Vaccine Effectiveness Against Acute Respiratory Illness Hospitalizations for Influenza-Associated Pneumonia During the 2015-2016 to 2017-2018 Seasons: US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN).

BACKGROUND: Evidence for vaccine effectiveness (VE) against influenza-associated pneumonia has varied by season, location, and strain. We estimate VE against hospitalization for radiographically identified influenza-associated pneumonia during 2015-2016 to 2017-2018 seasons in the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN). METHODS: Among adults aged ≥18 years admitted to 10 US hospitals for acute respiratory illness (ARI), clinician-investigators used keywords from reports of chest imaging performed during 3 days around hospital admission to assign a diagnosis of "definite/probable pneumonia." We used a test-negative design to estimate VE against hospitalization for radiographically identified laboratory-confirmed influenza-associated pneumonia, comparing reverse transcriptase-polymerase chain reaction-confirmed influenza cases with test-negative subjects. Influenza vaccination status was documented in immunization records or self-reported, including date and location. Multivariable logistic regression models were used to adjust for age, site, season, calendar-time, and other factors. RESULTS: Of 4843 adults hospitalized with ARI included in the primary analysis, 266 (5.5%) had "definite/probable pneumonia" and confirmed influenza. Adjusted VE against hospitalization for any radiographically confirmed influenza-associated pneumonia was 38% (95% confidence interval [CI], 17-53%); by type/subtype, it was 74% (95% CI, 52-87%) influenza A (H1N1)pdm09, 25% (95% CI, -15% to 50%) A (H3N2), and 23% (95% CI, -32% to 54%) influenza B. Adjusted VE against intensive care for any influenza was 57% (95% CI, 19-77%). CONCLUSIONS: Influenza vaccination was modestly effective among adults in preventing hospitalizations and the need for intensive care associated with influenza pneumonia. VE was significantly higher against A (H1N1)pdm09 and was low against A (H3N2) and B.

A Retrospective Test-Negative Case-Control Study to Evaluate Influenza Vaccine Effectiveness in Preventing Hospitalizations in Children.

BACKGROUND: Vaccination is the primary strategy to reduce influenza burden. Influenza vaccine effectiveness (VE) can vary annually depending on circulating strains. METHODS: We used a test-negative case-control study design to estimate influenza VE against laboratory-confirmed influenza-related hospitalizations among children (aged 6 months-17 years) across 5 influenza seasons in Atlanta, Georgia, from 2012-2013 to 2016-2017. Influenza-positive cases were randomly matched to test-negative controls based on age and influenza season in a 1:1 ratio. We used logistic regression models to compare odds ratios (ORs) of vaccination in cases to controls. We calculated VE as [100% × (1 - adjusted OR)] and computed 95% confidence intervals (CIs) around the estimates. RESULTS: We identified 14 596 hospitalizations of children who were tested for influenza using the multiplex respiratory molecular panel; influenza infection was detected in 1017 (7.0%). After exclusions, we included 512 influenza-positive cases and 512 influenza-negative controls. The median age was 5.9 years (interquartile range, 2.7-10.3), 497 (48.5%) were female, 567 (55.4%) were non-Hispanic Black, and 654 (63.9%) children were unvaccinated. Influenza A accounted for 370 (72.3%) of 512 cases and predominated during all 5 seasons. The adjusted VE against influenza-related hospitalizations during 2012-2013 to 2016-2017 was 51.3% (95% CI, 34.8% to 63.6%) and varied by season. Influenza VE was 54.7% (95% CI, 37.4% to 67.3%) for influenza A and 37.1% (95% CI, 2.3% to 59.5%) for influenza B. CONCLUSIONS: Influenza vaccination decreased the risk of influenza-related pediatric hospitalizations by >50% across 5 influenza seasons.

Simple models to include influenza vaccination history when evaluating the effect of influenza vaccination.

