Host genetic factors as determinants of immunologic and adverse responses on influenza vaccination in humans

Poster Session: VaccinesBackground: Seasonal influenza epidemics cause a great burden of illnesses, hospitalizations, and deaths worldwide. Although influenza vaccination has generally been regarded as safe and effective in preventing influenza infection, some people do develop poor immune responses or occasional serious adverse events on receiving the vaccination. Little is known about how host genetic determinants are affecting responses to influenza vaccination in humans. Materials and Methods: We used a genetic association study with a candidate gene approach based on a randomized placebocontrolled trial on influenza vaccination to examine the role of host genetic variation on immune years were randomized to receive either an inactivated trivalent seasonal influenza vaccine (TIV) (Vaxigrip, Sanofi Pasteur) or placebo in phases from 2009 to 2010. Vaccine response was defined by a post-vaccination antibody titer of 1:40 or ≥ 4-fold rise in all TIV components. An adverse vaccine responder was defined by an aggregated symptom score ≥ 2 on day 1 post-vaccination, based on 10 symptoms each on a scale of 0 (absent), 1 (mild), 2 (moderate, or 3 (severe), thus having at least 2 mild or 1 moderate symptoms. All participants kept a daily symptom dairy. Whole blood samples from 535 participants receiving TIV were collected for genetic analysis in this study. DNA was extracted and genotyped for single nucleotide polymorphisms for IL-1B-511G>A (rs16944), IL-6-5843A/G (rs1818879), IL-8-251T/A (rs4073), IL-10-082A/G (rs1800896), -819T/C (rs1800871), -592A/C (rs1800872), MBL-2-5232G>A (rs1800451), 221C/G (rs7096206), -34C>T (rs5030737), -550G>C (rs11003125), MxA-88G/T (rs2071430), OSA1-347A/G (rs2660), RIG1 G/C (rs9695310), TLR3- 1377T/G (rs3755290), -7G/T (rs3775296), TLR4 G/A (rs5030718), Asp299Gly (rs4986790), TLR7 Gln11Leu (rs179008), 1817G/T (rs5741880), TLR8-129G/C (rs3764879), Met1Val (rs3764880), and (rs11003131)G/T. Logistic regression models were used to evaluate the relationship of polymorphisms with various outcomes and to compute the ORs and 95% confidence interval (CIs) in relation to vaccination response and adverse vaccination reaction. The heterozygous and homozygous variant genotypes were analyzed both as a nominal and an ordinal variable as consisting, respectively, of one and two variant alleles and compared with the wild-type homozygous genotype. The heterozygous genotype was also grouped with either of the two homozygous genotypes to analyze in a dominant or recessive model. Two-sided P values are reported and P ≤ .05 was considered to indicate statistical significance. Results: Among 535 subjects receiving TIV, 295 were classified as vaccine responders. Polymorphisms IL-6 rs1818879 G mutation in an ordinal model (OR = 1.56, CI = 1.054-2.31), AG (OR = 1.667, CI = 1.109-2.504), and combined AG/GG (OR = 1.637, CI = 1.093-2.454) in a dominant model were associated with increased odds of response. TLR7 rs5741880 GT (OR = 0.161, CI = 0.046-0.566), combined GT/TT (OR = 0.371, CI = 0.159- 0.866) in a dominant model, and TLR3 rs3755290 GG (OR = 0.572, CI = 0.335-0.976) in a recessive model compared with GT/TT were associated with lower odds of response. No serious vaccine response, including anaphylaxis or shock, was reported by any recipient. With a symptom score ≥ 2, 26.1% were classified as adverse responders for TIV. IL-6 rs1818879 AG (OR = 1.833, CI = 1.14- 2.945) and combined AG/GG (OR = 1.778, CI = 1.108-2.854) were associated with a higher risk, while CCL1 rs2282691 AT (OR = 0.578, CI = 0.347-0.963) was associated with a lower risk of adverse response. All these effects of polymorphisms in relation to vaccination response are compatible with the current understanding regarding the role played by those genes in either the pathogenesis or immunological response to influenza infection. Conclusions: Our findings suggest the potential role of host genetic variation and identified genetic determinants that affect the immunological and adverse responses to seasonal influenza vaccination in humans. These findings may help to explain the great variability in protection achieved by influenza vaccination.published_or_final_versio

