Prophylaxis and vaccination of viral hepatitis

Introduction

Understanding the biology and modes of transmission of hepatitis viruses has significantly
improved over the last decades. Fortunately, the incidence of hepatitis
virus infections has significantly decreased in most areas around the world. Still,
prophylactic vaccines are only available against HAV and HBV. Although an
enormous amount of basic and clinical research has been performed to develop a
vaccine against hepatitis C, it is very unlikely that a prophylactic or therapeutic
HCV vaccine will be licensed within the next 5-7 years. A first phase II vaccine
trial against hepatitis E has been successful; nevertheless, the completion of this
vaccine development will not be in the near future. Prophylaxis for HCV, HDV (for
HBV-infected patients) and HEV therefore must happen by avoiding all possible
routes of exposure to the respective hepatitis viruses discussed in detail in chapters
1-4.

Prophylaxis of hepatitis viruses

Hepatitis A and E
The hepatitis A and E viruses are usually transmitted by oral ingestion of contaminated
food or water. Thus, particular caution is warranted when individuals from
low endemic areas such as Western Europe and the USA travel to countries with a
high prevalence of HAV and HEV infections. We must remember that hepatitis E
can also be a zoonosis. A recent German case-control study identified 32% of all
reported HEV infections as being autochthonous infections, meaning not associated
with travelling to endemic countries (Wichmann 2008). In these patients consumption
of offal and wild boar meat is independently associated with HEV infection.
This may have significant implications for immunosuppressed patients as cases of
chronic hepatitis E with the development of advanced fibrosis have been described
in patients after organ transplantation (Kamar 2008). HEV has frequently been detected
in the meat of pigs; Danish farmers show a higher prevalence of HEV antibodies.
Importantly, zoonotic HEV infection is usually caused by HEV genotype 3
while HEV genotype 1 can be found in travelling-associated hepatitis E. HAV and
HEV are also transmitted by blood transfusion although cases are extremely rare.
Hepatitis B and D
HBV and HDV were transmitted frequently by blood transfusion before HBsAg
testing of all blood products was introduced in the 1970s. Since then, vertical
transmission and sexual exposure have become the most frequent routes of HBV
infection. Medical procedures still represent a potential source for HBV transmissions
and thus strict and careful application of standard hygienic precautions for all
medical interventions are absolutely mandatory not only in endemic areas but also
in Western countries. This holds true in particular for immunocompromised individuals
who are highly susceptible to HBV infection as HBV is characterized by a
very high infectivity (Wedemeyer 1998). Moreover, immunosuppressed patients are
at risk for reactivation of occult HBV infection after serological recovery from
hepatitis B. Treatments with high doses of steroids and rituximab have especially
been identified as major risk factors for HBV reactivation (Lalazar 2007). After a
new diagnosis of HBV infection, all family members of the patient need to be tested
for their immune status against HBV. Immediate active vaccination is recommended
for all anti-HBc-negative contact persons. HBsAg-positive individuals
should use condoms during sexual intercourse if it is not known if the partner has
been vaccinated.
Hepatitis C
Less than 1% of individuals who are exposed to HCV by an injury via contaminated
needles develop acute HCV infection. At Hannover Medical School, not a single
HCV seroconversion occurred after 166 occupational exposures with anti-HCV
positive blood in a period of 6 years (2000-2005). Earlier studies published in the
mid-nineties suggested higher rates of HCV transmission by needle stick injury.
However, more recent and larger studies have reported significantly lower rates of
acute hepatitis C after needle-stick injury. We recently performed a systematic review
of the literature identifying 22 studies with a total of 6,956 injuries with HCV
contaminated needles. Only 52 individuals (0.75%) became infected. The risk of
acute HCV infection was lower in Europe at 0.42% compared to Eastern Asia at
1.5% (Kubitschke 2007). Thus, the risk of acquiring HCV infection after a needlestick
injury is lower than frequently reported. Worldwide differences in HCV seroconversion
rates may suggest that genetic factors may provide some level of natural
resistance against HCV. Factors associated with a higher risk of HCV transmission
are likely to be the level of HCV viremia in the index patient, the amount of
transmitted fluid and the duration between contamination of the respective needle
and injury. Suggested follow-up procedures after needle stick injury are shown in
Figure 1.
Sexual intercourse with HCV-infected persons has clearly been identified as a risk
for HCV infection, as about 10-20% of patients with acute hepatitis C report this as
a potential risk factor (Table 1). However, there is also large evidence that the risk
of acquiring HCV sexually is extremely low in individuals with stable partnerships
who avoid injuries. Cohort studies including >500 HCV-infected patients followed
over periods of more than 4 years could not identify any cases of confirmed HCV
transmission. Thus, guidelines generally do not recommend the use of condoms in
monogamous relationships. However, this statement does not hold true for HIVpositive
homosexual men. Recently, several outbreaks of acute hepatitis C have
been described in this scenario (Fox 2008; Low 2008). Transmitted cases had more
sexual partners, increased levels of high-risk sexual behaviour (in particular, fisting)
and were more likely to have shared drugs via a nasal or anal route than controls
(Turner 2006).
Due to the low HCV prevalence in most European countries and due to a relatively
low vertical transmission rate of 1-6%, general screening of pregnant women for
anti-HCV is not recommended. Interestingly, transmission may be higher for girls