BackgroundMost reports of influenza vaccine effectiveness consider current-season vaccination only.AimWe evaluated a method to estimate the effect of influenza vaccinations (EIV) considering vaccination history.MethodsWe used a test-negative design with well-documented vaccination history to evaluate the average EIV over eight influenza seasons (2011/12-2018/19; n = 10,356). Modifying effect was considered as difference in effects of vaccination in current and previous seasons and current-season vaccination only. We also explored differences between current-season estimates excluding from the reference category people vaccinated in any of the five previous seasons and estimates without this exclusion or only for one or three previous seasons.ResultsThe EIV was 50%, 45% and 38% in people vaccinated in the current season who had previously received none, one to two and three to five doses, respectively, and it was 30% and 43% for one to two and three to five prior doses only. Vaccination in at least three previous seasons reduced the effect of current-season vaccination by 12 percentage points overall, 31 among outpatients, 22 in 9-65 year-olds, and 23 against influenza B. Including people vaccinated in previous seasons only in the unvaccinated category underestimated EIV by 9 percentage points on average (31% vs 40%). Estimates considering vaccination of three or five previous seasons were similar.ConclusionsVaccine effectiveness studies should consider influenza vaccination in previous seasons, as it can retain effect and is often an effect modifier. Vaccination status in three categories (current season, previous seasons only, unvaccinated) reflects the whole EIV.

Vaccine Effectiveness Against Lineage-matched and -mismatched Influenza B Viruses Across 8 Seasons in Canada, 2010-2011 to 2017-2018.

Vaccine effectiveness (VE) against influenza B was derived separately for Victoria and Yamagata lineages across 8 seasons (2010-2011 to 2017-2018) in Canada when trivalent influenza vaccine was predominantly used. VE was ≥50% regardless of lineage match to circulating viruses, except when the vaccine strain was unchanged from the prior season.

Factors associated with recruitment, surveillance participation, and retention in an observational study of pregnant women and influenza.

BACKGROUND: This report describes the results of recruitment efforts and the subsequent participation of pregnant women in study activities in a 2010-2012 observational study focused on influenza illness and vaccination in California and Oregon, USA. METHODS: Socio-demographic and health characteristics extracted from electronic medical records were compared among pregnant women who enrolled in the study, refused to participate, or were never reached for study invitation. These characteristics plus additional self-reported information were compared between women who enrolled in two study tracks: a prospective cohort vs. women enrolled following an acute respiratory illness (ARI) medical encounter. The characteristics of women who participated in weekly ARI surveillance (cohort enrollees, year one) and a 6-month follow-up interview (all enrollees) were also examined. RESULTS: In year one, we reached 51% (6938/13,655) of the potential participants we tried to contact by telephone, and 20% (1374/6938) of the women we invited agreed to join the prospective cohort. Women with chronic medical conditions, pregnancy complications, and medical encounters for ARI (prior to pregnancy or during the study period) were more likely to be reached for recruitment and more likely to enroll in the cohort. Twenty percent of cohort enrollees never started weekly surveillance reports; among those who did, reports were completed for 55% of the surveillance weeks. Receipt of the influenza vaccine was higher among women who joined the cohort (76%) than those who refused (56%) or were never reached (54%). In contrast, vaccine uptake among medical enrollees in year one (54%; 53/98) and two (52%; 79/151) was similar to other pregnant women in those years. Study site, white race, non-Hispanic ethnicity, and not having a child aged < 13 years at home were most consistently associated with joining as a cohort or medical enrollee and completing study activities after joining. CONCLUSIONS: We observed systematic differences in socio-demographic and health characteristics across different levels of participant engagement and between cohort and medical enrollees. More methodological research and innovation in conducting prospective observational studies in this population are needed, especially when extended participant engagement and ongoing surveillance are required.

End of season influenza vaccine effectiveness in adults and children in the United Kingdom in 2017/18.

