High-dose trivalent influenza vaccine: safety and immunogenicity

Adults aged 65 years or older suffer the most severe health effects of seasonal flu. Although the influenza vaccine is effective in preventing influenza virus infection and its complications, it is not as effective in the elderly due to age-associated immunosenescence phenomenon. Since 2009, a high-dose trivalent influenza vaccine has been approved in the United States for the immunization of people ≥ 65 years with an antigen concentration four times higher than the standard vaccine. Multiple clinical trials carried out over different seasons, and using different methodologies, have shown that the high-dose trivalent influenza vaccine is not only more effective, but it also has a similar safety profile and is more immunogenic than the standard dose vaccine in the prevention of flu and its complications in the elderly. This document reviews the current scientific evidence on the safety and immunogenicity of high-dose influenza vaccine in people aged 65 years and over, and includes information from randomized clinical trials, observational studies with data from real clinical practice, and systematic reviews, and meta-analysis.

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High-dose trivalent influenza vaccine. Efficacy and effectiveness

Revista Española de Quimioterapia ◽

10.37201/req/043.2020 ◽

2020 ◽

Vol 33 (4) ◽

pp. 226-239

Author(s):

Ángel Gil de Miguel ◽

Esther Redondo Marguello ◽

Javier Díez Domingo ◽

Raúl Ortiz de Lejarazu ◽

Federico Martinón Torres ◽

...

Keyword(s):

Clinical Trials ◽

Influenza Virus ◽

Virus Infection ◽

Influenza Vaccine ◽

Older People ◽

Standard Dose ◽

Influenza Virus Infection ◽

High Dose ◽

Trivalent Influenza Vaccine ◽

Dose Vaccine

Seasonal influenza is a major public health problem, particularly in older people. Influenza vaccine is the most effective way to prevent influenza virus infection and its complications, but due to immunosenescence, older people do not respond efficiently to immunization. In 2009, a high-dose trivalent influenza vaccine (IIV3-HD), containing four times more antigen than the standard-dose vaccine, was approved in the United States for the immunization of people aged 65 years and over. Numerous clinical trials, carried out at different seasons and using different methodologies, have shown that the IIV3-HD vaccine is, as well as safe, more immunogenic and more effective than the standard-dose vaccine in preventing influenza virus infection and its complications in older people. This paper reviews the available evidence on the efficacy and effectiveness of the IIV3-HD influenza vaccine in the elderly, with information from randomized clinical trials, as well as observational studies of real-world clinical practice and in systematic reviews/meta-analyses.

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Vaccine effectiveness for influenza in the elderly in welfare nursing homes during an influenza A (H3N2) epidemic

Epidemiology and Infection ◽

10.1017/s0950268899004410 ◽

2000 ◽

Vol 125 (2) ◽

pp. 393-397 ◽

Cited By ~ 10

Author(s):

Y. DEGUCHI ◽

Y. TAKASUGI ◽

K. NISHIMURA

Keyword(s):

Nursing Homes ◽

Influenza Vaccine ◽

Influenza A ◽

Hospital Admissions ◽

Influenza Virus Infection ◽

Severe Infection ◽

The Elderly ◽

Trivalent Influenza Vaccine ◽

Homes For The Elderly ◽

Vaccine Effect

Influenza vaccine effect on the occurrence and severity of influenza virus infection in a population residing in nursing homes for the elderly was studied as a cohort study during an influenza A (H3N2) epidemic in Japan. Of 22462 individuals living in 301 welfare nursing homes, 10739 voluntarily received inactivated, sub-unit trivalent influenza vaccine in a programme supported by the Osaka Prefectural Government. There were statistically significantly fewer cases of influenza, hospital admissions due to severe infection, and deaths due to influenza in the vaccinated cohort compared to the unvaccinated controls. No serious adverse reactions to vaccination were recorded. Thus influenza vaccination is effective for preventing influenza disease in persons aged 65 years and over, and should be an integral part of the care of this population residing in nursing homes.

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LB14. Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine Administered by Intramuscular Route in Subjects Aged 65 Years and Older

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy229.2188 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S764-S764 ◽

Cited By ~ 1

Author(s):

Lee-Jah Chang ◽

Ya Meng ◽

Helene Janosczyk ◽

Victoria Landolfi ◽

H Keipp Talbot ◽

...