than for boys (European Pediatric Hepatitis C Virus Network 2005). Transmission
rates may be higher in HIV-infected women so pregnant women should be tested
for hepatitis C. Other factors possibly being associated with high transmission rates
are the level of HCV viremia, maternal intravenous drug use, and specific HLA
types of the children. Caesarean sections are not recommended for HCV RNA
positive mothers as there is no clear evidence that Caesarean sections reduce transmission
rates. Children of HCV-infected mothers should be tested for HCV RNA
after 1 month as maternal anti-HCV antibodies can be detected for several months
after birth. Mothers with chronic hepatitis C can breast-feed their children as long
as they are HIV-negative and do not use intravenous drugs (European Pediatric
Hepatitis C Virus Network 2001).
The Spanish Acute HCV study group has recently identified hospital admission as a
significant risk factor for acquiring HCV infection in Spain (Martinez-Bauer 2008).
The data are in line with other reports from Italy (Santantonio 2006) and the USA
(Corey 2006). We have recently reported data from the German Hep-Net Acute
HCV studies and found 38 cases (15% of the entire cohort) of acute HCV patients
who reported a medical procedure as the most likely risk factor for having acquired
HCV (Deterding 2008). The majority of those were hospital admissions with surgery
in 30 cases; other invasive procedures including dental treatment were present
in only 4 cases. Medical procedures were significantly more often the probable
cause of infection in patients older than 30 years of age (p = 0.002) but not associated
with disease severity or time from exposure to onset of symptoms. Thus, medical
treatment per se represents a significant risk factor for HCV infection – even in
developed countries. Strict adherence to universal precaution guidelines is urgently
warranted.
Vaccination against hepatitis A
The first active vaccine against HAV was licensed in 1995. The currently available
inactive vaccines are manufactured from cell culture-adapted HAV, grown either in
human fibroblasts or diploid cells (Nothdurft 2008). Two doses of the vaccine are
recommended. The second dose should be given between 6 and 18 months after the
first dose. All vaccines are highly immunogenic and basically all vaccinated healthy
persons develop protective anti-HAV antibodies. Similar vaccine responses are obtained
in children and adults and no relevant regional differences in response to
HAV vaccination have been observed. The weakest vaccine responses have been
described for young children receiving a 0, 1, 2 months schedule (Hammitt 2008).
Patients with chronic liver disease do respond to vaccination but may display lower
anti-HAV titers (Keeffe 1998). Since 1996 a combined vaccine against HAV and
HBV is available that needs to be administered three times, on a 0, 1, 6 months
schedule. More than 80% of healthy individuals have detectable HAV antibodies by
day 21 applying an accelerated vaccine schedule of 0, 7 and 21 days using the combined
HAV/HBV vaccine, and all study subjects are immune against HAV by 2
months (Kallinowski 2003).
HAV vaccines are very well tolerated and no serious adverse events have been
linked with the administration of HAV vaccines (Nothdurft 2008). The vaccine can
safely be given together with other vaccines or immunoglobulins without compromising
the development of protective antibodies.
Vaccination is recommended for different groups of individuals including nonimmune
individuals who plan to travel to endemic countries, medical health professionals,
homosexual men, persons in contact with hepatitis A patients, and individuals
with chronic liver diseases. Some studies have suggested that patients with
chronic hepatitis C have a higher risk to develop fulminant hepatitis A (Vento
1998), however this finding has not been confirmed by several other investigators
(Deterding 2006). The implementation of childhood vaccination programs has led
to a significant and impressive declines of HAV infections in several countries,
justifying further efforts aiming to control the spread of HAV in endemic countries
(Hendrickx 2008). It is important to highlight that most studies have also shown
that HAV vaccination is cost-effective (Rein 2008; Hollinger 2007).
Recently, long-term follow-up studies after complete HAV vaccination have been
published. Interestingly, anti-HAV titers sharply decline during the first year after
vaccination but remain detectable in almost all individuals for at least 10 years after
vaccination. Based on these studies it was estimated that protective anti-HAV antibodies
should persist for at least 27 years after successful vaccination of children or
young adults (Hammitt 2008).
Vaccination against hepatitis B
The hepatitis B vaccine is the first vaccine able to reduce the incidence of cancer. In
Taiwan, a significant decline in cases of childhood hepatocellular carcinoma has
been observed after the implementation of programs to vaccinate all infants against
HBV (Chang 1997). This landmark study impressively highlighted the usefulness
of universal vaccination against HBV in endemic countries. Controversial discussions
are ongoing regarding to what extent universal vaccination against HBV may
be cost-effective in low-endemic places such as the UK, the Netherlands or Scandinavia
(Zuckerman 2007). In 1992 the World Health Organization recommended
general vaccination against hepatitis B everywhere. In the long run, hepatitis B can
be eradicated by worldwide implementation of this recommendation, because humans
are the only epidemiologically relevant virus host. 164 countries have introduced
a hepatitis B vaccine in their national infant immunization schedules by the
end of 2006 (www.who.int; accessed Nov 12th 2008).
The first plasma-derived hepatitis B vaccine was approved by the FDA in 1981.
Recombinant vaccines consisting of HBsAg produced in yeast became available in
1986. In the USA, two recombinant vaccines are licensed (Recombivax® and Engerix-
B®) while additional vaccines are used in other countries. The vaccines are
administered three times on a 0, 1, 6 months schedule.

