Immunogenicity Persistence Research Articles

Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial

Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16-65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4-91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.

Comparison of the safety and persistence of immunogenicity of bivalent HPV16/18 vaccine in healthy 9–14-year-old and 18–26-year-old Chinese females: A randomized, double-blind, non-inferiority clinical trial

BackgroundWe assessed the safety, immunogenicity and antibody persistence of two- and three-dose schedules of the novel bivalent HPV16/18 vaccine (HPV-2, Walrinvax) in the per-protocol target population of initially seronegative 9–14 year-old girls, including a non-inferiority comparison with the three-dose schedule in 18–26 year-old women. MethodsThis randomized phase 3b trial in Guangxi Zhuang Autonomous Region, China, involved healthy Chinese females in two age cohorts; 600 girls aged 9–14 years and 300 women aged 18–26 years. Girls were randomly assigned (1:1) to receive either two (Months 0,6) or three (Months 0,2,6) intramuscular doses of HPV-2. All participants were monitored for immunogenicity as neutralizing antibodies up to 36 months. Primary objectives were non-inferiority analyses of immunogenicity between two- and three-dose girl groups and adult women at Month 7; safety assessments were based on participant-completed diary cards. ResultsAll groups demonstrated marked increases in neutralizing antibodies against HPV 16 and 18 that persisted above baseline to 36 months. Month 7 responses in both girl groups were non-inferior to those in the women and were statistically higher after two-doses than girls or women who received three doses. GMTs waned after month 7, but then maintained a plateau level until month 36. Vaccination was well tolerated in all groups with no serious adverse events reported. ConclusionsImmune responses to two doses of HPV-2 vaccine in adolescent girls were non-inferior to those after three doses in young women, an age cohort in which clinical efficacy of HPV-2 against cervical cancer has been demonstrated.

Immunogenicity persistence of hepatitis A vaccines Healive® and Havrix® among children:15 years follow-up and long-term prediction

ABSTRACT Healive® was the only Chinese WHO-prequalified inactivated vaccine for the hepatitis A virus, which has been widely used in national immunization programs in China. Long-term follow-up studies are needed to estimate the persistence of vaccine-induced antibody levels and the necessity for booster vaccines. During the trial, geometric mean concentrations (GMCs) and seroconversion rates (SRs) of anti-HAV antibodies were compared based on two different inactivated hepatitis A vaccines, Healive® and Havrix®. Four hundred children were randomly assigned to receive two doses of Healive® or Havrix® at 0 and 6 months. The current study assessed antibody persistence for both vaccines 15 years post-immunization. A mixed linear model was used to predict long-term antibody persistence. The GMCs were significantly higher for Healive® compared to Havrix® at 1, 6, 7, 66, 138 months (P < .001) and 186 months (P = .004 < .05) post-vaccination. Healive® and Havrix® reached a GMC of 164.8 mIU/ml and 105.7 mIU/ml post-15 years of vaccination, respectively. The seroconversion rates of both vaccines showed no statistically significant differences (97.9% for Healive® and 94.7% for Havrix®, P = .20). The prediction showed that Healive® would provide protection for a minimum of 30 years following immunization, with a lower limit of the 95% confidence intervals for GMCs greater than 20mIU/mL. Compared to Havrix®, the vaccine Healive® showed a stronger protective effect and better persistence among children at 15 years post-full immunization. Prediction indicated at least 30 years of antibody persistence for Healive® and at least 25 years for Havrix®.

Antibody response to the COVID-19 ChAdOx1nCov-19 and BNT162b vaccines after temporary suspension of DMARD therapy in immune-mediated inflammatory disease: an extension study (RESCUE 2)

The persistence of immunogenicity in patients with immune-mediated inflammatory diseases (IMID) on disease-modifying antirheumatic therapy (DMARD) has been less well studied. This extension study evaluates the SARS-CoV2 antibody decay kinetics...

