scholarly journals 2753. Induction of Broadly Cross-Reactive Immune Responses Against A(H3N2) Airuses: Results of a Phase 2 Trial of a Novel Recombinant Hemagglutinin Saponin-Adjuvanted Nanoparticle Seasonal Influenza Vaccine

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S970-S970
Author(s):  
Vivek Shinde ◽  
Rongman Cai ◽  
Joyce S Plested ◽  
Bin Zhou ◽  
Haixia Zhou ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Seasonal Influenza ◽  
Antibody Responses ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
High Dose ◽  
Phase 2 ◽  
Adaptive Mutations ◽  
Phase 2 Trial

Abstract Background We developed a recombinant saponin-adjuvanted (Matrix-M1) quadrivalent hemagglutinin nanoparticle influenza vaccine (qNIV; NanoFlu) for older adults to address two impediments to efficacy of current, predominantly egg-derived, seasonal influenza vaccines: (1) limited protection against antigenic drift variants, particularly H3N2 viruses; and (2) antigenic mismatch between vaccine and circulating strains due to egg-adaptive mutations arising during manufacturing. In a prior Phase 1 trial, we showed that qNIV induced robust, broadly cross-reactive antibody responses against multiple antigenically drifted H3N2 viruses, which were 47–64% better than the egg-derived comparator trivalent high-dose inactivated influenza vaccine (IIV3-HD; Fluzone-High Dose). We undertook a Phase 2 trial to optimize the formulation of qNIV, and to compare qNIV immune responses to those of IIV3-HD and quadrivalent recombinant influenza vaccine (RIV4; FluBlok). Methods In this phase 2 dose and formulation finding RCT, we randomized 1,375 subjects aged ≥65 years to be immunized with 1 of 7 test vaccines: 5 different formulations of qNIV, IIV3-HD, or RIV4; and assessed wild-type hemagglutinin-inhibition (wt-HAI) and microneutralization (wt-MN) antibody responses (Day 0/28/56). Results Matrix-M1-adjuvanted qNIV induced 15–29% higher wt-HAI titers across 5 vaccine homologous or drifted H3N2 strains at Day 28 relative to unadjuvanted qNIV (statistically significantly superior for 5 of 6 strains tested). At Day 28, several qNIV formulations induced significantly superior wt-HAI titers vs. IIV3-HD (39–45%, 17–22%, and 44–48% greater titers for homologous A/Singapore/INFIMH-16–0019/2016—H3N2, historic-drifted A/Switzerland/9715293/2013—H3N2, and forward-drifted A/Wisconsin/19/2017—H3N2, respectively); and comparable HAI titers vs. RIV4. Wt-MN and wt-HAI data showed concordant patterns across treatment groups. Conclusion qNIV induced superior wt-HAI antibody responses vs. IIV3-HD against homologous or drifted H3N2 viruses and similar responses to RIV4. qNIV may address several critical challenges confronting current egg-derived influenza vaccines, especially in the older adult population. Disclosures All authors: No reported disclosures.

scholarly journals Effectiveness of the MF59-adjuvanted trivalent or quadrivalent seasonal influenza vaccine among adults 65 years of age or older, a systematic review and meta-analysis

2021 ◽  
Author(s):  
Brenda Coleman ◽  
Ruth Sanderson ◽  
Mendel Haag ◽  
Ian McGovern
Keyword(s):  
Influenza Vaccine ◽  
Seasonal Influenza ◽  
Standard Dose ◽  
Meta Analysis ◽  
Grey Literature ◽  
Influenza Vaccines ◽  
High Dose ◽  
Case Control Studies ◽  
Cluster Randomized ◽  
Meta Analyses

Background: Standard dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response. Objective: To determine the effectiveness of seasonal MF59-adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high dose egg-based influenza vaccines among people ≥65 years old. Methods: Cochrane methodological standards and PRISMA-P guidelines were followed. Real-world evidence from non-interventional studies published in peer reviewed journals and grey literature from 1997 through to July 15, 2020, including cluster-randomized trials, were eligible. Two reviewers independently extracted data and risk of bias was assessed using the ROBINS-I tool. Results: Twenty-one studies conducted during the 2006/07-2019/20 influenza seasons were included in the qualitative review; 16 in the meta-analyses. Meta-analysis of test-negative studies found that aTIV reduced medical encounters due to lab-confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I2=0%) for general practitioner visits and 58.5% (40.7, 70.9; I2=52.9%) for hospitalized patients. The pooled estimate of VE from case-control studies was 51.3% (39.1, 61.1; I2=0%) against influenza- or pneumonia-related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza related medical encounters were 13.9% (4.2, 23.5; I2=95.9%) compared with TIV, 13.7% (3.1, 24.2; I2=98.8%) compared with QIV, and 2.8% (-2.9, 8.5; I2=94.5%) compared with HD TIV. Conclusions: Among adults ≥65 years aTIV demonstrated significant absolute VE, improved relative VE compared to non-adjuvanted standard-dose TIV/QIV, and comparable relative VE to high-dose TIV.

