Plasma-derived Vaccine Research Articles

The seroepidemiology of isolated core antibody against hepatitis B among Taiwanese adults - A large hospital-based study

This study aims to investigate the prevalence of isolated core antibodies against hepatitis B (IAHBc) in different birth cohorts using a large medical record database. Hepatitis B viral serological test data were collected from a chart cloud database at a medical center in Taiwan between January 2006 and December 2018. The data collected included birth year, sex, hepatitis B viral markers (HBsAg, anti-HBs or anti-HBc), and hepatitis B vaccination records. Enrolled patients were grouped according to their birth year into three categories:≤1986, 1987-1992, and≥1993, which correspond to no neonatal hepatitis B immunization, plasma-derived HB vaccine (PDHBV), and recombinant hepatitis B vaccine (RHBV), respectively. Prevalence of hepatitis B viral seromarkers, including IAHBc, was calculated by sex, age groups, and birth cohorts. Those who underwent repeated hepatitis B serology tests were included for further analysis to follow up their serostatus. A total of 117,335 adults with complete hepatitis B serologic data were analyzed. Among them, 6641 individuals (5.7%) were found to have IAHBc. The prevalence of IAHBc was 11.4%, 0.8%, and 0.3% among those born before 1986, between 1987 and 1992, and after 1992, respectively. Among the 690 subjects with repeated blood tests and complete hepatitis B serologic data, 551 cases (79.9%) remained IAHBc. The other cases included resolved infection status (13.9%), seronegativity for three HB seromarkers (3%), and carrier of hepatitis B virus (2.3%). The management of individuals with IAHBc should be tailored to their age, vaccination status, and risk factors for occult hepatitis B viral infection.

Vaccination Campaign against Hepatitis B Virus in Italy: A History of Successful Achievements.

In Italy, the vaccination campaign against hepatitis B virus has been characterized by two phases. In the first phase (1984-1991), vaccination with plasma-derived vaccines was first recommended for the high-risk group. In the second phase (1991-nowadays), recombinant vaccine targeted, by law, infants 2 months old and teenagers 12 years old (limited to the first 12 years of campaign); screening for HBsAg became compulsory for all pregnant women during the third trimester of pregnancy. Successful achievements have been attained: No acute HBV case has been observed in the age group targeted by vaccination, the pool of chronic HBsAg carriers is strongly reduced, perinatal HBV transmission is under control, and acute delta virus hepatitis cases are nearly eliminated. The key point of this success has been the peculiar vaccination policy adopted. The combined vaccination of teenagers has generated an early immune cohort of youths, who are no longer at risk of acquiring HBV infection by sources of exposure (i.e., drug use and unsafe sex practices) typical of the young adults. Vaccination of household contacts with HBsAg-positive subjects represents an area of improvement; providing migrants and refugees access to healthcare services is also a focal point. In 2020, Italy became the first country in Europe to achieve the WHO's regional hepatitis targets.

Epidemiology of Chronic Hepatitis B Infection in the Cohort of College Students with Vaccination in Taiwan.

After the mass vaccination project in Taiwan, the prevalence of the hepatitis B virus (HBV) infection for the college-aged population of 18 to 21 years is uncertain. We aimed to investigate the prevalence of hepatitis B markers in different birth cohorts. A total of 38,075 students in universities in Kaohsiung area undergoing entrance examinations between July 2006 to September 2020 were included. Seroprevalence of the hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) status and laboratory data were collected. The seropositive rate of HBsAg was less than 1% for students born after 1991. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were significantly higher, and body mass index (BMI) was significantly lower in HBV carriers compared to those who were not carriers (all p < 0.001). Multivariate logistic regression showed that age, male, higher BMI, and positive HBsAg were risk factors of abnormal ALT value. A decrease in the positive rate of anti-HBs which was significantly higher in the cohort of plasma-derived vaccines than recombinant vaccines was found. We concluded that there were decreasing trends in seropositive rates of HBsAg and anti-HBs for students of the college-aged population in the Kaohsiung area. The status of HBsAg was a predictive factor of abnormal ALT levels. The period effect on anti-HBs seropositivity for DNA recombinant vaccine somehow existed.

