[Anti-HBs persistence after revaccination with three doses of hepatitis B vaccine among low-responder infants following primary vaccination: 4-year of follow-up].

Objective: Assess the 4-year antibody against hepatitis B surface antigen (anti-HBs) persistence after revaccination with 3-dose of hepatitis B vaccine (HepB) among low-responder infants following primary vaccination. Methods: According to stratified cluster sampling, a total of 4 147 infants were enrolled and primarily vaccinated with 5 µg HepB derived in Saccharomyces Cerevisiae (HepB-SC) at 0-1-6 months schedule from 75 towns of Jinan, Weifang, Yantai, Weihai prefectures, Shandong Province, China in Aug and Sep 2009. Blood samples were collected one to six months after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). 717 infants who appeared low response (10 mU/ml ≤ anti-HBs<100 mU/ml) were revaccinated with 3-dose of HepB. Blood samples were collected from a total of 315 infants one month (T(0)), four years (T(1)) after revaccination and anti-HBs, antibody against hepatitis B core antigen (anti-HBc) and hepatitis B surface antigen (HBsAg) were detected by CMIA. Information about their birth, primary vaccination were collected. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple non-conditional logistic regression analysis and multifactor linear regression model analysis, respectively. Results: Among 315 children, 165 (52.38%) were male and 150 (47.62%) were female. The positive rate was 83.81% (264/315) at T(0) and it decreased to 16.51% (149/529) at T(1). The corresponding GMC decreased from 473.15 mU/ml to 17.37 mU/ml. The average annual decreasing rate of positive rate and GMC was 33.38% and 56.23% from T(0) to T(1). Multivariable analysis showed the positive rate and GMC among those whose anti-HBs titer higher at T(0) were significantly higher at T(1). The positive rate at T(1) among those whose anti-HBs titer 400-<600, 600-<800, 800-<1 000, ≥1 000 mU/ml at T(0) were significantly higher than those whose anti-HBs titer less than 200 mU/ml. The OR (95%CI) of the positive rate was 4.29 (1.03-17.84), 4.53 (1.25-16.47), 4.19 (1.10-15.97) and 9.13 (2.91-28.63), respectively. The GMC at T(1) among those whose anti-HBs titer 400-<600, 600-<800, 800-<1 000 mU/ml and those whose anti-HBs titer ≥1 000 mU/ml at T(0) were higher than those whose anti-HBs titer<200 mU/ml. The b value (95% CI) of GMC was 0.84 (0.06-1.62), 1.13 (0.46-1.79), 1.33 (0.65-2.01) and 1.88 (1.33-2.44), respectively. GMC among full-term infants were significantly higher than premature infants at T(1). The b value (95% CI) of GMC was 0.86 (0.04-1.68). Conclusion: Anti-HBs GMC decreased rapidly 4 years after revaccination among low-responder infants, but still kept good protection. The anti-HBs persistence after revaccination was associated with anti-HBs level of titer one month after revaccination.

Research progress of therapeutic vaccines for treating chronic hepatitis B.

Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.

[Anti-HBs persistence following primary vaccination with three doses of hepatitis B vaccine among normal and high-responder adults: a 3-year follow-up study].

