Seasonal Influenza Vaccine Strains Research Articles

Impact of Therapy on the Anamnestic Response to Seasonal Influenza Vaccination in Patients with Myeloid Malignancies

Myelodysplastic syndromes (MDS) are diseases of bone marrow failure that result in dysplasia of multiple hematopoietic lineages producing anemia, thrombocytopenia, and increased risk of infections. While progression to acute myeloid leukemia (AML) is a phenomenon that receives most of the focus in managing this disease, prior studies have shown that infection is the leading cause of mortality. This is true across all MDS risk groups and highlights the critical importance of research into the clinical management and prevention of infection in patients with MDS, especially in the age of emergent pandemics such as COVID-19. We have previously observed that patients with MDS exhibit decreased responses to vaccination against SARS-CoV-2 (Bellusci, et al., Blood, 2022). There remains a gap in our knowledge regarding the success of vaccination against common seasonal pathogens in patients with MDS, such as influenza. Although patients with MDS and AML are routinely offered yearly influenza vaccination during the flu season, the efficacy of vaccination in producing immunity in the context of the underlying disease biology and the impact of therapies used for treatment of the disease (azacitidine & decitabine (HMAs), venetoclax + HMA and cytarabine based intensive chemotherapy) remains understudied. We hypothesized that MDS/AML patients would exhibit a decreased response to vaccination against seasonal influenza compared to healthy age-matched controls. To test this hypothesis, we enrolled patients in an IRB-approved non-randomized study (I-54017) that spanned the 2017-2018 to 2020-2021 influenza seasons. This study examined 5 patient groups: Cohort 1: Patients with MDS on best supportive care (ESAs, growth factors, transfusions, antibiotics; no disease modifying therapy; n = 28); Cohort 2: Patients with MDS or AML early in HMA therapy (≤5 cycles; n = 26); Cohort 3: Patients with MDS or AML on longer term HMA (> 6 cycles; n = 28); Cohort 4: Patients with AML receiving cytarabine based intensive chemotherapy ("7+3", HIDAC, CLAG+/-M, FLAG+/-Ida, etc.). Patients in this arm should not have received an HMA in the 6 months prior to enrollment (n = 10); Cohort 5: Healthy volunteers of similar age profile without antecedent or concurrent hematologic disorders (n = 12). All subjects received the yearly Fluzone High-Dose vaccine (Sanofi). Serum samples were collected at 1) baseline; 2) days 25-95 after vaccination; and 3) days 115-185 after vaccination. Viral titers were measured using the viral microneutralization assay against seasonal influenza vaccine strains based upon the yearly vaccine product. Positive responses to vaccination were defined as a 4-fold increase in titer compared to baseline. For each subject, we calculated a strain score (range 0-1) based on the fraction of 4-fold changes across either 3 to 4 influenza strains depending upon the yearly vaccination product; a score of 1 indicates a 4-fold increase in titers against all tested strains. Strain score was modeled as a function of study year, disease cohort, and age; blood-type, gender, race, and IPSS-M were analyzed but were not statistically significant. The primary analysis was a generalized linear model (GLM). In concert with prior reports, we found that compared to healthy donors, AML patients receiving intensive chemotherapy showed decreased vaccine response (Fig.1). In contrast, those with MDS responded equivalently to vaccination compared with healthy donors. Overall, these results demonstrate that in contrast with vaccination against newly emergent diseases (COVID-19) against which MDS patients appear to have inferior immune response, anamnestic responses to vaccination against previously encountered pathogens (influenza) are normal. As reported previously, patients with AML receiving intensive chemotherapy exhibit reduced protection from vaccination against both emergent pathogens (COVID-19) and amnestic vaccines (influenza). These results indicate that vaccination boosters, such as those given yearly against influenza, against previously encountered pathogens are likely to provide protection in MDS patients irrespective of standard therapy, but the efficacy of vaccination against novel pathogens may be less effective. These data highlight the complex immune milieu in patients with MDS and emphasize the importance of careful individualized vaccination strategies in those with hematological malignancy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Functional and structural modifications of influenza antibodies during pregnancy