Seroconversion of hepatitis B surface antigen among those with previously successful immune response in Southern China

ABSTRACT Recommendations promoted worldwide have suggested a period of protection lasting more than 20 years against hepatitis B (HB) following primary immunization. Starting in 1987, universal HB vaccinations were carried out in Long An County, Guangxi Province, one of the earliest counties in which plasma-derived HB vaccine was delivered to newborns across China. Data collection targeted toward understanding the long term (26–33 years since primary immunization) immune effects of the plasma-derived HB vaccine was conducted in 2015; a second data collection was carried out in 2019 to assess seroconversion in the same cohort. This study qualitatively compared positive vs negative results and quantitatively assessed HB biomarkers – HB surface antigen (HBsAg), antibody to HBsAg (anti-HBs), HB e-antigen (HBeAg), antibody to HBeAg (anti-HBe), and antibody to HB core antigen (anti-HBc) – in serum 26–33 years after the full initial course of HB vaccination, then analyzed anti-HBs seroconversion using the two-phase sampling method in the same cohort and calculated the anti-HBs seroconversion rate from 2015 to 2019. The protective sero-conversion rate (anti-HBs ≥10mIU/mL) was 37.6% (192/511); the HBsAg-positive rate was 5.3% (27/511); the anti-HBs mean geometric titer (GMT) was 11.1 mIU/mL. Among the 143 participants involved in both 2015 and 2019 data collections, the seroconversion rate was 3.5% (5/143); two individuals had protective anti-HBs levels in 2015. These findings indicate that anti-HBs status can be seroconverted to a protective concentration level 4 years earlier in a high HBV epidemic region. The role of genomic mutations and the disappearance of immune memory and seroconversion should be investigated.

Response of Preterm Infants of Mothers Who Are Chronic Carriers of Both HBsAg and HBeAg to Pre-52 Containing Hepatitis 8 Vaccine (TGP 943) - A Preliminary Report

This study aimed to examine the immunogenccity and protective efficacy of a pre-S2 containing hepatitis B vaccine (TGP 943, Takada, Japan) in 9 preterrn infants. A control group of preterm infants were given plasma derived hepatitis B vaccine (Korean Green Cross, Korea). All these preterm infants were born to both HBsAG and HBeAg posistive mothers and born in central General Hospital Sanglah Denpasar from January 3, 1992 to October 30, 1992. The gestational ages were 35-37 weeks and birth weights were 2000-2500 grams. The difference of the anti pre-S2 antibody between two groups of preterm infants was evident at month 6. Anti-HBs antibody response was almost same in the two groups of preterm infants. None in preterm infants in this study became positive for HBsAg during follow-up for at least 6 months. 2 of 8 preterm infants in control group become positive for HBsAg during follow up for a t least 6 months. Our study demonstrated a better anti pre-S2 antibody response and also comparable anti-Hbs antibody response in preterms infants vaccinated with a pre-S2 containing hepatitis B vaccine, compared with those with conventional plasma-derived vaccine.

PIN24 - Hepatitis B Virus (HBV) Vaccine in Pregnancy and Impact on Pregnancy Outcome

Studies have demonstrated the effectiveness of HBV vaccination in pregnancy to reduce risk of transmission, but the risk/benefit of HBV vaccination in pregnancy has not been fully elucidated due to limited data on pregnancy outcomes. This study evaluated data on HBV vaccination in pregnancy and impact on pregnancy outcomes. MEDLINE was searched in Jan 2018 using the search terms: hepatitis B vaccine, pregnancy, major congenital malformations (MCMs), preterm birth, spontaneous abortion (SAB), and fetal/neonatal death. The search identified 1 RCT, 5 prospective cohort studies, and 1 Vaccine Adverse Event Reporting System (VAERS) study; 5 of 7 studies were conducted in the 1980’s-90’s. The RCT and 2 cohort studies examined recombinant HBV vaccines in 284 pregnant women. Vaccination occurred in the 1st trimester in the cohort studies and 3rd trimester in the RCT. No MCMs and 1 SAB were reported. The preterm birth rate was comparable to general population rates. The other 3 cohort studies examined plasma-derived HBV vaccines in 97 pregnant women. Vaccination occurred in the 1st trimester in 1 study and 2nd/3rd trimester in the other 2. No MCMs, SABs, or preterm births were reported. The stillbirth rate was comparable to the comparator (1.4 vs 1.2). The VAERS study included 192 pregnant women receiving HBV vaccines from 1990-2015. Most were vaccinated in the 1st trimester and 110 adverse events were reported, including the following pregnancy-related events: 5 unique MCMs, 23 SABs, 1 neonatal death, 2 stillbirths, and 7 preterm births. The majority of prospective studies identified are old, have limited sample sizes, and inappropriate exposure windows. The VAERS study is recent but has limitations (recall bias, inconsistent data, lack of denominator data) due to the spontaneous/voluntary nature of the reporting of adverse events. While the data from these limited studies are reassuring, more research is needed.

