Influence of disease attenuation on relative influenza vaccine effectiveness by vaccine type

Benefit conferred by “enhanced” influenza vaccines is often measured by relative vaccine effectiveness, (rVE), which compares disease risk among groups of people who received alternative vaccines. Differences in attenuation of illness severity by vaccine types could manifest as differences in rVE. Using a simulated VE study and cohort of adults aged ≥ 65 years, we examined how rVE varied with assumptions about attenuation of disease severity conferred by standard and enhanced vaccines and how this variation could lead to differing estimates of rVE for prevention of moderate (i.e., outpatient) versus severe (i.e., inpatient) influenza illness. We found that if enhanced vaccines attenuated severe illness more than moderate illness, then rVE observed against severe disease could be higher than rVE observed against moderate disease. Thus, if differences in disease attenuation by vaccine type occurs, estimates of rVE may vary for influenza outcomes of differing levels of severity.     

Influenza vaccine effectiveness against laboratory-confirmed influenza in a vaccine-mismatched influenza B-dominant season

BackgroundThe 2017–2018 influenza season in Israel was characterized by the predominance of influenza B Yamagata, with a lesser circulation of influenza A(H1N1)pdm09 and influenza A(H3N2). We estimated vaccine effectiveness (VE) of the inactivated influenza vaccine which was selected for use that season.MethodsEnd-of-season VE and 95% confidence intervals (CI) against laboratory-confirmed influenza-like illness (ILI) were estimated by means of the test-negative design. Age-specific VE analysis was carried out using a moving age interval.ResultsSpecimen were obtained from 1,453 community ILI patients; 610 (42.0%) were influenza-positive, among which 69.7% were B, 17.2% A(H1N1)pdm09 and 13.4% A(H3N2). A 98.6% of molecularly characterized influenza B belonged to the Yamagata lineage. Of the sampled individuals, 1320 were suitable for VE analysis. Of those vaccinated, 90.6% received the inactivated trivalent influenza vaccine (TIV) containing a Victoria lineage influenza B-like virus. VE against influenza A differed by age, with the highest VE of 72.9% (95%CI 31.9–89.2%) observed in children 0.5–14 years old, while all ages VE was 46.6% (95%CI 10.4–68.2%). All ages VE against influenza B was 23.2% (95%CI −10.1–46.4%) with age-specific analysis showing non-significant VE estimates. Utilizing a moving age interval of 15 years, afforded a detailed age-specific insight into influenza VE against the influenza viruses circulating during the 2017–2018 season.ConclusionsThe moderate-high 2017–2018 influenza A VE among children and adolescents, supports seasonal influenza vaccination at a young age. The low VE against influenza B in Israel, is most likely the result of influenza B/TIV-mismatch.     

Comparison of local influenza vaccine effectiveness using two methods

BackgroundIn some settings, research methods to determine influenza vaccine effectiveness (VE) may not be appropriate because of cost, time constraints, or other factors. Administrative database analysis of viral testing results and vaccination history may be a viable alternative. This study compared VE estimates from outpatient research and administrative databases.MethodsUsing the test-negative, case-control design, data for 2017–2018 and 2018–2019 influenza seasons were collected using: 1) consent, specimen collection, RT-PCR testing and vaccine verification using multiple methods; and 2) an administrative database of outpatients with a clinical respiratory viral panel combined with electronic immunization records. Odds ratios for likelihood of influenza infection by vaccination status were calculated using multivariable logistic regression. VE = (1 ? aOR) × 100.ResultsResearch participants were significantly younger (P < 0.001), more often white (69% vs. 59%; P < 0.001) than non-white and less frequently enrolled through the emergency department (35% vs. 72%; P < 0.001) than administrative database participants. VE was significant against all influenza and influenza A in each season and both seasons combined (37–49%). Point estimate differences between methods were evident, with higher VE in the research database, but insignificant due to low sample sizes. When enrollment sites were separately analyzed, there were significant differences in VE estimates for all influenza (66% research vs. 46% administrative P < 0.001) and influenza A (67% research vs. 49% administrative; P < 0.001) in the emergency department.Conclusions:The selection of the appropriate method for determining influenza vaccine effectiveness depends on many factors, including sample size, subgroups of interest, etc., suggesting that research estimates may be more generalizable. Other advantages of research databases for VE estimates include lack of clinician-related selection bias for testing and less misclassification of vaccination status. The advantages of the administrative databases are potentially shorter time to VE results and lower cost.     

