Inactivated hepatitis A vaccine-induced antibodies: follow-up and estimates of long-term persistence

To estimate the long-term persistence of anti-HAV antibodies, 120 (schedule 0-6) and 194 (schedule 0-12) adults were vaccinated and followed-up annually for 6 years. Shortly after the last dose, anti-HAV levels fell sharply (annual decline rate delta > 65%). Thereafter, delta diminished to 10-15%. GMTs 5.5 years after the last dose were 522 mIU/ml (0-6 group) and 749 mIU/ml (0-12 group); all subjects except one maintained detectable antibodies. The average delta over the whole follow-up period was 15-20%, resulting in an estimated persistence of anti-HAV levels > or =20 mIU/ml for 20-25 years. These estimates were similar for both applied calculation methods (GMT or individual based) and both vaccination schedules. Because the individual antibody levels tended to stabilise between the last two measurements, the hypothesis of a slow, log-linear decrease and its matching calculation methods might be subject to reconsideration. With the current methodology, however, detectable antibodies are estimated to persist for 20-25 years.     

Inactivated hepatitis A vaccine: immunogenicity,efficacy, safety and review of official recommendations for use

There is 10 years of marketing experience with the hepatitis A vaccine Havrix. It is highly immunogenic, provides lasting protection in healthy individuals and generates protective levels of antibodies in patients with chronic liver disease or impaired immunity. Postmarketing surveillance data have confirmed the outstanding safety profile of the vaccine. The timing of the booster dose is not critical to effectiveness, which has advantages for the protection of travelers to regions of high endemicity. The vaccine is effective in curbing outbreaks of hepatitis A and also when administered postexposure, due to rapid seroconversion and the long incubation period of the disease. In intermediate endemic regions, an epidemiological shift in hepatitis A infection has driven the development of universal preventive strategies to be added to the targeting of at-risk groups. Existing official recommendations and future directions for vaccine use are reviewed.     

Comparison of long-term systemic and secretory antibody responses in children given live, attenuated, or inactivated influenza A vaccine

A comparison of inactivated intramuscular and live intranasal influenza A vaccines in young children undergoing primary immunization might be expected to show differences in serum and local mucosal antibody responses. To demonstrate such differences, serum and local respiratory tract antibody responses of young children vaccinated with intranasal live, attenuated, cold-adapted (H3N2 or H1N1), or intramuscular inactivated (H3N2) influenza A vaccines were examined for one year after vaccination. Antibody responses were measured by hemagglutination-inhibition (HAI) and class-specific enzyme-linked immunosorbent assay (ELISA). One year after vaccination, live intranasal vaccinees had significantly less decay of serum HAI (p = 0.025) and IgG antibody (p = 0.01) directed against the influenza hemagglutinin and neuraminidase than did intramuscular inactivated vaccinees. Nasal secretory IgA developed almost exclusively in live vaccinees and persisted for up to one year. Persistent nasal secretory IgG was detected in both live and inactivated vaccinees. Live vaccination not only stimulates a more durable serum antibody response, but also induces long-lasting local respiratory tract IgA antibody that may play an important role in host protection.     

国产甲型肝炎灭活疫苗的安全性和免疫原性研究

目的 评价一种国产甲型肝炎（甲肝）灭活疫苗对人体的安全性和免疫原性。方法 为Ⅰ期临床试验。31名对甲肝易感的成年人被随机分为两组,实验组16个,接种国产甲肝灭活疫苗,对照组15人,接种史克必成公司生产的甲肝灭活疫苗。按0、3程序进行接种。国产疫苗剂量为每针1000U／0．5ml,史克疫苗剂量为每针720ELISAU／1ml。观察并比较两种接种后的局部和全身反应以及接种后1、3、4个月血清抗体阳转率和滴率。结果 两组初免和加强接种后个别接种对象表现轻微局部或全身反应,未发现肝功能损害。初次免疫后1个月、3个月和加强后1个月,国产疫苗的抗体阳转率分别为94％,100％和100％;史克疫苗为73％,80％和100％。国产疫苗抗体几何平均滴度分别为139．2mIU/ml、137．7mIU/ml和1066．7mIU/ml;史克必成疫苗分别为104．3mIU/ml、111．3mIU／ml和760．7mIU／ml。结论 国产甲肝灭活疫苗具有良好的安全性和免疫原性。     