114. Long-term Protection Against Herpes Zoster (HZ) by the Adjuvanted Recombinant Zoster Vaccine (RZV): Interim Efficacy, Immuno and Safety Results at Approximately 10 Years after Initial Vaccination

Abstract Background For the first time, we present data describing vaccine efficacy (VE), immunogenicity persistence and safety up to approximately 10 years after primary vaccination against HZ with RZV. We have previously shown that RZV demonstrated high VE against HZ in adults ≥ 50 years of age (YOA) participating in 2 phase 3 clinical trials (ZOE-50, NCT01165177 and ZOE-70, NCT01165229), and VE persisted up to year (Y) 2 in the interim analysis of the extension study (ZOSTER-049, NCT02723773). Here we describe the interim analysis for Y4 of the extension study. Understanding the persistence of VE and long-term protection against HZ can help to optimize the use of RZV in adults ≥ 50 YOA. Methods The study design is detailed in Figure 1. Primary objective included VE against HZ over the ZOSTER-049 study. Secondary objectives included VE against HZ from 1 month post-dose 2 in the ZOE-50/-70 studies until the end of Y4 of ZOSTER-049 (Y10 after vaccination), persistence of vaccine-induced humoral immunogenicity (HI) in terms of anti-glycoprotein E (gE) antibody and cell-mediated immune (CMI) response in terms of frequency of gE-specific CD4[2+] T-cells and safety. VE analysis for ZOSTER-049 used historical control estimates from the ZOE-50/-70 placebo groups. Results In ZOSTER-049, 7,413 participants were enrolled and 7,277 were included in VE analysis (Figure 2). During 4 years of follow-up in ZOSTER-049, overall VE against HZ was 81.6% (95% confidence interval [CI]: 75.2–86.6). From 1 month post-dose 2 in ZOE-50/-70 until Y4 of ZOSTER-049, the overall VE was 89.0% (95% CI: 85.6–91.3). In ZOSTER-049, anti-gE antibody concentrations persisted &amp;gt; 5 times above pre-vaccination up to Y10 after vaccination (Figure 3A). The frequency of gE-specific CD4[2+] T-cells remained above pre-vaccination from Y6 to Y10 after vaccination (until the end of Y4 of ZOSTER-049) (Figure 3B). No safety signals were identified until the end of Y4 of ZOSTER-049. Conclusion Efficacy against HZ and immune responses to RZV remained high until the end of the observation period for this Y4 interim analysis suggesting that the clinical benefit of the RZV in adults ≥ 50 YOA is sustained for at least 10 years after vaccination. RZV safety profile remained clinically acceptable. Funding GlaxoSmithKline Biologicals SA Disclosures Ana Strezova, MD, MSc, GSK: I am an employee of GSK group of companies and hold shares from GSK group of companies as part of my employee remuneration Javier Diez-Domingo, MD, PhD, GSK: Grant/Research Support|GSK: Honoraria|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: Consulting fees to the author and his institution|SANOFI: Advisor/Consultant|SANOFI: Grant/Research Support|SANOFI PASTEUR: Consulting fees to the author and his institution|SEQIRUS: Honoraria|SEQIRUS: Honoraria to the author and his institution Kamal Al Shawafi, MD, Modis: I am an employee of Modis, working on behalf of the GSK group of companies Juan Carlos Tinoco, MD, GSK: Grant/Research Support Meng Shi, MS, GSK: I am an employee of GSK group of companies Paola Pirrotta, n/a, GSK: I am an employee of GSK group of companies and hold shares from GSK group of companies as part of my employee remuneration Agnes Mwakingwe-Omari, MD/PhD, GSK: I am an employee of GSK group of companies.