2013-2014年度季节性流行性感冒疫苗对儿童保护效果的病例对照研究

目的 评价2013-2014年度季节性流行性感冒疫苗（流感疫苗）对6~59月龄儿童的保护效果。方法 选择2013-2014年度6~59月龄的实验室诊断流感病例为病例组,在广州市免疫规划系统中随机选择健康儿童为对照组,进行成组病例对照研究,采用非条件Logistic回归计算保护效果。结果 本研究共纳入2 690名研究对象。2013-2014年度,流感疫苗对6~59月龄儿童的保护效果为42.3%（95% CI：27.8%~53.8%）,对36~59月龄儿童的保护效果高于6~35月龄儿童,完全免疫的保护效果高于部分免疫,性别间保护效果无统计学差异。结论 流感疫苗对6~59月龄儿童具有中等保护效果,建议6~59月龄儿童每年接种流感疫苗。     

In silico prediction of influenza vaccine effectiveness by sequence analysis

The effectiveness of seasonal influenza vaccines varies with the matching of vaccine strains to circulating strains. Based on the genetic distance of hemagglutinin and neuraminidase gene of the influenza viruses to vaccine strains, we statistically quantified the relationship between the genetic mismatch and vaccine effectiveness (VE) for influenza A/H1N1pdm09, A/H3N2 and B. We also proposed a systematic approach to integrate multiple genes and influenza types for overall VE estimation. Evident linear relationships were identified and validated in independent data. The modelling framework may enable in silico prediction for VE on a real-time basis and inform the influenza vaccine selection strategy.     

Challenges in evaluating influenza vaccine effectiveness and the mortality benefits controversy

Randomized, controlled trials are the gold standard study design. However, ethical constraints and practical considerations may necessitate other types of studies for evaluating influenza vaccine effectiveness in the elderly—a high priority group for annual vaccination in many countries. Observational studies therefore comprise the bulk of the vaccine effectiveness evidence in older persons, but these types of studies can be susceptible to selection bias and residual confounding. All observational studies should utilize strategies to minimize the impact of bias and confounding. Recent studies questioning the plausibility of reported mortality benefits among vaccinated elderly persons may themselves be based on assumptions that are susceptible to important limitations and multiple biases. Future studies that incorporate prospectively collected information on functional status, life expectancy, and other types of data may provide additional insights into these concerns. At present, even after taking into account the potential for residual bias and confounding, most studies confirm the benefits of vaccination among the elderly for reducing hospitalization and death.     

Estimating influenza vaccine effectiveness using data routinely available in electronic primary care records

Background

To support timely, annual estimation of influenza vaccine effectiveness (VE), we explored the use of automated data extraction from general practice records to estimate VE over four consecutive southern hemisphere influenza seasons.

Trends in effectiveness of inactivated influenza vaccine in children by age groups in seven seasons immediately before the COVID-19 era

