Risk Wise

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Hepatitis B virus:

its vaccines and global epidemiology

SangJeom Ahn, Vaccine Research Institute, Crucell|Berna Biotech, Korea

or thousands of years hepatitis has been one of the most

serious diseases to affect human beings. According to several

reports epidemic jaundice, one of the representative symp-

toms of hepatitis B, was described as early as the fifth century BC

by Hippocrates. Much scientific investigation throughout the ages

has also focused on identifying the etiological agent of the disease.

In 1965 Baruch Blumberg identified the Australian antigen,

HBsAg (hepatitis B surface antigen) in the serum of patients

suffering from hepatitis. Shortly after in 1970, Dane identified

the complete hepatitis B virion (HBV) causing hepatitis B, there-

after known as the Dane particle. Saul Krugman subsequently

clarified the epidemiology of hepatitis B and its prevention. In

1971 he conducted tests on humans – they and chimpanzees are

the only species to host HBV – which involved giving them heat-

inactivated crude HBV-infected serum. From the results it was

proven that giving the boiled HBV-infected serum to humans was

immunogenic and partially protective. Based on Krugman’s exper-

iments, Maurice R. Hilleman at Merck developed the first

plasma-derived subunit vaccine against HBV infection in 1975.

Acute and chronic infections

HBV is a partially double-stranded, enveloped DNA virus belonging

to the hepadnaviridae family that replicates in the liver. When

humans are infected by HBV, it can result in either acute or chronic

infection. Generally, in the case of acute infection, its clinical mani-

festations are highly age-dependent. Newborns commonly do not

show any clinical symptoms, but adults are highly symptomatic.

Occasionally, acute infection can lead to a fatal fulminant hepatitis

in the proportion of one to two per cent. The risk of developing a

chronic infection, defined as the presence of HBsAg in serum for

over six months, is inversely age-dependent. Infants infected in the

perinatal period have a 90 per cent chance of developing chronic

infection, whereas older children and adults are at a much lower risk

with just a six to ten per cent chance. It is reported that there are at

least 200 million chronic carriers around the world, approximately

15 per cent of whom will develop chronic hepatitis and roughly 25

per cent of whom will die of either cirrhosis or hepatic cancer.

Furthermore, chronic infection by HBV results in up to an 80 per

cent chance of contracting hepatic cancer. Accordingly, HBV is one

of the most serious viruses resulting in fatality and vaccination

against it is particularly important.

Importance of vaccination and development of recombinant

subunit vaccines

During the neonatal period, vaccination against HBV with current

plasma-derived or recombinant-derived HBsAg vaccines can protect at

least 95 per cent of infants from HBV infection. Because

of this ability, vaccination has been regarded as one of the

best preventative methods against HBV infection.

It is estimated that there are approximately 100,000 new

hepatitis B cases per year worldwide, and studies focus-

ing on vaccine production technologies have to satisfy the

demands of both developing and developed countries.

Developed countries have been asking for advanced types

of vaccines that provide greater safety, efficacy and conve-

nience, yet many infections occur in developing countries

where they face issues of low income, lack of medical infra-

structure, and lack of cold chain facilities.

As indicated earlier, vaccination to prevent persons

from being infected by HBV was initially conducted

using a plasma-derived subunit vaccine developed with

HBsAg particles derived from the plasma of chronic HBV

carriers as an active pharmaceutical ingredient.

However, the plasma-derived subunit vaccine had

several drawbacks, including limitation of the blood

supply, the risk of contamination with potential adven-

titious viruses, and a high vaccine price due to blood

procurement. To overcome these drawbacks, a recom-

binant subunit vaccine using the S gene, which codes a

small-sized HBsAg protein (S protein), was developed

using S. cerevisiae in 1984. Later, in an attempt to signif-

icantly increase HBsAg productivity by circumvention

of the yeast ‘crab-tree’ effect, commonly encountered in

high cell density cultures of S. cerevisiae produced in

fed-batch culture mode, host replacement with methy-

lotrophic yeasts such as H. polymorpha and P. pastoris

was applied to HepB vaccine production. A recombinant

subunit vaccine based on M gene (preS2-S), which codes

a middle-sized protein (M protein), was also developed

using Chinese hamster ovary cells, and its protective

efficacy is similar to that of the S protein based vaccine.

Recombinant subunit HBV vaccines have many advan-

tages in that they are independent of plasma

procurement, their production cost is much lower, and

their quality control is easier in terms of consistency

when compared to plasma-derived vaccines containing

a variety of HBsAg subtypes (primarily, adr, adw, ayr and

ayw) and genotypes, as well as different sized HBsAg

proteins (S, M and L protein) in the HBsAg particles.

Due to these benefits, recombinant subunit vaccines

with one subtype (primarily S protein) have become

dominant in the market despite the fact that they have