Long-term immunogenicity of an inactivated virosome hepatitis A vaccine

The aim of this study was to predict the long-term protection induced after immunisation with inactivated, aluminium-free virosome hepatitis A vaccine. The study population consisted of adult volunteers enrolled in four different clinical trials. Lower 95% confidence interval limits and seroconversion rate were calculated by using a linear mixed model to estimate the persistence of serum antibodies over time. To assess the robustness of the mathematical model, several sensitivity analyses were performed with more conservative protective threshold (20 mIU/ml vs. 10 mIU/ml), higher yearly decline rate, and exclusion of volunteers who had increasing titres over time. Based on 190 volunteers with at least two valid assessments of titres from year 3 onward, the median duration of protection was 55.5 years, with a lower limit of the 95% CI of 48.7 years. Duration below 25.3 years was predicted for only 5% of the subjects. Women tended to have higher titres to start with, but their rate of decline was higher, resulting in similar duration of protection overall. The use of a more conservative threshold, higher yearly decline rate, and exclusion of volunteers with increasing titres over time did not affect these results. According to this model, 95% of the volunteers should have anti-HAV titres above the minimum protective threshold for 20 years or more following immunisation with two doses of this aluminium-free vaccine.     

Reactogenicity, safety and immunogenicity of a recombinant bivaccine against smallpox and hepatitis B in limited clinical trials

The reactogenicity of the embryonic live recombinant variola and hepatitis B bivaccine as tablets (Revax-BT) as well as its safety and immunogenicity were evaluated in clinical trials made in volunteers who had previously immunized or not with variola vaccine. A preliminary conclusion was made on a lack of side effects and drug safety in primary vaccination and been revaccination with low and high doses. Primary immunization of volunteers and as bivaccination with high doses stimulated the most pronounced immune response to the vaccine virus versus such effect observed in immunization of volunteers with low vaccine doses. Humoral immune response to HBs was observed in 75% of volunteers of both groups after as bivaccination. Such response was most pronounced in examinees immunized with low vaccine doses versus those who received high bivaccine doses. At the same time, no protective levels of humoral immunity response to HBs Ag were observed in volunteers first vaccinated.     

Post-transfusion hepatitis: antigen/antibody systems correlated with non-A, non-B hepatitis

In seven patients post-transfusion hepatitis (PTH) was due to non-A, non-B virus(es) (38.9% of all PTH, while 61.1% were due to hepatitis B virus (HBV). No clinical or biochemical differences were observed in non-A, non-B PTH when compared with PTH due to HBV, while incubation period was very ample, from 15 days to nine months (generally 45 days to two months). An antigen/antibody system was shared by five of our patients (their sera showed precipitin lines when assayed by immunodiffusion with known sources of antigen or antibody), while in one patient an antigen/antibody system was detected when onset serum was assayed with self-recovery serum but not when assayed with known sources of antigen and antibodies, nor with sera of the other five patients. Antigen was detected during the first weeks of illness, antibody at recovery, for both systems. The results suggest that there may be at least two antigen/antibody systems correlated to non-A, non-B hepatitis not necessarily linked to incubation period.     