SummaryPregnancy represents a unique tolerogenic immune state which may alter susceptibility to infection and vaccine response. Here, we characterized humoral immunity to seasonal influenza vaccine strains in pregnant and non-pregnant women. Although serological responses to influenza remained largely intact during late pregnancy, distinct modifications were observed. Pregnant women had reduced hemagglutinin subtype-1 (H1)- IgG, IgG1, IgG2, and IgG3, hemagglutination inhibition, and group 1 and 2 stem IgG titers. Intriguingly, H1-specific avidity and FcγR1 binding increased, and influenza antibodies had distinct Fc and Fab glycans characterized by increased di-galactosylation and di-sialylation. H1-specific Fc-functionality (i.e. monocyte phagocytosis and complement deposition) was moderately reduced in pregnancy. Multivariate antibody analysis revealed two distinct populations (pregnant vs. non-pregnant) segregated by H1 FcγR1 binding, H1-IgG levels, and Fab and Fc glycosylation. Our results demonstrated a structural and functional modulation of influenza humoral immunity during pregnancy that was antigen-specific and consistent with reduced inflammation and efficient placental transport

Antigenic evolution of influenza virus and the implications for influenza vaccine development

Influenza virus has a continuous and extensive impact on human health around the world. Its extensive animal host characteristics and highly variable characteristics lead to continuous antigen drift and change of susceptible populations, causing repeated global influenza epidemics, and also affecting the protective effect of seasonal influenza vaccine. This research in a number of subtypes of influenza a virus, for example, from the antigenic drift of antigenicity, influence of the seasonal influenza vaccine strains and popular strain compatibility, broad-spectrum flu vaccine development train of thought, etc. summarizes the progress of relevant research, to deepen the understanding of the influenza virus antigenic evolution, provide reference for flu vaccine development in the future.

Automated recommendation of the seasonal influenza vaccine strain with PREDAC

Vaccination is currently the most effective way to protect against influenza viruses. This study presents PREDAC (PREDict Antigenic Cluster), a sequence-based computational method to model antigenic clusters of influenza viruses. PREDAC could improve vaccine recommendations for influenza viruses and has been used to support the influenza vaccine strain recommendations at the Chinese National Influenza Center. Moreover, a PREDAC server which includes tools for the prediction of antigenic variants and antigenic clusters of both influenza A and B viruses was built and made publicly available at http://www.computationalbiology.cn/home/. PREDAC could not only facilitate systematic studies of the antigenic evolution of influenza viruses but also provide user-friendly tools for vaccine strain recommendations for influenza viruses.

Quantification of Humoral Immune Response to Influenza Vaccination in MDS

Quantification of Humoral Immune Response to Influenza Vaccination in MDS

Cross-protection to new drifted influenza A(H3) viruses and prevalence of protective antibodies to seasonal influenza, during 2014 in Portugal

