A Real-World Clinical and Economic Analysis of Cell-derived Quadrivalent Influenza Vaccine Compared to Standard Egg-derived Quadrivalent Influenza Vaccines During the 2019-20 Influenza Season in the United States

Abstract Background Cell-derived influenza vaccines are not subject to egg adaptive mutations that have potential to decrease vaccine effectiveness. This retrospective analysis estimated the relative vaccine effectiveness (rVE) of cell-derived quadrivalent influenza vaccine (IIV4c) compared to standard egg-derived quadrivalent influenza vaccines (IIV4e) among recipients aged 4-64 years in the US during the 2019-20 influenza season. Methods The IQVIA PharMetrics® Plus administrative claims database was utilized. Study outcomes were assessed post-vaccination through the end of the study period (March 7, 2020). Inverse probability of treatment weighting (IPTW) was implemented to adjust for covariate imbalance. Adjusted rVE against influenza-related hospitalizations/emergency room (ER) visits and other clinical outcomes was estimated through IPTW-weighted Poisson regression models for the IIV4c and IIV4e cohorts and for the subgroup with ≥1 high-risk condition. Sensitivity analyses modifying the outcome assessment period as well as a doubly-robust analysis were also conducted. IPTW-weighted generalized linear models were used to estimate predicted annualized all-cause costs. Results The final sample comprised 1,138,969 IIV4c and 3,926,357 IIV4e recipients following IPTW adjustment. IIV4c was more effective in preventing influenza-related hospitalizations/ER visits as well as respiratory-related hospitalizations/ER visits compared to IIV4e. IIV4c was also more effective for the high-risk subgroup and across the sensitivity analyses. IIV4c was also associated with significantly lower annualized all-cause total costs compared to IIV4e (-$467), driven by lower costs for outpatient medical services and inpatient hospitalizations. Conclusions IIV4c was significantly more effective in preventing influenza-related hospitalizations/ER visits compared to IIV4e and was associated with significantly lower all-cause costs.

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1341. Relative Vaccine Effectiveness Against Influenza-related Hospitalizations and Respiratory Events During the 2019/20 Influenza seAson in U.S. Children and Adults. A Real-World Evidence Comparison Between Quadrivalent Cell-based and Egg-based Influenza Vaccines

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1533 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S758-S758

Author(s):

Stephen I Pelton ◽

Maarten Postma ◽

Victoria Divino ◽

Joaquin F Mould-Quevedo ◽

Ruthwik Anupindi ◽

...

Keyword(s):