BackgroundWe have reported the vaccine effectiveness of inactivated influenza vaccine in children aged 6 months to 15 years between the 2013/14 and 2018/19 seasons. Younger (6–11 months) and older (6–15 years old) children tended to have lower vaccine effectiveness. The purpose of this study is to investigate whether the recent vaccine can be recommended to all age groups.MethodsThe overall adjusted vaccine effectiveness was assessed from the 2013/14 until the 2020/21 season using a test-negative case-control design based on rapid influenza diagnostic test results. Vaccine effectiveness was calculated by influenza type and by age group (6–11 months, 1–2, 3–5, 6–12, and 13–15 years old) with adjustments including influenza seasons.ResultsA total of 29,400 children (9347, 4435, and 15,618 for influenza A and B, and test-negatives, respectively) were enrolled. The overall vaccine effectiveness against influenza A, A(H1N1)pdm09, and B was significant (44% [95% confidence interval (CI), 41–47], 63% [95 %CI, 51–72], and 37% [95 %CI, 32–42], respectively). The vaccine was significantly effective against influenza A and B, except among children 6 to 11 months against influenza B. The age group with the highest vaccine effectiveness was 1 to 2 years old with both influenza A and B (60% [95 %CI, 55–65] and 52% [95 %CI, 41–61], respectively). Analysis for the 2020/21 season was not performed because no cases were reported.ConclusionsThis is the first report showing influenza vaccine effectiveness by age group in children for several seasons, including immediately before the coronavirus disease (COVID-19) era. The fact that significant vaccine effectiveness was observed in nearly every age group and every season shows that the recent vaccine can still be recommended to children for the upcoming influenza seasons, during and after the COVID-19 era.     

2017－2018年流感流行季儿童接种流感疫苗效果社区队列研究

目的 评价6~72月龄儿童接种流感疫苗效果。方法 采用社区队列研究设计,2017年10-12月,从浙江省永康和义乌两市10家儿童接种门诊招募了1 752名6~72月龄儿童。每名儿童入队列后,完成知情同意和问卷调查,并随访至2018年4月30日,观察记录流感样病例（ILI）发病、门诊就诊和自行服药及流感疫苗接种情况。以ILI、门诊就诊和自行服药的发生次数为因变量,采用广义线性模型（GLM）拟合,估算流感疫苗效果（VE）值。结果 1 752名儿童中,男童925名（52.80%）,月龄M=30.00月,累计随访观察308 166人天,平均每天有5.27‰发生ILI、3.41‰因ILI去医院门诊就诊、1.45‰因ILI自行服药治疗;共有643名儿童接种了流感疫苗,与未接种儿童相比,流感疫苗对ILI、门诊就诊和自行服药的VE值分别为23.5%（95% CI：15.1%~31.1%）、19.3%（95% CI：8.2%~29.1%）和25.8%（95% CI：9.3%~39.3%）。643名接种儿童,接种后与接种前比,流感疫苗针对36~72月龄儿童ILI、门诊就诊和自行服药的VE值分别为31.9%（95% CI：12.7%~46.9%）、32.6%（95% CI：8.6%~50.3%）和44.3%（95% CI：11.9%~64.8%）,而对6~35月龄儿童,VE值均无统计学意义。2016-2018年流感疫苗不同接种暴露VE值评估,两个流感流行季均有接种史的,仅2017-2018年流感流行季有接种史的,流感疫苗VE值,均有统计学意义;仅2016-2017年流感流行季有接种史的,VE值均无统计学意义。结论 流感流行季接种流感疫苗一定程度可预防ILI发病、门诊就诊和自行服药,且对36~72月龄儿童保护效果优于6~35月龄儿童。     

Bias of influenza vaccine effectiveness estimates from test-negative studies conducted during an influenza pandemic