IntroductionImmune profile for influenza viruses is highly changeable over time. Serological studies can assess the prevalence of influenza, estimate the risk of infection, highlight asymptomatic infection rate and can also provide data on vaccine coverage. The aims of the study were to evaluate pre-existing cross-protection against influenza A(H3) drift viruses and to assess influenza immunity in the Portuguese population. Materials and methodsWe developed a cross-sectional study based on a convenience sample of 626 sera collected during June 2014, covering all age groups, both gender and all administrative health regions of Portugal. Sera antibody titers for seasonal and new A(H3) drift influenza virus were evaluated by hemagglutination inhibition assay (HI). Seroprevalence to each seasonal influenza vaccine strain virus and to the new A(H3) drift circulating strain was estimated by age group, gender and region and compared with seasonal influenza-like illness (ILI) incidence rates before and after the study period. ResultsOur findings suggest that seroprevalences of influenza A(H3) (39.9%; 95% CI: 36.2–43.8) and A(H1)pdm09 (29.7%; 95% CI: 26.3–33.4) antibodies were higher than for influenza B, in line with high ILI incidence rates for A(H3) followed by A(H1)pdm09, during 2013/2014 season. Low pre-existing cross-protection against new A(H3) drift viruses were observed in A(H3) seropositive individuals (46%). Both against influenza A(H1)pdm09 and A(H3) seroprotection was highest in younger than 14-years old. Protective antibodies against influenza B were highest in those older than 65years old, especially for B/Yamagata lineage, 33.3% (95% CI: 25.7–41.9). Women showed a high seroprevalence to influenza, although without statistical significance, when compared to men. A significant decreasing trend in seroprotection from north to south regions of Portugal mainland was observed. ConclusionsOur results emphasize that low seroprotection increases the risk of influenza infection in the following winter season. Seroepidemiological studies can inform policy makers on the need for vaccination and additional preventive measures.

Neutralizing activities against seasonal influenza viruses in human intravenous immunoglobulin.

Influenza viruses A/H1N1, A/H3N2, and B are known seasonal viruses that undergo annual mutation. Intravenous immunoglobulin (IVIG) contains anti-seasonal influenza virus globulins. Although the virus-neutralizing (VN) titer is an indicator of protective antibodies, changes in this titer over extended time periods have yet to be examined. In this study, variations in hemagglutination inhibition (HI) and VN titers against seasonal influenza viruses in IVIG lots over extended time periods were examined. In addition, the importance of monitoring the reactivity of IVIG against seasonal influenza viruses with varying antigenicity was evaluated. A/H1N1, A/H3N2, and B influenza virus strains and IVIG lots manufactured from 1999 to 2014 were examined. The HI titer was measured by standard methods. The VN titer was measured using a micro-focus method. IVIG exhibited significant HI and VN titers against all investigated strains. Our results suggest that the donor population maintains both specific and cross-reactive antibodies against seasonal influenza viruses, except in cases of pandemic viruses, despite major antigen changes. The titers against seasonal influenza vaccine strains, including past strains, were stable over short time periods but increased slowly over time.

Dynamic patterns of circulating influenza virus from 2005 to 2012 in Shandong Province, China.

To identify circulating emerging/reemerging viral strains and epidemiological trends, an influenza sentinel surveillance network was established in Shandong Province, China, in 2005. Nasal and/or throat swabs from patients with influenza-like-illness were collected at sentinel hospitals. Influenza viruses were detected by reverse transcription polymerase chain reaction (RT-PCR) or virus isolation. From October 2005 to March 2012, 7763 (21.44%) of 36,209 swab samples were positive for influenza viruses, including 5221 (67.25%) influenza A and 2542 (32.75%) influenza B. While the influenza viruses were detected year-round, their type/subtype distribution varied significantly. Peak influenza activity was observed from November to February. The proportion of laboratory-confirmed influenza cases was highest among participants aged 0-4years (14.97%) in the 2005-2009 and 2010-2012 influenza seasons and the positivity rate of influenza A(H1N1)pdm09 was highest in the 15 to 24year age group during the 2009-2010 influenza season. Genetic analysis of hemagglutinin (HA) and neuraminidase (NA) genes revealed that the viruses matched seasonal influenza vaccine strains in general, with some amino acid mutations. Influenza A(H1N1)pdm09 strains isolated in Shandong Province were characterized by an S203T mutation that is specific to clade 7 isolates. This report illustrates that the Shandong Provincial influenza surveillance system was sensitive in detecting influenza virus variability by season and by genetic composition. This system will help official public health target interventions such as education programs and vaccines.