High Risk ◽

Influenza Vaccine ◽

Influenza Season ◽

Standard Dose ◽

The United States ◽

Negative Control ◽

Vaccine Effectiveness ◽

Administrative Claims ◽

Real World Evidence ◽

Quadrivalent Influenza Vaccine

Abstract Background Non-egg-based influenza vaccine manufacturing reduces egg adaptation and therefore has the potential to increase vaccine effectiveness. This study evaluated whether the cell-based quadrivalent influenza vaccine (QIVc) improved relative vaccine effectiveness (rVE) compared to standard-dose egg-based quadrivalent influenza vaccine (QIVe-SD) in the reduction of influenza-related and respiratory-related hospitalizations/emergency room (ER) visits among subjects 4-64 years old during the 2019/20 influenza season. Methods A retrospective analysis was conducted among subjects 4-64 years old vaccinated with QIVc or QIVe-SD using administrative claims data in the United States of America (U.S.) (IQVIA PharMetrics® Plus). Inverse probability of treatment weighting (IPTW) was used to adjust for baseline confounders. Post-IPTW, the number of events and rates (per 1,000 vaccinated subject-seasons) of influenza-related hospitalizations/ER visits, respiratory-related hospitalizations/ER visits and all-cause hospitalizations were assessed. Poisson regression was used to estimate adjusted rVE. To avoid any influenza outcome misclassification with COVID-19 infection, the study period ended March 7,2020. A sub-analysis for a high-risk subgroup was conducted. Urinary tract infection (UTI) hospitalization was assessed as a negative control endpoint. Results During the 2019/20 influenza season, 1,150,134 QIVc and 3,924,819 QIVe-SD recipients were identified post-IPTW. Overall adjusted analyses (4-64 years old) found that QIVc was associated with a significantly higher rVE compared to QIVe-SD against influenza-related hospitalizations/ER visits (5.3% [95% CI: 0.5%-9.9%]), all-cause hospitalizations (14.5% [95% CI: 13.1%-15.8%]) and any respiratory-related hospitalization/ER visit (8.2% [95% CI: 6.5%-9.8%]). A similar trend was seen for the high-risk subgroup; for instance, rVE for QIVc compared to QIVe-SD against influenza-related hospitalizations/ER visits was 10.5% [95% CI: 2.9%-17.4%]. No effect was identified for the negative control outcome. Conclusion QIVc was significantly more effective in preventing influenza-related and respiratory-related hospitalizations/ER visits, as well as all-cause hospitalizations, compared to QIVe-SD. Disclosures Stephen I. Pelton, MD, Seqirus (Consultant) Maarten Postma, Dr., Seqirus (Consultant) Victoria Divino, PhD, Seqirus (Consultant) Joaquin F. Mould-Quevedo, PhD, Seqirus (Employee) Ruthwik Anupindi, PhD, Seqirus (Consultant) Mitchell DeKoven, PhD, Seqirus (Consultant) myron J. levin, MD, GSK group of companies (Employee, Research Grant or Support)

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Clinical and Economic Outcomes Associated with Cell-Based Quadrivalent Influenza Vaccine vs. Standard-Dose Egg-Based Quadrivalent Influenza Vaccines during the 2018–19 Influenza Season in the United States

Vaccines ◽

10.3390/vaccines9020080 ◽

2021 ◽

Vol 9 (2) ◽

pp. 80

Author(s):

Girishanthy Krishnarajah ◽

Victoria Divino ◽

Maarten J. Postma ◽

Stephen I. Pelton ◽

Vamshi Ruthwik Anupindi ◽

...

Keyword(s):

Influenza Vaccine ◽

Influenza Season ◽

Standard Dose ◽

Estimating Equation ◽

The United States ◽

Vaccine Effectiveness ◽

Economic Outcomes ◽

Influenza Vaccines ◽

Administrative Claims ◽

Respiratory Event

Non-egg-based influenza vaccines eliminate the potential for egg-adapted mutations and potentially increase vaccine effectiveness. This retrospective study compared hospitalizations/emergency room (ER) visits and all-cause annualized healthcare costs among subjects aged 4–64 years who received cell-based quadrivalent (QIVc) or standard-dose egg-based quadrivalent (QIVe-SD) influenza vaccine during the 2018–19 influenza season. Administrative claims data (IQVIA PharMetrics® Plus, IQVIA, USA) were utilized to evaluate clinical and economic outcomes. Adjusted relative vaccine effectiveness (rVE) of QIVc vs. QIVe-SD among overall cohort, as well as for three subgroups (age 4–17 years, age 18–64 years, and high-risk) was evaluated using inverse probability of treatment weighting (IPTW) and Poisson regression models. Generalized estimating equation models among the propensity score matched sample were used to estimate annualized all-cause costs. A total of 669,030 recipients of QIVc and 3,062,797 of QIVe-SD were identified after IPTW adjustments. Among the overall cohort, QIVc had higher adjusted rVEs against hospitalizations/ER visits related to influenza, all-cause hospitalizations, and hospitalizations/ER visits associated with any respiratory event compared to QIVe-SD. The adjusted annualized all-cause total costs were higher for QIVe-SD compared to QIVc ((+$461); p < 0.05).

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Effectiveness of the Cell–Derived Inactivated Quadrivalent Influenza Vaccine in Individuals at High Risk of Influenza Complications in the 2018-2019 US Influenza Season

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab167 ◽

2021 ◽

Author(s):

Constantina Boikos ◽

Mahrukh Imran ◽

Van Hung Nguyen ◽

Thierry Ducruet ◽

Gregg C Sylvester ◽

...

