Immunogenicity Persistence Research Articles

Enterovirus 71: a whole virion inactivated enterovirus 71 vaccine

ABSTRACTIntroduction: Enterovirus A71 (EV71) is the predominant causative agent of hand, foot, and mouth disease (HFMD), which is often associated with severe cases and even deaths. EV71-associated epidemics have emerged as a serious threat to public health, particularly in the Asia-Pacific region.Areas covered: We searched PubMed using the terms ‘enterovirus 71’, ‘hand, foot, and mouth disease’, and ‘vaccine’, with no date or language restrictions for all publications before April 27, 2016. Among various vaccine candidates, the alum-adjuvant inactivated EV71 vaccines are most promising. Three alum-adjuvant inactivated EV71 vaccines developed by mainland China showed high efficacy, good immunogenicity persistence and acceptable safety profiles in clinical trials. Recently, two of these EV71 vaccines have been approved for marketing in China and the other one is undergoing the review process of licensure. In this manuscript, we summarized previous study results as well as discussed the regulatory affairs and post-market surveillances issues.Expert commentary: The marketing of EV71 vaccines is a milestone in the controlling of HFMD. International clinical trials are needed to further assess the efficacy and cross-immunogenicity. Establishing a sensitive pathogen monitoring system would be essential to monitor the variation of genotypes and control HFMD epidemics.

Comparison of two-dose priming plus 9-month booster with a standard three-dose priming schedule for a ten-valent pneumococcal conjugate vaccine in Nepalese infants: a randomised, controlled, open-label, non-inferiority trial

Use of pneumococcal conjugate vaccines (PCVs) in resource-poor countries has focused on early infant immunisation with little emphasis on protection in late infancy and beyond. Boosting of the immune response later in infancy might provide improved persistence of immunogenicity into early childhood, however data are scarce. The aim of this study was to investigate if a two-dose prime with booster at age 9 months compared with a three-dose prime-only PCV schedule provided non-inferior immunogenicity in early infancy and superior persistence of antibody responses in early childhood. We did an open-label, randomised, parallel group, controlled trial in healthy infants aged 40-60 days from Kathmandu, Nepal. Participants were randomly allocated (4:4:5 ratio) to receive PCV10 in addition to routine immunisations either as a two-dose prime and boost (2+1), three-dose prime (3+0), or two doses after completion of the initial study phase (0+2). We used a computer generated randomisation list with randomly varying block sizes. We followed up participants at age 2-4 years together with a group of unvaccinated controls. Sera were analysed for opsonophagocytic activity, protein D, and PCV10 serotype-specific IgG. Laboratory staff was masked to intervention group assignment. The primary outcome measure was to determine the proportion of participants in the 2+1 group at age 10 months with specific IgG for serotypes 1, 5, and 14 of at least 0·2 μg/mL in the per-protocol population. The secondary outcomes were non-inferiority (within 10% levels) at age 18 weeks for the proportion of participants in the 2+1 group compared with the 3+0 group with serotypes 1, 5, and 14 specific IgG of at least 0·2 μg/mL; the proportion of participants with PCV10 serotype-specific IgG of at least 0·2 μg/mL and opsonophagocytic activity reciprocal titre of at least 8 at ages 18 weeks and 10 months; and nasopharyngeal pneumococcal serotype-specific carriage rates at age 9 months in each study group. In the follow-up study, the primary outcome measure was the proportion of participants with IgG of at least 0·2 μg/mL for PCV10 serotypes at age 2-4 years in children previously immunised with a 3+0 schedule compared with a 2+1 schedule. The trial is registered with Current Controlled Trials, registration number ISRCTN56766232. Between May 10, 2010, and Jan 7, 2011, 390 children were randomly assigned to each group: 119 to the 2+1 group, 120 to the 3+0 group, and 151 to the 0+2 group. At age 10 months, the proportions of 2+1 participants with IgG of at least 0·2 μg/mL were 99·0% (95% CI 94·2-100·0) for serotype 1, 100% (96·2-100·0) for serotype 5, and 97·9% (92·5-99·7) for serotype 14. At age 18 weeks, non-inferiority (within 10% levels) of the 2+1 group was shown compared with the 3+0 group, and there was no difference between the 2+1 and 3+0 groups for the proportion with IgG of at least 0·2 μg/mL for any of the PCV10 serotypes. At age 10 months, proportions with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 23F, were higher in the 2+1 group than in the 3+0 group. At age 18 weeks, there were no differences in opsonophagocytic activity between the 2+1 and 3+0 groups for reciprocal titres of at least 8, but at age 10 months, proportions with an opsonophagocytic reciprocal titre of at least 8 for serotypes 1, 4, 5, 6B, 18C, 19F and 23F were higher in the 2+1 group than in the 3+0 group. At age 2-4 years, there were higher proportions in the 2+1 group versus the 3+0 group with IgG of at least 0·2 μg/mL for serotypes 1, 5, 6B, and 18C. Use of a 2+1 PCV schedule with booster at age 9 months in a resource-poor setting improved antibody persistence through early childhood without compromising antibody responses in early infancy. This schedule is now recommended by WHO for progressive introduction across Nepal, with PCV10 introduction having commenced on Jan 18, 2015. Concurrent pre-implementation and post-implementation surveillance is being done by a GAVI Alliance funded study. This study was supported by funding from the National Institute for Public Health and the Environment, The Netherlands; Oxford Vaccine Group, University of Oxford, UK; and GlaxoSmithKline Biologicals, Belgium.

Persistence of immune responses to the HPV-16/18 AS04-adjuvanted vaccine in women aged 15-55 years and first-time modelling of antibody responses in mature women: results from an open-label 6-year follow-up study.

ObjectiveEvaluation of the long-term HPV-16/18 AS04-adjuvanted vaccine immunogenicity persistence in women.DesignMulticentre, open-label, long-term follow-up (NCT00947115) of a primary phase–III study (NCT00196937).SettingSix centres in Germany and Poland.Population488 healthy women (aged 15–55 years, age-stratified into groups: 15–25, 26–45, and 46–55 years) who received three vaccine doses in the primary study.MethodsImmune responses were evaluated in serum and cervicovaginal secretion (CVS) samples 6 years after dose 1. Anti-HPV-16/18 geometric mean titres (GMTs) were measured by enzyme-linked immunosorbent assay (ELISA), and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) were recorded.Main outcome measuresAnti-HPV-16/18 seropositivity rates and GMTs 6 years after dose 1.ResultsAt 6 years after dose 1, all women were seropositive for anti-HPV–16 and ≥97% were seropositive for anti-HPV–18 antibodies. GMTs ranged from 277.7 to 1344.6 EU/ml, and from 97.6 to 438.2 EU/ml, for anti-HPV–16 and anti-HPV–18, respectively. In all age groups, GMTs were higher (anti-HPV–16, 9.3–45.1-fold; anti-HPV–18, 4.3–19.4-fold) than levels associated with natural infection (29.8 EU/ml). A strong correlation between serum and CVS anti-HPV-16/18 levels was observed, with correlation coefficients of 0.81–0.96 (anti-HPV–16) and 0.69–0.84 (anti-HPV–18). Exploratory modelling based on the 6–year data predicted vaccine-induced anti-HPV-16/18 levels above natural infection levels for at least 20 years, except for anti-HPV–18 in the older age group (piecewise model). One vaccine-related and two fatal SAEs were reported.ConclusionsAt 6 years after vaccination, immune responses induced by the HPV-16/18 AS04-adjuvanted vaccine were sustained in all age groups.

Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine

HPV-023 (NCT00518336; ClinicalTrial.gov) is a long-term follow-up of an initial double-blind, randomized (1:1), placebo-controlled study (HPV-001, NCT00689741) evaluating the efficacy against human papillomavirus (HPV)-16/18 infection and associated cyto-histopathological abnormalities, persistence of immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine. Among the women, aged 15–25 years, enrolled in HPV-001 and who participated in the follow-up study HPV-007 (NCT00120848), a subset of 437 women from five Brazilian centers participated in this 36-month long-term follow-up (HPV-023) for a total of 113 months (9.4 years). During HPV-023, anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay (ELISA) and pseudovirion-based neutralisation assay (PBNA). Cervical samples were tested for HPV DNA every 6 months, and cyto-pathological examinations were performed annually. During HPV-023, no new HPV-16/18-associated infections and cyto-histopathological abnormalities occurred in the vaccine group. Vaccine efficacy (VE) against HPV-16/18 incident infection was 100% (95%CI: 66.1, 100). Over the 113 months (9.4 years), VE was 95.6% (86.2, 99.1; 3/50 cases in vaccine and placebo groups, respectively) against incident infection, 100% (84·1, 100; 0/21) against 6-month persistent infection (PI); 100% (61·4, 100; 0/10) against 12-month PI; 97·1% (82.5, 99.9; 1/30) against ≥ ASC-US; 95·0% (68.0, 99.9; 1/18) against ≥ LSIL; 100% (45.2, 100; 0/8) against CIN1+; and 100% (–128.1, 100; 0/3) against CIN2+ associated with HPV-16/18. All vaccinees remained seropositive to HPV-16/18, with antibody titers remaining several folds above natural infection levels, as measured by ELISA and PBNA. There were no safety concerns. To date, these data represent the longest follow-up reported for a licensed HPV vaccine.

Persistence of immunogenicity of a monovalent influenza virus A/H1N1 2009 vaccine in healthy volunteers.

After WHO declared H1N1 pandemic, global vaccination was carried out immediately after much research. However, the data on long-term immunogenicity were lacking. We aimed to investigate the long-term immunogenicity of different H1N1 vaccine dosage groups 24 weeks after vaccination by a randomized clinical trial. A total of 218 participants were stratified into adult (≤60 years old) and elderly (>60 years old) groups. The adults were randomized in a 1:1:1 ratio. The first group received a single dose of vaccine with 15 μg hemagglutination antigen (HA). The other two groups received two doses with 15 μg or 30 μg HA triweekly. The elderly were randomized 1:1 for two doses of 15 or 30 μg HA. We evaluated serologic responses at prevaccination and weeks 3, 6, and 24. We also examined possible associated factors of immunogenicity by multivariate logistic regression analyses. At week 24, seroprotection (anti-HA antibody level ≥ 1:40) remained at 76.8% and 46.2% in the adult and elderly groups, respectively. The adult group had a higher seroprotection rate (odds ratio of 2.98, 95% confidence interval [CI]: 1.21 to 7.36) than the elderly group. There was no statistical difference in seroprotection and seroconversion rates between different adult and elderly dosage groups. Lower immunogenicity in the elderly than in the adults 24 weeks after the vaccination was observed. However, there was no statistically significant difference among different dose groups. Therefore, we suggest only a single vaccination dose of 15 μg HA for adults and two doses of 15 μg HA for the elderly in the future.

A novel mammalian cell-culture technique for consistent production of a well-tolerated and immunogenic trivalent subunit influenza vaccine

Conventional influenza vaccine production methods have limitations due to their reliance on chicken eggs. We evaluated whether a mammalian cell-culture system could reliably produce an influenza vaccine with favourable tolerability and immunogenicity profiles. Adult subjects ( n = 1200; 18–60 years of age) were randomized (2:2:2:1) to receive either one of three lots of a cell-culture-derived influenza vaccine (CCIV) or an egg-based trivalent inactivated influenza vaccine (TIV). Safety and reactogenicity were assessed using solicited indicators for 7 days post-vaccination, all other adverse events (AEs) were recorded for 21 days post-vaccination, and all serious AEs and AEs necessitating a physician's visit, and/or resulting in subject's withdrawal from the study, were collected for up to 6 months post-vaccination. Antibody titres were measured by haemagglutination inhibition (HI) assay using egg-based viral antigens. All three lots of CCIV had similar safety and tolerability profiles, analogous to those of the TIV. Lot-to-lot consistency was statistically demonstrated through bioequivalence for immunogenicity. Antibody titres assessed at 6 months demonstrated good persistence. This Phase III trial is the first to demonstrate lot-to-lot bioequivalence of a CCIV and persistence of immunogenicity in comparison with a TIV.

Long-term follow-up of hepatitis B vaccination in susceptible hospital personnel

Two hundred and sixty-seven susceptible hospital personnel who had been randomly divided into three groups to receive different doses (5 micrograms, 2 micrograms or 1 microgram) of a plasma-derived hepatitis B vaccine on a four-dose schedule were investigated annually for 4 years. Of them, 251 were vaccine responders. The percentages of persistence of antibody to hepatitis B surface antigen (anti-HBs) in these 3 groups were 95.5% (84/88), 92.3% (72/78) and 95.3% (81/85), respectively (P greater than 0.05). During the follow-up period, 12 of 21 (57.1%) responders with low anti-HBs titres (10-100 miu/mL) and 3 of 48 (6.3%) responders with medium anti-HBs titres (101-1000 miu/mL) were found to be anti-HBs seronegative, while none of the 182 candidates with high anti-HBs levels (greater than 1000 miu/mL) lost their anti-HBs. The 4 year cumulative rate of natural booster in the responders was 11.6% (29/251). None of the candidates became HBsAg positive during the follow-up period. This study revealed that low dose hepatitis B vaccine can provide satisfactory immunogenic response and long-term efficacy in Chinese adults and that the persistence of immunogenicity is not related to the vaccine dose but to the candidate's own initial anti-HBs response.

Persistence of immunogenicity of antigen after uptake by macrophages.

Peritoneal macrophages were cultured for several hours after uptake of (131)I-hemocyanin. The cells degraded most of the (131)I-labeled protein within 2-5 hr. Their ability to prime lymphocytes of syngeneic mice for a secondary immune challenge remained unchanged for long periods of time despite the loss of more than 90% of the original content of antigen. The persistence of immunogenicity was associated with a small percentage of antigen retained by the cell in a form which was protected from rapid breakdown and elimination.

Role of Macrophages in Antibody Production

Summary The present studies are concerned with the role of macrophages in antibody production to sheep red blood cells (SRBC). Intact thioglycollate (TG)-induced SRBC-containing peritoneal cells elicited antibodies in normal syngeneic recipient mice but not in irradiated mice. This suggests the release of immunogens by the antigen-carrying macrophages, inducing an immunologic response with kinetics similar to that after injection of non-phagocytized SRBC. Simultaneous administration of 15 million TG-induced peritoneal cells and SRBC did not decrease the immunogenicity of the SRBC. These results suggest that macrophages are not merely “scavenger” cells, and that the macrophage does not play a negative role in the immunization process. Mice exposed to SRBC 5 days after injection of TG, when their internal production of macrophages was maximal, exhibited an impaired immune response to threshold doses of SRBC. The significance of these results was discussed. Comparison of the persistence of immunogenicity of intracellular SRBC in vitro and in vivo suggests that the sharp decrease in immunogenicity in vitro is unphysiological.