Persistence of immunity against Omicron BA.1 and BA.2 variants following homologous and heterologous COVID-19 booster vaccines in healthy adults after a two-dose AZD1222 vaccination

ObjectivesThe SARS-CoV-2 Omicron variant presents numerous mutations potentially able to evade neutralizing antibodies (NAbs) elicited by COVID-19 vaccines. Therefore, this study aimed to provide evidence on a heterologous booster strategy to overcome the waning immunity against Omicron variants. MethodsParticipants who completed the Oxford/AstraZeneca (hereafter AZD1222) vaccine dose for 5-7 months were enrolled. The reactogenicity and persistence of immunogenicity in both humoral and cellular response after a homologous or heterologous booster with the AZD1222 and messenger RNA (mRNA) vaccines (BNT162b2, full, or half-dose mRNA-1273) administered 6 months after primary vaccination were determined. ResultsA total of 229 individuals enrolled, and waning of immunity was observed 5-7 months after the AZD1222-primed vaccinations. Total receptor-binding domain (RBD) immunoglobulin (Ig) levels, anti-RBD IgG, and focus reduction neutralization test against Omicron BA.1 and BA.2 variants and T cell response peaked at 14-28 days after booster vaccination. Both the full and half dose of mRNA-1273 induced the highest response, followed by BNT162b2 and AZD1222. At 90 days, the persistence of immunogenicity was observed among all mRNA-boosted individuals. Adverse events were acceptable for all vaccines. ConclusionA heterologous mRNA booster provided a significantly superior boost of binding and NAbs levels against the Omicron variant compared with a homologous booster in individuals with AZD1222-primed vaccinations.

Persistence of immunity and impact of third dose of inactivated COVID-19 vaccine against emerging variants

This is a comprehensive report on immunogenicity of COVAXIN® booster dose against ancestral and Variants of Concern (VOCs) up to 12 months. It is well known that neutralizing antibodies induced by COVID-19 vaccines wane within 6 months of vaccination leading to questions on the effectiveness of two-dose vaccination against breakthrough infections. Therefore, we assessed the persistence of immunogenicity up to 6 months after a two or three-dose with BBV152 and the safety of a booster dose in an ongoing phase 2, double-blind, randomized controlled trial (ClinicalTrials.gov: NCT04471519). We report persistence of humoral and cell mediated immunity up to 12 months of vaccination, despite decline in the magnitude of antibody titers. Administration of a third dose of BBV152 increased neutralization titers against both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, Delta Plus and Omicron) with a slight increase in B cell memory responses. Thus, seronversion rate remain high in boosted recipients compared to non-booster, even after 6 months, post third dose against variants. No serious adverse events observed, except pain at the injection site, itching and redness. Hence, these results indicate that a booster dose of BBV152 is safe and necessary to ensure persistent immunity to minimize breakthrough infections of COVID-19, due to newly emerging variants.Trial registration: Registered with the Clinical Trials Registry (India) No. CTRI/2021/04/032942, dated 19/04/2021 and on Clinicaltrials.gov: NCT04471519.

Persistence of immunogenicity after seven COVID-19 vaccines given as third dose boosters following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK: Three month analyses of the COV-BOOST trial.

ObjectivesTo evaluate the persistence of immunogenicity three months after third dose boosters. MethodsCOV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study. ResultsAmongst the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30–94) years. In the participants who had two initial doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd), schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461–10,085) following ChAd/ChAd/BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT)). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 μg) or BNT (30 μg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 μg) versus BNT (30 μg) ranging between 0.74–0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses. Conclusions84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentrations at D84 following BNT/BNT initial doses were similar to or even higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses.

Long-term Persistence of Immunogenicity After Primary Vaccination and Response to Booster Vaccination With Typhoid Conjugate Vaccine: Results of a Phase IV Extension Study

Long-term Persistence of Immunogenicity After Primary Vaccination and Response to Booster Vaccination With Typhoid Conjugate Vaccine: Results of a Phase IV Extension Study

Protection Duration of COVID-19 Vaccines: Waning Effectiveness and Future Perspective.

The coronavirus disease 2019 (COVID-19) vaccines have very successfully decreased the disease risk as we know; some key information remains unknown due to the short development history and the lack of long-term follow-up studies in vaccinated populations. One of the unanswered issues is the protection duration conferred after COVID-19 vaccination, which appears to play a pivotal role in the future impact of pathogens and is critical to inform the public health response and policy decisions. Here, we review current information on the long-term effectiveness of different COVID-19 vaccines, persistence of immunogenicity, and gaps in knowledge. Meanwhile, we also discuss the influencing factors and future study prospects on this topic.