OBJECTIVE: To assess the 3-year anti-HBs persistence after primary vaccination with three-dose of hepatitis B vaccine (HepB) among normal and high-responder adults. METHODS: A total of 24 237 healthy adults who had no histories of hepatitis B infection and hepatitis B vaccination, resided in local areas for more than six months and were aged 18-49 years were selected from 79 villages of Zhangqiu county, Shandong province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling method. Each group was vaccinated with one of the following four types of HepB at 0-1-6 months schedule: 20 µg HepB derived in Saccharomyces cerevisiae (HepB-SC), 20 µg HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 µg HepB-SC and 10 µg HepB derived in Hansenula polymorpha (HepB-HP). Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). During the follow-up to normal and high-responders, the following information was collected: the demographic characteristic (including age and gender), histories of hepatitis B infection, hepatitis B vaccination, smoking, drinking and chronic diseases. Blood samples were collected one month (T1) and three years after primary vaccination (T2) and anti-HBs, anti-HBc and HBsAg (if anti-HBs<10 mU/ml) were detected by CMIA. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple logistic regression analysis and multifactor linear regression model analysis, respectively. RESULTS: A total of 4 677 normal and high-responders were identified. Among 4 677 participants, 2 014 (43.06%) were males and 2 663 (56.94%) were females. The positive rate was 100% at T1 and it decreased to 80.99% (3 788/4 677) three years after vaccination. The corresponding GMC was decreased from 1 413.48 (95%CI: 1 358.86-1 470.30) mU/ml to 60.33 (95%CI: 56.97-63.90) mU/ml. When comparing with those vaccinated 20 µg HepB-CHO, the significantly lower positive rate of anti-HBs three years after vaccination was observed in those vaccinated 20 µg HepB-SC, 10 µg HepB-SC and 10 µg HepB-HP. The OR (95%CI) was 0.65 (0.50-0.84), 0.52 (0.41-0.67) and 0.31 (0.28-0.45), respectively. The GMC of anti-HBs was also significantly lower among those vaccinated 20 µg HepB-SC, 10 µg HepB-SC and 10 µg HepB-HP. The b (95%CI) was -0.33 (-0.47- -0.20), -0.41 (-0.55- -0.28) and -0.78 (-0.92- -0.65), respectively. The GMC of anti-HBs in those aged 30-39 years old and 40-49 years old were lower than that in 18-29 years. The b (95%CI) was -0.31 (-0.47- -0.15) and -0.24 (-0.39- -0.09), respectively. When comparing with those whose anti-HBs titer was less than 999 mU/ml at T1, the significantly higher positive rate of anti-HBs three years after vaccination was observed in those whose anti-HBs titer was 1 000-1 999 mU/ml, those whose anti-HBs titer was 2 000-9 999 mU/ml and those whose anti-HBs titer was ≥10 000 mU/ml. The OR (95%CI) was 4.97 (3.80-6.49), 7.87 (16.19-10.01) and 9.67 (6.47-14.44), respectively. When comparing with those whose anti-HBs titer was ≤999 mU/ml at T1, the GMC of anti-HBs three years after vaccination was also significantly higher among those whose anti-HBs titer at T1 was 1 000-1 999 mU/ml, those whose anti-HBs titer at T1 was 2 000-2 999 mU/ml and those whose anti-HBs titer at T1 was ≥10 000 mU/ml. The b (95%CI) was 1.00 (0.87-1.14), 1.85 (1.74-1.97) and 3.28 (3.12-3.44), respectively. Four subjects showed HBsAg seroconversion and anti-HBc conversion rate was 4.68% at T2. CONCLUSIONS: Anti-HBs GMC decreased rapidly three years after primary vaccination among normal and high-responder adults, while the positive rate of anti-HBs still kept at a high level. The anti-HBs persistence after primary vaccination was associated with HepB type, age and GMC of anti-HBs one month after vaccination.

[Anti-HBs persistence following revaccination with three doses of hepatitis B vaccine among low-responsive adults after primary vaccination: a 4-year follow-up study].

OBJECTIVE: To assess the 4-year anti-HBs persistence after revaccination with 3-dose of hepatitis B vaccine (HepB) among low-responsive adults. METHODS: A total of 24 237 healthy adults who had no history of hepatitis B infection and hepatitis B vaccination, resided in the local area for more than six months and were aged 18-49 years were selected from 79 villages of Zhangqiu county, Shandong province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling method. Each group was vaccinated with one of the following four types of HepB at 0-1-6 months schedule: 20 µg HepB derived in Saccharomyces cerevisiae (HepB-SC), 20 µg HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 µg HepB-SC and 10 µg HepB derived in Hansenula polymorpha (HepB-HP). Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). The 892 low-responders were revaccinated with three doses of HepB at 0-1-6 months schedule and the type of HepB was the same as which was used for primary immunization. During the follow-up to low-responders, the following informations were collected: the demographic characteristics (including age, gender), histories of hepatitis B infection, hepatitis B vaccination, smoking, drinking and chronic diseases. Blood samples were collected one month (T1) and four years after revaccination and anti-HBs, anti-HBc and HBsAg (if anti-HBs <10 mU/ml) were detected by CMIA. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple logistic regression analysis and multifactor linear regression model analysis respectively. Anti-HBs titer at T1 was grouped according to the level and was considered as the independent variable in the model analysis. RESULTS: A total of 529 participants were identified from 892 low-responders. Among 529 participants, 276 (52.2%) were males and 253 (47.8%) were females. The positive rate was 82.6% (437/529) at T1 and it decreased to 28.2% (149/529) four years after revaccination. The corresponding GMC decreased from 542.06 (95% CI: 466.72-629.56) mU/ml to 27.69 (95% CI: 23.08-33.23) mU/ml. Multivariable analysis showed the positive rate of anti-HBs 4 years after revaccination was independently associated with anti-HBs titer at T1. The positive rate among those whose anti-HBs titer more than 1 000 mU/ml at T1 was significantly higher than those whose anti-HBs titer less than 100 mU/ml. The OR (95%CI) was 39.67 (13.81-114.01). The GMC was associated with HepB type for revaccination and anti-HBs titer at T1. The GMC among those revaccinated 20 µg HepB was significantly higher than those revaccinated 20 µg HepB-CHO, 10 µg HepB-SC and 10 µg HepB-HP. The b (95% CI) was -0.40 (-0.78--0.02), -0.57 (-1.01- -0.15) and -0.63 (-1.03- -0.23), respectively. The GMC among those whose anti-HBs titer 100-999 mU/ml and those whose anti-HBs titer ≥1 000 mU/ml at T1 were higher than those whose anti-HBs titer <100 mU/ml. The b (95% CI) was 0.93 (0.53-1.33) and 3.31 (2.88-3.73) respectively. CONCLUSION: Anti-HBs GMC decreased rapidly 4 years after revaccination among low-responsive adults, but still kept good protecion. The anti-HBs persistence after revaccination was associated with HepB type for revaccination and anti-HBs level of titer one month after revaccination.

