The authors have declared that no competing interests exist.
Conceived and designed the experiments: YCL JH. Chuang WTH JH. Chou FYC. Performed the experiments: YCL HWK WTH YFH MTL CH. Chen HHH CH. Chang. Analyzed the data: YCL HWK WTH MTL HHH CH. Chang. Contributed reagents/materials/analysis tools: JH. Chou FYC TYL WTC. Wrote the paper: YCL JH. Chuang WTH FYC.
The 2011−12 trivalent influenza vaccine contains a strain of influenza B/Victoria-lineage viruses. Despite free provision of influenza vaccine among target populations, an epidemic predominated by influenza B/Yamagata-lineage viruses occurred during the 2011−12 season in Taiwan. We characterized this vaccine-mismatched epidemic and estimated influenza vaccine effectiveness (VE).
Influenza activity was monitored through sentinel viral surveillance, emergency department (ED) and outpatient influenza-like illness (ILI) syndromic surveillance, and case-based surveillance of influenza with complications and deaths. VE against laboratory-confirmed influenza was evaluated through a case-control study on ILI patients enrolled into sentinel viral surveillance. Logistic regression was used to estimate VE adjusted for confounding factors.
During July 2011−June 2012, influenza B accounted for 2,382 (72.5%) of 3,285 influenza-positive respiratory specimens. Of 329 influenza B viral isolates with antigen characterization, 287 (87.2%) were B/Yamagata-lineage viruses. Proportions of ED and outpatient visits being ILI-related increased from November 2011 to January 2012. Of 1,704 confirmed cases of influenza with complications, including 154 (9.0%) deaths, influenza B accounted for 1,034 (60.7%) of the confirmed cases and 103 (66.9%) of the deaths. Reporting rates of confirmed influenza with complications and deaths were 73.5 and 6.6 per 1,000,000, respectively, highest among those aged ≥65 years, 50−64 years, 3−6 years, and 0−2 years. Adjusted VE was −31% (95% CI: −80, 4) against all influenza, 54% (95% CI: 3, 78) against influenza A, and −66% (95% CI: −132, −18) against influenza B.
This influenza epidemic in Taiwan was predominated by B/Yamagata-lineage viruses unprotected by the 2011−12 trivalent vaccine. The morbidity and mortality of this vaccine-mismatched epidemic warrants careful consideration of introducing a quadrivalent influenza vaccine that includes strains of both B lineages.
The influenza B viruses comprise two antigenically distinct lineages, the Yamagata and Victoria lineages, which co-circulate among humans
Annual trivalent influenza vaccines contain three vaccine strains, each representing A (H1N1), A (H3N2), and one of the two influenza B lineages, to protect against influenza viruses that are expected to circulate in the upcoming influenza season. The strains are selected for the annual vaccine based on viral surveillance data. However, in some seasons, the vaccine strains did not match the predominant circulating influenza A or B viruses
The composition of the 2011−12 northern hemisphere influenza vaccines recommended by the World Health Organization included a B/Brisbane/60/2008-like virus from the B/Victoria lineage
The National Influenza Surveillance System (NISS) in Taiwan consists of sentinel viral surveillance, emergency department (ED) and outpatient influenza-like illness (ILI) syndromic surveillance, and case-based surveillance of influenza with complications and deaths
Viral surveillance was conducted through approximately 260 sentinel physicians at 160 health care facilities (36 [23%] pediatric-specific) in 21 of the 22 counties or cities in Taiwan. Each sentinel physician was requested to randomly collect throat or nasal swabs from 2–5 ILI outpatients weekly and submitted the swabs to one of the eight collaborating laboratories for influenza testing using viral culture and/or real-time polymerase chain reaction (RT-PCR)
TCDC conducts surveillance of ILI-related emergency department (ED) visits through the Real-time Outbreak and Disease Surveillance (RODS) system
Influenza with complications is a nationally notifiable condition in Taiwan. A suspected case was defined as a hospitalization or death ≤4 weeks of ILI onset associated with at least one of the following complications: pulmonary complications, neurological complications, cardiac complications (myocarditis or pericarditis), and invasive bacterial infection. A confirmed case was a suspected case with a positive influenza RT-PCR and/or viral culture at collaborating laboratories. Physicians are required to report suspected cases to corresponding local health departments ≤7 days of case identification and submit respiratory specimens (preferentially throat swabs) in all suspected cases to collaborating laboratories that participate in influenza viral surveillance. Local public health professionals verified case characteristics including presenting symptoms, dates of illness onset and hospitalizations, types of complications, vaccination status, and underlying medical conditions based on physician’s reports and hospital records. The National Death Registry was linked to identify deaths that had occurred ≤4 weeks of illness onset among confirmed cases.
