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Hepatitis A Overview


hepatitis a

Hepatitis A & Hepatitis A Vaccine Quick Facts

Hepatitis A

  • Hepatitis A is a viral disease of the liver that is contracted through contact with, or by swallowing human fecal waste, generally through eating or drinking contaminated food and/or water.1 The virus is typically spread when people eat or drink something that has been contaminated with the virus;2
  • Hepatitis A thrives in areas that lack proper sanitation, clean drinking water or where personal hygiene habits are poor.3 The virus can remain in the environment for several months. Formalin, chlorine, and high temperatures can kill the virus.4 5 Hepatitis A can be found in all areas of the world but is often endemic in Africa, Asia, the Western Pacific, the Middle East, and Central and South America;6
  • Symptoms of hepatitis A generally appear between two and seven weeks following exposure to the virus and infected individuals can spread the virus to others for up to two weeks before showing symptoms.7 Symptoms often occur suddenly and may include fatigue, abdominal and/or joint pain, loss of appetite, fever, nausea, jaundice, dark urine, clay-colored bowel movements, and diarrhea. Younger children often show no clinical symptoms of infection. Only lab testing can confirm a diagnosis of hepatitis A;8
  • Complications and deaths from hepatitis A are rare9 and most infected individuals recover fully within two months. In approximately 10 to 15 percent of individuals, symptoms may last up to six months.10

Hepatitis A Vaccine

  • There are three hepatitis A containing vaccines available for use in the United States. VAQTA,11 an inactivated hepatitis A virus vaccine, manufactured by Merck; HAVRIX,12 an inactivated hepatitis A virus vaccine manufactured by GlaxoSmithKline; and TWINRIX,13 a combination vaccine containing both inactivated hepatitis A virus vaccine (HAVRIX) and recombinant hepatitis B vaccine (ENGERIX-B), manufactured by GlaxoSmithKline. The CDC recommends that children receive two doses of hepatitis A vaccine with the first dose administered between the ages of 12 and 23 months, and the second dose given 6 months later;14
  • Common side effects from the hepatitis A vaccine include soreness around injection site, headache, low-grade fever, and fatigue.15 Reported serious side effects following hepatitis A (VAQTA, HAVRIX, & TWINRIX) vaccination include anaphylaxis, thrombocytopenia, encephalopathy, multiple sclerosis, Guillain-Barre Syndrome, and more;16 17 18
  • Thirteen states and the District of Columbia require hepatitis A vaccination for school entry; twenty-two states and the District of Columbia require hepatitis A vaccination for children to be enrolled in a childcare program;19
  • Using the MedAlerts search engine, as of February 28, 2019, there have been more than 40,637 reports of hepatitis A vaccine reactions, hospitalizations, injuries and deaths following hepatitis A vaccinations made to the federal Vaccine Adverse Events Reporting System (VAERS), including 141 related deaths, 3,246 hospitalizations, and 851 related disabilities;
  • On December 1, 2004, hepatitis A vaccine was added to the National Vaccine Injury Compensation Program's (VICP) Vaccine Injury Table, as published in the Federal Register.  As of May 1, 2019, there had been 144 claims filed in the federal Vaccine Injury Compensation Program (VICP) for injuries and deaths following hepatitis A vaccination, including 7 deaths and 137 serious injuries.

Food & Drug Administration (FDA)

Centers for Disease Control (CDC)

Vaccine Reaction Symptoms & Ingredients

Our Ask 8, If You Vaccinate webpage contains vaccine reaction symptoms and more. 

Search for Vaccine Reactions

NVIC hosts MedAlerts, a powerful VAERS database search engine. MedAlerts examines symptoms, reactions, vaccines, dates, places, and more.

Reporting a Vaccine Reaction

Since 1982 NVIC has operated a Vaccine Reaction Registry, which has served as a watchdog on VAERS. Reporting vaccine reactions to VAERS is the law. If your doctor will not report a reaction, you have the right to report a suspected vaccine reaction to VAERS is the law.

IMPORTANT NOTE: NVIC encourages you to become fully informed about Hepatitis A and the Hepatitis A vaccine by reading all sections in the Table of Contents, which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.

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What is Hepatitis A?   

Hepatitis A is viral disease of the liver caused by the hepatitis A virus (HAV). The hepatitis A virus is a nonenveloped RNA virus and considered to be a picornavirus. Humans are the only natural host of this virus.20 The hepatitis A virus is very stable and can remain present for several months in most environments. The virus, however, can be killed by high temperatures (temperatures greater than 85C/185F), or by solutions such as chlorine, or formalin.21 22

Hepatitis A is contracted orally and typically acquired by coming into contact with human fecal waste, generally through the consumption of contaminated food and/or water.23 Source of contamination may include raw shellfish, fruits and vegetables and ice.24

Hepatitis A replicates in the liver and can be found in the blood stream within 10 to 12 days following exposure. The virus is excreted by the biliary system into the feces of a contaminated individual.25 An infected individual can spread hepatitis A to others for one to two weeks prior to becoming symptomatic.26 27 Excretion of the virus may persist longer in children than adults, however, by the third week of the illness, most infected individuals no longer excrete the virus in their feces.28

It generally takes an average of four weeks (range of two to seven weeks) following exposure to hepatitis A for symptoms to develop. Symptoms often occur suddenly and include fatigue, abdominal and/or joint pain, loss of appetite, fever, nausea, jaundice, dark urine, clay-colored bowel movements, and diarrhea. Young children are often asymptomatic and show no clinical signs of infection.29 Most infected individuals recover fully within 2 months, however, approximately 10 to 15 percent of infected individuals can have lingering symptoms for up to 6 months.30

Hepatitis A infection does not result in chronic liver disease31 and persons who recover from the illness develop lifelong immunity.32

Is Hepatitis A contagious?

Hepatitis A is contagious and spread from person to person by exposure through oral contact with the feces of an infected person.33 Infection can occur from exposure to water or foods that are contaminated with the virus. Contamination sources may include raw shellfish, vegetables, fruits, and even contaminated ice.34 Transmission of the virus through blood is very rare. 35 Hepatitis A thrives in areas that lack proper sanitation and where personal hygiene habits are poor. 36 Contaminated water sources can also be a source of transmission. Hepatitis A may infect drinking water through several sources including malfunctioning sewage systems, pollution from storm runoff, and through the overflow of sewage. Wells may also become contaminated if they are shallow or if floodwaters have submerged them for long periods of time.37

Hepatitis A rarely occurs in the United States, however, the virus is endemic in many areas of the world including Africa, the Middle East, the Western Pacific, Asia, and Central and South America. 38 Individuals traveling to developing countries with high or intermediate levels of hepatitis A are at higher risk for contracting the virus and developing infection.39

In the United States, outbreaks are often traced to contaminated food sources and may affect restaurants, grocery stores, and work places. In the U.S., between 1998 and 2017, 97 reported outbreaks of hepatitis A from water or food sources have been reported. These outbreaks have been associated with 2,896 illnesses, 399 hospitalizations, and 8 deaths.40

Since 2016, multiple states have reported hepatitis A outbreaks linked primarily to persons experiencing homelessness and among individuals who use drugs. Since these outbreaks were first identified in 2016, over 15,000 cases have been reported, resulting in over 8,500 hospitalizations, and 140 deaths.41 It is believed that the higher number of hospitalizations and deaths that have occurred during this ongoing outbreak may be attributed to cofactors such as pre-existing health conditions, hepatitis B and hepatitis C co-infections, age, and additional risk behaviors found within this particular population.42

What is the history of Hepatitis A in America and other countries?

Hippocrates described outbreaks of jaundice in 5th Century B.C. and medical historians believe this is likely the first reported cases of hepatitis A infections. 43  Throughout more recent history, reports of the disease were often associated with wars, and descriptions of outbreaks, often referred to in medical literature as infectious hepatitis or epidemic jaundice, have been documented since the Napoleonic Wars.44

By the early part of the 20th century, physicians believed that transmission of infectious hepatitis occurred through food and water sources and from person to person.45 By 1931, it was hypothesized that outbreaks of this epidemic jaundice were caused by an “ultra-microscopic virus which is pathogenic only to man.”46

In the 1940’s, experiments on the transmission of hepatitis A were conducted in Germany, the United States, and the Middle East. In Germany, human subjects involved in these experiments were fed duodenal juice. In the United States, researchers fed hepatitis A contaminated stool or serum filtrate to 12 conscientious objectors who volunteered for the experiment in lieu of military service. In the Middle East, volunteers were injected with blood or serum from patients with jaundice. From these experiments, researchers were able to determine the incubation period of infectious hepatitis, as well as the difference in the incubation periods between infectious hepatitis, now referred to as hepatitis A, and serum hepatitis, now hepatitis B.47

In the mid 1940’s, researchers discovered that gamma globulins (immunoglobulins) could help in the prevention of illness, including hepatitis A. Small amounts of hepatitis A gamma globulins were found to prevent illness for up to nine months.48 This treatment continues to be an option for hepatitis A prevention even today. 49

Human experimentation with Hepatitis A continued in the United States in the 1950’s, most notably at the Willowbrook State School on Staten Island, New York. In 1956, Dr. Saul Krugman began experimenting on children with developmental and intellectual disabilities residing at the state run school.  Krugman wanted to learn more about the hepatitis virus as well as the available gamma globulin’s ability to reduce the risk of infection. As high rates of infectious hepatitis were well documented at Willowbrook, the institution was considered to be the perfect environment for Krugman to conduct further research. Krugman’s hepatitis experiments lasted for 14 years, and involved exposing new residents to the current circulating strain of infectious hepatitis found at the state school. Krugman, along with his assistant, Dr. Joan Giles, intentionally exposed intellectually disabled residents to the feces and serum of children who were known to have had the infection and proceeded to monitor their health status in an attempt to learn more information about the virus. Experiments performed by Krugman and Giles were not focused on treating the infection, but rather on observing the symptoms of hepatitis A infection for scientific gain. Krugman justified the experiments by reporting that the children of Willowbrook would most likely be exposed to the virus anyway due to the high rates of infection at the school, and that all children participating in the experiments would receive proper care and monitoring on a special hepatitis unit. Parental consent for participation was obtained, however, in many cases, parents who applied to have their children admitted to Willowbrook were informed that openings were only available for the particular unit where hepatitis experiments were taking place.50 51 52

Willowbrook was an overcrowded and unsanitary facility and few attempts were made to improve the living conditions of the residents. The facility lacked adequate staffing and residents often came from poor and minority families, most of whom had no other housing alternatives available for their children due to their financial situation or as a result of racial discrimination.53 Robert Kennedy visited Willowbrook in 1965 and called it a “snakepit,” 54  noting that children were living in filth. He recommended that changes be implemented to improve the living conditions, however, no improvements were ever made to the facility.55