Persistence of immunogenicity, contributing factors of an immune response, and reactogenicities after a single dose of the ChAdOx1 (AZD1222) COVID-19 vaccine in the Thai population

ABSTRACT Introduction Due to the vaccine’s short supply and the efficacy of a single dose of the ChAdOx1 (AZD1222) vaccine, many governments delayed the interval between prime and boost dose from 4 to 8–12 weeks. However, the waning of immune response in this period is a concern. This study evaluated the durability, contributing factors of anti-RBD antibody concentration, and reactogenicities after the single dose of AZD1222 vaccine in the Thai population. Methods This was a single-center, prospective cohort study at Chulabhorn Hospital, Bangkok, Thailand. Individuals 18 years or older who were negative for anti-SARS-CoV-2 antibody were eligible. Anti- receptor-binding domain antibody concentrations were tested at least three weeks after the first vaccination and immediately before the second dose of vaccine. Information on reactogenicities was obtained via a questionnaire sent by a short message service. Results Anti-RBD Antibody concentration at 2 and 3 months post-vaccination were significantly higher than at 1 months post-vaccination (20.14 BAU/mL (95%CI; 16.37, 24.77) at 1 month, 48.08 BAU/mL (95%CI; 42.76, 54.08) at 2 month, and 65.01 BAU/mL (95%CI; 58.88,71.61) at 3 month). Adverse events occurred in approximately 60% of participants. Factors influencing vaccine immunogenicity include age, sex, the time elapsed from the first dose of vaccine, and underlying disease with diabetes and hematologic disease. Conclusion A single dose of AZD1222 could elicit immune responses that did not decline within three months in Thai individuals. These data support the public health strategy of a delay between the prime and boost dose of AZD1222 of 4 to 12 weeks.

Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)

SummaryBackgroundCOVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose.MethodsIn this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting.FindingsBetween March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.InterpretationAn extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses.FundingUK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.

Immunogenicity and safety of an investigational quadrivalent meningococcal conjugate vaccine administered as a booster dose in children vaccinated against meningococcal disease 3 years earlier as toddlers: A Phase III, open-label, multi-center study

ABSTRACT Booster doses of meningococcal conjugate vaccines induce long-term protection against invasive meningococcal disease. We evaluated the immunogenicity and safety of a booster dose of MenACYW-TT in pre-school children who were primed 3 years earlier with MenACYW-TT or MCV4-TT (Nimenrix®). In this Phase III, open-label, multi-center study (NCT03476135), children (4–5 years old), who received a primary dose of MenACYW-TT or MCV4-TT as toddlers in a previous study, received a booster dose of MenACYW-TT. Titers of antibody against meningococcal serogroups A, C, W and Y were measured by serum bactericidal assay using human (hSBA) and baby rabbit (rSBA) complement in samples collected before (D0) and 30 days after (D30) booster vaccination. Safety was assessed over the 30-day study period. Ninety-one participants received the booster dose. In both study groups, hSBA titers increased from D0 to D30; serogroup C titers [95% confidence interval] were higher in the MenACYW-TT-primed vs MCV4-TT-primed group at D0 (106 [73.2, 153] vs 11.7 [7.03, 19.4], respectively) and D30 (5894 [4325, 8031] vs 1592 [1165, 2174], respectively); rSBA results were similar. Nearly all participants achieved ≥1:8 hSBA and rSBA titers at D30, which were higher or comparable to those observed post-primary dose, suggesting rapid booster responses. At D0, all hSBA and rSBA titers were higher than those observed pre-primary dose, suggesting persistence of immunogenicity. The MenACYW-TT booster dose was well-tolerated and had similar safety outcomes across study groups. These findings suggest that MenACYW-TT elicits robust booster responses in children primed 3 years earlier with MenACYW-TT or MCV4-TT.

