Hepatitis B vaccine: long-term efficacy, booster policy, and impact of HBV mutants on hepatitis B vaccination programmes (2004)

The Viral Hepatitis Prevention Board held its spring meeting, March 11-12, 2004, in Sevilla, Spain. The meeting comprised experts from the World Health Organization, the Centers for Disease Control and Prevention, and other organisations representing the public and private sectors from Europe, North America, the Middle East, and Asia.

The primary objectives of the meeting were to review the most recent data regarding long-term efficacy of hepatitis B vaccine and its long-term effectiveness in universal hepatitis B vaccination programmes. Other topics that were covered during the meeting focused on:

• recent data regarding the potential impact of HBV mutants on hepatitis B vaccination programmes; and
• current hepatitis B booster vaccination recommendations by the World Health Organization, the European Consensus Group on Hepatitis B Immunity, and the Centers for Disease Control and Prevention.

Long-term efficacy of hepatitis B vaccine

• The hepatitis B vaccine is effective in protecting against clinical HBV infection and chronic carriage for at least fifteen years among infants and children, and among adults who have responded to a complete hepatitis B primary vaccination series.
• In vitro studies show that, if the hepatitis B vaccine administered in a primary series induces an anti-HBs titre greater than or equal to 10 mIU/ml, then memory B- and T-helper cells retain the capacity to generate antibodies following re-exposure to HBsAg, even if the anti-HBs titre falls to less than 10 mIU/ml at a later point in time.
• Almost all adequately vaccinated individuals have shown evidence of immunity against HBV infection in the form of:
  • persisting anti-HBs and / or
  • in vitro B-cell stimulation or anamnestic response to a vaccine challenge.
• Long-term protection studies that have been carried out worldwide among infants, children, and adults from ten to fifteen years following initial hepatitis B vaccination have shown that:
  • no symptomatic infections occurred
  • development of chronic infections is very rare
  • despite a decline in anti-HBs, immune memory persists, providing long-term protection against HBV infection.

Long-term effectiveness of hepatitis B vaccination programmes

• Long-term surveillance data from countries in Europe, North America, Africa, the Middle East, and Asia point to the success of hepatitis B immunisation programmes, which have contributed to:
  • decreased incidence of acute hepatitis B virus infection
  • decreased incidence of hepatocellular carcinoma (HCC) in persons under thirty years of age
  • a decrease in HBsAg carrier rates providing indirect protection to non-vaccinated persons

Preventing hepatocellular carcinoma through hepatitis B vaccination

• HBV infection accounts for approximately half of all cases of HCC worldwide. HCC occurs in people of all ages. The main routes of HBV transmission may vary by geographical area. Studies carried out in Africa show horizontal transmission (sibling to sibling) of HBV as the dominant mode of transmission. In Asia, HCC frequently develops in childhood or adolescence after perinatal HBV transmission from HBeAgpositive mothers to their newborns.
• In Taiwan and Singapore, the incidence of HCC among children has declined since a universal hepatitis B vaccination programme was implemented. As the peak age of HCC is in adults between forty and sixty years of age, a substantial reduction in peak incidence of HCC will be seen thirty to forty years following the launch of this programme.

Potential impact of HBV mutants on hepatitis B vaccination programmes

• HBsAg mutants may cause persistent infection, and may be associated with chronic hepatitis. Although mutants can infect persons who are not vaccinated, there is still no clear evidence that they can infect persons who have been successfully immunised against hepatitis B virus, except in post-exposure situations.
• HBsAg mutants are more likely to be present with adw and adr serotypes. However, there is no convincing evidence to date that vaccine formulations need to be changed.
• There is no evidence to date that suggests that HBV mutants present a threat to established hepatitis B vaccination programmes and thus are not viewed as a major public health threat.
• An independent global network should be set up to monitor vaccine-escape / treatment-escape mutants.

Breakthrough infections

• Breakthrough infections have occurred in successfully vaccinated individuals; the vast majority of these infections are clinically benign (seroconversion for anti-HBc, in the absence of HBsAg).
• In studies that have investigated breakthrough infections and chronic carriage, the number of study participants was small, and vaccine doses and routes of administration varied, so that investigators were not able to assess formally which factors were the most influential. Questions still remain as to which determinants of duration of protection are the most important, such as:
  • age at vaccination (birth, infancy, childhood, adulthood)
  • gender
  • length of time since vaccination and peak antibody response
  • anti-HBs levels following the primary vaccination series
  • receipt of hepatitis B immunoglobulins (HBIg)
  • type of vaccine administered: plasma-derived or recombinant
  • infection pressure based on: level of hepatitis B endemicity
    • maternal HBV status
    • extent of vaccination coverage
  • nutritional status of vaccinated person
  • presence of other infections, particularly HIV infection
  • natural boosting

Booster doses

• Currently there are no data that support the need for booster doses of hepatitis B vaccine in completely vaccinated infants, children, and adolescents, and in immunocompetent individuals who have responded to a complete primary
  vaccination course. This conclusion is based on many longterm efficacy and booster-dose studies that have shown that long-term protection persists for as long as fifteen years and that immunological memory allows a protective anamnestic antibody response after exposure to HBsAg. These data are further supported by surveillance data from many countries around that world where no cases of acute hepatitis B are occurring among children and adolescents who are successfully vaccinated against hepatitis B.
• Some countries, however, have chosen to consider booster doses of hepatitis B vaccine as an option to provide reassurance of protective immunity against benign breakthough infection.

Need for further studies

• Cohort studies of immunised subjects are still needed to determine if booster doses are needed beyond fifteen years after hepatitis B vaccination, and if immunological memory persists into adolescence and adulthood among persons at higher risk of infection due to their lifestyle or to professional exposure to HBV, especially in industrialised countries.
• In hepatitis-B-endemic countries, further studies need to be carried out to determine whether susceptibility to persistent carriage of HBV increases with time.

In addition, further research is still needed in the following areas:

• long-term studies to identify breakthrough infections
• long-term follow-up studies to determine the burden of disease from breakthrough infections occurring among vaccinees who were on a 2-dose primary schedule
• data to distinguish between sub-clinical and breakthrough infection
• humoral and cell-mediated immune basis of memory
• the significance of core antibodies in terms of:
  • whether the apparently transient infection of hepatocytes could result in long-term liver disease, and whether the reactivation of HBV infection could occur in immunocompromised patients (e.g., HIV/AIDS patients).

 Further information is available in the corresponding Viral Hepatitis Issue or  meeting web page.