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  1. Science & Research (Biologics)

New Approaches to the Development and Evaluation of Vaccines Against Hepatitis Viruses

 

Photograph of Marian Major, PhD

Marian Major, PhD

Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Hepatitis Viruses

Marian.Major@fda.hhs.gov


Biosketch

Dr. Major is a virologist who currently holds the position of Chief, Laboratory of Hepatitis Viruses, Division of Viral Products, CBER/FDA. She obtained a Ph.D. from the University of Warwick, U.K. Dr. Major has been studying vaccine approaches for the prevention of HCV infection since 1994. She was one of the first people to show that natural infection from HCV can elicit protective T cell responses, opening the door for further vaccine development. She has written several reviews on the progress of HCV vaccines; completed a pivotal meta-analysis of HCV vaccine studies in chimpanzees; and showed, using an in silico model, that a vaccine against HCV would reduce transmission among people who inject drugs without necessarily achieving sterilizing immunity. The lab’s research findings have been published in international, peer-reviewed journals, and Dr. Major has co-authored several book chapters and review articles on HCV, including co-authoring publications with two of the 2020 recipients of the Nobel Prize in Physiology and Medicine, Dr. Charles Rice and Dr. Harvey Alter. As a result of her research, Dr. Major is a co-inventor on four patents: one on HCV peptide vaccines (2004), the second on HCV neutralization (2013), the third on an HCV neutralizing antibody (2016), and a fourth on HCV neutralizing epitopes, antibodies and methods (2017).


General Overview

Despite the development of direct-acting antivirals, vaccines against hepatitis C virus (HCV) are still needed. Our research program focuses on learning more about the way hepatitis C virus (HCV) causes disease in people and how the immune system responds to this virus or to vaccines designed to prevent HCV infection.

This research addresses a serious public health threat: an estimated 3.2 million Americans have chronic HCV infection, and studies suggest that over 150 million people worldwide are infected (about 3.3% of the world's population). Approximately 85% of people infected with HCV develop persistent infections that can eventually cause severe liver problems, such as cirrhosis and liver cancer (hepatocellular carcinoma, or HCC). HCV infection is considered one of the major risk factors for liver cancer in the U.S., Europe, and Japan. Furthermore, HCC is one of the few cancers that is increasing in frequency and rate of mortality in the US: studies show that about 50% of HCC cases arise from chronic HCV infection.

Despite these statistics, no vaccine has been developed to prevent HCV infection. Therapy for HCV has improved over the past ten years, with the advent of direct-acting antiviral drugs. Yet for most of the world, daily treatment with these drugs is not realistic, because they are expensive and may have undesirable side effects. In addition, little evidence indicates that patients cured of a chronic HCV infection have protective immune responses that would prevent HCV reinfection. A vaccine against HCV would therefore contribute enormously to reducing the incidence of disease.

In response to this need, our laboratory is developing tools to help us study immune responses to HCV infection and to HCV vaccines. These studies include using a small-animal model for HCV infection; identifying the types of immune responses that demonstrate that a vaccine may be successful; and the development of neutralization tests for the virus (i.e., tests that show whether effective antibodies have been induced against the virus). We are also working with collaborators to develop mathematical models for HCV transmission, so that intervention strategies can be tested in silico before testing in at-risk populations. These studies will be critical to our ability to guide manufacturers of HCV vaccines and to the ability of FDA to evaluate the safety and efficacy of these products.


Scientific Overview

Our laboratory is focused on developing scientific tools to better understand and characterize immune responses to hepatitis C virus (HCV).

Studies include the identification of immunologic correlates of protection, development of neutralization tests for the virus, and assessment of effective methods for induction of protective immune responses. Many of these studies have used reagents and data previously obtained from chimpanzees, the only animal model for HCV infection and immunity.

Previously, HCV could not be propagated in a robust cell culture system, which made classical in vitro neutralization tests impossible. In 2005 other investigators showed that RNA from a genotype 2a strain of HCV replicates in Huh 7.5 cells (a human hepatoma cell line) and produces infectious virus (HCVcc). However, several HCV genotypes have great variability in the envelope region, which is targeted by neutralizing antibodies. We therefore generated genotype 1a/2a, 1b/2a and 3a/2a chimeric viruses carrying the respective structural proteins (core, E1, E2, p7) in the replicating backbone of a 2a virus. We showed that these chimeric viruses replicate in cell culture as efficiently as the 2a genotype and have used them to assess cross-neutralizing antibody in large sets of samples.

We are developing biomarkers to predict clearance of virus in vaccinees. We have performed qualitative comparisons of the recall T-cell responses in recovered or re-challenged chimpanzees with the recall responses in vaccinated chimpanzees. The results demonstrated specific differences in memory T-cells associated with HCV clearance. To replace the chimpanzee model, we have now transitioned to using immunocompetent mice to compare T-cell responses induced by different vaccine vectors. Even though these mice cannot be challenged with HCV, qualitative and quantitative differences in T-cells induced following vaccination can be studied.