Comparison of two techniques for detecting antibody to HBsAg during a hepatitis B vaccine study

Two assays for the detection of antibody against hepatitis B surface antigen (anti-HBs) were compared. The first was a direct sandwich radioimmunoassay (RIA) which detects, in principle, antibody against any epitope of hepatitis B surface antigen (HBsAg). The second assay was an inhibition enzyme-linked immunosorbent assay (ELISA). In this assay a fixed amount of HBsAg which can be blocked by anti-HBs is measured in a direct sandwich test. Prevaccination screening sera (n = 191) and follow-up sera obtained from high risk groups (n₁ = 85; n₂ = 41) during two hepatitis B vaccine studies were compared in RIA and ELISA. In prevaccination sera either HBsAg or anti-HBs were detected by ELISA. Full agreement between the results of RIA and ELISA for anti-HBs was obtained in sera containing more than 10 IU/1 anti-HBs. Both tests showed variable results at low titres. Experiments with monoclonal anti-HBs indicated that ELISA is less sensitive for subtype specific antibodies (anti-d, anti-y), which may explain that there were consistent differences between RIA and ELISA in a minority of cases.     

Safety and immunogenicity of a recombinant hepatitis B vaccine

A hepatitis B vaccine produced in yeast by recombinant DNA technology was evaluated using 5-micrograms and 10-micrograms doses in a randomized trial lasting 7 months in 110 male armed forces recruits aged 17-19 years. Results were compared to those of an identical trial of a plasma-derived vaccine. No allergic reactions were observed, and the rate of mild side effects was similar to the plasma-derived vaccine. Seroconversion rates in the first month were 60% (33/55) and 67% (37/55) with the 5-micrograms and 10-micrograms doses of the recombinant vaccine, respectively. All participants seroconverted by 3 months, and none lost antibody. These results are very similar to those for plasma-derived vaccine. Comparison of titres of antibody to hepatitis B surface antigen (anti-HBs) showed a slightly higher level with the 10-micrograms than with the 5-micrograms dose of the recombinant vaccine. Geometric mean titres of anti-HBs after the booster dose were similar in the 5-micrograms and 10-micrograms dose recombinant vaccine groups (2,620 and 2,748 IU/l, respectively) and in the 5-micrograms plasma-derived vaccine group (3,591 IU/l) but significantly higher (9,227 IU/l) with the 10-micrograms dose of the plasma-derived vaccine. These results confirm the safety and immunogenicity of the recombinant vaccine, although further study is needed on the duration of immunity.     

A review of the efficacy, immunogenicity and tolerability of a combined hepatitis A and B vaccine

Hepatitis A and B are two of the most common vaccine-preventable liver diseases and continue to be a significant cause of morbidity and mortality worldwide, with their severity related to the individual's age upon initial infection. Twinrix (GlaxoSmithKline), a combined vaccine providing protection against both hepatitis A and B, has been available in more than 72 countries worldwide since 1997. This paper provides a critical review of clinical data on the efficacy, immunogenicity and tolerability of the combined vaccine, with particular focus on the clinical benefits of dual vaccination.     

Cytokine release and dynamics of leukocyte populations after CD3/TCR monoclonal antibody treatment

Cytokine release and clinical side effects resulting from the use of OKT3 and BMA 031 monoclonal antibodies in the treatment of kidney graft recipients were evaluated and compared. The rise observed in serum levels of interferon , TNF, and IL-8 was similar after administration of either monoclonal antibody. Furthermore, both OKT3 and BMA 031 resulted in rapid disappearance not only of virtually all T cells, but also of substantial percentages of all major leukocyte populations from the circulation; this effect is probably due to cytokine release activating endothelial cells and thereby causing extravasation even of leukocytes not specifically recognized by the administered antibodies. Evidence has thus been obtained that BMA 031 is as potent as OKT3 in inducing unequivocal signs of T cell activationin vivo. However, while OKT3 therapy was accompanied by adverse side effects in our study as in previous ones, we saw no such reactions in any of the patients receiving BMA 031. This contrast might be due to different mechanisms of leukocyte activation possibly inducing other mediators in the case of OKT3, which then, in combination with the cytokines, could generate treatment-associated morbidity.     