[Anti-HBs persistence after revaccination with three doses of hepatitis B vaccine among non-responsive adults: a 4-year of follow-up study].

OBJECTIVE: To explore anti-HBs persistence four years after revaccination with hepatitis B vaccine (HepB) among adults who were non-responsive to HepB primary immunization. METHODS: A total of 24 237 healthy adults who had no history of hepatitis B infection and hepatitis B vaccination, resided in the local area for more than six months and aged 18-49 years were selected from 79 villages of Zhangqiu County, Shandong Province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling methods. Each group was vaccinated with one of the following four types of HepB at 0-1-6months schedule: 20 µg HepB derived in Saccharomyces cerevisiae (HepB-SC), 20 µg HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 µg HepB-SC and 10 µg HepB derived in Hansenula polymorpha (HepB-HP). Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). The non-responders were followed up and their basic information and the histories of hepatitis B infection, HepB vaccination, smoking and drinking were investigated. Then they were revaccinated with three doses of HepB with the same schedule as the primary immunization. Blood samples were collected from all of them one month (T1), two years and four years after revaccination and anti-HBs, anti-HBc and HBsAg were detected by CMIA. A total of 356 participants were followed up from 645 low-responders four years after revaccination, and the ratio was 55.2%. The risk factors associated with the positive rate and geometric mean concentration (GMC) of anti-HBs after four years of revaccination were analyzed using multivariate unconditional logistic regression model and multivariate linear regression model, respectively. RESULTS: Among 356 participants, 172 (48.3%) were males and 184 (51.7%) were females. The anti-HBs positive rate was 90.4% (322 cases) at T1 and was 55.9% (199 cases) four years after revaccination. The GMC of anti-HBs was 240.5 (95% CI: 186.4-310.4)mU/ml at T1 and decreased to 15.0 (95%CI: 12.2-18.5) mU/ml four years after revaccination. The average annual decreasing rate of GMC was 50.63% from one month after revaccination to four years after revaccination. The corresponding rate was 64.89% in the first two years, which was 2.12 times the rate in the latter two years (30.57%). When compared with those whose anti-HBs titer was less than 99 mU/ml at T1, the significantly higher anti-HBs four years after revaccination was observed in those whose anti-HBs titer at T1 was 100-999 mU/ml and those whose anti-HBs titer at T1 was ≥1 000 mU/ml. The OR (95%CI) was 7.14 (3.90-13.05) and 28.40 (13.16-61.30) respectively. When compared with those whose anti-HBs titer was ≤99 mU/ml at T1, the GMC of anti-HBs four years after revaccination was also significantly higher among those whose anti-HBs titer at T1 was 100-999 mU/ml and those whose anti-HBs titer at T1 was ≥1 000 mU/ml. The b (95%CI) was 1.66 (1.26-2.05) and 3.16 (2.72-3.60), respectively. CONCLUSION: The positive rate and GMC of anti-HBs decreased four years after revaccination among non-responsive adults, but still kept anti-HBs above protective level. The immunity durability after revaccination is mainly associated with anti-HBs titer one month after revaccination.

[Anti-HBs persistence after revaccination with three doses of hepatitis B vaccines among non-responsive adults: 24-month of follow-up].

