Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

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.

Standard-dose versus MF59-adjuvanted, high-dose or recombinant-hemagglutinin influenza vaccine immunogenicity in older adults: comparison of A(H3N2) antibody response by prior season's vaccine status.

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 2017/18 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 (2016/17) 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 2017/18 standard-dose and enhanced vaccine recipients with (range, 1.7-3.0) vs. without (range, 4.3-14.3) prior 2016/17 vaccination. MFR was significantly reduced by about one half to four fifths for previously vaccinated recipients of standard-dose and all three enhanced vaccines (ß range, 0.21-0.48). 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 vs. 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.

Reconstructing household transmission dynamics to estimate the infectiousness of asymptomatic influenza virus infections.

There has long been controversy over the potential for asymptomatic cases of the influenza virus to have the capacity for onward transmission, but recognition of asymptomatic transmission of COVID-19 stimulates further research into this topic. Here, we develop a Bayesian methodology to analyze detailed data from a large cohort of 727 households and 2515 individuals in the 2009 pandemic influenza A(H1N1) outbreak in Hong Kong to characterize household transmission dynamics and to estimate the relative infectiousness of asymptomatic versus symptomatic influenza cases. The posterior probability that asymptomatic cases [36% of cases; 95% credible interval (CrI): 32%, 40%] are less infectious than symptomatic cases is 0.82, with estimated relative infectiousness 0.57 (95% CrI: 0.11, 1.54). More data are required to strengthen our understanding of the contribution of asymptomatic cases to the spread of influenza.

Impact of host genetic polymorphisms on response to inactivated influenza vaccine in children.

In randomized controlled trials of influenza vaccination, 550 children received trivalent-inactivated influenza vaccine, permitting us to explore relationship between vaccine response and host single nucleotide polymorphisms (SNPs) in 23 candidate genes with adjustment of multiple testing. For host SNPs in TLR7-1817G/T (rs5741880), genotype GT was associated with lower odds (OR: 0.22, 95% CI: 0.09, 0.53) of have post-vaccination hemagglutination-inhibiting (HAI) titers ≥40, compared with genotype GG and TT combined under the over-dominant model. For host SNPs in TLR8-129G/C (rs3764879), genotype GT was associated with lower odds (OR: 0.47; 95% CI: 0.28, 0.80) of have post vaccination HAI titers ≥40 compared with genotype GG and AA combined under the over-dominant model. Our results could contribute to the development of better vaccines that may offer improved protection to all recipients.

Indirect Protection from Vaccinating Children against Influenza A Virus Infection in Households.

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.

Investigation of CD4 and CD8 T cell-mediated protection against influenza A virus in a cohort study.

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.

Estimating excess septicaemia mortality and hospitalisation burden associated with influenza in Hong Kong, 1998 to 2019.

Influenza virus infections can lead to a number of secondary complications, including sepsis. We applied linear regression models to mortality and hospital admission data coded for septicaemia from 1998 to 2019 in Hong Kong, and estimated that septicaemia was associated with an annual average excess mortality rate of 0.23 (95% CI 0.04-0.40) per 100 000 persons per year and an excess septicaemia hospitalisation rate of 1.73 (95% CI 0.94-2.50) per 100 000 persons per year. The highest excess morbidity and mortality was found in older adults and young children, and during influenza A(H3N2) epidemics.

Biphasic Waning of Hemagglutination Inhibition Antibody Titers After Influenza Vaccination in Children.

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.

Reconstructing antibody dynamics to estimate the risk of influenza virus infection.

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.

Immunogenicity of standard, high-dose, MF59-adjuvanted, and recombinant-HA seasonal influenza vaccination in older adults.

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.

Variation by lineage in serum antibody responses to influenza B virus infections.

Two lineages of influenza B virus currently co-circulate and have distinct antigenicity, termed Victoria and Yamagata after the B/Victoria/2/87 and B/Yamagata/16/88 strains, respectively. We analyzed antibody titer dynamics following PCR-confirmed influenza B virus infection in a longitudinal community-based cohort study conducted in Hong Kong from 2009-2014 to assess patterns in changes in antibody titers to B/Victoria and B/Yamagata viruses following infections with each lineage. Among 62 PCR-confirmed cases, almost half had undetectable hemagglutination inhibition (HAI) antibody titers to the lineage of infection both pre-infection and post-infection. Among those infected with influenza B/Victoria who showed an HAI titer response after infection, we found strong rises to the lineage of infection, positive but smaller cross-lineage HAI titer boosts, a small dependence of HAI titer boosts on pre-infection titers, and a shorter half-life of HAI titers in adults. Our study is limited by the low HAI sensitivity for non-ether-treated IBV antigen and the incapacity of performing other assays with higher sensitivity, as well as the mismatch between the B/Yamagata lineage circulating strain and the assay strain in one of the study seasons.

Comparison of alternative full and brief versions of functional status scales among older adults in China.