Single dose inactivated hepatitis A vaccine: Rationale and clinical assessment of the safety and immunogenicity

In comparison with the classical immunisation schedules (0-1-6 or 0-1-12 months) for hepatitis A, a 0- and 12- or a 0- and 6-month schedule would have important advantages by reducing the number of injections and discomfort and increasing scheduling convenience and patient compliance. It would be convenient if a single dose with enough antigen could protect both rapidly and for at least 12 months, when the booster dose would be given. Several clinical trials have been carried out with an inactivated hepatitis A vaccine containing 1,440 ELU. (1 ml), according to a 0–12 and a 0–6 vaccination schedule. This hepatitis A vaccine is safe and well tolerated. It offers a rapid seroresponse: 14 days after a single dose the seroconversion is 88% (95% C.I.: 84.6–90.9). The 0–12 schedule study showed good persistence of hepatitis A virus (HAV) antibodies with a seroconversion rate of almost 95% at month 12. Booster doses given at 6 or 12 months result in a substantial rise in antibody levels; according to these antibody litres, the 1,440 EL. U. vaccine can be expected to confer comparable duration of protection as the 720 EL. U. vaccine, i.e., 10–20 years. Preliminary data show that tinning of the booster may not be critical for the antibody response. In conclusion, the 1,440 EL. U. hepatitis A vaccine is safe, offers rapid seroconversion, and is highly immunogenic. The persistence of HAV antibodies until month 12 allows a certain flexibility in the administration of the booster: month 6 or 12, and a 0–12 or 0–6 schedule can increase the vaccination compliance. copy; 1994 Wiiey-Liss, inc.     

Antibody persistence and immune memory in healthy adults following vaccination with a two-dose inactivated hepatitis A vaccine: long-term follow-up at 15 years

Long‐term persistence of vaccine‐induced immune response in adults was assessed annually for 15 years following primary immunization with a two‐dose inactivated hepatitis A vaccine. In 1992, 119 and 194 subjects aged 17–40 years and naïve for hepatitis A virus (HAV) were enrolled in two studies to receive 1,440 ELISA units (El.U) of inactivated hepatitis A vaccine (Havrix?, GlaxoSmithKline Biologicals, Belgium) according to a standard 0, 6 or an extended 0, 12 months schedule, respectively. Serum samples were taken 1 month after the second vaccine dose and every consecutive year up to 15 years after primary vaccination for measurement of anti‐HAV antibody concentrations (NCT00291876 and NCT00289757). At year 15, 100% (48/48) and 97.3% (108/111) of subjects vaccinated at 0, 6 or 0, 12 months remained seropositive for anti‐HAV antibodies, with geometric mean concentrations (GMCs) of 289.2 and 367.4 mIU/ml, respectively. An additional dose of HAV vaccine (1,440 El.U) was administered to the six subjects who had become seronegative for anti‐HAV antibodies since year 11. All subjects mounted a humoral immune response to the additional HAV challenge dose, although post‐challenge anti‐HAV antibody levels remained low in one subject. These studies represent the longest annual follow‐up of hepatitis A vaccine in healthy adults. The immune response induced by two doses of this inactivated HAV vaccine was shown to persist for at least 15 years. No difference in long‐term antibody persistence was observed between the two primary vaccination schedules, reinforcing the potential for flexibility in the timing of the second primary vaccine dose. J. Med. Virol. 83:1885–1891, 2011. © 2011 Wiley‐Liss, Inc.     

抗吗啡疫苗抗体的制备及其特性鉴定

目的制备高效价的抗吗啡疫苗的抗体,并对其特性进行鉴定。方法将人工合成的6-琥珀酰吗啡(M-6-S)与BSA在pH9.0碳酸盐缓冲液中交联成M-6-S-BSA。经凝胶柱过滤和硫酸铵法纯化后,用两种不同方案免疫BALB/c小鼠和SD大鼠,用ELISA法和中和抑制试验分别测定抗体的滴度和进行特异性鉴定;用辐射热甩尾(TF)反射试验检测M-6-S-BSA疫苗的免疫效果。结果用合成的M-6-S-BSA疫苗连续免疫小鼠8次,所获抗血清的效价可达1∶200000,大鼠免疫4次后抗血清的效价超过1∶20000。中和抑制试验表明,抗M-6-S抗体对吗啡和与吗啡有共同母环结构的6-单乙酰吗啡、海洛因及可待因具有较高的特异性。免疫大鼠腹腔注射2mg/kg的吗啡后,其甩尾(TF)反射受到明显抑制,最大效应百分率(%MPE)减少了74.7%,TF潜伏期回到基线水平的时间明显快于对照组。结论成功地制备M-6-S-BSA疫苗,用其免疫小鼠和大鼠均可产生高滴度和特异性抗吗啡抗体。该抗体可明显减低大鼠对吗啡的抗伤害感受,为进一步研究吗啡疫苗抗体对抗吗啡的成瘾作用奠定了基础。     

