Cell culture-derived influenza vaccines in the severe 2017–2018 epidemic season: a step towards improved influenza vaccine effectiveness

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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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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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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab604 ◽

2021 ◽

Author(s):

Victoria Divino ◽

Vamshi Ruthwik Anupindi ◽

Mitch DeKoven ◽

Joaquin Mould-Quevedo ◽

Stephen I Pelton ◽

...

Keyword(s):

High Risk ◽

Influenza Vaccine ◽

Influenza Season ◽

The United States ◽

Vaccine Effectiveness ◽

Influenza Vaccines ◽

Sensitivity Analyses ◽

Administrative Claims ◽

Adaptive Mutations ◽

Quadrivalent Influenza Vaccine

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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Viral Subpopulation Screening Guides in Designing a High Interferon-Inducing Live Attenuated Influenza Vaccine by Targeting Rare Mutations in NS1 and PB2 Proteins

Journal of Virology ◽

10.1128/jvi.01722-20 ◽

2020 ◽

Vol 95 (2) ◽

pp. e01722-20

Author(s):

Amir Ghorbani ◽

Michael C. Abundo ◽

Hana Ji ◽

Kara J. M. Taylor ◽

John M. Ngunjiri ◽

...

Keyword(s):

Cell Culture ◽

Influenza Vaccine ◽

Influenza Viruses ◽

Translation Initiation Factor ◽

Influenza Vaccines ◽

Effective Control ◽

Live Vaccines ◽

Live Attenuated Influenza Vaccine ◽

Nonstructural Protein 1 ◽

Interferon Responses

ABSTRACTInfluenza A viruses continue to circulate among wild birds and poultry worldwide, posing constant pandemic threats to humans. Effective control of emerging influenza viruses requires new broadly protective vaccines. Live attenuated influenza vaccines with truncations in nonstructural protein 1 (NS1) have shown broad protective efficacies in birds and mammals, which correlate with the ability to induce elevated interferon responses in the vaccinated hosts. Given the extreme diversity of influenza virus populations, we asked if we could improve an NS1-truncated live attenuated influenza vaccine developed for poultry (PC4) by selecting viral subpopulations with enhanced interferon-inducing capacities. Here, we deconstructed a de novo population of PC4 through plaque isolation, created a large library of clones, and assessed their interferon-inducing phenotypes. While most of the clones displayed the parental interferon-inducing phenotype in cell culture, few clones showed enhanced interferon-inducing phenotypes in cell culture and chickens. The enhanced interferon-inducing phenotypes were linked to either a deletion in NS1 (NS1Δ76-86) or a substitution in polymerase basic 2 protein (PB2-D309N). The NS1Δ76-86 deletion disrupted the putative eukaryotic translation initiation factor 4GI-binding domain and promoted the synthesis of biologically active interferons. The PB2-D309N substitution enhanced the early transcription of interferon mRNA, revealing a novel role for the 309D residue in suppression of interferon responses. We combined these mutations to engineer a novel vaccine candidate that induced additive amounts of interferons and stimulated protective immunity in chickens. Therefore, viral subpopulation screening approaches can guide the design of live vaccines with strong immunostimulatory properties.IMPORTANCE Effectiveness of NS1-truncated live attenuated influenza vaccines relies heavily on their ability to induce elevated interferon responses in vaccinated hosts. Influenza viruses contain diverse particle subpopulations with distinct phenotypes. We show that live influenza vaccines can contain underappreciated subpopulations with enhanced interferon-inducing phenotypes. The genomic traits of such virus subpopulations can be used to further improve the efficacy of the current live vaccines.

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Effectiveness of 2 Influenza Vaccines in Nationwide Cohorts of Finnish 2-Year-Old Children in the Seasons 2015–2016 Through 2017–2018

Clinical Infectious Diseases ◽

10.1093/cid/ciaa050 ◽

2020 ◽

Vol 71 (8) ◽

pp. e255-e261

Author(s):

Ulrike Baum ◽

Sangita Kulathinal ◽

Kari Auranen ◽

Hanna Nohynek

Keyword(s):

Influenza Vaccine ◽

Virus Type ◽

Real Life ◽

Vaccine Effectiveness ◽

Influenza Vaccines ◽

Type B ◽

Live Attenuated Influenza Vaccine ◽

Vaccine Type ◽

Decision Making Processes ◽

Study Population

Abstract Background From 2015–2016 through 2017–2018, injectable, trivalent inactivated influenza vaccines (IIV3) and a nasal spray, tetravalent live-attenuated influenza vaccine (LAIV4) were used in parallel in Finland. To understand how well vaccination with each vaccine type protected children against influenza under real-life conditions, vaccine effectiveness in 2-year-olds was estimated for all 3 seasons. Methods Each season, a nationwide register-based cohort study was conducted. The study population comprised 60 088, 60 860, and 60 345 children in 2015–2016, 2016–2017, and 2017–2018, respectively. Laboratory-confirmed influenza was the study outcome. Seasonal influenza vaccination with either LAIV4 or IIV3 was the time-dependent exposure of interest. Vaccine effectiveness was defined as 1 minus the hazard ratio comparing vaccinated with unvaccinated children. Results From 2015–2016 through 2017–2018, the effectiveness of LAIV4 against influenza of any virus type was estimated at 54.2% (95% confidence interval, 32.2–69.0%), 20.3% (−12.7%, 43.6%), and 30.5% (10.9–45.9%); the corresponding effectiveness of IIV3 was 77.2% (48.9–89.8%), 24.5% (−29.8%, 56.1%), and −20.1% (−61.5%, 10.7%). Neither influenza vaccine clearly excelled in protecting children. The LAIV4 effectiveness against type B was greater than against type A and greater than the IIV3 effectiveness against type B. Conclusions To understand how influenza vaccines could be improved, vaccine effectiveness must be analyzed by vaccine and virus type. Effectiveness estimates also expressing overall protection levels are needed to guide individual and programmatic decision-making processes. Supported by this analysis, the vaccination program in Finland now recommends LAIV4 and injectable, tetravalent inactivated influenza vaccines replacing IIV3.