Keyword(s):

United States ◽

Immune Response ◽

Influenza Vaccine ◽

Standard Dose ◽

The United States ◽

Influenza Vaccines ◽

High Dose ◽

Post Vaccination ◽

B Lineage ◽

Research Grant

Abstract Background Older adults (≥65 years of age) remain at increased risk of influenza because they do not respond to standard dose influenza vaccines as well as younger adults. A high dose, inactivated trivalent influenza vaccine, IIV3-HD, containing four times the antigen content (60 µg hemagglutinin per influenza strain) of standard-dose influenza vaccines has been available in the United States since 2010. Two distinct B influenza lineages (Victoria and Yamagata) have co-circulated for over a decade, making it difficult to predict which will predominate the next season. IIV4-HD has been developed to address the frequent influenza B strain mismatches by incorporating a strain from each B lineage. This pivotal Phase III study evaluated the safety and immunogenicity of IIV4-HD as compared with two IIV3-HD vaccines. Method A randomized, modified double-blind, multicenter study (NCT03282240) was conducted in 2670 healthy subjects in the United States, who were randomly assigned to receive IIV4-HD, a licensed IIV3-HD, or an IIV3-HD with the alternate B influenza strain. Using the hemagglutinin inhibition (HAI) assay at baseline and 28 days after vaccination, post-vaccination geometric mean titers and seroconversion rates were measured. Safety data were collected through 6 months post-vaccination. Result IIV4-HD was noninferior to the licensed IIV3-HD and the investigational IIV3-HD (containing the alternate B strain) for all four influenza strains as assessed by HAI GMTs and seroconversion rates. Moreover, IIV4-HD induced a superior immune response (HAI GMTs and seroconversion rates) compared with the immune response induced by the IIV3-HD that does not contain the corresponding B strain. Reactogenicity profiles were comparable across all study groups. Most unsolicited adverse events were of Grade 1 or Grade 2 intensity. One serious adverse event considered related by the Investigator was reported in the IIV4-HD group. Conclusion Vaccination of adults 65 years of age and older with IIV4-HD was found to be noninferior to two IIV3-HD vaccines with a similar safety profile. The addition of a second B lineage strain does not adversely affect the safety or immunogenicity profile of IIV4-HD compared with IIV3-HD. Disclosures L. J. Chang, Sanofi Pasteur: Employee, Salary. Y. Meng, Sanofi Pasteur: Employee, Salary. H. Janosczyk, Sanofi Pasteur: Employee, Salary. V. Landolfi, Sanofi Pasteur: Employee, Salary. H. K. Talbot, Sanofi Pasteur: Investigator, Research grant. Gilead: Investigator, Research grant. MedImmune: Investigator, Research grant. Vaxinnate: Safety Board, none. Seqirus: Safety Board, none.

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150. Relative Effectiveness of High-Dose and Standard-Dose Influenza Vaccine Against Influenza-Related Hospitalization Among Older Adults—United States, 2015–2017

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy209.020 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S10-S10

Author(s):

Joshua Doyle ◽

Lauren Beacham ◽

Elif Alyanak ◽

Manjusha Gaglani ◽

Emily T Martin ◽

...

Keyword(s):