Comparative study of the reactivity, safety and immunogenicity of "Havrix" inactivated hepatitis A vaccine

This paper sums up the results of controlled field clinical trials of adult and childhood variants of Harvix, inactivated vaccine from hepatitis A. The vaccine is weakly reactogenic and safe. After a single injection of Harvix-1440 vaccine to adults the percentage of seroconversions in previously seronegative individuals was 80.6%, with the mean geometrical antibody titer 119 mIU/ml. In children aged 3-10 years the percentage of seroconversions after a single injection of Harvix-720 vaccine was 100%, the mean geometrical of antibody titer being 427 mIU/ml. Results of laboratory control and field clinical trials recommend both variants of Harvix vaccine for prevention of hepatitis A in the Russian Federation.     

Safety and immunogenicity of inactivated hepatitis A vaccine in patients with chronic liver disease

The safety and immunogenicity of inactivated hepatitis A vaccine was evaluated in patients with chronic liver disease. Sixty hepatitis A virus antibody (anti-HAV) seronegative patients A virus antibody (anti-HAV) seronegative patients with chronic liver disease (56 chronic hepatitis B and four chronic hepatitis C) and from 17 to 47 years of age received a dose of 1440 ELISA units of the inactivated hepatitis A vaccine at month 0, and a booster at month 6. Anti-HAV seroconversion (⩾ 33 mlU/mL) was 57.6% (34/59) on day 15, and reached 93.2% (55/59) 1 month after primary vaccination. At month 6, the seropositivity of anti-HAV decreased before the booster to 69.0% (40/58). All vaccinees had measurable titers of anti-HAV 1 month after booster vaccination, and were still seropositive at month 12. After initial vaccination, the geometric mean titers of anti-HAV among vaccine responders were 158, 264, 74, 1309, and 409 mlU/ml at day 15 and months 1, 6, 7, and 12. Overall, 59.7% (71/119) of the vaccine doses administered were followed by mostly minor reactions. The majority of symptoms reported were local, all of which resolved within 3 days after vaccination. No significant changes in serum liver enzyme levels were detected after vaccination. Thus, an inactivated hepatitis A vaccine was safe in patients with chronic liver disease while the immune response was inferior to that observed in healthy subjects reported in a previous study. J. Med. Virol. 52:215–218, 1997. © 1997 Wiley-Liss, Inc.     

Reactivity and immunogenicity of Engerix B, the recombinant DNA vaccine against hepatitis B

A group of 67 health workers with no markers indicating previous hepatitis B infection were vaccinated against hepatitis B with a new DNA recombinant vaccine, Engerix B (commercially manufactured by Smith-Kline-RIT, Belgium). Three injections were given according to the 0-1-6 schedule. One month after the last injection the vaccinees were tested for anti-HBs antibodies by the enzyme-linked assay. Antibody titers equal or less than 10 mIU/ml were found only in three subjects or in 4.5% of them. Titers ranging from 11 to 99 mIU/ml were found in 7 subjects (10.4%), from 100 to 999 mIU/ml in 28 (41.8%) and those equal or more than 1000 mIU/ml in 29 subjects (43.3%). It is inferred that the seroconversion rate is 95.5%. Only one subject did not develop detectable antibodies but three subjects had titers over 10000 mIU/ml. No one developed overt hepatitis B during the trial nor did the high responders experienced inapparent infections. They were tested for anti HBc with negative results. Postvaccinal reactions were mild and almost exclusively local. There were no complications. For its high immunogenicity and acceptable reactogenicity the Engerix B vaccine has a promising future.     