scholarly journals Comparison of the Safety and Immunogenicity of a Novel Matrix-M-adjuvanted Nanoparticle Influenza Vaccine with a Quadrivalent Seasonal Influenza Vaccine in Older Adults: A Randomized Controlled Trial

2020 ◽  
Author(s):  
Vivek Shinde ◽  
Iksung Cho ◽  
Joyce S Plested ◽  
Sapeckshita Agrawal ◽  
Jamie Fiske ◽  
...  
Keyword(s):  
Older Adults ◽  
Influenza Vaccine ◽  
Seasonal Influenza ◽  
Controlled Trial ◽  
Geometric Mean ◽  
Community Dwelling ◽  
Antibody Responses ◽  
Influenza Vaccines ◽  
P Values ◽  
Cytokine Analysis

Background: Improved seasonal influenza vaccines for older adults are urgently needed, which can induce broadly cross-reactive antibodies and enhanced T-cell responses, particularly against A(H3N2) viruses, while avoiding egg-adaptive antigenic changes. Methods: We randomized 2654 clinically-stable, community-dwelling adults ≥65 years of age 1:1 to receive a single intramuscular dose of either Matrix-M-adjuvanted quadrivalent nanoparticle influenza vaccine (qNIV) or a licensed inactivated influenza vaccine (IIV4) in this randomized, observer-blinded, active-comparator controlled trial conducted during the 2019-2020 influenza season. The primary objectives were to demonstrate the non-inferior immunogenicity of qNIV relative to IIV4 against 4 vaccine-homologous strains, based on Day 28 hemagglutination-inhibiting (HAI) antibody responses, described as geometric mean titers and seroconversion rate difference between treatment groups, and to describe the safety of qNIV. Cell-mediated immune (CMI) responses were measured by intracellular cytokine analysis. Findings: qNIV demonstrated immunologic non-inferiority to IIV4 against 4 vaccine-homologous strains as assessed by egg-based HAI antibody responses. Corresponding wild-type HAI antibody responses by qNIV were significantly higher than IIV4 against all 4 vaccine-homologous strains (22-66% increased) and against 6 heterologous A(H3N2) strains (34-46% increased), representing multiple genetically and/or antigenically distinct clades/subclades (all p-values <0.001). qNIV induced 3·1- to 3·9- and 4·0- to 4·9-fold increases in various polyfunctional phenotypes of antigen-specific effector CD4+ T-cells against A(H3N2) and B/Victoria strains at Day 7 post-vaccination, respectively, while corresponding fold-rises induced by IIV4 at Day 7 were 1·3-1·4 and 1·7-2·0 representing a 126-189% improvement in CMI responses for qNIV (all p-values <0·001). Local reactogenicity, primarily mild to moderate and transient pain, was higher in the qNIV group. Interpretation: qNIV was well tolerated and produced a qualitatively and quantitatively enhanced humoral and cellular immune response in older adults. These enhancements may be critical to improving the effectiveness of currently licensed influenza vaccines.

scholarly journals Development of a Pan-H1 Influenza Vaccine

2018 ◽  
Vol 92 (22) ◽  
Author(s):  
Nicole Darricarrère ◽  
Svetlana Pougatcheva ◽  
Xiaochu Duan ◽  
Rebecca S. Rudicell ◽  
Te-Hui Chou ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Immune Responses ◽  
Influenza Vaccine ◽  
Seasonal Influenza ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
The Past ◽  
Individual Strain ◽  
Humoral Responses ◽  
Virus Strains

