Understanding of the biology and modes of transmission of hepatitis viruses has significantly improved over the last decades. Even so, prophylactic vaccines are only available for hepatics A (HAV) and B (HBV). Although an enormous amount of basic and clinical research has been performed in trying to develop a vaccine against hepatitis C (HCV), it is unlikely that either a prophylactic or therapeutic HCV vaccine will be available soon. A phase 3 vaccine trial against hepatitis E (HEV) in China resulted in the vaccine being licensed there; it is currently unknown whether or when this vaccine will become available in other countries. Prophylaxis of HCV, HDV (for patients) and HEV infection therefore involves avoiding the routes of exposure to the respective hepatitis viruses discussed in detail in chapters 1–4.
HAV and HEV 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. Several recent outbreaks of HEV infection have occurred in different regions of the world were associated with significant morbidity and mortality, e.g., the recent outbreak of HEV in refugee camps in South Sudan of more than 5000 acute jaundice cases within five months showed a fatality rate of about 10% in pregnant women (CDC 2013). In addition, HEV (but not HAV) can also be a zoonosis. Consumption of offal and wild boar is associated with a risk for HEV. This may have significant implications for immunosuppressed patients as cases of chronic HEV with the development of advanced fibrosis have been described in patients after organ transplantation (Wedemeyer 2012). HEV has frequently been detected in the pork and occupational exposure has frequently been identified as a risk factor for being anti-HEV positive (Pischke 2014). Importantly, zoonotic HEV is usually caused by HEV genotype 3 while HEV genotype 1 can be found in travel-associated HEV (Wedemeyer 2012; Pischke 2014). It is important to note that HEV is heat sensitive (>70°C; >2 min) (Johne 2016). HAV (Hettman 2016) and HEV can also be transmitted by blood transfusion as recently confirmed in a large study from England screening more than 200.000 blood products (Hewitt 2014). Of note, up to 10% of pooled plasma products can contain HEV RNA in Europe. The overall relevance of HEV transmission by blood products is discussed in more detail in chapter 4. Distinct genetic polymorphisms may be associated with the risk of becoming infected with HAV (Zhang 2012) and HEV (Wedemeyer 2012).
HBV and HDV were frequently transmitted by blood transfusion before HBsAg testing of 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 and thus strict and careful application of standard hygienic precautions for all medical interventions are mandatory, and not only in endemic areas. This holds true in particular for immunocompromised individuals who are highly susceptible to HBV as HBV is characterised by a very high infectivity (Wedemeyer 1998). Moreover, immunosuppressed patients are at risk for reactivation of occult HBV after serological recovery from HBV. Treatments with high doses of steroids and rituximab have especially been identified as major risk factors for HBV reactivation (Loomba 2008). The FDA highlighted attention to the potential risk for fatal HBV reactivations in patients receiving B cell depleting therapies (Di Bisceglie 2014). However, also other immunosuppressive drugs may lead to increased HBV replication and thus all patients receiving immune modulating agents should be screened for HBsAg and anti-HBc. The need for pre-emptive antiviral differs according to the HBV serostatus (anti-HBs positive or negative, HBsAg positive or negative) and the level of immune-modulation induced by the respective drug (Perillo 2015).
After a new diagnosis of HBV, family members of the patient need to be tested for their immune status against HBV. Immediate active vaccination is recommended for contacts who are anti-HBc negative. 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 immunisation with anti-HBs as soon as possible, preferentially within 2–12 hours (Cornberg 2011).
Less than 1% of individuals who are exposed to HCV by an injury with contaminated needles develop acute HCV infection. At Hannover Medical School, no HCV seroconversions occurred after 166 occupational exposures with anti-HCV positive blood over six years (2000–2005). A systematic literature review identified 22 studies including a total of 6956 injuries with HCV contaminated needles. Only 52 individuals (0.75%) became infected. The risk of acute HCV 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. Global differences in HCV seroconversion rates may suggest that genetic factors provide some level of natural protection. Indeed, distinct polymorphisms have been identified that are associated either with protection from HCV or with a higher likelihood of recovering spontaneously from acute HCV (Schaefer 2011). Factors associated with a higher risk of HCV transmission are likely to be HCV viraemia 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 episode include:
Sexual transmission has clearly been identified as a risk for HCV, as about 10–20% of patients with acute HCV report this as having been a potential risk factor (Deterding 2009). 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 positive patients followed over periods of more than four years could not identify any cases of confirmed HCV transmission. The risk for HCV transmission has recently been estimated to be about 1 per 190,000 sexual contacts (Terrault 2013). There was no association between specific sexual practices and HCV infection in monogamous heterosexual couples. Thus, current guidelines do not recommend the use of condoms in monogamous heterosexual relationships (EASL 2011). However, this does not hold true for HIV positive gay men. Several outbreaks of acute HCV have been described in this population (Boesecke 2012, Bradshaw 2013). Transmission was associated with 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.
