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Background: Annual influenza vaccination is recommended for older adults but repeated vaccination with standard-dose influenza vaccine has been linked to reduced immunogenicity and effectiveness, especially against A(H3N2) viruses., Methods: Community-dwelling Hong Kong adults aged 65-82 years were randomly allocated to receive 2017-2018 standard-dose quadrivalent, MF59-adjuvanted trivalent, high-dose trivalent, and recombinant-HA quadrivalent vaccination. Antibody response to unchanged A(H3N2) vaccine antigen was compared among participants with and without self-reported prior year (2016-2017) standard-dose vaccination., Results: Mean fold rise (MFR) in antibody titers from day 0 to day 30 by hemagglutination inhibition and virus microneutralization assays were lower among 2017-2018 standard-dose and enhanced vaccine recipients with (range, 1.7-3.0) versus without (range, 4.3-14.3) prior 2016-2017 vaccination. MFR was significantly reduced by about one-half to four-fifths for previously vaccinated recipients of standard-dose and all 3 enhanced vaccines (β range, .21-.48). Among prior-year vaccinated older adults, enhanced vaccines induced higher 1.43 to 2.39-fold geometric mean titers and 1.28 to 1.74-fold MFR versus standard-dose vaccine by microneutralization assay., Conclusions: In the context of unchanged A(H3N2) vaccine strain, prior-year vaccination was associated with reduced antibody response among both standard-dose and enhanced influenza vaccine recipients. Enhanced vaccines improved antibody response among older adults with prior-year standard-dose vaccination., Competing Interests: Potential conflicts of interest. B. J. C. has consulted for AstraZeneca, Fosun Pharma, GSK, Haleon, Moderna, Novavax, Pfizer, Roche, and Sanofi Pasteur. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Previous studies suggest that influenza virus infection may provide temporary non-specific immunity and hence lower the risk of non-influenza respiratory virus infection. In a randomized controlled trial of influenza vaccination, 1 330 children were followed-up in 2009-2011. Respiratory swabs were collected when they reported acute respiratory illness and tested against influenza and other respiratory viruses. We used Poisson regression to compare the incidence of non-influenza respiratory virus infection before and after influenza virus infection. Based on 52 children with influenza B virus infection, the incidence rate ratio (IRR) of non-influenza respiratory virus infection after influenza virus infection was 0.47 (95% confidence interval: 0.27-0.82) compared with before infection. Simulation suggested that this IRR was 0.87 if the temporary protection did not exist. We identified a decreased risk of non-influenza respiratory virus infection after influenza B virus infection in children. Further investigation is needed to determine if this decreased risk could be attributed to temporary non-specific immunity acquired from influenza virus infection.

Influenza vaccination is an important intervention to prevent influenza virus infection. Our previous analysis suggested that indirect protection is limited in an influenza B epidemic in Hong Kong. We further analyzed six influenza A epidemics to determine such potential. We applied a statistical model to estimate household transmission dynamics in the 3 influenza A(H3N2) and 3 pandemic influenza A(H1N1) epidemics. Then, we estimated the reduction in infection risk among unvaccinated household members when all children in households are vaccinated, with different assumptions on vaccine efficacy (VE). In the optimal scenario that VE was 70%, the reduction to the total probability of infection was only marginal, with relative probabilities ranged from 0.91-0.94 when all children in households were vaccinated because community was by far the main source of infection during the six epidemics in our study. The proportion of cases attributed to household transmission was 10% (95% CrI: 7%, 13%). Individual influenza vaccination is important even when other household members are vaccinated, given the degree of indirect protection is small.