BackgroundIn the United Kingdom (UK), in recent influenza seasons, children are offered a quadrivalent live attenuated influenza vaccine (LAIV4), and eligible adults mainly trivalent inactivated vaccine (TIV).AimTo estimate the UK end-of-season 2017/18 adjusted vaccine effectiveness (aVE) and the seroprevalence in England of antibodies against influenza viruses cultured in eggs or tissue.MethodsThis observational study employed the test-negative case-control approach to estimate aVE in primary care. The population-based seroprevalence survey used residual age-stratified samples.ResultsInfluenza viruses A(H3N2) (particularly subgroup 3C.2a2) and B (mainly B/Yamagata/16/88-lineage, similar to the quadrivalent vaccine B-virus component but mismatched to TIV) dominated. All-age aVE was 15% (95% confidence interval (CI): -6.3 to 32) against all influenza; -16.4% (95% CI: -59.3 to 14.9) against A(H3N2); 24.7% (95% CI: 1.1 to 42.7) against B and 66.3% (95% CI: 33.4 to 82.9) against A(H1N1)pdm09. For 2-17 year olds, LAIV4 aVE was 26.9% (95% CI: -32.6 to 59.7) against all influenza; -75.5% (95% CI: -289.6 to 21) against A(H3N2); 60.8% (95% CI: 8.2 to 83.3) against B and 90.3% (95% CI: 16.4 to 98.9) against A(H1N1)pdm09. For ≥ 18 year olds, TIV aVE against influenza B was 1.9% (95% CI: -63.6 to 41.2). The 2017 seroprevalence of antibody recognising tissue-grown A(H3N2) virus was significantly lower than that recognising egg-grown virus in all groups except 15-24 year olds.ConclusionsOverall aVE was low driven by no effectiveness against A(H3N2) possibly related to vaccine virus egg-adaption and a new A(H3N2) subgroup emergence. The TIV was not effective against influenza B. LAIV4 against influenza B and A(H1N1)pdm09 was effective.

Effectiveness of inactivated quadrivalent influenza vaccine in the 2015/2016 season as assessed in both a test-negative case-control study design and a traditional case-control study design.

Both traditional case-control studies (TCCSs) and test-negative case-control studies (TNCCSs) are commonly used to assess influenza vaccine effectiveness (VE). To compensate for the fact that observational studies are susceptible to bias, we combined both methods to assess VE in one geographical area during the 2015/2016 season, when influenza A (H1N1)pdm was dominant. Our TNCCS covered 331 children aged 6 months to 15 years who visited our hospital with fever, including 182 with influenza, and our TCCS covered 812 pediatric outpatients aged 6 months to 15 years, including 214 with influenza. Influenza infection and vaccination history were reviewed, and VE was calculated as (1 - odds ratio) × 100. In the TNCCS, VE against influenza A was 68% (95% CI 47-81) overall, and 70% (48-83) for those given two doses; against influenza B, VE was 37% (- 12-64) overall and 49% (2-74) for two doses. In the TCCS, VE against influenza A was 44% (15-63) overall and 44% (13-64) for two doses, and VE against influenza B was 24% (- 19-52) overall and 41% (3-64) for two doses. CONCLUSION: Both studies confirmed significant VE against influenza A, significant two-dose VE against influenza B, and better two-dose VE than one-dose VE. What is Known: • Influenza vaccine effectiveness (VE) varies from year to year. • Observational studies are conventionally used for VE assessment. However, they are inherently susceptible to bias and confounding. What is New: • This is the first report of influenza VE assessment using more than one observational study and performed in a specific area during the same season. • VE estimates obtained in our traditional case-control study were lower than those in our test-negative case-control study, but both studies found significant VE against influenza.

Influenza vaccine showed a good preventive effect against influenza-associated hospitalization among elderly patients, during the 2016/17 season in Japan.

The 2016/17 influenza season in Japan was characterized by a predominance of influenza A (H3N2) activity; with H3N2 accounting for 85% of all detected influenza virus infections. We assessed the vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine (IIV4) in adult patients, using a test-negative case-control design study based on the results of a rapid influenza diagnostic test (RIDT). Between November 2016 and March 2017, a total of 1048 adult patients were enrolled: including 363 RIDT positive for influenza A, 9 RIDT-positive for influenza B, and 676 RIDT-negative. During the 2016/17 season, the overall adjusted VE was 28.8% (95% confidence interval [CI]: 6.3-46%). The adjusted VE against influenza A was 27.4% (95%CI: 4.4-45%). The VE against influenza B could not be estimated because of the very low number of influenza B patients. Twenty-nine patients were hospitalized due to influenza-associated illness-during the present study, all of whom were infected with influenza A virus. The adjusted VE, determined using a case-control study, for preventing hospitalization for influenza A infection was 72.6% (95%CI: 30.7-89.1%). In addition, the VE for preventing hospitalization of influenza patients with comorbidities was 78.2% (95%CI: 41.1-92%). Our study showed that, during the 2016/17season, IIV4 was effective for preventing both the onset of influenza and influenza-associated hospitalization.

