Clinical trial of inactivated hepatitis A vaccine

A clinical trial was carried out for a lypophilized inactivated hepatitis A vaccine in order to confirm its safety and antibody response. The vaccine used for the study has been developed by Denka Institute of Biological Science (Lot. D-01), Chiba Serum Institute (Lot. C-01) and The Chemo-Sero-Therapeutic Research Institute (Lot. K-02). Thirty-six volunteers were selected and employed for the present study from healthy male adults carrying no antibody against hepatitis A virus (HAV). They were divided into three dose groups; 1.0 microgram, 0.5 microgram and 0.25 microgram viral protein respectively. Each groups were injected intramuscularly 3 times with 0, 1 and 6 months interval. As the results, though, slight side effects such as local pain were found in 16 cases out of 99 total injected, but no abnormal value was observed in the blood and urine examinations. On the other hand, the mean values of serum anti-HAV at 2 months after the first injection in 1.0 microgram, 0.5 microgram and 0.25 microgram dose-groups were 562 mIU/ml, 323 mIU/ml and 134 mIU/ml, respectively, and at the 7 months, 3630 mIU/ml, 1288 mIU/ml and 1000 mIU/ml, respectively. Namely, the high immunogenicity and safety of the vaccine were confirmed in this trail.     

Immunogenicity and safety of an inactivated hepatitis A vaccine in Taiwanese adults and children

The safety and immunogenicity of an inactivated hepatitis A vaccine (AVAXIM, 160 antigen units) was evaluated in 190 subjects: 50 children aged from 2 to 5 years, 70 children aged from 6 to 17 years and 70 adults aged from 18 to 30 years in a monocentric, open, non-controlled, phase III trial conducted in Taipei, Taiwan from December 1996 to October 1997. The vaccine was administered intramuscularly, with a two-dose schedule 6 months apart. Clinical adverse events were monitored during the seven days following each injection. Hepatitis A virus (HAV) antibody titers were measured by modified radioimmunoassay on the day of inclusion and four weeks after both the first dose and booster injection. Among the 190 subjects who received the first dose, 174 (91.6%) were initially HAV seronegative and 16 (8.4%) were HAV seropositive at inclusion. One hundred and seventy-four subjects (91.6%) received the booster dose and completed the study. One month after the first dose, all the subjects, whatever the age, presented HAV antibody titers over 20 mIU/ml. In children (2 to 17 years), the GMT was 136 mIU/ml at week 4 and 7,906 mIU/ml four weeks after the booster dose. In adults (> or = 18 years), GMT values were 93 mIU/ml at week 4 and 3,655 mIU/ml four weeks after the booster. These results show a strong anamnestic response to the second dose of vaccine and are compatible with long-term antibody persistence in each age group. The vaccine was safe and well tolerated. No vaccine-related serious adverse event occurred. No immediate reaction occurred. The majority of the reactions were reported by adults after the primary injection. Local reactions (pain and redness) were reported by 9.0% and 4.0% of the subjects after the primary and the booster doses, respectively. Systemic reactions (mainly myalgia/arthralgia or asthenia) affected less than 10% of the subjects after the first dose and less than 3% after the booster. Results from this study in a Taiwanese population are consistent with those obtained with the same vaccine in previous European studies in children and adults, and suggest that AVAXIM (160 AU) is suitable for use in all subjects aged over 2 years.     

Persistence of immunity against hepatitis A in Brazilian children vaccinated with a single dose of inactivated virus vaccine

In 2014, the Brazilian National Immunization Program implemented the universal vaccination against the hepatitis A virus (HAV) for children aged 12 months and older, applying a single dose of the inactivated virus vaccine. It is essential to carry out follow-up studies in this population, aiming to verify the longevity of HAV immunological memory. This study evaluated the humoral and cellular immune response of a cohort of children vaccinated between 2014 and 2015, and further investigated between 2015 and 2016, and who had their initial antibody response assessed after the single dose. A second evaluation took place in January 2022. We examined 109 children out of the 252 that took part in the initial cohort. Seventy (64.2%) of them had anti-HAV IgG antibodies. Cellular immune response assays were performed in 37 anti-HAV-negative and 30 anti-HAV-positive children. Production of interferon-gamma (IFN-y) stimulated with the VP1 antigen was demonstrated in 34.3% of these 67 samples. Of the 37 negative anti-HAV samples, 12 (32.4%) produced IFN-y. Among the 30 anti-HAV-positive, 11 (36.7%) produced IFN-y. In total, 82 (76.6%) children presented some type of immune response against HAV. These findings demonstrate the persistence of immunological memory against HAV in the majority of children vaccinated between 6 and 7 years with a single dose of the inactivated virus vaccine.     