Face masks to prevent transmission of influenza virus: a systematic review

Influenza viruses circulate around the world every year. From time to time new strains emerge and cause global pandemics. Many national and international health agencies recommended the use of face masks during the 2009 influenza A (H1N1) pandemic. We reviewed the English-language literature on this subject to inform public health preparedness. There is some evidence to support the wearing of masks or respirators during illness to protect others, and public health emphasis on mask wearing during illness may help to reduce influenza virus transmission. There are fewer data to support the use of masks or respirators to prevent becoming infected. Further studies in controlled settings and studies of natural infections in healthcare and community settings are required to better define the effectiveness of face masks and respirators in preventing influenza virus transmission. Copyright © Cambridge University Press 2010.published_or_final_versio

Predictors and Consequences of In-hospital Formula Supplementation for Healthy Breastfeeding Newborns

BACKGROUND: Although exclusive breastfeeding is recommended for the first 6 months, the use of breast milk substitutes is widespread around the world. OBJECTIVES: To describe the patterns of infant formula supplementation among healthy breastfeeding newborns, to identify factors contributing to in-hospital formula supplementation, and to assess the dose-response relationship between the amount of in-hospital formula supplementation and the duration of any breastfeeding. METHODS: A sample of 1246 breastfeeding mother-infant pairs was recruited from 4 public hospitals in Hong Kong and followed prospectively for 12 months or until weaned. Multiple logistic regression analysis was used to examine factors associated with in-hospital supplementation. Cox regression analysis was used to explore the impact of in-hospital supplementation on breastfeeding duration. RESULTS: Of the total, 82.5% of newborns were supplemented in the hospital; one-half received formula within 5 hours of birth. Assisted vaginal delivery (odds ratio [OR] = 2.06, 95% confidence interval [CI] 1.03, 4.15), cesarean section (OR = 3.45, 95% CI 1.75, 6.80), and higher birth weight (OR = 1.56, 95% CI 1.12, 2.18) were positively associated with in-hospital formula supplementation, whereas initiating breastfeeding in the delivery room (OR = 0.55, 95% CI 0.33, 0.89) was associated with decreased likelihood of in-hospital supplementation. Any infant formula in the first 48 hours was associated with a shorter duration of breastfeeding (hazard ratio [HR] = 1.51, 95% CI 1.27, 1.80), but there was no dose-response effect. CONCLUSION: In-hospital formula supplementation is common in Hong Kong hospitals and appears to be detrimental to breastfeeding duration. Continued efforts should be made to avoid the provision of infant formula to breastfeeding babies while in the hospital unless medically indicated.postprin

Using health-seeking pattern to estimate disease burden from sentinel surveillance

Lightning Talk - oral presentationBy characterizing the health-seeking behavior of the general population, surveillance data of consultation rates could be further utilized to obtain the population and age-specific burden of diseasepublished_or_final_versio

An analysis of target recipient groups for monovalent 2009 pandemic influenza vaccine and trivalent seasonal influenza vaccines in 2009-10 and 2010-11

Poster Presentation: SPA5 - How to Evaluate Vaccine Effectiveness and Efficacy?: abstract no. A513PINTRODUCTION: Vaccination is generally considered to be the best primary prevention measure against influenza virus infection. Many countries encourage specific target groups of people to undertake vaccination, often with financial subsidies or a list of priority. To understand differential patterns of national target groups for influenza vaccination before, during and after the 2009 influenza pandemic, we reviewed and identified changes in national target groups for trivalent seasonal influenza and the monovalent 2009 pandemic influenza vaccines dur...postprin

Household transmission of 2009 pandemic influenza A (H1N1): a systematic review and meta-analysis

BACKGROUND: During the 2009 influenza A (H1N1) pandemic, household transmission studies were implemented to better understand the characteristics of the transmission of the novel virus in a confined setting. METHODS: We conducted a systematic review and meta-analysis to assess and summarize the findings of these studies. We identified 27 articles, around half of which reported studies conducted in May and June 2009. RESULTS: In 13 of the 27 studies (48%) that collected respiratory specimens from household contacts, point estimates of the risk of secondary infection ranged from 3% to 38%, with substantial heterogeneity. Meta-regression analyses revealed that a part of the heterogeneity reflected varying case ascertainment and study designs. The estimates of symptomatic secondary infection risk, based on 20 studies identifying febrile acute respiratory illness among household contacts, also showed substantial variability, with point estimates ranging from 4% to 37%. CONCLUSIONS: Transmission of the 2009 pandemic virus in households appeared to vary among countries and settings, with differences in estimates of the secondary infection risk also partly due to differences in study designs.published_or_final_versio