In 1971, several physicians publicly condemned the ongoing experiments on intellectually disabled children and voiced serious ethical concerns. In letters published by The Lancet in 1971, concerns expressed by physicians critical of the study included the ethics of experimentation on intellectually disabled children, the fact that the experiments would offer no improvement to the health of the child, the lack of any attempt to control the outbreak of infectious hepatitis by improving sanitation within the school, and more.56 57 58 In 1972, investigative reporter Geraldo Rivera exposed the horrors of Willowbrook in an award winning documentary aired on ABC news. Rivera’s news report prompted the families of Willowbrook’s residents to take action and file a class action lawsuit against the State of New York. The hepatitis experiments were halted following public outcry and eventually federal laws were passed to protect the rights of individuals living in institutions.59

While the experiments that took place at Willowbrook resulted in a gain in scientific knowledge about the hepatitis virus, including the confirmation of a distinction between infectious hepatitis, now known as hepatitis A, and serum hepatitis, or hepatitis B, as well as the differentiation between their modes of transmission,60 the ethics of Krugman’s experiments continue to be questioned today.61

In 1973, the hepatitis A virus was finally detected and isolated in the feces62 and additional techniques to adequately test samples to definitively determine a diagnosis of hepatitis A infection and differentiate it between hepatitis B were also developed during this time.63 Hepatitis A vaccine development began following virus isolation, and by 1991, the first published research on the use of an inactivated hepatitis A vaccine in humans appeared in medical literature.64

Hepatitis became a reportable disease in the early 1950’s65 and in 1961, there were 72,651 reported cases of both infectious and serum hepatitis reported to the CDC. 66 In 1961, the CDC reported on an increase in the number of cases, noted it to be “the largest number reported since hepatitis was added to the list of notifiable diseases ten years ago.”67 It was also reported that there was a seven year interval between high rates of hepatitis infection, and most cases were reported in the later part of the winter and the early part of spring.68

In 1966, the CDC began differentiating between infectious hepatitis, now referred to as hepatitis A, and serum hepatitis, or hepatitis B. Prior to 1966, the CDC collected data on the rates of both types of hepatitis infection, however, no distinction was made between the two. In 1966, there were 32,859 reported cases of hepatitis A and 1,497 reported cases of hepatitis B, an over 50 percent decrease from the number of reported cases five years earlier.69

Between 1966 and 1995, the year prior to the Food and Drug Administration’s (FDA) approval of the inactivated hepatitis A vaccine (1996), reported rates of hepatitis A infection varied between a high of 59,606 in 1971, and a low of 21,532 in 1983,70 with higher numbers of outbreaks occurring in the U.S. approximately every 10 years.71 Hepatitis A infection rates were noted to be highest among Alaskan Natives and American Indians and more prevalent in the western part of the United States. Children under the age of fifteen were found to have the highest rates of infection, with 30 percent of cases occurring within this population.72 Outbreaks occurred most frequently between family members or sexual contacts, daycare workers, and international travelers. Only between two and three percent of all hepatitis A infections were the result of an identified water or food source and 50 percent of all reported cases had no identified source of infection. 73

It was also reported in 1996 that one third of all Americans had lifelong hepatitis A immunity due to previous exposure to the virus and exposure to hepatitis A directly correlated to age. 75 percent of adults over the age of 70 were found to be immune to hepatitis A, whereas only 10 percent of children under the age of 10 had previous exposure to the virus and determined to be immune. 74

At the time of the CDC’s Advisory Committee on Immunization Practices (ACIP) recommendation of the newly available hepatitis A vaccines, VAQTA, and HAVRIX in 1996, ACIP acknowledged that the number of cases of hepatitis A had declined over the past several decades primarily as a result of an improvement in sanitation and hygiene practices.75 In 1996, there were 31,032 cases of hepatitis A infection reported to the CDC.76

In 2007, one year following the ACIP’s recommendation for routine administration of two doses of hepatitis A vaccine for all children beginning at 12 months of age,77 there were 2,979 reported cases of hepatitis A infections reported.  At this time, it was noted that hepatitis A infections were highest among adults between the ages of 25 and 39 and lowest in children under the age of five. However, as children under the age of five are often asymptomatic when exposed to hepatitis A, infection rates in young children may have actually been much higher than reported. 18 percent of all cases of hepatitis A were attributable to international travel with approximately 85 percent of all travel-related cases associated with trips to Mexico and Central or South America. Six percent of cases occurred in men who had sex with other men, and one percent of cases involved injectable drug users. Information on risk factors for hepatitis A infection were absent from nearly half of the reported cases.78

The number of reported hepatitis A infections steadily decreased until 2013, when a large multistate outbreak occurred in association with imported pomegranate arils from Turkey resulted in 165 reported infections,79 and put the total number of reported cases for the year at 1,781.80 In 2016, reported rates of hepatitis A infection increased yet again as a result of two separate outbreaks associated with contaminated food, with one in Hawaii linked to raw scallops imported from the Philippines81 and a second multi-state outbreak linked to frozen strawberries imported from Egypt.82 There were 2,007 reported cases of hepatitis A infections in 2016,83 including 418 cases linked to the contaminated food sources.84 The CDC reported that only 1,026 of the 2,007 reported cases of hepatitis A infection included clinical data pertaining to death, and from these reported cases, seven deaths were associated with hepatitis A.85

Between 1998 and 2017, 97 hepatitis A outbreaks associated with either food or water sources have been reported. These outbreaks resulted in 2,896 infections, 399 hospitalizations and 8 deaths.86 Imported foods continue to be a source of potential hepatitis A infections.87

In the United States, risk factors for acquiring hepatitis A infection include international travel, exposure to a person with hepatitis A infection, employment at a day care center, being a man who has sex with another man, being an injection drug user, or becoming exposed from a contaminated food or water source. It is important to note that in 2014, only 7 percent of reported cases of hepatitis A infection listed a risk factor, with the overwhelming majority of cases missing information or reporting no known etiology for the infection.88 

Since 2016, several states have reported hepatitis A infections that have primarily impacting persons who use drugs or who are experiencing homelessness. Over 15,000 cases, 8,500 hospitalizations and 140 deaths have been attributed to this outbreak. In October of 2018, the CDC added homelessness as a risk factor for developing hepatitis A and recommended hepatitis A vaccination for this particular population.89

What Is the Incidence of Hepatitis A in the Rest of the World?

Globally, hepatitis A is the most common form of acute hepatitis, with an estimated 1.5 million clinical cases occurring each year. 90  Hepatitis A infections are often cyclical and closely associated with sanitation and hygiene practices. In developing countries that lack adequate sanitation and where hygiene habits are poor, most children become infected with hepatitis A prior to the age of ten. As infection in most young children tends to be asymptomatic, outbreaks are uncommon as most individuals have been exposed to the virus early in life and have lifelong immunity.91

In countries that are developing and may have varying conditions of sanitation and personal hygiene, hepatitis A exposure may be avoided in childhood and delayed until an older age during which infection will often be symptomatic. As a result, these countries are noted to have higher rates of hepatitis A infection.92

In developed countries, such as the United States, Canada, Western Europe, Japan, and Australia, where good hygiene and sanitation practices exist, rates of hepatitis A infection are very low, and occur mainly as a result of international travel, exposure in residential or childcare centers, or by water or food borne contamination. Risk factors for hepatitis A infection in developed countries include men who have sex with other men, drug users, international travelers, and persons experiencing homelessness.93 94

Hepatitis A infection does not result in chronic liver disease and rarely results in death. When death occurs, it is often a result of fulminant hepatitis or acute liver failure.95

Can Hepatitis A cause injury and/or death?      

Complications from hepatitis A are extremely uncommon. In rare cases, severe clinical symptoms of hepatitis A can result in neurological, immunological, and hematological impairments and the virus can also affect the kidneys and the pancreas. Additional complications that have been reported include autoimmune hepatitis, relapsing hepatitis, cholestatic hepatitis, subfulminant and fulminant hepatitis. Fulminant hepatitis is the most severe complication resulting in a nearly 80 percent fatality rate.96

While historically, hepatitis A complications have been rare, the 2017 hepatitis A outbreak among persons who use drugs and who are experiencing homelessness has resulted in a higher number of hospitalizations and deaths than what was reported in 2016. Public health officials have speculated that this may be the result of age, pre-existing illnesses, including hepatitis B and hepatitis C co-infections, and high risk activities such as heavy alcohol consumption and drug use that tend to be found among persons within this population.97  

Most infected individuals recover fully from hepatitis A within two months, however, approximately 10 to 15 percent of infected individuals can have lingering symptoms for up to six months.98

Who is at highest risk for getting Hepatitis A? 

United States public health officials state that, while anyone can become infected with hepatitis A, those most at risk include:99 100

  • Men who have sexual relations with other men
  • Persons having sexual relations with an infected individual
  • Individuals using recreational drugs, whether they are injected or not
  • Persons residing in or traveling to countries where Hepatitis A is endemic
  • Caregivers or household members who are living with someone who is infected with hepatitis A
  • Hemophiliacs or persons with a similar blood clotting disorder
  • HIV-positive individuals
  • Families who may be adopting a child from countries considered to have intermediate or high hepatitis A infection rates
  • Persons working with the hepatitis A virus including those working with hepatitis A infected primates
  • Homeless individuals

A 2015 published study found that adults, rather than children, were at a higher risk of developing hepatitis A infection and that infections were not limited to high risk groups, primarily due to the increasing number of foods imported to the United States as some have been found to be the source of hepatitis A infections.101 102 Infection rates in the United States and other developed countries are considered to be very low due to proper sanitation and hygiene practices, and most outbreaks tend to end very quickly.103 However, since 2016, many U.S. states have experienced hepatitis A outbreaks, primarily among persons who use drug or who are experiencing homelessness and as of March 2019, multiple states continue to be impacted by the ongoing outbreaks.104

In developing countries, however, 90 percent of children will develop hepatitis A prior to the age of ten due to poor personal hygiene practices and inadequate sanitation. The majority of these infected children will show no clinical symptoms of disease and exposure to the virus will result in lifelong hepatitis A immunity. As a result, the rates of symptomatic disease in developing countries are very low and epidemics are rare. In developing countries where personal hygiene practices and proper sanitation are variable, symptomatic outbreaks may be much more common. In these countries, children may not become exposed to the hepatitis A virus at a young age and this may result in a higher rate of adults without immunity to the illness. In these countries, hepatitis A disease rates may be much higher. 105

Who is at highest risk for suffering complications from Hepatitis A?