Characterization of a whole,inactivated influenza (H5N1) vaccine

Objectives Effective vaccines against the highly pathogenic influenza A/H5N1 virus are being developed worldwide. In Japan, two adjuvanted, inactivated, whole‐virion influenza vaccines were recently developed and licensed as mock‐up, pre‐pandemic vaccine formulations by the Ministry of Health and Labor Welfare of Japan. During the vaccine design and development process, various obstacles were overcome and, in this report, we introduce the non clinical production, immunogenicity data in human and development process that was associated with egg‐derived adjuvanted, inactivated, whole‐virion influenza A (H5N1) vaccine. Design Pilot lots of H5N1 vaccine were produced using the avirulent H5N1 reference strain A/Vietnam/1194/2004 (H5N1) NIBRG‐14 and administered following adsorption with aluminum hydroxide as an adjuvant. Quality control and formulation stability tests were performed before clinical trials were initiated (phase I‐III).
The research foundation for microbial diseases of Osaka University (BIKEN) carried out vaccine production, quality control, stability testing and the phase I clinical trial in addition to overseeing the licensing of this vaccine. Mitsubishi Chemical Safety Institute Ltd. carried out the non clinical pharmacological toxicity and safety studies and the Japanese medical association carried out the phase II/III trials. Phase I‐III trials took place in 2006. Results The production processes were well controlled by established tests and validations. Vaccine quality was confirmed by quality control, stability and pre‐clinical tests, and the vaccine was approved as a mock‐up, pre‐pandemic vaccine by the Ministry of Health and Labor Welfare of Japan. Conclusions Numerous safety and efficacy procedures were carried out prior to the approval of the described vaccine formulation. Some of these procedures were of particular importance e.g., vaccine development, validation, and quality control tests that included strict monitoring of the hemagglutinin (HA) content of the vaccine formulations.
Improving vaccine productivity, shortening the production period and improving antigen yield of the avirulent vaccine strains were also considered important vaccine development criteria.     

Safety and immunogenicity of an inactivated hepatitis A vaccine in children 2 to 5 years old

Summary The reactogenicity and immunogenicity of an inactivated hepatitis A vaccine were assessed. Seventy healthy children aged between 2 and 5 years old, who lacked antibodies against the hepatitis A virus, were enrolled in this study. With a 0-, 1-, and 6-month vaccination schedule, the children received three doses of 360 enzyme-linked immunosorbent assay (ELISA) units of hepatitis A vaccine intramuscularly (deltoid). Safety parameters were recorded in standardized diary cards by the parents on the day of injection and the three following days. Blood tests for liver enzymes and anti-hepatitis A virus antibody analyses were performed the day of screening and 1, 2, 6 and 7 months after the first dose. Anti-hepatitis A virus antibody was tested by ELISA. Titres < 20 mIU/ml were considered negative. For the three hepatitis A vaccine doses administered, 22% (46/210) of the diary cards reported any kinds of signs or symptoms. Soreness at the injection site (9%, 18/210) and malaise (6%, 12/210) were the most common local and systemic reactions reported, respectively. The seroconversion rates were 83, 99 and 100% one month after the 1st, 2nd, and 3rd doses, respectively. The corresponding geometric mean titres were 124, 352, and 2,778 mIU/ml. We conclude that this HAV vaccine is safe and immunogenic in healthy children. As the hepatitis A epidemiology pattern is rapidly changing in our country (and other regions), resulting in an increasing population of susceptible adolescents and young adults, we suggest that the routine vaccination against hepatitis A in pre-school children attending day-care centres should be seriously considered.

