Harvey M. Friedman, MD
Professor of Medicine
Graduate Group Affiliations
522E Johnson Pavilion
36th & Hamilton Walk
Philadelphia, PA 19104-6073
36th & Hamilton Walk
Philadelphia, PA 19104-6073
McGill University, 1965.
McGill University, 1969.
McGill University, 1965.
McGill University, 1969.
Description of Research ExpertiseResearch Interests
- Vaccines for prevention of genital herpes
- Immune evasion strategies of Herpes Simplex Virus
Key words: Genital herpes vaccine, HSV immune evasion, glycoprotein gC, glycoprotein gD, glycoprotein E, complement, pathogenesis, antibodies.
Description of Research
Harvey Friedman’s laboratory is developing vaccines for preventing and treating genital herpes. The vaccine design is based on basic discoveries made by the lab about immune evasion strategies of the virus. We showed that HSV-1 and HSV-2 glycoprotein gC bind complement component C3b, a critical complement protein in the complement cascade. We determined that gC inhibits complement activation, rendering the complement system ineffective against the virus. HSV mutant viruses unable to bind C3b are highly susceptible to complement-mediated neutralization or lysis. In vivo studies in guinea pigs and mice demonstrated that these mutant viruses are 50- to 100-fold less virulent than wild-type virus. Studies in C3-deficient animals demonstrated that virulence of gC mutant viruses returned to wild-type levels, supporting an important role for gC in immune evasion.
The lab also determined that HSV-1 and HSV-2 evade antibody attack. Glycoprotein gE binds the Fc domain of IgG. When the Fab domain of an antibody molecule binds to an HSV antigen, the Fc end of the same antibody molecule binds to gE, blocking activities mediated by the Fc domain, such as complement activation and antibody-dependent cellular cytotoxicity. The impact is that gE reduces the effectiveness of antibodies in host defense. HSV-1 and HSV-2 gE mutant viruses are more susceptible to antibody and complement attack than wild-type virus. These studies establish an important role for gC- and gE-mediated immune evasion in HSV-1 and HSV-2 pathogenesis.
Vaccine efforts are the focus of the lab. Our approach is to block virus entry by targeting glycoprotein D (gD), an entry molecule. In addition, we target immune evasion molecules gC and gE. These molecules are expressed at the cell surface and on the virion envelope; therefore, they are accessible to antibodies produced by immunization that bind to the glycoproteins and block their functions. We use nucleoside-modified mRNA in lipid nanoparticles to deliver the gC2, gD2 and gE2 antigens. Studies in mice and guinea pig models of genital herpes indicate that this approach is highly effective as a vaccine. We expect our vaccine candidate for prevention of genital herpes to proceed to human trials by summer 2022. We are now working on a vaccine as treatment for genital herpes that will reduce the frequency of outbreaks for people already infected. We are also evaluating whether we can develop a vaccine to prevent and treat oral herpes.
Sita Awasthi, PhD, Research Associate Professor. Dr. Awasthi is leading the trivalent gC, gD, gE glycoprotein immunization studies in mice and guinea pigs.
Lauren M. Hook, PhD, Research Assistant Professor. Dr. Hook is investigating the antibody correlates of protection for the trivalent gC, gD, gE genital herpes vaccine. Her approach is to evaluate the epitope specific antibody responses produced by immunization with the gC, gD and gE immunogens.
Kevin Egan, PhD, Post-doctoral Fellow. Dr. Egan is evaluating protection provided by the HSV-2 trivalent gC2/gD2/gE2 vaccine against genital and oral infection by HSV-1.
Angela Desmond, MD/PhD, Post-doctoral Fellow. Dr. Desmond is an Instructor in Pediatric Infectious Disease at The Children’s Hospital of Philadelphia. She is evaluating the efficacy of the gC2, gD2, gE2 mRNA vaccine in preventing neonatal herpes in mice.
John Lubinski, PhD. Dr Lubinski is a Senior Research Scientist evaluating efficacy of HSV vaccines as therapy for genital herpes in the guinea pig genital herpes model.
Bernard Fowler, MS, Research Specialist. Mr. Fowler is evaluating the immune responses to the mRNA vaccine in mice and guinea pigs and performing assays to measure HSV DNA copy number in tissues as an approach to assess vaccine efficacy.
Zauraiz Syeda, BA, Research Specialist. Ms. Syeda is performing immunology assays on sera obtained from mice and guinea pigs after vaccination with our experimental herpes vaccines.
Valerie Bromberg is a Penn undergraduate assessing the accuracy of antibody testing as a marker of infection in naïve and vaccinated animals.
Awasthi, S., Knox, J. J., Desmond, A., Alameh, M. G., Gaudette, B. T., Lubinski, J. M., Naughton, A., Hook, L. M., Egan, K. P., Tam, Y. K., Pardi, N., Allman, D., Luning Prak, E. T., Cancro, M. P., Weissman, D., Cohen, G. H., Friedman, H. M.: Trivalent nucleoside-modified mRNA vaccine yields durable memory B cell protection against genital herpes in preclinical models. J Clin Invest, October 2021.