Important Links


Publications

  1. Vaccine 2023 Dec 23 [Epub ahead of print]
    Vaccine-associated respiratory pathology correlates with viral clearance and protective immunity after immunization with self-amplifying RNA expressing the spike (S) protein of SARS-CoV-2 in mouse models.
    Kachko A, Selvaraj P, Liu S, Kim J, Rotstein D, Stauft CB, Chabot S, Rajasagi N, Zhao Y, Wang T, Major M
  2. Int J Mol Sci 2023 Feb 14;24(4):3774
    Distinct conformations of SARS-CoV-2 Omicron spike protein and its interaction with ACE2 and antibody.
    Lee M, Major M, Hong H
  3. Vaccine 2023 Jan 23;41(4):955-64
    Assessing the impact of hepatitis B immune globulin (HBIG) on responses to hepatitis B vaccine during co-administration.
    Zubkova I, Zhao Y, Cui Q, Kachko A, Gimie Y, Chabot S, Murphy T, Schillie S, Major M
  4. J Virol 2022 Sep;96(18):e0116621
    Enhanced in vitro and in vivo potency of a T cell epitope in the Ebola virus glycoprotein following amino acid replacement at HLA-A*02:01 binding positions.
    Chabot S, Gimie Y, Obeid K, Kim J, Meseda CA, Konduru K, Kaplan G, Sheng Fowler L, Weir JP, Peden K, Major ME
  5. PLoS One 2022 Mar 10;17(3):e0264983
    Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago.
    Tatara E, Gutfraind A, Collier NT, Echevarria D, Cotler SJ, Major ME, Ozik J, Dahari H, Boodram B
  6. Gastroenterology 2022 Feb;162(2):562-74
    An antigenically diverse, representative panel of envelope glycoproteins for HCV vaccine development.
    Salas JH, Urbanowicz RA, Guest JD, Frumento N, Figueroa A, Clark KE, Keck Z, Cowton VM, Cole SJ, Patel AH, Fuerst TR, Drummer HE, Major M, Tarr AW, Ball JK, Law M, Pierce BG, Foung SKH, Bailey JR
  7. Proc Winter Simul Conf 2019 Dec;2019:1008-1019
    Multi-objective model exploration of hepatitis C elimination in an agent-based model of people who inject drugs.
    Tatara E, Collier NT, Ozik J, Gutfraind A, Cotler SJ, Dahari H, Major M, Boodram B
  8. Vaccine 2019 May 1;37(19):2608-16
    Modeling indicates efficient vaccine-based interventions for the elimination of hepatitis C virus among persons who inject drugs in metropolitan Chicago.
    Echevarria D, Gutfraind A, Boodram B, Layden J, Ozik J, Page K, Cotler SJ, Major M, Dahari H
  9. Methods Mol Biol 2019;1911:421-32
    Detection of antibodies to HCV E1E2 by lectin-capture ELISA.
    Major M, Law M
  10. Sci Transl Med 2018 Jul 11;10(449):eaao4496
    Modeling of patient virus titers suggests that availability of a vaccine could reduce hepatitis C virus transmission among injecting drug users.
    Major M, Gutfraind A, Shekhtman L, Cui Q, Kachko A, Cotler SJ, Hajarizadeh B, Sacks-Davis R, Page K, Boodram B, Dahari H
  11. J Virol 2018 Mar;92(6):e01742-17
    Determinants in the IgV domain of human HAVCR1 (TIM-1) are required to enhance hepatitis C virus entry.
    Kachko A, Costafreda MI, Zubkova I, Jacques J, Takeda K, Wells F, Kaplan G, Major ME
  12. Antiviral Res 2017 Aug;144:281-5
    Modeling HCV cure after an ultra-short duration of therapy with direct acting agents.
    Goyal A, Lurie Y, Meissner EG, Major M, Sansone N, Uprichard SL, Cotler SJ, Dahari H
  13. PLoS One 2017 Jul 21;12(7):e0181578
    Qualitative differences in cellular immunogenicity elicited by hepatitis C virus T-Cell vaccines employing prime-boost regimens.
    Tan WG, Zubkova I, Kachko A, Wells F, Adler H, Sutter G, Major ME
  14. Gut 2016 Jan;65(1):4-5
    Hepatitis C: new clues to better vaccines?
    Major ME
  15. Hepatology 2015 Dec;62(6):1670-82
    Antibodies to an interfering epitope in hepatitis C Virus E2 can mask vaccine-induced neutralizing activity.
    Kachko A, Frey SE, Sirota L, Ray R, Wells F, Zubkova I, Zhang P, Major ME
  16. PLoS One 2015 Sep 30;10(9):e0137993
    Agent-based model forecasts aging of the population of people who inject drugs in metropolitan Chicago and changing prevalence of hepatitis C infections.
    Gutfraind A, Boodram B, Prachand N, Hailegiorgis A, Dahari H, Major ME
  17. PLoS One 2015 Aug 21;10(8):e0135901
    Mathematical modeling of hepatitis C prevalence reduction with antiviral treatment scale-up in persons who inject drugs in metropolitan Chicago.
    Echevarria D, Gutfraind A, Boodram B, Major M, Del Valle S, Cotler SJ, Dahari H
  18. EBioMedicine 2015 Jun 30;2(8):857-65
    Reverse engineering of vaccine antigens using high throughput sequencing-enhanced mRNA display.
    Guo N, Duan H, Kachko A, Krause BW, Major ME, Krause PR
 
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