Research on the use of formalin-inactivated hepatitis A vaccine in human subjects was first published in 1991 by a group of scientists at the Walter Reed Army Institute of Research. According to the published study, scientists were able to demonstrate that the inactivated vaccine could produce antibodies against hepatitis A.⁽¹⁾ Also in 1991, research was published on the use of a live attenuated hepatitis A vaccine capable of producing antibodies against hepatitis A 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 to independently develop their inactivated hepatitis A vaccines, and in 1992 Merck scientists published research on the VAQTA hepatitis A vaccine. The published article reported a study involving approximately 1000 children between the ages of two and 16 living in a Hasidic Jewish community in upstate New York. 519 children were given the vaccine which 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 together with a 1:20.000 dilution of thimerosal. The published study reported the vaccine's ability to prevent clinical cases of hepatitis A infection, but also stated that researchers were unable to demonstrate that the vaccine was able to prevent subclinical infections.⁽⁴⁾ In 1994, GlaxoSmithKline published research on its HAVRIX hepatitis A vaccine, reporting that the vaccine was 94% effective in preventing cases of hepatitis A infection.⁽⁵⁾

On February 22, 1995, HAVRIX received FDA approval for use in adults and children two years of age and older.⁽⁶⁾ A year later, Merck's hepatitis A vaccine, VAQTA, received FDA approval for use in people as young as 2 years of age.⁽⁷⁾

In December 1996, the CDC's Advisory Committee on Immunization Practices (ACIP) published its first recommendations on the use of the hepatitis A vaccine. The ACIP recommended hepatitis A vaccination for all persons traveling or reside in countries known to have intermediate or high rates of hepatitis A infections, with the first dose recommended at least four weeks before departure. However, it has been suggested that a pre-vaccination test for hepatitis A antibodies be performed in older people, due to the likelihood of prior exposure and current immunity to hepatitis A. Hepatitis A vaccination it was also recommended for all children aged 2 years and older who reside in communities with high rates of hepatitis A infection or where periodic outbreaks have occurred. The CDC noted, however, that children ages 10 to 15 who reside in these high-risk communities likely do not require vaccination due to the likelihood of prior exposure and current immunity to hepatitis A.⁽⁸⁾

On May 11, 2001, GlaxoSmithKline's TWINRIX vaccine, a bivalent vaccine containing the HAVRIX vaccine for hepatitis A and the ENGERIX-B vaccine for hepatitis B, received approval for use in adults starting from 18 years, after clinical trials involving fewer than 2.200 healthy adults. TWINRIX, which contains both aluminum phosphate and aluminum hydroxide, thimerosal, neomycin, formalin, yeast, and 2-phenoxyethanol as a preservative, was declared by GlaxoSmithKline to be as effective as separate doses of HAVRIX and ENGERIX-B.^(9-10)

Hepatitis A infection rates have fallen from 17.047 cases reported in 1999 to 4.488 cases reported in 2005, despite low hepatitis A vaccination rates. In 2004, the National Immunization Survey found that only 54% of children aged 24 to 35 months residing in states where hepatitis A vaccination was recommended had received hepatitis A vaccine. Furthermore, only 27% of children in states where vaccination should be recommended received the vaccine. Furthermore, only 27% of children in states where vaccination should be considered have been vaccinated. Child vaccination rates in the remaining states have been reported as low as 2%.13⁽¹¹⁾

In 2005, both Merck's VAQTA and GlaxoSmithKline's HAVRIX received FDA approval for use in children starting at one year of age, rather than two years of age.^(12-13) Merck's VAQTA received approval for use in children aged one year and older following clinical trials involving just 706 children,⁽¹⁴⁾ while GlaxoSmithKline's HAVRIX received approval following clinical trials involving 723 children under two years of age.⁽¹⁵⁾ In early 2006, following FDA approval to lower the age of administration of both hepatitis A vaccines, ACIP recommended routine hepatitis A vaccination for all children , with the first dose to be administered between 12 and 23 months of age and the second dose at least six months later.