Cross ref: See the entries below including two Hepatitis A Virus Vaccine, Inactivated products marketed in the U.S. - Havrix (#463) from GlaxoSmithKline Inc. and Vaqta (#464) from Merck & Co.

Description: Hepatitis A virus (HAV) vaccines, involving inactivated whole virus cultured in mammalian cells, are used for prevention of disease due to HAV.

Nomenclature: Hepatitis A Vaccine Products [BIO]; Hepatitis A Virus, Inactivated [FDA]; HAV [SY CDC]

Biological: The hepatitis A virus is a small (27 nm) single-stranded RNA virus classified as a picornavirus. There is only one major serotype. Humans are the only natural reservoir of the virus. Hepatitis A cannot be differentiated from other types of viral hepatitis based on clinical or epidemiologic features alone. Serologic testing to detect IgM antibodies to the capsid proteins of hepatitis A virus is required to confirm a diagnosis of acute hepatitis A infection. In most persons, IgM antibodies become detectable 5-10 days after infection and can persist for up to 6 months after infection. IgG antibodies remain detectable for the person's lifetime after infection, and prior infection confers lifelong protection against the disease (mimicked by use of HAV vaccines). Commercial diagnostic tests are available for the detection of IgM and total (IgM and IgG) hepatitis A antibodies in serum.

The conformation (3-dimensional structure) of the viral epitopes (immunogenic protein sequences) primarily responsible for induction of protective antibodies, particularly the hepatitis A virus VP1 and VP3 capsid polypeptides (encoded by the P1 segment of the viral open reading frame), was reported in 1992. These epitopes are highly conserved, despite the genomic variation (about 10%) between different hepatitis A virus strains. Prophylactic immunogenicity from hepatitis A virus vaccines apparently requires the 3-dimensional conformation arising from the association of the VP1, VP2, and VP3 polypeptides in the viral capsid. Synthetic peptides and subunit vaccines containing purified natural or recombinant capsid proteins, theoretically, could provide protection against hepatitis A virus infection. However, to date, these have not been shown to adopt the conformation of the native neutralizing epitope(s) and generally have shown low potency.

Injection of inactivated whole hepatitis A virus vaccine induces production of long-lasting IgG antibodies that confer protection against hepatitis A infection, mimicking the lifelong antibody protection from infection provided by natural hepatitis A virus infection. Formalin (formaldehyde) inactivation does not impair the reactivity of the major immu-no-dominant epitopes of the native virus. Inactivated vaccines induce protection against viral challenge in non-human primates (chimpanzees and marmosets). Immune globulin prepared from the blood plasma of vaccinated individuals provides protection against viral challenge in chimpanzees.

History: Transmission of hepatitis A virus infection from humans to marmoset was reported in 1967, facilitating study of the disease and virus. The virus was first visualized by electron microscopy in 1973. These advances led, in the 1970s, to the development of experimental inactivated vaccines prepared from infected marmoset livers capable of protecting marmosets from infection. The isolation of hepatitis A virus from marmoset cell culture was reported in 1979, and the isolation of virus from human specimens was reported by various groups in 1981. Poor growth of the virus in culture initially hampered vaccine development. The first clinical trials using an inactivated vaccine began in April 1988, and were reported in 1989.

Status: In 1996, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), recommended vaccination of children aged ³24 months in populations with the highest incidence of hepatitis A (e.g., American Indian/Alaska Native, Asian/Pacific Islander, and selected Hispanic and religious communities). In 1999, these guidelines were expanded to recommend routine vaccination for children residing in 11 states where average annual hepatitis A incidence during 1987-1997 was at least 20 per 100,000 population (twice the national average) and to consider routine vaccination for children in six states where average annual incidence was 10-20 per 100,000 population. Essentially, all persons over two years of age at high high-risk should be vaccinated against hepatitis A. This includes travelers to countries where hepatitis A is endemic; sexually active homosexual men; injectable drug users; children in communities experiencing hepatitis A outbreaks; persons potentially occupationally exposed to hepatitis A, such as day care, food service, and certain laboratory workers; and patients with chronic liver disease. Routine vaccination of children and adolescents in communities with high and intermediate rates of hepatitis A infection is recommended to help control outbreaks. However, awareness of the need for protection against hepatitis A among travelers from the U.S. and other developed countries remains low.