We explored the potential for a biphasic pattern in waning of antibody titers after influenza vaccination. We collected blood samples in a randomized controlled trial of influenza vaccination in children and tested them with hemagglutination inhibition assays for influenza A(H3N2) and influenza B/Victoria lineage. Using piecewise log-linear mixed-effects models, we found evidence for a faster initial waning of antibody titers for the first 1-2 years after vaccination and then slower longer-term declines. Children with higher postvaccination titers had faster antibody decay., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The protective effect of T cell-mediated immunity against influenza virus infections in natural settings remains unclear, especially in seasonal epidemics., Methods: To explore the potential of such protection, we analyzed the blood samples collected longitudinally in a community-based study and covered the first wave of pandemic H1N1 (pH1N1), two subsequent pH1N1 epidemics, and three seasonal H3N2 influenza A epidemics (H3N2) for which we measured pre-existing influenza virus-specific CD4 and CD8 T cell responses by intracellular IFN-γ staining assay for 965 whole blood samples., Results: Based on logistic regression, we found that higher pre-existing influenza virus-specific CD4 and CD8 T cell responses were associated with lower infection odds for corresponding subtypes. Every fold increase in H3N2-specific CD4 and CD8 T cells was associated with 28% (95% CI 8%, 44%) and 26% (95% CI 8%, 41%) lower H3N2 infection odds, respectively. Every fold increase in pre-existing seasonal H1N1 influenza A virus (sH1N1)-specific CD4 and CD8 T cells was associated with 28% (95% CI 11%, 41%) and 22% (95% CI 8%, 33%) lower pH1N1 infection odds, respectively. We observed the same associations for individuals with pre-epidemic hemagglutination inhibition (HAI) titers < 40. There was no correlation between pre-existing influenza virus-specific CD4 and CD8 T cell response and HAI titer., Conclusions: We demonstrated homosubtypic and cross-strain protection against influenza infections was associated with T cell response, especially CD4 T cell response. These protections were independent of the protection associated with HAI titer. Therefore, T cell response could be an assessment of individual and population immunity for future epidemics and pandemics, in addition to using HAI titer., (© 2022. The Author(s).)

For >70 years, a 4-fold or greater rise in antibody titer has been used to confirm influenza virus infections in paired sera, despite recognition that this heuristic can lack sensitivity. Here we analyze with a novel Bayesian model a large cohort of 2353 individuals followed for up to 5 years in Hong Kong to characterize influenza antibody dynamics and develop an algorithm to improve the identification of influenza virus infections. After infection, we estimate that hemagglutination-inhibiting (HAI) titers were boosted by 16-fold on average and subsequently decrease by 14% per year. In six epidemics, the infection risks for adults were 3%-19% while the infection risks for children were 1.6-4.4 times higher than that of younger adults. Every two-fold increase in pre-epidemic HAI titer was associated with 19%-58% protection against infection. Our inferential framework clarifies the contributions of age and pre-epidemic HAI titers to characterize individual infection risk., (© 2022. The Author(s).)

Background: Enhanced influenza vaccines may improve protection for older adults, but comparative immunogenicity data are limited. Our objective was to examine immune responses to enhanced influenza vaccines, compared to standard-dose vaccines, in community-dwelling older adults., Methods: Community-dwelling older adults aged 65-82 years in Hong Kong were randomly allocated (October 2017-January 2018) to receive 2017-2018 Northern hemisphere formulations of a standard-dose quadrivalent vaccine, MF59-adjuvanted trivalent vaccine, high-dose trivalent vaccine, or recombinant-hemagglutinin (rHA) quadrivalent vaccine. Sera collected from 200 recipients of each vaccine before and at 30-days postvaccination were assessed for antibodies to egg-propagated vaccine strains by hemagglutination inhibition (HAI) and to cell-propagated A/Hong Kong/4801/2014(H3N2) virus by microneutralization (MN). Influenza-specific CD4+ and CD8+ T cell responses were assessed in 20 participants per group., Results: Mean fold rises (MFR) in HAI titers to egg-propagated A(H1N1) and A(H3N2) and the MFR in MN to cell-propagated A(H3N2) were statistically significantly higher in the enhanced vaccine groups, compared to the standard-dose vaccine. The MFR in MN to cell-propagated A(H3N2) was highest among rHA recipients (4.7), followed by high-dose (3.4) and MF59-adjuvanted (2.9) recipients, compared to standard-dose recipients (2.3). Similarly, the ratio of postvaccination MN titers among rHA recipients to cell-propagated A(H3N2) recipients was 2.57-fold higher than the standard-dose vaccine, which was statistically higher than the high-dose (1.33-fold) and MF59-adjuvanted (1.43-fold) recipient ratios. Enhanced vaccines also resulted in the boosting of T-cell responses., Conclusions: In this head-to-head comparison, older adults receiving enhanced vaccines showed improved humoral and cell-mediated immune responses, compared to standard-dose vaccine recipients., Clinical Trials Registration: NCT03330132., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

