The Use and Efficacy of Vaccines for Hepatitis NOV CHEN (STEVEN) GUAN ZARAH KHAN ZUBEIR KHAN PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

What is hepatitis?  Hepatitis is the inflammation of the liver.  Can be caused by virus, autoimmune disease, toxic substances, and overdose of certain medication  There are five main types of hepatitis viruses: A, B,C,D, and E  Hepatitis A & E are transmitted fecal-orally  Typically cause acute and self-limiting infections  B, C, and D are transmitted by blood, semen, and other body fluids  Typically result in chronic hepatitis  Symptoms include: flu-like symptoms (acute), cirrhosis, liver failure, jaundice, and liver cancer

Viral Hepatitis Vaccines  Vaccines work by causing the body to produce its own protection in the form of antibodies against the disease  Hepatitis A and B vaccines are available  Hepatitis E vaccine is approved in China  Hepatitis A vaccine contain either inactivated hepatitis A virus or live but attenuated form of the virus  Hepatitis B vaccine contains HBsAg  Surface antigen of HBV

Hepatitis A Vaccine  Monovalent vaccines : HAVRIX® 1440 AVAXIM® VAQTA®  Combined Vaccines (Hep A and Hep B) TWINRIX®

Hepatitis A Vaccine Uses  Pre-exposure immunization:  For long-term prevention of HAV infection  Used for high risk individuals  Illicit drug users  Travellers to HA endemic countries  Individuals from communities that have high endemic rates of HA  Post –exposure prophylaxis :  household and sexual contacts of people infected with HA  contacts in group child care centres and kindergartens  co-workers and clients of infected food handlers

Hepatitis A Vaccine Schedule and Efficacy  Schedule  Primary immunization  Booster dose  6 to 36 months later  Efficacy  Safe, clinically well-tolerated, and highly immunogenic  A seroconversion rate of 100%  Booster dose expected to protect against hepatitis A for > 20 years.

Hepatitis B Vaccine  Indicated for active immunisation against infection caused by all known HBV subtypes.  Different vaccine types include a.) Recombinant (Hep B) b.) Combination (Hep A + Hep B) c.) Hepatitis B immune globulin (HBIg)  The vaccine is available as a 0.5 or 1mL suspension containing 10 or 20[micro]g of Hepatitis B surface antigen (HBsAg).  Administered intramuscularly in the deltoid region in adults and in the anterolateral thigh in neonates and infants

Hepatitis B Vaccine  Monovalent vaccines:  ENGERIX®-B  RECOMBIVAX HB®  Combined Vaccines (Hep A and Hep B)  TWINRIX® and TWINRIX® Junior  INFANRIX hexa™ (DTaP-HB-IPV-Hib)

Hepatitis B Vaccine Uses Routine HB immunization is recommended for all children Pre-exposure HB immunization :  Used for high risk individuals which includes  Infants and young children  Immuno-compromised individulas  Individulas from communities that have high endemic rates of HepB Post –exposure prophylaxis:  infants born to HB-infected mothers  persons potentially exposed to blood or bodily fluids containing HB virus  household and sexual contacts of an acute HB case or chronic carrier

Hepatitis B Vaccination Schedule and Seroprotection Rates Healthy individuals : Pre-exposure Prophylaxis  Neonates and infants: 10 mcg of HepB  Three Dose: 0, 1, 6-Month SPR: 96.2 – 100%  In Older Children and Adolescents: 10 mcg of HepB  Three Dose: 0, 1, 6-Month SPR: 94.8 – 100%  In Healthy Adults: 20 mcg of HepB  Three Dose: 0, 1, 6-Month SPR: 85 – 100% High risk individuals: Post-exposure Prophylaxis  Neonates of Hepatitis B Carrier Mothers: mcg of HepB  Three Dose: 0, 1, 6-Month SPR: %  Healthcare workers: 20mcg of HepB  Three Dose: 0, 1, 6-Month SPR: %  Patients Undergoing Haemodialysis : 40mcg of HepB  Four Dose: 0, 1,2, 6-Month SPR: %