OBJECTIVE: To access the antibody persistence 24-month after revaccination with 3-dose of hepatitis B vaccine (HepB) among non-response adults. METHODS: A total of 24 237 healthy adults who had no histories of hepatitis B infection and hepatitis B vaccination, resided in the local area for more than six months and were aged 18-49 years were selected from 79 villages of Zhangqiu county, Shandong province, China in 2009. Blood samples were obtained and hepatitis B surface antigen (HBsAg), antibody against hepatitis B surface antigen (anti-HBs) and antibody against hepatitis B core antigen (anti-HBc) were detected using ELISA method. A total of 11 590 persons who were negative for all of these indicators were divided into four groups by cluster sampling methods. Each group was vaccinated with one of the following four types of HepB at 0-, 1-, 6-months schedule: 20 µg HepB derived in Saccharomyces Cerevisiae (HepB-SC), 20 µg HepB derived in Chinese hamster ovary cell (HepB-CHO), 10 µg HepB-SC and 10 µg HepB derived in Hansenula Polymorpha (HepB-HP). Blood samples were collected one month after the third dose of primary immunization and tested for anti-HBs using chemiluminescence microparticle immunoassay (CMIA). The non-responders were revaccinated with three doses of HepB at 0-, 1-, 6-months schedule and the type of HepB was the same as which was used for primary immunization. Blood samples were collected one month (T1) and two years (T24) after revaccination and anti-HBs, antibody against hepatitis B core antigen (anti-HBc) and hepatitis B surface angtigen (HBsAg) (if anti-HBs < 10 mU/ml) were detected by CMIA. χ(2) test was used to compared age, gender and body mass index (BMI) between different groups and the anti-HBs positive rate at T1 and T24; analysis of variance (ANOVA) was used to compare the geometric mean concentration (GMC) of anti-HBs between difference groups. The risk factors associated with positive rate of anti-HBs and GMC of anti-HBs were identified by multiple logistic regression analysis and multifactor linear regression model analysis respectively. RESULTS: A total of 900 non-responders were identified and 71.7% (645/900) of them completed three-dose revaccination and blood collection after revaccination. 467 (72.4%) non-responsive adults were followed up at T24. The anti-HBs positive rate decreased from 85.65% (95% CI: 82.14%-88.71%) at T1 to 60.60% (95% CI: 56.01%-65.06%) at T24 and the corresponding GMC decreased from 175.62 (95% CI: 139.03-221.84) mU/ml to 21.43 (95% CI: 17.62-26.06) mU/ml. Multivariate analysis showed that positive rate of anti-HBs at T24 was associated with gender, HepB type for revaccination and anti-HBs level at T1, but only anti-HBs level at T1 was associated with the anti-HBs titer at T24. No subject showed HBsAg seroconversion and anti-HBc conversion rate was 3.64% (17/467) at T24. CONCLUSION: Anti-HBs titer decreases rapidly two years after HepB revaccination among non-responsive adults, but more than half non-responderd still kept anti-HBs above protective level. The immunity durability after revaccination was associated with gender, HepB type for revaccination and anti-HBs titer one month after revaccination.

Actualización sobre hepatitis B / Upgrade in hepatitis B

El virus de la hepatitis B (VHB), es un virus DNA, el cual tiene varios antígenos, como el antígeno de superficie, y antígeno core. Colombia, es un país de baja endemicidad, sin embargo, en la Sierra Nevada de Santa Marta, está endemicidad es alta. El VHB tiene como una de sus complicaciones la hipertensión porta. En general, el VHB no atraviesa la placenta, por lo que la infección es rara in utero. Son pocos los pacientes que se presentan con HB y falla hepática fulminante y por lo tanto, son pocos los antivirales que han sido utilizados, con muy poca experiencia.

The hepatitis B virus (HBV) is a DNA virus, which has several antigens such as surface antigen and core antigen. Colombia is a country of low endemicity, however, in the Sierra Nevada of Santa Marta, is endemic is high. HBVis one of the complications of portal hypertension. In general, HBV does not cross the placenta, so the infection is rare in utero. Few patients who present with HB and fulminant hepatic failure and therefore, few antiviral drugs that have been u s e d , wi t h v e r y l i t t l e e x p e r i e n c e.

[Overview on safety of hepatitis B vaccine].

At home and abroad by analyzing the literature of the hepatitis B vaccine adverse reactions, especially multiple sclerosis, leukemia, autoimmune diseases, death and other serious adverse reaction to evaluate the safety of hepatitis B vaccine.

[Comparison of the kinesis of immune responses in mice vaccinated by different kinds of recombinant hepatitis B vaccines].