Keyword(s):

High Risk ◽

Influenza Vaccine ◽

Influenza Season ◽

Health Condition ◽

Geographic Region ◽

Vaccine Effectiveness ◽

Influenza Viruses ◽

Influenza Vaccines ◽

Study Cohort ◽

Medical Conditions

Abstract Background Higher rates of influenza-related morbidity and mortality occur in individuals with underlying medical conditions. To improve vaccine effectiveness, cell-based technology for influenza vaccine manufacturing has been developed. Cell–derived inactivated quadrivalent influenza vaccines (cIIV4) may improve protection in seasons where egg-propagated influenza viruses undergo mutations that affect antigenicity. This study aimed to estimate the relative vaccine effectiveness (rVE) of cIIV4 versus egg-derived inactivated quadrivalent influenza vaccines (eIIV4) in preventing influenza-related medical encounters in individuals with underlying medical conditions putting them at high risk of influenza complications during the 2018-2019 U.S. influenza season. Methods An integrated dataset, linking primary care electronic medical records with claims data, was used to conduct a retrospective cohort study among individuals aged ≥4 years, with ≥1 health condition, vaccinated with cIIV4 or eIIV4 during the 2018-2019 season. Adjusted odds ratios (ORs) were derived using a doubly robust inverse probability of treatment-weighting (IPTW) model, adjusting for age, sex, race, ethnicity, geographic region, vaccination week, and health status. rVE was estimated by (1- OR)*100 and presented with 95% confidence intervals (CI). Results The study cohort included 471,301 cIIV4 and 1,641,915 eIIV4 recipients. Compared with eIIV4, cIIV4 prevented significantly more influenza-related medical encounters among individuals with ≥1 health condition (rVE 13.4% [95% CI 11.4-15.4]); chronic pulmonary disease (18.7% [16.0-21.3]); and rheumatic disease (11.8% [3.6-19.3]). Conclusions Our findings support the use of cIIV4 in individuals ≥4 years of age at high risk of influenza complications and provide further evidence supporting improved effectiveness of cIIV4 compared to eIIV4.

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Relative Effectiveness of the Cell-Derived Inactivated Quadrivalent Influenza Vaccine Versus Egg-Derived Inactivated Quadrivalent Influenza Vaccines in Preventing Influenza-Related Medical Encounters During the 2018-2019 Influenza Season in the United States

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1944 ◽

2021 ◽

Author(s):

Constantina Boikos ◽

Lauren Fischer ◽

Dan O’Brien ◽

Joe Vasey ◽

Gregg C Sylvester ◽

...

Keyword(s):

Influenza Vaccine ◽

Influenza Season ◽

Relative Effectiveness ◽

The United States ◽

Geographic Region ◽

Vaccine Effectiveness ◽

Influenza Viruses ◽

Study Cohort ◽

Doubly Robust ◽

Quadrivalent Influenza Vaccine

Abstract Background The cell-propagated inactivated quadrivalent influenza vaccine (ccIIV4) may offer improved protection in seasons where egg-derived influenza viruses undergo mutations that affect antigenicity. This study estimated the relative vaccine effectiveness (rVE) of ccIIV4 versus egg-derived inactivated quadrivalent influenza vaccine (eIIV4) in preventing influenza-related medical encounters in the 2018-2019 U.S. season. Methods A dataset linking primary care electronic medical records with medical claims data was used to conduct a retrospective cohort study among individuals ≥4 years vaccinated with ccIIV4 or eIIV4 during the 2018-2019 season. Adjusted odds ratios (ORs) were derived from a doubly robust inverse probability of treatment-weighted approach adjusting for age, sex, race, ethnicity, geographic region, vaccination week, and health status. Relative vaccine effectiveness (rVE) was estimated by (1-OR)*100 and presented with 95% confidence intervals (CI). Results Following the application of inclusion/exclusion criteria, the study cohort included 2,125,430 ccIIV4 and 8,000,903 eIIV4 recipients. Adjusted analyses demonstrated a greater reduction in influenza-related medical encounters with ccIIV4 versus eIIV4, with the following rVE: overall, 7.6% (95% CI 6.5-8.6); age 4-17 years, 3.9% (0.9-7.0); 18-64 years, 6.5% (5.2-7.9); 18-49 years, 7.5% (5.7-9.3); 50-64 years, 5.6% (3.6-7.6); and ≥65 years, -2.2% (-5.4 to 0.9). Conclusions Adjusted analyses demonstrated statistically significantly greater reduction in influenza-related medical encounters in individuals vaccinated with ccIIV4 vs eIIV4 in the 2018-2019 U.S. influenza season. These results support ccIIV4 as a potentially more effective public health measure against influenza than an egg-based equivalent.