In the Sept. 27, 2003 issue of The Lancet, an international consensus panel concluded that the hepatitis A primary vaccination course provides long-term immunity against the virus into adulthood, with no need for a booster vaccine for healthy individuals. A full primary vaccination course of hepatitis A (two doses monovalent vaccine or three doses of combined hepatitis A and hepatitis B vaccine) was found to provide protective antibody levels persisting beyond 10 years in healthy people. Mathematical models predicted that these antibodies should persist for at least 25 years.

Hepatitis A vaccine is becoming a universal (required) vaccine, although it is not included in the national vaccine insurance program (and not subject to the associated federal excise tax). In Oct. 2005, the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), recommended that all children between 1-2 years of age in the U.S. receive hepatitis A vaccine, and that this be integrated into the routine childhood vaccination schedule. The previous recommendation of ACIP in 1999 had only called for vaccinations in states with the highest rates of hepatitis A. ACIP continued to recommend hepatitis A vaccination for travelers to countries with a high prevalence of hepatitis A, men who have sex with men, illegal drug users and persons with chronic liver disease.

By 2007, with widespread adoption of the vaccine, the incidence of hepatitis A in adults in immunizing states in the U.S. has decreased significantly, suggesting a strong herd immunity effect associated with immunization. In April 2007, as the next step in the implementation of the incremental universal vaccine immunization strategy, the American Academy of Pediatrics (AAP) recommended routine administration of hepatitis A vaccine to all children 12 to 23 months of age in all states according to a CDC-approved immunization schedule.

Medical: Havrix and Vaqta compete in the U.S. Both have shown high (95-100%) levels of protection from hepatitis A infection in clinical and field trials. The potency of the vaccines are measured differently, and are not directly comparable.

A concentration of 20 mIU/ml of hepatitis A virus antibodies (the lower limit of conventional antibody assays) has been recognized in trials as the lower limit for seroconversion (induction of protective antibodies). However, some investigators have suggested 10 mIU/ml constitutes a minimum level for protective antibody concentration. Note, Havrix and Vaqta use different methods for measuring vaccine-induced hepatitis A virus antibodies.

Disease: Hepatitis A virus is a highly contagious virus that affects the liver. It is spread by the enteric or fecal-oral route through close person-to-person contact or by ingesting contaminated food or water. The incubation period for hepatitis A is about 28 days (range 15-50). The course of infection is highly variable, ranging from asymptomatic to life-threatening icteric hepatitis. Healthy adults who contract hepatitis A often develop flu-like symptoms, including chills and high fever, as well as nausea, vomiting, diarrhea, fatigue, abdominal pain, loss of appetite, jaundice (yellowing of the skin and eyes), and dark urine.

Hepatitis A is the most common type of hepatitis, with an estimated 90,000 in the U.S. infected each year (according to an international consensus group). Hepatitis A virus is commonly reported to infect 125,000 to 200,000 Americans each year. The disease causes approximately 100 deaths in the U.S. each year, and up to 22% of adults with infection eventually require hospitalization. The highest incidence of hepatitis A is among children 5-14 years of age with almost 30% of reported cases occurring among children younger than 15 years of age. Children are at high risk because they often come into close contact with other children in school and daycare settings. Although hepatitis A infection in very young children is often mild or asymptomatic, the virus is easily transmitted to older children and adults who are likely to develop severe symptoms. Children and infants can shed hepatitis A virus in feces for longer periods than do adults. Thus, it is considered prudent to vaccinate infants.

Individuals considered at increased risk of infection or adverse consequences of infection (in developed countries) include travelers, men who have sex with men, users of illicit injectable drugs, close contacts of people infected with hepatitis A, chronic liver disease patients, and people for whom hepatitis A exposure is an occupational hazard, such as day care center employees.

There are an estimated 10 million cases of hepatitis A infection worldwide each year, with most infections occurring in lesser developed countries. Hepatitis A is one of the most common vaccine-preventable infectious diseases in the world.

There are no antiviral drug or other therapeutics available for treatment or prophylaxis against hepatitis A virus infection and disease. Standard immune globulin confers immunity against hepatitis A virus infection, but this is temporary and repeated administration is required at 3-5 month intervals (and entails potential risk of blood-borne infection). The active immunity induced by hepatitis A vaccines is essentially indistinguishable from that of pooled immune globulin but is of much greater duration.