Test-negative (TN) studies have become the most widely used study design for the estimation of influenza vaccine effectiveness (VE) and are easily incorporated into existing influenza surveillance networks. We seek to determine the bias of TN-based VE estimates during a pandemic using a dynamic probability model. The model is used to evaluate and compare the bias of VE estimates under various sources of bias when vaccination occurs after the beginning of an outbreak, such as during a pandemic. The model includes two covariates (health status and health awareness), which may affect the probabilities of vaccination, developing influenza and non-influenza acute respiratory illness (ARI), and seeking medical care. Specifically, we evaluate the bias of VE estimates when (1) vaccination affects the probability of developing a non-influenza ARI; (2) vaccination affects the probability of seeking medical care; (3) a covariate (e.g. health status) is related to both the probabilities of vaccination and developing an ARI; and (4) a covariate (e.g. health awareness) is related to both the probabilities of vaccination and of seeking medical care. We considered two outcomes against which the vaccine is supposed to protect: symptomatic influenza and medically-attended influenza.When vaccination begins during an outbreak, we found that the effect of delayed onset of vaccination is unpredictable. VE estimates from TN studies were biased regardless of the source of bias present. However, if the core assumption of the TN design is satisfied, that is, if vaccination does not affect the probability of non-influenza ARI, then TN-based VE estimates against medically-attended influenza will only suffer from small (<0.05) to moderate bias (≥0.05 and <0.10). These results suggest that if sources of bias listed above are ruled out, TN studies are a valid study design for the estimation of VE during a pandemic.     

Assessing the effectiveness of high-dose influenza vaccine in preventing hospitalization among seniors,and observations on the limitations of effectiveness study design

BackgroundThe availability of high-dose (HD) influenza vaccine for seniors should decrease influenza-related hospitalization. Studies to date show a range of mostly moderate increased HD vaccine effectiveness (VE). While a ‘healthy vaccinee’ phenomenon can inflate VE, for influenza and particularly an HD vaccine targeted at frailer adults, an ‘at-risk vaccinee’ bias may deflate VE estimates. We assessed senior HD vaccine effectiveness against influenza-related hospitalization by linking immunization registry records to hospitalizations. We also examined whether adding strata typically ignored in case-control matching schemas, such as residence areas, exact age, and provider biases, would increase VE.MethodsFor the 2016–17 influenza season in the Portland metropolitan area, the differential VE for the HD vaccine in preventing PCR-confirmed influenza hospitalization was assessed by a nested series of models across matching strata. For an exact match for high-dose and standard-dose seniors, matching elements included exact age, gender, residence type, race-ethnicity, provider bias, and residence area (zipcode).ResultsAs a first step, a simple aggregate comparison of influenza-related hospitalization risk showed no added HD effectiveness. For the nested models, adding strata increased VE. In the final model, among 23,712 matched pairs of HD to SD vaccinated seniors, the HD vaccine was 30.7% (95%CI: 8–48%) more effective in preventing influenza-related hospitalization.ConclusionFor this study, the high-dose influenza vaccine provided superior protection for seniors against influenza hospitalization. Including matching elements as exact year of age and residence zipcode all added to the calculation of VE. As a warning, non-matched or overly simple matched VE study designs may substantially under-estimate VE.     

Pandemic influenza H1N1 2009 infection in Victoria, Australia: no evidence for harm or benefit following receipt of seasonal influenza vaccine in 2009

Conflicting findings regarding the level of protection offered by seasonal influenza vaccination against pandemic influenza H1N1 have been reported. We performed a test-negative case control study using sentinel patients from general practices in Victoria to estimate seasonal influenza vaccine effectiveness against laboratory proven infection with pandemic influenza. Cases were defined as patients with an influenza-like illness who tested positive for influenza while controls had an influenza-like illness but tested negative. We found no evidence of significant protection from seasonal vaccine against pandemic influenza virus infection in any age group. Age-stratified point estimates, adjusted for pandemic phase, ranged from 44% in persons aged less than 5 years to −103% (odds ratio = 2.03) in persons aged 50-64 years. Vaccine effectiveness, adjusted for age group and pandemic phase, was 3% (95% CI −48 to 37) for all patients. Our study confirms the results from our previous interim report, and other studies, that failed to demonstrate benefit or harm from receipt of seasonal influenza vaccine in patients with confirmed infection with pandemic influenza H1N1 2009.     