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Influenza vaccine effectiveness among patients with high-risk medical conditions in the United States, 2012–2016

Vaccine ◽

10.1016/j.vaccine.2018.10.093 ◽

2018 ◽

Vol 36 (52) ◽

pp. 8047-8053 ◽

Cited By ~ 9

Author(s):

Mei Shang ◽

Jessie R. Chung ◽

Michael L. Jackson ◽

Lisa A. Jackson ◽

Arnold S. Monto ◽

...

Keyword(s):

United States ◽

High Risk ◽

Influenza Vaccine ◽

The United States ◽

Vaccine Effectiveness ◽

Medical Conditions

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Relative Effectiveness of the Cell-Cultured Quadrivalent Influenza Vaccine Compared to Standard, Egg-derived Quadrivalent Influenza Vaccines in Preventing Influenza-like Illness in 2017–2018

Clinical Infectious Diseases ◽

10.1093/cid/ciaa371 ◽

2020 ◽

Vol 71 (10) ◽

pp. e665-e671 ◽

Cited By ~ 4

Author(s):

Constantina Boikos ◽

Gregg C Sylvester ◽

John S Sampalis ◽

James A Mansi

Keyword(s):

Cell Culture ◽

Health Status ◽

Influenza Vaccine ◽

Influenza Season ◽

Relative Effectiveness ◽

Geographic Region ◽

Influenza Vaccines ◽

Study Cohort ◽

Influenza Like Illness ◽

Adaptive Mutations

Abstract Background Influenza antigens may undergo adaptive mutations during egg-based vaccine production. In the 2017–2018 influenza season, quadrivalent, inactivated cell-derived influenza vaccine (ccIIV4) vaccine was produced using A(H3N2) seed virus propagated exclusively in cell culture, thus lacking egg adaptive changes. This United States study estimated relative vaccine effectiveness (rVE) of ccIIV4 vs egg-derived quadrivalent vaccines (egg-derived IIV4) for that season. Methods Vaccination, outcome, and covariate data were ascertained retrospectively from a electronic medical record (EMR) dataset and analyzed. The study cohort included patients ≥ 4 years of age. rVE was estimated against influenza-like illness (ILI) using diagnostic International Classification of Diseases, Ninth or Tenth Revision codes. The adjusted odds ratios used to derive rVE estimates were estimated from multivariable logistic regression models adjusted for age, sex, race/ethnicity, geographic region, and health status. Results Overall, 92 187 individuals had a primary care EMR record of ccIIV4 and 1 261 675 had a record of egg-derived IIV4. In the ccIIV4 group, 1705 narrowly defined ILI events occurred, and 25 645 occurred in the standard egg-derived IIV4 group. Crude rVE was 9.2% (95% confidence interval [CI], 4.6%–13.6%). When adjusted for age, sex, health status, comorbidities, and geographic region, the estimated rVE changed to 36.2% (95% CI, 26.1%–44.9%). Conclusions ccIIV4, derived from A(H3N2) seed virus propagated exclusively in cell culture, was more effective than egg-derived IIV4 in preventing ILI during the 2017–2018 influenza season. This result suggests that cell-derived influenza vaccines may have greater effectiveness than standard egg-derived vaccines.

