Hepatitis B vaccination is the most effective means to prevent and control hepatitis B epidemic, and it is of great significance in preventing and controlling hepatitis B epidemic. However, there are still some questions in the process of vaccine application, such as:how long is the protection period of hepatitis B vaccine, whether booster vaccination is needed, what are the reasons for no or weak response after vaccination and what are the treatment measures, etc. In this paper, we analyze the causes of no response after hepatitis B vaccination from vaccine factors, organism (including immune, genetic and individual) factors and vaccination factors. 1. Vaccine factors 1.1 Vaccine type: The antigen expression system, degree of glycosylation and surface protein structure of recombinant hepatitis B vaccines from different sources differ, and their positive conversion rates of anti-HBs are also different. 1.2 Vaccine dose: There must be a certain amount of antigen to stimulate the body to cause an immune response, the more antigenic protein the vaccine contains, the stronger its antigenicity, the larger the dose of the vaccine, the higher the anti-HBs positive conversion rate and the longer the maintenance time. The immune effect of 20μg per dose has been fully confirmed. However, the higher the dose, the better the immune effect, too high a dose and too low a dose can cause immune tolerance and lead to no or weak response. 2, the body factors 2.1 immune factors: non-responders in the body of the immune response occurs abnormally, can not mediate the formation of normal cellular immune response. 2.2 Genetic factors: The immune response gene associated with the major human histocompatibility complex (MHC) may control the response to hepatitis B vaccination. Studies on the relationship between hepatitis B vaccine nonresponse and genetic factors, and differences in the results of local studies suggest that different ethnic and regional populations may have different genes regulating the occurrence of nonresponse. 2.3 Individual factors 2.3.1 Age and gender: The immune response to HBsAg in humans is age-related, and generally the responsiveness to HBV vaccine decreases with age, and the response rate gradually decreases. Neonates have the highest immune response rate, followed by children. The response rate and antibody titer were lower in those aged 40 years or older, and the anti-HBs positive response rate was only 75.3% or even lower in those aged >50 years, and the response rate was worst in those aged 60 years or older, with a positive antibody response rate of only about 45%. The response rate and anti-HBs GMT of HBV vaccine are also influenced by gender, and it is generally believed that the positive antibody transfer rate and antibody titer of women are higher than those of men. 2.3.2 Body weight: Premature infants are potential non-responders. The immature development of the immune system in preterm infants leads to a decrease in the activity, number or ratio of immune cells and immune molecules, causing the occurrence of non-response to hepatitis B vaccine. The risk of non-response in severely obese individuals is 13.3 times higher than in those of normal weight. 2.3.3 Potential HBV infection or variation of HBV: occult HBV infection (HBsAg negative by serological test but HBV DNA positive by PCR in serum or liver tissue) has occurred before vaccination and is one of the important reasons for immunization failure. About 3% of HBV-infected individuals in our population test negative for HBsAg. Although these individuals have been infected with hepatitis B virus, which cannot be detected by general serological tests due to their low amount of HBsAg, they are often anti-HBc positive, suggesting previous infection with hepatitis B virus, and it is necessary to use sensitive reagents to detect HBV-DNA. 2.3.4 Infant mother’s HBV infection status: intrauterine Infection with hepatitis B virus is an important cause of hepatitis B vaccine immunization failure. A family history of HBV has a high rate of no or weak response to HBV vaccine, rapid disappearance of anti-HBs, and a high likelihood of reinfection. double-positive mothers with HBsAg and HBeAg have high HBV infectivity, which often leads to immunization failure in their infants. Anti-HBs-positive mothers with high placental antibody titers have an enhanced response to hepatitis B vaccination for their infants. 2.3.5 Low immune function: Whether antibodies are produced after vaccination is closely related to the immune status of the organism itself. Human immunodeficiency virus (HIV) infected patients and hemodialysis patients with chronic kidney disease have disorders of the body’s immune function and have a significantly lower response rate to HBV vaccine. Other conditions leading to low immune function (such as malnutrition, malignant tumor, intestinal worm infection, diabetes, etc.), long-term use of immunosuppressants after kidney transplantation or liver transplantation, and radiation therapy will reduce the body’s ability to respond to HBV vaccine. 2.3.6 Bad habits: Bad habits can also affect the immune effect, such as long-term heavy smoking, drug and alcohol abuse, which often impair the immune function and may affect the vaccine response. Nicotine in cigarettes can cause chronic peripheral vasoconstriction, which delays the absorption of vaccination and damages the body’s immune system, resulting in low vaccine immune response. 3. Vaccination factors 3.1 Vaccination site and route: the best site for vaccination against hepatitis B is the upper arm deltoid muscle, and the effect is better than that of the buttocks. This is because the upper arm deltoid muscle is well developed and the subcutaneous fat layer is thin. As the fat layer of the buttocks is thick, the antigen does not reach the buttocks muscle but only in the fat layer after vaccination, which delays the entry into the blood circulation, thus affecting the contact between the vaccine and macrophages and the reaction of lymphocytes, and cannot present the antigen to the immunologically active cells; meanwhile, the antigen exists in the fat for a long time and can be denatured by the action of enzymes. 3.2 Vaccination regimen: The 0, 1, 6 month regimen recommended by WHO is the earliest and most widely used regimen for HBV vaccine worldwide, mainly for neonates. However, this regimen has a long interval and late appearance of anti-HBs, which has certain limitations for certain populations. In recent years, some countries and regions have adopted different regimens for HB immunization in different populations. 0, 1, 2 month regimen has early emergence of anti-HBs positive conversion rate, with the highest anti-HBs positive conversion rate reaching 3-4 months after the first dose and peak at GMT. 0, 1, 2, 12 month 4-dose immunization regimen is the best for high-risk groups, including infants born to HBsAg and HBeAg double positive mothers. The 0, 7, and 21-day regimens showed earlier anti-HBs positive transitions and faster GMT peaks than the other regimens, but further studies are needed to determine the duration of long-term maintenance protection.