Efficacy and Safety of Reinforced Versus Standard Vaccine Schedule Towards Hepatitis B In Chronic Kidney Disease: A Systematic Review and Meta-Analysis

Context: The immunogenicity of the hepatitis B virus vaccine is reduced in patients with renal failure compared with the non-uraemic population. A variety of approaches have been suggested to improve the immune response in uraemic population including an increase in dose of the hepatitis B vaccine. Objective: To compare the efficacy and safety of hepatitis B vaccine schedules based on greater versus standard doses of HB vaccine in patients with chronic kidney disease stages 3 - 5. Evidence Acquisition: We carried out a systematic review of the medical literature with a meta-analysis of randomized trials comparing seroprotection rates after greater vs. standard doses of the HB vaccine. The odds ratio to obtain seroprotection among patients who received greater (study group) vs. standard (control group) doses was the end-point of interest. We used a random-effects approach, as described by DerSimonian and Laird, with heterogeneity and subgroup analyses. Results: We retrieved 11 clinical trials (n = 870 unique patients); 2 (n = 141 patients) and 8 studies (n = 689) included CKD patients on pre-dialysis and dialysis stage, respectively. Three trials (n = 368 patients) employed plasma-derived vaccine; 8 (n = 502) adopted recombinant vaccine. Aggregation of study results (n = 10 studies) showed that the seroprotection rate (short-term follow-up) towards HB virus was higher among patients receiving greater than standard doses of vaccine [pooled OR, 2.10, 95% confidence intervals, 1.15 - 3.82]. The P-value was 0.0001 for our test to study heterogeneity. The seroprotection rate towards HBV was much greater in the subset of trials (n = 2) based on plasma-derived vaccine (OR, 3.78; 95% CI, 2.35; 6.07), and no heterogeneity was found (NS). In the subset of RCTs (n = 8 studies), the seroprotection rate was higher among patients receiving greater doses of vaccine towards HBV, OR, 2.01 (95% CI, 0.92; 4.39), with significant heterogeneity (P = 0.002). Tolerance was satisfactory and no dropouts due to side effects were reported. Conclusions: Vaccine schedules based on greater than standard doses of HB vaccine offer higher immunogenicity in patients with chronic kidney disease. These results support the current recommendations to give higher doses of HBV vaccine to susceptible dialysis population in order to increase the sero-protection rate. Further research is needed to assess whether these findings apply to HB vaccines provided with novel adjuvants.

Long-term effectiveness of plasma-derived hepatitis B vaccine 22-28 years after immunization in a hepatitis B virus endemic rural area: is an adult booster dose needed?

Longan County is considered a highly endemic area for hepatitis B virus (HBV). The plasma-derived vaccine has been used in newborns in this area since 1987. A cross-sectional survey was conducted to evaluate the long-term effectiveness of this vaccine. In total, 1634 participants born during 1987-1993 and who had received a series of plasma-derived HB vaccinations at ages 0, 1, and 6 months were enrolled. Serological HBV markers were detected and compared with previous survey data. Overall the prevalence of hepatitis B surface antigen (HBsAg) in all participants was 3·79%; 3·47% of subjects who had received the first dose within 24 h were HBsAg positive, and 8·41% of subjects who had received a delayed first dose were also HBsAg positive. There were 1527 subjects identified who had received the first dose within 24 h and whose HBsAg and anti-HBc prevalence increased yearly after immunization, while the anti-HBs-positive rate and vaccine effectiveness declined. The geometric mean concentration of antibody in the anti-HB-positive participants was 55·13 mIU/ml and this declined after immunization. Fewer than 2·0% of participants had anti-HB levels ⩾1000 mIU/ml. The data show that the protective efficacy of the plasma-derived vaccinations declined and administration of HB vaccine within 24 h of birth was very important. To reduce the risk of HBV infection in this highly endemic area, a booster dose might be necessary if anti-HBs levels fall below 10 mIU/ml after age 18 years. Furthermore, studies on the immune memory induced by plasma-derived HB vaccine are needed.