Due to the low HCV prevalence in most European countries and 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 Paediatric Hepatitis C Virus Network 2005). Transmission rates are higher in HIV positve women so pregnant women should be tested for HCV. Other factors possibly associated with high transmission rates are the level of HCV viraemia, maternal intravenous drug use, and the specific HLA types of the children. Immunoregulatory changes during pregnancy reduce the pressure by cytotoxic T cells which may select viruses with optimised replication fitness and thereby facilitate vertical transmission (Honegger 2013). Cesarean sections are not recommended for HCV RNA positive mothers as there is no clear evidence that these reduce transmission rates. It is not clear yet whether direct-acting antivirals (DAAs) against HCV can reduce transmission rates of HCV when given during the last trimester of pregnancy. HCV therapy should be considered in all HCV positive women who want to become pregnant (EASL 2017). Children of HCV positive mothers should be tested for HCV RNA after one month as maternal anti-HCV antibodies can be detected for several months after birth. Mothers with chronic HCV can breastfeed their children as long as they are HIV negative and do not use intravenous drugs (European Paediatric Hepatitis C Virus Network 2001, EASL 2011). This clinical recommendation is supported by experimental data showing inactivation of HCV by human breast milk in a dose dependent manner. Of note this effect is specific to human breast milk and the mechanism is destruction of the lipid envelope but not of viral RNA or capsids (Pfaender 2013).
Medical treatment still represents a risk factor for acquiring HCV. This has been demonstrated for Spain (Martinez-Bauer 2008), Italy (Santantonio 2006), France (Brouard 2008) and the US (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, Deterding 2016). Thus, medical treatment per se still represents a significant risk factor for HCV – even in high-income countries. Strict adherence to universal precaution guidelines is urgently warranted.
HCV is surprisingly stable and can be infectious for at least six months if stored in liquids at 4° C (Ciesek 2010) and for up to three weeks in bottled water (Doerrbecker 2013). HCV is also associated with filter material used by people who inject drugs (Doerrbecker 2013). Moreover, HCV shows a prolonged survival in lipid-containing fluids such as propofol (Steinmann 2011). These findings demonstrate that it is critical to strictly follow hygienic standards in medical practice to prevent HCV transmission.
The first active HAV vaccine 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 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 and 2 month schedule (Hammitt 2008). Of note, maternal anti-HAV positive children vaccinated at age 6 months have lower vaccine responses and are less likely to maintain HAV antibodies through age 10 years (Spradling 2016). Patients with chronic liver disease do respond to vaccination but may display lower anti-HAV titres (Keeffe 1998). HAV vaccination in HIV positive people is more effective if HIV replication is already suppressed by antiretroviral therapy and patients have higher CD4+ T-cell counts (Tseng 2013). A combined vaccine against HAV and HBV is 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, gay men, people in contact with patients with HAV, and individuals with chronic liver diseases. Some studies have suggested that patients with chronic HCV have a higher risk of developing fulminant HAV (Vento 1998), although this finding has not been confirmed by other investigators (Deterding 2006). The recommendation to vaccinate all patients with HCV against HAV has recently been challenged. A meta-analysis including studies on mortality from HAV in people with HCV revealed a number-needed-to-vaccinate to prevent one death of more than 800,000 (Rowe 2012), thus questioning the use of routine HAV vaccination in HCV positive people.
The implementation of childhood vaccination programmes 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).
Several long-term follow-up studies after complete HAV vaccinations have been published in recent years (Stuurman 2016). Anti-HAV titres usually 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) which also has been confirmed by systematic reviews (Ott 2012). Based on these studies it was estimated that protective anti-HAV antibodies should persist for ≥30 years after successful vaccination (Hammitt 2008, Bovier 2010, Spradling 2016).