Interim 2017/18 influenza seasonal vaccine effectiveness: combined results from five European studies.

Between September 2017 and February 2018, influenza A(H1N1)pdm09, A(H3N2) and B viruses (mainly B/Yamagata, not included in 2017/18 trivalent vaccines) co-circulated in Europe. Interim results from five European studies indicate that, in all age groups, 2017/18 influenza vaccine effectiveness was 25 to 52% against any influenza, 55 to 68% against influenza A(H1N1)pdm09, -42 to 7% against influenza A(H3N2) and 36 to 54% against influenza B. 2017/18 influenza vaccine should be promoted where influenza still circulates.

Influenza vaccine effectiveness in adults based on the rapid influenza diagnostic test results, during the 2015/16 season.

We assessed the influenza vaccine effectiveness (VE) of an inactivated quadrivalent influenza vaccine in adult patients, in our test-negative case-control design study based on the results of a rapid influenza diagnostic test. During the 2015/16 season in Japan, influenza A(H1N1)pdm09 virus and influenza B virus were epidemic. The overall adjusted VE was 44% (95% confidence interval [CI]: 13.6%-63.7%). The adjusted VE was 52.9% (95%CI: 20%-72.3%) against any influenza virus among those < 65 years of age and -5% (95%CI: 136%-53.5%) among the elderly ≧ 65 years of age. The adjusted VE against influenza A was 49.1% (95%CI: 13.9%-69.9%). Although the VE was 55.5% (95%CI: 14.8%-76.8%) among those <65 years of age, it was only 15.3% (95%CI: 120%-67.4%) among the elderly ≧ 65 years of age. The adjusted VE against influenza B was 33.8% (95%CI: 25%-64.8%) among adult patients (≧16 years of age) and 46.8% (95%CI: 13%-75%) among those < 65 years of age, the VE against influenza B could not be estimated in those ≧65 years of age because of the low number of elderly patients with that virus.

Influenza Vaccine Effectiveness Against 2009 Pandemic Influenza A(H1N1) Virus Differed by Vaccine Type During 2013-2014 in the United States.

BACKGROUND: The predominant strain during the 2013-2014 influenza season was 2009 pandemic influenza A(H1N1) virus (A[H1N1]pdm09). This vaccine-component has remained unchanged from 2009. METHODS: The US Flu Vaccine Effectiveness Network enrolled subjects aged ≥6 months with medically attended acute respiratory illness (MAARI), including cough, with illness onset ≤7 days before enrollment. Influenza was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). We determined the effectiveness of trivalent or quadrivalent inactivated influenza vaccine (IIV) among subjects ages ≥6 months and the effectiveness of quadrivalent live attenuated influenza vaccine (LAIV4) among children aged 2-17 years, using a test-negative design. The effect of prior receipt of any A(H1N1)pdm09-containing vaccine since 2009 on the effectiveness of current-season vaccine was assessed. RESULTS: We enrolled 5999 subjects; 5637 (94%) were analyzed; 18% had RT-PCR-confirmed A(H1N1)pdm09-related MAARI. Overall, the effectiveness of vaccine against A(H1N1)pdm09-related MAARI was 54% (95% confidence interval [CI], 46%-61%). Among fully vaccinated children aged 2-17 years, the effectiveness of LAIV4 was 17% (95% CI, -39% to 51%) and the effectiveness of IIV was 60% (95% CI, 36%-74%). Subjects aged ≥9 years showed significant residual protection of any prior A(H1N1)pdm09-containing vaccine dose(s) received since 2009, as did children <9 years old considered fully vaccinated by prior season. CONCLUSIONS: During 2013-2014, IIV was significantly effective against A(H1N1)pdm09. Lack of LAIV4 effectiveness in children highlights the importance of continued annual monitoring of effectiveness of influenza vaccines in the United States.