ABSTRACT The efficacy of current seasonal influenza vaccines varies greatly, depending on the match to circulating viruses. Although most vaccines elicit strain-specific responses, some present cross-reactive epitopes that elicit antibodies against diverse viruses and remain unchanged and effective for several years. To determine whether combinations of specific H1 hemagglutinin (HA) antigens stimulate immune responses that protect against diverse H1 influenza viruses, we evaluated the antibody responses elicited by HA-ferritin nanoparticles derived from six evolutionarily divergent H1 sequences and two computationally optimized broadly reactive antigen (COBRA) HA antigens. Humoral responses were assessed against a panel of 16 representative influenza virus strains from the past 80 years. HAs from the strains A/NewCaledonia/20/1999 (NC99), A/California/04/2009 (CA09), A/HongKong/117/1977 (HK77), COBRA X6, or P1 elicited neutralization against diverse strains, and a combination of three wild-type HA or two COBRA HA nanoparticles conferred significant additional breadth beyond that observed with any individual strain. Therefore, combinations of H1 HAs may constitute a pan-H1 influenza vaccine. IMPORTANCE Seasonal influenza vaccines elicit strain-specific immune responses designed to protect against circulating viruses. Because these vaccines often show limited efficacy, the search for a broadly protective seasonal vaccine remains a priority. Among different influenza virus subtypes, H1N1 has long been circulating in humans and has caused pandemic outbreaks. In order to assess the potential of a multivalent HA combination vaccine to improve the breadth of protection against divergent H1N1 viruses, HA-ferritin nanoparticles were made and evaluated in mice against a panel of historical and contemporary influenza virus strains. Trivalent combinations of H1 nanoparticles improved the breadth of immunity against divergent H1 influenza viruses.

scholarly journals A Strategy to Elicit M2e-Specific Antibodies Using a Recombinant H7N9 Live Attenuated Influenza Vaccine Expressing Multiple M2e Tandem Repeats

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 133
Author(s):  
Daria Mezhenskaya ◽  
Irina Isakova-Sivak ◽  
Tatiana Kotomina ◽  
Victoria Matyushenko ◽  
Min-Chul Kim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Influenza Vaccine ◽  
Seasonal Influenza ◽  
Tandem Repeats ◽  
Phase 1 ◽  
Public Health Problem ◽  
Influenza Viruses ◽  
Antibody Responses ◽  
Passive Protection ◽  
Live Attenuated Influenza Vaccine

Influenza viruses remain a serious public health problem. Vaccination is the most effective way to prevent the disease; however, seasonal influenza vaccines demonstrate low or no effectiveness against antigenically drifted and newly emerged influenza viruses. Different strategies of eliciting immune responses against conserved parts of various influenza virus proteins are being developed worldwide. We constructed a universal live attenuated influenza vaccine (LAIV) candidate with enhanced breadth of protection by modifying H7N9 LAIV by incorporating four epitopes of M2 protein extracellular part into its hemagglutinin molecule. The new recombinant H7N9+4M2e vaccine induced anti-M2e antibody responses and demonstrated increased protection against heterosubtypic challenge viruses in direct and serum passive protection studies, compared to the classical H7N9 LAIV. The results of our study suggest that the H7N9+4M2e warrants further investigation in pre-clinical and phase 1 clinical trials.

scholarly journals Summary of the National Advisory Committee on Immunization (NACI) Seasonal Influenza Vaccine Statement for 2021–2022

2021 ◽  
Vol 47 (09) ◽  
pp. 372-380
Author(s):  
Angela Sinilaite ◽  
◽  
Kelsey Young ◽  
Robyn Harrison
Keyword(s):  
High Risk ◽  
Influenza Vaccine ◽  
Advisory Committee ◽  
Seasonal Influenza ◽  
Health Agency ◽  
Influenza Vaccines ◽  
High Dose ◽  
Influenza Immunization ◽  
Vaccine Recommendations ◽  
Adults And Children

