Hepatitis A Strains

Hepatitis A

 

The pathogen and the disease

HAV is a member of the Picornaviridae family that includes both the enteroviruses and rhinoviruses of humans. Being the only species member, it constitutes its own genus named hepatovirus. HAV is a non-enveloped (naked) virus of 27–28 nm diameter without morphological features differentiating it from other picornaviruses. Four structural proteins encapsulate the RNA genome. Neutralization sites for anti-HAV antibodies are mainly contained in two of these proteins. Although six genotypes of HAV have been identified, there appears to be no variation detectable by serology in these neutralization sites. The virus is relatively stable at low pH and moderate temperatures, but is inactivated by high temperature (almost instantly at 85°C/185°F), and by formalin or chlorine. HAV itself is not cytopathic and the liver-cell damage is caused by the cell-mediated immune response.

The clinical course of acute hepatitis A is indistinguishable from other types of acute viral hepatitis. Symptoms typically include fever, malaise, anorexia, nausea and abdominal discomfort, followed by dark urine and jaundice. The severity of disease and mortality increases in older age groups. The convalescence following hepatitis A may be slow, and is characterized by fatigue, nausea and lack of appetite. Complications of hepatitis A include relapsing hepatitis, cholestatic hepatitis and fulminant hepatitis. Fulminant hepatitis occurs in approximately 0.01% of clinical infections and is characterized by rapid deterioration in liver function and a very high fatality rate. Chronic infection with HAV does not occur. No specific antiviral therapy is currently available.

The aetiological diagnosis is made by the demonstration of IgM antibodies to HAV (IgM anti-HAV) in serum. Detection of the virus or viral antigens in the stool is of limited value for routine diagnosis.

 

Strains

Only one serotype of HAV has been identified and a single infection confers lifelong immunity. However, genetic heterogeneity between HAV isolates from different parts of the world has enabled the classification of HAV strains into seven different genotypes, designated I to VII. Four of these have been associated with human disease, I, II, III, and VII. Most human HAV strains belong to genotypes I and III, with 80% of them being genotype I. Genotypes I and III are further divided into subtypes A and B. Genotypes II and VII are represented only by one human strain each, and genotypes IV, V, and VI include strains recovered from simians (Arauz-Ruiz et al., 2001). Genotype IA appears to be the agent responsible for the majority of hepatitis A cases worldwide and has been isolated from all parts of the world. Genotype IB appears to occur in the Mediterranean region, whereas genotype III viruses have been isolated from diverse sources such as Panamanian owl monkeys, drug abusers in Sweden and patients from India and Nepal. Single representatives of genotype II and VII were isolated from individual patients from Sierra Leone and France (Lu et al., 2004). Several studies have indicated that HAV strains in North America mainly belong to subtype IA (Arauz-Ruiz et al., 2001).

Variant(s):  (Click link to the list of all the variant strains)

 

Hepatitis A vaccines

Techniques for growing HAV in cell culture have made it possible to generate sufficient amounts of virus for vaccine production. Several inactivated or live attenuated vaccines against hepatitis A have been developed, but only four inactivated hepatitis A vaccines are currently available internationally. All four vaccines are similar in terms of efficacy and side-effect profile. The vaccines are given parenterally, as a two-dose series, 6-18 months apart. The dose of vaccine, vaccination schedule, ages for which the vaccine is licensed, and whether there is a paediatric and adult formulation varies from manufacturer to manufacturer. No vaccine is licensed for children younger than one year of age.

Three vaccines are manufactured from cell-culture-adapted HAV propagated in human fibroblasts. Following purification from cell lysates, the HAV preparation is formalin-inactivated and adsorbed to an aluminium hydroxide adjuvant. One vaccine is formulated without preservative; the other two are prepared with 2-phenoxyethanol as a preservative. The fourth vaccine is manufactured from HAV purified from infected human diploid cell cultures and inactivated with formalin. This preparation is adsorbed to biodegradable, 150 nm phospholipid vesicles spiked with influenza haemagglutinin and neuramidase. These virosomes are thought to directly target influenza-primed antibody-presenting cells as well as macrophages, thus stimulating a rapid vaccine-induced B-cell and T-cell proliferation in the majority of vaccinees. A combination vaccine containing inactivated hepatitis A and recombinant hepatitis B vaccines has been licensed since 1996 for use in children aged one year or older in several countries. The combination vaccine is given as a three-dose series, using a 0, 1, 6 month schedule.