Long-term persistent immunogenicity after successful standard and triple-dosed hepatitis B vaccine in hemodialysis patients: A 3-year follow-up study in China

BackgroundAlthough the efficacy of hepatitis B vaccines among hemodialysis patients has been documented, the long-term persistence of immunogenicity in this population remains largely unknown. We explored the long-term persistence of immunogenicity induced by different hepatitis B vaccine regimens in hemodialysis patients. MethodsIn initial study, we conducted a randomized, multicenter, double-blind, parallel-controlled trial among hemodialysis patients in 13 hospitals in Shanxi Province, China. A total of 352 hemodialysis patients were allocated to receive 3-dose 20 μg (IM20 group) and 3-dose 60 μg (IM60 group) recombinant hepatitis B vaccine at months 0, 1, and 6. Vaccine-induced immune responses were measured at month 7. In this study, the responders (anti-HBs ≥ 10 mIU/mL) were followed up at months 18, 24, 30, 36 and 42, respectively. We used the generalized log-rank test and generalized estimating equations (GEE) to analyze the long-term durability of responses and the kinetics of anti-HBs levels, respectively. ResultsA total of 284 patients were involved in the extended follow-up period. The duration of vaccine-induced response with 75% of patients maintained protective antibody were 12 months and 18 months in the IM20 group and IM60 group, respectively (P = 0.291). The long-term persistent immunogenicity induced by 3-dose 60 μg was more satisfactory than that by 3-dose 20 μg hepatitis B vaccine in patients with hemodialysis duration ≥ five years (P = 0.023). The peak anti-HBs levels in 100–1000 mIU/mL or ≥ 1000 mIU/mL were more likely to maintain long-term protective antibody compared to anti-HBs levels in 10–100 mIU/mL (P ＜ 0.05). The kinetic profile was similar between the two groups (P = 0.334). ConclusionHigh-dose 60 μg hepatitis B vaccine could lead a satisfactory long-term durability of immunogenicity among patients with hemodialysis duration of five years or more. Peak anti-HBs level after vaccination was associated with the long-term persistence of immunogenicity.

Tolerability and Immunogenicity After a Late Second Dose or a Third Dose of ChAdOx1 nCoV-19 (AZD1222)

Background: COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between first and second dose extends. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose, the immunity after an extended interval between the first and second dose of ChAdOx1 nCoV-19(AZD1222), and the response to a third dose as a late booster. Methods: Volunteers aged 18-55 years who were enrolled in a Phase 1/2 or Phase 2/3 clinical trial of ChAdOx1 nCoV-19 and had received either a single dose or two doses of 5×10 10 viral particles were invited back for vaccination. Reactogenicity and immunogenicity of a delayed second dose or a third dose are reported here.Findings: Antibody titres after a single dose and measured on d362 remain higher than the titres measured on d0 (62.61 EU; 95% CI 47.43-82.64 vs 1 EU 95% CI 1-16). 30 participants received a late second dose of ChAdOx1 nCoV-19 (median 44 weeks after first dose), antibody titres were higher in those with a longer interval between first and second dose (median EU for 8-12, 15-25, and 44-46 weeks were 923 [IQR 525-1764], 1860 [IQR 917-4934] and 3738 [IQR 1824-6625] respectively). 90 participants received a third dose and antibody titres were significantly higher following a third dose (FRNT50 612 [IQR 351-920]) when compared with the response 28 days after a second dose (FRNT 50 319 [IQR 176-591]. T-cell responses were also boosted after a third dose. Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.Interpretation: A longer delay before the second dose of ChAdOx1 nCoV-19 leads to an increased antibody titre after the second dose. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlate with high efficacy after second dose and boosts T-cell responses.Funding: UK Research and Innovation (MC_PC_19055), Engineering and Physical Sciences Research Council (EP/R013756/1), National Institute for Health Research (COV19 OxfordVacc-01), Coalition for Epidemic Preparedness Innovations (Outbreak Response To Novel Coronavirus (COVID-19)), National Institute for Health Research Oxford Biomedical Research Centre (BRC4 Vaccines Theme), Thames Valley and South Midland’s NIHR Clinical Research Network, and AstraZeneca. The views expressed in this publication are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.Declaration of Interest: Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. AstraZeneca reviewed the data from the study and the final manuscript before submission, but the authors retained editorial control. SCG and AVSH are cofounders of and shareholders in Vaccitech (collaborators in the early development of this vaccine candidate) and named as inventors on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and a patent application covering this SARS-CoV-2 vaccine (SCG only). TL is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines (PCT/GB2012/000467) and was a consultant to Vaccitech. PMF is a consultant to Vaccitech. AJP is Chair of the UK Department of Health and Social Care’s JCVI, but does not participate in policy advice on coronavirus vaccines, and is a member of the WHO Strategic Advisory Group of Experts (SAGE). AJP is a NIHR Senior Investigator.Ethical Approval: In the UK, the COV001 and COV002 studies were approved by the South Central Berkshire Research Ethics Committee (COV001 reference 20/SC/0145, March 23, 2020; and COV002 reference 20/SC/0179; conditional approval April 8, full approval April 19, 2020).

8. The Adjuvanted Recombinant Zoster Vaccine (RZV) Confers Long-term Protection Against Herpes Zoster: Interim Results of an Extension Study (ZOSTER-049) of Two Clinical Trials (ZOE-50 and ZOE-70)

BackgroundTwo large-scale phase 3 clinical trials (ZOE-50 [NCT01165177] and ZOE-70 [NCT01165229]) demonstrated that, in adults ≥ 50 years of age followed over a mean period of 3.1 and 3.7 years respectively, the adjuvanted recombinant zoster vaccine (RZV) was efficacious against herpes zoster (HZ), highly immunogenic and had a clinically acceptable safety profile. In this extension study (ZOSTER-049 [NCT02723773]), RZV-induced immunogenicity persistence and long-term vaccine efficacy (VE) against HZ were evaluated; we report interim results after at least 2 years of follow-up (starting and ending ≈5.1 and 7.1 years, respectively, after initial vaccination during the parent studies).MethodsThe study design is detailed in Figure 1. Primary objective: VE against HZ over the ZOSTER-049 study. Secondary objectives: VE against HZ from 1 month post-dose 2 in ZOE-50/-70 until the end of observation for year (Y)2 of ZOSTER-049, persistence of vaccine-induced humoral immunogenicity (HI) in terms of anti-gE antibody concentrations (by ELISA) and cell-mediated immune (CMI) response in terms of frequency of gE-specific CD4+ T-cells (by intracellular cytokine staining).Figure 1. Study design of the extension study in relation to the parent studies. ZOSTER-049 study procedures, timing, endpoints and cohorts ResultsOf the 7,413 participants enrolled in ZOSTER-049, 7,277 were included in the VE analysis (Figure 2) and 6,972 reached Y2 of this study. The overall VE against HZ during at least 2 years of follow-up in ZOSTER-049 was 84.0% (95% confidence interval [CI]: 75.9–89.8%). From 1 month post-dose 2 in the ZOE-50/-70 studies until the end of observation for Y2 of ZOSTER-049, the overall VE was 90.9% (95% CI: 88.2–93.2%). Anti-gE antibody concentrations persisted ≈6 times above pre-vaccination levels up to Y8 after vaccination (Figure 3A) and the frequency of gE-specific CD4[2+] T-cells remained above baseline from Y6 to Y8 after vaccination (i.e. until the end of observation for Y2 of ZOSTER-049) (Figure 3B).Figure 2. Demographic characteristics of participants included in the ZOSTER-049 study, for the analysis of vaccine efficacy against herpes zoster (mTVC) Figure 3. Long-term persistence of humoral immunogenicity (HI) and cell-mediated immune (CMI) responses up to year 8 post-vaccination dose 2 administered in the ZOE-50/-70 studies ConclusionRZV demonstrated high VE against HZ until the end of the observation period for this Y2 interim analysis. The HI and CMI responses remained stable and high until the end of observation (i.e. 7.1 years after initial vaccination). Funding: GlaxoSmithKline Biologicals SA Acknowledgements: LA Truta/S Hulsmans (Modis c/o GSK) provided writing/editorial supportDisclosures Céline Boutry, PhD, Aixial (Consultant) Andrew Hastie, MD, GSK group of companies (Employee) Meng Shi, MS, GSK group of companies (Employee) Javier Diez-Domingo, MD, GSK group of companies (Board Member, Scientific Research Study Investigator, Advisor or Review Panel member)MSD (Board Member, Scientific Research Study Investigator, Advisor or Review Panel member) Paola Pirrotta, PharmD, GSK group of companies (Employee) George Kalema, PhD, GSK group of companies/Keyrus Biopharma (Consultant) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

