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108 Hepatology 2012
7. Prophylaxis and Vaccination
Heiner Wedemeyer
Introduction
Understanding the biology and modes of transmission of hepatitis viruses has
significantly improved over the last decades. 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 in the
next few years. A first Phase III vaccine trial against hepatitis E has been successful
in China; nevertheless, it is currently unknown if or when this vaccine will become
available in other countries. Prophylaxis of HCV, HDV (for HBV-infected patients)
and HEV infection therefore must still occur by avoiding all 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 US travel to countries with
a high prevalence of HAV and HEV infections. In addition, hepatitis E can also be a
zoonosis. A 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 was 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, Pischke 2010). 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.
Prophylaxis and Vaccination 109
HAV and HEV can also be 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, and not only in
endemic areas. 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, Loomba 2008).
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. Non-immune individuals who have experienced an
injury and were exposed to HBsAg-positive fluids should undergo passive
immunization with anti-HBs as soon as possible, preferentially within 2-12 hours
(Cornberg 2011).
Hepatitis C
Less than 1% of individuals who are exposed to HCV by an injury with
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). A systematic review of
the literature identified 22 studies including 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 needle-stick injury is lower than frequently reported. Worldwide differences in HCV se-roconversion rates may suggest that genetic factors 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 needlestick 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 (Deterding 2009; Table 1). However, there is also evidence
that the risk of acquiring HCV sexually is extremely low in individuals in stable
partnerships who avoid injuries. Cohort studies including more than 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
110 Hepatology 2012
recommend the use of condoms in monogamous relationships (EASL 2011).
However, this does not hold true for HIV-positive homosexual men. Several
outbreaks of acute hepatitis C have been described in this scenario (Fox 2008, Low
2008, van de Laar 2009). 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 associated with high
transmission rates are the level of HCV viremia, maternal intravenous drug use, and
specific HLA types of the children. Cesarean sections are not recommended for
HCV RNA positive mothers as there is no clear evidence that these 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, EASL 2011).
The Spanish Acute HCV Study Group has identified hospital admission as a
significant risk factor for acquiring HCV infection in Spain (Martinez-Bauer 2008).
The data are in line with reports from Italy (Santantonio 2006) and the USA (Corey
2006). We have 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 still 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 both 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). A combined vaccine against HAV and HBV is
Prophylaxis and Vaccination 111
available that needs to be administered three times, on a 0, 1, and 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 were 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 non-immune 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 of
developing fulminant hepatitis A (Vento 1998) although this finding has not been
confirmed by other investigators (Deterding 2006). The implementation of
childhood vaccination programs has led to significant and impressive declines of
HAV infections in several countries, justifying further efforts aiming at controlling
the spread of HAV in endemic countries (Hendrickx 2008). It is important to
highlight that most studies have confirmed that HAV vaccination is cost-effective
(Rein 2008, Hollinger 2007).
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 10-15 years
after vaccination (Van Herck 2011). Based on these studies it was estimated that
protective anti-HAV antibodies should persist for at least 27-30 years after
successful vaccination (Hammitt 2008, Bovier 2010).
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 since 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. It should be possible to
eradicate hepatitis B by worldwide implementation of this recommendation,
because humans are the only epidemiologically relevant host for HBV. 179
countries have introduced a hepatitis B vaccine in their national infant immunization
schedules by the end of 2010, including parts of India and the Sudan (WHO 2011).
The first plasma-derived hepatitis B vaccine was approved by FDA in 1981.
Recombinant vaccines consisting of HBsAg produced in yeast became available in
1986. In the US, 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, and 6 months schedule.
112 Hepatology 2012
Who should be vaccinated? (The German Guidelines (Cornberg 2011))
− 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.