Background: Studies that correlate maternal antibodies with protection from influenza A or B virus infection in young infants in areas with prolonged influenza circulation are lacking., Methods: We conducted a prospective, observational study to evaluate the effects of maternally transferred antibodies against influenza A and B viruses against laboratory-confirmed influenza in a cohort born over 24 months. Cord blood samples were retrieved at birth and infants were actively followed for the first 6 months of life. Nasal swabs were collected and tested for influenza A and B by reverse transcriptase-polymerase chain reaction whenever an illness episode was identified. Cord blood samples were tested by the hemagglutination inhibition (HAI) assay to viruses that circulated during the follow-up period., Results: 1162 infants were born to 1140 recruited women: 1092 (94%) infants completed 6 months of follow-up. Proportions of cord blood with HAI antibody titers ≥40 against A(H1N1), A(H3N2), B/Victoria, and B/Yamagata were 31%, 24%, 31%, and 54%, respectively. Only 4% of women had maternal influenza vaccination. Cord blood antigen-specific HAI titers ≥40 were found to correlate with protection from infection only for influenza B/Yamagata. No influenza B virus infection occurred in infants ≤60 days old. Proportional hazards analysis showed that a cord blood HAI titer of 40 was associated with 83% (95% confidence interval, 44-95%) reduction in the risk of influenza B/Yamagata infections compared with a cord blood titer <10., Conclusions: We documented that maternal immunity against influenza B/Yamagata was conferred to infants within the first 6 months of life., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: We analyzed data from a randomized controlled trial on the reactogenicity of 3 enhanced influenza vaccines compared with standard-dose (SD) inactivated influenza vaccine., Methods: We enrolled community-dwelling older adults in Hong Kong, and we randomly allocated them to receive 2017-2018 northern hemisphere formulations of SD vaccine (FluQuadri; Sanofi Pasteur), MF59-adjuvanted vaccine (FLUAD; Seqirus), high-dose (HD) vaccine (Fluzone High-Dose; Sanofi Pasteur), or recombinant hemagglutinin vaccine (Flublok; Sanofi Pasteur). Local and systemic reactions were evaluated at days 1, 3, 7, and 14 after vaccination., Results: Reported reactions were generally mild and short-lived. Systemic reactions occurred in similar proportions of participants by vaccine. Some local reactions were slightly more frequently reported among recipients of the MF59-adjuvanted and HD vaccines than among SD vaccine recipients. Participants reporting feverishness 1 day after vaccination had mean fold rises in postvaccination hemagglutination inhibition titers that were 1.85-fold higher (95% confidence interval, 1.01-3.38) for A(H1N1) than in those who did not report feverishness., Conclusions: Some acute local reactions were more frequent after vaccination with MF59-adjuvanted and HD influenza vaccines, compared with SD inactivated influenza vaccine, whereas systemic symptoms occurred at similar frequencies in all groups. The association between feverishness and immunogenicity should be further investigated in a larger population., Clinical Trials Registration: NCT03330132., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Immune responses to influenza vaccination can be weaker in older adults than in other age groups. We hypothesized that antibody responses would be particularly weak among repeat vaccinees when the current and prior season vaccine components are the same., Methods: An observational study was conducted among 827 older adults (aged ≥75 years) in Hong Kong. Serum samples were collected immediately before and 1 month after receipt of the 2015-2016 quadrivalent inactivated influenza vaccine. We measured antibody titers with the hemagglutination inhibition assay and compared the mean fold rise from prevaccination to postvaccination titers and the proportions with postvaccination titers ≥40 or ≥160., Results: Participants who reported receipt of vaccination during either of the previous 2 years had a lower mean fold rise against all strains than with those who did not. Mean fold rises for A(H3N2) and B/Yamagata were particularly weak after repeated vaccination with the same vaccine strain, but we did not generally find significant differences in the proportions of participants with postvaccination titers ≥40 and ≥160., Conclusions: Overall, we found that reduced antibody responses in repeat vaccinees were particularly reduced among older adults who had received vaccination against the same strains in preceding years., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: The hemagglutination inhibition (HAI) assay is an established correlate of protection for the inactivated influenza vaccine. However, the proportion of vaccine-induced protection that is mediated by the post-vaccination HAI titer has not been assessed., Methods: We used data from a randomized, placebo-controlled trial of a split-virion inactivated influenza vaccine in children aged 6-17 years. Sera were collected before and 30 days after receipt of vaccination or placebo and tested by the HAI assay against B/Brisbane/60/2008-like (B/Victoria lineage). We fitted Cox proportional hazards models to the time to laboratory-confirmed influenza B. We used causal mediation analysis to estimate the proportion of the total effect of vaccination that was mediated by higher HAI titers., Results: We estimated that vaccine efficacy against confirmed B/Victoria infection was 68% (95% confidence interval, 33%, 88%), and post-vaccination HAI titers explained 57% of the effect of vaccination on protection., Conclusions: The majority of the effect of inactivated influenza vaccination in children is mediated by the increased HAI titer after vaccination; however, other components of the immune response to vaccination may also play a role in protection and should be further explored. Causal mediation analysis provides a framework to quantify the role of various mediators of protection., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Vaccination is an important intervention to prevent influenza virus infection, but indirect protection of household members of vaccinees is not fully known. Here, we analyze a cluster household randomized controlled trial, with one child in each household randomized to receive influenza vaccine or placebo, for an influenza B epidemic in Hong Kong. We apply statistical models to estimate household transmission dynamics and quantify the direct and indirect protection of vaccination. Direct vaccine efficacy was 71%. The infection probability of unvaccinated household members in vaccinated households was only 5% lower than in control households, because only 10% of infections are attributed to household transmission. Even when that proportion rises to 30% and all children are vaccinated, we predict that the infection probability for unvaccinated household members would only be reduced by 20%. This suggests that benefits of individual vaccination remain important even when other household members are vaccinated.