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The Epidemiological and Economic Impact of a Cell-Based Quadrivalent Influenza Vaccine in Adults in the US: A Dynamic Modeling Approach

Vaccines ◽

10.3390/vaccines9101095 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1095

Author(s):

Van Hung Nguyen ◽

Yvonne Hilsky ◽

Joaquin Mould-Quevedo

Keyword(s):

Public Health ◽

Influenza Vaccine ◽

Economic Impact ◽

Influenza Vaccines ◽

Sensitivity Analyses ◽

Life Years ◽

The Us ◽

A Cell ◽

The Impact ◽

Quadrivalent Influenza Vaccine

Mutations of the H3N2 vaccine strain during the egg-based vaccine manufacturing process partly explain the suboptimal effectiveness of traditional seasonal influenza vaccines. Cell-based influenza vaccines improve antigenic match and vaccine effectiveness by avoiding such egg-adaptation. This study evaluated the public health and economic impact of a cell-based quadrivalent influenza vaccine (QIVc) in adults (18–64 years) compared to the standard egg-based quadrivalent influenza vaccine (QIVe) in the US. The impact of QIVc over QIVe in public health and cost outcomes was estimated using a dynamic age-structured SEIR transmission model, which accounted for four circulating influenza strains [A/H1N1pdm9, A/H3N2, B(Victoria), and B(Yamagata)] and was calibrated on the 2013–2018 influenza seasons. The robustness of the results was assessed in univariate and probabilistic sensitivity analyses. Switching from QIVe to QIVc in 18- to 64-year-olds may prevent 5.7 million symptomatic cases, 1.8 million outpatient visits, 50,000 hospitalizations, and 5453 deaths annually. The switch could save 128,000 Quality-Adjusted Life Years (QALYs) and US $ 845 M in direct costs, resulting in cost-savings in a three-year time horizon analysis. Probabilistic sensitivity analyses confirmed the robustness of the cost-saving result. The analysis shows that QIVc is expected to prevent hospitalizations and deaths, and result in substantial savings in healthcare costs.

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Effects of Influenza Vaccination in the United States During the 2018–2019 Influenza Season

Clinical Infectious Diseases ◽

10.1093/cid/ciz1244 ◽

2020 ◽

Vol 71 (8) ◽

pp. e368-e376 ◽

Cited By ~ 7

Author(s):

Jessie R Chung ◽

Melissa A Rolfes ◽

Brendan Flannery ◽

Pragati Prasad ◽

Alissa O’Halloran ◽

...

Keyword(s):

United States ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Influenza Season ◽

The United States ◽

Vaccine Effectiveness ◽

Influenza Viruses ◽

Monte Carlo Algorithm ◽

Medical Visits ◽

The Us

Abstract Background Multivalent influenza vaccine products provide protection against influenza A(H1N1)pdm09, A(H3N2), and B lineage viruses. The 2018–2019 influenza season in the United States included prolonged circulation of A(H1N1)pdm09 viruses well-matched to the vaccine strain and A(H3N2) viruses, the majority of which were mismatched to the vaccine. We estimated the number of vaccine-prevented influenza-associated illnesses, medical visits, hospitalizations, and deaths for the season. Methods We used a mathematical model and Monte Carlo algorithm to estimate numbers and 95% uncertainty intervals (UIs) of influenza-associated outcomes prevented by vaccination in the United States. The model incorporated age-specific estimates of national 2018–2019 influenza vaccine coverage, influenza virus–specific vaccine effectiveness from the US Influenza Vaccine Effectiveness Network, and disease burden estimated from population-based rates of influenza-associated hospitalizations through the Influenza Hospitalization Surveillance Network. Results Influenza vaccination prevented an estimated 4.4 million (95%UI, 3.4 million–7.1 million) illnesses, 2.3 million (95%UI, 1.8 million–3.8 million) medical visits, 58 000 (95%UI, 30 000–156 000) hospitalizations, and 3500 (95%UI, 1000–13 000) deaths due to influenza viruses during the US 2018–2019 influenza season. Vaccination prevented 14% of projected hospitalizations associated with A(H1N1)pdm09 overall and 43% among children aged 6 months–4 years. Conclusions Influenza vaccination averted substantial influenza-associated disease including hospitalizations and deaths in the United States, primarily due to effectiveness against A(H1N1)pdm09. Our findings underscore the value of influenza vaccination, highlighting that vaccines measurably decrease illness and associated healthcare utilization even in a season in which a vaccine component does not match to a circulating virus.