BACKGROUND: Brief assessments of functional status for community-dwelling older adults are needed given expanded interest in the measurement of functional decline. METHODS: As part of a 2015 prospective cohort study of older adults aged 60-89 years in Jiangsu Province, China, 1506 participants were randomly assigned to two groups; each group was administered one of two alternative 20-item versions of a scale to assess activities of daily living (ADL) and instrumental activities of daily living (IADL) drawn from multiple commonly-used scales. One version asked if they required help to perform activities (ADL-IADL-HELP-20), while the other version provided additional response options if activities could be done alone but with difficulty (ADL-IADL-DIFFICULTY-20). Item responses to both versions were compared using the binomial test for differences in proportion (with Wald 95% confidence interval [CI]). A brief 9-item scale (ADL-IADL-DIFFICULTY-9) was developed favoring items identified as difficult or requiring help by ≥4%, with low redundancy and/or residual correlations, and with significant correlations with age and other health indicators. We repeated assessment of the measurement properties of the brief scale in two subsequent samples of older adults in Hong Kong in 2016 (aged 70-79 years; n = 404) and 2017 (aged 65-82 years; n = 1854). RESULTS: Asking if an activity can be done alone but with difficulty increased the proportion of participants reporting restriction on 9 of 20 items, for which 95% CI for difference scores did not overlap with zero; the proportion with at least one limitation increased from 28.6% to 34.2% or an absolute increase of 5.6% (95% CI = 0.9-10.3%), which was a relative increase of 19.6%. The brief ADL-IADL-DIFFICULTY-9 maintained excellent internal consistency (α = 0.93) and had similar ceiling effect (68.1%), invariant item ordering (H trans = .41; medium), and correlations with age and other health measures compared with the 20-item version. The brief scale performed similarly when subsequently administered to older adults in Hong Kong. CONCLUSIONS: Asking if tasks can be done alone but with difficulty can modestly reduce ceiling effects. It's possible that the length of commonly-used scales can be reduced by over half if researchers are primarily interested in a summed indicator rather than an inventory of specific types of deficits.

Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults.

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.

Assessment of enhanced influenza vaccination finds that FluAd conveys an advantage in mice and older adults.

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.

The Effect of Influenza Vaccination History on Changes in Hemagglutination Inhibition Titers After Receipt of the 2015-2016 Influenza Vaccine in Older Adults in Hong Kong.

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.

Maternal Antibodies Against Influenza in Cord Blood and Protection Against Laboratory-Confirmed Influenza in Infants.

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.

Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial.

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.

Burden of influenza-associated outpatient influenza-like illness consultations in China, 2006-2015: A population-based study.

BACKGROUND: Human influenza virus infections cause a considerable burden of morbidity and mortality worldwide each year. Understanding regional influenza-associated outpatient burden is crucial for formulating control strategies against influenza viruses. METHODS: We extracted the national sentinel surveillance data on outpatient visits due to influenza-like-illness (ILI) and virological confirmation of sentinel specimens from 30 provinces of China from 2006 to 2015. Generalized additive regression models were fitted to estimate influenza-associated excess ILI outpatient burden for each individual province, accounting for seasonal baselines and meteorological factors. RESULTS: Influenza was associated with an average of 2.5 excess ILI consultations per 1000 person-years (py) in 30 provinces of China each year from 2006 to 2015. Influenza A(H1N1)pdm09 led to a higher number of influenza-associated ILI consultations in 2009 across all provinces compared with other years. The excess ILI burden was 4.5 per 1000 py among children aged below 15 years old, substantially higher than that in adults. CONCLUSIONS: Human influenza viruses caused considerable impact on population morbidity, with a consequent healthcare and economic burden. This study provided the evidence for planning of vaccination programs in China and a framework to estimate burden of influenza-associated outpatient consultations.

Cross-reactive antibody-dependent cellular cytotoxicity antibodies are increased by recent infection in a household study of influenza transmission.

OBJECTIVES: Influenza causes a spectrum of disease from asymptomatic infection to fatal outcome, and pre-existing immunity can alter susceptibility and disease severity. In a household transmission study, we recruited outpatients with confirmed influenza virus infection and prospectively identified secondary infections in their household contacts, therefore identifying infection cases with baseline samples for determining immune-mediated protection from influenza infection. METHODS: We examined baseline broadly reactive immune correlates of relevance to universal vaccine development, specifically antibody-dependent cytotoxic (ADCC) antibodies and T-cell responses in functional assays. Antibodies were assessed in a cell-based NK cell degranulation assay by flow cytometry, and T-cell responses were assessed by IFN-γ intracellular cytokine staining flow cytometry assay. RESULTS: The magnitude of antibody responses and ADCC function for multiple influenza-specific proteins was lower in participants who became infected, consolidating the role of pre-existing antibodies in protection from seasonal influenza virus infection. Among H1N1-infected contacts, we found that higher levels of pre-existing H1-haemagglutinin ADCC responses correlated with reduced symptom severity. Recent infection boosted the titre and magnitude of haemagglutinin-, neuraminidase- and nucleoprotein-specific ADCC antibodies. Limited T-cell samples precluded conclusions on the role of pre-existing T-cell responses. CONCLUSIONS: Overall, ADCC responses are a protective correlate against influenza virus infection that should be considered in future vaccine development and evaluation.Influenza-specific ADCC responses are elevated in uninfected subjects, associated with reduced symptoms and boosted by recent infection, whilst HA stem and NA IgG are also elevated in uninfected participants irrespective of ADCC function.