Background: Influenza vaccination is the most effective intervention to prevent influenza virus infections. Vaccine effectiveness (VE) can vary due to factors such as matching between vaccine strains and prevailing strains, age and other characteristics of the vaccine recipients., Objective: To evaluate influenza VE against medically-attended illness in different age groups and against specific influenza types/subtypes in Hong Kong., Methods: A test-negative study was conducted from December 2014 through August 2017 in 20 outpatient clinics. Patients at least 6 months of age presenting with at least two symptoms of acute respiratory illness, ARI (fever ≥37.8 °C, cough, sore throat, runny nose, headache, myalgia and phlegm) within 72 h of onset were tested for influenza virus by reverse transcription polymerase chain reaction (PCR). Vaccination history was assessed by self-report or medical records at the clinics. VE against medically-attended illness was estimated using conditional logistic regression for influenza PCR result versus vaccination history, matching by calendar time and adjusting for age, age-squared, sex, and chronic medical illness. Additional analyses examined VE by age group and by influenza type/subtype., Results: We enrolled 2566 patients, of whom 1118 (43.6%) tested positive for influenza A or B virus by PCR. Test-positive subjects were generally older, more likely to present with one of the symptoms of ARI, and less likely to receive vaccination against influenza. VE estimates for influenza A(H1N1), A(H3N2), B/Yamagata and B/Victoria were 61.6% (95% confidence interval, CI: 21.8%, 81.1%), 26.4% (95% CI: -1.3%, 46.6%), 67.0% (95% CI: 25.9%, 85.3%), 60.4% (95% CI: 0.3%, 84.3%), respectively. Estimates of VE by age group were generally higher in adults aged 50-64 and lower among children and older adults., Conclusions: VE against medically-attended influenza was moderate in Hong Kong, confirming the impact of influenza vaccination in reducing disease burden. The reduced VE for influenza A(H3N2) is a continuing concern., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Many health authorities recommend influenza vaccination of older adults to reduce disease burden. We hypothesized that in tropical and subtropical areas with more prolonged influenza seasons, twice-annual influenza vaccination might provide older adults with improved immunity against influenza., Methods: In 2014-2015, Hong Kong experienced a substantial A(H3N2) winter epidemic with a mismatched vaccine. Local authorities procured and administered to older adults the 2015 southern hemisphere influenza vaccine, which included an updated and matching A/Switzerland/9715293/2013(H3N2) strain. We compared immune parameters in pre- and postvaccination sera from older adults ≥75 years of age who received 1 vs 2 influenza vaccines per year., Results: We enrolled 978 older adults with 470 vaccinations for summer 2015 and 827 vaccinations for winter 2015-2016. Recipients of southern hemisphere vaccination had higher geometric mean titers (GMTs) by the hemagglutination inhibition assay against all 3 vaccine strains. When receiving influenza vaccination for the subsequent winter, the southern hemisphere vaccine recipients had higher prevaccination GMTs but lower postvaccination GMTs, compared to those who had not received the southern hemisphere vaccine. Furthermore, cellular immunity was impacted by biannual vaccination, with reduced influenza-specific CD4 T-cell responses in the second season of vaccination., Conclusions: We observed some reductions in immune responses in the twice-annual vaccination group compared with the once-annual vaccination group, in the context of unchanging vaccine strains, while protection was likely to have been improved during the summer and autumn for the twice-annual vaccination group due to the continued circulation of the A/Switzerland/9715293/2013(H3N2) virus., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Correlations between hemagglutination-inhibition titers (hereafter "titers") and protection against infection have been identified in historical studies. However, limited information is available about the dynamics of how titer influences protection., Methods: Titers were measured in randomized, placebo-controlled vaccine trials in Hong Kong among pediatrics during September 2009-December 2010 and the United States among adults during Oct 2007-April 2008. Intermediate unobserved titers were imputed using three interpolation methods. As participants were recruited at different times leading to varying exposure to infection relative to entry, a modified proportional hazards model was developed to account for staggered entry into the studies and to quantify the correlation of titers with protection against influenza infections, adjusting for waning in titers. The model was fitted using Markov chain Monte Carlo and importance sampling., Results: A titer of 1:40 was associated with a reduced infection risk of 40%-70% relative to a titer of 1:10, depending on the circulating strain; the corresponding protection associated with a titer of 1:80 was 54%-84%. Results were robust across interpolation methods. The trivalent-inactivated vaccine reduced cumulative incidence of influenza B and influenza A(H3N2) infections by six percentage points (pp; 95% credible interval = 2 pp, 10 pp) and 1 pp (95% credible interval = 0.3 pp, 2 pp) respectively, but not for influenza A(H1N1)pdm09. The live-attenuated vaccine showed little efficacy against influenza A(H3N2) infections., Conclusions: Titers are correlated with protection against influenza infections. The trivalent inactivated vaccine can reduce the risk of influenza A(H3N2) and influenza B infections in the community.