Who should be vaccinated? (The German guidelines (Cornberg 2007))

• Hepatitis B high-risk persons working in health care settings including
trainees, students, cleaning personnel;
• Personnel in psychiatric facilities or comparable welfare institutions for
cerebrally damaged or disturbed patients; other persons who are at risk because
of blood contact with possibly infected persons dependent on the
risk evaluation, e.g., persons giving first aid professionally or voluntarily,
employees of ambulance services, police officers, social workers, and
prison staff who have contact with drug addicts;
• Patients with chronic kidney disease, dialysis patients, patients with frequent
blood or blood component transfusions (e.g., hemophiliacs), patients
prior to extensive surgery (e.g., before operations using heart-lung machine.
The urgency of the operation and the patient’s wish for vaccination
protection are of primary importance);
• Persons with chronic liver disease including chronic diseases with liver involvement
as well as HIV-positive persons without HBV markers;
• Persons at risk of contact with HBsAg carriers in the family or shared
housing, sexual partners of HBsAg carriers;
• Patients in psychiatric facilities or residents of comparable welfare institutions
for cerebrally damaged or disturbed persons as well as persons in
sheltered workshops;
• Special high-risk groups, e.g., homosexually active men, regular drug users,
sex workers, prisoners serving extended sentences;
• Persons at risk of contacting HBsAg carriers in facilities (kindergarten,
children’s homes, nursing homes, school classes, day care groups);
• Persons travelling to regions with high hepatitis B prevalence for an extended
period of time or with expected close contact with the local population;
• Persons who have been injured by possibly contaminated items, e.g., needle
puncture (see post-exposition prophylaxis);
• Infants of HbsAg-positive mothers or of mothers with unknown HBsAg
status (independent of weight at birth) (see post-exposition prophylaxis);
Routine testing for previous contact with hepatitis B is not necessary before vaccination
unless the person belongs to a risk group and may have acquired hepatitis B
before. Pre-vaccine testing is usually not cost-effective in populations with anti-
HBc prevalence below 20%. Vaccination of an HBsAg-positive individual can be
performed without any danger – however, it is ineffective.
A response to HBV vaccination is determined by the development of anti-HBs antibodies
which detectable in 90-95% of individuals one month after a complete vaccination
schedule (Wedemeyer 2007; Coates 2001). Responses are lower in elderly
people and much weaker in immunocompromised persons such as organ transplant
recipients, patients receiving haemodialysis and HIV-infected individuals. In case
of vaccine non-response, another three courses of vaccine should be administered
and the dose of the vaccine should be increased. Other possibilities to increase the
immunogenicity of HBV vaccines include intradermal application and coadministration
of adjuvants and cytokines (Cornberg 2007). The response to vaccination
should be controlled in high-risk individuals such as medical health profes
sionals and immune-compromised persons. Some guidelines also recommend to test
elderly persons after vaccinations as vaccine response does decline more rapidly in
the elderly (Wolters 2003).