Persistence of Immunogenicity Following Reduced PCV Dosing Schedules in South African Children

Persistence of Immunogenicity Following Reduced PCV Dosing Schedules in South African Children

Immunogenicity persistence in children of hepatitis A vaccines Healive® and Havrix®: 11 years follow-up and long-term prediction

ABSTRACT Background: Hepatitis A vaccine has been used in mass and routine public vaccination programs in China. Long-term follow-up studies are required to determine the duration of protection and the need for booster vaccinations. Methods: A prospective, randomized, open-label clinical trial was performed to compare the geometric mean concentration (GMC) and seroprotection rates of anti-Hepatitis A virus (HAV) antibodies elicited by the inactivated vaccines Healive and Havrix. 400 healthy children were randomly assigned 3:1 ratio to receive two doses of Healive or Havrix at 0 and 6 months. Persistence of anti-HAV antibodies for 5 years post immunization has been reported The current study reports new data at 11 years post immunization for the purpose of showing antibody persistence. Sensitivity analyzes were performed to assess the results. In addition, predictions for long-term antibody persistence were performed using a statistical model. Two different serological assays were used that were shown to be 98.3% concordant for detecting anit-HAV antibody. Results: GMCs were significantly higher following Healive compared to Havrix at 1, 6, 7, 66, 112 and 138 months post-vaccination. In addition, the GMCs obtained using sensitivity analysis were very similar to those obtained using the original models. Prediction analysis indicated that the duration of protection for both vaccines was at least 30 years after immunization, with a lower limit of the 95% confidence interval for GMC of greater than 20mIU/mL. Conclusions: Healive is more immunogenic than Havrix in children at 11 years post full immunization. Prediction analysis indicated at least 30 years of antibody persistence for both vaccines.

Long-term immunogenicity of a quadrivalent human papillomavirus vaccine in systemic lupus erythematosus

ObjectivesTo evaluate the 5-year immunogenicity of a quadrivalent human papillomavirus (HPV) vaccine (GARDASIL) in patients with systemic lupus erythematosus (SLE). MethodsFemale SLE patients and controls, aged 18–35 years, who received GARDASIL in 2011 and sero-converted 12 months post-vaccination were followed for persistence of immunogenicity. Antibody measurement to HPV serotypes 6, 11, 16, 18 was repeated at 5 years. The rate of sero-reversion was compared between patients and controls, and factors associated with sero-reversion of the anti-HPV antibodies were studied. Results50 SLE patients and 50 controls were vaccinated with GARDASIL. Among subjects who sero-converted at 1 year and consented for this study, antibodies to HPV serotypes 6, 11, 16 and 18 at 5 years were persistent in 24/27 (89%), 26/31 (84%), 32/34 (94%) and 24/25 (96%) of the SLE patients; and 32/33 (97%), 32/33 (97%), 32/32 (100%) and 23/24 (96%) of the controls, respectively. Antibody titers to HPV-6 and 16 were significantly lower in patients than controls. Seven (21%) SLE patients had sero-reversion of ≥1 anti-HPV antibodies. Sero-reverted patients experienced significantly more SLE flares, particularly renal, and had received significantly higher cumulative doses of prednisolone, mycophenolate mofetil and tacrolimus than those with persistent immunogenicity. The cumulative doses of prednisolone correlated inversely and significantly with the anti-HPV 6, 11, and 16 titers at 5 years. ConclusionsImmunogenicity of the quadrivalent HPV vaccine was retained in a high proportion of SLE patients at 5 year. Patients with more SLE renal flares and had received more immunosuppression were more likely to have sero-reversion of the anti-HPV antibodies.Clinical trial registration number: US ClinicalTrials.gov (NCT00911521 & NCT02477254).

Immunogenicity and safety of the multicomponent meningococcal B vaccine (4CMenB) in children and adolescents: a systematic review and meta-analysis

The multicomponent meningococcal serogroup B vaccine (4CMenB) has been licensed in more than 35 countries. However, uncertainties remain about the lowest number of doses required to induce satisfactory, persistent immune responses. We did a systematic review and meta-analysis to provide quantitative estimates for the immunogenicity, persistence of immunogenicity, and safety of 4CMenB vaccine in children and adolescents. For this systematic review and meta-analyses (proportion, head to head, and network), we searched MEDLINE, Scopus, Embase, and ClinicalTrials.gov from database inception to June 30, 2017, for randomised trials that compared the immunogenicity or safety of the 4CMenB vaccine with its originator meningococcal B recombinant vaccine or routine vaccines in children or adolescents. For proportion meta-analyses, we also included single arm trials and follow-up studies of randomised controlled trials. Trials that assessed immunogenicity against at least one of four Neisseria meningitidis serogroup B reference strains (44-76/SL, 5/99, NZ98/254, and M10713) and included participants younger than 18 years who had received two or more doses of the 4CMenB vaccine were eligible for inclusion. We requested individual patient-level data from study authors and extracted data from published reports and online trial registries. We did meta-analyses to assess 4CMenB safety and immunogenicity against the four reference strains 30 days after a primary immunisation course (three doses for children, two doses for adolescents), 30 days after the primary course plus one booster dose (children only), 6 months or more after primary course, and 6 months or more after the booster dose. 736 non-duplicate records were screened, and ten randomised trials and eight follow-on extension trials on 4CMenB met the inclusion criteria. In intention-to-treat analyses, the overall proportion of children and adolescents who achieved seroconversion 30 days after the primary course of 4CMenB was 92% (95% CI 89-95 [I2=95%, p<0·0001]) for the 44/76-SL strain, 91% (87-95 [I2=95%, p<0·0001]) for the 5/99 strain, 84% (77-90 [I2=97%, p<0·0001]) for the NZ98-254 strain, and 87% (68-99 [I2=97%, p<0·0001]) for the M10713 strain. 6 months after the primary course, the immunogenicity remained adequate to high against all three tested strains (5/99, 44/76-SL, and NZ98/254) in adolescents (≥77%), and against two of four strains (5/99 and 44/76-SL) in children (≥67%): the proportion of patients who achieved seroconversion substantially declined for M10713 (<50%) and NZ98/254 (<35%). A booster dose re-enhanced the proportion of patients who achieved seroconversion (≥93% for all strains). However, immunogenicity remained high 6 months after the booster dose for strains 5/99 (95%) and M10713 (75%) only, whereas the proportion of patients who achieved seroconversion against strains 44/76-SL and NZ98/254 returned to similar proportions recorded 6 months after the primary course (62% for 44/76-SL, 35% for NZ98/254). The incidence of potentially vaccine-related, acute serious adverse events in individuals receiving 4CMenB was low (5·4 per 1000 individuals), but was significantly higher than routine vaccines (1·2 per 1000 individuals). 4CMenB has an acceptable short-term safety profile. The primary course is sufficient to achieve a satisfactory immune response within 30 days of vaccination. A booster dose is required for children to prolong the protection against strain M10713, and the long-term immunogenicity against strain NZ98/254 remains suboptimal. None.