Background: School-aged children suffer high rates of influenza virus infections and associated illnesses each year, and are a major source of transmission in the community. However, information on the cumulative incidence of infection in specific epidemics is scarce, and there are limited studies with sufficient follow-up to identify the strength and duration of protection against reinfection., Methods: We randomly allocated children 5-17 years of age to receive trivalent inactivated influenza vaccine (TIV) or placebo from September 2009 through January 2010, and then conducted follow-up for 3 years including regular collection of sera, symptom diaries, and collection of nose and throat swabs during illness episodes in participants or their household members., Results: Of 796 children initially randomized, 484 continued to participate for all 3 years. In unvaccinated children, cumulative incidence of infection was estimated to be 59% in the first wave of H1N1pdm09 in 2009-2010, and 7%, 14%, 20%, and 31% in subsequent epidemics of H3N2 (2010), H1N1pdm09 (2011), B (2012), and H3N2 (2012), respectively. Infection with H1N1pdm09 in 2009-2010 and H3N2 in 2010 was associated with protection against infection with subsequent epidemics of the same subtype in 2011 and 2012, respectively, but we found no evidence of heterotypic or heterosubtypic protection against infection., Conclusions: We identified substantial incidence of influenza virus infections in children in Hong Kong in 5 major epidemics over a 3-year period, and evidence of homosubtypic but not heterosubtypic protection following infection., Clinical Trials Registration: NCT00792051., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Antibody titers measured by hemagglutination inhibition (HAI) correlate with protection against influenza virus infection and are used to specify criteria for vaccine licensure. In a randomized, controlled trial of seasonal influenza vaccination in 773 children aged 6-17 years, we estimated that HAI titers of 1:40 against A(H1N1)pdm09 and B(Victoria lineage) were associated with 48% (95% confidence interval [CI], 30%-62%) and 55% (95% CI, 32%-70%) protection against PCR-confirmed infection with each strain. Our analysis accounted for waning in antibody titers over time, and could be particularly useful in settings where influenza activity is delayed or prolonged relative to measurement of antibody titers.

