24 Augustus 2023 Episode 346 What about Hepatitis E vaccines?

Episode 345: Hepatitis E and the need for vaccination?

Dear colleagues,

While vaccines for hepatitis A and B/D are widely applied and the search for a vaccine against hepatitis C is a top priority, at first view, it seems a bit strange that existing vaccines against hepatitis E with proven efficacy receive much less attention, despite the fact that this form of hepatitis can be quite pathogenic as well.

Par 1 To set the stage:

1. For those, who are confused about the ABCDE of hepatitis, see this overview

Pisano WJG 2021 vol 27 p 4018

2. Recent summary by WHO (Ep 345-1 July 2023)

Incidence: every year 20 million HEV infections worldwide,

leading to an estimated 3.3 million symptomatic cases of hepatitis E.

Hepatitis E is found worldwide, but the disease is most common in East and South Asia.

Mortality: approximately 44 000 deaths in 2015  (=  3.3 % of viral hepatitis mortality).

A vaccine to prevent hepatitis E virus infection is licensed in China, but not elsewhere.

3. Worldwide distribution (Ep 345-2)

IgG seroprevalence in A and viral RNA in C: South-East Asia is hotspot

4. Genotypes: 4 (out of 8) are important in humans (Ep 345-3)

5. ECDC: last report 2017  (Ep 345-4)

Increasing numbers of clinical cases (approx. 6000 in 2015) with limited mortality. 

To compare with 16, 187 cases of hepatitis B and 14,560 cases of hepatitis C in EU/EEA in 2021.

Much higher seroprevalence (antibodies) against hepatitis E: up to 20 % in France and Germany, with still higher levels in certain occupations persons working in slaughterhouses, forestry workers, hunters, farmers or veterinarians → Many asymptomatic infections.

Par 2 More on Virology: Ep 345-3; -5 and -6

Par 3 Clinical manifestations Ep 345-3; -5 and -6

Factors in course:

1. Host:

• Immunocompetent, non-pregnant: mostly self-limiting
• Pre-existing chronic liver disease: at risk of liver failure
• Pregnant women:
  • at risk for fulminant even fatal hepatitis: up to 20-30 % in third trimester
  • obstetrical complications,
  • but also cerebral edema,  intravascular coagulopathy with mortality
• Vertical transmission:
  • may lead to miscarriage, pre-term, and/or stillbirth
  • Newborns: hepatitis may be asymptomatic or fulminant with mortality
• Immunocompromised:  High risk of chronic hepatitis and extra-hepatic manifestation

2. Viral genotype:

• HEV-1 and -2 mainly cause acute illness and can lead to acute liver failure or acute-on-chronic liver failure
• HEV-3 and -4 infections are often asymptomatic
  • Rarely lead to acute-on-chronic liver failure in elderly or patients with underlying liver disease.
  • Immunocompromised subjects risk of chronic hepatitis

Diagnostic approach:

Clearly be more careful in immunocompromised: lower threshold of suspicion to test for HEV RNA  

Treatment: Ribavirin has been used:

• In acute Hep E: few case reports of beneficial effect, but no controlled studies, hence spontaneous healing possible
• In chronic Hep E of immunocompromised patients: 600 mg Ribavirin for at least 3 months: 78 % success rate in retrospective study

Par 4 Vaccines Ep 345-7

All candidates based on recombinant capsid

rHEV [56 kDa] by Glaxo Smith Kline and HEV 239 derived from genotype 1 and the third (p179) is based on HEV genotype 4.

HEV 239 and 179 have been developed in China, where genotype 4 is dominant.

As shown in the Table, most clinical experience is with HEV239. 

 Ep 345-8 : Zhang NEJM 2015: Very large phase 3 study (> 110,000 participants) with prolonged (55 months) follow-up after 3 doses 30 µg HEV 239 IM as compared to Hep B vaccine.

Overall 60 cases of hepatitis E:  7 in vaccine group and 53 in control → vaccine efficacy of 86.8 %

HEV antibodies in originally seronegative vaccinees: 87 % at 4.5 years after vaccination

HEV antibody titers developed in 9% in the control group.

Clearly, The HEV 239 vaccine has been proven to be safe, effective, and highly immunogenic

Ep 345-9: Shresta NEJM 2007: rHEV56 GSK

Much smaller phase 3 of only 2000 subjects in Nepal over 800 days after 3 doses of 20 µg

Very high efficacy: 3 infections in vaccine group versus 66 in placebo group = 95 %

LIMITATIONS of both studies: no available data on HEV vaccination:

• in low-income countries where HEV genotypes 1 and 2 are prevalent, but a favorable result is to be expected, since both HEV56 and HEV339 are based on genotype 1.   
• in children, people with underlying conditions such as cirrhosis, or immunosuppressed populations.

Cost-effectiveness? Studies in China in pregnant women in epidemic areas, women of childbearing age, and individuals of advanced age showed that screening-and-vaccination approach was more cost-effective

than the universal vaccination strategy in these populations

Nevertheless there seems potential for these vaccines to mitigate or prevent large outbreaks in high-risk setting such as large refugee camps where sanitation cannot be guaranteed: e.g. successful MSF campaign in refugee camp with Hep E outbreak in Southern Sudan in 2022.  

CONCLUSIONS:

1. Hepatitis E is usually self-limiting in immunocompetent non-pregnant individuals without underlying liver disease, but is potentially very dangerous for pregnant women and their offspring, in subjects with chronic liver disease and in immune compromised subjects, with also increased susceptibility in the very young and old individuals. There is certainly also an increased risk for large and deadly outbreaks in situations of civil wars etc.
2. At least two vaccines, based on recombinant capsid have shown efficacy in the general adult population during phase 3 trials.  They have the potential to mitigate the burden of disease and mortality.
3. Although confirmation of safety and efficacy in high risk populations and in low income countries is needed, it is a bit surprising that international organizations and agencies are taking a “wait and see” attitude.    

Best wishes,

Guido