A Single Center Analysis of the Positivity of Hepatitis B Antibody after Neonatal Vaccination Program in Korea

The antibody to hepatitis B surface antigen (anti-HBs) seropositivity rate after 3 doses of hepatitis B virus (HBV) vaccination during infancy period is known to be higher than 90%. However, a considerable number of vaccines do not form protective anti-HBs or chronologic decrease of anti-HBs. We retrospectively collected data of HBV serologic test results in 20,738 individuals from 2000 to 2015. After exclusion criteria were applied, 19,072 individuals were included. We analyzed the anti-HBs seropositivity rate, anti-HBs disappearance rate, anti-HBs positive seroconversion rate after receiving a booster vaccine, and the difference in anti-HBs positivity between the 2 groups; group A (born before 2005, while both recombinant vaccines and plasma-derived vaccines were used) and group B (born after 2005, when only recombinant vaccines were used by national regulation). The anti-HBs seropositivity rate was 55.8%, but there was a significant difference in the rate of seropositivity for anti-HBs between the group A and B (53.0% vs. 78.1%, P < 0.001). There was no significant age-adjusted difference in the mean seropositivity rate between the 2 groups (P = 0.058). In addition, the anti-HBs positivity rate was significantly lower in the group A as compared with the group B during infancy (83.1% vs. 92.1%, P < 0.001). A total of 1,106 anti-HBs-positive subjects underwent serologic tests more than twice. Of these, 217 subjects (19.6%) showed anti-HBs disappearance. After booster vaccinations, 87.4% (83/95) achieved seroconversion from seronegative to seropositive. Our results highlight the importance of lifelong protection against HBV and the possible necessity of booster vaccination after adolescent period.

The long-term efficacy, 13–23 years, of a plasma-derived hepatitis B vaccine in highly endemic areas in China

ObjectiveTo evaluate the long-term effectiveness of the plasma-derived hepatitis B vaccine that has been applied widely in five areas of China where HBV prevalence was highly endemic. MethodA cross-sectional investigation was conducted in 2009 at five HBV surveillance sites around China. The target study subjects of 6772 were born between 1986 and 1996 and received plasma-derived HBV vaccine. Serum samples were collected to test for HBV markers using the microparticle enzyme immunoassay. ResultsThe number of participants enrolled was 6772. The average hepatitis B surface antigen (HBsAg) prevalence was 2.01%. The birth dose group included 5052 children. In this group, the average positive rates of HBsAg and hepatitis B core antibody (anti-HBc) were 1.58% and 6.39%, respectively, and these values declined gradually from 1986 to 1996. The positive rates of anti-hepatitis B surface antibody (HBs) and the geometric mean concentration (GMC) of anti-HBs-positive subjects were 41.69% and 115.8mIU/ml. ConclusionThe long-term effectiveness of the plasma-derived hepatitis B vaccine still provided protection 13–23 years after vaccination. It seems that a booster dose is not necessary. Enhancing the rate of the birth dose within 24h is one of the most important measures to prevent and control HBV infection.

Protective effect of different anti-rabies virus VHH constructs against rabies disease in mice.