Background: Several influenza vaccines are authorized in Canada and the evidence on influenza immunization is continually evolving. The National Advisory Committee on Immunization (NACI) provides recommendations regarding the use of seasonal influenza vaccines annually to the Public Health Agency of Canada (PHAC). Objective: To summarize NACI recommendations regarding the use of seasonal influenza vaccines for 2021–2022 and to highlight new recommendations. Methods: Annual influenza vaccine recommendations are developed by NACI's Influenza Working Group for consideration and approval by NACI. The development of the recommendations is based on the NACI evidence-based process. Results: The following new recommendations were made: 1) Influvac® Tetra may be considered as an option among the standard dose quadrivalent inactivated influenza vaccines (IIV4-SD) offered to adults and children three years of age and older; 2) Fluzone High Dose Quadrivalent (IIV4-HD) may be considered an option for individuals 65 years of age and older who are currently recommended to receive Fluzone® High Dose (trivalent); and 3) Flucelvax® Quad may be considered amongst the quadrivalent influenza vaccines offered to adults and children nine years of age and older for annual influenza immunization. Guidance for use of influenza immunizations during the coronavirus disease 2019 pandemic is also highlighted. Conclusion: NACI continues to recommend that an age-appropriate influenza vaccine should be offered annually to anyone six months of age and older who does not have contraindications to the vaccine. Vaccination should be offered as a priority to people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk of complications, and others as indicated.

scholarly journals An Antigenic Thrift-Based Approach to Influenza Vaccine Design

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 657
Author(s):  
Jai S. Bolton ◽  
Hannah Klim ◽  
Judith Wellens ◽  
Matthew Edmans ◽  
Uri Obolski ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Influenza Season ◽  
Vaccine Design ◽  
Antigenic Drift ◽  
Influenza Vaccines ◽  
Immune Protection ◽  
Immune Selection ◽  
Drift Theory ◽  
Gradual Accumulation ◽  
Additional Constraints

The antigenic drift theory states that influenza evolves via the gradual accumulation of mutations, decreasing a host’s immune protection against previous strains. Influenza vaccines are designed accordingly, under the premise of antigenic drift. However, a paradox exists at the centre of influenza research. If influenza evolved primarily through mutation in multiple epitopes, multiple influenza strains should co-circulate. Such a multitude of strains would render influenza vaccines quickly inefficacious. Instead, a single or limited number of strains dominate circulation each influenza season. Unless additional constraints are placed on the evolution of influenza, antigenic drift does not adequately explain these observations. Here, we explore the constraints placed on antigenic drift and a competing theory of influenza evolution – antigenic thrift. In contrast to antigenic drift, antigenic thrift states that immune selection targets epitopes of limited variability, which constrain the variability of the virus. We explain the implications of antigenic drift and antigenic thrift and explore their current and potential uses in the context of influenza vaccine design.

scholarly journals Intersection of Sex and Frailty in Humoral Immune Responses to Influenza Vaccine in Community-Dwelling Older Adults

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 271-272
Author(s):  
Janna Shapiro ◽  
Helen Kuo ◽  
Rosemary Morgan ◽  
Huifen Li ◽  
Sabra Klein ◽  
...  
Keyword(s):  
Older Adults ◽  
Immune Responses ◽  
Influenza A ◽  
Community Dwelling ◽  
Influenza Vaccines ◽  
Health Study ◽  
Cardiovascular Health Study ◽  
High Dose ◽  
Humoral Immune ◽  
Humoral Immune Responses

Abstract Older adults bear the highest burden of severe disease and complications associated with seasonal influenza, with annual vaccination serving as the best option for protection. Variability in vaccine efficacy exists, yet the host factors that affect immune responses to inactivated influenza vaccines (IIV) are incompletely understood. We hypothesized that sex and frailty interact to affect vaccine-induced humoral responses among older adults. To test this hypothesis, community-dwelling adults above 75 years of age were recruited yearly, assessed for frailty (as defined by the Cardiovascular Health Study criteria), and vaccinated with the high-dose trivalent IIV. Humoral immune responses were evaluated via hemagglutination inhibition titers. The study began during the 2014-2015 influenza season, with yearly cohorts ranging from 76-163 individuals. A total of 617 vaccinations were delivered from 2014-2019. In preliminary analyses, the outcome of interest was seroconversion, defined as ≥ 4-fold rise in titers. Crude odds ratios suggest that females are more likely to seroconvert to influenza A strains (H1N1: OR = 1.39, (0.98-1.96) ; H3N2: 1.17 (0.85 – 1.62)), while males are more likely to seroconvert to the B strain (OR = 0.85 (0.60 – 1.22)). Furthermore, this sex difference was modified by frailty – for example, the odds of seroconversion to H1N1 were 65% higher for females than males among those who were nonfrail, and only 30% higher among females who were frail. Together, these results suggest that sex and frailty interact to impact immune responses to influenza vaccines. These findings may be leveraged to better protect vulnerable populations.

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