United States ◽

Older Adults ◽

Influenza Vaccine ◽

Influenza A ◽

Standard Dose ◽

Relative Effectiveness ◽

The United States ◽

Vaccine Effectiveness ◽

High Dose ◽

Research Grant

Abstract Background Seasonal influenza causes substantial morbidity and mortality, and older adults are disproportionately affected. Newer vaccines have been developed for use in people 65 years and older, including a trivalent inactivated vaccine with a 4-fold higher dose of antigen (IIV-HD). In recent years, the use of IIV-HD has increased sufficiently to evaluate its effectiveness compared with standard-dose inactivated influenza vaccines (IIV-SD). Methods Hospitalized patients with acute respiratory illness were enrolled in an observational vaccine effectiveness study at 8 hospitals in 4 states participating in the United States Hospitalized Adult Influenza Vaccine Effectiveness Network during the 2015–2016 and 2016–2017 influenza seasons. Predominant influenza A virus subtypes were H1N1 and H3N2, respectively, during these seasons. All enrolled patients were tested for influenza virus with polymerase chain reaction. Receipt and type of influenza vaccine was determined from electronic records and chart review. Odds of laboratory-confirmed influenza were compared among vaccinated and unvaccinated patients. Relative odds of laboratory-confirmed influenza were determined for patients who received IIV-HD or IIV-SD, and adjusted for potential confounding variables via logistic regression. Results Among 1,744 enrolled patients aged ≥ 65 years, 1,105 (63%) were vaccinated; among those vaccinated, 621 (56%) received IIV-HD and 484 (44%) received IIV-SD. Overall, 315 (18%) tested positive for influenza, including 97 (6%) who received IIV-HD, 86 (5%) who received IIV-SD, and 132 (8%) who were unvaccinated. Controlling for age, race, sex, enrollment site, date of illness, index of comorbidity, and influenza season, the adjusted odds of influenza among patients vaccinated with IIV-HD vs. IIV-SD were 0.72 (P = 0.06, 95% CI: 0.52 to 1.01). Conclusion Comparison of high-dose vs. standard-dose vaccine effectiveness during 2 recent influenza seasons (1 H1N1 and 1 H3N2-predominant) suggested relative benefit (nonsignificant) of high-dose influenza vaccine in protecting against influenza-associated hospitalization among persons aged 65 years and older; additional years of data are needed to confirm this finding. Disclosures H. K. Talbot, sanofi pasteur: Investigator, Research grant. Gilead: Investigator, Research grant. MedImmune: Investigator, Research grant. Vaxinnate: Safety Board, none. Seqirus: Safety Board, none.

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Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial

Clinical and Vaccine Immunology ◽

10.1128/cvi.00604-15 ◽

2016 ◽

Vol 23 (3) ◽

pp. 228-235 ◽

Cited By ~ 31

Author(s):

Andrew J. Dunning ◽

Carlos A. DiazGranados ◽

Timothy Voloshen ◽

Branda Hu ◽

Victoria A. Landolfi ◽

...

Keyword(s):

Influenza Vaccine ◽

Vaccine Efficacy ◽

Standard Dose ◽

The Elderly ◽

High Dose ◽

Efficacy Trial ◽

Correlates Of Protection ◽

Immune Correlates ◽

Immunologic Assays ◽

Dose Vaccine

ABSTRACTAlthough a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus—the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.)

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Relative and Absolute Effectiveness of High-Dose and Standard-Dose Influenza Vaccine Against Influenza-Related Hospitalization Among Older Adults—United States, 2015–2017

Clinical Infectious Diseases ◽

10.1093/cid/ciaa160 ◽

2020 ◽

Cited By ~ 3

Author(s):

Joshua D Doyle ◽

Lauren Beacham ◽

Emily T Martin ◽

H Keipp Talbot ◽

Arnold Monto ◽

...

Keyword(s):

United States ◽

Older Adults ◽

Influenza Vaccine ◽

Standard Dose ◽

Relative Effectiveness ◽

Respiratory Illness ◽

The United States ◽

Vaccine Effectiveness ◽

High Dose ◽

Confounding Variables

Abstract Background Seasonal influenza causes substantial morbidity and mortality in older adults. High-dose inactivated influenza vaccine (HD-IIV), with increased antigen content compared to standard-dose influenza vaccines (SD-IIV), is licensed for use in people aged ≥65 years. We sought to evaluate the effectiveness of HD-IIV and SD-IIV for prevention of influenza-associated hospitalizations. Methods Hospitalized patients with acute respiratory illness were enrolled in an observational vaccine effectiveness study at 8 hospitals in the United States Hospitalized Adult Influenza Vaccine Effectiveness Network during the 2015–2016 and 2016–2017 influenza seasons. Enrolled patients were tested for influenza, and receipt of influenza vaccine by type was recorded. Effectiveness of SD-IIV and HD-IIV was estimated using a test-negative design (comparing odds of influenza among vaccinated and unvaccinated patients). Relative effectiveness of SD-IIV and HD-IIV was estimated using logistic regression. Results Among 1487 enrolled patients aged ≥65 years, 1107 (74%) were vaccinated; 622 (56%) received HD-IIV, and 485 (44%) received SD-IIV. Overall, 277 (19%) tested positive for influenza, including 98 (16%) who received HD-IIV, 87 (18%) who received SD-IIV, and 92 (24%) who were unvaccinated. After adjusting for confounding variables, effectiveness of SD-IIV was 6% (95% confidence interval [CI] −42%, 38%) and that of HD-IIV was 32% (95% CI −3%, 54%), for a relative effectiveness of HD-IIV versus SD-IIV of 27% (95% CI −1%, 48%). Conclusions During 2 US influenza seasons, vaccine effectiveness was low to moderate for prevention of influenza hospitalization among adults aged ≥65 years. High-dose vaccine offered greater effectiveness. None of these findings were statistically significant.