Rabies virus causes lethal brain infection in about 61000 people per year. Each year, tens of thousands of people receive anti-rabies prophylaxis with plasma-derived immunoglobulins and vaccine soon after exposure. Anti-rabies immunoglobulins are however expensive and have limited availability. VHH are the smallest antigen-binding functional fragments of camelid heavy chain antibodies, also called Nanobodies. The therapeutic potential of anti-rabies VHH was examined in a mouse model using intranasal challenge with a lethal dose of rabies virus. Anti-rabies VHH were administered directly into the brain or systemically, by intraperitoneal injection, 24 hours after virus challenge. Anti-rabies VHH were able to significantly prolong survival or even completely rescue mice from disease. The therapeutic effect depended on the dose, affinity and brain and plasma half-life of the VHH construct. Increasing the affinity by combining two VHH with a glycine-serine linker into bivalent or biparatopic constructs, increased the neutralizing potency to the picomolar range. Upon direct intracerebral administration, a dose as low as 33 µg of the biparatopic Rab-E8/H7 was still able to establish an anti-rabies effect. The effect of systemic treatment was significantly improved by increasing the half-life of Rab-E8/H7 through linkage with a third VHH targeted against albumin. Intraperitoneal treatment with 1.5 mg (2505 IU, 1 ml) of anti-albumin Rab-E8/H7 prolonged the median survival time from 9 to 15 days and completely rescued 43% of mice. For comparison, intraperitoneal treatment with the highest available dose of human anti-rabies immunoglobulins (65 mg, 111 IU, 1 ml) only prolonged survival by 2 days, without rescue. Overall, the therapeutic benefit seemed well correlated with the time of brain exposure and the plasma half-life of the used VHH construct. These results, together with the ease-of-production and superior thermal stability, render anti-rabies VHH into valuable candidates for development of alternative post exposure treatment drugs against rabies.

Hepatitis B virus vaccination booster does not provide additional protection in adolescents: a cross-sectional school-based study.

BackgroundCurrent consensus does not support the use of a universal booster of hepatitis B virus (HBV) vaccine because there is an anamnestic response in almost all children 15 years after universal infant HBV vaccination. We aimed to provide a booster strategy among adolescents as a result of their changes in lifestyle and sexual activity.MethodsThis study comprised a series of cross-sectional serological surveys of HBV markers in four age groups between 2004 and 2012. The seropositivity rates of hepatitis B surface antigen (HBsAg) and its reciprocal antibody (anti-HBs) for each age group were collected. There were two parts to this study; age-specific HBV seroepidemiology and subgroup analysis, including effects of different vaccine types, booster response for immunogenicity at 15 years of age, and longitudinal follow-up to identify possible additional protection by HBV booster.ResultsWithin the study period, data on serum anti-HBs and HBsAg in a total of 6950 students from four age groups were collected. The overall anti-HBs and HBsAg seropositivity rates were 44.3% and 1.2%, respectively. The anti-HBs seropositivity rate in the plasma-derived subgroup was significantly higher in both 15- and 18-year age groups. Overall response rate in the double-seronegative recipients at 15 years of age was 92.5% at 6 weeks following one recombinant HBV booster dose. Among the 24 recipients showing anti-HBs seroconversion at 6 weeks after booster, seven subjects (29.2%) had lost their anti-HBs seropositivity again within 3 years. Increased seropositivity rates and titers of anti-HBs did not provide additional protective effects among subjects comprehensively vaccinated against HBV in infancy.ConclusionsHBV booster strategy at 15 years of age was the main contributor to the unique age-related phenomenon of anti-HBs seropositivity rate and titer. No increase in HBsAg seropositivity rates within different age groups was observed. Vaccination with plasma-derived HBV vaccines in infancy provided higher anti-HBs seropositivity at 15–18 years of age. Overall booster response rate was 92.5% and indicated that intact immunogenicity persisted at least 15 years after primary HBV vaccination in infancy. Booster vaccination of HBV did not confer additional protection against HBsAg carriage in our study.