The Vaccines Available:

 

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine]

 

 

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine containing the antigenic components used in producing HAVRIX® (Hepatitis A Vaccine, Inactivated) and ENGERIX-B® [Hepatitis B Vaccine (Recombinant)]. TWINRIX is a sterile suspension of inactivated hepatitis A virus (strain HM175) propagated in MRC-5 cells, and combined with purified surface antigen of the hepatitis B virus. The purified hepatitis B surface antigen (HBsAg) is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic media containing inorganic salts, amino acids, dextrose, and vitamins. Bulk preparations of each antigen are adsorbed separately onto aluminum salts and then pooled during formulation.

A 1.0-mL dose of vaccine contains 720 ELISA Units of inactivated hepatitis A virus and 20 mcg of recombinant HBsAg protein. One dose of vaccine also contains 0.45 mg of aluminum in the form of aluminum phosphate and aluminum hydroxide as adjuvants, amino acids, sodium chloride, phosphate buffer, polysorbate 20, Water for Injection, traces of formalin (not more than 0.1 mg), and residual MRC-5 cellular proteins (not more than 2.5 mcg). Neomycin sulfate, an aminoglycoside antibiotic, is included in the cell growth media; only trace amounts (not more than 20 ng) remain following purification. The manufacturing procedures used to manufacture TWINRIX result in a product that contains no more than 5% yeast protein.

 

VAQTA® (HEPATITIS A VACCINE, INACTIVATED)

 

VAQTA* [Hepatitis A Vaccine, Inactivated] is an inactivated whole virus vaccine derived from hepatitis A virus (HAV) grown in cell culture in human MRC-5 diploid fibroblasts. It contains inactivated virus of a strain which was originally derived by further serial passage of a proven attenuated strain. The virus is grown, harvested, purified by a combination of physical and high performance liquid chromatographic techniques developed at the Merck Research Laboratories, formalin inactivated, and then adsorbed onto amorphous aluminum hydroxyphosphate sulfate. One milliliter of the vaccine contains approximately 50 units (U) of hepatitis A virus antigen, which is purified and formulated without a preservative. Within the limits of current assay variability, the 50U dose of VAQTA contains less than 0.1 mcg of non-viral protein, less than 4 x 10–6 mcg of DNA, less than 10–4 mcg of bovine albumin, and less than 0.8 mcg of formaldehyde. Other process chemical residuals are less than 10 parts per billion (ppb).

Pediatric/Adolescent Formulation (12 Months Through 18 Years of Age): each 0.5 mL dose contains approximately 25U of hepatitis A virus antigen adsorbed onto approximately 0.225 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

Adult Formulation (19 Years of Age and Older): each 1 mL dose contains approximately 50U of hepatitis A virus antigen adsorbed onto approximately 0.45 mg of aluminum provided as amorphous aluminum hydroxyphosphate sulfate, and 70 mcg of sodium borate as a pH stabilizer, in 0.9% sodium chloride.

 

HAVRIX ®(Hepatitis A Vaccine)

 

HAVRIX (Hepatitis A Vaccine) is a sterile suspension of inactivated virus for intramuscular administration. The virus (strain HM175) is propagated in MRC-5 human diploid cells. After removal of the cell culture medium, the cells are lysed to form a suspension. This suspension is purified through ultrafiltration and gel permeation chromatography procedures. Treatment of this lysate with formalin ensures viral inactivation. Viral antigen activity is referenced to a standard using an enzyme linked immunosorbent assay (ELISA), and is therefore expressed in terms of ELISA Units (EL.U.).

Each 1-mL adult dose of vaccine consists of 1440 EL.U. of viral antigen, adsorbed on 0.5 mg of aluminum as aluminum hydroxide.

 

Each 0.5-mL pediatric dose of vaccine consists of 720 EL.U. of viral antigen, adsorbed onto 0.25 mg of aluminum as aluminum hydroxide.

