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Vaccines and Related Biological Products

Advisory Committee MeetingNovember 15, 2012

Hepatitis B Vaccine (Recombinant), Adjuvanted

(HBV Surface Antigen (HBsAg) Protein with 1018 ISS(CpGs))

(HEPLISAV)

Applicant: Dynavax Technologies Corporation

Marian Major, Ph.D.

Office of Vaccines Research and Review/CBER/FDA

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Approved for immunization against infection caused by all known subtypes of

hepatitis B virus (HBV)

ENGERIX-B Manufactured by GlaxoSmithKline

Licensed in 1989

Recombinant HBV surface antigen produced from yeast cells

Adsorbed onto aluminum hydroxide

RECOMBIVAX HB

Manufactured by Merck

Licensed in 1986

Recombinant HBV surface antigen produced from yeast cells

Adsorbed onto aluminum hydroxyphosphate sulfate

Currently Licensed Hepatitis B Vaccines

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Dosage and Administration

ENGERIX-B (intramuscular administration)

Persons from birth through 19 years of age: 3 doses (0.5 mL each (10 mcg

rHBsAg)) given on a 0, 1, and 6 month schedule

Persons 20 years of age and older: 3 doses (1.0 mL each (20 mcg

rHBsAg)) given on a 0, 1, and 6 month schedule Adults on hemodialysis: A series of 4 doses (2mL each (40 mcg rHBsAg))

given on a 0, 1, 2, and 6 month schedule

RECOMBIVAX HB (intramuscular administration)

Persons from birth through 19 years of age: 3 doses (0.5 mL each (5 mcgrHBsAg)) given on a 0, 1, and 6 month schedule

Persons 20 years of age and older: 3 doses (1.0 mL each (10 mcg

rHBsAg)) given on a 0, 1, and 6 month schedule

Adults on hemodialysis: 3 doses (1mL each (40 mcg rHBsAg)) given on a

0, 1, and 6 month schedule

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Hepatitis B component is the same as that contained in the monovalent

vaccines ENGERIX-B or RECOMBIVAX HB

Manufactured by GlaxoSmithKline

TWINRIX (hepatitis B and hepatitis A) (Persons 18 and older)

PEDIARIX (diphtheria, tetanus, pertussis, hepatitis B, and polio)

(Children 6 weeks through 6 years)

Manufactured by Merck

COMVAX (Haemophilus influenzae type b and hepatitis B)

(Infants 6 weeks to 15 months)

Currently Licensed Combination

Hepatitis B Vaccines

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Alternate Dosing Schedules

ENGERIX-B (intramuscular administration)

Infants born of HBsAg-positive mothers and children from birth

through 10 years of age : 4 doses (0.5 mL each (10 mcg rHBsAg))

given on a 0, 1, 2, and 12 month schedule

Children 5 through 10 years of age and adolescents 11 through 16

years of age : 3 doses (0.5 mL each (10 mcg rHBsAg)) given on a


Adolescents 11 through 19 years of age: 3 doses (1.0 mL each (20

mcg rHBsAg)) given on a 0, 1, and 6 month schedule

Adolescents 11 through 19 years of age and adults 20 years of age

and older : 4 doses (1.0 mL each (20 mcg rHBsAg)) given on a 0,


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Alternate Dosing Schedules

TWINRIX (Accelerated schedule)

18+ years of age: 4 doses (1mL each (20 mcg HBsAg, 720 EUinactivated hepatitis A virus) given on a 0, 7 and 21-30 days and 12

months

RECOMBIVAX HB

Adolescents 11 through 15 years of age: 2 doses (1.0 mL each (10

mcg rHBsAg)) given on a 0, and 4-6 month schedule

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HEPLISAV: Composition, ProposedIndication and Dosage

Recombinant HBsAg produced from yeast cells

Combined with 1018 ISS adjuvant (a cytosine

phosphoguanosine oligodeoxynucleotide, CpG-ODN)

This adjuvant is not contained in any currently licensed

US vaccines

Immunization against infection caused by all known

subtypes of hepatitis B virus in adults 18 through 70years of age

2 doses (0.5 mL each (20 mcg rHBsAg, 3000 mcg 1018

ISS)) given on a 0 and 1 month schedule

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What are CpG-ODNs? Synthetic DNA molecules, oligodeoxynucleotides

(ODNs) with phosphorothioate backbone, containing

unmethylated cytosine phosphoguanosine (CpG) motifs

CpG motifs occur at higher frequency in bacterial and

viral DNA than vertebrate DNA

CpG motifs have different immune enhancement effects

in different species

CpG-ODN adjuvants have been found to trigger B cell

activation and preferentially induce a Th1-like over a

Th2-like CD4+ T helper immune response

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Th1 responses: characterized by the production of

proinflammatory cytokines, such as IFN- and TNF-,which leads to cell mediated immunity and an opsonizing

antibody response (IgG2a isotype)

Th2 responses: characterized by interleukin-4 production

which leads to a humoral immune response dominatedby IgG1 and IgE antibodies

Th1 versus Th2 responses

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CpG Mode of Action

CpGs are classed as toll-like receptor (TLR) agonists

TLRs are proteins on innate (first-responder) immune

cells (monocytes and dendritic cells) that recognizemolecules from invading microbes.

TLRs recognize molecules shared by many different

microbes, but these are distinguishable from host

molecules.

CpGs function via TLR-9

TLR9 is expressed mainly on plasmacytoid dendritic

cells and memory B cells

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1018 ISS Proposed Mechanism of Action

1018 immunostimulatory sequence (ISS):

Stimulates TLR9 in pDCs that have taken up rHBsAg

Converts pDCs into activated DCs that present HBsAg

epitopes to the immune system (CD4+ cells)

Promotes differentiation of CD4+ cells that leads to

antibody secretion by HBsAg-specific B cells

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Early hepatitis B vaccine trials used prevention of HBV

infection as the clinical endpoint

Data from early HBV vaccine studies (using Heptavax, a

plasma-derived HBsAg vaccine) showed anti-HBs

antibody levels of > 10 mIU/mL correlated with protection(Szmuness et al. 1981 Hepatology Vol 1 No.5 p 377)

Post-vaccination an anti-HBs level 10 mIU/mL isaccepted as conferring protection

This type of correlate of protection can be used as an

indicator of clinical effectiveness in a traditional route for

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Use of Anti-HBs to Predict Protection

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Initial anti-HBs levels have been associated with greaterpersistence of antibody in vaccinees

However, decreased titers to

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Data from prolonged follow-up studies using plasma-derived hepatitis B vaccine (McMahon et al. JID 2009) :

an estimated 92.5% of primary responders hadevidence of continued protection after 22 years

no vaccine recipients became chronicallyinfected

Recombinant HBsAg vaccines have also been shown toconfer long-term protection and persistent immunologicalmemory for at least 10 years (Zanetti et al. Lancet 2005; Mastet al. MMWR 2005)

Duration of Protection

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Questions to the Committee

1. Are the immunogenicity data adequate to

support the effectiveness of HEPLISAV for the

prevention of hepatitis B virus infection inadults 18 through 70 years of age?

Please vote Yes or No.

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Questions to the Committee

2. Are the available data adequate to support the safety

of HEPLISAV when administered to adults 18 through

70 years of age?Please vote Yes or No.

If yes, is the proposed pharmacovigilance plan

adequate to further evaluate the safety of HEPLISAV

post-licensure?

If no, please discuss what additional studies (pre- &

post-licensure) are needed to further evaluate the

safety of HEPLISAV.

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