Complication from hepatitis A are very rare. Persons most at risk from developing complications as a result of hepatitis A include adults over the age of forty106 and persons previous diagnosed with chronic liver disease.107

In 2017, however, public health officials noted an increase in the rate of hospitalizations and deaths from hepatitis A among persons experiencing homelessness and those who use drugs in comparison to data from 2016. Health officials have speculated that the elevated risk of complications within this particular population may be related to additional pre-existing illnesses such as hepatitis B, hepatitis C, in addition to participating in high risk activities, such as increased alcohol consumption and drug use.108

Can Hepatitis A be prevented and are there treatment options?

Prevention strategies to decrease the risk of hepatitis A infection include the following:109

  • Consistent thorough handwashing with soap and water after using the restroom or following contact with an infected person’s bodily fluids such as blood, urine and feces.
  • Washing of hands before and after diaper changes
  • Thoroughly handwashing before cooking or serving food
  • Avoiding the consumption of contaminated food and water, especially when traveling

When traveling to areas where the risk of hepatitis A infection may be high, avoidance of unclean water and food is important. Strategies to prevent hepatitis A while traveling include the following:110

  • Avoiding undercooked and raw fish and meat
  • Avoiding dairy products
  • Drinking carbonated bottle water
  • Using only carbonated bottle water to brush teeth
  • Avoiding the use of ice in beverages
  • Promptly consuming food that is hot to the touch
  • Refraining from purchasing food from street vendors
  • Boiling water at full boil for at least one minute if bottled water sources are unavailable.

If a person has been exposed to hepatitis A virus, it may be possible to prevent infection with hepatitis A immune globulin within 2 weeks of exposure to the virus.111 Hepatitis A immune globulin can also be administered prior to traveling to countries where rates of hepatitis A virus may be high.112 113

As hepatitis A is a viral infection, there are no specific treatment options for the infection itself. Treatments are targeted towards the management the symptoms. These treatment options may include assuring adequate nutritional status, maintaining comfort, and replacing fluids that may be lost as a result of diarrhea or vomiting. The use of acetaminophen or medications to prevent emesis are not recommended.114 It is, however, recommended that affected persons avoid alcohol, ensure adequate water intake and consume a healthy diet.115

What is Hepatitis A vaccine?        

The CDC’s Advisory Committee on Immunization Practices currently recommends that all children receive the first dose of hepatitis A vaccine between 12 and 23 months of age and the second dose is recommended 6 months or longer following the first dose of the vaccine. Additionally, hepatitis A vaccination is recommended for person considered at high risk for developing hepatitis A related to travel, employment, pre-existing health issues, lifestyle and in the event of an outbreak situation.116

Read the Product Information Insert

NVIC strongly recommends reading the vaccine manufacturer product information insert before you or your child receives any vaccine, including a shot containing hepatitis A vaccine. Product inserts are published by drug companies making vaccines and list important information about vaccine ingredients, reported health problems (adverse events) associated with the vaccine, and directions for who should and should not get the vaccine.

Links to hepatitis A vaccine product inserts are available below or you can ask your doctor to give you a copy of the vaccine product insert to read before you or your child is vaccinated. It is best to ask your doctor for a copy of the product inserts for the vaccines you or your child is scheduled to receive well in advance of the vaccination appointment.

Hepatitis A Vaccines Licensed for Use in the U.S.

The U.S. Food and Drug Administration and U.S. Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC) has approved three different hepatitis A containing shots. There are different rules for use of these vaccines by different aged groups.

VAQTA: a vaccine containing inactivated hepatitis A vaccine virus approved for use in adults and children 12 months of age and older. This vaccine is manufactured by Merck. Two doses of VAQTA vaccine are recommended and doses should be given at least six months apart or longer.117

VAQTA vaccine is made from hepatitis A virus grown in human MRC-5 diploid fibroblasts. Human MRC-5 cells are derived from a cell line that was developed in 1966 from lung tissue taken from a 14 week aborted fetus and contains viral antigens.118 The inactivated strain is derived by the further processing of an attenuated strain that has been grown, selected, purified and inactivated by formalin. Following inactivation, the virus is combined with amorphous aluminum hydroxyphosphate sulfate, an aluminum adjuvant with the potential to cause autoimmune/auto inflammatory conditions and noted to be linked to adverse events.119

Each adult dose of VAQTA contains 50U of hepatitis A virus antigen and 450mcg of aluminum in the form of amorphous aluminum hydroxyphosphate sulfate. Each pediatric dose of VAQTA contains 25U of hepatitis A virus antigen and 225 mcg of aluminum. VAQTA also contains DNA, non-viral protein, bovine albumin, formaldehyde, neomycin, sodium borate, and sodium chloride.120 121

The vial stopper, the syringe plunger stopper, and the tip cap contain dry natural latex rubber that may cause allergic reactions in latex-sensitive persons.122

HAVRIX: a vaccine containing inactivated hepatitis A vaccine virus approved for use in adults and children 12 months of age and older. This vaccine is manufactured by GlaxoSmithKline. Two doses of HAVRIX vaccine are recommended and doses should be given at least six months apart or longer.123

HAVRIX vaccine is manufactured by propagating the hepatitis A virus in MRC-5 human diploid cells. Human MRC-5 cells are derived from a cell line that was developed from lung tissue taken from a 14 week aborted fetus in 1966 and contains viral antigens.124 The cells are lysed to form a suspension and purified. It is inactivated by formalin and absorbed into aluminum hydroxide.125

Each 1-ml adult dose of the vaccine contains 500mcg of aluminum and each 0.5ml pediatric dose contains 250mcg of aluminum, both in the form of aluminum hydroxide.126

Additional ingredients in the vaccine include MRC-5 human diploid cells, polysorbate 20, formalin, neomycin sulfate, amino acid supplement in a phosphate-buffered saline solution, and an aminoglycoside antibiotic.127 128

TWINRIX: a vaccine containing both inactivated hepatitis A vaccine (HAVRIX) and hepatitis B recombinant vaccine (ENGERIX-B) approved for use in adults 18 years of age and older. This vaccine is manufactured by GlaxoSmithKline. There are two different dosing options for TWINRIX vaccine. The most common dosing schedule of TWINRIX vaccine involves the administration of three vaccine doses, with the second dose administered one month following the initial dose, and the third dose administered six months after the first dose was administered. An accelerated dosing option has also been approved and involves three doses administered within three weeks, with the second dose at Day 7 and the third dose at Day 21, followed by a fourth dose at 12 months. 129

TWINRIX vaccine is bivalent vaccine containing the HAVRIX vaccine (see above) and the ENGERIX-B (hepatitis B vaccine). ENGERIX-B is comprised of a suspension of hepatitis B virus surface antigen (HBsAg) and contains purified surface antigen of the hepatitis B virus obtained by culturing genetically engineered Saccharomyces cerevisiae cells (yeast cells), which carry the surface antigen gene of the hepatitis B virus. The HBsAg expressed in the cells is purified and adsorbed on aluminum hydroxide. ENGERIX-B should contain no more than 5 percent yeast protein.130

Each 1-ml dose of TWINRIX contains 450mcg of aluminum, in the form of aluminum hydroxide and aluminum phosphate, as an adjuvant. Additional ingredients in the vaccine include formalin, amino acids, phosphate buffer, polysorbate 20, sodium chloride, neomycin sulfate, yeast protein, and MRC-5 human diploid cells (residual DNA).131 132

The tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions.133

Is the Hepatitis Vaccine Mandated?

Federal health officials make recommendations for vaccine use and states enact laws that require vaccine use. Currently, 22 states and the District of Columbia require hepatitis A vaccine for either childcare enrollment, K-12 school enrollment, or both.134  Medical exemptions to vaccination are allowed in every state but few medical conditions qualify for a medical exemption, which must be written by a medical doctor (M.D.) or Doctor of Osteopathy (D.O.) or other licensed professional approved by the state.

Depending upon which state you live in, you may be legally allowed to exercise a religious or philosophical/conscientious belief exemption to vaccination, including hepatitis A vaccination. For more information about which vaccines your state requires and exemptions, go here on NVIC’s website.

What is the history of Hepatitis A vaccine use in America?

Research involving the use of formalin-inactivated hepatitis A vaccine in human subjects was first published in 1991 by a group of scientists from Walter Reed Army Institute of Research. According to the published study, scientists were able to show that the inactivated vaccine could produce antibodies against hepatitis A.135 Additionally in 1991, research was also published on the use of a live attenuated hepatitis A vaccine capable of producing hepatitis A antibodies in humans.136 While no live hepatitis A vaccine has ever received FDA approval for use in the United States, live attenuated hepatitis A vaccines are currently in use in both India and China.137

Merck and GlaxoSmithKline continued independently to develop their inactivated hepatitis A vaccines and in 1992, Merck scientists published research on the VAQTA hepatitis A vaccine. The published paper reported on a study involving approximately 1000 children between the ages of 2 and 16 living in a Hasidic Jewish community in upstate New York. 519 children were administered the vaccine that contained 300mcg of aluminum hydroxide and thimerosal at a 1:20,000 dilution, while 518 children received a “placebo” dose of 300mcg of aluminum hydroxide along with a 1:20,000 dilution of thimerosal. The published study reported on the vaccine’s ability to prevent clinical cases of hepatitis A infection, however, it also stated that researchers were not able to prove that the vaccine could prevent subclinical infections.138 GlaxoSmithKline published research in 1994 on its HAVRIX hepatitis A vaccine, reporting the vaccine to be 94 percent effective in preventing cases of hepatitis A infections. This particular vaccine was tested on over 40,000 children between the ages of 1 and 16 living in Thailand.139

On February 22nd, 1995, HAVRIX received FDA approval for use in adults and children two years of age and older.140 One year later, Merck’s hepatitis A vaccine, VAQTA, received FDA approval for use in persons aged 2 and older.141

In December of 1996, the CDC’s Advisory Committee on Immunization Practices (ACIP) released its first recommendations on the use of hepatitis A vaccine. ACIP recommended hepatitis A vaccination for all persons traveling to or residing in countries noted to have intermediate or high rates of hepatitis A infections, with the first dose recommended at least four weeks prior to departure. It was, however, suggested that pre-vaccination testing for the presence of hepatitis A antibodies be performed in older persons, due to the likelihood of previous exposure and current immunity to hepatitis A. Hepatitis A vaccination was also recommended for all children ages 2 and older residing in communities with high rates of hepatitis A infection or where periodic outbreaks occurred. The CDC, however, noted that children aged 10 to 15 years who resided in these high risk communities would probably not require vaccination due to the likelihood of previous exposure and current immunity to hepatitis A.142