Effectiveness of seasonal influenza vaccine in Australia, 2015: An epidemiological,antigenic and phylogenetic assessment

BackgroundA record number of laboratory-confirmed influenza cases were notified in Australia in 2015, during which type A(H3) and type B Victoria and Yamagata lineages co-circulated. We estimated effectiveness of the 2015 inactivated seasonal influenza vaccine against specific virus lineages and clades.MethodsThree sentinel general practitioner networks conduct surveillance for laboratory-confirmed influenza amongst patients presenting with influenza-like illness in Australia. Data from the networks were pooled to estimate vaccine effectiveness (VE) for seasonal trivalent influenza vaccine in Australia in 2015 using the case test-negative study design.ResultsThere were 2443 eligible patients included in the study, of which 857 (35%) were influenza-positive. Thirty-three and 19% of controls and cases respectively were reported as vaccinated. Adjusted VE against all influenza was 54% (95% CI: 42, 63). Antigenic characterisation data suggested good match between vaccine and circulating strains of A(H3); however VE for A(H3) was low at 44% (95% CI: 21, 60). Phylogenetic analysis indicated most circulating viruses were from clade 3C.2a, rather than the clade included in the vaccine (3C.3a). VE point estimates were higher against B/Yamagata lineage influenza (71%; 95% CI: 57, 80) than B/Victoria (42%, 95% CI: 13, 61), and in younger people.ConclusionsOverall seasonal vaccine was protective against influenza infection in Australia in 2015. Higher VE against the B/Yamagata lineage included in the trivalent vaccine suggests that more widespread use of quadrivalent vaccine could have improved overall effectiveness of influenza vaccine. Genetic characterisation suggested lower VE against A(H3) influenza was due to clade mismatch of vaccine and circulating viruses.     

Influenza vaccine effectiveness against hospitalisation with influenza in adults in Australia in 2014

We provide estimates of the influenza vaccine protection against hospitalisation with laboratory-confirmed influenza in the 2014 Australian season where the A/H1N1/pdm09 strain predominated. This was performed using a case-test negative study design as part of a national sentinel surveillance system in Australia. Vaccine effectiveness was estimated as (1-OR) × 100% where the odds ratio of vaccination in cases vs test negative participants was estimated from a conditional logistic regression. Between April and November, 1692 adult patients were admitted with laboratory-confirmed influenza. Vaccine effectiveness was estimated from 1283 patients with influenza and 1116 test negative patients where vaccination status was ascertained. Vaccination was associated with a reduction in the risk of hospitalisation with influenza of 51.5% (95% CI: 41.6%, 59.7%) in all patients, and a reduction of 50.7% (95% CI: 40.1%, 59.3%) in the target population for vaccination. We estimate that the influenza vaccine was moderately protective against hospitalisation with laboratory-confirmed influenza during the 2014 influenza season in Australia.     

The test-negative design for estimating influenza vaccine effectiveness

Objective

The test-negative design has emerged in recent years as the preferred method for estimating influenza vaccine effectiveness (VE) in observational studies. However, the methodologic basis of this design has not been formally developed.

Methods

In this paper we develop the rationale and underlying assumptions of the test-negative study. Under the test-negative design for influenza VE, study subjects are all persons who seek care for an acute respiratory illness (ARI). All subjects are tested for influenza infection. Influenza VE is estimated from the ratio of the odds of vaccination among subjects testing positive for influenza to the odds of vaccination among subjects testing negative.

Results

With the assumptions that (a) the distribution of non-influenza causes of ARI does not vary by influenza vaccination status, and (b) VE does not vary by health care-seeking behavior, the VE estimate from the sample can generalized to the full source population that gave rise to the study sample. Based on our derivation of this design, we show that test-negative studies of influenza VE can produce biased VE estimates if they include persons seeking care for ARI when influenza is not circulating or do not adjust for calendar time.

Conclusions

The test-negative design is less susceptible to bias due to misclassification of infection and to confounding by health care-seeking behavior, relative to traditional case-control or cohort studies. The cost of the test-negative design is the additional, difficult-to-test assumptions that incidence of non-influenza respiratory infections is similar between vaccinated and unvaccinated groups within any stratum of care-seeking behavior, and that influenza VE does not vary across care-seeking strata.     