Background: There is some evidence that annual vaccination of trivalent inactivated influenza vaccine (TIV) may lead to reduced vaccine immunogenicity but evidence is lacking on whether vaccine efficacy is affected by prior vaccination history. The efficacy of one dose of TIV in children 6-8 y of age against influenza B is uncertain. We examined whether immunogenicity and efficacy of influenza vaccination in school-age children varied by age and past vaccination history., Methods and Findings: We conducted a randomized controlled trial of 2009-10 TIV. Influenza vaccination history in the two preceding years was recorded. Immunogenicity was assessed by comparison of HI titers before and one month after receipt of TIV/placebo. Subjects were followed up for 11 months with symptom diaries, and respiratory specimens were collected during acute respiratory illnesses to permit confirmation of influenza virus infections. We found that previous vaccination was associated with reduced antibody responses to TIV against seasonal A(H1N1) and A(H3N2) particularly in children 9-17 y of age, but increased antibody responses to the same lineage of influenza B virus in children 6-8 y of age. Serological responses to the influenza A vaccine viruses were high regardless of vaccination history. One dose of TIV appeared to be efficacious against confirmed influenza B in children 6-8 y of age regardless of vaccination history., Conclusions: Prior vaccination was associated with lower antibody titer rises following vaccination against seasonal influenza A vaccine viruses, but higher responses to influenza B among individuals primed with viruses from the same lineage in preceding years. In a year in which influenza B virus predominated, no impact of prior vaccination history was observed on vaccine efficacy against influenza B. The strains that circulated in the year of study did not allow us to study the effect of prior vaccination on vaccine efficacy against influenza A.

Background: Annual vaccination against seasonal influenza viruses is recommended for school-age children in some countries. There are limited data on the immunogenicity and efficacy of repeated influenza vaccinations., Methods: In a randomized controlled trial, we administered seasonal trivalent inactivated influenza vaccine (TIV) or placebo to 64 children 6-15 years of age in two consecutive years and explored their humoral antibody responses., Results: Receipt of TIV in the first year was associated with lower antibody titer rises in the second year to seasonal influenza A(H1N1) and A(H3N2) strains for which the vaccine strains remained unchanged. Antibody response to a different influenza B strain in the second year was unaffected by receipt of TIV in the first year. Children who received TIV in both years showed higher antibody titers against pandemic A(H1N1) which was not included in either TIV., Conclusions: Results from our study suggest that humoral antibody response to TIV may be lower in children receiving repeated vaccination, but receipt of TIV induced seroprotection in most subjects. Our study was underpowered to explore whether differences in immunogenicity translated to differences in vaccine efficacy.

Background: The efficacy of seasonal influenza vaccination against 2009 pandemic influenza A(H1N1) remains unclear., Methods: One child aged 6-17 years in each of 796 households was randomized to receive 2009-2010 seasonal trivalent inactivated influenza vaccine (TIV) or saline placebo between August 2009 and February 2010. Households were followed up with serology, symptom diaries, and collection of respiratory specimens during illnesses. The primary outcomes were influenza infection confirmed by reverse-transcription polymerase chain reaction (RT-PCR) or a ≥4-fold rise in serum antibody titer measured by hemagglutination inhibition assay., Results: Receipt of TIV led to 8-13-fold mean geometric rises in antibody titers against seasonal A and B viruses, but only 1.5-fold mean geometric rises against the pandemic A(H1N1) virus that was not included in the vaccine. Children who received TIV had a reduced risk of seasonal influenza B confirmed by RT-PCR, with a vaccine efficacy estimate of 66% (95% confidence interval [CI], 31%-83%). Children who received TIV also a had reduced risk of pandemic influenza A(H1N1) indicated by serology, with a vaccine efficacy estimate of 47% (95% CI, 15%-67%)., Conclusions: Seasonal TIV prevented pandemic influenza A(H1N1) and influenza B infections in children. Pandemic A(H1N1) circulated at the time of vaccination and for a short time afterward with no substantial seasonal influenza activity during that period. The potential mechanism for seasonal TIV to provide protection, possibly short lived, for children against pandemic A(H1N1) infection despite poor cross-reactive serologic response deserves further investigation. Clinical Trials Registration. NCT00792051.

We randomized 115 children to trivalent inactivated influenza vaccine (TIV) or placebo. Over the following 9 months, TIV recipients had an increased risk of virologically-confirmed non-influenza infections (relative risk: 4.40; 95% confidence interval: 1.31-14.8). Being protected against influenza, TIV recipients may lack temporary non-specific immunity that protected against other respiratory viruses.