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Successes and failures of the live-attenuated influenza vaccine, can we do better?

10.1101/424275 ◽

2018 ◽

Author(s):

Laura Matrajt ◽

M. Elizabeth Halloran ◽

Rustom Antia

Keyword(s):

United States ◽

Influenza Vaccine ◽

Mathematical Models ◽

Viral Infections ◽

Influenza Season ◽

The United States ◽

Vaccine Effectiveness ◽

Effective Protection ◽

Live Attenuated Vaccines ◽

Live Attenuated Influenza Vaccine

Live-attenuated vaccines are usually highly effective against many acute viral infections. However, the effective- ness of the live attenuated influenza vaccine (LAIV) can vary widely, ranging from 0% effectiveness in some studies done in the United States to 50% in studies done in Europe. The reasons for these discrepancies remain largely unclear. In this paper we use mathematical models to explore how the efficacy of LAIV is affected by the degree of mismatch with the currently circulating influenza strain and interference with pre-existing immunity. The model incorporates two key antigenic distances - the distance between pre-existing immunity and the currently circulating strain as well as the LAIV strain. Our models show that a LAIV that is matched with the currently circulating strain is likely to have only modest efficacy. Our results suggest that the efficacy of the vaccine would be increased (optimized) if, rather than being matched to the circulating strain, it is antigenically slightly further from pre-existing immunity compared with the circulating strain. The models also suggest two regimes in which LAIV that is matched to circulating strains may provide effective protection. The first is in children before they have built immunity from circulating strains. The second is in response to novel strains (such as antigenic shifts) which are at substantial antigenic distance from previously circulating strains. Our models provide an explanation for the variation in vaccine effectiveness, both between children and adults as well as between studies of vaccine effectiveness observed during the 2014-15 influenza season in different countries.

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Influenza vaccines: the potential benefits of cell-culture isolation and manufacturing

Therapeutic Advances in Vaccines and Immunotherapy ◽

10.1177/2515135520908121 ◽

2020 ◽

Vol 8 ◽

pp. 251513552090812

Author(s):

Sankarasubramanian Rajaram ◽

Constantina Boikos ◽

Daniele K. Gelone ◽

Ashesh Gandhi

Keyword(s):

Cell Culture ◽

Influenza Vaccine ◽

Vaccine Development ◽

The United States ◽

Vaccine Effectiveness ◽

Influenza Vaccines ◽

World Health ◽

Severe Illness ◽

Vaccine Production ◽

Culture Technology

Influenza continues to cause severe illness in millions and deaths in hundreds of thousands annually. Vaccines are used to prevent influenza outbreaks, however, the influenza virus mutates and annual vaccination is required for optimal protection. Vaccine effectiveness is also affected by other potential factors such as the human immune system, a mismatch with the chosen candidate virus, and egg adaptation associated with egg-based vaccine production. This article reviews the influenza vaccine development process and describes the implications of the changes to the cell-culture process and vaccine strain recommendations by the World Health Organization since the 2017 season. The traditional manufacturing process for influenza vaccines relies on fertilized chicken eggs that are used for vaccine production. Vaccines must be produced in large volumes and the complete process requires approximately 6 months for the egg-based process. In addition, egg adaptation of seed viruses occurs when viruses adapt to avian receptors found within eggs to allow for growth in eggs. These changes to key viral antigens may result in antigenic mismatch and thereby reduce vaccine effectiveness. By contrast, cell-derived seed viruses do not require fertilized eggs and eliminate the potential for egg-adapted changes. As a result, cell-culture technology improves the match between the vaccine virus strain and the vaccine selected strain, and has been associated with increased vaccine effectiveness during a predominantly H3N2 season. During the 2017–2018 influenza season, a small number of studies conducted in the United States compared the effectiveness of egg-based and cell-culture vaccines and are described here. These observational and retrospective studies demonstrate that inactivated cell-culture vaccines were more effective than egg-based vaccines. Adoption of cell-culture technology for influenza vaccine manufacturing has been reported to improve manufacturing efficiency and the additional benefit of improving vaccine effectiveness is a key factor for future policy making considerations.

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