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.1 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.2 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.3
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.4 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.5
On February 22nd, 1995, HAVRIX received FDA approval for use in adults and children two years of age and older.6 One year later, Merck’s hepatitis A vaccine, VAQTA, received FDA approval for use in persons aged 2 and older.7
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.8
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.9
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.10
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.11 12
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.13
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.14 15 Merck’s VAQTA received approval for use in children at 1 year of age and older following clinical trials involving only 706 children while16 GlaxoSmithKline’s HAVRIX received their approval following clinical trials that involved 723 children younger than two years.17In 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.18 In 2007, the CDC updated hepatitis A vaccine recommendations for post-exposure to hepatitis A and for international travelers19 and in 2009, the vaccine was recommended for families and close contacts of newly adopted international adoptees.20
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.21 By 2014, this number had only increased to 57.5 percent.22
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.23 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.24
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. 25
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.26 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.27 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.28
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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1 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.
2 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.
3 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
4 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.
5 Innis BL, Snitbhan R, Kunasol P et al. Protection against hepatitis A by an inactivated vaccine. JAMA. 1994 May 4;271(17):1328-34.
6 Altman, LK, F.D.A. Approves First Vaccine To Prevent Hepatitis A Infection. The New York Times. Feb. 23, 1995
7 FDA March 29, 1996 Approval Letter – VAQTA. Mar. 29, 1996
8 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
10 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
11 FDA May 11, 2001 Approval Letter – Twinrix. May 11, 2001
12 CDC Notice to Readers: FDA Approval for a Combined Hepatitis A and B Vaccine. MMWR. Sept. 21, 2001; 50(37);806-7
13 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
14 CDC August 11, 2005 Approval Letter – VAQTA. Aug. 11, 2005
15 CDC October 17, 2005 Approval Letter – Havrix. Oct. 17, 2005
16 CDC Notice To Readers: FDA Approval of VAQTA (Hepatitis A Vaccine, Inactivated) for Children Aged >1 Year. MMWR. Oct. 14, 2005; 54(40);1026
17 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
18 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
19 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
20 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
21 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
22 National Center for Health Statistics. Chapter 23: Immunization and Infectious Diseases. Healthy People 2020 Midcourse Review. Hyattsville, MD. 2016.
23 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
24 CDC Surveillance of Vaccination Coverage Among Adult Populations — United States, 2015. MMWR. May 5, 2017; 66(11);1–28
25 Immunization Action Coalition State Information - Hepatitis A Vaccine Mandates for Children in Daycare Facilities, Elementary, and Secondary Schools. Nov. 11, 2018
26 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
27 CDC Viral Hepatitis Widespread outbreaks of hepatitis A across the United States Apr. 29, 2019
28 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