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Sicherheit und Immunogenität einer inaktivierten Hepatitis A-Vakzine bei 2–5 Jahre alten Kindern

Zusammenfassung Eine inaktivierte Hepatitis A-Vakzine wurde auf ihre Verträglichkeit und Immunogenität untersucht. In die Studie wurden 70 gesunde Kinder ohne Antikörper gegen das Hepatitis A-Virus aufgenommen. Das Impfschema bestand aus der intramuskulären Gabe (M. deltoideus) von drei Dosen von 360 ELISA-Einheiten der Hepatitis A-Vakzine zum Zeitpunkt 0, 1 und 6 Monaten. Die Sicherheitsparameter wurden von den Eltern auf Tagebuchkarten am Tag der Injektion und an den drei folgenden Tagen dokumentiert. Am Tag des Screening, nach 1, 2, 6 und 7 Monaten wurden die Leberenzyme und anti-Hepatitis A Virus-Antikörper im Blut bestimmt. Die anti-Hepatitis A Virus-Antikörperbestimmung erfolgte mittels ELISA. Titer von 20 mIU/ml wurden als negativ eingestuft. Bei 22% (46/210) der in drei Dosen applizierten Impfungen fanden sich in den Aufzeichnungen auf den Tagebuchkarten keine Symptome oder Beschwerden. Die häufigsten lokalen und Allgemeinbeschwerden waren Schmerzen an der Injektionsstelle (9%; 18/20) und schlechtes Befinden (6%; 12/210). Einen Monat nach der ersten, zweiten und dritten Dosis lagen die Konversionsraten bei 83, 99 und 100%. Dabei fanden sich die entsprechenden Titer (geometrisches Mittel) von 124, 352 und 2 778 mIU/ml. Wir schließen aus den Ergebnissen, daß diese HAV-Vakzine bei gesunden Kindern sicher und immunogen ist. Da sich das epidemiologische Muster der Hepatitis A in unserem Land (und anderen Regionen) rasch ändert und ein immer größerer Anteil der Bevölkerung im Adoleszentenalter und frühen Erwachsenenalter empfänglich für die HAV Infektion ist, empfehlen wir die Routineimpfung gegen Hepatitis A bei Vorschulkindern, die in Tagesstätten untergebracht sind, ernsthaft zu erwägen.

     

Immunogenicity and safety of a new inactivated hepatitis A vaccine in Thai young adults

In view of the increasing median age of hepatitis A virus (HAV) infection observed recently in Asia, and the resulting increased number of symptomatic cases occurring in adults, with the concomitant risk of outbreaks, immunization against this agent on a national scale might be considered. An open clinical trial was conducted in Thai adolescents and young adults in order to establish the immunogenicity and safety of a new inactivated hepatitis A vaccine. At 24-week intervals, two doses (primary dose and booster) of the hepatitis A vaccine (160 antigenic units per dose) were administered to 80 HAV-seronegative healthy volunteers, their ages ranging from 16 to 25 years. Local and systemic reactions were recorded within the first 7 days after each injection. Anti-hepatitis A virus antibody concentrations were measured by a modified radioimmunoassay before and one month after each injection. No serious adverse reactions were reported. Local reactions were confined to transient pain at the injection site, occurring within 24 hours after injection in 42.5% of the subjects after the first dose and 24.1% of the patients after the booster dose. Systemic reactions (particularly asthenia or myalgia) were observed in 35.0% and 8.9% of subjects after the first and the booster injection, respectively. Most of these reactions were transient. One month after the first dose, all 78 formerly seronegative subjects had attained satisfactory seroconversion levels of anti-HAV antibody concentrations (> or = 20 mIU/ml) which they maintained until the booster. The booster dose elicited a 21-fold increase of HAV antibody levels, with a geometric mean titer of 2,964 mIU/ml (95% CI, 2,467-3,560), indicative of long-term protection. This new inactivated hepatitis A vaccine appears to be safe and highly immunogenic upon administration of a primary dose followed by a booster dose after 24 weeks. In countries where socio-economic improvement has postponed hepatitis A infection from early childhood (mostly asymptomatic) towards adolescence and adulthood, with the symptoms increasing in severity, inclusion of inactivated hepatitis A vaccine in a preventive vaccination program might be of benefit.     