OBJECTIVE: To evaluate the kinesis of cellular and humoral immune responses to different kinds of recombinant hepatitis B(rHB) vaccines in the immunized mice. METHODS: At serial time points, the levels of IFN-gamma and IL-2 secreted by spleens mononuclear cells (MNC) of the vaccinated mice were detected by enzyme-linked immunospot methods (ELISPOT) after stimulation in vitro with HBsAg MHC class I peptide S28-39 or HBsAg. The lymphocytotoxicity of the immunized mice were also detected (CTL) by a specific lysis assay and the levels of anti-HBs were measured by the Abbott IMX kit. RESULTS: The peak values of IFN-gamma and IL-2 in vaccinated mice were detected by ELISPOT, 10 - 14 days after immunization. The CTL and the level of IFN-gamma induced by rHB vaccine derived from yeast cells (Hansenula polymorpha) (rHP vaccine) were significantly higher than the other two vaccines (P < 0.05). The maximum lysis of CTL appeared in the vaccinated mice on day 10 after immunization, with the percentage of 39.8%. The levels of IL-2 induced by rHP vaccine were significantly higher than the other two vaccines (P < 0.05). However, the IL-2 levels in the rSC (saccharomyces cerevisiae) vaccine group were higher as compared with the rCHO vaccine group at day 7 and day 14 (7 d t = 4.595, P = 0.001 < 0.05; 14 d t = 5.721, P = 0.000 < 0.05) after immunization. The cellular immune response to the rHP vaccine was the strongest while it was the lowest to the rCHO vaccine at day 7 after immunization. The sero-positive rates and the titers of anti-HBs in the vaccinated mice increased with time after vaccination. The titers of anti-HBs in the rCHO vaccine group at day 7 were similar to the rSC vaccine group, but significantly higher than that of the rHP vaccine group (P = 0.044 < 0.05). The anti-HBs titers of the rCHO vaccine group at day 14 were significantly higher as compared to the rSC (P = 0.012 < 0.05) and rHP (P = 0.009 < 0.05) vaccine groups. CONCLUSION: The immune responses induced by the three kinds of rHB vaccines were different in their patterns and levels. According to the intensity of early cellular immune response, the two yeast HB vaccines were superior to the rCHO vaccine, especially to the rHP vaccine. In contrast, the rCHO vaccine induced early seroconversion and high levels of anti-HBs.

[Comparing immunogenicity and efficacy of two hepatitis B vaccines in newborn infants of hepatitis B surface antigen (+)/hepatitis B e antigen (+) carrier mothers].

OBJECTIVE: To evaluate the effect of yeast recombinant HBV vaccine on protecting the newborns from HBV carrier mothers and to compare with plasma-derived vaccine. METHODS: There were 117 neonates from HBsAg(+)/HBeAg(+) carrier mothers involved in the study. Study group [76 of them received RECOMBIVAX HB(5 mcg/0.5 ml)] and control group (41 neonates receive plasma derived vaccine) had blood samples collected and received vaccine at 0, 1, 6, 9 month after birth respectively. HBV-DNA, HBsAg/HBeAg, HBsAb were determined by PCR, ELISA, RIA independently. RESULTS: (1) Children chronic HBV infection rates at 6, 9 month of age in study group were 7.89%, 5.26% respectively, which were lower than that of control group(14.63%, 17.07%). (2) The vaccine efficacy (VE) in study group was 93.82%, vs, that of control group was 79.92%. (3) The HBsAb positive rate in study group at 9 month of age was 94.74% which was significantly higher than that of control group(80.49%) (P < 0.05). (4) The difference of side-effect rates between the two groups was not significant. CONCLUSION: Immunogenicity and efficacy of yeast-recombinant hepatitis B vaccine is better than that of plasma derived vaccine in newborn infants of HBsAg(+)/HBeAg(+) carrier mothers.

[Protein subunit vaccines: example of vaccination against hepatitis B virus]. / Vaccins sous-unités protéiques: exemple de la vaccination contre le virus de l'hépatite B.

Hepatitis B vaccine has been used for over 10 years. It is efficient and safe. Protection of risk groups against hepatitis B virus infection is now achieved and vaccination of newborns and adolescents is a main public health problem. Bad responders are well characterized and immunomodulatory interventions (cytokines) must be tested in these patients. Response to hepatitis B vaccine is genetically determined and the possibility of vaccine induced escape mutants should lead to careful epidemiological studies of the spread of hepatitis B virus infection.

Contribution to hepatitis B prevention.

Hepatitis B is widely recognized as an important public health problem. The only effective way to control hepatitis B is by vaccination. First generation plasma-derived hepatitis B vaccines have limitations. Advances in recombinant DNA technology have led to the development of yeast-derived recombinant hepatitis B vaccine which is now used extensively in the developed world. This article reviews the development of this new generation vaccine and the efforts to facilitate universal vaccination programmes particularly in the developing world. The issue of the cost of new generation vaccines, in relation to the major investment required for research and development and also the quality of the final product, is discussed.