Risk Wise

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] 45

Hepatitis A virus:

its vaccines and global epidemiology

John A. Lewis, Crucell NV, Crucell Holland BV, Leiden, The Netherlands

he seminal isolation and propagation of hepatitis A virus

(HAV) in cell culture

in vitro

reported by P. Provost and M.

Hilleman at Merck and Co. in 1979 invited the development

of vaccines against HAV infection according to the paradigms

applied successfully for the national and global control of poliovirus

by formalin inactivated and live attenuated virus vaccines. The

subsequent report of the exquisite immunogenicity of a single dose

of formalin inactivated alum adsorbed vaccine reported by Merck

and Co. in 1989 encouraged the notion that future HAV vaccines

could be delivered conveniently as a simple one-dose prime and

one-dose boost regimen. Indeed, the demonstration of protective

efficacy of even a single priming dose in children in Monroe, New

York, US supported the licensure of the formalin inactivated alum

adsorbed VAQTA

in 1995 by Merck and Co. In parallel, industrial

development at GlaxoSmithKline, Aventis Pasteur and Berna

Biotech led to licensures in the US and Europe of HAVRIX

Avaxim

and Epaxal

respectively.

The manufacture of the four licensed inactivated hepatitis A vaccines is

in many ways similar. All four vaccines are prepared with HAV adapted

to cell culture grown by serial propagation in the substrate and serum

dependent primary human diploid fibroblast cell line MRC-5, and the

HAV is purified to varying extents before inactivation by formalin. The

general industrial manufacturing dependence on the MRC-5 cell

substrate dictates the economic realities of inactivated HAV vaccine cost

of goods, and will have significant implications for any eventual attempts

at global control of HAV. Unlike the inactivated polio virus vaccines first

developed by Jonas Salk and brought to large-scale commercial manu-

facturing consistency and practicality by Sanofi Aventis, VAQTA,

HAVRIX and Avaxim are adjuvanted by adsorption to alum, whereas

Epaxal is adjuvanted by association with virosomes, unilamellar lipo-

somal structures with the hemagluttinin (HA) of influenza A Singapore

virus embedded in PE.

These vaccines have been demonstrated to be very safe, and in many

ways similarly immune potent, inducing more than 85 per cent sero-

conversion of paediatric and adult recipients. However, studies suggest

that the rapidity with which the virosomal Epaxal induces seroconver-

sion makes it especially attractive for those travelling or deployed on

especially short notice to regions where HAV remains endemic. These

vaccines can be used essentially interchangeably for adults, priming with

the vaccine product of one manufacturer and boosting with the vaccine

product of a second. The interchangeability of paediatric dosing in the

US is restricted to VAQTA and HAVRIX. Avaxim is yet to be licensed

with a paediatric formulation.

At the time of writing, the use of HAV vaccines in a two-dose regimen

has led to the accumulation of nearly 15 years worth of data on the long-

term persistence of humoral immunity, demonstrating by

direct assay a level of protective neutralizing antibodies,

which extend over ten years and, from those titres, inferred

levels of protection for nearly 20 years. These findings have

prompted debate over the necessity of a boosting dose, a

discussion which centres on the contribution of immuno-

logical memory to long-term protection. These long-term

persistence data are of course valuable to discussions of the

health economics of inactivated vaccine use in developed

nations. Perhaps of even greater value to global control

would be data on the protective efficacy of a single priming

dose in paediatric recipients in an endemic setting. From

that it might be reasoned that the priming dose would

dispose the vaccinee to a vigorous response to wild type

HAV infection conferring in the paradigm established for

poliovirus, both an especially durable humoral and cell-

mediated immunity with value to the vaccinee as well as

community control of HAV.

In the US, the Advisory Committee on Immunization

Practices (ACIP) recommends a universal childhood immu-

nization with the standard course of a single priming dose

followed by a boost dependent on vaccine at 6-18 month

intervals. Epidemiological studies of the effects of these

recommendations, both in community-based vaccination

studies and in routine vaccination, find the incidences of

HAV to be greatly reduced by these interventions, though

those countries free of endemic disease continue to be liable

to outbreak in seronegative populations. This is down to

the importation of HAV by travellers or foodstuffs imported

from countries where HAV is endemic. An outbreak in the

US of food-borne HAV in November 2003 from green

onions sourced in Mexico led to more than 600 cases, of

which 125 were hospitalized with a case fatality rate of 0.5

per cent. These incidences can be expected to continue in

the western hemisphere until the time that universal immu-

nization is ultimately realized.

As expected, the inactivated HAV vaccines, since their

licensure in the US and numerous other countries world-

wide in 1995, have little altered global patterns of

endemicity of HAV infections. In the western hemisphere

only the US and Canada remain free of endemic disease, as

do most countries in Western Europe and Australia. By

contrast, HAV remains a globally distributed infectious

disease pathogen with nearly four billion persons at risk

worldwide resulting in nearly 1.5 million cases of clinical

hepatitis annually. The transmission of HAV by the faecal