ss 2017: challenges in hepatitis b vaccination

Challenges in Hepatitis B Vaccination

(a personal view)

Graham P Taylor

Section of Virology

Carrier status depends on timing of infection

Timing of Infection Risk of carrier

status

Infancy 90%

Childhood ( ages

1<5)

20 – 30%

Adult <5%

Risk of Hepatitis B infant infection depends on mother’s

infection status

Maternal Status Transmission Risk

HBeAg+ 70 – 90%

HBeAg-ve; anti-Hbe -

ve

25%

HBeAg-ve; anti-Hbe

+ve

12%

Consequences of chronic carriage

http://www.stanford.edu/group/virus/flavi/2004gallo/cirrhosis.jpg

http://www.utmb.edu/surgicalpathology/picts/photo_of_the_month_2006_2007/pom_aug_06.jpg

Occurs in 30 – 40% of carriers

Hepatitis B discovery

1965 - Discovery of Australia antigen

1976 - Nobel Prize awarded to Baruch Blumberg

1981 – Plasma derived Hepatitis B vaccine

1982 – Vaccinated

Challenge 1 - Safety

1985 “ a proportion of the plasma of triply inactivated, plasma-derived

hepatitis B vaccine produced in the US is obtained from homosexual men”

The 15 month serum samples from 100 vaccinated and 100 placebo

vaccinated Healthcare Workers were tested for HTLV-III.

No evidence of HTLV-III infection

Dienstag JL et al. JAMA 1985;254:1064-6





1982 – Vaccinated

1986 – Recombinant vaccine

Challenge 2

Is the Recombinant vaccine as good as the original?

Healthcare Workers:

mean Anti-HBs

31 10mg Recombinant

25 25mg Plasma-derived

Response rate similar at 7 months

Jeijtink RA et al Antiviral Res 1985 Suppl 1: 273-9

Healthcare Workers:

mean Anti-HBs

31 10mg Recombinant 857 IU/L

25 25mg Plasma-derived 6,736 IU/L

Response rate similar at 7 months

Jeijtink RA et al Antiviral Res 1985 Suppl 1: 273-9

Challenge 3: How long does the protective effect last?

N 1 month

%

“protected”

1

month

GMT

36 months

%

“protected”

36

months

GMT

0,1,6 months

Recombinant 63 100 4078 98 309

Plasma-derived 39 100 6598 97 345

0,1,2 + recombinant booster at 12 months

Recombinant 14 100 13752 100 778

Plasma-derived 22 100 19959 100 1041

“Protection out to 36 months”

Just M et al Vaccine 1988;6:401-2

“Healthy Young Adults”

Two doses not enough

N 8 month

%

“protected”

8

month

GMT

60 months

%

“protected”

60

months

GMT

0,1,6 months

Recombinant

5mg

0,1 months

99 93% 113

7547

Recombinant

5mg

0,1, 6 months

99 99% 4136

87131

Plasma-derived

10mg

0,1, 6 months

107 99% 2994

84250

No infections, Protection out to 60 months and evidence of anamnestic responses

Lai CL et al Hepatology 1993;18:763-7

“Children age 3months to 11 years”

Challenge 4: Cost – can this be reduced?

Stockholm, Sweden health care workers

Recombinant vaccine (Engerix B)

protective anti-HBs levels

286 20mg IM 94%

382 2mg ID 89%

Predictive factors for higher response rates and higher anti-HBs were:

Female gender

IM injection

Younger age

Non-Smoker

If an 85% response rate is acceptable

ID injection can be used in females and non-smoking males <age 30

Struve J et al: Scand J Infect Dis 1992;24: 423-9

Challenge 4: Cost – can this be reduced? YES

Challenge 5: Non or Sub-optimal responders

20mg Plasma-derived vaccine, 0, 1 & 6 months

MSM

Low/No antibody titre in 7/16 HIV+ v 6/68 HIV-ve

Median anti-HBs titre 15.5 v 205 (sample ratio units)

Ann Int Med 1988;109:101-5

Challenge 5: Non-Responders

Japan

31 non-responders to sc vaccination

Px

5mg Plasma-derived vaccine intradermally every two weeks until delayed

type hypersensitivity (DTH) skin reaction to HBsAg became positive

97% developed DTH after 2.3 +/- 1.2 revaccinations

94% developed >10 IU/L of anti-HBs in plasma

74% remain “protected” at 1 year

Nagafuchi et al, JAMA 1991; 265:2679-83

can be managed

How long does “protection” last? At least 16 years

Taiwan National HBV Vaccination programme launched in 1984 for infants

of HBsAg+ mothers and extended to all infants in 1986

Plasma derived vaccine at 0,1,2 and 12 months

Recombinant vaccine at 0,1 and 6 months from 1992

96.6%, 95.2% and 92.8% uptake by dose

Study subjects age 16 entering healthcare training

Response to Booster

Plasma-derived 43.2% protected 92.9%

Recombinant 32.3% protected 95.9%

Antibodies wane over time but no increase in HBV infection in Taiwan this

period.