Evaluation of a new highly purified pertussis vaccine in infants and children

Purified acellular pertussis vaccine (12.5 micrograms of lymphocytosis promoting factor [LPF] and 12.5 micrograms of filamentous hemagglutinin [FHA]) was compared with conventional pertussis vaccine in a randomized double-blind study involving 40 children aged 4-6 y, 40 children aged 18-24 mo, and 50 infants. Increases in antibody were significantly greater among recipients of acellular vaccine than among recipients of conventional vaccine for antibodies to LPF in all age groups and for antibodies to FHA in infants and children aged 4-6 y; the increase in FHA antibody was also greater with acellular vaccine among children aged 18-24 mo but not significantly so. Compared with conventional vaccine, acellular vaccine was significantly associated with reduced frequency of leg pain and fretfulness at all ages and less frequent fever and anorexia at some ages. The reduced reaction rates and comparable or enhanced immunogenicity of the acellular vaccine make it an attractive candidate for larger field trials, particularly among infants.     

Evaluation in humans of a new, inactivated vaccine for Venezuelan equine encephalitis virus (C-84)

A new, formalin-inactivated vaccine for Venezuelan equine encephalitis (VEE) virus (C-84), prepared from an attenuated vaccine strain of virus (TC-83), was tested in humans. Only occasional, mild, local and systemic reactions were noted in 28 volunteers; no meaningful changes in clinical laboratory values occurred. The vaccine augmented preexisting titers of serum neutralizing antibody to VEE virus in seropositive recipients of TC-83 vaccine, and it induced high titers of neutralizing antibody in nonimmune subjects after one primary and two booster vaccinations. Circulating antibody persisted for at least 14 months in these persons. The neutralizing antibody produced after one dose of C-84 vaccine in immune subjects and after booster doses in nonimmune subjects had broad cross-reactivity within the VEE virus complex. The C-84 vaccine induced a VEE virus-specific lymphocyte transformation response. The vaccine was safe, and immunologic results showed it to be highly antigenic in healthy immune and nomimmune adults.     

Immunity to influenza A virus infection in young children: a comparison of natural infection, live cold-adapted vaccine, and inactivated vaccine

Live attenuated, cold-adapted (ca) influenza A vaccines administered intranasally have been well characterized as safe and immunogenic, but comparative data on protective efficacy are required for further development. In this study, 59 young children were divided into the following four groups based on prior exposure to influenza A (H3N2) virus: natural infection, live ca vaccine given intranasally, inactivated vaccine given im, and no previous exposure. Virus challenge with homologous live ca vaccine occurred 12 months after vaccination or natural infection. Prior natural infection and live ca vaccine significantly reduced ca virus shedding after challenge compared with inactivated vaccine or no prior exposure to influenza A virus. Prechallenge nasal IgA, detected almost exclusively in subjects naturally infected or vaccinated with live ca virus, was associated with protection. Although inactivated vaccine failed to produce significant local IgA during the primary response, it seemed to prime for secondary local antibody responses after challenge with live ca virus.     

Effectiveness of trivalent inactivated influenza vaccine in influenza-related hospitalization in children: a case-control study

Influenza is known to be associated with asthma exacerbation but the effectiveness of the trivalent inactivated flu vaccine (TIV) in children, especially children with asthma, in preventing hospitalization is unknown. We assessed the effectiveness of the TIV in all children and especially children with asthma to prevent hospitalization with influenza. We conducted a nested case control study of all pediatric subjects (6 months to 18 years old) who were evaluated at the Mayo Clinic, Rochester, MN, who had laboratory-confirmed influenza during each flu season from 1999 to 2006 to evaluate the efficacy of TIV in preventing hospitalization. A case-control analysis was performed with the cases and the controls being the subjects who did and did not required hospitalization with the influenza illness, respectively. There were 261 subjects with laboratory-confirmed influenza from 1996 to 2006. There was an overall trend toward higher rates of hospitalization in subjects who got the TIV when compared with the ones who did not get the TIV (odds ratio [OR], 3.67; CI, 1.6, 8.4). Using the Cochran-Mantel-Haenszel test for asthma status stratification, there was a significant association between hospitalization in asthmatic subjects and TIV (p = 0.001). TIV did not provide any protection against hospitalization in pediatric subjects, especially children with asthma. On the contrary, we found a threefold increased risk of hospitalization in subjects who did get the TIV vaccine. This may be a reflection not only of vaccine effectiveness but also the population of children who are more likely to get the vaccine.     

