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

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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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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899. Influenza Vaccine Effectiveness Against Laboratory-Confirmed Influenza in Children Hospitalized with Respiratory Illness in the United States, 2016–2017 and 2017–2018 Seasons

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz359.058 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S26-S27

Author(s):

Angela P Campbell ◽

Constance E Ogokeh ◽

Craig McGowan ◽

Brian Rha ◽

Rangaraj Selvarangan ◽

...

Keyword(s):

Influenza Vaccine ◽

Influenza A ◽

Respiratory Illness ◽

The United States ◽

Vaccine Effectiveness ◽

Severe Illness ◽

Surveillance Network ◽

Pediatric Hospitals ◽

Significant Difference ◽

National Estimates

Abstract Background Annual national estimates of influenza vaccine effectiveness (VE) typically measure protection against outpatient medically attended influenza illness. We assessed influenza VE in preventing laboratory-confirmed influenza hospitalization in children across two influenza A(H3N2)-predominant seasons. Methods Children < 18 years hospitalized with acute respiratory illness were enrolled at 7 pediatric hospitals in the New Vaccine Surveillance Network. We included subjects ≥6 months with ≤10 days of symptoms enrolled during the 2016–2017 and 2017–2018 seasons (date of first through last influenza-positive case for each site). Combined mid-turbinate and throat swabs were tested using molecular assays. We estimated age-stratified VE from a test-negative design using logistic regression to compare the odds of vaccination among cases positive for influenza with controls testing negative, adjusting for age, enrollment month, site, underlying comorbidities, and race/ethnicity. Full/partial vaccination was defined using ACIP criteria. We verified vaccine receipt from state immunization registries and/or provider records. Results Among 3441 children with complete preliminary data, in 2016–2017, 156/1,710 (9%) tested positive for influenza: 91 (58%) with influenza A(H3N2), 5 (3%) with A(H1N1), and 60 (38%) with B viruses. In 2017–2018, 193/1,731 (11%) tested positive: 87 (45%) with influenza A(H3N2), 47 (24%) with A(H1N1), and 58 (30%) with B. VE for all vaccinated children (full and partial) against any influenza was 48% (95% confidence interval, 26%–63%) in 2016–2017 and 45% (24%–60%) in 2017–2018. Combining seasons, VE for fully and partially vaccinated children against any influenza type was 46% (32%–58%); by virus, VE was 30% (4%–49%) for influenza A(H3N2), 71% (46%–85%) for A(H1N1), and 57% (36%–70%) for B viruses. There was no statistically significant difference in VE by age or full/partial vaccination status for any virus (table). Conclusion Vaccination in the 2016–2017 and 2017–2018 seasons nearly halved the risk of children being hospitalized with influenza. These findings support the use of vaccination to prevent severe illness in children. Our study highlights the need for a better understanding of the lower VE against influenza A(H3N2) viruses. Disclosures All Authors: No reported Disclosures.

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

npj Vaccines ◽

10.1038/s41541-018-0079-z ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 35

Author(s):

Ian G. Barr ◽

Ruben O. Donis ◽

Jacqueline M. Katz ◽

John W. McCauley ◽

Takato Odagiri ◽

...

Keyword(s):

Cell Culture ◽

Influenza Vaccine ◽

Vaccine Effectiveness ◽

Influenza Vaccines ◽

Epidemic Season

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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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Prevention of Influenza Hospitalization Among Adults in the United States, 2015–2016: Results From the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN)

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy723 ◽

2018 ◽

Vol 220 (8) ◽

pp. 1265-1275 ◽

Cited By ~ 19

Author(s):

Jill M Ferdinands ◽

Manjusha Gaglani ◽

Emily T Martin ◽

Don Middleton ◽

Arnold S Monto ◽

...

Keyword(s):