Lin et al Am J Infect Control 2011;39:408-14

How long does “protection” last?





1982 – Vaccinated

1986 – Recombinant vaccine

2017 – Still have adequate titres

Protection after 30 years?

Alaska

Indigenous 1578 adults and children

3 doses Plasma derived vaccine in 1981

(10mg if <20years; 20mg if > 20 years)

435 were followed up at 30 years

22 years after vaccination 60% remained “protected”

40% were given booster

At 30 years 125/243 (56%) anti-HBs >10 IU/L (un boosted)

85 <10 IU/L given booster – 75(88%) response at 30 days

From: Antibody Levels and Protection After Hepatitis B Vaccine: Results of a 30-Year Follow-up Study and

Response to a Booster DoseJ Infect Dis. 2016;214(1):16-22. doi:10.1093/infdis/jiv748

J Infect Dis | Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by

(a) US Government employee(s) and is in the public domain in the US.

Protection after 30 years?

Alaska

Indigenous 1578 adults and children

3 doses Plasma derived vaccine in 1981

(10mg if <20years; 20mg if > 20 years)

435 were followed up at 30 years

22 years after vaccination 60% remained “protected”

40% were given booster

At 30 years 125/243 (56%) anti-HBs >10 IU/L (un boosted)

85 <10 IU/L given booster – 75(88%) response at 30 days

No incident infections were documented

Challenge 6: cold chain

Previous study demonstrated cold chain breached 23% of time by being

too high and 47% of the time by being too low

To determine immunity to HBV in adolescents vaccinated in infancy 1989 -

1990 in a remote aboriginal community

n= 37

4 (11%) HBV infected

7 (19%) past HBV infection

15 (41%) no seroprotection (<10 IU/L)

11 (29%) Seroprotected

Dent et al, Commun Dis Intell 2010;34:435-9

Cold Chain Solution

Monovalent HepB Vaccine (LG Lifescience) is relatively heat stable and

can be stored outside the cold chain.

Tolerance 37C for one month or 45C for one week

(similar antibody titres to vaccine stored at 2-8C for 1 month)

Study in Guadalcanal, Makira and Western Province of Birth Dose

Hepatitis B vaccine OCC

Cold Chain Solution

Timely HepB Birth Dose increased from 38/125 (30%) births to

104/152 (68%) p 0.0005

Late BD (first dose before 42 days) increased from 80 – 85%

For home deliveries HepB Birth Dose increased from 2/46 (4%)

to 9/38 (24%)

Late BD increased from 4/46 (9%) to 20/38 (53%)

Breakwell et al Vaccine 2017;35: 2770-4

Cold Chain Solution – use a vaccine that is heat stable

Challenge : loss of anti-HBs

Hepatitis B specific T-cell responses 30 years after vaccination

Anti-HBV Group 1 <10IU/L Group 2 >10IU/L

IFNg 6/13 (46%) 16/31 (52%)

SFC/106 PBMC 4 (0-335) 5 (0-780)

Anti-HBsAg Group 1 <10IU/L Group 2 >10IU/L

IFNg 6/13 (46%) 16/31 (52%)

SFC/106 PBMC 4 (0-335) 5 (0-780)

Supernatant

pg/ml

100% 100%

TNF-a 564 335

IL-10 198 92

IL-6 6863 6478

Anti-HBc Group 1 <10IU/L Group 2 >10IU/L

IFNg 2 (15%) 6 (19%)

SFC/106 PBMC 0 (0-94) 0 (0-43)

Simmons et al, JID 2016;214:273-280

Challenge : loss of anti-HBs may not = loss of protection

Challenge 7: Global prevalence of HBsAg+ persons

60

115

39

21

15

7

257 millionWHO Global Report 2017

Vaccination infants and children

has prevented 210 million infections

will avert 1.1 million deaths by 2030

Without scale up: 2015-2030

63 million new CHRONIC infections

17 million deaths

Nayagam et al, Lancet 2016,16:1399-408

Challenge 8: Elimination of HBV by 2090

Scale up to:

90% infant coverage

80% birth dose

80% HBeAg+ mothers

peripartum antivirals

80% population Test and

Treat

?HBV Cure

Annual cost will peak at $7.5

Billion worldwide then

decrease rapidly

Nayagam et al, Lancet 2016,16:1399-408

The Final Challenge

ss 2017: challenges in hepatitis b vaccination

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