Center for Global Health

Improving Timely Hepatitis B Birth Dose Vaccination through Use of the Vaccine Outside the Cold Chain:

The Asia Pacific Experience

Viral Hepatitis Prevention Board Asia Meeting

Hanoi, VietnamJuly 25-26, 2018

Rania Tohme, MD, MPH

Team Lead—Global Immunization Division, US CDC

Objectives

Present some challenges to timely HepB-BD vaccination

Present the thermostability of HepB

Review use of HepB-BD outside de cold chain (OCC) in Western Pacific region and Indonesia

Summarize current situation of licensing HepB-BD for Controlled Temperature Chain (CTC) use at global level

Challenges for Hepatitis B Vaccination at Birth

Lack of functional cold chain – 22% of health facilities without fridges– 12% of cold chain equipment is non functional– 2011: 2.8 million vaccine doses lost in five countries due to

cold-chain failures 1

Significant correlations between HepB-BD, skilled birthing attendance and institutional deliveries in African, South-East Asia and Western Pacific Regions2

1.http://apps.who.int/iris/bitstream/handle/10665/131568/WHO_IVB_14.05_eng.pdf;jsessionid=A1F745A84DC344E82735B6D0E9CECE1C?sequence=12. Allison RD, Patel MK, Tohme RA. Hepatitis B Vaccine Birth Dose Coverage Correlates Worldwide with Rates of Institutional Deliveries and Skilled Attendance at Birth. Vaccine 2017; 35 (33): 4094-4098

Spectrum of Freeze and Heat Sensitivity—HepBFreeze sensitivity Heat sensitivity

http://www.who.int/immunization/programmes_systems/supply_chain/resources/VaccineStability_EN.pdf

Heat-Stability of Hepatitis B Vaccine

Hepatitis B extremely heat stable vaccine

1. Van Damme et al. Heat Stability of a Recombinant DNA Hepatitis B Vaccine . Vaccine. 1992. 10 (6) ; 366-367.2. WHO. Temperature Sensitivity of Vaccines. 2006.3. http://www.who.int/immunization/sage/meetings/2016/october/6_Thermostability_HBV_04102016.pdf?ua=1

HepB Vaccine Package Inserts

Use of Hepatitis B-BD OCC in WPR and Indonesia

2006: Supporting guidance from WHO-WPRO for OCC

“The hepatitis B vaccine for the birth dose may be stored and used out of the cold chain (at ambient temperature) at point of use whenever the regular cold chain cannot be maintained (e.g. in the lowest-level health facility or by a midwife for home births).”

2015Hepatitis B Control Through Immunization: A Reference GuideRegional Action Plan for Viral Hepatitis in the Western Pacific

Promote the use of controlled temperature chain (CTC) for hepatitis B vaccine to increase coverage with the birth dose in health facilities with no continuous cold chain and for home births

Vietnam: 1998-2000

Locally produced plasma derived monovalent hepB(2.5 mcg/0.5mL)

Implemented in 2 districts inside (6 communes) and outside (12 communes) the cold chain

HBsAg and anti-HBs tested at 9–18 months of age

No difference in anti-HBs and GMT

Hipgrave et al. Immunogenicity of a locally produced hepatitis B vaccine with the birth dose stored outside the cold chain in rural Vietnam. AJTMH. 2006 74 (2) 255-260.

Vietnam: 2005

Group 1: HepB-BD in cold chain (ICC) for hospital births (n=625)

Group 2: HepB-BD OCC for births at commune health centers and home (n=325)– VVM attached to vaccine

Anti-HBs 30 days to 6 months after the 3rd dose No difference in coverage with timely BD No major AEFIs HCW and mothers were satisfied with OCC use

of HepB-BD

Huong, V. et al. Out-of-cold-chain delivery of the HB birth dose in four districts of Vietnam., PATH, unpublished.

# Tested Seroconversion GMT (mIU/ml)

Vaccine OCC 351 91.7% 293.5 (257.1-335.1)

Vaccine ICC 616 85.7% 281.5 (237.5-333.5)

China: 2003-2004

Locally produced HepB with VVM 3 counties in Hunan Province with high rates of births outside hospitals

(40-60%) Group1: HepB single-dose ampoules ICC in hospitals Group 2: HepB single-dose ampoules OCC given by village HCW at home Group 3: HepB Uniject OCC given by village HCW at home

Wang et al. Hepatitis B vaccination of newborn infants in rural China: evaluation of a village-based, out of cold chain delivery strategy . Bulletin of the World Health Organization. 2007. 85: 688-694.

Group % seropositive GMT (mIU/mL)

1: ICC hospital 89% 95.5

2: OCC ampoule 91% 93.3

3: OCC Uniject 89% 102.3

Wang et al. Hepatitis B vaccination of newborn infants in rural China: evaluation of a village-based, out of cold chain delivery strategy . Bulletin of the World Health Organization. 2007. 85: 688-694.

Papua New Guinea: 2008–2010

Uniject used and administered by trained village health volunteers (VHVs) in East Sepik province

After 2 years– 74% HepB-BD coverage home births (baseline 0%)– 93% HepB-BD coverage for health facility births – 83% HepB-BD coverage overall (baseline 18%)– VHVs proved competent at providing vaccination with Uniject, reading

VVMs, managing vaccine supplies OCC– The program was well accepted by communities

Scale up stalled by high $5 per dose costMorgan et al. unpublished report

Lao PDR: 2012 38% births in health facilities

– Cold chain only available in 80% of health facilities– ~30% of cold chain not functional

6-months pilot OCC use in 11 HC in 2 districts (Viengthon and Bolikhanh)– Comparison in 2 neighboring districts with similar characteristics (13 HC) with HepB-BD ICC

Kolwaite et al. Hepatitis B vaccine stored outside the cold chain setting: a pilot study in rural Lao PDR. Vaccine. 2016; 34(28):3324-30.