Fluzone® High-Dose Influenza Vaccine with a Booster Is Associated with Low Rates of Influenza Infection in Patients with Plasma Cell Disorders

Background:Patients with plasma cell disorders (PCDs) are among the most susceptible to common infections including influenza and these infections are a major source of morbidity. Although seasonal influenza vaccination is routinely employed in patients with PCDs, the data about its efficacy are limited, as few studies have focused on this population. Based on historical data, PCD patients have a 10 fold increased risk of influenza and an expected yearly flu infection rate of at least 20%. The major surrogates for influenza vaccine response are hemaglutination antibody inhibition (HAI) titers; however rates of achieving protective HAI titers after standard influenza vaccination in PCD patients range from 5-19%. One approach to enhancing the efficacy of influenza vaccination is the use of standard dose boosters, and a recent study in multiple myeloma patients suggested improved seroprotection. Another approach may be increasing the amount of antigen in vaccines. Fluzone® high-dose vaccine was FDA approved in 2009 for adults aged 65 and older based on data regarding higher seroprotection rates but has not been studied specifically in PCD patients.Methods:In order to directly address the significant unmet need of improving vaccination strategies in patients with PCDs, we evaluated a novel vaccine strategy in patients with PCDs over the 2014-15 flu season that involved two doses of Fluzone® High-Dose influenza vaccination 30 days apart, regardless of age. Eligibility criteria allowed any patient with a PCD and no contraindication to trivalent inactivated influenza vaccine. The primary endpoint was laboratory confirmed flu infection rate. Patients were asked to report all flu-like illnesses for viral testing (PCR) and patients were asked about infectious symptoms at all study visits and at the end of the flu season in May 2015. A secondary endpoint is comparing rates of seroprotection with HAI titers and virus neutralization assays. Another secondary endpoint is to explore cell-mediated immunity through characterization of T cell subpopulations, cytokine profiles, and flu-specific T-cell responsiveness.Results:51 total PCD patients were enrolled (41 with disease requiring therapy and 10 with asymptomatic gammopathy) and all patients received two doses of Fluzone High-Dose vaccine. Median age was 75 years (range 36-90). This novel vaccination strategy was safely tolerated in all patients with no ≥ grade 2 adverse events attributed to vaccine. With close clinical follow-up, only 4% (2/51) of patients developed laboratory confirmed influenza. Preliminary data on a cohort of 30 multiple myeloma patients demonstrates that only 7% (2/30) had baseline protective HAI titers to all three seasonal influenza vaccine strains and after one Fluzone® High-Dose vaccine the seroprotection rate increased to 33% (10/30). Final seroprotection analysis and measurements of cell-mediated immunity are underway.Conclusions:This pilot study demonstrates that the two dose strategy of Fluzone® High-Dose influenza vaccine was safely tolerated in patients with PCD. The observed rate of seroprotective HAI after one dose of high dose vaccine was 33%, approximately double the historically observed rate of 5-19% after standard dose vaccine. The rate of seroconversion after the second dose is currently being analyzed and will be presented. Interestingly the rate of documented flu infections was only 4% compared to an expected 20% and may be due in part to the higher rate of seroconversion. These results suggest that this novel vaccination strategy is safe and may have a clinical benefit in improving HAI seroprotection and reducing documented flu infections in PCD patients. Given these encouraging clinical results, we are planning a randomized trial for the upcoming 2015-2016 influenza season comparing this novel vaccination strategy to standard of care vaccination in patients with plasma cell disorders. DisclosuresOff Label Use: In order to directly address the significant unmet need of improving vaccination strategies in patients with plasma cell disorders, we present a pilot study which evaluated a novel vaccine strategy over the 2014-15 flu season. Fluzone® High-Dose influenza vaccine was administered in a booster strategy (two doses 30 days apart)..

Challenges in antigenic characterization of circulating influenza A(H3N2) viruses during the 2011-2012 influenza season: an ongoing problem?