Additionally, the CDC recommended the vaccine for use in populations consider at high risk for hepatitis A infection. These groups included illegal drug users, both injection and non-injection users, men who had sex with other men, persons with chronic liver disease, including those who were liver transplant recipients or awaiting transplant, persons working with hepatitis A exposed primates in laboratory settings, and those with clotting factor disorders. As well, it was suggested that vaccination of food handlers be considered should it be deemed cost effective by local or state regulators or by private employers. Further guidelines were issued on the use of hepatitis A vaccine in response to outbreaks, however, the CDC admitted that the ease and cost of vaccination, as well as the ability to continually sustain high rates of vaccination in young children may factor into the decision on how to proceed in the event of an outbreak. The CDC declined to recommend routine vaccination of persons residing or working in potentially high risk settings such as daycare centers, prisons, and institutions for developmentally disabled, but recommended the use of hepatitis A immune globulin in these particular populations in event of an outbreak.143

In 1999, the CDC’s Advisory Committee on Immunization Practices (ACIP), updated recommendations for the use of the hepatitis A vaccine to include routine vaccination of all children two and older living in areas where hepatitis A infection rates were twice or more the 1987 to 1997 national average rates. The CDC also suggested that routine vaccination be considered as a tool to decrease the number of hepatitis A infections in areas found to be above the 1987-1997 national average. Recommendations for travelers and persons considered high risk for exposure to hepatitis A as defined in the 1996 ACIP recommendations remained unchanged.144

On May 11th, 2001, GlaxoSmithKline’s TWINRIX vaccine, a bivalent vaccine containing HAVRIX hepatitis A vaccine, and ENGERIX-B hepatitis B vaccine, received approval for use in adults ages 18 and older, following a clinical studies involving less than 2,200 healthy adults. TWINRIX, containing both aluminum phosphate and aluminum hydroxide, thimerosal, neomycin, formalin, yeast as well as 2-phenoxyethanol as a preservative, was reported by GlaxoSmithKline to be as effective as separate doses of HAVRIX and ENGERIX-B.145 146

Hepatitis A infection rates dropped from 17,047 reported cases in 1999 to 4,488 reported cases in 2005 despite low hepatitis A vaccination rates. In 2004, the National Immunization Survey found that only 54 percent of children between the ages of 24 and 35 months residing in states where hepatitis A vaccination was recommended had received the hepatitis A vaccine. As well, only 27 percent of children in states where vaccination should be considered were vaccinated. Vaccination rates of children in the remaining states were reported to be at only 2 percent.147

In 2005, both Merck’s VAQTA and GlaxoSmithKline’s HAVRIX received FDA approval for use in children beginning at 1 year of age, instead of two years.148 149 Merck’s VAQTA received approval for use in children at 1 year of age and older following clinical trials involving only 706 children while150 GlaxoSmithKline’s HAVRIX received their approval following clinical trials that involved 723 children younger than two years.151In early 2006, following the FDA’s approval to lower the age of administration of both hepatitis A vaccines, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended routine hepatitis A vaccination of all children, with the first dose to be administered between 12 and 23 months of age, and the second dose at least six month later.152  In 2007, the CDC updated hepatitis A vaccine recommendations for post-exposure to hepatitis A and for international travelers153 and in 2009, the vaccine was recommended for families and close contacts of newly adopted international adoptees.154

Since the 2006 CDC recommendation for routine vaccination of all children with two doses of hepatitis A vaccine beginning at 12 months, vaccination rates for have remained low. A 2010 CDC published survey found that by 2009, only 15 percent of children between the ages of 12 and 35 months had received the recommended two doses of hepatitis A vaccine.155 By 2014, this number had only increased to 57.5 percent.156

In 2018, a published report found that less than 65 percent of adolescents between the ages of 13 and 17 had received the recommended two doses of hepatitis A vaccine.157 Adult vaccination rates have also remained low, with a 2015 study reporting that only 9 percent of adults ages 19 and older to be vaccinated with the hepatitis A vaccine.158

Currently, only thirteen states and the District of Columbia require hepatitis A vaccination for school entry and only twenty-two states and the District of Columbia require hepatitis A vaccination for children enrolled in childcare. 159

At the October 2018 CDC Advisory Committee on Immunization Practices (ACIP) meeting, committee members voted to recommend routine vaccination of hepatitis A vaccine for all persons 12 months of age and older who were experiencing homelessness.160 This recommendation was made in response to the multi-state outbreak of hepatitis A first identified in 2016 among persons who use drugs and those experiencing homelessness.161 In this recommendation, committee members reported that alternative strategies to prevent exposure to hepatitis A such as adequate handwashing, access to sanitary toilet facilities, and avoidance of crowded living spaces would be difficult to implement, therefore vaccination would likely be the best strategy to prevent hepatitis A among homeless individuals.162

How Effective Is Hepatitis A Vaccine?

Vaccine acquired immunity is only temporary and in some cases, vaccines may also fail to provide even temporary immunity for some individuals.

A systematic review on the efficacy of the hepatitis A vaccine completed in 2003 reported the inactivated hepatitis A vaccine to be 86 percent effective at preventing hepatitis A.163

The duration of immunity following hepatitis A vaccine is unknown. A 2017 published study reviewing the antibody levels of 52 hepatitis A vaccine recipients found that 88.5 percent had measurable antibody levels after 20 years.164 It is important to note that while protection from hepatitis A infection may be related to the presence of antibodies, the lowest levels of antibody protection is not known.165 166

According to GlaxoSmithKline’s package insert for TWINRIX (bivalent vaccine containing both Hepatitis A and Hepatitis B vaccine), when blood antibody levels were tested in 264 healthy adults in the U.S. one month after the completion of three doses of TWINRIX vaccine, 99.6 percent of individuals developed hepatitis A antibodies and 95.1 percent developed hepatitis B antibodies. When the blood antibody levels were tested one month following completion of the accelerated dosing schedule in 194-204 healthy adults, 100 percent of people developed hepatitis A antibodies and 96.4 percent developed hepatitis B antibodies. GlaxoSmithKline reports that TWINRIX vaccine acquired antibodies for both hepatitis A and hepatitis B persist for at least 4 years.167

Persons who are immunocompromised may not develop antibodies against hepatitis A following vaccination. The package inserts for Merck’s VAQTA vaccine, and GlaxoSmithKline’s HAVRIX and TWINRIX vaccines state that vaccination may not result in protective antibodies against hepatitis A.168 169 170 Published studies on the use of hepatitis A vaccine in HIV positive individuals determined the vaccine to be effective approximately 50 percent of the time.171 172

Can Hepatitis A Vaccine Cause Injury & Death?

The Institute of Medicine (IOM) has acknowledged that there is individual susceptibility to vaccine reactions for genetic, biological and environmental reasons, but that vaccine providers cannot accurately predict prior to a vaccine’s administration who will suffer complications, injury or death from vaccination.173 However, a person who has previously had a serious reaction to a vaccination or is acutely or chronically ill should become informed about all potential risks associated with vaccination and discuss any concerns with a trusted health care professional before receiving a hepatitis A vaccine or any other vaccine.

According to the CDC, possible side effects from the hepatitis A vaccine include: 174

  • Redness or pain at the injection site
  • Headache
  • Fatigue
  • Fever
  • Fainting
  • Persistent severe shoulder pain
  • Allergic reaction
  • Death

VAQTA: Adverse events reported to have occurred during pre-licensing clinical trials of Merck’s VAQTA hepatitis A vaccine included: injection site warmth, bruising, pain, redness, and swelling; headache; fever; bronchial constriction; asthma; wheezing; swelling/edema; generalized redness; rash; eye irritation; itching; dermatitis; irritability; diaper dermatitis; upper respiratory infection; diarrhea; teething; rhinorrhea; vomiting; constipation; otitis media; insomnia; nasopharyngitis; rhinitis; viral infection; croup; Streptococcal pharyngitis; laryngotracheobronchitis; viral exanthema; viral gastroenteritis; roseola; anorexia; febrile seizure; dehydration; cellulitis and insomnia.175

Serious complications reported by Merck in the VAQTA product insert during vaccine post-marketing surveillance have included:  Diarrhea/gastroenteritis; thrombocytopenia; Guillain-Barre Syndrome; encephalitis and cerebellar ataxia. 176

In all of Merck’s pre-licensing clinical safety trials involving children under the age of 2, VAQTA vaccine was administered either alone, or in combination with additional vaccines. No pre-clinical safety studies were ever completed to compare the health outcomes of VAQTA against a true placebo or even against another previously licensed vaccine. In one study, vaccine recipients received either VAQTA vaccine alone or else VAQTA vaccine in combination with Merck’s ProQuad (Measles-Mumps-Rubella-Varicella) vaccine, a vaccine found to be associated with an increased risk of febrile seizures,177 178 along with Wyeth’s Prevnar vaccine, for the first dose of the vaccine. For the second dose of the vaccine, pre-licensure clinical trials compared the safety of VAQTA vaccine against the safety of VAQTA vaccine administered in combination with Merck’s highly reactive ProQuad vaccine. An additional clinical safety trial compared health outcomes of children who received either VAQTA alone or else VAQTA in combination with Merck’s  Haemophilus B Conjugate Vaccine, PedvaxHIB or both PedvaxHIB and GlaxoSmithKline’s Infanrix, a diphtheria, tetanus and acellular pertussis vaccine. Health outcomes of clinical trial vaccine recipients were monitored for only 2 weeks. 179

In pre-licensing clinical trials involving children between the ages of 2 and 18 years of age, clinical trial participants received either VAQTA or a dose of amorphous aluminum hydroxyphosphate sulfate, an aluminum adjuvant linked to adverse events and associated with autoimmune/autoinflammatory conditions.180 In this particular clinical trial, the second dose of the aluminum adjuvant was not administered to the control group because “code for the trial was broken.” 181 As with pre-licensing clinical trials involving children under the age of 2 years of age, the health outcomes of the clinical trial participants were limited to 14 days. 182

Only 240 healthy adults ages 19 and older were studied in the initial VAQTA vaccine pre-licensing clinical trials and participants received either VAQTA alone, or VAQTA in combination with the Typhoid Vi polysaccharide vaccine and the yellow fever vaccine. Four additional clinical trials involving 1,645 healthy adults compared VAQTA against differing amounts of viral antigens of hepatitis A and/or aluminum, VAQTA when administered alone or in combination with hepatitis A immune globulin, three different lots of VAQTA vaccine, and VAQTA against differing amounts of the hepatitis A viral antigens. Again, the evaluation of health outcomes of the pre-licensing clinical trial participants were limited to 14 days.183