 

HAVRIX contains the following excipients: Amino acid supplement (0.3% w/v) in a phosphate-buffered saline solution and polysorbate 20 (0.05 mg/mL). From the manufacturing process, HAVRIX also contains residual MRC-5 cellular proteins (not more than 5 mcg/mL), formalin (not more than 0.1 mg/mL), and neomycin sulfate (not more than 40 ng/mL), an aminoglycoside antibiotic included in the cell growth media.

 

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Hepatitis A Treatment

Hepatitis-Helpful Nutrients by Maureen Kennedy Salaman:

 

Hepatitis occurs when infection or toxins cause the liver to inflame. Symptoms first resemble the flu: fever, swollen lymph glands, weakness, drowsiness, stomach discomfort and headache, often followed by extreme fatigue and loss of appetite. Soon the liver is unable to eliminate poisons, allowing them to build up and no longer store and process certain nutrients vital to the body.

Hepatitis A can be caused by eating contaminated shellfish (prevented by cooking for at least six minutes), drinking contaminated water, or inhaling airborne germs from infected persons or body secretions.

To recover from hepatitis, one must rest, abstain from alcohol, and follow a diet rich in essential nutrients: high in vegetable protein and complex carbohydrates, unsaturated fatty acids, including coldwater fish, liberal amounts of fluids, and vitamins B complex, C and E. This regimen should be continued long after recovery, since sensitivity to toxins may persist. Along with whole foods and nutritional supplementation, consume plenty of filtered water. Drinking fresh lemon juice in water every morning and evening followed by a vegetable juice is believed to be beneficial. Do this consistently for two to four weeks and then several mornings a week for several months and whenever liver symptoms occur.

Because hepatitis results from toxic substances in the body, vitamin C therapy is particularly important. Large intravenous doses of vitamin C (sodium ascorbate) along with B complex and calcium supplements can help reduce the severity of the infectious hepatitis symptoms and speed up the healing process.

This treatment originated with Dr. Frederick Klenner, M.D., of North Carolina in the 1940s and has been used successfully elsewhere, most recently by Dr. Akira Murata of Saga University in Japan.

Hepatitis A

Hepatitis A is a viral disease that thrives in poor sanitation areas. It can spread when people consume something that has been contaminated with human body waste products. Children often show no symptoms, and the disease can be more serious in adults.  Hepatitis A does not cause chronic, long term infection and death is rare.  Infection with hepatitis A gives a person lifelong immunity and it has been shown that in some populations around the world, close to 100 percent of all inhabitants have natural antibodies to hepatitis A. 

HAV infection usually causes an abrupt onset of fever, malaise, loss of appetite, nausea and abdominal discomfort. These symptoms can be followed by jaundice (yellowing of the skin and white of the eyes) within a few days. Not everyone infected with hepatitis A becomes jaundiced and children often do not have any symptoms of infection.

 
 
 
 
 

 

The CDC Pink Book  information on Hepatitis A-  

 

The likelihood of symptomatic illness from HAV infection is directly related to age. In children younger than 6 years of age, most (70%) infections are asymptomatic. In older children and adults, infection is usually symptomatic, with jaundice occurring in more than 70% of patients.

 

The package inserts  for Havrix, Twinrix and Vaqta.  Natural immunity occurs with having the disease but the vaccine does not provide the same. The efficacy of hepatitis A vaccines in early childhood is unknown.  SmithKline Beecham states: 

At present the duration of protection afforded [by HAVRIX] has not been established. Therefore it is unknown if the protection provided to immunized children will last until adulthood.”

Here’s an interesting report:

 

 “Infection with the hepatitis A virus may provide some protection against asthma and allergies, but only in people with a common form of a gene important in the immune system, a new study finds.  
 
“But while hepatitis A was an unpleasant infection — causing few or no symptoms in young children but jaundice, nausea, diarrhea and other complaints in adults — contact with the virus seems to help the immune system mature. One piece of circumstantial evidence is that hepatitis A rates have fallen in the West while allergy rates have soared, doubling in the last two decades alone.  
 