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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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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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Rapid assessment of influenza vaccine effectiveness: analysis of an internet-based cohort

Epidemiology and Infection ◽

10.1017/s0950268811001804 ◽

2011 ◽

Vol 140 (7) ◽

pp. 1309-1315 ◽

Cited By ~ 20

Author(s):

K. T. D. EAMES ◽

E. BROOKS-POLLOCK ◽

D. PAOLOTTI ◽

M. PEROSA ◽

C. GIOANNINI ◽

...

Keyword(s):

Influenza Vaccine ◽

Pandemic Influenza ◽

Seasonal Influenza ◽

Influenza Season ◽

Rapid Assessment ◽

Vaccine Effectiveness ◽

Influenza Vaccines ◽

Seasonal Influenza Vaccine ◽

Effectiveness Analysis ◽

Self Reports

SUMMARYThe effectiveness of influenza vaccination programmes is seldom known during an epidemic. We developed an internet-based system to record influenza-like symptoms and response to infection in a participating cohort. Using self-reports of influenza-like symptoms and of influenza vaccine history and uptake, we estimated vaccine effectiveness (VE) without the need for individuals to seek healthcare. We found that vaccination with the 2010 seasonal influenza vaccine was significantly protective against influenza-like illness (ILI) during the 2010–2011 influenza season (VE 52%, 95% CI 27–68). VE for individuals who received both the 2010 seasonal and 2009 pandemic influenza vaccines was 59% (95% CI 27–77), slightly higher than VE for those vaccinated in 2010 alone (VE 46%, 95% CI 9–68). Vaccinated individuals with ILI reported taking less time off work than unvaccinated individuals with ILI (3·4 days vs. 5·3 days, P<0·001).

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Vaccine effectiveness of cell-culture relative to egg-based inactivated influenza vaccine during the 2017-18 influenza season

PLoS ONE ◽

10.1371/journal.pone.0229279 ◽

2020 ◽

Vol 15 (2) ◽

pp. e0229279 ◽

Cited By ~ 3

Author(s):

Nicola P. Klein ◽

Bruce Fireman ◽

Kristin Goddard ◽

Ousseny Zerbo ◽

Jason Asher ◽

...

Keyword(s):

Cell Culture ◽

Influenza Vaccine ◽

Influenza Season ◽

Vaccine Effectiveness

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Estimation of Reduction in Influenza Vaccine Effectiveness Due to Egg-Adaptation Changes—Systematic Literature Review and Expert Consensus

Vaccines ◽

10.3390/vaccines9111255 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1255

Author(s):

Raul Ortiz de Lejarazu-Leonardo ◽

Emanuele Montomoli ◽

Radek Wojcik ◽

Solomon Christopher ◽

Anne Mosnier ◽

...

Keyword(s):

Literature Review ◽

Influenza Vaccine ◽

Systematic Literature Review ◽

Manufacturing Process ◽

Main Tool ◽

Vaccine Effectiveness ◽

Antigenic Drift ◽

Influenza Vaccines ◽

Age Group ◽

The Impact

Background: Influenza vaccines are the main tool to prevent morbidity and mortality of the disease; however, egg adaptations associated with the choice of the manufacturing process may reduce their effectiveness. This study aimed to estimate the impact of egg adaptations and antigenic drift on the effectiveness of trivalent (TIV) and quadrivalent (QIV) influenza vaccines. Methods: Nine experts in influenza virology were recruited into a Delphi-style exercise. In the first round, the experts were asked to answer questions on the impact of antigenic drift and egg adaptations on vaccine match (VM) and influenza vaccine effectiveness (IVE). In the second round, the experts were presented with the data from a systematic literature review on the same subject and aggregated experts’ responses to round one questions. The experts were asked to review and confirm or amend their responses before the final summary statistics were calculated. Results: The experts estimated that, across Europe, the egg adaptations reduce, on average, VM to circulating viruses by 7–21% and reduce IVE by 4–16%. According to the experts, antigenic drift results in a similar impact on VM (8–24%) and IVE (5–20%). The highest reduction in IVE was estimated for the influenza virus A(H3N2) subtype for the under 65 age group. When asked about the frequency of the phenomena, the experts indicated that, on average, between the 2014 and 19 seasons, egg adaptation and antigenic drift were significant enough to impact IVE that occurred in two and three out of five seasons, respectively. They also agreed that this pattern is likely to reoccur in future seasons. Conclusions: Expert estimates suggest there is a potential for 9% on average (weighted average of “All strains” over three age groups adjusted by population size) and up to a 16% increase in IVE (against A(H3N2), the <65 age group) if egg adaptations that arise when employing the traditional egg-based manufacturing process are avoided.

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