HAVRIX: Adverse events reported to have occurred during pre-licensing clinical trials of GlaxoSmithKline (GSK) HAVRIX hepatitis A vaccine included: injection site warmth, bruising, pain, redness, induration, and swelling; headache; fever; anorexia; nausea; fatigue; malaise; vertigo; photophobia; lymphadenopathy; dysgeusia; hypertonia; rash; urticaria; pruritus; abdominal pain; diarrhea; vomiting; insomnia; muscle and joint pain; pharyngitis; upper respiratory infections; seizure; bronchial hyper-reactivity and respiratory distress.184

Serious complications reported by GlaxoSmithKline (GSK) in the HAVRIX product insert during vaccine post-marketing surveillance have included: rhinitis; vasculitis; hepatitis; jaundice; anaphylaxis and anaphylactoid reactions; serum sickness-like syndrome; thrombocytopenia; shortness of breath; dizziness; vasculitis; shortness of breath; multiple sclerosis; Guillain-Barre Syndrome; musculoskeletal stiffness; injection site reaction; local swelling; paresthesia; encephalopathy, syncope, myelitis, neuropathy, angioedema, erythema multiforme, hyperhidrosis, chills, influenza-like symptoms and congenital anomaly.185

The HAVRIX vaccine package insert reports that clinical trials involving the vaccine have occurred in over 37,000 individuals, however, GSK provides very limited information on these trials in their vaccine product insert. The only study detailed as part of its package insert, HAVRIX Study 231, involved 1,241 healthy children between the ages of 11 and 25 months.186 Safety studies in this clinical trial compared the health outcomes of individuals receiving HAVRIX alone, HAVRIX in combination with Merck’s MMR vaccine and Merck’s varicella vaccine, or MMR and Varicella vaccine followed by a dose of HAVRIX vaccine 42 days later. Solicited adverse events such as fever, irritability, drowsiness, loss of appetite, redness, pain, and swelling were recorded by parents on diary cards for 3 days following vaccination and submitted to clinical trial monitors. Information on unsolicited adverse events occurring between Day 4 and Day 31 post vaccination were collected from the parents of trial participants and a telephone follow up occurred 6 months later. While the vaccine product insert provides limited information on health outcomes of the 1,241 trial participants, further data on this particular study was released in February of 2013 as part of GSK’s “commitment to further clinical transparency through public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.”187

According to the clinical trial documents of HAVRIX Study 231 released by GSK in 2013, over 62 percent of trial participants receiving HAVRIX alone, nearly 58 percent of trial participants receiving HAVRIX in combination with MMR and varicella vaccine, and over 66 percent of participants receiving MMR and varicella vaccine followed by HAVRIX at Day 42, experienced an adverse reaction in the first 30 days following vaccination.188 Of the 1,241 children who participated in this clinical trial, 51, or 4 percent, experienced a serious adverse event following vaccination, with half of those serious reactions occurring in children who received HAVRIX in combination with the MMR and varicella vaccine.189 In the United States, the hepatitis A vaccine is routinely administered with the MMR, varicella, and pneumococcal vaccines, in accordance to the CDC’s recommended vaccine schedule.190

Details on the serious adverse events that occurred during HAVRIX Study 231 remain unknown, as the information was redacted by GSK prior to release. The document, however, reports that one serious adverse reaction, a diagnosis of autism following vaccination with HAVRIX in combination with the MMR and varicella vaccine, “was considered by the investigator to have a possible causal relationship to vaccination.” 191

The HAVRIX Study 231 document released by GSK also noted that a diagnosis of or suspected immunodeficient condition such as HIV or a newly diagnosed neurologic disorder, in addition to other possible medical events that occurred during the clinical trial, would result in the removal of the individual’s results from the study’s final outcome.192 1,474 children were initially enrolled in the study, however, final data includes the outcomes of only 1,241 children. In the Study 231 document, GSK states that four children who suffered adverse events were removed from the study and that seven others were eliminated for “other reasons”, with further details redacted by GSK.193

TWINRIX: Adverse events reported to have occurred during pre-licensing clinical trials of GlaxoSmithKline (GSK)’s TWINRIX hepatitis A/ hepatitis B vaccine included: injection site redness, pain, induration, and swelling; headache; fatigue; nausea; diarrhea; vomiting; upper respiratory infections; insomnia; anorexia; dizziness; migraine; paresthesia; somnolence; syncope; vertigo; muscle and joint pain; back pain; constipation; weakness; agitation; irritability, abdominal pain; influenza-like illness; erythema; petechiae; rash; sweating; urticaria; lymphadenopathy; dysgeusia; hypertonia; tingling; migraine; flushing; photophobia and hypotension.194

Serious complications reported by GSK in the TWINRIX product insert during vaccine post-marketing surveillance have included: meningitis, herpes zoster; allergic reaction, anaphylactoid reaction, anaphylaxis, serum sickness–like syndrome days to weeks after vaccination (including arthralgia/arthritis; fever; urticaria; erythema multiforme; ecchymoses; and erythema nodosum) thrombocytopenia; thrombocytopenic purpura; Bell's palsy; convulsions; encephalitis; encephalopathy; Guillain-Barré Syndrome; myelitis; multiple sclerosis; neuritis; neuropathy; optic neuritis; paralysis; paresis; transverse myelitis; hepatitis; jaundice; shortness of breath; bronchospasm, including asthma-like symptoms; conjunctivitis; visual disturbances; earache; tinnitus; palpitations; tachycardia; vasculitis; dyspepsia; arthritis; alopecia; eczema; erythema multiforme; erythema nodosum; hyperhidrosis; lichen planus and muscular weakness.195

Pre-licensure clinical trials of TWINRIX, a bivalent vaccine combining HAVRIX (inactivated Hepatitis A vaccine) and ENGERIX-B (recombinant Hepatitis B vaccine), were limited to approximately 2,500 trial participants. In the United States, TWINRIX was studied for use in only 773 healthy adults between the ages of 18 and 70. In this U.S. pre-clinical vaccine trial, study participants received either TWINRIX, a dose of HAVRIX (hepatitis A vaccine), a dose ENGERIX-B (Hepatitis B vaccine), or a dose of both HAVRIX and ENGERIX-B. Adverse events such as fever, irritability, and drowsiness, loss of appetite, redness, pain, and swelling were actively solicited by clinical trial monitors for only 3 days following vaccination. Data on unsolicited adverse reactions were collected between Day 4 and Day 31 following vaccine administration. GSK reports that the data collected from U.S. clinical trials were comparable to those reported from other clinical trials, however, this data has not been published. Adverse events reported during the pre-licensure clinical trials included injection site redness, swelling, and induration, agitation, insomnia, abdominal pain, vomiting, anorexia, respiratory tract infections, vertigo, dizziness, migraine, rash, weakness, and more.196

In the comprehensive report evaluating scientific evidence, Adverse Effects of Vaccines: Evidence and Causality197, published in 2012 by the Institute of Medicine (IOM), eight reported vaccine adverse events following the hepatitis A vaccine were evaluated by a physician committee198. These adverse events included acute disseminated encephalomyelitis, transverse myelitis, multiple sclerosis, Guillain Barre Syndrome, chronic inflammatory disseminated polyneuropathy, Bell’s palsy, anaphylaxis, and autoimmune hepatitis.

Of the eight vaccine-related adverse events evaluated, the IOM committee concluded that there was inadequate evidence to support or reject a causal relationship between the hepatitis A vaccine and all eight vaccine related adverse events, because of the complete absence of methodologically sound published studies required to make a determination.199

A 2011 published study linked hepatitis A vaccination to Henoch-Schönlein purpura, a disorder that causes bleeding and swelling of the small blood vessels.200 In 2012, an epidemiological study examining the risk of immune thrombocytopenic purpura (ITP), a blood disorder causing unusually low levels of platelets in the body, following vaccination found a significantly higher number of reported cases in individuals between the ages of 7 and 17 following vaccination with the hepatitis A vaccine. The study authors recommended further research on this association, however, no additional studies have been published.201

Acute disseminated encephalomyelitis (ADEM) combined with acute motor axonal neuropathy following the hepatitis A vaccine and an infection with Campylobacter jejuni, a bacteria commonly associated with food poisoning, was documented in a 1999 published case study.202 In 2009, doctors from Singapore submitted a case report of retrobulbar optic neuritis in an HIV positive man following vaccination with the hepatitis A vaccine.203

Using the MedAlerts search engine, as of  February 28, 2019, there have been more than 40,637 reports of hepatitis A vaccine reactions, hospitalizations, injuries and deaths following hepatitis A vaccinations made to the federal Vaccine Adverse Events Reporting System (VAERS), including 141 related deaths, 3,246 hospitalizations, and 851 related disabilities. However, the numbers of vaccine-related injuries and deaths reported to VAERS may not reflect the true number of serious health problems that occur after hepatitis A vaccination.

Even though the National Childhood Vaccine Injury Act of 1986 legally required pediatricians and other vaccine providers to report serious health problems following vaccination to federal health agencies (VAERS), many doctors and other medical workers giving vaccines to children and adults fail to report vaccine-related health problem to VAERS. There is evidence that only between one and 10 percent of serious health problems that occur after use of prescription drugs or vaccines in the U.S. are ever reported to federal health officials, who are responsible for regulating the safety of drugs and vaccines and issue national vaccine policy recommendations.204,205,206,207 208

As of May 1, 2019, there had been 144 claims filed in the federal Vaccine Injury Compensation Program (VICP) for injuries and deaths following Hepatitis A vaccination, including 7 deaths and 137 serious injuries. Of that number, the U.S. Court of Claims administering the VICP has compensated 72 children and adults, who have filed for hepatitis A vaccine injury.209

Who is at highest risk for complications from Hepatitis A vaccine?

There is a gap in medical knowledge in terms of doctors being able to predict who will have an adverse reaction to hepatitis A vaccination, and who will not.

In the clinical trials of children receiving HAVRIX, higher rates of serious adverse reactions occurred in children who received HAVRIX in combination with MMR and varicella vaccine, in comparison to children who received HAVRIX alone or in children who received MMR and varicella vaccine followed by HAVRIX vaccine at Day 42 of the clinical trial.210

According to the CDC, most serious adverse reactions following hepatitis A vaccination occur in adults, with one-third of those reported reactions occurring when hepatitis A vaccine was administered in combination with other vaccines.211

Who should not get Hepatitis A vaccine?

According to the CDC, certain persons should not get hepatitis A vaccine, or should postpone getting it. Those persons are:212

  • Anyone who has ever had a severe (life-threatening) allergic reaction to a previous dose of hepatitis A vaccine or to any component of the hepatitis A vaccine. It is important to tell your doctor if you have any severe allergies.
  • Anyone who is moderately or severely ill at the time the shot is scheduled should wait until they recover before receiving hepatitis A vaccine.