Post-exposure prophylaxis

Non-immune persons who have been in contact with HBV-contaminated materials
(e.g., needles) or who have had sexual intercourse with an HBV-infected person
should undergo active-passive immunization (active immunization plus hepatitis B
immunoglobulin) as soon as possible – preferentially within the first 48 hours of
exposure to HBV. Individuals previously vaccinated but who have an anti-HBs titer
of <10 IU/L should also be vaccinated both actively and passively. No action is
required if an anti-HBs titer of >100 IU/l is documented; active vaccination alone is
sufficient for persons with intermediate anti-HBs titers between 10 and 100 IU/L
(Cornberg 2007).

Safety of HBV vaccines

Several hundred million individuals have been vaccinated against hepatitis B. The
vaccine is very well tolerated. Injection site reactions in the first 1-3 days and mild
general reactions are common, although they are usually not long lasting. Whether
there is a causal relationship between the vaccination and the seldomly-observed
neurological disorders occurring around the time of vaccination is not clear. In the
majority of these case reports the concomitant events most likely occurred coincidentally
and are independent and not causally related. That hepatitis B vaccination
causes and induces acute episodes of multiple sclerosis or other demyelating diseases
is repeatedly discussed (Geier 2001; Hernan 2004; Girard 2005). However,
there are no scientific facts proving such a relationship. Numerous studies have not
been able to find a causal relationship between the postulated disease and the vaccination
(Sadovnick 2000; Monteyne 2000; Ascherio 2001; Confavreux 2001; Institute
of Medicine Report 2002; CDC 2004; Schattner 2005)

What is the long-term immunogenicity of the hepatitis B vaccination?

Several studies have been published in recent years investigating the long-term efficacy
of HBV vaccination. After 10-15 years, between one third and two thirds of
vaccinated individuals have completely lost anti-HBs antibodies and only a minority
maintain titers of >100 IU/L. However, in low/intermediate endemic countries
such as Italy, this loss in protective humoral immunity did not lead to many cases of
acute or even chronic HBV infection (Zanetti 2005). To what extent memory Band
T-cell responses contribute to a relative protection against HBV in the absence
of anti-HBs remains to be determined. Nevertheless, in high-endemic countries
such as Gambia a significant proportion of infants develop anti-HBc indicating active
HBV infection (18%) and some children develop chronic hepatitis B (van der
Sande 2007). Thus, persons at risk should receive booster immunization if HBs
antibodies have been lost.

Prevention of vertical HBV transmission

Infants of HBsAg positive mothers should be immunized actively and passively
within 12 hours of birth. This is very important as the vertical HBV transmission
rate can be reduced from 95% to <5% (Ranger-Rogez 2004). Mothers with very
high HBV viremia, of >50 million IU/ml, should receive in addition antiviral therapy
with a potent HBV polymerase inhibitor (European Association For The Study
Of The Liver 2008). If active/passive immunization has been performed, there is no
need to recommend Caesarean section. Mothers of vaccinated infants can breast
feed unless oral antiviral medications are being taken by the mother, which can be
detected in the breast milk.