Long-term immunogenicity and safety of an inactivated hepatitis A vaccine in haemophilic patients

Summary. As a consequence of recent outbreaks of HAV infection by blood products, 91 patients, haemophiliacs and subjects with bleeding disorders (10 of whom were also anti-HIV positive) susceptible to HAV infection received a formalin-inactivated hepatitis A vaccine (HAVRIX 720 Elisa Units, SmithKline Beecham). Subcutaneous injections were given in the deltoid region at 0, 1 and 6 months. The seroconversion rates and litres, expressed in GMT IU/1, were determined at 1, 2, 6, 7, 12, 18 and 24 months. No adverse reactions to the vaccine were observed. The highest percentage of responders observed was 98.7% in anti-HIV negative and 71.4% in anti-HIV positive patients. The anti-HAV GMT titres were higher in anti-HIV negative than in anti-HIV positive patients. The inactivated hepatitis A vaccine is safe, clinically well tolerated, and provides long-term protection against HAV infection.     

Immunogenicity, safety, and interchangeability of two inactivated hepatitis A vaccines in Chilean children.

OBJECTIVES: To compare the immunogenicity, safety, and interchangeability of two pediatric hepatitis A vaccines, Avaxim 80U-Pediatric and Havrix 720, in Chilean children. METHODS: In this randomized trial, 332 hepatitis A virus (HAV) seronegative children from 1 to 15 years of age received two doses of Avaxim, two doses of Havrix, or Havrix followed by Avaxim, 6 months apart. Anti-HAV antibody titers were measured before and 14 days after the first dose of vaccine, and before and 28 days after the second dose of vaccine. Immediate reactions were monitored; reactogenicity was evaluated from parental reports. RESULTS: Seroconversion rates after the first vaccination were 99.4% and 100% for Avaxim and Havrix, respectively. Anti-HAV geometric mean concentrations (GMCs) were 138 mIU/ml for Havrix (95% confidence interval (CI): 120; 159) and 311 mIU/ml for Avaxim (95% CI: 274; 353). GMCs increased to 4008 mIU/ml after two doses of Havrix, 8537 mIU/ml following two doses of Avaxim, and 7144 mIU/ml in children who received Havrix with Avaxim as the second dose. Following the first injection, 36% of subjects given Avaxim and 44% given Havrix reported local reactions; 38% of subjects in the Avaxim group and 40% in the Havrix group reported systemic reactions related to vaccination. Solicited reactions were less frequent after the second dose of Avaxim or Havrix, occurring in 27% to 37% of subjects. CONCLUSIONS: No significant difference in seroconversion rates was seen 14 days after a single dose of vaccine. A two-dose schedule with either vaccine or with Havrix/Avaxim provided a strong booster response. Both vaccines were well tolerated and can be recommended for routine vaccination of Chilean children. Avaxim 80 may be used to complete a vaccine schedule begun with Havrix 720.     

Long-term efficacy of plasma-derived hepatitis B vaccine among Chinese children: a 12-year follow-up study

INTRODUCTION To evaluate long-term efficacy of a plasma-derived hepatitis B vaccine and provide evidence for decision-making on the vaccine booster doses, we conducted a prevalent follow-up study to examine serologic changes in hepatitis markers and vaccine efficacy in 350 children from the original cohort of 513 children who participated in a randomized, double-blind and placebo-controlled trial on a plasma-derived hepatitis B vaccine in Longan County, Guangxi Autonomous Region, China, in 1982.