In preparation for pandemic influenza, TCDC has stocked approximately 5.75 million courses of antiviral medications including oseltamivir, zanamivir, and peramivir to cover 25% of the population. A committee consisting of virologists, infectious disease specialists, and public health professionals advised TCDC on the policy of antiviral stockpile release based on magnitude of the epidemic, amount and expiration dates of stockpiled antivirals, and prevalence of drug resistance among circulating strains. During the 2011−12 season, pandemic influenza antiviral stockpile was continually released for free medical use with the following indications: (1) suspected or confirmed cases of influenza with complications; (2) ILI with signs and symptoms of progressive disease
We included surveillance data and cases reported during the TCDC-defined 2011−12 influenza season (July 1, 2011−June 30, 2012) which started in week 26, 2011 and ended in week 26, 2012. The Taiwan Census data as of June 2011 available from the Department of Household Registration were used as denominators to calculate overall and age-specific reporting rates of influenza with complications and influenza-associated mortality rates. Descriptive statistics were calculated and figures were produced by using Microsoft Excel (2007). Bivariate analyses were conducted using Wilcoxin two-sample test for continuous variables and chi-square or Fisher’s exact test for categorical variables.
Effectiveness of the 2011−12 trivalent vaccine against laboratory-confirmed influenza in Taiwan was evaluated through a case-control study using the sentinel viral surveillance data. From November 1, 2011 through April 30, 2012, each sentinel physician was requested to randomly select up to five ILI outpatients aged ≥6 months weekly with nasal/throat swabs and information of demographics, vaccination status and comorbidity collected. The enrollment period ended on April 30, 2012 to provide in-season VE estimates. Patients were included into this VE analysis if results of influenza testing on nasal/throat swabs and information of vaccination status were both available. We defined those with a positive influenza culture and/or RT-PCR as case-patients and those with negative influenza test results as controls. A valid vaccination was defined as >14 days between receiving a dose of the 2011−12 influenza vaccine and symptom onset. VE was calculated as (1 - odds ratio [OR] for laboratory-confirmed influenza among vaccinated versus unvaccinated patients) x 100%. Logistic regression was used to estimate adjusted VE and 95% confidence intervals (CI) using OR adjusted for age (<9, 9−49, or >49 years), residing regions (northern or southern Taiwan), underlying medical conditions (presence or not), and intervals between symptom onset and specimen collection (0−2 or >2 days). Variables were analyzed using SAS version 9.2® (SAS Institute Incorporated, Cary, North Carolina, USA).
Data obtained for this study was for surveillance purposes. TCDC determined this analysis a public health response and exempt from Institutional Review Board review.
During the 2011−2012 season, 3,285 (22.0%) of 14,943 respiratory specimens tested positive for influenza. Among the influenza-positive specimens, 2,382 (72.5%) were influenza B, 757 (23.0%) were influenza A (H3N2), and 146 (4.4%) were influenza A (H1N1) 2009. Influenza B was the predominantly circulating type during July 2011−February 2012 (week 26, 2011−week 9, 2012) whereas influenza A (H3N2) predominated during March to June 2012 (week 10, 2011−week 26, 2012) (
Of 329 influenza B viral isolates tested during the 2011−2012 season, 287 (87.2%) belonged to the Yamagata lineage and were antigenically similar to the B/Florida/4/2006-like strain contained in the 2008−09 influenza trivalent vaccine. All of the other 42 influenza B/Victoria-lineage viruses were antigenically similar to the B/Brisbane/60/2008-like strain contained in the 2011−12 influenza trivalent vaccine. Oseltamivir resistance testing was conducted among 293 influenza B, 213 influenza A (H3N2), and 52 influenza A (H1N1) 2009 viruses during the 2011−2012 season. No mutation associated with oseltamivir resistance was detected.