While the CDC recommends that infants 6 to 11 months of age traveling outside the United States receive a dose of hepatitis A vaccine,213 both VAQTA and HAVRIX are not FDA approved for use in children under the age of 12 months. Further, product inserts for both VAQTA and HAVRIX state that the safety and effectiveness of their products have not been established in children younger than 12 months of age.214 215

VAQTA: Contraindications to receiving the VAQTA (hepatitis A inactivated) vaccine documented in Merck’s product insert include persons who have experienced a severe allergic reaction or anaphylaxis to any component of VAQTA, including neomycin, or to a previous dose of any hepatitis A vaccine. As well, both the syringe plunger and vial stopper of VAQTA contain latex that may cause an allergic reaction in persons who are sensitive to latex. 216

Merck also cautions that immunocompromised individuals and persons receiving immunosuppressive therapy may have a decreased immune response to vaccination with VAQTA.217

VAQTA is approved for use in children and adults 12 months and older. Children under the age of 12 months should not receive VAQTA.218

There are no adequate and well-controlled studies designed to evaluate VAQTA in pregnant women. It is also unknown whether VAQTA is excreted in human milk. 219

HAVRIX: Contraindications to receiving the HAVRIX (hepatitis A inactivated) vaccine documented in GlaxoSmithKline’s insert include persons who have experienced anaphylaxis or a severe allergic reaction to a previous dose of any hepatitis A vaccine or to any component of HAVRIX, including neomycin. The tip caps of the prefilled HAVRIX vaccine syringes contain latex and may cause an allergic reaction in individuals who are sensitive to latex. 220

GlaxoSmithKline also cautions that fainting may occur following administration with HAVRIX and can include symptoms such as paresthesia, tonic-clonic limb movements, and visual disturbances. Immunocompromised individuals and persons receiving immunosuppressive therapy may have a decreased immune response to HAVRIX. 221

HAVRIX is approved for use in children and adults 12 months and older and children under the age of 12 months should not receive HAVRIX.

There are no adequate and well-controlled studies of HAVRIX in pregnant women in the United States and no animal studies have ever been completed to guide the use of HAVRIX during pregnancy. There is no information regarding HAVRIX in human milk, the effects of HAVRIX on the breastfeeding child, or the impact that the vaccine may have on milk production. 222  

Clinical trials of HAVRIX vaccine did not include a sufficient number of persons above the age of 65 years and it is unknown whether this population responds to HAVRIX in a similar manner as the younger population.223

TWINRIX: Contraindications to receiving the TWINRIX (hepatitis A inactivated/hepatitis B Recombinant) vaccine documented in GlaxoSmithKline’s insert include persons who have experienced a severe allergic reaction to a previous dose of any hepatitis A or hepatitis B vaccine or to any component of TWINRIX, including yeast and neomycin. The tip caps of the prefilled TWINRIX vaccine syringes contain latex and may cause an allergic reaction in individuals who are sensitive to latex. 224

GlaxoSmithKline also cautions that syncope can occur following administration of TWINRIX and can include symptoms such as tonic-clonic limb movements, visual disturbances and paresthesia. GlaxoSmithKline recommends postponing vaccination with TWINRIX in persons who are exhibiting signs of moderate or severe acute illness to avoid any confusion between a possible reaction to the vaccine and signs of an impending acute infection.225

Immunocompromised individuals and persons receiving immunosuppressive therapy may have a decreased immune response to TWINRIX. In clinical trials, TWINRIX was not studied for use with any other vaccine and no information on safety or effectiveness of giving TWINRIX simultaneously with any other vaccine is available. 226

TWINRIX is approved for use in persons 18 years of age and older. Persons under the age of 18 should not receive TWINRIX. Clinical trials of TWINRIX did not include a sufficient number of persons over the age of 65 years of age and it is unknown whether this population responds to TWINRIX in a similar manner as the younger population.227

There are no well-controlled and adequate studies of TWINRIX in pregnant women in the United States. There is no information regarding TWINRIX in human milk, the effects of TWINRIX on the breastfeeding child, or the impact that the vaccine may have on milk production.228

NVIC Note: Some doctors only vaccinate children who are healthy and are not sick at the time of vaccination with a coinciding viral or bacterial infection. If you do not want your acutely ill child vaccinated and your doctor disagrees with you, you may want to consider consulting one or more other trusted health care professionals before vaccinating.

What questions should I ask my doctor about the Hepatitis A vaccine?

NVIC’s If You Vaccinate, Ask 8! Webpage downloadable brochure suggests asking eight questions before you make a vaccination decision for yourself, or for your child. If you review these questions before your appointment, you will be better prepared to ask your doctor questions.  Also make sure that the nurse or doctor gives you the relevant Vaccine Information Statement (VIS) for the vaccine or vaccines you are considering well ahead of time to allow you to review it before you or your child gets vaccinated. Copies of VIS for each vaccine are also available on the CDC's website and there is a link to the VIS for vaccines on NVIC's “Quick Facts” at the top of this page.

It is also a good idea to read the vaccine manufacturer product insert that can be obtained from your doctor or public health clinic because federal law requires drug companies marketing vaccines to include certain kinds of vaccine benefit, risk and use information in product information inserts that may not be available in other published information. Merck’s VAQTA and GlaxoSmithKline’s HAVRIX and TWINRIX vaccine product inserts are located on the Food and Drug Administration’s website.

Other questions that may be useful to discuss with your doctor before getting the hepatitis A (or hepatitis A & hepatitis B combination) vaccine are: 

  • If other vaccines in addition to hepatitis A vaccine are scheduled for my child at this office visit, am I allowed to modify the schedule so fewer vaccines are given at once?
  • What should I do if my child has a high fever or appears very ill after vaccination?
  • What other kinds of reaction symptoms should I call to report after hepatitis A vaccination?
  • If the hepatitis A vaccine doesn’t protect my child, do I have any other options for preventing hepatitis A infection?

Under the National Childhood Vaccine Injury Act of 1986, doctors and all vaccine providers are legally required to give you vaccine benefit and risk information before vaccination; record serious health problems following vaccination in the permanent medical record; keep a permanent record of all vaccines given, including the manufacturer’s name and lot number; and report serious health problems, injuries and deaths that follow vaccination to VAERS.

Remember, if you choose to vaccinate, always keep a written record of exactly which shots/vaccines you or your child have received, including the manufacturer’s name and vaccine lot number. Write down and describe in detail any serious health problems that develop after vaccination, and keep vaccination records in a file you can access easily.  

It also is important to be able to recognize a vaccine reaction and seek immediate medical attention if the reaction appears serious, as well as know how to make a vaccine reaction report to federal health officials at the Vaccine Adverse Reporting System (VAERS). NVIC’s Report Vaccine Reactions—It’s the Law webpage can help you file a vaccine reaction report yourself to VAERS if your doctor fails or refuses to make a report. 

NVIC Press Releases, Statements, and Commentaries Related to Hepatitis A

The Vaccine Reaction

Additional Bibliography of References

Manufacturer Product Information Inserts:

World Health Organization

Centers for Disease Control (CDC)

Selected Media Articles

Medical Literature

References

1 MedlinePlus Hepatitis A Feb 7, 2019

2 WebMD Hepatitis A FAQ. Nov. 14, 2018

3 WHO Hepatitis A Sep. 19, 2018

4 CDC Hepatitis A – Hepatitis A Virus Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

5 CDC Hepatitis A Questions and Answers for Health Professionals - How is the hepatitis A virus (HAV) killed? May 8, 2019

6 CDC Hepatitis A – Epidemiology Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

7 CDC Hepatitis A Questions and Answers for the Public- Symptoms. Mar. 13, 2019

8 CDC Hepatitis A – Laboratory Diagnosis Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

9 CDC Hepatitis A – Complications Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

10 CDC Hepatitis A Questions and Answers for Health Professionals. When symptoms occur, how long do they last? May 8, 2019

11 FDA VAQTA Product Insert Dec. 20, 2018

12 FDA HAVRIX Product Insert Dec. 19, 2018

13 FDA TWINRIX Product Insert Dec. 18, 2018

14 CDC Hepatitis A VIS July 20, 2016

15 Ibid

16 FDA VAQTA Product Insert Dec. 20, 2018

17 FDA HAVRIX Product Insert Dec. 19, 2018

18 FDA TWINRIX Product Insert Dec. 18, 2018

19 Immunization Action Coalition State Information - Hepatitis A Vaccine Mandates for Children in Daycare Facilities, Elementary, and Secondary Schools. Nov. 11, 2018

20 CDC Hepatitis A – Hepatitis A Virus Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

21 CDC Hepatitis A Questions and Answers for Health Professionals - How is the hepatitis A virus (HAV) killed? Mar. 13, 2019

22 CDC Hepatitis A – Hepatitis A Virus Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

23 MedlinePlus Hepatitis A Feb. 7, 2019

24 WebMD Hepatitis A FAQ. Nov 14, 2018

25 CDC Hepatitis A – Hepatitis A Virus Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

26 WebMD Hepatitis A FAQ. Nov 14, 2018

27 CDC Hepatitis A – Epidemiology Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

28 CDC Hepatitis A – Pathogenesis Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

29 CDC Hepatitis A Questions and Answers for the Public - What are the symptoms of hepatitis A? Mar. 13, 2019

30 CDC Hepatitis A – Clinical Features Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

31 CDC Hepatitis A Questions and Answers for Health Professionals -Can Hepatitis A become chronic? May 8, 2019

32 CDC Hepatitis A Questions and Answers for Health Professionals -Can persons become re-infected with hepatitis A? May 8, 2019

33 MedlinePlus Hepatitis A Feb. 7, 2019

34 WebMD Hepatitis A FAQ. Nov. 18, 2018

35 Nelson NP, Murphy TV, Hepatitis A: The Changing Epidemiology of Hepatitis A. Clin Liver Dis (Hoboken). 2013 Dec; 2(6): 227–230.

