vaccine has gained wide interest with the discovery of human neutralizing antibodies that are able to variably cross neutralize and protect against different influenza strains, subtypes, groups and lineages. These antibodies, which bind to a highly conserved epitope in the hemagglutinin stem, are often encoded by rearranged IGHV1-69 germline genes that alone make contact with HA and prevent virus entry and emergence of escape mutants. Our study was undertaken to gain an understanding of what structural requirements enable a rearranged IGHV1-69 Ab to become a potent cross-neutralizing antibody. We found that in addition to a critical amino acid triad consisting of a pair of anchor residues in CDR-H2 and a properly positioned CDRH3 Tyr, distinctive V-segment substitutions that arise in positions that are distinct from phase I AID somatic hypermutation (SHM) hotspot motifs are often required. As few as two V-segment SHM can fulfill this role which appears to facilitate the optimal binding of CDR-H2 Phe54 and CHR-H3-Tyr into adjacent hydrophobic pockets in the HA stem. These studies provide new information on the SHM requirements for IGHV1-69-encoded B cells to produce HV1-69-sBnAbs and suggest that there may exist alternative routes to their elicitation by vaccination.
Avnir Y, Tallarico AS, Zhu Q, Bennett AS, Connelly G, Sheehan J, Sui J, Fahmy A, Huang C-Y, Cadwell G, Bankston LA, McGuire AT, Stamatatos L, Wagner G, Liddington RC, Marasco WA. Molecular Signatures of Hemagglutinin Stem-Directed Heterosubtypic Human Neutralizing Antibodies Against Influenza A Viruses PLOS Pathogens. May 1, 2014, Vol 10, Issue 5 DOI:10.1371 pdf
April 28, 2014
The recently emerged Middle East Respiratory Syndrome coronavirus (MERS-CoV) causes severe respiratory disease with ∼43% mortality. There is no licensed vaccine or antiviral for MERS. Here we identified seven human neutralizing Abs (nAbs) against MERS-CoV. These nAbs bind to three epitope groups in the viral Spike protein–receptor interface, blocking virus attachment. Five residues in the viral receptor-binding domain critical for neutralization escape were identified. Further study indicated that four of five mutations not only confer neutralization resistance but also impair receptor binding and viral fitness. This panel of nAbs offers the possibility of developing human mAb-based immunotherapy.
Tang XC, Agnihothram SS, Jiao Y, Stanhope J, Graham RL, Peterson EC, Avnir Y, Tallarico AS, Sheehan J, Zhu Q, Baric RS, Marasco WA. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution. PNAS April 28, 2014 PMID: 24778221
In the Media (featuring Dr. Marasco):
Why a MERS Vaccine Won't Be Easy, National Geographic, 5/23/14
Dana-Farber researcher blocks MERS virus in experiment, Boston Globe, 5/20/14
Scientists Searching for Antibodies Against Deadly Respiratory Disease, Boston Magazine 5/14/2014
How Cancer Researchers Are WOrking to Help FIght MERS Virus, DFCI Insight Blog, 5/15/2014
Boston institute developing effective treatments for MERS, NECN (New England Cable News) 5/14/2014
The MERS Virus-Dr. Wayne Marasco, WRKO AM680 Boston, 5/13/2014
Second US Case of Mers confirmed: What You Need To Know, Forbes magazine, 5/13/2014
Second U.S. case of deadly MERS virus found in Orlando, USA Today, 5/13/2014
Logan travelers warnered about MERS virus, Boston Globe, 5/12/2014
First U.S. case of deadly MERS virus confirmed, USA Today article reprinted in the Israeli English Newspaper, 5/3/2014
Antibody Discovery may help combat deadly emerging disease, DFCI Inside the Institute, 5/12/14
Scientists identify antibodies against deadly emerging respiratory disease, Dana-Farber Cancer Institute Spotlight, 4/28/14
MERS virus weakened by mutations, researchers found, Nature Middle East, 5/6/14
First Mers Case Reported in US, Still Not A Concern, US Finance Post, 5/6/2014
MERS outbreak picks up pace in Middle East, ScienceNews 5/5/14
First US case of deadly MERS virus confirmed: CDC, Reuters, 5/2/14
Two MERS antibody studies may help quest for treatment. Center for Infectious Disease Research and Policy News, 4/28/14
Scientists Identify Antibodies against Deadly Emerging MERS, Global Biodefense News on Pathogens & Preparedness, 4/9/14
Antibodies against deadly emerging disease MERS discovered, Science Daily, 4/28/14
MERS Cases & Research in the News this Week, ImmunoSEQ, 4/30/14