Comparison of long-term immunogenicity (23 y) of 10 μg and 20 μg doses of hepatitis B vaccine in healthy children

To compare the long-term immunogenicity and seroprotection rates in healthy children following 23 years of vaccination with 10 μg or 20 μg doses of plasma-derived hepatitis B vaccine, we revisited all participants from our previous randomized controlled trial. At year 23, 81 participants were tested for HBV serological markers and HBV-DNA, and a booster dose was given to those with anti-HBs titer < 10 mIU/mL. After eliminating the interference of a Year 11 booster dose and vaccines received outside of the trial, around 50% of participants still maintained anti-HBs titers ≥ 10 mIU/mL in both 10 μg and 20 μg groups (p > 0.05). The peak immune response of vaccination (anti-HBs antibody levels at 12 mo after 1st vaccine dose) and Year 11 anti-HBs levels were significantly associated with Year 23 seroprotection rates. Most of the participants in both groups, regardless of their prior immune status, developed a rapid and robust anamnestic antibody response after the booster dose at year 23. No case of clinically significant HBV infection was observed during the entire study period of 23 y with only one transient HBsAg seroconversion in 10 μg vaccine group. We concluded that seroprotection provided by 10μg or 20 μg doses of hepatitis B vaccine persists for 23 years in more than half of vaccinated individuals in highly HBV-endemic areas, irrespective of 10 μg or 20 μg vaccine doses. Future studies with larger sample sizes comparing long-term efficacy of various doses of plasma-derived and recombinant HBV vaccines are recommended.

Valuation on the immunization efficacy on the 23 years who had received plasma-derived HBV vaccine as newborns

To observe the long-term effect of plasma-derived HBV vaccine. The effect of a plasma-derived HBV vaccine which was given to children born in 1986 in Huangpu district in Shanghai were followed up once every two years and testing for HBsAg, anti-HBs and anti-HBc was carried out. Compared to background results from cross-sectional survey of hepatitis B virus in 1984 and 1985 (as internal control) as well as finding of survey targeted in non-plasma-derived HBV vaccine of children born in the same time in the nearby area from results investigated in 1991 (as external control), positive rate was calculated to assess the effect of protection. The population immunized was followed up for 23 years and 5993 blood samples were collected. During the period of follow-up, the positive rate of anti-HBs decreased from 89.01% to 18.77% and the average level was 40.39%. The average positive rate of anti-HBc was 1.87%. The annual positive rate fluctuated around the average level. HBsAg positive rate remained less than 1.00% (0.46% - 0.98%), with an average of 0.62% (37/5993). Ranges of positive efficacy were from 81.37% to 95.78% against background control and 72.76% against external control. The plasma-derived HBV vaccine showed a good long-term protective effect and there was no need for boosting the immunization 23 years later.

Meta-Analysis: The Impact of Nutritional Status on the Immune Response to Hepatitis B Virus Vaccine in Chronic Kidney Disease

Patients with chronic kidney disease (CKD) typically show a diminished immune response to hepatitis B virus (HBV) vaccine compared with individuals with intact kidney function. A number of inherited or acquired factors have been implicated in this suboptimal response. Patients with chronic kidney disease frequently have a compromised nutritional status; however, the impact of malnutrition on the immune response to hepatitis B virus vaccine in chronic kidney disease patients remains unclear. To evaluate the influence of nutrition status on the immune response to HBV vaccine in CKD population by performing a systematic review of the literature with a meta-analysis of clinical studies. Study-specific relative risks were weighted by the inverse of their variance to obtain fixed- and random-effects pooled estimates of impaired vaccine response across the published studies. The risk of poor serological response to HBV vaccine in chronic kidney disease population according to nutritional parameters was regarded as the most reliable outcome end-point. Only studies performing multivariate analysis in order to make adjustments for potential confounders were included. We identified seven studies (15,172 unique patients with CKD). The serum protection rate after a full course of recombinant or plasma-derived vaccine towards HBV ranged between 40 and 86%. Aggregation of study results showed an independent and adverse effect of poor nutrition status, as mostly detected by serum albumin levels, on the protection rate after HBV vaccine course; the summary estimate for adjusted RR was 1.50 with a 95% confidence interval (CI) of 1.02, 2.21; R( i )=0.01 (random-effects model). The P value for study heterogeneity was significant (Q=0.0001). In the subgroup of patients who received HBV recombinant vaccine, the relative risk of impaired serological response after HBV vaccination was 1.63 (95% CI, 1.08, 2.45), R( i )=0.90, Q=0.00001, with poor nutritional parameters at baseline. An increased risk exists of impaired serologic response to HBV vaccine response among chronic kidney disease patients having poor nutrition status. Additional studies are needed to understand better the mechanisms underlying the relationship between nutritional status and serological response to HBV vaccine among patients with CKD.