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High Dose Chemotherapy and Autologous Stem Cell Transplantation in the Primary Therapy of Advanced Follicular Lymphoma in Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Blood ◽

10.1182/blood.v114.22.2314.2314 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2314-2314

Author(s):

Murtadha K. Al-Khabori ◽

John de Almeida ◽

Gordon Guyatt ◽

John Kuruvilla ◽

Michael Crump

Keyword(s):

Systematic Review ◽

Overall Survival ◽

Clinical Trials ◽

Randomized Clinical Trials ◽

Meta Analysis ◽

P Value ◽

High Dose ◽

High Dose Therapy ◽

Dose Therapy ◽

American Society

Abstract Abstract 2314 Poster Board II-291 Background: The impact of high dose therapy and autologous stem cell transplantation (ASCT) in the upfront management of adults with advanced follicular lymphoma (FL) on overall survival remains uncertain. A number of randomized clinical trials (RCTs) compared ASCT to conventional dose chemotherapy regimens. We performed a systematic review to address this question. Objective: To compare the overall survival (OS), event free survival (EFS), treatment related mortality (TRM), incidence of secondary myelodysplasia/acute myeloid leukemia (t-MDS/AML) and secondary solid tumors within the ASCT strategy and chemotherapy. Methods: We performed a search of MEDLINE, EMBASE, CENTRAL, American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO), BIOSIS, PAPERSFIRST, PROCEEDINGS, clinical trials registries (National Cancer Institute, clinicaltrials.gov) and bibliographies of relevant studies for randomized controlled trials comparing myelo-ablative chemotherapy with ASCT to any chemotherapy in adults with untreated advanced (Ann Arbor stage III-IV) FL. Two reviewers recorded study characteristics, methodology and outcomes. Disagreement was resolved by discussion. Results: Seven trials were identified and included in the systematic review but only four with available data reporting 941 patients were included in the meta-analysis. Three trials excluded: one was never reported; the second was stopped early due to the increased toxicities in the transplant arm; and the third showed no significant difference in EFS or OS at an interim analysis with insufficient data for the meta-analysis. None of these studies has been published. In one of the 7 trials patients in both arms received rituximab during the induction treatment. High dose therapy and ASCT did not result in improved OS compared to standard therapy, Hazard Ratio (HR) 1.15 (0.85, 1.55). The HR for EFS was 0.61 (0.34, 1.11) with substantial heterogeneity, I2 =91%, Chi2 p value <0.00001. Only the duration of the follow up could explain this heterogeneity with statistically significant subgroup interaction, P <0.00001. The incidence of t-MDS/AML ranged from 1% to 7% in the ASCT arms of the four studies, with a difference in favour of standard chemotherapy, Risk Difference (RD) 4% (95%CI: -1%, 8%), and significant heterogeneity (Chi2 p value of 0.008, I2=75%) due to difference in duration of follow up (p=0.005 for the subgroup differences).There was no increase in mortality directly attributable to treatment (RD 0%, 95%CI: -2%, 1%) nor in secondary solid tumors (RD 1%, 95%CI: -2%, 4%). Conclusions: High dose therapy and ASCT as part of initial does not improve overall survival despite a trend towards better disease control, likely because of the effectiveness of second and subsequent lines of treatment for FL. T-MDS/AML occurs more commonly following ASCT and represents a significant risk to patients. With one exception, these studies were conducted before the introduction of monoclonal B cell antibodies. Future trials of ASCT in the context of current chemo-immunotherapy approaches to FL would further inform this issue. Disclosures: No relevant conflicts of interest to declare.

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