Recombinant-yeast-derived hepatitis B vaccine in healthy adults: safety and two-year immunogenicity of early investigative lots of vaccine

We tested the safety and long-term immunogenicity of two of the early investigative lots of a recombinant-yeast-derived hepatitis B vaccine in immunocompetent adults. Three 10-micrograms doses of recombinant hepatitis B vaccine (Merck Sharp & Dohme Research Laboratories, West Point, PA) were administered by deltoid intramuscular injection at time 0, 1, and 6 months to 65 seronegative adult health workers. Following a complete three-injection course, 98% of vaccinees acquired anti-HBs, 97% at levels greater than 10 mlU/ml, and 95% maintained such "protective" antibody levels at 1 year. At 2 years, 93% retained antibody, but only 68% had levels greater than 10 mlU/ml. In those who responded to vaccination by achieving any detectable level of antibody, the peak geometric mean titer of anti-HBs, measured at 9 months, was 741 +/- 6 mlU/ml; the geometric mean titer fell to 348 +/- 6 at 1 year and to 66 +/- 7 at 2 years. Side effects were trivial, and levels of yeast antibody, as measured by radioimmunoassay, were not changed from prevaccine levels. No serious adverse effects were encountered, and neither type B nor non-B hepatitis occurred in any vaccine. These findings demonstrate that the recombinant yeast hepatitis B vaccine is safe and immunogenic but that 10 micrograms of the early investigative lots of the recombinant vaccine is less immunogenic than 20 micrograms of the plasma-derived vaccine. Recipients of early investigative vaccine lots should be considered for booster vaccination with currently available, more immunogenic vaccine lots.     

Ad5-nCoV booster and Omicron variant breakthrough infection following two doses of inactivated vaccine elicit comparable antibody levels against Omicron variants

Little information is available for antibody levels against SARS-CoV-2 variants of concern induced by Omicron breakthrough infection and a third booster with an inactivated vaccine (InV) or Ad5-nCoV in people with completion of two InV doses. Plasma was collected from InV pre-vaccinated Omicron-infected patients (OIPs), unvaccinated OIPs between 0 and 22 days, and healthy donors (HDs) 14 days or 6 months after the second doses of an InV and 14 days after a homogenous booster or heterologous booster of Ad5-nCoV. Anti-Wuhan-, Anti-Delta-, and Anti-Omicron-receptor binding domain (RBD)-IgG titers were detected using enzyme-linked immunosorbent assay. InV pre-vaccinated OIPs had higher anti-Wuhan-, anti-Delta-, and anti-Omicron-RBD-IgG titers compared to unvaccinated OIPs. Anti-Wuhan-RBD-IgG titers sharply increased in InV pre-vaccinated OIPs 0–5 days postinfection (DPI), while the geometric mean titers (GMTs) of anti-Delta- and anti-Omicron-RBD-IgG were 3.3-fold and 12.0-fold lower. Then, the GMT of anti-Delta- and anti-Omicron-RBD-IgG increased to 35 112 and 28 186 during 11–22 DPI, about 2.6-fold and 3.2-fold lower, respectively, than the anti-Wuhan-RBD-IgG titer. The anti-Wuhan-, anti-Delta-, and anti-Omicron-RBD-IgG titers declined over time in HDs after two doses of an InV, with 25.2-fold, 5.6-fold, and 4.5-fold declination, respectively, at 6 months relative to the titers at 14 days after the second vaccination. Anti-Wuhan-, anti-Delta-, and anti-Omicron-RBD-IgG titers elicited by a heterologous Ad5-nCoV booster were significantly higher than those elicited by an InV booster, comparable to those in InV pre-vaccinated OIPs. InV and Ad5-nCoV boosters could improve humoral immunity against Omicron variants. Of these, the Ad5-nCoV booster is a better alternative.