In 2005, Merck gained FDA approval to lower the age indication of their existing Hepatitis A vaccine (VAQTA) from 2 years of age to 12 months. HAVRIX soon followed.


Years ago only a handful of states mandated Hepatitis A for school entry, but once the age level was lowered for the vaccines, more states have begun to mandate it.

 

States that have had the highest incidence of hepatitis A:

  • Alaska
  • Arizona
  • California
  • Idaho
  • Nevada
  • New Mexico
  • Oklahoma
  • Oregon
  • South Dakota
  • Utah
  • Washington

The best tool for prevention of hepatitis A is to wash your hands with soap and water after using the bathroom, changing a diaper or preparing and eating food. It’s just common sense!

 
Hepatitis A Vaccine Can Cause Reactions:

 

 In clinical trials conducted by SmithKline Beecham, between 9 and 14 percent of adults and children reported headache after vaccination and between 21 and 56 percent had local reactions. Up to 10 percent had fever, fatigue, malaise, nausea and loss of appetite. Other reported reactions included stomach pain, diarrhea, vomiting, and joint pain. Post marketing vaccine reaction reports have included anaphylaxis, jaundice, convulsions, multiple sclerosis, Guillain-Barre syndrome, and neuropathy.

 

Since the vaccine was licensed in 1996, there have been nearly 3,000 reports of hepatitis A vaccine related adverse events made to the government (VAERS), including serious events and deaths.
  • Vaccine Components Not Adequately Evaluated:
 
Hepatitis A vaccines manufactured by SmithKline Beecham and Merck are made using human fetal diploid (lung) cells to propagate the virus. HAVRIX contains aluminum as well as phenoxyethanol as a preservative. Traces of formalin and residual fetal human diploid cellular proteins are also present. VAQTA contains aluminum and small amounts of non-viral protein, DNA, bovine albumin, and formaldehyde.  Both HAVRIX and VAQTA have “not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.”
  •  No Long Term Studies:

 There were no long term studies to evaluate whether hepatitis A vaccine given alone or in combination with other vaccines is associated with chronic illness or disability, such as the development of diabetes, asthma, seizure disorders, learning disabilities, ADHD, or autism. The Merck product insert for VAQTA states:

 “Subjects were observed during a 5-day period for fever and local complaints and during a 14-day period for systemic complaints.”

  • References:
    1. CDC Hepatitis A Fact Sheet www.cdc.gov/ncidod/diseases/hepatitis/a/fact.htm
    2. WHO Position Paper on Hepatitis A Vaccines: Weekly Epidemiological Record, No. 5. Feb. 4, 2000.
    3. Immunization Requirements www.sabin.org/map.htm
    4. SmithKline Beecham Product Manufacturer Insert (Hepatitis A Vaccine, Inactivated (HAVRIX). From Physicians Desk Reference (PDR), 2001.
    5. Merck Product Manufacturer Insert (Hepatitis A Vaccine, Inactivated (VAQTA). Issued March 2001.
    6. CDC. Prevention of Hepatitis A Through Active or Passive Immunization. Recommendations of the ACIP. MMWR. Dec. 27, 1996: Vol. 45, No. RR-15.
    7. Selected notifiable disease rates: United States, 1950-99 http://www.cdc.gov/nchs/products/pub…1/01hus052.pdf
    8. Vaccine Adverse Event Reporting System (VAERS) Report data
    9. Associated Press press report: More Hepatitis Vaccinations Urged. Dec. 18, 2001.

 

Source: Risk factors associated with reported hepatitis A, 1990-2000, United States.
Notes: From 1990 through 2000, the most frequently reported source of infection was personal contact (household or sex) with an infected person (14%). Two percent of cases involved a child or employee in day-care; 6% of cases were a contact of a child or employee in day-care; 5% of cases reported recent international travel; and 4% of cases reported being part of a recognized foodborne outbreak. Injection drug use was a reported risk factor in 6% of cases; men who have sex with men represented 10% of cases. Forty-six percent of reported hepatitis A cases could not identify a risk factor for their infection. (Risk factor percentages rounded to nearest percent.)
Adapted from: Centers for Disease Control and Prevention, Division of Viral Hepatitis. 
http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_a/slide_18.htm