Case-Control Study of Vaccine Effectiveness in Preventing Laboratory-Confirmed Influenza Hospitalizations in Older Adults, United States, 2010-2011.

BACKGROUND: Older adults are at increased risk of influenza-associated complications, including hospitalization, but influenza vaccine effectiveness (VE) data are limited for this population. We conducted a case-control study to estimate VE to prevent laboratory-confirmed influenza hospitalizations among adults aged ≥50 years in 11 US Emerging Infections Program hospitalization surveillance sites. METHODS: Cases were influenza infections (confirmed by reverse-transcription polymerase chain reaction) in adults aged ≥50 years hospitalized during the 2010-2011 influenza season, identified through Emerging Infections Program surveillance. Community controls, identified through home telephone lists, were matched by age group (±5 years), county, and month of hospitalization for case patients. Vaccination status was determined by self-report (with location and date) or medical records. Conditional logistic regression models were used to calculate adjusted VE (aVE) estimates (100 × [1 - adjusted odds ratio]), adjusting for sex, race, socioeconomic factors, smoking, chronic medical conditions, recent hospitalization for a respiratory condition, and functional status. RESULTS: Among case patients, 205 of 368 (55%) were vaccinated, compared with 489 of 773 controls (63%). Case patients were more likely to be of nonwhite race and more likely to have ≥2 chronic health conditions, a recent hospitalization for a respiratory condition, an income <$35 000, and a lower functional status score (P < .01 for all). The aVE was 56.8% (95% confidence interval, 34.1%-71.7%) and was similar across age groups, including adults ≥75 years (aVE, 57.3%; 15.9%-78.4%). CONCLUSIONS: During 2010-2011, influenza vaccination was associated with a significant reduction in the risk of laboratory-confirmed influenza hospitalization among adults aged ≥50 years, regardless of age group.

Influenza Vaccine Effectiveness Against Antigenically Drifted Influenza Higher Than Expected in Hospitalized Adults: 2014-2015.

BACKGROUND: The 2014-2015 influenza season was severe, with circulating influenza A (H3N2) viruses that were antigenically drifted from the vaccine virus. Reported vaccine effectiveness (VE) estimates from ambulatory care settings were markedly decreased. METHODS: Adults, hospitalized at 2 hospitals in southeast Michigan for acute respiratory illnesses, defined by admission diagnoses, of ≤10 days duration were prospectively enrolled. Throat and nasal swab specimens were collected, combined, and tested for influenza by real-time reverse transcription polymerase chain reaction. VE was estimated by comparing the vaccination status of those testing positive for influenza with those testing negative in logistic regression models adjusted for age, sex, hospital, calendar time, time from illness onset to specimen collection, frailty score, and Charlson comorbidity index (CCI). RESULTS: Among 624 patients included in the analysis, 421 (68%) were vaccinated, 337 (54%) were female, 220 (35%) were age ≥65 years, and 92% had CCI > 0, indicating ≥1 comorbid conditions. Ninety-eight (16%) patients tested positive for influenza A (H3N2); among 60 (61%) A (H3N2) viruses tested by pyrosequencing, 53 (88%) belonged to the drifted 3C.2a genetic group. Adjusted VE was 43% (95% confidence interval [CI], 4-67) against influenza A (H3N2); 40% (95% CI, -13 to 68) for those <65 years, and 48% (95% CI, -33 to 80) for those ≥65 years. Sensitivity analyses largely supported these estimates. CONCLUSIONS: VE estimates appeared higher than reports from similar studies in ambulatory care settings, suggesting that the 2014-2015 vaccine may have been more effective in preventing severe illness requiring hospitalization.

Seasonal influenza vaccine (A/New York/39/2012) effectiveness against influenza A virus of health care workers in a long term care facility attached with the hospital, Japan, 2014/15: A cohort study.

