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 2011−12 influenza epidemic had a similar number of cases and deaths, indicating that influenza B could result in an epidemic with substantial morbidity and mortality.
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 
. However, our results demonstrated an unexpected harmful effect from the vaccine with respect to influenza B. An explanation was unmeasured confounding such as healthy vaccinee effect and social determinants 
. However, these confounding would have erroneously reduced VE estimates against influenza A as well, which did not seem to have occurred in our study. During the influenza A (H1N1) 2009 pandemic, several studies demonstrated increased risk of A (H1N1) 2009 illness among recipients of the 2008−09 trivalent vaccine 
. Hypotheses of possible biologic mechanisms included cross-protection block, antibody-dependent enhancement, and temporary immunity 
. Trivalent influenza vaccine recipients were reportedly at increased risk of non-influenza respiratory virus infection from lack of temporary non-specific immunity following influenza virus infection 
. A recent study based on animal models and virus neutralization assays in children concluded that seasonal influenza vaccination was associated with reduced virus-specific CD8+ T cell response and impaired induction of heterosubtypic immunity against influenza A 
. Interference of trivalent vaccines on cross-lineage immunity against influenza B has not been reported. Further studies are needed to determine whether trivalent influenza vaccine recipients are less likely than non-recipients to develop cross-lineage immunity against strains of a vaccine-unmatched influenza B lineage.
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 
. Predominance of B/Yamagata-lineage viruses was not evident until July 2011 when production of the 2011−12 trivalent vaccine was already in progress. This epidemic underscores the limitation of annual trivalent vaccines in containing only one influenza B strain that might not match the predominant B lineage in the upcoming season. In Taiwan, vaccine mismatches of influenza B had occurred in five of 10 influenza seasons during July 2002−June 2012 
. Such mismatches are common and could likely lead to reduced willingness of the public towards vaccination against seasonal influenza. A quadrivalent influenza vaccine that contains viruses from both circulating B lineages is a proposed solution and could reduce influenza-related morbidities and mortalities if vaccine production capacity is not adversely affected 
. However, a quadrivalent vaccine is likely associated with increased cost, resulting in additional financial burden to the government-funded free influenza vaccination program in Taiwan. Inclusion of an additional strain might prolong the vaccine production process. Earlier selection of candidate strains would facilitate timely production but might increase the likelihood of vaccine mismatches. These issues should be considered before adaptation of a quadrivalent influenza vaccine into the vaccination program.
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.