Background: The relationship between seasonal influenza vaccine and susceptibility to 2009 pandemic A/H1N1 virus infection is not fully understood., Methods: One child 6-15 years of age from each of 119 households was randomized to receive 1 dose of inactivated trivalent seasonal influenza vaccine (TIV) or saline placebo in November 2008. Serum samples were collected from study subjects and their household contacts before and 1 month after vaccination (December 2008), after winter (April 2009) and summer influenza (September-October 2009) seasons. Seasonal and pandemic influenza were confirmed by serum hemagglutinination inhibition, viral neutralization titers, and reverse-transcription polymerase chain reaction performed on nasal and throat swab samples collected during illness episodes., Results: TIV recipients had lower rates of serologically confirmed seasonal A/H1N1 infection (TIV group, 8%; placebo group, 21%; P=.10) and A/H3N2 infection (7% vs 12%; P=A9), but higher rates of pandemic A/H1N1 infection (32% vs 17%; [Formula: see text]). In multivariable analysis, those infected with seasonal influenza A during the study had a lower risk of laboratory-confirmed pandemic A/H1N1 infection (adjusted odds ratio [OR], 0.35; 95% confidence interval [CI], 0.14-0.87), and receipt of seasonal TIV was unassociated with risk of pandemic A/H1N1 infection (adjusted OR, 1.11; 95% CI, 0.54-2.26)., Conclusions: TIV protected against strain-matched infection in children. Seasonal influenza infection appeared to confer cross-protection against pandemic influenza. Whether prior seasonal influenza vaccination affects the risk of infection with the pandemic strain requires additional study., Clinical Trials Registration: ClinicalTrials.gov number NCT00792051 .

The vaccine efficacy of standard-dose seasonal inactivated influenza vaccines (S-IIV) can be improved by the use of vaccines with higher antigen content or adjuvants. We conducted a randomized controlled trial in older adults to compare cellular and antibody responses of S-IIV versus enhanced vaccines (eIIV): MF59-adjuvanted (A-eIIV), high-dose (H-eIIV), and recombinant-hemagglutinin (HA) (R-eIIV). All vaccines induced comparable H3-HA-specific IgG and elevated antibody-dependent cellular cytotoxicity (ADCC) activity at day 30 post vaccination. H3-HA-specific ADCC responses were greatest following H-eIIV. Only A-eIIV increased H3-HA-IgG avidity, HA-stalk IgG and ADCC activity. eIIVs also increased polyfunctional CD4+ and CD8+ T cell responses, while cellular immune responses were skewed toward single-cytokine-producing T cells among S-IIV subjects. Our study provides further immunological evidence for the preferential use of eIIVs in older adults as each vaccine platform had an advantage over the standard-dose vaccine in terms of NK cell activation, HA-stalk antibodies, and T cell responses. [ABSTRACT FROM AUTHOR]

Objectives: Enhanced inactivated influenza vaccines (eIIV) aim to increase immunogenicity and protection compared with the widely used standard IIV (S‐IIV). Methods: We tested four vaccines in parallel, FluZone high dose, FluBlok and FluAd versus S‐IIV in a randomised controlled trial of older adults and in a mouse infection model to assess immunogenicity, protection from lethal challenge and mechanisms of action. Results: In older adults, FluAd vaccination stimulated a superior antibody profile, including H3‐HA antibodies that were elevated for up to 1 year after vaccination, higher avidity H3HA IgG and larger HA stem IgG responses. In a mouse model, FluAd also elicited an earlier and larger induction of HA stem antibodies with increased germinal centre responses and upregulation and long‐term expression of B‐cell switch transcription factors. Long‐term cross‐reactive memory responses were sustained by FluAd following lethal heterosubtypic influenza challenge, with reduced lung damage and viral loads, coinciding with increased T‐ and B‐cell recall. Advantages were also noted for the high‐dose FluZone vaccine in both humans and mice. Conclusion: The early, broadly reactive and long‐lived antibody response of FluAd indicates a potential advantage of this vaccine, particularly in years when there is a mismatch between the vaccine strain and the circulating strain of influenza viruses. [ABSTRACT FROM AUTHOR]

In winter 2018, schools in Hong Kong were closed 1 week before the scheduled Chinese New Year holiday to mitigate an influenza B virus epidemic. The intervention occurred after the epidemic peak and reduced overall incidence by ≈4.2%. School-based vaccination programs should be implemented to more effectively reduce influenza illnesses. [ABSTRACT FROM AUTHOR]