Hepatitis B needle-free vaccines: a step closer

Since the time of Edward Jenner and his discovery of the smallpox vaccine, and during the 200 years that have followed, vaccination has been successfully applied to protect against some of the most important infectious diseases. Moreover, in the case of smallpox, the dream of eradication of a pathogen causing a potentially deadly disease, especially in infants, has come true, with the last case of natural contraction of smallpox observed in 1977 in Somalia [101]. The only other eradicated disease is rinderpest, as will be officially announced by the UN in 2011 [1]. In campaigns to eradicate smallpox, the vaccine was administered using a bi furcated needle or a needle-free jet injector. Both devices deposit the antigen in the subcutaneous tissue. Curiously, before Jenner, a Chinese medical text described several ways of inoculation against smallpox practiced in China. In one of the methods, the nose was plugged with powdered scabs on cotton wool [102]. In another, white cow fleas were ground into powder and made into pills. These may have been the first attempts to formulate a vaccine to be applied by mucosal routes (intranasal and oral, respectively). We may therefore consider that needle-free vaccines were developed even before injectable vaccine formulations, possibly caused by the lack of technology available. At present, the term ‘vaccination’ is generally considered to be equal to ‘injection’. This conception is due to the fact that vaccines are typically given by intramuscular injection. By analyzing some of the exceptions in the market, such as the polio and rotavirus oral vaccines, it can be observed that both contain the live attenuated virus, which does explain, at least in part, the strong immune response observed after oral administration of these vaccines. In the new era of vaccine development, with the emergence of subunit vaccines, the formulation of needle-free vaccines is undoubtedly more challenging. Novel vaccines obtained by recombinant technology are, in principle, safer with regards to toxicity; however, they are also less immunogenic, making it mandatory to include adjuvants in the formulation of such vaccines. The hepatitis B vaccine, licensed in 1981, was the world’s first recombinantly expressed plasma-derived subunit vaccine. Despite being on the market for over 30 years, the European Centre for Disease Prevention and Control estimates a prevalence of 8000 newly diagnosed cases of hepatitis B in the EU alone [103]. Numerous efforts made by the scientific community to develop needle-free vaccine formulations are justifiable by several distinct advantages. An obvious one is the possibility of painless self administration of the vaccine. Moreover, vaccine delivery via mucosal surfaces elicits mucosal immune responses at the site of pathogen entry as well as enhanced cellular immunity through Toll-like receptors stimulation [2], thus improving overall effectiveness. Since the hepatitis B virus can be transmitted perinatally or by exchange of body fluids (e.g., blood, semen and vaginal fluid), the design of new hepatitis B vaccines with the additional possibility to induce mucosal

Antibody levels and immune memory 23 years after primary plasma-derived hepatitis B vaccination: Results of a randomized placebo-controlled trial cohort from China where endemicity is high

The duration of protection of hepatitis B vaccine remains incompletely understood. To assess the long-term protection provided by a primary vaccine series, the current study again recruited all subjects of a previous randomized placebo-controlled trial cohort 23 years after vaccination. Two hundred and sixty-one healthy children aged 5–9 years living in a highly HBV-endemic country were enrolled in the primary trial and received three doses of plasma-derived vaccine or placebo. The primary placebo receivers who did not receive any immunization against hepatitis B were used as non-vaccinated controls in the current study. After eliminating the interference of an early booster dose and vaccines outside the study, 48.1% (39/81) vaccinees still maintained anti-HBs titers ≥10 mIU/mL at Year 23, higher than 34.7% (26/75) in non-vaccinated controls ( P = 0.088). 75–100% of vaccinees with anti-HBs titer <10 mIU/mL at Year 23 in different sub-groups divided according to early immune backgrounds developed a rapid and robust antibody anamnestic response after a booster dose, highly significantly different from non-vaccinated controls who received the same dose of vaccine (7.5%, P < 0.01). No case of clinically significant HBV infection was found in the primary cohort during the whole 23 years, but 10 transient HBsAg seroconversions in the primary placebo group and one in the primary vaccine group were determined. Anti-HBc positive rate obviously tended to be lower in vaccinees compared with non-vaccinated controls at Year 23. These results suggest a persisting immune memory and certain protection for 23 years after primary vaccination in children living in highly HBV-endemic areas. Clinically insignificant infections, which cannot be avoided and may often occur in vaccinees, play a positive role in the maintaining of immunity to HBV. Booster doses should be unnecessary for more than 20 years after a full primary immunization in children (as catch-up vaccination) and, also likely, in newborns living in highly HBV-endemic areas.

