EDITORIAL COMMENT Hepatitis B vaccine: Using skin when muscle does not work Amit Goel,* Amita Aggarwal † and Rakesh Aggarwal* *Departments of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India and † Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India Hepatitis B virus (HBV) has the propensity to persist in a subset of those infected. Such chronic HBV infection can, over years, progress to liver cirrhosis and liver cancer, and is a common cause of these serious liver diseases in several countries, particularly in Southeast Asia and Africa. 1 Fortunately, highly effective and safe vaccines are available against HBV. These vaccines contain non-glycosylated form of the viral surface protein, with alum as an adjuvant. Two types of hepatitis B vaccines have been produced—from plasma of HBV-infected individuals (plasma-derived vaccines) and in yeast cells using recombinant DNA technology (recombinant vaccines). Though these vaccines are equally effective and safe, most of the vaccines currently in use are of recombinant origin. 2 Inclusion of hepatitis B vaccine in national childhood immuniza- tion programs with high-vaccine coverage rates has led to a marked reduction in rates of chronic HBV infection and even liver cancer. 3,4 The efficacy of these vaccines in preventing transmission from infected mothers to their newborns is even higher if the first dose is administered on the day of birth. Besides newborn children, HBV vaccination is highly recommended for those adults who are at a high risk of acquiring HBV, such as health-care workers (HCWs), persons with injection drug use, persons receiving multiple blood transfusions (with thalassemia, hemophilia, etc.) or on mainte- nance hemodialysis, or those likely to have adverse outcomes if HBV infection occurs, for example those with chronic liver disease. Primary immunization against HBV in adults consists of three doses of the vaccine (each containing 20 μg [10 μg for some prepa- rations] of hepatitis B surface antigen [HBsAg] protein) adminis- tered by intramuscular (IM) route in the arm (injections in gluteal muscle have lower seroconversion rates) at 0, 1, and 6 months. This schedule induces protective immunity, defined as anti-HBs titer >10mIU/mL 1 month after the last dose, in 90–95% of immuno- competent individuals. However, it fails to induce protective anti- body titers in some healthy adults. These non-responders are more likely to be elderly, obese, and to have history of alcoholism or smoking. Presence of certain human leukocyte antigens or polymor- phisms in cytokine and chemokine genes appears to predispose to non-response. In addition, persons with conditions such as chronic kidney disease, liver cirrhosis, celiac disease, or an immunocompro- mised state have a suboptimal response to the vaccine. 5 Because im- munization in adults is directed primarily at those with higher risk of acquiring HBV infection, risk factors for which often overlap with those for non-response, it is important to find ways to overcome this non-response. Several methods have been tried to circumvent the non-response to hepatitis B vaccine. These have included the use of higher amount of vaccine per dose (double the usual amount), a larger number of vaccine doses (usually a repetition of the usual 3-dose series), use of different adjuvants, and simultaneous administration of immune modulators, such as granulocyte-macrophage colony- stimulating factor, interleukin-2, and levamisole. 5 Each of these approaches provides some increment in response rate to the primary vaccination series. Newer vaccines that contain additional viral pro- teins (pre-S2 and pre-S1), providing additional epitopes for develop- ment of immune response, have also been tried; though these have higher response rate, their use is limited by higher cost and limited availability. 2 Another approach has been to change the route of vaccine admin- istration from IM to intradermal (ID). The ID route for hepatitis B vaccine was first tried during the 1980s for primary vaccination—pri- marily as a cost-cutting exercise because it needed only 1–5 μg anti- gen per dose compared with 20 μg per dose for IM route. 6–9 In such use, ID administration led to seroconversion rates similar to those with IM route in healthy persons including HCWs; however, the an- tibody titers achieved with it were lower than with the IM route. 10 The frequency of adverse events was similar with the two routes, except that the ID injections more often led to pigmentation at the injection site. 9 Thereafter, this route has been tried in special groups as well as in non-responders to IM vaccine. In patients with chronic kidney disease or on maintenance dialysis, whether hepatitis B vaccine- naïve or non-responders to prior IM vaccine series, ID administration has been found, in several randomized trials and systematic reviews, to be associated with higher seroconversion rates as well as antibody titers. 11–13 In another study, 69% of 42 non-responders with chronic liver disease seroconverted after a 3-dose ID regimen. 14 Similarly, children with celiac disease who had not responded to infant hepati- tis B immunization and were randomly assigned to receive boosters by ID route seroconverted earlier and with higher anti-HBs levels than those assigned to IM boosters. 15 Also, in observational studies, a large proportion of non-responders who were otherwise healthy have been found to seroconvert following ID doses of the vaccine. 8,16 In this issue of the Journal, Kalchiem-Dekel et al report the results of another study on the use of ID route for hepatitis B vaccine in non-responders to IM administration. 17 The authors enrolled 27 HCWs from their institution who had failed to respond to two previous 3-dose IM regimens of a well-known HBV vaccine (Engerix-B), were still seronegative, otherwise healthy and lacked conditions associated with poor immune response. Each participant received three ID doses (0.25 ml or 5 μg each) of the same vaccine at 0, 2, and 4 weeks. More doi:10.1111/jgh.13234 524 Journal of Gastroenterology and Hepatology 31 (2016) 524–526 © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd