Geometric Mean Titer Ratio Research Articles

Reactogenicity and Immunogenicity of Heterologous ChAdOx1-nCoV19 and BNT162b2 Vaccination: A Systematic Review and Meta-Analysis of the Heterologous COVID-19 Vaccination Outcomes

Background: To date, the reactogenicity and immunogenicity of heterologous ChAdOx1-nCoV19/BNT162b2 (ChAd/BNT) vaccination remain unclear. Here, we systematically assessed the reactogenicity and immunogenicity of the heterologous ChAd/BNT vaccination regimens. Methods: The publicly available studies on heterologous COVID-19 vaccination were systematically searched on PubMed, Web of Science, Embase and MedRxiv for the available literature up to August 1, 2021. We evaluated the immunogenicity by the geometric mean titers (GMTs) of the neutralizing antibody and anti-spike IgG. The reactogenicity was evaluated using the pooled risk ratios (RRs) calculated by the random-effects model about the adverse events after vaccination. Subgroup analyses based on vaccination regimens and interval between the two doses of vaccines were conducted to evaluate the impact of the different regimens. Findings: Nine studies (n=4,286) were included in the analyses. Compared to the homologous ChAd/ChAd vaccination, the heterologous ChAd/BNT vaccination showed significantly higher immunogenicity (pooled GMTR [geometric mean titers ratio] in terms of the neutralizing antibody: 11·92 [95% CI 5·65-25·13, I2=49·1%, P2=50·7%, P2=36·9%, P=0·803]; and GMTR of anti-spike IgG: 1·02 [95%CI 0·86-1·21, I2=48·3%, P=0·826]) and similar reactogenicity (RR: 1·22, 95%CI 0·92-1·63, P=0·17). Additionally, there was no significant difference in immunogenicity among different ChAd/BNT vaccination intervals (4 weeks; 8-12 weeks). Interpretation: Heterologous ChAd/BNT vaccination showed robust immunogenicity and tolerable reactogenicity. Further studies are needed to determine the optimal vaccine combinations and vaccination intervals.Registration Details: Our study was registered with PROSPERO, CRD42021265165. Funding Information: This research work was supported by the SINO-GERMAN rapid response funding call for COVID-19 related research (C-0073).Declaration of Interests: All the authors declare no competing interest.

160. Safety and Immunogenicity of Escalating Dose Formulations of High-dose Quadrivalent Influenza Vaccine in Children 6 Months Through < 18 Years of Age

BackgroundChildren do not respond immunologically as well as adults to standard-dose (SD) influenza vaccination and remain at increased risk of influenza and its complications. A method to improve efficacy in children may be to increase antigen amount per dose, a successful strategy used in older adults. Trivalent high-dose (HD) influenza vaccine (60ug hemagglutinin/strain) showed significantly improved effectiveness for prevention of clinical outcomes related to influenza in adults ≥65 years; moreover, a quadrivalent HD formulation was approved by US FDA (2019) for use in this group.MethodsA Phase 2, randomized, modified double blind study (NCT03698279) was conducted in US and Canadian children to evaluate safety and immunogenicity of IIV4-HD compared to an IIV4-SD and adjuvanted trivalent influenza vaccine (aIIV3). Children (n=661, 6 months through < 18 years) were assigned to receive intramuscularly 1 of 3 formulations of IIV4-HD (30, 45, or 60 µg HA/strain/dose), a licensed IIV4-SD, or a licensed aIIV3. Depending on child’s previous influenza vaccination status and age, they received 1 or 2 doses of study vaccine 28 days apart. Post-vaccination (28 days after each vaccination) geometric mean titers (GMTs) and seroconversion rates were measured using hemagglutinin inhibition (HAI) assay. Reactogenicity data were collected through 1 week; safety data were collected through 6 months post-vaccination.ResultsIIV4-HD was more reactogenic than IIV4-SD, but unsolicited related adverse events were similar (Table 1). No related serious adverse events or deaths occurred. A dose-related increase in HAI GMT ratio was observed across the age range for A/H3N2 but only in children 6 months through < 3 years for A/H1N1 and the 2 B strains (Table 2). Compared with IIV4-SD, the 60 µg HA/strain/dose formulation of IIV4-HD generated highest HAI GMT ratios and high seroconversion rates for all 4 strains in US children 6 months through < 3 years. Canadian children receiving IIV4-HD generated HAI titers incongruent to those of US children receiving IIV4-HD, limiting direct comparison against aIIV3.Safety Overview (US and Canadian subjects 6 months through <18 years) HAI GMT Ratios (QIV-HD/QIV-SD) at 28 days After the Last Vaccination (US subjects 6 months through <18 years) ConclusionThe favorable safety profile and the HAI GMT ratios support pediatric dose selection of 60µg HA/strain/dose as most appropriate to evaluate in Phase 3.DisclosuresLeejah Chang, MD, Sanofi Pasteur (Employee) Evan J. Anderson, MD, Sanofi Pasteur (Scientific Research Study Investigator) Robert Jeanfreau, MD, Sanofi Pasteur (Scientific Research Study Investigator) Ying He, PhD, Otsuka Pharmaceutical (Employee)Sanofi Pasteur (Other Financial or Material Support, Former employee) Bryony Hicks, BSc, Sanofi Pasteur (Employee) Anju Shrestha, MD, Sanofi Pasteur (Employee) Aseem Pandey, PhD, Sanofi Pasteur (Employee)Sanofi Pasteur (Employee) Rawia Khoury, BSc, Sanofi Pasteur (Employee) Iris De Bruijn, PhD, Sanofi Pasteur (Employee) Victoria Landolfi, MS, MBA, Sanofi Pasteur (Employee)

3. Phase 3 Pivotal Evaluation of 20-valent Pneumococcal Conjugate Vaccine (PCV20) Safety, Tolerability, and Immunologic Noninferiority in Participants 18 Years and Older

BackgroundPCV20 contains the 13-valent pneumococcal conjugate vaccine (PCV13) components, and 7 additional conjugates (for serotypes 8, 10A, 11A, 12F, 15B, 22F, and 33F), extending pneumococcal serotype coverage. Key data from the pivotal Phase 3 evaluation of PCV20 in adults are presented.MethodsAdults naïve to pneumococcal vaccination were enrolled into 3 age cohorts (≥60, 50–59, and 18–49 years of age). Participants ≥60 years received either PCV20 and saline 1 month later, or PCV13 and 23-valent pneumococcal polysaccharide (PPSV23) 1 month later (1:1 randomization, double blind). Participants 50–59 and 18–49 years received either a dose of PCV20 or PCV13 (3:1 randomization, double blind). Tolerability, safety and immunogenicity (opsonophagocytic activity [OPA] responses) were assessed.Results3889 participants received vaccine. 1507 and 1490 participants ≥60 years received PCV20 or control respectively. All 20 vaccine serotypes induced robust responses and OPA geometric mean titers (GMTs) to all 13 matched serotypes were noninferior to PCV13. In addition, the OPA GMTs to 6 of the 7 additional serotypes 1 month after PCV20 were noninferior compared to the same serotypes in PPSV23. The OPA GMT of serotype 8 missed noninferiority by a very narrow margin (2-sided 95% lower bound of GMT ratio [20vPnC/PPSV23] was 0.49, with noninferiority criterion of >0.5); this is unlikely to be clinically significant given the high geometric mean fold rise of OPA titers after PCV20 (22-fold above baseline). GMTs after PCV20 in each of the younger age cohorts (18–49 years, 50–59 years) were noninferior to adults 60–64 years. The tolerability and safety profile of PCV20 was similar to PCV13.ConclusionBased on the robust immune responses and comparability to licensed pneumococcal vaccines, as well as bridging to the younger age group, these data support that PCV20 will be protective against pneumococcal disease due to the 20 serotypes in adults.Disclosures Charu Sabharwal, MD, MPH, Pfizer (Employee, Shareholder) Xia Xu, PhD, Pfizer (Employee, Shareholder) Vani Sundaraiyer, PhD, MS, Pfizer (Independent Contractor) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Lisa Moyer, BS, Pfizer (Employee, Shareholder) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)

Comparison of influenza antibody titers among women who were vaccinated in the 2nd and the 3rd trimesters of pregnancy

BackgroundWe compared cord blood antibody titers in unvaccinated pregnant women to those vaccinated with seasonal influenza vaccine during the 2nd and the 3rd trimesters. MethodsPregnant women had cord blood collected at delivery for hemagglutination inhibition assay against vaccine reference viruses: A/California/07/2009 (H1N1)pdm09, A/Switzerland/9715293/2013 (H3N2), and B/Phuket/3073/2013 (Yamagata lineage). Geometric mean titer (GMT) ratios were calculated comparing vaccinated versus unvaccinated pregnant women, and women vaccinated in the 2nd and the 3rd trimesters. Proportions of women achieving defined titers were compared using the χ2 test. ResultsOf 307 women, 190 (62%) were unvaccinated. Fifty and 67 were vaccinated during the 2nd and the 3rd trimesters, respectively. Median enrollment age was 29 years (interquartile range 24–34). Sixteen (5%) women had pre-existing conditions, but none were immunocompromised. GMT ratios comparing vaccinated and unvaccinated women were 5.90 (95% confidence interval [CI] 5.06–6.96) for influenza A/California, 5.39 (95% CI 4.18–6.08) for influenza A/Switzerland, and 5.05 (95% CI 4.43–5.85) for influenza B/Phuket. Similarly, the GMT ratios comparing the 3rd and the 2nd trimester vaccinated women were 2.90 (95% CI 2.54–3.39), 2.82 (95% CI 2.56–3.13), and 2.83 (95% CI 2.56–3.14), respectively. The proportions of women with defined titers for the three vaccine reference viruses did not differ between 2nd and 3rd trimester vaccinated women (titers ≥40: 68–92% versus 70–93%; ≥110: 32% versus 33–63%; and ≥330: 4–10% versus 3–21%). ConclusionsPregnant women vaccinated against influenza had more placental transfer of influenza antibodies to their infants than unvaccinated women. Placental transfer of antibodies was higher among those vaccinated in the 3rd trimester than in the 2nd trimester. There was no difference in the proportions of women achieving antibody titers corresponding to protection against influenza in children. Findings support the current World Health Organization’s recommendation that pregnant women may be vaccinated in either 2nd or 3rd trimester of pregnancy.

A Randomized Trial of Two 2-Dose Influenza Vaccination Strategies for Patients Following Autologous Hematopoietic Stem Cell Transplantation.

Seroprotection and seroconversion rates are not well understood for 2-dose inactivated influenza vaccination (IIV) schedules in autologous hematopoietic stem cell transplantation (autoHCT) patients. A randomized, single-blind, controlled trial of IIV in autoHCT patients in their first year post-transplant was conducted. Patients were randomized 1:1 to high-dose (HD) IIV followed by standard dose (SD) vaccine (HD-SD arm) or 2 SD vaccines (SD-SD arm) 4 weeks apart. Hemagglutination inhibition (HI) assay for IIV strains was performed at baseline, 1, 2, and 6 months post-first dose. Evaluable primary outcomes were seroprotection (HI titer ≥40) and seroconversion (4-fold titer increase) rates and secondary outcomes were geometric mean titers (GMTs), GMT ratios (GMRs), adverse events, influenza-like illness (ILI), and laboratory-confirmed influenza (LCI) rates and factors associated with seroconversion. Sixty-eight patients were enrolled (34/arm) with median age of 61.5 years, majority male (68%) with myeloma (68%). Median time from autoHCT to vaccination was 2.3 months. For HD-SD and SD-SD arms, percentages of patients achieving seroprotection were 75.8% and 79.4% for H1N1, 84.9% and 88.2% for H3N2 (all P > .05), and 78.8% and 97.1% for influenza-B/Yamagata (P = .03), respectively. Seroconversion rates, GMTs and GMRs, and number of ILI or LCIs were not significantly different between arms. Adverse event rates were similar. Receipt of concurrent cancer therapy was independently associated with higher odds of seroconversion (OR, 4.3; 95% CI, 1.2-14.9; P = .02). High seroprotection and seroconversion rates against all influenza strains can be achieved with vaccination as early as 2 months post-autoHCT with either 2-dose vaccine schedules. Australian New Zealand Clinical Trials Registry: ACTRN12619000617167.

Zika and Dengue Interactions in the Context of a Large Dengue Vaccine Clinical Trial in Latin America.

.A phase III dengue vaccine trial including 9- to 16-year-olds in Latin America (NCT01374516) was ongoing at the time of a Zika outbreak. We explored interactions between dengue and Zika, in the context of dengue vaccination. Symptomatic virologically confirmed Zika (VCZ) was evaluated using acute-phase sera from febrile participants (January 2013–March 2018). Neutralizing antibody geometric mean titers (GMTs) were evaluated pre- and post-Zika outbreak (months 25 and 72) in 2,000 randomly selected participants. Baseline dengue serostatus was determined using the plaque reduction neutralization test or inferred post hoc using nonstructural protein 1 IgG ELISA at M13 (case–cohort analysis). Vaccine efficacy against VCZ and serologically suspected Zika (SSZ) was estimated. Overall, 239/10,157 (2.4%) acute-phase samples were VCZ positive during the study. Dengue vaccine efficacy against VCZ was 27.8% (95% CI: 0.3; 47.7) among baseline dengue-seropositive participants. No vaccine effect was evident against SSZ. Zika antibody GMTs increased from pre- to post-Zika epidemic, with smaller increases observed for participants who were dengue seropositive at baseline than for those who were dengue seronegative: post-/pre-Zika GMT ratios for baseline dengue-seropositive participants were 21.5 (vaccine group) and 30.8 (placebo); and for dengue seronegatives, 88.1 and 89.5, respectively. Dengue antibody GMTs post-Zika were higher in dengue vaccine and placebo recipients with SSZ than those without SSZ in both dengue seropositives and seronegatives. Dengue vaccine did not enhance symptomatic Zika illness in dengue-seropositive individuals, rather it reduced the risk of VCZ. Zika infection boosted preexisting vaccine-induced or naturally occurring dengue-neutralizing antibodies.

Repeated exposure to an MF-59 adjuvanted quadrivalent subunit influenza vaccine (aQIV) in children: Results of two revaccination studies

BackgroundPediatric adjuvanted seasonal influenza vaccines induce higher immune responses and have the potential to confer better protection against influenza among young vaccine-naïve children. Limited data describe benefits and risks of repeated administration of adjuvanted influenza vaccines in children. Two revaccination studies assess the safety and immunogenicity of repeated exposure to an MF59-adjuvanted quadrivalent influenza vaccine (aQIV; Fluad®) compared to routine non-adjuvanted quadrivalent influenza vaccine (QIV). MethodsChildren previously enrolled in the parent study, who received vaccination with aQIV or nonadjuvanted influenza vaccine (TIV or QIV), were recruited in Season 1 (n = 607) or Season 2 (n = 1601) of the extension trials. Season 1 participants remained in their original randomization groups (aQIV-aQIV or TIV-QIV); Season 2 subjects were re-randomized to either vaccine, resulting in four groups (aQIV-aQIV, aQIV-QIV, QIV-aQIV, or QIV-QIV). All subjects received a single-dose vaccination. Blood samples were taken for immunogenicity assessment prior to vaccination and 21 and 180 days after vaccination. Reactogenicity (Days 1–7) and safety were assessed in all subjects. ResultsHemagglutination inhibition (HI) geometric mean titer (GMT) ratios demonstrated superiority of aQIV revaccination over QIV revaccination for all strains in Season 1 and for A/H1N1, B/Yamagata, and B/Victoria in Season 2. Higher HI titers against heterologous influenza strains were observed after aQIV vaccination during both seasons. Mild to moderate severity and short duration reactogenicity was more common in the aQIV than QIV groups, but the overall safety profiles were similar to the parent study. ConclusionThe safety and immunogenicity results from this study demonstrate benefit of aQIV for both priming and revaccination of children aged 12 months to 7 years.

Immunogenicity of Alternative Dosing Schedules for HPV Vaccines among Adolescent Girls and Young Women: A Systematic Review and Meta-Analysis.

Alternative dosing schedules for licensed human papilloma virus (HPV) vaccines, particularly single dose and extended intervals between doses (>12 months), are being considered to address vaccine shortages and improve operational flexibility. We searched PUBMED/MEDLINE for publications reporting immunogenicity data following administration of one of the licensed HPV vaccines (2vHPV, 4vHPV, and 9vHPV) to females aged 9–26 years. We conducted non-inferiority analyses comparing alternative to standard schedules using mixed effects meta-regression controlling for baseline HPV status and disaggregated by vaccine, subtype, time point, and age group (9–14 and 15–26 years). Non-inferiority was defined as the lower bound of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio being greater than 0.5. Our search returned 2464 studies, of which 23 were included in data analyses. When evaluated against standard schedules, although robust immunogenicity was demonstrated across all multi-dose groups, non-inferiority of extended interval dosing was mixed across vaccines, subtypes, and time points. Single dose did not meet the criteria for non-inferiority in any comparisons. Sparse data limited the number of possible comparisons, and further research is warranted.

Immune response at 12–23 months following a single dose of Vero cell culture-derived Japanese encephalitis (JE) vaccine in adults previously vaccinated with mouse brain-derived JE vaccine

BackgroundJapanese encephalitis (JE) virus is an important cause of neurological disease in Asia. JE vaccine is recommended for travelers with higher JE risk itineraries. Inactivated Vero cell culture-derived JE vaccine (JE-VC) is the only JE vaccine currently available in the United States. An inactivated mouse brain-derived JE vaccine (JE-MB) previously was available but production was discontinued. One JE-VC dose administered to adults previously vaccinated with ≥3 doses of JE-MB provides good short-term protection for at least one month, but data on longer-term protection are limited. We evaluated non-inferiority of the JE virus neutralizing antibody response at 12–23 months in JE-MB-vaccinated adults administered one JE-VC dose compared with JE vaccine-naïve adults administered a JE-VC two-dose primary series. MethodsWe obtained archived sera from U.S. military personnel and performed a 50% plaque reduction neutralization test for anti-JE virus neutralizing antibodies. We compared the geometric mean titer (GMT) and seroprotection rate at 12–23 months after one JE-VC dose in previously JE-MB-vaccinated personnel and after the second JE-VC dose in previously JE vaccine-naïve personnel. Non-inferiority was concluded if the lower bound of the two-sided 95% confidence interval (CI) of the GMT ratio in previously vaccinated to vaccine-naïve personnel was >1/1.5. ResultsThe GMT in previously JE-MB-vaccinated persons was 75 (95% CI 63–90) and in previously JE vaccine-naïve persons was 12 (95% CI 11–14), and seroprotection rates were 94% (235/250) and 54% (135/250), respectively. The ratio of GMTs was 6.3 (95% CI: 5.0–7.7), satisfying the criterion for non-inferiority. ConclusionsOne JE-VC dose in previously JE-MB-vaccinated military personnel provides good protection for at least 1–2 years. The benefits of administration of a single JE-VC dose in previously JE-MB-vaccinated adults include a shorter time to completion of re-vaccination before travel, a decrease in the risk of adverse events, and reduced costs.

Immunogenicity, safety and inter-lot consistency of a meningococcal conjugate vaccine (MenACYW-TT) in adolescents and adults: A Phase III randomized study

BackgroundMenACYW-TT is an investigational quadrivalent (serogroups A, C, W and Y) meningococcal conjugate vaccine that is being developed for protection against invasive meningococcal disease. MethodsIn this Phase 3, blinded, randomized study, 3344 meningococcal vaccine-naïve 10–55-year-olds were randomized (3:3:3:2) to receive one of three lots of MenACYW-TT or licensed quadrivalent meningococcal conjugate vaccine, MCV4-DT (NCT02842853). Antibody titers were assessed by human and rabbit complement serum bactericidal antibody assays. The co-primary objectives were to demonstrate lot-to-lot consistency of MenACYW-TT by the between-lot geometric mean titer ratios (GMTR) at Day 30, and non-inferiority of Day 30 vaccine seroresponses (titers ≥ 1:16 if pre-vaccination titers < 1:8, or ≥ 4-fold increase if pre-vaccination titers ≥ 1:8) with MenACYW-TT vs MCV4-DT. Further objectives included safety and immunogenicity. ResultsLot consistency was demonstrated for all three lots, with GMTRs ranging from 0.87 to 1.1. The proportion of participants achieving seroresponse in the MenACYW-TT group (data pooled from the 3 lots) was non-inferior to MCV4-DT (A: 74% vs 55%; C: 89% vs 48%; W: 80% vs 61%; Y: 91% vs 73%, respectively). MenACYW-TT and MCV4-DT had similar safety profiles; no safety concerns were identified. ConclusionsThe study met both co-primary endpoints, demonstrating lot-to-lot consistency and non-inferiority of MenACYW-TT vs MCV4-DT in adolescents and adults.

Immunogenicity and safety of the AS04-HPV-16/18 and HPV-6/11/16/18 human papillomavirus vaccines in asymptomatic young women living with HIV aged 15–25 years: A phase IV randomized comparative study

BackgroundWomen living with HIV (WLWH) are at higher risk of acquisition and progression of human papillomavirus (HPV) infection. Evidence on effect of HPV vaccination in this population is limited. MethodsThis phase IV randomized controlled observer-blind study assessed immunogenicity and safety of two HPV vaccines (AS04-HPV-16/18 vs. 4vHPV) given in WLWH (stage 1) and HIV- females aged 15–25 years. Co-primary endpoints were to demonstrate, in WLWH subjects, non-inferiority (and if demonstrated, superiority) of AS04-HPV-16/18 vs. 4vHPV for HPV-16 and HPV-18 by pseudovirion-based neutralization assay (PBNA) at month 7 and safety. Non-inferiority criteria was lower limit (LL) of the 95% confidence interval (CI) of the GMT ratio AS04-HPV-16/18/4vHPV above 0.5, in the according to protocol population. NCT01031069 FindingsAmong 873 subjects recruited between 26-Oct-2010 and 14-May-2015, 546 were randomized (1:1) and received at least one vaccine dose (total vaccinated cohort, TVC): 257 were WLWH (129 AS04-HPV-16/18; 128 4vHPV) and 289 were subjects without HIV (144 AS04-HPV-16/18; 145 4vHPV). Baseline CD4 cell count in WLWH was at least 350 cells/mm3.At month 7, AS04-HPV-16/18 showed immunological superiority to 4vHPV in WLWH. Neutralizing anti-HPV-16 and HPV-18 antibody GMTs were 2·74 (95% CI: 1·83; 4·11) and 7·44 (95% CI: 4·79; 11·54) fold higher in AS04-HPV-16/18 vs. 4vHPV (LL of the GMT ratio >1 in TVC, p<0·0001), respectively. Similar results were observed by ELISA up to month 24.Solicited local and general symptoms were in line with product labels. The number of reported serious adverse events (SAEs) was balanced throughout the study. InterpretationBoth vaccines showed an acceptable safety profile in all subjects. Despite the absence of an immunological correlate of protection for HPV, differences in immune responses elicited by the vaccines especially for HPV-18 may translate into longer lasting or more robust protection against cervical cancer with the AS04-HPV-16/18 vaccine in WLWH. FundingGlaxoSmithKline Biologicals S.A. funded this study (NCT01031069) and related publications. Trial registrationwww.clinicaltrials.gov - NCT01031069

An Investigation of Japanese Neonatal and Maternal Antibody Status against Pertussis.

To clarify the pertussis immune status of the Japanese population, we investigated levels of serum pertussis toxin (PT)-specific immunoglobulin G (IgG) antibody in infants and mothers between April 2016 and March 2018. A total of 206 infants (n = 22, < 32 weeks of gestational age [wGA]; n = 70, 32-36 wGA; n = 114, ≥ 37 wGA) and 170 mothers were enrolled. The maternal seroprevalence and antibody geometric mean titer (GMT) were 52.4% and 10.7 EU/mL, respectively. The antibody GMT, seroprevalence, and mean ratio of infant to maternal antibody titers of infants at < 32 wGA were 3.2 EU/mL, 13.6%, and 42.5%, respectively, and were significantly lower than those of infants at 32-36 wGA (9.7 EU/mL, 54.3%, and 110.2%) and infants at ≥ 37 wGA (12.1 EU/mL, 57.9%, and 112.6%). Of the 21 infants who underwent a second examination, five were positive in the first examination. Of those five, the GMT for PT had decreased by an average of 52.6% at 4.3- week intervals. In the second examination, two infants were seropositive. Approximately half of the mothers and infants were negative for anti-PT antibody. Thus, new vaccination strategies, such as the vaccination of pregnant women, are needed to prevent pertussis infection in early infancy.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine: a randomized, double-blind, controlled phase III clinical trial in children aged 6–35 months in China

ABSTRACT Mismatch between circulating influenza B viruses and vaccine strains occurs frequently. In a randomized, double-blind, controlled phase III clinical study, healthy children aged 6–35 months were randomized into three groups at a ratio of 2:1:1, received two doses of quadrivalent influenza vaccines (QIVs) or licensed trivalent influenza vaccines (TIVs). The primary objective was to evaluate the non-inferiority immunogenicity of QIV compared with the two TIVs, containing B/Victoria or B/Yamagata strain. Safety information was collected for 28 days after each vaccination. Serious adverse events (SAEs) were monitored for 6 months after the second vaccination. A total of 2146 subjects (QIV: 1069, TIV–Vic: 540, TIV-Yam: 537) were enrolled in this study. QIV was found non-inferior to TIVs for shared strains (A/H1N1 and A/H3N2) and corresponding BY strain based on hemagglutination inhibition (HI) antibodies 28 days after the second dose of vaccination. The resulted geometric mean titer (GMT) ratios (QIV/TIV) were 0.98 (0.89, 1.07) for H1N1, 0.95 (0.85, 1.05) for H3N2 and 0.89 (0.81, 0.98) for BY. And the seroconversion rate differences (QIV-TIV) were −0.46% (−3.24%, 2.31%) for H1N1, −1.95% (−5.54%, 1.65%) for H3N2 and −3.58% (−8.11%, 0.95%) for BY. The BV strain in QIV did not reach the non-inferiority criteria, with GMT of 1:52.25 (vs. 1:61.02 of TIV–Vic) and seroconversion rate of 59.49% (vs. 66.85% of TIV–Vic). No increased safety concerns occurred in QIV group. Candidate QIV can provide good protection for children aged 6 to 35 months, and its immunogenicity and safety were proved. Clinical Trials Registration ClinicalTrials.gov number: NCT03859141.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in healthy subjects aged 3 to 17 years old: A phase III, open label, single-arm study

BackgroundQuadrivalent influenza vaccines are particularly valuable during seasons in which a mismatch occurs between the predicted influenza B lineage for the trivalent influenza vaccine and the circulating strain. This study evaluated the immunogenicity and safety of a quadrivalent inactivated influenza vaccine AdimFlu-S manufactured in Taiwan for the 2016–2017 influenza season in healthy children. MethodsA total of 174 healthy children aged 3 to 17 years old were separated into 3 groups (Group A: 3–8 years old, vaccine naïve; Group B: 3–8 years old, vaccine non-naïve; Group C: 9–17 years old, any vaccine status). Sera was collected pre and post vaccination for each participant. A hemagglutination inhibition (HAI) assay was utilized to calculate geometric mean titer (GMT), seroprotection rate, and seroconversion rate. ResultsAll enrolled participants completed the study. For the four vaccine strains four weeks after the last vaccination, geometric mean titer ratios (GMTRs) were between 2.9 and 20.9, seroconversion rates were between 42.9% and 90.9%, and seroprotection rates were all above 96.4%. This achieved all immunogenicity endpoints and fulfilled the criteria of the European Medical Agency’s Committee for Medicinal Products for Human Use (CHMP). No serious adverse events (AEs) were reported during the follow-up period of 6 months. ConclusionThis quadrivalent influenza vaccine is demonstrated to be well tolerated and displays robust immunogenicity for each influenza strain. This could potentially improve protection against the antigenically distinct B/Yamagata and B/Victoria lineages.

A Phase 2/3 double blinded, randomized, placebo-controlled study in healthy adult participants in Vietnam to examine the safety and immunogenicity of an inactivated whole virion, alum adjuvanted, A(H5N1) influenza vaccine (IVACFLU-A/H5N1)

BackgroundA global shortfall of vaccines for avian influenza A(H5N1) would occur, especially in low- and-middle income countries, if a pandemic were to occur. To address this issue, development of a pre-pandemic influenza vaccine was initiated in 2012, leveraging a recently established influenza vaccine manufacturing capacity in Vietnam. MethodsThis was a Phase 2/3, double-blinded, randomized, placebo-controlled study to test the safety and immunogenicity of IVACFLU-A/H5N1 vaccine in healthy adults. Phase 2 was a dose selection study, in which 300 participants were randomized to one of the three groups (15 mcg, 30 mcg, or placebo). Safety and immunogenicity were assessed in all participants. In Phase 3, 630 participants were randomized to receive the IVACFLU-A/H5N1 vaccine dose selected in Phase 2 (15 mcg, n = 525) or placebo (n = 105). Safety was assessed in all Phase 3 participants and immunogenicity was measured in a subset of participants. ResultsThe vaccine was well tolerated and most of the adverse events were mild and of short duration. Mild pain at the injection site was the most common adverse event seen in 60 percent of participants in the vaccine group in Phase 3. In Phase 2, both 15 mcg and 30 mcg doses were immunogenic, so the lower dose was selected for further testing in Phase 3. In Phase 3 overall seroconversion rates were 68 percent for hemagglutination inhibition (HI), 51 percent for microneutralization (MN) and 56 percent for single radial hemolysis (SRH). The seroprotection rates were 44 percent for HI, 41 percent for MN and 55 percent for SRH. The GMT ratio was 5.31 and 3.7 for HI and MN respectively; GMA was 4.75 for the SRH. ConclusionThe IVACFLU A/H5N1 was safe and immunogenic. Development of this pandemic avian influenza vaccine is a welcome addition to the limited global pool of these vaccines.ClinicalTrials.gov register NCT02612909.

Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis

BackgroundIdentifying optimal priming strategies for children <2 years could substantially improve the public health benefits of influenza vaccines. Adjuvanted seasonal influenza vaccines were designed to promote a better immune response among young vaccine-naïve children. MethodsWe systematically reviewed randomized trials to assess hemagglutination inhibition (HAI) antibody response to MF59-adjuvanted inactivated influenza vaccine (aIIV) versus nonadjuvanted IIV among children. We estimated pooled ratios of post-vaccination HAI geometric mean titer (GMT) for aIIV versus IIV and confidence intervals (CIs) using the pooled variances derived from reported CIs. ResultsMean age was 28 months (range, 6–72 months). Children received vaccines with either 7.5 μg (6–35 months) or 15 μg (≥36 months) hemagglutinin of each strain depending on age. Seven of eight trials administered trivalent vaccines and one used quadrivalent vaccine. Pooled post-vaccination GMT ratios against the three influenza vaccine strains were 2.5–3.5 fold higher after 2-dose-aIIV versus 2-dose-IIV among children 6–72 months, and point estimates were higher among children 6–35 months compared with older children. When comparing 1-dose-aIIV to 2-dose-IIV doses, pooled GMT ratios were not significantly different against A/H1N1 (1.0; 95% CI: 0.5–1.8; p = 0.90) and A/H3N2 viruses (1.0; 95% CI: 0.7–1.5; p = 0.81) and were significantly lower against B viruses (0.6; 95% CI: 0.4–0.8; p < 0.001) for both age groups. Notably, GMT ratios for vaccine-mismatched heterologous viruses after 2-dose-aIIV compared with 2-dose-IIV were higher against A/H1N1 (2.0; 95% CI: 1.1–3.4), A/H3N2 (2.9; 95% CI: 1.9–4.2), and B-lineage viruses (2.1; 95% CI: 1.8–2.6). ConclusionsTwo doses of adjuvanted IIV consistently induced better humoral immune responses against Type A and B influenza viruses compared with nonadjuvanted IIVs in young children, particularly among those 6–35 months. One adjuvanted IIV dose had a similar response to two nonadjuvanted IIV doses against Type A influenza viruses. Longer-term benefits from imprinting and cell-mediated immunity, including trials of clinical efficacy, are gaps that warrant investigation.

Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5–6 years after completion of the primary series

ABSTRACT The tetravalent dengue vaccine (CYD-TDV; Dengvaxia®) is administered on a three-dose schedule, 6 months apart in those aged ≥9 years in a number of dengue-endemic countries in Asia and Latin America. In this study, CYD63 (NCT02824198), participants aged 9–45 years at first vaccination, and who had received three doses of CYD-TDV in the CYD28 study more than 5 years previously, were randomized 3:1 to receive a booster CYD-TDV dose (Group 1) or placebo (Group 2). Dengue neutralizing antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were assessed in sera collected before and 28 days after booster injections. Non-inferiority of the booster immune response versus that induced after the third dose was demonstrated for each serotype if the lower limit of the two-sided 95% confidence interval (CI) was >0.5 for the GMT ratios (GMTRs) between post-booster CYD-TDV dose and post-dose 3 in Group 1. Overall, 118 participants received CYD-TDV booster or placebo and 116 (98.3%) completed the study; two participants were withdrawn because of noncompliance. GMTs in the booster CYD-TDV group increased across all serotypes post-booster injection by 1.74- (serotype 1) to 3.58-fold (serotype 4). No discernible increases were observed in the placebo group. Non-inferiority was demonstrated for serotypes 1, 3, and 4, but not for serotype 2 (GMTR; 0.603 [95% CI, 0.439– 0.829]). No safety issues were observed. These data show that the CYD-TDV booster given 5 or more years later tended to restore GMTs back to levels observed post-dose 3.

Quadrivalent Influenza Vaccine-Induced Antibody Response and Influencing Determinants in Patients ≥ 55 Years of Age in the 2018/2019 Season.

The effects of immunization with subunit inactivated quadrivalent influenza vaccine (QIV) are not generally well assessed in the elderly Polish population. Therefore, this study evaluated vaccine-induced antibody response and its determinants. Methods: Consecutive patients ≥ 55 years old, attending a Primary Care Clinic in Gryfino, Poland, received QIV (A/Michigan/ 45/2015(H1N1)pdm09, A/Singapore/INFIMH-16-0019/2016 (H3N2), B/Colorado/06/2017, B/Phuket/ 3073/2013) between October-December 2018. Hemagglutination inhibition assays measured antibody response to vaccine strains from pre/postvaccination serum samples. Geometric mean titer ratio (GMTR), protection rate (PR) and seroconversion rate (SR) were also calculated. Results: For 108 patients (54.6% males, mean age: 66.7 years) the highest GMTR (61.5-fold) was observed for A/H3N2/, then B/Colorado/06/2017 (10.3-fold), A/H1N1/pdm09 (8.4-fold) and B/Phuket/ 3073/2013 (3.0-fold). Most patients had post-vaccination protection for A/H3N2/ and B/Phuket/3073/ 2013 (64.8% and 70.4%, respectively); lower PRs were observed for A/H1N1/pdm09 (41.8%) and B/Colorado/06/ 2017 (57.4%). The SRs for A/H3N2/, A/H1N1/pdm09, B Victoria and B Yamagata were 64.8%, 38.0%, 46.8%, and 48.2%, respectively. Patients who received QIV vaccination in the previous season presented lower (p < 0.001 and p = 0.03, respectively) response to B Victoria and B Yamagata. Conclusions: QIV was immunogenic against the additional B lineage strain (B Victoria) without significantly compromising the immunogenicity of the other three vaccine strains, therefore, adding a second B lineage strain in QIV could broaden protection against influenza B infection in this age group. As the QIV immunogenicity differed regarding the four antigens, formulation adjustments to increase the antigen concentration of the serotypes that have lower immunogenicity could increase effectiveness. Prior season vaccination was associated with lower antibody response to a new vaccine, although not consistent through the vaccine strains.

2775. Safety and Immunogenicity of a Seasonal Influenza Vaccine and Ad26.RSV.preF Vaccine With and Without Co-Administration: A Randomized, Double-Blind, Placebo-Controlled Phase 2a Study in Adults Aged ≥ 60 Years

BackgroundInfluenza and RSV can cause respiratory tract infections leading to severe illness, hospitalization and mortality in at-risk populations, particularly the elderly. The seasonality of influenza and RSV present the potential to co-administer vaccines. This study aimed to demonstrate the non-inferiority of co-administration of the experimental RSV vaccine Ad26.RSV.preF with an influenza vaccine (Fluarix) vs. Fluarix alone in terms of immunogenicity against influenza.MethodsThis was a single-center, randomized, double-blind, placebo-controlled Phase 2a study (NCT03339713) in healthy adults ≥60 years old. Volunteers were randomized 1:1 to receive Fluarix + 1 × 1011 vp Ad26.RSV.preF on Day 1 and placebo on Day 29 (Group 1), or Fluarix + placebo on Day 1 and 1 × 1011 vp Ad26.RSV.preF on Day 29 (Group 2). Blood samples were taken prior to each vaccination and at Day 57. The primary endpoints were geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibody titers against Fluarix strains (A/Michigan, A/Hong Kong, B/Brisbane and B/Phuket) and the safety and tolerability of Ad26.RSV.preF administered with or without Fluarix. A key secondary endpoint was neutralizing antibody titers to RSV A2.ResultsVolunteers (N = 180) were included in Group 1 (n = 90) or Group 2 (n = 90). Most volunteers were white (89%) and female (63%), with a median age of 65 years. Both groups exhibited an increase from baseline in HI antibody response on Day 29. The 95% one-sided upper confidence limit of all GMT ratios were below the non-inferiority margin of 2. The frequency of solicited adverse events (AE) after Ad26.RSV.preF vaccination was similar with and without influenza co-administration. Solicited AEs were mainly of Grade 1 and 2 and of transient duration. Most unsolicited AEs were considered unrelated to the study vaccination and were Grade 1 or 2. There were no serious AEs related to the study vaccine and there were no discontinuations due to AEs. RSV neutralizing antibody titers 29 days post- Ad26.RSV.preF immunization were similar in both groups (1404, Group 1; 1690, Group 2).ConclusionCo-administration of Ad26.RSV.preF with Fluarix was non-inferior to Fluarix alone in terms of immunogenicity against influenza and had an acceptable tolerability profile.Disclosures All authors: No reported disclosures.

Immunogenicity and safety of MF59-adjuvanted quadrivalent influenza vaccine versus standard and alternate B strain MF59-adjuvanted trivalent influenza vaccines in older adults

ObjectiveEvaluate whether adjuvanted quadrivalent influenza vaccine (aQIV) elicits a noninferior immune response compared with a licensed adjuvanted trivalent influenza vaccine (aTIV-1; Fluad™) and aTIV-2 containing an alternate B strain, examine whether aQIV had immunological superiority for the B strain absent from aTIV comparators, and evaluate reactogenicity and safety among adults ≥65 years. MethodsIn a multicenter, double-blind, randomized controlled trial, adults ≥65 years were randomized 2:1:1 to vaccination with aQIV (n = 889), aTIV-1 (n = 445), or aTIV-2 (n = 444) during the 2017-2018 influenza season. Immunogenicity was assessed by hemagglutination inhibition (HI) assay conducted on serum samples collected before vaccination and 21 days after vaccination for homologous influenza strains. ResultsaQIV met non-inferiority criteria for geometric mean titer ratios (GMT ratios) and seroconversion rate (SCR) differences against aTIV. The upper bounds of the 2-sided 95% confidence interval (CI) for GMT ratios were <1.5 for all 4 strains (A/H1N1 = 1.27, A/H3N2 = 1.09, B-Yamagata = 1.08, B-Victoria = 1.08). The upper bounds of the 95% CI of the SCR differences were <10% for all 4 strains (A/H1N1 = 7.76%, A/H3N2 = 4.96%, B-Yamagata = 3.27%, B-Victoria = 2.55%). aQIV also met superiority criteria (upper bound of 95% CI for GMT ratios <1 and SCR differences <0) for B strain absent from aTIV comparators (B-Yamagata GMT ratio = 0.70, SCR difference = −8.81%; B-Victoria GMT ratio = 0.78, SCR difference = −8.11%). aQIV and aTIV vaccines were immunogenic and well-tolerated. The immunological benefit of aQIV was also demonstrated in age subgroups 65–74 years, 75–84 years, and ≥85 years and in those with high comorbidity risk scores. Reactogenicity profiles were generally comparable. ConclusionaQIV induces a similar immune response as the licensed aTIV vaccine against homologous influenza strains and has a comparable reactogenicity and safety profile. Superior immunogenicity against the additional B strain was observed, indicating that aQIV could provide a broader protection than aTIV against influenza in older adults (NCT03314662).