Influenza Vaccine ◽

Influenza A ◽

The United States ◽

Vaccine Effectiveness ◽

Severe Illness ◽

Influenza B Virus ◽

Influenza B ◽

Negative Case ◽

Influenza A H1n1 ◽

The Us

Abstract Background Evidence establishing effectiveness of influenza vaccination for prevention of severe illness is limited. The US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) is a multiyear test-negative case-control study initiated in 2015–2016 to estimate effectiveness of vaccine in preventing influenza hospitalization among adults. Methods Adults aged ≥18 years admitted to 8 US hospitals with acute respiratory illness and testing positive for influenza by polymerase chain reaction were cases; those testing negative were controls. Vaccine effectiveness was estimated with logistic regression adjusting for age, comorbidities, and other confounding factors and stratified by frailty, 2-year vaccination history, and clinical presentation. Results We analyzed data from 236 cases and 1231 controls; mean age was 58 years. More than 90% of patients had ≥1 comorbidity elevating risk of influenza complications. Fifty percent of cases and 70% of controls were vaccinated. Vaccination was 51% (95% confidence interval [CI], 29%–65%) and 53% (95% CI, 11%–76%) effective in preventing hospitalization due to influenza A(H1N1)pdm09 and influenza B virus infection, respectively. Vaccine was protective for all age groups. Conclusions During the 2015–2016 US influenza A(H1N1)pdm09–predominant season, we found that vaccination halved the risk of influenza-association hospitalization among adults, most of whom were at increased risk of serious influenza complications due to comorbidity or age.

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Influenza vaccination and the risk of COVID-19 infection and severe illness in older adults in the United States

Scientific Reports ◽

10.1038/s41598-021-90068-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kelly Huang ◽

Shu-Wen Lin ◽

Wang-Huei Sheng ◽

Chi-Chuan Wang

Keyword(s):

Immune Responses ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

The United States ◽

Cross Sectional Study ◽

Severe Illness ◽

Cross Sectional ◽

Global Pandemic ◽

Study Population ◽

Health Database

AbstractThe coronavirus disease of 2019 (COVID-19) has caused a global pandemic and led to nearly three million deaths globally. As of April 2021, there are still many countries that do not have COVID-19 vaccines. Before the COVID-19 vaccines were developed, some evidence suggested that an influenza vaccine may stimulate nonspecific immune responses that reduce the risk of COVID-19 infection or the severity of COVID-19 illness after infection. This study evaluated the association between influenza vaccination and the risk of COVID-19 infection. We conducted a retrospective cross-sectional study with data from July 1, 2019, to June 30, 2020 with the Claims data from Symphony Health database. The study population was adults age 65 years old or older who received influenza vaccination between September 1 and December 31 of 2019. The main outcomes and measures were odds of COVID-19 infection and severe COVID-19 illness after January 15, 2020. We found the adjusted odds ratio (aOR) of COVID-19 infection risk between the influenza-vaccination group and no-influenza-vaccination group was 0.76 (95% confidence interval (CI), 0.75–0.77). Among COVID-19 patients, the aOR of developing severe COVID-19 illness was 0.72 (95% CI, 0.68–0.76) between the influenza-vaccination group and the no-influenza-vaccination group. When the influenza-vaccination group and the other-vaccination group were compared, the aOR of COVID-19 infection was 0.95 (95% CI, 0.93–0.97), and the aOR of developing a severe COVID-19 illness was 0.95 (95% CI, 0.80–1.13). The influenza vaccine may marginally protect people from COVID-19 infection.

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Influenza vaccine effectiveness against hospitalization in the United States, 2019-2020

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa800 ◽

2020 ◽

Author(s):

Mark W Tenforde ◽

H Keipp Talbot ◽

Christopher H Trabue ◽

Manjusha Gaglani ◽

Tresa M McNeal ◽

...

Keyword(s):

United States ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Respiratory Illness ◽

The United States ◽

Vaccine Effectiveness ◽

Influenza Viruses ◽

Current Season ◽

Hospital Resources ◽

Negative Controls

Abstract Background Influenza causes significant morbidity and mortality and stresses hospital resources during periods of increased circulation. We evaluated the effectiveness of the 2019-2020 influenza vaccine against influenza-associated hospitalizations in the United States. Methods We included adults hospitalized with acute respiratory illness at 14 hospitals and tested for influenza viruses by reserve transcription polymerase chain reaction. Vaccine effectiveness (VE) was estimated by comparing the odds of current-season influenza vaccination in test-positive influenza cases versus test-negative controls, adjusting for confounders. VE was stratified by age and major circulating influenza types along with A(H1N1)pdm09 genetic subgroups. Results 3116 participants were included, including 18% (553) influenza-positive cases. Median age was 63 years. Sixty-seven percent (2079) received vaccination. Overall adjusted VE against influenza viruses was 41% (95% confidence interval [CI]: 27-52). VE against A(H1N1)pdm09 viruses was 40% (95% CI: 24-53) and 33% against B viruses (95% CI: 0-56). Of the two major A(H1N1)pdm09 subgroups (representing 90% of sequenced H1N1 viruses), VE against one group (5A+187A,189E) was 59% (95% CI: 34-75) whereas no significant VE was observed against the other group (5A+156K) [-1%, 95% CI: -61-37]. Conclusions In a primarily older population, influenza vaccination was associated with a 41% reduction in risk of hospitalized influenza illness.

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