Solomon Islands: 2015-2016

6-month HepB-BD OCC pilot in 3 provinces (28 days) Timely HepB-BD coverage significantly increased for

– Health facility births (30% to 68%)– Home births (4% to 24%)

HCW stored and handled vaccines well Deviations > 37°C were rare Biggest challenges

– Vaccine stock-out – Vaccine wastage– Lack of staff for outreach to home births

Scale-up currently underway to other provinces/sitesBreakwell L, Anga J, Dadari I, Sadr-Azodi N, Ogaoga D, Patel M. Evaluation of storing hepatitis B vaccine outside the cold chain in the Solomon Islands: Identifying opportunities and barriers to implementation. Vaccine 2017; 35(21):2770-2774.

Indonesia: 1996 Only country that provides HepB-BD Uniject OCC as part of EPI Early assessments:

– Group 1: Birth dose with Uniject stored OCC for up to one month– Group 2: Birth dose with Uniject stored ICC– Group 3: Control group standard disposable syringe and 10-dose HepB-BD vial stored

ICC

Otto et al. At birth immunization against hepatitis B using a novel pre-filed immunization device stored outside the cold chain. Vaccine 2000 18: 498-502.

All community midwives said they could deliver vaccine earlier because vaccine in their home

No VVM changes

No negative comments about OCC

No evidence they were lax on cold chain for other vaccines

No confusion with other vaccines

Indonesia: 1996

Sutanto et al. Home delivery of heat stable vaccines in Indonesia.: outreach immunization with a prefilled single use injection device. Bull WHO 1999; 77(2):119-126

Current Situation at the Global Level

http://www.who.int/immunization/policy/position_papers/hepatitis_b/en/

Status of Availability of CTC —Hepatitis B Vaccines

SAGE urged all vaccine manufacturers with prequalified monovalent Hep B vaccine to pursue regulatory approval for CTC use (2016)

Two manufacturers have expressed interest in seeking licensure of an on-label indication for hepatitis B vaccines to be used in a CTC

Manufacturers Presentation Licensure for Hep B

use

WHO

prequalification

VVM

type

Shelf life

(months)

LG Life Science,

South Korea

1 dose 45°C for 4 days

37°C for 28 days

No 30 36

Biologicals E,

Ldt, India

10- and 20-

dose

No No 30 24

Slide from Immunization Practices Advisory Committee Meeting, July 11 2018

Conclusions

Children vaccinated with HepB-BD OCC had an immune response as good as those vaccinated using vaccine stored in the cold chain

Safety of HepB-BD stored OCC same as ICC Timely HepB-BD increased by using vaccine OCC especially for home births Health workers and mothers accepted use of HepB-BD OCC Vaccine availability contributor to increase in coverage irrespective of strategy WHO SAGE and IPAC finally promoting use of HepB-BD OCC after >20 years of

evidence Challenges

– Reluctance to scale-up use of HepB-BD OCC (off-label use)– Lack of manufacturer interest to relabel for CTC use (potential increase in

pricing)

For more information, contact CDC1-800-CDC-INFO (232-4636)TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Thank You

Vaccine Manufacturer

(Country)

Format (paediatric dose) Shelf life (months) VVM Type

Engerix B GSK (Belgium) 1-, 10-, and 20-dose vials 24 None

Euvax B LG Chemical Ltd (Korea) 1- and 10-dose vials 36 30

Heberbiovac HB Center for Genetic Engineering

and Biotechnology (Cuba)

1- and 10-dose vials 48 30

Hepatitis B vaccine,

recombinant

PT BioFarma (Indonesia) 1-dose in Uniject 24 30

Hepatitis B vaccine (rDNA) Serum Institute of India Ltd

(India)

1-dose vial or ampoule, and

10-dose vial

36 30 (no VVM on

ampoule)

Shanvac-B Shanta Biotechnics (India) 1-, 2-, 6-, 10-, and 20-dose

vials

36 30

08/08/2018 24

Current WHO Prequalified Hepatitis B Vaccines for Pediatric Use

CTC | 08 August 2018

Comparing CTC to OCC

CTC

• Label specifications in terms

of highest temperature and

duration: 40° or more,

minimum of three days

• Tested, Licensed,

prequalified – on label use

• VVM plus Peak Threshold

Temperature Indicator

OCC

• No specificity in terms of

temperatures and time

• Not Tested (for safety &

stability), Licensed &

Prequalified – Off-license

use

• VVM monitoring, but no

Peak Threshold Temperature

Indicator

Suggested product profile characteristics for CTC prequalified hepatitis B vaccines

Product Profile Characteristic Minimally Acceptable Target Optimal Target

Time and temperature for CTC use To be determined. 28 days at 40°C

Doses per container and container type Single-dose containers* – especially for

outreach to homes, though use by lesser-

trained health workers may not be

possible.

Multi-dose containers – especially for

birthing facilities without cold chain

where vaccine wastage is expected to be

low within the CTC duration timeframe.

Single-dose containers* – for all scenarios

except where lesser trained health

workers are meant to deliver the birth

dose.

Single dose compact Prefilled Autodisable

Devices – for use by lesser trained health

workers and where shown to be cost-

effective.

Temperature indicator Vaccine vial monitor 30 (VVM30) or above

with separate peak temperature

threshold indicators (PTTIs) accompanying

the vaccine during CTC use

VVM with integrated threshold indicator

(VVM-TI)

Slide from WHO IPAC Meeting July 2018