Waning immunity and booster responses in nursing and medical technology students who had received plasma-derived or recombinant hepatitis B vaccine during infancy

The national hepatitis B virus (HBV) vaccination program was launched in Taiwan in 1984. After November 1992, arecombinant HBV vaccine replaced the plasma-derived HBV vaccine. A total of 1,812 nursing and medical technology freshman students was tested to evaluate their waning immunity toward hepatitis B. In the 2007 (2008) academic year, 438 (382) students testing nonprotective antibodies received 3 (1) booster doses of HBV vaccine according to suggestions from Taiwan's Center for Disease Control (CDC). The seroprevalences of hepatitis B surface antigen (+) were 0.8% and 0.7% in the plasma-derived and recombinant group, respectively; for antibody to hepatitis B surface antigen (anti-HBs) (+), they were 43.2% and 33.3% (P < .001), respectively. In the 2007 freshman group, 99.1% of the students previously vaccinated with plasma-derived HBV vaccine exhibited anti-HBs seroconversion. In the 2008 freshman group, the booster dose induced anti-HBs seroconversions of 92.1% and 95.9% in the students who had received the plasma-derived and recombinant HBV vaccine, respectively (P = .370). Most students exhibited signs of immune memory after receiving the booster, regardless of having received plasma-derived or recombinant HBV. Only a small number of vaccinees lost their immune memory after 16 years, suggesting that some students might benefit from boosting before proceeding to clinical practice.

Preventing primary liver cancer: the HBV vaccination project in the Gambia (West Africa)

The Gambia Hepatitis Intervention Study (GHIS) consisted in the progressive introduction of HBV plasma-derived vaccine in different zones of this African country during the period 1986-1990. The study was launched and coordinated by IARC and is one of the most effective examples of an intervention project that both substantially contributed to our knowledge and to the health of local populations. Similar intervention studies have been carried out in South-East Asia. The studies indicate that the natural history of HBV infection differs in different populations , having a direct relevance for the implementation of HBV vaccination programmes in various parts of the world.

No Increase in Prevalence of Hepatitis B Surface Antigen Mutant in a Population of Children and Adolescents Who Were Fully Covered by Universal Infant Immunization

Mutants of the a determinant of hepatitis B surface antigen (HBsAg) can escape neutralization by vaccine-induced antibodies and prevail in an immunized population. We evaluated the a mutants in a pediatric population surveyed in 2004 and compared these findings with the data of previous surveys. There were 38 children and 74 adolescents who were HBsAg positive, and serum hepatitis B virus (HBV) DNA was obtained and tested from 31 and 34 of them, respectively. The a mutants were found in 7 (22.6%) of 31 HBV DNA-positive children and in 7 (0.10%) of 7234 children, the entire population that was surveyed in 2004. After the beginning of universal immunization, the very low prevalence of mutants has remained unchanged for 20 years. More a mutants were found in immunized than in nonimmunized HBV DNA-positive children aged 1-4 years old (31% vs 4%, P = .016) but not in those children aged 5-12 years old. Approximately 68% of immunized, mutant-infected children had carrier mothers. More a mutants emerged in children immunized with plasma-derived vaccines than in those immunized with recombinant vaccines (14 of 5166 vs 3 of 4970, respectively; P = .04). HBV DNA levels were significantly lower in hepatitis B e antigen-positive sera containing the G145R mutant than were levels in sera containing wild-type virus. HBsAg-negative sera containing a mutants had very low HBV DNA levels. Less infectivity of G145R, recombinant vaccine use, and mutant loss with older age seem to decrease the a mutant prevalence in an immunized population over time.