The proportions of ILI-related visits among all NHI-covered outpatient visits and all RODS-enrolled ED visits had both steadily increased since week 46, 2011 and reached the first peaks at week 2, 2012 (
During the 2011−2012 season, TCDC were notified of 2,675 suspected cases of influenza with complications. Of them, 1,704 were confirmed cases, including 154 (9.0%) deaths. The number of confirmed cases, predominated by influenza B, had steadily increased since week 46, 2011 and reached the peak at week 1, 2012 (
During the 2011−12 season, the overall reporting rates of confirmed influenza with complications and deaths were 73.5 and 6.6 per 1,000,000 people, respectively, and were the highest among the age groups of ≥65 years, 50−64 years, 3−6 years, and 0−2 years, respectively (
Age group (years) | B cases (deaths) | A(H3N2) cases (deaths) | A(H1N1) cases (deaths) | A(untyped) cases (deaths) | All cases (deaths) | Age-specific reporting rate (mortality rate) |
0−2 | 22 (2) | 13 (1) | 2 (0) | 0 (0) | 37 (3) | 67.4 (5.5) |
3−6 | 50 (5) | 18 (1) | 3 (1) | 2 (0) | 73 (7) | 87.8 (8.4) |
7−18 | 72 (4) | 14 (2) | 2 (0) | 0 (0) | 88 (6) | 25.3 (1.7) |
19−24 | 12 (0) | 4 (0) | 10 (0) | 0 (0) | 26 (0) | 13.6 (0) |
25−49 | 220 (7) | 70 (3) | 27 (1) | 10 (0) | 327 (11) | 34.7 (1.2) |
50−64 | 273 (28) | 122 (8) | 18 (3) | 9 (1) | 422 (40) | 94.1 (8.9) |
≥65 | 385 (57) | 307 (26) | 25 (3) | 14 (1) | 731 (87) | 293.2 (34.9) |
Total | 1034 (103) | 548 (41) | 87 (8) | 35 (2) | 1704 (154) | 73.5 (6.6) |
Age-specific reporting rates and mortality rates were per 1,000,000 people.
Administration of the 2011−12 trivalent influenza vaccine before illness was reported in 173 (10.2%) of the 1,704 confirmed cases, including 19 (12.3%) of the 154 deaths. Vaccination rates among confirmed cases of influenza B, A (H3N2), A (H1N1) 2009, and A (untyped) were 10.2%, 10.9%, 6.9%, and 5.7%, respectively (p = 0.54).
During the 2011−12 season, 387,608 courses of stockpiled antiviral agents were released and prescribed, comprising 6.7% of TCDC’s pandemic influenza antiviral stockpile. Of them, 370,297 (95.5%) courses were prescribed under the two newly added indications during December 2011−March 2012, including 361,037 courses of oseltamivir, 6,779 courses of zanamivir, and 153 courses of peramivir.