A single dose administration of an inactivated HAV vaccine can induce protective antibody levels which can persist for more than 10 years. Thus, future research is needed to explore single dose vaccine approaches which would be cost-saving and increase overall vaccine coverage (Ott 2013).
The HBV vaccine was the first vaccine able to reduce the incidence of cancer. In Taiwan, a significant decline in cases of childhood hepatocellular carcinoma (HCC) has been observed since the implementation of programmes to vaccinate all infants against HBV (Chang 1997). This landmark study impressively highlighted the usefulness of universal vaccination against HBV in endemic countries. The findings were confirmed in various additional studies and a reduced incidence of HCC not only in infants but also in young adults has recently been shown in a 30 year follow-up of a randomised neonatal vaccination study (Qu 2014). 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 HBV. It should be possible to eradicate HBV by worldwide implementation of this recommendation, because humans are the only epidemiologically relevant host for HBV.
The first plasma-derived HBV 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 month timetable.
Who should be vaccinated? The German Guidelines (Cornberg 2011)
*This list is based on the German Guidelines for Hepatitis B and can be considered as a recommendation for most countries.
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 (Coates 2001). Responses are lower in elderly people and much weaker in immunocompromised persons such as organ transplant recipients, patients receiving haemodialysis and HIV positive individuals who have low CD4 counts. 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 co-administration of adjuvants and cytokines (Cornberg 2011). The response to vaccination should be monitored 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).
People who are not immune who have been in contact with HBV-contaminated materials (e.g., needles) or who have had recent sex with an HBV positive person should undergo active-passive immunisation (active immunisation plus HBV immunoglobulin) as soon as possible – preferentially within the first 48 hours of exposure to HBV. Individuals previously vaccinated but who have an anti-HBs titre of <10 IU/L should also be vaccinated both actively and passively. No action is required if an anti-HBs titre of >100 IU/L is documented; active vaccination alone is sufficient for persons with intermediate anti-HBs titres between 10 and 100 IU/L (Cornberg 2011).
Several hundred million individuals have been vaccinated against HBV. The vaccine is very well tolerated. Injection site reactions in the first 1 to 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 seldom 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 HBV vaccination causes and induces acute episodes of multiple sclerosis or other demyelinating diseases have been repeatedly discussed 10 to 15 years ago (Geier 2001, Hernan 2004, Girard 2005). However, there is no scientific proof of 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).
Numerous studies have been published in recent years investigating the long-term efficacy of HBV vaccination. After 10 to 30 years, between one third and two thirds of vaccinated individuals have completely lost anti-HBs antibodies and only a minority maintain titres 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 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 vaccinated infants still seroconvert to anti-HBc indicating active HBV infection (18%) and some children even develop chronic HBV (van der Sande 2007). A very high efficacy of a single booster vaccine after 15 to 30 years has been shown in several studies (e.g. Su 2013, Bruce 2016) suggesting that immune memory is maintained in the majority of initial vaccine responders. However, protective titres are frequently lost again a few years after booster vaccination. Overall, these data indicate that no regular HBV booster doses are recommended in vaccine responders. Still, booster vaccinations should be considered in persons at risk including medical health professionals.
Infants of HBsAg positive mothers should be immunised 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 viraemia, of >200.000 million IU/mL, should receive in addition antiviral therapy with a potent HBV polymerase inhibitor (EASL 2012). Randomised trials showed that both tenofovir (Pan 2016) and telbivudine (Han 2011, Wu 2015) can reduce the risk for vertical HBV transmission when antiviral treatment is started during the third trimester of pregnancy. 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 (FDA pregnancy exposure registries 2013). If active/passive immunisation has been performed, there is no need to recommend cesarean section (Wong 2014). Mothers of vaccinated infants can breastfeed unless antiviral medications are being taken by the mother, which can pass through breast milk. If exposure to HBV polymerase inhibitors to infants by breast milk is associated with any specific risk is currently unknown.