Genetic and antigenic characterization of 37 representative influenza A(H3N2) virus strains isolated in Greece during the 2011-2012 winter season was performed to evaluate matching of the viruses with the seasonal influenza vaccine strain A/Perth/16/2009. Hemagglutinin gene sequence analysis revealed that all Greek strains clustered within the Victoria/208 genetic clade. Furthermore, substitutions in the antigenic and glycosylation sites suggested potential antigenic drift. Our hemagglutination inhibition (HI) analysis showed that the Greek viruses were Perth/16-like; however, these viruses were characterized as Victoria/208-like when tested at the United Kingdom WHO Collaborating Centre (CC) with HI assays performed in the presence of oseltamivir, a finding consistent with the genetic characterization data. Variability in the HI test performance experienced by other European laboratories indicated that antigenic analysis of the A(H3N2) virus has limitations and, until its standardization, national influenza reference laboratories should include genetic characterization results for selection of representative viruses for detailed antigenic analysis by the WHO CCs.

Immunization with cross-conserved H1N1 influenza CD4+ T-cell epitopes lowers viral burden in HLA DR3 transgenic mice

The emergence of the pandemic H1N1 strain of influenza in 2009 was associated with a unique w-shaped age-related susceptibility curve, with higher incidence of morbidity and mortality among young persons and lower incidence among older persons, also observed during the 1918 influenza pandemic. Pre-existing H1N1 antibodies were not cross-reactive with the prior seasonal vaccine, forcing influenza experts to scramble to develop a new vaccine specific for the pandemic virus. We hypothesized that response to T-cell epitopes that are cross-conserved between pandemic H1N1 and the 2008 seasonal influenza vaccine strains might have contributed to partial protection from clinical illness among older adults, despite the lack of cross-reactive humoral immunity. Using immunoinformatics tools, we previously identified hemagglutinin and neuraminidase epitopes that were highly conserved between seasonal and pandemic H1N1. Here, we validated predicted CD4+ T-cell epitopes for their ability to bind HLA and to stimulate interferon-γ production in peripheral blood mononuclear cells from a cohort of donors presenting with influenza-like illness during the 2009 pandemic and a separate cohort immunized with trivalent influenza vaccine in 2011. A limited-epitope heterologous DNA-prime/peptide-boost vaccine composed of these sequences stimulated immune responses and lowered lung viral loads in HLA DR3 transgenic mice challenged with pandemic 2009 H1N1 influenza. Cross-priming with conserved influenza T-cell epitopes such as these may be critically important to T cell-mediated protection against pandemic H1N1 in the absence of cross-protective antibodies.

Cross immunity study of two different influenza A3 virus vaccine strain

To explore the cross immunity response between two similar strains of influenza A3 virus vaccine from 2007 to 2008. Healthy adults aged 18-60 years old without history of flu vaccination were inoculated Anflu ™( 52 cases) or VAXIGRIP ® (137 cases) influenza split vaccine. A micro-hemagglutination inhibition (HI) assay was used to test the serum specimens collected from the subjects before and after vaccination. The seroconversion rate, geometric mean titer (GMT) and antibody protective rate were used to evaluate the effect. The seroconversion rates of Anflu ™ and VAXIGRIP ® tested by A/Hiroshima/52/2005 virus antigen were 82.7% (95%CI: 69.2% - 91.8%) and 80.3% (95%CI: 72.4% - 86.5%) respectively and there was no significant difference (χ(2) = 0.141, P > 0.05). The seroconversion rates of Anflu™ and VAXIGRIP ® tested by A/Wisconsin/67/2005 (H3N2)-like virus antigen were 71.2% (95%CI: 56.7% - 82.8%) and 73.7% (95%CI: 65.4% - 80.8%) respectively and there was no significant difference observed (χ(2) = 0.126, P > 0.05). GMT of Anflu™ and VAXIGRIP ® tested by A/Hiroshima/52/2005 virus antigen after vaccination increased 11.5 (95%CI: 7.5 - 17.5) times and 13.0 (95%CI: 10.0 - 16.9) times without significant difference (F = 0.497, P > 0.05). GMT of Anflu ™ and VAXIGRIP ® tested by A/Wisconsin/67/2005 (H3N2)-like virus antigen after vaccination increased 9.5 (95%CI: 6.3 - 14.3) and 10.9 (95%CI: 8.5 - 13.7) times, and there was no significant difference either (F = 0.554, P > 0.05). The antibody protective rate of two vaccines before and after immunity tested by A/Hiroshima/52/2005 virus antigen were 48.1% and 54.7% before vaccination and 98.1% and 95.6%after vaccination respectively without significant difference (χ(2) = 0.135 - 0.673, P > 0.05). The antibody protective rates of two vaccines tested by A/Wisconsin/67/2005 (H3N2)-like virus antigen were 11.5% and 13.9%before vaccination and 80.8% and 86.1%after vaccination respectively, and there was no significant difference (χ(2) = 0.178 - 0.834, P > 0.05). But the results tested by A/Hiroshima/52/2005 virus antigen were higher than those of A/Wisconsin/67/2005 (H3N2)-like virus antigen (χ(2) = 7.111 - 52.155, P < 0.01). The two similar seasonal influenza vaccine strains recommended by WHO had a good cross immunity response, but the systematic error of test existed in two similar stains and the same strains should be used.