During the 6-month study period, nasal/throat swabs and information of vaccination status were collected in 918 patients. Seven patients were excluded because of age <6 months (5 patients) and mislabeled specimens (2 patients). Of 911 patients included for the VE study, 602 (66.1%) were aged <9 years and 259 (28.4%) were aged 9−49 years, and 50 (5.5%) were aged >49 years. A total of 495 (54.3%) resided in northern Taiwan. Underlying medical conditions were present in 39 (4.3%) patients. Intervals between symptom onset and specimen collection were 0−2 days in 558 (83.2%) patients. Influenza testing was positive in 296 (32.5%) patients (case-patients) and negative in 615 (67.5%) patients (controls). Case-patients and controls differed significantly in age group distribution and residing regions, but did not differ significantly in sex, presence of underlying medical conditions, and intervals between symptom onset and specimen collection (
Characteristics | Cases (N = 296) | Controls (N = 615) |
|
n (%) | n (%) | ||
Age group (years) | 0.0002 | ||
0.5−8 | 169 (57) | 433 (70) | |
9−49 | 110 (37) | 149 (24) | |
≥50 | 17 (6) | 33 (5) | |
Sex | 0.86 | ||
Female | 138 (47) | 283 (46) | |
Male | 158 (53) | 332 (54) | |
Residing region | <0.0001 | ||
Northern Taiwan | 131 (44) | 364 (59) | |
Central and southern Taiwan | 165 (56) | 251 (41) | |
Underlying medical conditions | 0.25 | ||
Yes | 16 (5) | 23 (4) | |
No | 280 (95) | 592 (96) | |
Interval between symptom onset and specimen collection (days) | 0.53 | ||
0−2 | 243 (82) | 515 (84) | |
≥3 | 53 (18) | 100 (16) |
Vaccinated patients accounted for 9 (18.4%) of 49 influenza A-positive cases, 87 (35.2%) of 247 influenza B-positive cases, and 169 (27.5%) of 615 controls. Crude VE was −27% (95% CI: −71, 6) against all influenza, 47% (95% CI: −11, 75) against influenza A, and −49% (95% CI: −103, −9) against influenza B. In logistic regression, adjusted VE was −31% (95% CI: −80, 4) against all influenza, 54% (95% CI: 3, 78) against influenza A, and −66% (95% CI: −132, −18) against influenza B.
The 2011−12 seasonal influenza epidemic in Taiwan was predominantly caused by the B/Florida/4/2006-like strain from the B/Yamagata lineage. Over the past decade, the largest seasonal influenza epidemic in Taiwan occurred during the 2010−2011 season and was predominated by influenza A (H3N2) and A (H1N1) 2009 viruses, resulting in 1,785 confirmed cases of influenza with complications, including 181 (10.1%) deaths
The VE study results suggested the 2011−12 trivalent influenza vaccine moderately protected against influenza A, consistent with the VE estimates of 43−54% against medically attended influenza A (H3N2) reported in two European studies in the context of A (H3N2) antigenic variation from the vaccine strain
The 2009−10 and 2010−11 seasons in Taiwan was predominated by vaccine-matched influenza A viruses, leading the public to confide in the effectiveness and benefits of influenza vaccination
During this vaccine-mismatched epidemic, release of pandemic antiviral stockpile was used as a control measure to reduce viral transmission. Although all of the circulating influenza viruses sampled during the 2011−12 season remained susceptible, acquired antiviral resistance was not optimally assessed because the NISS did not target populations at increased risk for antiviral resistance such as those who had received antiviral treatment or were immunocompromised. Epidemic-driven release of pandemic antiviral stockpile should be balanced with stockpile adequacy, cost associated with antiviral procurement and distribution, risk of emergence of oseltamivir resistance, and reportedly low sensitivity of influenza B viruses to oseltamivir
This study is subject to the following limitations. First, the number of influenza with complications and deaths might have been underestimated because of underdiagnoses and underreporting. However, underreporting was likely uncommon because a patient would be eligible for free antivirals once reported as a suspected or confirmed case. Second, the dramatic increase in the proportions of ILI-related ED and outpatient visits during the 2012 Lunar New Year Holidays (week 4) reflected change in availability of clinical services and were not necessarily indicative of an increased frequency of ILIs in the community. Because routine outpatient services are generally closed during Lunar New Year Holidays, patients tend to seek medical help only when they experience acute illnesses, including ILIs, and have an increased likelihood to present to EDs. The first deflection point (week 2) might rather represent the true peak of this epidemic, which also approximated the peaks detected by sentinel viral surveillance (week 52) and case-based surveillance (week 1). Third, the VE study sample underrepresented elderly patients and might overrepresent those with increased access to medical services or care-seeking behaviors (healthy vaccinee effect). The sample was also too small for age- or target population-stratified estimates. Finally, we only evaluated VE against laboratory-confirmed influenza in outpatient settings; other outcomes (for example, hospitalization) were not assessed.
In conclusion, the 2011−12 seasonal influenza epidemic in Taiwan was predominated by the influenza B/Yamagata-lineage viruses that were not protected by the 2011−12 trivalent vaccine. The morbidity and mortality of this influenza epidemic call for the need of careful consideration of a quadrivalent influenza vaccine that includes viruses of both circulating B lineages to prevent vaccine mismatches.