36 WHO Hepatitis A Sep. 19, 2018

37 CDC Diseases and Contaminants - Hepatitis A and Drinking Water from Private Wells. July 1 , 2015

38 CDC Hepatitis A – Epidemiology Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

39 CDC Travelers’ Health-Hepatitis A. Jan. 15, 2019

40 CDC National Outbreak Reporting System (NORS) Dashboard. Dec. 10, 2018 See Etiology – Hepatitis

41 CDC Emergency Preparedness and Response - Update: Widespread Outbreaks of Hepatitis A among People Who Use Drugs and People Experiencing Homelessness across the United States. Health Alert Network. Mar. 25, 2019

42 CDC Hepatitis A Virus Outbreaks Associated with Drug Use and Homelessness — California, Kentucky, Michigan, and Utah, 2017 MMWR Nov. 2, 2018; 67(43);1208–1210

43 Krugman S, The Gordon Wilson Lecture. The ABC's of viral hepatitis. Trans Am Clin Climatol Assoc. 1992; 103: 145–156.

44 Conrad ME, Infectious Hepatitis: An Unsolved Military Problem. Mil. Med. 1965 Jun; 130(6) 594–600

45 Cuthbert JA, Hepatitis A: Old and New. Clin Microbiol Rev. 2001 Jan;14(1):38-58.

46 Ibid

47 Ibid

48 Ibid

49 CDC Updated Dosing Instructions for Immune Globulin (Human) GamaSTAN S/D for Hepatitis A Virus Prophylaxis. MMWR. Sept 15, 2017; 66(36);959–960

50 Ely, M Disinterestedness at Willowbrook. COLFA Conference. University of Texas at San Antonio, Spring 2014

51Stephen Goldby, Saul Krugman, M.H. Pappworth, and Geoffrey Edsall: The Willowbrook Letters, “Criticism and Defense”; Paul Ramsey, “Judgment on Willowbrook” Published on Philosophy at TAMUCC. No Date

52 Diamond, EF The Willowbrook Experiments The Linacre Quarterly. 1973 May; 40 (2)9 133-137

53 Ely, M Disinterestedness at Willowbrook. COLFA Conference. University of Texas at San Antonio, Spring 2014

54 Dugger, CW. Big Day for Ex-Residents Of Center for the Retarded. The New York Times. Mar. 12, 1993

55 Ibid

56Stephen Goldby, Saul Krugman, M.H. Pappworth, and Geoffrey Edsall: The Willowbrook Letters, “Criticism and Defense”; Paul Ramsey, “Judgment on Willowbrook” Published on Philosophy at TAMUCC. No Date

57 Goldby S. Experiments at the Willowbrook State School. Lancet. 1971 Apr 10;1(7702):749.

58 Pappworth MH, THE WILLOWBROOK EXPERIMENTS. Lancet. 1971 June 5; 297(7710);1181

59 Gunderman D, Revisiting the atrocities that once consumed the halls of Willowbrook State School in Staten Island – WARNING GRAPHIC CONTENT. The New York Daily News. Apr. 9 , 2017

60 Krugman S, The Gordon Wilson Lecture. The ABC's of viral hepatitis. Trans Am Clin Climatol Assoc. 1992; 103: 145–156.

61 Carroll TM, Gutmann MP, The Limits of Autonomy: The Belmont Report and the History of Childhood. J Hist Med Allied Sci. 2011 Jan; 66(1): 82–115.

62 Feinstone SM, Kapikian AZ, Purceli RH. Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness. Science. 1973 Dec 7;182(4116):1026-8.

63 Cuthbert JA, Hepatitis A: Old and New. Clin Microbiol Rev. 2001 Jan;14(1):38-58.

64 Sjogren MH, Hoke CH, Binn LN et al. Immunogenicity of an inactivated hepatitis A vaccine. Ann Intern Med. 1991 Mar 15;114(6):470-1.

65 CDC December-1951 Bulletin. Dec. 1951. vol. X, no. 12.

66 CDC Annual Supplement: Reported Incidence of Notifiable Diseases in the United States, 1961. MMWR. Oct 31, 1962; 10 (53); 1-29

67 Ibid

68 Ibid

69 CDC Reported incidence of notifiable diseases in the United States 1966. MMWR. Nov. 1967. 15(53); 1-60

70 CDC Table 1a. Reported number and rate per 100,000 population of cases of acute, symptomatic, viral hepatitis, by type and year, United States, 1966-2008. June 25, 2010

71 CDC Prevention of Hepatitis A Through Active or Passive Immunization MMWR Dec 27, 1996; 45 (RR-15)

72 Ibid

73 Ibid

74 Ibid

75 Ibid

76 CDC Summary of Notifiable Diseases, United States 1996. MMWR. Oct. 31, 1997; 45(53);1-87

77 CDC Prevention of Hepatitis A Through Active or Passive Immunization Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. May 19, 2006; 55(RR07);1-23

78 CDC Surveillance for Acute Viral Hepatitis – United States, 2007. MMWR. May 22, 2009; 58 (3) 1-27

79 CDC Multistate outbreak of hepatitis A virus infections linked to pomegranate seeds from Turkey (Final Update). Oct. 28, 2013

80 CDC Summary of Notifiable Infectious Diseases and Conditions — United States, 2013. MMWR Oct. 23, 2015; 62(53);1-119

81 CDC Outbreak of hepatitis A in Hawaii linked to raw scallops. Aug. 19, 2016

82 CDC 2016 - Multistate outbreak of hepatitis A linked to frozen strawberries (Final Update). Dec. 16, 2016

83 CDC National Notifiable Infectious Diseases and Conditions: United States – Table 2g. Reported cases of notifiable diseases, by region and reporting area- United States and U.S. territories, 2016 Atlanta, GA. CDC Division of Health Informatics and Surveillance, 2017

84 CDC National Outbreak Reporting System (NORS) – NORS Dashboard. Dec. 10, 2018. See Etiology – Hepatitis; Year – 2016.

85 CDC Table 2.2. Select clinical characteristics of hepatitis A cases* reported in the United States, 2016. Apr. 16, 2018

86 CDC National Outbreak Reporting System (NORS) – NORS Dashboard. Dec. 10, 2018. See Etiology – Hepatitis.

87 Gould L, Kline J, Monahan C, Vierk K. Outbreaks of Disease Associated with Food Imported into the United States, 1996–2014. Emerg Infect Dis. 2017;23(3):525-528.

88 CDC. Surveillance Manual – Chapter 3: Hepatitis A. – Background. May 18, 2018

89  CDC Emergency Preparedness and Response - Update: Widespread Outbreaks of Hepatitis A among People Who Use Drugs and People Experiencing Homelessness across the United States. Health Alert Network. Mar. 25, 2019

90  Franco E, Meleleo C, Serino L, et al. Hepatitis A: Epidemiology and prevention in developing countries. World J Hepatol. 2012 Mar 27; 4(3): 68–73.

91 WHO Hepatitis A Sep. 19, 2018

92 Ibid

93 Franco E, Meleleo C, Serino L, et al. Hepatitis A: Epidemiology and prevention in developing countries. World J Hepatol. 2012 Mar 27; 4(3): 68–73.

94 CDC Recommendations of the Advisory Committee on Immunization Practices for Use of Hepatitis A Vaccine for Persons Experiencing Homelessness MMWR Feb.15, 2019; 68(6);153–156

95 WHO Hepatitis A Sep. 19, 2018

96 CDC Hepatitis A – Complications Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

97 CDC Hepatitis A Virus Outbreaks Associated with Drug Use and Homelessness — California, Kentucky, Michigan, and Utah, 2017 MMWR Nov. 2, 2018; 67(43);1208–1210

98 CDC Hepatitis A – Clinical Features Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

99 CDC Recommendations of the Advisory Committee on Immunization Practices for Use of Hepatitis A Vaccine for Persons Experiencing Homelessness MMWR Feb.15, 2019; 68(6);153–156

100 Kahn, A Hepatitis A - Who is at risk of getting hepatitis A? Healthline May 7, 2018

101 Ly KN, Klevens, RM, Trends in disease and complications of hepatitis A virus infection in the United States, 1999-2011: a new concern for adults. J Infect Dis. 2015 Jul 15;212(2):176-82.

102 Gould L, Kline J, Monahan C, Vierk K. Outbreaks of Disease Associated with Food Imported into the United States, 1996–2014. Emerg Infect Dis. 2017;23(3):525-528.

103 WHO Hepatitis A Sep. 19, 2018

104 CDC Emergency Preparedness and Response - Update: Widespread Outbreaks of Hepatitis A among People Who Use Drugs and People Experiencing Homelessness across the United States. Health Alert Network. Mar. 25, 2019

105 WHO Hepatitis A Sep. 19, 2018

106 CDC Hepatitis A – Complications Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

107 Kahn, A Hepatitis A - Are there complications from hepatitis A? Healthline May 7, 2018

108 CDC Hepatitis A Virus Outbreaks Associated with Drug Use and Homelessness — California, Kentucky, Michigan, and Utah, 2017 MMWR Nov. 2, 2018; 67(43);1208–1210

109 Medline Plus Preventing Hepatitis A. Aug 1, 2017

110 Ibid

111 CDC Hepatitis A Questions and Answers for the Public- What is postexposure prophylaxis (PEP)? Apr. 20, 2018

112 CDC Hepatitis A Questions and Answers for Health Professionals - Who should receive protection against hepatitis A before travel? July 27, 2018

113 Medline Plus Preventing Hepatitis A. Aug 1, 2017

114 WHO Hepatitis A Sep. 19, 2018

115 Kahn, A Hepatitis A - Are there complications from hepatitis A? Healthline May 7, 2018

116 CDC Prevention of Hepatitis A Through Active or Passive Immunization Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. May 19, 2006; 55(RR07);1-23

117 FDA VAQTA Product Insert Dec. 20, 2018

118 Jacobs JP The status of human diploid cell strain MRC-5 as an approved substrate for the production of viral vaccines. J Biol Stand. 1976 Apr;4(2):97-9.

119 Mold M, Shardlow E, Exley C Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations Sci Rep. 2016; 6: 31578.

120 FDA VAQTA Dec. 20, 2018

121 CDC Vaccine Excipient & Media Summary Excipients Included in U.S. Vaccines, by Vaccine Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015. Updated Oct. 2018

122 FDA VAQTA Product Insert Dec. 20, 2018

123 FDA HAVRIX Product Insert Dec. 19, 2018

124 Jacobs JP The status of human diploid cell strain MRC-5 as an approved substrate for the production of viral vaccines. J Biol Stand. 1976 Apr;4(2):97-9.

125 FDA HAVRIX Product Insert Dec. 19, 2018

126 Ibid

127 Ibid

128 CDC Vaccine Excipient & Media Summary Excipients Included in U.S. Vaccines, by Vaccine Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015. Updated Oct. 2018

129 FDA TWINRIX Product Insert Dec. 18, 2018

130 Ibid

131 Ibid

132 CDC Vaccine Excipient & Media Summary Excipients Included in U.S. Vaccines, by Vaccine Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015. Updated Oct. 2018

133 FDA Twinrix Dec. 18, 2018

134 Immunization Action Coalition State Information - Hepatitis A Vaccine Mandates for Children in Daycare Facilities, Elementary, and Secondary Schools. Nov. 11, 2018

135 Sjogren MH, Hoke CH, Binn LN et al. Immunogenicity of an inactivated hepatitis A vaccine. Ann Intern Med. 1991 Mar 15;114(6):470-1.