There are no prophylactic or therapeutic vaccines against HCV. As reinfections after spontaneous or treatment-induced recovery from HCV infection have frequently been reported, the aim of a prophylactic vaccine would 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 (Rehermann 2013). 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 negative individuals who were exposed to HCV by occupational exposure or as household members of HCV positive partners, but who never became HCV RNA positive. A 10-year longitudinal study involving 72 healthcare workers showed that about half of the individuals developed HCV specific T cell responses detectable most frequently four weeks after exposure (Heller 2013). These observations suggest that HCV specific T cells may be induced upon subclinical exposure and may contribute to protection against clinically apparent HCV infection. However, it might also be that repeated subinfectious exposure to HCV may not protect from HCV but rather increase susceptibility by expansion of regulatory T cells which suppress effector T cells (Park 2013). T cell responses are usually much weaker in chronic HCV. 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 2013, Owusu Sekyere 2015).
To what extent humoral immune responses against HCV contribute to spontaneous clearance of acute HCV is less clear. Higher levels of neutralising antibodies early during the infection are associated with viral clearance (Pestka 2007). Antibodies with neutralising properties occur at high levels during chronic infection, although HCV constantly escapes these neutralising antibodies (von Hahn 2007). Yet, no completely sterilising humoral anti-HCV immunity exists in the long-term after recovery (Rehermann 2013). Attempts to use neutralising antibodies to prevent HCV reinfection after liver transplant have not been successful even though onset of viraemia may be delayed by administration of HCV antibodies (Gordon 2011, Chung 2013). Still, novel neutralising antibodies have been developed which also prevented HEV infection in a humanised mouse model of HCV infection (Desombere 2016). Furthermore, induction of neutralising antibodies by vaccination was possible with protected infection in mice (Li 2016).
Few phase 1 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. Particular broad, rather strong and sustained CD4 and CD8+ T cell responses could be induced by a vaccine based on human and chimpanzee adenoviruses expressing non-structural HCV proteins (Barnes 2012, Swadling 2014) Studies in chimpanzees have shown that it is likely that a vaccine will not 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 HCV to chronic infection. In any case, there are no vaccine programmes that have reached phase 3 yet (Halliday 2011). Therapeutic vaccination against HCV has also been explored (Klade 2008, Wedemeyer 2009, Torresi 2011). These studies show that induction of HCV specific humoral 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). Therapeutic vaccination was also able to enhance responses to interferon α and ribavirin treatment (Pockros 2010, Di Bisceglie 2014). However, even with potent viral-vector based vaccines, most patients do not restore HCV specific T cell immunity upon vaccination (Swadling 2016) – unless there is a mismatch between the endogenous virus and the vaccine (Kelly 2016). Considering the approval of extremely potent and safe direct acting antivirals against HCV, therapeutic vaccination is no longer explored as a treatment concept for chronic HCV.
A phase 2 vaccine trial performed in Nepal with 2000 soldiers showed a 95% efficacy for an HEV recombinant protein (Shrestha 2007). However, the development of this vaccine was stopped. In September 2010, data from a very large phase 3 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 HEV. Further observation confirmed the ability of the vaccine to prevent clinical hepatitis. However, the induction of HEV antibodies does not induce sterilising immunity and thus does not completely protect from HEV infection. Still, vaccination largely reduces infection rates with a RR of 0.15 during further follow-up of the Chinese vaccine trial (Huang 2014). Similarly, naturally acquired immunity against HEV does not provide complete protection (Huang 2014). It remains to be formally determined if the HEV genotype 1-derived vaccine also prevents against zoonotic HEV genotype 3, while the vaccine was effective in China against HEV genotype 4. HEV-specific T cell immunity has been shown to be cross-HEV genotype-specific in patients with acute HEV (Gisa 2016). One can therefore assume that the vaccine should induce pan-genotypic immunity. Moreover, vaccine efficacy in special risk groups such patients with end-stage liver disease, immunocompromised individuals or elderly persons are unknown. Finally, the duration of protection needs to be determined as antibody titres have been shown to decline after vaccination (Shrestha 2007, Zhu 2010, Wedemeyer 2011). To what extent cellular immunity against HEV is important in the context of HEV vaccination is also unknown but HEV specific T cell response has been associated with the control of chronic (Suneetha 2012) and acute (Gisa 2016, Brown 2016) HEV infection. It is currently unknown if and when the 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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