The major market for hepatitis A vaccines is among travelers from developed countries and military personnel traveling to countries where the disease is endemic or more common. The disease is a threat to travelers even if they stay in expensive Western-style resorts and hotels. Smaller markets include those occupationally exposed to hepatitis A and those (particularly children) in areas of hepatitis A outbreaks (relatively rare in the U.S. and other developed countries). In unprotected travelers, hepatitis A occurs 400 times more often than typhoid fever, and 1,000 more often than cholera.

The Centers for Disease Control and Prevention (CDC) reported in the May 2002 issue of Pediatrics that cases of hepatitis A virus infection have been vastly underreported in the U.S. Using a mathematical model to account for under-reporting, it was estimated that an average of 271,000 cases occurred in each year from 1980-1999; 10.4 times higher than the number formerly/formally reported. Almost 60% of cases were estimated to be in children nine years of age or younger, with half presenting recognizable jaundice symptoms.

Universal vaccination of children has been proposed by CDC and other public health authorities, with this expected to provide herd immunity that would prevent transmission to other children and adults. Hepatitis A is a significant drain on the U.S. economy, costing more than $450 million annually. Experts consider routine vaccination programs for children a cost-effective way to reduce the spread of the disease and, in turn, decrease the economic burden. However, with hepatitis A being a non-fatal disease, not commanding much attention in the U.S., and with many already complaining about the high number and cost of vaccines administered to infants/children, adoption of universal pediatric vaccination appears unlikely.

In the July 13, 2005, issue of the Journal of the American Medical Association, the CDC, it was reported that following implementation of federal programs for hepatitis A vaccination of children (after vaccines became available), the overall hepatitis A incidence rate in the U.S. declined by 76%. uring the 1980s and 1990s, an average of 26,000 cases were reported annually to public health agencies, representing an estimated 270,000 infections per year when anicteric (without jaundice) disease and asymptomatic infections are taken into account. More than half of the estimated infections occurred among children. Between the baseline period (1990-1997) and 2003, overall hepatitis A rates declined 76% to 2.6 per 100,000, significantly lower than previous lows in 1983 (9.2/100,000) and 1992 (9.1/100,000). The rate of hepatitis A in vaccinating states declined 88% to 2.5 per 100,000 compared with 53% elsewhere (to 2.7/100,000). A decline in hepatitis A infection rates in children helped reduce transmission in other age groups, supporting the hypothesis of a strong herd immunity effect.

In Dec. 2005, an Israeli study reported that vaccination of all children against hepatitis A at 18 and 24 months in one Israeli community reduced overall incidence of the disease for all ages by 95%. Before vaccination, one-fifth of toddlers in a hepatitis A endemic community had high hepatitis A antibody levels indicating previous exposure. This was reduced by 90% within three years after initiation of a toddler-only universal vaccination program

In Jan. 2009, CDC and the Alaska Native Tribal Health Consortium reported finding that antibodies against hepatitis A virus persist for up to 27 years after vaccination.. The subjects had received vaccination when 3-6 years old. The estimated duration of antibody persistence was 21-27 years, depending on the vaccination schedule. Based on this, CDC stated "Hepatitis A booster doses after completion of the primary vaccination series do not appear to be warranted and are not currently recommended"

Market.: In Feb. 2005, CDC reported on U.S. coverage with hepatitis A vaccine. In 2003, vaccination coverage levels with at least 1 dose of hepatitis A vaccine for children aged 24-35 months varied from 6.4% to 72.7% in areas where routine vaccination is recommended. Hepatitis A vaccination coverage rates for children aged 24-35 months are lower than overall rates for other vaccines recommended for children. Sustaining and improving vaccination coverage among young children is needed to ensure continued declines in hepatitis A incidence in the U.S. Low coverage rates for young children might be the result of (1) a focus by healthcare providers and immunization programs on older children, (2) the few areas with hepatitis A vaccine mandates, and/or (3) the lack of a licensed hepatitis A vaccine that can be administered to children aged <24 months.

In June 2005, it was reported that over 200 children in China (PRC) had become ill after vaccination of about 2,500 children with an unauthorized (counterfeit) hepatitis A vaccine manufactured in China by Zhejiang Pukang Biotechnology.

Competition: All of the licensed inactivated hepatitis A vaccines worldwide are inactivated vaccines produced by viral culture on MRC-5 cells. Various vaccines not included in this reference are primarily those manufactured in lesser-developed countries. For example, in May 2004, Vaccine and Bio-product Company 1 (Vietnam) launched its hepatitis A virus vaccine in Vietnam.