136 Midthun K, Ellerbeck E, Gershman K et al. Safety and immunogenicity of a live attenuated hepatitis A virus vaccine in seronegative volunteers. J Infect Dis. 1991 Apr;163(4):735-9.

137 WHO Global Vaccine Safety: Live Attenuated hepatitis A vaccine. Extract from report of GACVS meeting of 16-17 June 2010, published in the WHO Weekly Epidemiological Record on 23 July 2010

138 Werzberger A, Mensch B, Kuter B et al. A controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children. N Engl J Med. 1992 Aug 13;327(7):453-7.

139 Innis BL, Snitbhan R, Kunasol P et al. Protection against hepatitis A by an inactivated vaccine. JAMA. 1994 May 4;271(17):1328-34.

140 Altman, LK, F.D.A. Approves First Vaccine To Prevent Hepatitis A Infection. The New York Times. Feb. 23, 1995

141 FDA March 29, 1996 Approval Letter – VAQTA. Mar. 29, 1996

142 CDC Prevention of Hepatitis A Through Active or Passive Immunization: Recommendations of the Advisory Committee on Immunization Practices. MMWR. Dec 27, 1996; MMWR 45(RR15);1-30

143 Ibid

144 CDC Prevention of Hepatitis A Through Active or Passive Immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Oct. 1, 1999; 48(RR12);1-37

145 FDA May 11, 2001 Approval Letter – Twinrix. May 11, 2001

146 CDC Notice to Readers: FDA Approval for a Combined Hepatitis A and B Vaccine. MMWR. Sept. 21, 2001; 50(37);806-7

147 CDC Prevention of Hepatitis A Through Active or Passive Immunization Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. May 19, 2006; 55(RR07);1-23

148 CDC August 11, 2005 Approval Letter – VAQTA. Aug. 11, 2005

149 CDC October 17, 2005 Approval Letter – Havrix. Oct. 17, 2005

150 CDC Notice To Readers: FDA Approval of VAQTA (Hepatitis A Vaccine, Inactivated) for Children Aged >1 Year. MMWR. Oct. 14, 2005; 54(40);1026

151 CDC Notice to Readers: FDA Approval of Havrix (Hepatitis A Vaccine, Inactivated) for Persons Aged 1--18 Years. MMWR. Dec. 9, 2005; 54(48);1235-1236

152 CDC Prevention of Hepatitis A Through Active or Passive Immunization Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. May 19, 2006; 55(RR07);1-23

153 CDC Update: Prevention of Hepatitis A After Exposure to Hepatitis A Virus and in International Travelers. Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. Oct. 19, 2007; 56(41);1080-1084

154 CDC Updated Recommendations from the Advisory Committee on Immunization Practices (ACIP) for Use of Hepatitis A Vaccine in Close Contacts of Newly Arriving International Adoptees. MMWR. Sep. 18, 2009; 58(36);1006-1007

155 CDC Hepatitis A Vaccination Coverage Among U.S. Children Aged 12--23 Months --- Immunization Information System Sentinel Sites, 2006—2009. MMWR. July 2, 2010; 59(25);776-779

156 National Center for Health Statistics. Chapter 23: Immunization and Infectious Diseases. Healthy People 2020 Midcourse Review. Hyattsville, MD. 2016.

157 Nelson NP, Yankey D, Singleton JA et al. Hepatitis A vaccination coverage among adolescents (13-17 years) in the United States, 2008-2016. Vaccine. 2018 Mar 14;36(12):1650-1659

158 CDC Surveillance of Vaccination Coverage Among Adult Populations — United States, 2015. MMWR. May 5, 2017; 66(11);1–28

159 Immunization Action Coalition State Information - Hepatitis A Vaccine Mandates for Children in Daycare Facilities, Elementary, and Secondary Schools. Nov. 11, 2018

160 CDC Recommendations of the Advisory Committee on Immunization Practices for Use of Hepatitis A Vaccine for Persons Experiencing Homelessness MMWR Feb. 15, 2019; 68(6);153–156

161 CDC Viral Hepatitis Widespread outbreaks of hepatitis A across the United States Apr. 29, 2019

162 CDC Recommendations of the Advisory Committee on Immunization Practices for Use of Hepatitis A Vaccine for Persons Experiencing Homelessness MMWR Feb. 15, 2019; 68(6);153–156

163 Demicheli V, Tiberti D. The effectiveness and safety of hepatitis A vaccine: a systematic review. Vaccine. 2003 Jun 2;21(19-20):2242-5.

164 Plumb ID, Bulkow LR, Bruce MG et al. Persistence of antibody to Hepatitis A virus 20 years after receipt of Hepatitis A vaccine in Alaska. J Viral Hepat. 2017 Jul;24(7):608-612

165 FDA VAQTA Product Insert Dec. 20, 2018

166 FDA HAVRIX Product Insert Dec. 19, 2018

167 FDA Twinrix Product Insert Dec. 18, 2018

168 FDA VAQTA Product Insert Dec. 20, 2018

169 FDA HAVRIX Product Insert Dec. 19, 2018

170 FDA Twinrix Product Insert Dec. 18, 2018

171 Overton ET, Nurutdinova D, Sungkanuparph S et al. Predictors of immunity after hepatitis A vaccination in HIV-infected persons. J Viral Hepat. 2007 Mar;14(3):189-93.

172 Weissman S, Feucht C, Moore BA Response to hepatitis A vaccine in HIV-positive patients. J Viral Hepat. 2006 Feb;13(2):81-6.

173 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Effects of Vaccines: Evidence and Causality. Evaluating Biological Mechanisms of Adverse Events (p. 57-102), Increased Susceptibility (p. 82). Washington, DC: The National Academies Press 2012.

174 CDC Hepatitis A VIS  July 20, 2016

175 FDA VAQTA Product Insert Dec. 20, 2018

176 Ibid

177 MacDonald SE, Dover DC, Simmonds KA, et al. Risk of febrile seizures after first dose of measles–mumps–rubella–varicella vaccine: a population-based cohort study. CMAJ. 2014 Aug 5; 186(11): 824–829.

178 Ma SJ, Xiong YQ, Jiang LN et al. Risk of febrile seizure after measles-mumps-rubella-varicella vaccine: A systematic review and meta-analysis. Vaccine. 2015 Jul 17;33(31):3636-49

179 FDA VAQTA Product Insert Dec. 20, 2018

180 Mold M, Shardlow E, Exley C Insight into the cellular fate and toxicity of aluminium adjuvants used in clinically approved human vaccinations Sci Rep. 2016; 6: 31578.

181 FDA VAQTA Product Insert Dec. 20, 2018

182 Ibid

183 Ibid

184 FDA HAVRIX Product Insert Dec. 19, 2018

185 Ibid

186 Ibid

187GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011

188 GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011. Page 10.

189 GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011. Page 11

190 CDC 2019 Recommended Vaccinations for Infants and Children (birth though 6 years) Parent-Friendly Format Feb. 5, 2019

191 GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011. Page 11

192 GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011. Page 44

193 GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011. Page 71

194 FDA Twinrix Product Insert Dec. 18, 2018

195 Ibid

196 Ibid

197 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Effects of Vaccines: Evidence and Causality. (Evaluating Biological Mechanisms for Adverse Events: Increased Susceptibility). Washington, DC: The National Academies Press. 2012

198 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Effects of Vaccines: Evidence and Causality. (Evaluating Biological Mechanisms for Adverse Events: Increased Susceptibility). Washington, DC: The National Academies Press. 2012. Chapter 7: Hepatitis A.

199 Ibid

200 Jariwala S, Vernon N, Shliozberg J. Henoch-Schönlein purpura after hepatitis A vaccination. Ann Allergy Asthma Immunol. 2011 Aug;107(2):180-1.

201 O'Leary ST, Glanz JM, McClure DL et al, The risk of immune thrombocytopenic purpura after vaccination in children and adolescents. Pediatrics. 2012 Feb;129(2):248-55

202 Huber S, Kappos L, Fuhr P, et al. Combined acute disseminated encephalomyelitis and acute motor axonal neuropathy after vaccination for hepatitis A and infection with Campylobacter jejuni. J Neurol. 1999 Dec;246(12):1204-6.

203 Huang EHZ, Lim SA, Lim PL et al. Retrobulbar optic neuritis after Hepatitis A vaccination in a HIV-infected patient Eye (Lond). 2009 Dec;23(12):2267-71

204 Kessler DA, the Working Group, Natanblut S, et al. A New Approach to Reporting Medication and Device Adverse Effects and Product Problems. JAMA. 1993; 269(21):2765-2768.

205 FDA.gov. Kessler DA. Introducing MEDWatch: A New Approach to Reporting Medication and Device Adverse Effects and Product Problems. Reprint from JAMA. June 9, 1993.

206 Braun M. Vaccine adverse event reporting system (VAERS): usefulness and limitations. Johns Hopkins Bloomberg School of Public Health

207 Rosenthanl S, Chen R. The reporting sensitivities of two passive surveillance systems for vaccine adverse events. Am J Public Health 1995; 85: pp. 1706-9.

208 AHRQ Electronic Support for Public Health–Vaccine Adverse Event Reporting System (ESP:VAERS) Dec 1, 2007-Sep. 30, 2010

209 U.S. Department of Health and Human Services. National Vaccine Injury Compensation Program Data—May 1, 2019. National Vaccine Injury Compensation Program. May. 1, 2019

210 GlaxoSmithKline Clinical Study Report for Study 208109/231 (HAV-231). Feb. 10, 2011. Page 11

211 CDC Prevention of Hepatitis A Through Active or Passive Immunization: Recommendations of the Advisory Committee on Immunization Practices. MMWR. Dec 27, 1996; MMWR 45(RR15);1-30

212 CDC Hepatitis A VIS. Jul. 20, 2016

213 CDC Update: Recommendations of the Advisory Committee on Immunization Practices for Use of Hepatitis A Vaccine for Postexposure Prophylaxis and for Preexposure Prophylaxis for International Travel MMWR Nov. 2, 2018; 67(43);1216–1220

214 FDA VAQTA Product Insert Dec. 20, 2018

215 FDA HAVRIX Product Insert Dec. 19, 2018

216 FDA VAQTA Product Insert Dec. 20, 2018

217 Ibid

218 Ibid

219 Ibid

220 FDA HAVRIX Product Insert Dec. 19, 2018

221 Ibid

222 Ibid

223 Ibid

224 FDA TWINRIX Product Insert Dec. 18, 2018

225 Ibid

226 Ibid

227 Ibid

228 Ibid


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