The 2014/15 influenza season started earlier than usual, and intense activity was reflection of circulation of antigenically-drifted and vaccine-mismatched dominant A(H3N2) viruses. Although inpatients and health-care workers (HCWs) had a high influenza vaccination coverage rate well prior to the beginning of influenza season, numerous outbreaks of influenza A(H3N2) infection with fatal cases were reported in long-term care facilities (LTCFs) in Japan during 2014/15 influenza season. In January 2015, we were given opportunity to conduct outbreak investigation of influenza A at facility A (LTCF attached with hospital) in Western part of Japan. We evaluated overall and occupation-stratified influenza vaccine effectiveness (VE) among HCWs at facility A using a retrospective cohort design. Overall VE, occupation-stratified VE and adjusted VE (AVE) with 95% confidence intervals (CIs) were estimated using the following formula: (1-relative risks (RR) or 1-adjusted RR) × 100%. Overall vaccine coverage rate among HCWs was 85%. Overall VE for HCWs was 28% (95% CI: -70 to 67) and overall AVE was 3% (95% CI: -34 to 30). Although there was no severe cases, our results indicated that even with high vaccination coverage rate with appropriate vaccination timing, the VE was low for HCWs, which echoes with previously reported VE from other northern hemisphere countries. However, rehabilitation group who had high awareness against influenza as a group and carried out intensive precautions from early influenza season had no cases. We conclude that multiple preventive measures in addition to high vaccination rate is necessary for preventing influenza of HCWs working at LCTFs.

Vaccine effectiveness in preventing laboratory-confirmed influenza in primary care patients in a season of co-circulation of influenza A(H1N1)pdm09, B and drifted A(H3N2), I-MOVE Multicentre Case-Control Study, Europe 2014/15.

Influenza A(H3N2), A(H1N1)pdm09 and B viruses co-circulated in Europe in 2014/15. We undertook a multicentre case-control study in eight European countries to measure 2014/15 influenza vaccine effectiveness (VE) against medically-attended influenza-like illness (ILI) laboratory-confirmed as influenza. General practitioners swabbed all or a systematic sample of ILI patients. We compared the odds of vaccination of ILI influenza positive patients to negative patients. We calculated adjusted VE by influenza type/subtype, and age group. Among 6,579 ILI patients included, 1,828 were A(H3N2), 539 A(H1N1)pdm09 and 1,038 B. VE against A(H3N2) was 14.4% (95% confidence interval (CI): -6.3 to 31.0) overall, 20.7% (95%CI: -22.3 to 48.5), 10.9% (95%CI -30.8 to 39.3) and 15.8% (95% CI: -20.2 to 41.0) among those aged 0-14, 15-59 and  ≥60 years, respectively. VE against A(H1N1)pdm09 was 54.2% (95%CI: 31.2 to 69.6) overall, 73.1% (95%CI: 39.6 to 88.1), 59.7% (95%CI: 10.9 to 81.8), and 22.4% (95%CI: -44.4 to 58.4) among those aged 0-14, 15-59 and  ≥60 years respectively. VE against B was 48.0% (95%CI: 28.9 to 61.9) overall, 62.1% (95%CI: 14.9 to 83.1), 41.4% (95%CI: 6.2 to 63.4) and 50.4% (95%CI: 14.6 to 71.2) among those aged 0-14, 15-59 and ≥60 years respectively. VE against A(H1N1)pdm09 and B was moderate. The low VE against A(H3N2) is consistent with the reported mismatch between circulating and vaccine strains.

Influenza vaccine prevents medically attended influenza-associated acute respiratory illness in adults aged ≥50 years.

