Vaccination remains a key means to prevent hepatitis A disease . Childhood vaccination offering long-term protection provides a means to protect children as they grow into adolescents and adults, who are difficult to vaccinate in large numbers. With current practice, it is easier to vaccinate children, but moving forward a trend towards vaccinating adolescents and adults as part of healthy ageing would be welcomed. A long-term childhood vaccination study with inactivated hepatitis A vaccine showed 100% of subjects remained protected at 15 years follow-up after 2 doses of HAB 720 EU . Long-term data from children in Argentina vaccinated with another 2-dose inactivated hepatitis A vaccine also found good long-term persistence, as 97.9% of children at the 10-year follow-up still had protective concentrations of hepatitis A antibody . However, longer-term data beyond this are needed.
We found that antibody GMC trends from the study in children were comparable to those from studies in adults that used 3-dose HAB 720 EU and 2-dose HAV 1440 EU with 20-year follow-up and up to 50-year model-predicted outcomes. Based on the very similar GMC outcomes and 15-year trends across these studies, we conclude that childhood vaccination is likely to provide comparable longer-term protection that will extend to adulthood.
Both humoral and cell-mediated immune responses are induced after one dose of vaccine, and can be boosted after receiving a second dose, with cell-mediated immunity providing long-term protection regardless of decreasing antibody levels. The GMC trends over time showed that antibody levels tend to decline faster initially, which could be due to short-lived plasma cells. However, after a certain period, antibody GMC decline slows, due to long lived plasma cells that continue to produce antigen-specific antibodies . This suggests that, even if antibody titres decline over time, vaccinated individuals coming into contact with hepatitis A virus will be able to mount an appropriate immune response as a result of a deposit of memory immune cells.
Immunological Mechanisms for Long-Term Immunity Persistence with Hepatitis A Vaccine
Detectable antibody levels of 10–33 EU/ml, depending on the assay, are used to indicate protection from hepatitis A infection. However, from clinical experience, vaccine-induced protection may exist, even in the absence of detectable anti-hepatitis A antibodies , which is usually due to the cell-mediated immune response.
A World Health Organization review (2011) reported evidence of inactivated hepatitis A vaccination leading to an important and long-lasting cell-mediated immune response that can be boosted, in addition to its rapid effective humoral response. The response was seen within 2 weeks of vaccination, reaching a peak after 1 month, followed by a subsequent decline in T cells and B cells; this decline could be reversed, with a booster dose at week 24 following the primary vaccination, leading to a significant increase in humoral and cell-mediated immunity .
Evidence from long-term follow-up clinical studies and mathematical models have shown that humoral responses to hepatitis A vaccination lasts for decades, with second dose resulting in rapid proliferation of memory B cells and high antibody titres. In studies where a challenge dose was administered 15–20 years after primary immunisation with HAB 720  and HAV 1440 [8, 16], subjects mounted a strong anamnestic response indicating the presence of immune memory.
The evidence supporting the role of vaccine-induced cell-mediated immunity, through cytokines and T-helper cells, was based on documented interferon (IFN) gamma secretion [21, 22], IFN gamma and interleukin (IL)-10 production by peripheral blood lymphocytes 10 days after vaccination , and observation of a direct correlation between cytokine concentrations (IL-2, IFN gamma and IL-10) and anti-hepatitis A antibody levels before and after booster vaccination . In one study, peripheral blood mononuclear cells were observed in 100% of vaccinees 1 month after a single dose of HAV 1440 EU, and the subsequent 60% decline of cellular immune responses by week 12 was reversed after a 6-month booster dose producing an over sevenfold increased response compared to that following primary vaccination .
The main limitations of this study relate to the methodology of extrapolating data to ascertain long-term persistence of immunity in children instead of doing the actual follow-up for that period. It was not possible to carry out a long-term study (this would have taken decades in real time). The only study in children in the analysis had a mean age of 13.4 years. Similar long-term persistence would, however, be expected in younger children vaccinated with inactivated hepatitis A vaccine. A non-GSK study in children in China (mean age 3.7 years) found that after 11 years of follow-up, all children vaccinated with two doses of HAV 720 remained seroprotected .
Despite these limitations, hepatitis A studies worldwide show that the vaccine is highly immunogenic, has long-term persistence and has been successful in disease control. A national two-dose hepatitis A toddler program started in 1999 in Israel, and has had a positive long-term impact with significant incidence declines in all age groups: overall, a 95% decline after 3 years  and a 98% decline after 9 years  was observed in annual incidence compared with the pre-vaccination period.