Efficacy of vaccination against hepatitis B
A response to HBV vaccination is determined by the development of anti-HBs
antibodies, 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 hemodialysis 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
Prophylaxis and Vaccination 113
increase the immunogenicity of HBV vaccines include intradermal application and
coadministration of adjuvants and cytokines (Cornberg 2011). The response to
vaccination should be controlled in high-risk individuals such as medical health
professionals and immunocompromised persons. Some guidelines also recommend
testing 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 2011).
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 are 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, Schattner 2005).
Long-term immunogenicity of 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 B and
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.
114 Hepatology 2012
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 high
HBV viremia, of >1 million IU/ml, should receive in addition antiviral therapy with
a potent HBV polymerase inhibitor (European Association For The Study Of The
Liver 2009, Peterson 2011, Han 2011). Tenofovir and telbivudine have been
classified as Category B drugs by the FDA and can therefore be given during
pregnancy as no increased rates of birth defects have been reported. If active/passive
immunization has been performed, there is no need to recommend cesarean section.
Mothers of vaccinated infants can breastfeed unless antiviral medications are being
taken by the mother, which can pass through breast milk.
Vaccination against hepatitis C
No prophylactic or therapeutic vaccine against hepatitis C is available. As re-infections after spontaneous or treatment-induced recovery from hepatitis C virus
infection have frequently been reported, the aim of a prophylactic 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 (Torresi 2011).
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+ T
cell 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 (Wiegand 2007).
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 subclinical 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 (Tregs), altered dendritic cell activity, upregulation of inhibitory
molecules such as PD-1, CTL-A4 or 2B4 on T cells and escape mutations. HCV
proteins can directly or indirectly contribute to altered functions of different
immune cells (Rehermann 2009).
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). Antibodies with neutralizing properties occur at high levels during chronic
infection, although HCV constantly escapes these neutralizing antibodies (von Hahn
2007). Yet, no completely sterilizing humoural anti-HCV immunity exists in the
long-term after recovery (Rehermann 2009). Attempts to use neutralizing antibodies
Prophylaxis and Vaccination 115
to prevent HCV re-infection after liver transplant have not been successful (Gordon
2011).
Few Phase I vaccine studies based either on vaccination with HCV peptides, HCV
proteins alone or in combination with distinct adjuvants or recombinant viral vectors
expressing HCV proteins have been completed (Torresi 2011). HCV-specific T cells
or antibodies against HCV were induced by these vaccines in healthy individuals.
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. In any case, there are no vaccine programs that have reached
Phase III yet (Halliday 2011). Therapeutic vaccination against hepatitis C has also
been explored (Klade 2008, Wedemeyer 2009, Torresi 2011). These studies show
that induction of HCV-specific humoural or cellular immune responses is possible
even in chronically infected individuals. The first studies showed a modest antiviral
efficacy of HCV vaccination in some patients (Sallberg 2009, Habersetzer 2011,
Wedemeyer 2011). Therapeutic vaccination was also able to enhance responses to
interferon α and ribavirin treatment (Pockros 2010, Wedemeyer 2011). Future
studies will need to explore the potential role of HCV vaccines in combination with
direct acting antivirals against hepatitis C.
Vaccination against hepatitis E
A Phase II vaccine trial performed in Nepal with 200 soldiers showed a vaccine
efficacy of 95% for an HEV recombinant protein (Shrestha 2007). However, the
development of this vaccine has been stopped. Since then, in September 2010, data
from a very large Phase III trial were reported involving about 110,000 individuals
in China (Zhu 2010). The vaccine efficacy of HEV 239 was 100% after three doses
to prevent cases of symptomatic acute hepatitis E. However, it is currently unknown
if this HEV genotype 1 vaccine also prevents against zoonotic HEV genotype 3
infections. Moreover, vaccine efficacy in special risk groups such patients with end-stage liver disease, immunocompromised individuals or elderly persons is unknown.
Finally, the duration of protection needs to be determined (Wedemeyer 2011). It is
currently unknown if and when the Chinese vaccine HEV-239 will become
available in other countries. Until then, preventive hygienic measures remain the
only option to avoid HEV infection.
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