Philip C. LaTourette II, Sita Awasthi, Angela Desmond, Norbert Pardi, Gary H. Cohen, Drew Weissman, Harvey M. Friedman: Protection against herpes simplex virus type 2 infection in a neonatal murine model using a trivalent nucleoside-modified mRNA in lipid nanoparticle vaccine. Vaccine 38 (47): 7409-7413, November 2020.
Kevin P Egan, Lauren M Hook, Alexis Naughton, Norbert Pardi, Sita Awasthi, Gary H Cohen,
Drew Weissman, Harvey M Friedman: An HSV-2 nucleoside-modified mRNA genital herpes vaccine containing glycoproteins gC, gD, and gE protects mice against HSV-1 genital lesions and latent infection. PLoS Pathog 16 (7): e1008795, July 2020.
Awasthi S, Hook LM, Pardi N, Wang F, Myles A, Cancro MP, Cohen GH, Weissman D, Friedman HM: Nucleoside-modified mRNA Encoding HSV-2 Glycoproteins C, D, E Prevents Clinical and Subclinical Genital Herpes. Science Immunology 4 (39): eaaw7083, September 2019.
Awasthi S, Hook LM, Swaminathan G, Cairns TM, Brooks B, Smith JS, Ditto NT, Gindy ME, Bett AJ, Espeseth AS, Cohen GH, Friedman HM.: Antibody responses to crucial functional epitopes as a novel approach to assess immunogenicity of vaccine adjuvants. Vaccine 37 (29): 3770-3778, June 2019.
Lauren M Hook, Sita Awasthi, Jonathan Dubin, Jessica Flechtner, Deborah Long, Harvey M. Friedman: A trivalent gC2/gD2/gE2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gC2 better than natural infection. Vaccine 37 (4): 664-669, January 2019.
D. Bernstein, R. Cardin, F. Bravo, S. Awasthi, P. Lu, D. Pullum, D. Dixon, A. Iwasaki, H. Friedman: Successful application of prime and pull strategy for a therapeutic HSV vaccine. npj Vaccines 4: DOI. 10.1038/s41541-019-0129-1, December 2019.
Hook LM, Cairns TM, Awasthi S, Brooks BD, Ditto NT, Eisenberg RJ, Cohen GH, Friedman HM: Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs.la PLOS Pathogens 14 (5): e1007095, May 2018.
Selected PublicationsAwasthi S, Hook LM, Swaminathan G, Cairns TM, Brooks B, Smith JS, Ditto NT, Gindy ME, Bett AJ, Espeseth AS, Cohen GH, Friedman HM.: Antibody responses to crucial functional epitopes as a novel approach to assess immunogenicity of vaccine adjuvants. Vaccine 37: 3770-3778, May 2019.
Lauren M Hook, Sita Awasthi, Jonathan Dubin, Jessica Flechtner, Deborah Long, Harvey M. Friedman: A trivalent gC2/gD2/gE2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gC2 better than natural infection. Vaccine 37: 664-669, January 2019.
D. Bernstein, R. Cardin, F. Bravo, S. Awasthi, P. Lu, D. Pullum, D. Dixon, A. Iwasaki, H. Friedman : Successful application of prime and pull strategy for a therapeutic HSV vaccine. npj Vaccines Page: DOI. 10.1038/s41541-019-0129-1, August 2019.
Hook LM, Cairns TM, Awasthi S, Brooks BD, Ditto NT, Eisenberg RJ, Cohen GH, Friedman HM: Vaccine-induced antibodies to herpes simplex virus glycoprotein D epitopes involved in virus entry and cell-to-cell spread correlate with protection against genital disease in guinea pigs. PLOS Pathogens May 2018.
Awasthi S, Hook LM, Shaw CE, Pahar B, Stagray JA, Liu D, Veazey RS, Friedman HM: An HSV-2 trivalent vaccine is immunogenic in rhesus macaques and highly efficacious in guinea pigs. PLOS Pathogens( ), January 2017 Notes: http://dx.doi.org/10.1371/journal.ppat.1006141.
S. Awasthi, L. M. Hook, C. E. Shaw, H. M. Friedman : A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model. Human Vaccines & Immunotherapeutics 13(12): 2785-2793, May 2017.
Awasthi, S and Friedman, HM: Molecular association of herpes simplex virus type 1 glycoprotein E with membrane protein Us9. Archives of Virology 161(11): 3203-13, Nov 2016.
Michael JA Reid, Andrew P Steenhoff, James Thompson, Lesgo Gabaitiri, Mark S Cary, Katherine Steele, Susan Mayisela, Diana Dickinson, Peter Ehrenkranz, Harvey M Friedman, Daren R Linkin: Evaluation of effect of cellular SMS reminders on consistency of antiretroviral therapy pharmacy pick-ups in HIV-infected adults in Botswana: a randomized control trial. Health Psychology and Behavioral Medicine 5(1): 101-109, January 2017.
Gersh JK, Feldman Z, Greenberger E, Chandra A, Friedman HM, Lere T, Ho-Foster A, Haas MK : Tuberculosis among individuals with community-acquired pneumonia presenting to emergency in Gaborone, Botswana. Journal of Public Health in Africa 21(9): 25-28, May 2018.
T.E. Major, B. Koyabe, M. Narashmhamurthy, O. Nkomazana, H.M. Friedman: Research mentoring plan involving North-South collaborations. Journal of Global Oncology in press, 2019.