BACKGROUND: There are few estimates of effectiveness influenza vaccine in preventing serious outcomes due to influenza in older adults. METHODS: Adults aged ≥50 years who sought medical care for acute respiratory illness were enrolled. A nose/throat swab was tested for influenza virus by reverse transcription-polymerase chain reaction. Clinical and demographic data were collected, including verification of receipt of trivalent inactivated influenza vaccination (IIV-3). Adjusted odds ratios were estimated by multivariable logistic regression models with an L1 penalty on all covariates except vaccination status. RESULTS: A total of 1047 subjects were enrolled from November through April during 5 influenza seasons during 2006-2012, excluding the 2009-2010 season. Of those enrolled, 927 (88%) had complete influenza virus testing, vaccination status, and demographic data obtained. Of 86 (9.3%) influenza virus-positive patients, 47 (55%) were vaccinated. Of 841 influenza virus-negative patients, 646 (76.8%) were vaccinated. Over 5 influenza seasons, IIV-3 was 58.4% effective (95% confidence interval [CI], 37.0%-75.6%) for the prevention of medically attended laboratory-confirmed influenza illness in adults aged ≥50 years and 58.4% effective (95% CI, 7.9%-81.1%) in adults aged ≥65 years. CONCLUSIONS: Influenza vaccine was moderately effective in preventing influenza-associated medical care visits in older adults.

Influenza vaccine effectiveness during the 2012 influenza season in Victoria, Australia: influences of waning immunity and vaccine match.

Vaccine effectiveness may wane with increasing time since vaccination. This analysis used the Victorian sentinel general practitioner (GP) network to estimate vaccine effectiveness for trivalent inactivated vaccines in the 2012 season. A test-negative design was used where patients presenting to GPs with influenza-like illness who tested positive for influenza were cases and noncases were those who tested negative. Vaccination status was recorded by GPs. Vaccine effectiveness was calculated as (1-odds ratio) × 100%. Estimates were compared early versus late in the season and by time since vaccination. Virus isolates were assessed antigenically by hemagglutination inhibition assay in a selection of positive samples and viruses from healthy adults who experienced a vaccine breakthrough were analyzed genetically. The adjusted vaccine effectiveness estimate for any type of influenza was 45% (95% CI: 8,66) and for influenza A(H3) was 35% (95% CI: -11,62). A non-significant effect of waning effectiveness by time since vaccination was observed for A(H3). For those vaccinated <93 days of presentation vaccine effectiveness was 37% (95% CI: -29,69), while for those vaccinated ≥93 days before presentation it was 18% (95% CI: -83,63). Comparison of early versus late in the season estimates was very sensitive to the cut off week chosen for analysis. Antigenic data suggested that low vaccine effectiveness was not associated with poor vaccine match among the A(H3) viruses. However, genetic analysis suggested nucleotide substitutions in antigenic sites. In 2012, the trivalent influenza vaccine provided moderate protection against influenza and showed limited evidence for waning effectiveness. Antigenic and genetic data can provide additional insight into understanding these estimates.

Investigating confounding in network-based test-negative design influenza vaccine effectiveness studies-Experience from the DRIVE project.

BACKGROUND: Establishing a large study network to conduct influenza vaccine effectiveness (IVE) studies while collecting appropriate variables to account for potential bias is important; the most relevant variables should be prioritized. We explored the impact of potential confounders on IVE in the DRIVE multi-country network of sites conducting test-negative design (TND) studies. METHODS: We constructed a directed acyclic graph (DAG) to map the relationship between influenza vaccination, medically attended influenza infection, confounders, and other variables. Additionally, we used the Development of Robust and Innovative Vaccines Effectiveness (DRIVE) data from the 2018/2019 and 2019/2020 seasons to explore the effect of covariate adjustment on IVE estimates. The reference model was adjusted for age, sex, calendar time, and season. The covariates studied were presence of at least one, two, or three chronic diseases; presence of six specific chronic diseases; and prior healthcare use. Analyses were conducted by site and subsequently pooled. RESULTS: The following variables were included in the DAG: age, sex, time within influenza season and year, health status and comorbidities, study site, health-care-seeking behavior, contact patterns and social precautionary behavior, socioeconomic status, and pre-existing immunity. Across all age groups and settings, only adjustment for lung disease in older adults in the primary care setting resulted in a relative change of the IVE point estimate >10%. CONCLUSION: Our study supports a parsimonious approach to confounder adjustment in TND studies, limited to adjusting for age, sex, and calendar time. Practical implications are that necessitating fewer variables lowers the threshold for enrollment of sites in IVE studies and simplifies the pooling of data from different IVE studies or study networks.