Impact of seasonal influenza vaccination in the presence of vaccine interference

BackgroundAnnual influenza vaccination is a key to preventing widespread influenza infections. Recent reports of influenza vaccine effectiveness (VE) indicate that vaccination in prior years may reduce VE in the current season, suggesting vaccine interference. The purpose of this study is to evaluate the potential effect of repeat influenza vaccinations in the presence of vaccine interference.MethodsUsing literature-based parameters, an age-structured influenza equation-based transmission model was used to determine the optimal vaccination strategy, while considering the effect of varying levels of interference.ResultsThe model shows that, even in the presence of vaccine interference, revaccination reduces the influenza attack rate and provides individual benefits. Specifically, annual vaccination is a favored strategy over vaccination in alternate years, as long as the level of residual protection is less than 58% or vaccine interference effect is minimal. Furthermore, the negative impact of vaccine interference may be offset by increased vaccine coverage levels.ConclusionsEven in the presence of potential vaccine interference, our work provides a population-level perspective on the potential merits of repeated influenza vaccination. This is because repeat vaccination groups had lower attack rates than groups that omitted the second vaccination unless vaccine interference was at very high, perhaps implausible, levels.     

Incompletely matched influenza vaccine still provides protection in frail elderly

A cluster-randomised controlled trial of antiviral treatment to control influenza outbreaks in aged-care facilities (ACFs) provided an opportunity to assess VE in the frail, institutionalised elderly. Data were pooled from five influenza outbreaks in 2007. Rapid testing methods for influenza were used to confirm outbreaks and/or identify further cases. Vaccination coverage among ACF residents ranged from 59% to 100%, whereas it was consistently low in staff (11–33%). The attack rates for laboratory-confirmed influenza in residents ranged from 9% to 24%, with the predominate strain determined to be influenza A. Sequencing of the hemagglutinin gene from a sub-sample demonstrated an incomplete match with the 2007 southern hemisphere influenza vaccine. Influenza VE was estimated to be 61% (95%CI 6%, 84%) against laboratory-confirmed influenza, 51% (95%CI −16%, 79%) against influenza-like illness, 82% (95%CI 27%, 96%) against pneumonia-related and influenza-related hospitalisations and 71% (95%CI −28%, 95%) against death from all causes. This supports the continued policy of targeted vaccination of the institutionalised, frail elderly. There is also reassurance that influenza vaccine can be effective against disease and severe outcomes, despite an incomplete vaccine match. This benefit is additional to protection from antivirals.     

Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study

BackgroundRecombinant influenza vaccine (RIV) has been in use in US adults since 2013. This study evaluated the safety of quadrivalent recombinant influenza vaccine (RIV4, Flublok® Quadrivalent, Sanofi Pasteur) compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) in self-identified Chinese adults at Kaiser Permanente Northern California (KPNC).MethodsThis study evaluated adults aged 18–64 years within KPNC during the 2018–2019 influenza season who self-identified as Chinese (NCT03694392). We compared the rates of prespecified diagnoses of interest in the emergency department and inpatient settings as done in prior influenza studies, for three risk intervals: 0–2 days, 0–13 days, and 0–41 days following influenza vaccination, as well as number of deaths within 0–180 days after vaccination. We estimated the odds ratios (ORs) and 95% confidence intervals using logistic regression adjusted for sex, age group, presence of comorbidities, and same-day concomitant vaccination.ResultsComparing 15,574 adults who received RIV4 with 27,110 who received SD-IIV4, there was no statistically significant difference in the prespecified diagnoses of interest and deaths between the 2 groups. There were 35 deaths total, none of which were considered to be related to influenza vaccination.ConclusionsThis study did not identify any safety concerns regarding RIV4 use among 18–64-year-olds who self-identified as Chinese. This study supports the safety of RIV4 vaccine in this population.