Vaccination against hepatitis C

No prophylactic or therapeutic vaccine against hepatitis C is available. As reinfections
after spontaneous or treatment-induced recovery from hepatitis C virus
infection have frequently been reported, the aim of a vaccine will very likely be not
to prevent completely an infection with HCV but rather to modulate immune responses
in such a way that the frequency of evolution to a chronic state can be reduced.
HCV specific T-cell responses play an important role in the natural course of HCV
infection. The adaptive T-cell response is mediated both by CD4+ helper T-cells
and CD8+ killer T-cells. Several groups have consistently found an association
between a strong, multispecific and maintained HCV-specific CD4+ and CD8+ Tcell
response and the resolution of acute HCV infection. While CD4+ T-cells seem
to be present for several years after recovery, there are conflicting data whether
HCV-specific CD8+ T-cells responses persist or decline over time. However, several
studies have observed durable HCV-specific T-cells in HCV-seronegative individuals
who were exposed to HCV by occupational exposure or as household members
of HCV-positive partners, but who never became HCV RNA positive. These
observations suggest that HCV-specific T-cells may be induced upon sub-clinical
exposure and may contribute to protection against clinically apparent HCV infection.
T-cell responses are usually much weaker in chronic hepatitis C. The frequency
of specific cells is low but also effector function of HCV-specific T-cells is
impaired. Different mechanisms are discussed as being responsible for this impaired
T-cell function, including higher frequencies of regulatory T-cells (T-regs),
altered dendritic cell activity, upregulation of the inhibitory molecules PD-1 on Tcells
and many others. HCV proteins can directly or indirectly contribute to altered
functions of different immune cells.
To what extent humoral immune responses against HCV contribute to spontaneous
clearance of acute hepatitis C is less clear. Higher levels of neutralizing antibodies
early during the infection are associated with viral clearance (Pestka 2007). However,
antibodies with neutralizing properties occur at high levels during chronic
infection. Yet, no completely sterilizing humoural anti-HCV immunity exists in the
long-term after recovery (Rehermann 2005).
Few phase I vaccine studies based either on vaccination with HCV peptides, HCV
proteins or recombinant vectors expressing HCV proteins have been completed.
HCV-specific T-cells or antibodies against HCV can be induced by these vaccines
in healthy individuals. However, it will be difficult to prove vaccine efficacy and
vaccine effectiveness. Studies in chimpanzees have shown that it is very unlikely
that a vaccine will be completely protective against heterologous HCV infections.
However, a reasonable approach might be the development of a vaccine that does
not confer 100% protection against acute infection but prevents progression of
acute hepatitis C to chronic infection. This approach has, however, to compete with
antiviral treatment of acute hepatitis C. It is very unlikely that a vaccine against
hepatitis C will be licensed within the next 5-7 years.
Some studies regarding therapeutic vaccination have taken place (Wedemeyer
2006; Klade 2008). These studies show that induction of HCV-specific humoural or
cellular immune responses is possible even in chronically infected individuals.
However, so far neither therapeutic vaccination nor other immunomodulatory attempts
such as treatment with cytokines (interferon gamma; IL-2; IL-10; Il-12) or
toll-like receptor agonists have shown significant clinical benefits in patients with
chronic hepatitis C.

Vaccination against hepatitis E

A phase II vaccine trial performed in Nepal showed a vaccine efficacy of 95% for
an HEV recombinant protein (Shrestha 2007). 2000 soldiers received three vaccines
on a 0, 1, 6 months schedule or placebo and subjects were followed for a median of
800 days. Except injection site reactions side effects were similar in both groups.
Importantly, of the 69 subjects who developed hepatitis E, 66 were in the placebo
group. However, and unfortunately, no phase III study to complete the vaccine’s
development has yet started to our knowledge. Thus, no HEV vaccine will be available
in the next few years. Until then, preventive hygienic measures remain the only
option to avoid HEV infection.