Hepatitis C Vaccine Development  There are currently no approved vaccine for Hepatitis C virus  Hepatitis virus exist as 7 distinct genotypes with at least 50 subtypes  Highly mutation rate  Limited animal models  Only chimpanzees  Difficult to enroll at risk individuals for trial  Lack of clear marker for protection

Hepatitis C Vaccine Development  Chiron Corp gpE1/gpE2 heterodimer vaccine  Developed after discovery of E2 surface protein  High CD4+ response  Stopped at phase II planning stage  Okairos N23-5B Vaccine  Adenoviral vector vaccine  Broad CD4+ and CD8+ T cells secreting multiple cytokines, targeting multiple epitopes  Presence of polyfunctional and proliferative long-term memory population after 1 year  Ongoing phase 2 with results expected in early 2016

Summary  Hepatitis is the inflammation of the liver, mostly caused by viral infection  The main types of Hepatitis are A, B, C, D, and E  A and E cause acute infection  B, C, and D cause chronic infections  Hepatitis A and B vaccines are available.  Hep A vaccine is given to people one year of age or older  Havrix consists of the inactivated Hepatitis A virus  Seroconversion rate of 100% after primary vaccination  Booster dose of Havrix given 6-12 months after the first is expected to protect against Hepatitis A for >20 years

Summary  Engerix-B[R] (Hep-B [Eng]) is a non-infectious recombinant DNA vaccine containing hepatitis B surface antigen (HBsAg)  IM Hep-B [Engernix] (0, 1, 6 month schedule] has excellent immunogenicity in healthy neonates, infants, children, adolescents, and adults  Seroprotection rate of % seen 1 month after final dose of vaccine  Hep-B (Eng) was well tolerated and had excellent protective efficacy against HBsAg carriage in infants, children, and neonates born to hepatitis B carrier mothers, as well as other high-risk groups  Hepatitis C currently has no vaccine  Hepatitis vaccine design is very difficult due to virus’s high degree of genetic variation and difficulty with experiment design  Chiron Corp gpE1/E2 vaccine based on surface glycoprotein trial stopped at Phase 2  Okairos N23-5B vaccine using adenovirus to deliver a non-structure protein to stimulate immune memory has shown good promise

References 1. Adkins, Julie C., and Antona J. Wagstaff. "Recombinant Hepatitis B Vaccine*." BioDrugs, 1998, André, Francis, Pierre Van Damme, Assad Safary, and Jangu Banatvala. "Inactivated Hepatitis A Vaccine: Immunogenicity, Efficacy, Safety and Review of Official Recommendations for Use." Expert Review of Vaccines, 2002, Halliday, John, Paul Klenerman, and Eleanor Barnes. "Vaccination for Hepatitis C Virus: Closing in on an Evasive Target." Expert Review of Vaccines, 2011, "Hepatitis." WHO. Accessed November 10, "Hepatitis A Questions and Answers for Health Professionals." Centers for Disease Control and Prevention. May 31, Accessed November 10, "Hepatitis B Vaccine." Canadian Immunization Guide. Accessed November 10, "Hepatitis: MedlinePlus Medical Encyclopedia." U.S National Library of Medicine. Accessed November 10, 2015.

References 8. Kong, L., I.a. Wilson, and M. Law. "Structure of Hepatitis C Virus Envelope Glycoprotein E2 Core Bound to Broadly Neutralizing Antibody AR3C." Law, Lok Man John, Abdolamir Landi, Wendy C Magee, D Lorne Tyrrell, and Michael Houghton. "Progress towards a Hepatitis C Virus Vaccine." Emerg Microbes Infect Emerging Microbes & Infections, Strickland, G Thomas, Samer S El-Kamary, Paul Klenerman, and Alfredo Nicosia. "Hepatitis C Vaccine: Supply and Demand." The Lancet Infectious Diseases, 2008, Whiteman, Honor. "Hepatitis C Vaccine Shows Promise in Early Clinical Trial." Medical News Today. November 16, Accessed November 10, Zingaretti, C., R. De Francesco, and S. Abrignani. "Why Is It so Difficult to Develop a Hepatitis C Virus Preventive Vaccine?" Clinical Microbiology and Infection, 2013,