Symposium on viral respiratory disease surveillance

Recognition of the need for respiratory disease surveillance for informing prevention strategies dates back to the late 1940’s. Sir Christopher Andrews realized that the development of a successful influenza vaccination programme would be hindered by the unpredictable nature of the influenza virus and proposed the formation of a world influenza centre and a network of linked national laboratories which tracked influenza epidemics, to the World Health Organization (WHO). This network, now the WHO Global Influenza Surveillance Network (GISN) remains in place today and, although it’s primary goal is still to inform seasonal influenza vaccine strain selection, it has had to widen its activities to address emerging public health needs. There has been a renewed focus on understanding the overall burden of disease caused by influenza, especially in countries with no seasonal influenza prevention programmes, as a strategy to increase influenza awareness. While the zoonotic and pandemic threats from the highly pathogenic avian influenza (HPAI) H5N1 and H7N7 viruses and the realization that pandemic influenza arises from avian influenza viruses have stimulated global and national pandemic preparedness activities. Nevertheless, improved surveillance systems for both animal (avian and pig) and human influenza viruses are needed for informing and refining prevention strategies. Although the public health focus globally has been on influenza, the burden of disease caused by other respiratory viruses is also substantial and is largely under-recognised. A range of respiratory viruses are implicated in pneumonia, a disease recognised as a major killer of young children in developing countries and of the elderly in developed countries. There is also evidence that some respiratory viruses may be evolving allowing virulent variants to cause outbreaks in certain at-risk populations presenting another possible pandemic risk, highlighting the need to monitor unusual outbreaks of respiratory disease and the importance of the surveillance of respiratory viruses in general. Overall, prevention strategies for respiratory viruses other than influenza are less well defined, undoubtedly contributing to their perceived lower public health priority. Major advances in the diagnosis of respiratory virus infections have been made through the wider use of molecular diagnostic techniques which are now enabling rapid and sensitive respiratory pathogen surveillance. It is now possible to identify a wide range of respiratory pathogens in a higher proportion of respiratory infections, along with multiple pathogen infections. The application of these molecular techniques has also lead to the discovery of a number of new respiratory viruses; the clinical importance of the human metapneumovirus (hMPV) is now well established, while with others such as the human bocavirus (HBoV) and human rhinovirus type C (HRV-C), their clinical correlates are only just being elucidated. The knowledge base on these viruses urgently needs expanding through well designed controlled studies and other activities, including widened surveillance. The future challenge is to build on what has been achieved for the global surveillance of influenza by establishing standardized surveillance protocols which incorporate a widening range of respiratory viruses. The purpose being to inform and refine respiratory disease prevention strategies. These strategies must then be communicated to governments and public health messages developed for the education of the general public. DOI:10.1111/j.1750-2659.2010.00140.x www.influenzajournal.com