Increases in absenteeism among health care workers in Hong Kong during influenza epidemics, 2004–2009

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Susceptibility of influenza B viruses to neuraminidase inhibitors: findings from the first 4 years (2008–2012) of the global Influenza Resistance Information Study (IRIS)

Poster Session: Antiviral Drugs and ResistanceBackground: Type B influenza virus infections continue to account for a substantial proportion of clinical illness. Little is known about comparative disease profiles by virus lineage. A global observational trial (the Influenza Resistance Information Study or IRIS; NCT00884117) was initiated to study neuraminidase inhibitor (NAI) susceptibility and the clinical and virological course of influenza in treated and untreated patients. Materials and Methods: Patients in the northern and southern hemispheres (USA, France, Germany, Poland, Norway, Hong Kong, Australia) with influenza-like illness and/or a positive rapid influenza test result were enrolled. Throat/nasal swabs were performed on Days 1, 3 (self-swab), 6 and 10 and tested for influenza A and B viruses by RT-PCR. Influenzapositive samples collected on Days 1, 6 or 10 were cultured and subsequently sequenced (HA and NA) and phenotypically tested for NAI susceptibility. The lineage of B viruses was determined from sequencing. Clinical information, including the scoring of seven influenza symptoms (scale: 0 [absent], 1 [mild], 2 [moderate], 3 [severe]), was recorded on diary cards by the patient or the patient’s legal guardian (Days 1–12). Symptoms were also assessed by the investigator at each visit. The decision to prescribe an NAI was left to the physician’s discretion. Results: In the first 4 years of IRIS (December 2008 to March 2012), 2262 influenza-positive (RT-PCR) patients were enrolled, of whom 697 presented with a type B influenza virus infection (564 Victoria, 98 Yamagata, 35 undetermined lineage). Most type B patients (402; 58%) were children aged < 13 years. A total of 330 (47%) type B patients were treated with oseltamivir (as monotherapy) within 2 days of symptom onset; a further 26 started oseltamivir 2 days after symptom onset. Eleven patients received zanamivir, one received amantadine and another received rimantidine. A total of 328 (47%) did not receive any influenza antiviral. Symptoms were mild to moderate on Day 1 (mean total score: 12.8, treated; 12.9, untreated), and the mean temperature on Day 1 was 38.2°C. All viruses obtained at baseline or postbaseline were susceptible to NAIs: mean (SD) IC50 values for oseltamivir were 4.8 nM (2.5 nM) and 5.5 nM (2.3 nM) for the Victoria and Yamagata viruses, respectively; the corresponding values for zanamivir were 2.0 nM (1.4 nM) and 2.9 nM (1.6 nM), respectively. No known NAI resistance mutations were detected by NA or HA population sequencing. The proportion of RT-PCR–positive patients on Day 6 was 130/309 (42.1%) for patients treated with oseltamivir and 152/312 (48.7%) for untreated patients. In Kaplan–Meier analyses, no significant differences in median time to influenza RNA clearance were found between oseltamivir-treated and -untreated patients, either in adults or children. The time to symptom resolution (all symptom scores ≤ 1) was 5 days (95% CI, 4–5 days) in oseltamivir-treated children and 6 days (95% CI, 5–6 days) in untreated children (P = .026), but no significant difference in symptom resolution time was found in adults (Kaplan–Meier analysis). Conclusions: Analysis of type B influenza viruses obtained globally between 2008 and 2012 showed that all pre-treatment B/Victoria and B/Yamagata viruses were susceptible to oseltamivir and zanamivir. Moreover, no resistant viruses were detected during treatment. Given the non-randomised design of this study, no definitive conclusions can be drawn with regard to the clinical benefit of oseltamivir in patients infected with type B influenza viruses.published_or_final_versio

Interpreting Seroepidemiologic Studies of Influenza in a Context of Nonbracketing Sera

Background: In influenza epidemiology, analysis of paired sera collected from people before and after influenza seasons has been used for decades to study the cumulative incidence of influenza virus infections in populations. However, interpretation becomes challenging when sera are collected after the start or before the end of an epidemic, and do not neatly bracket the epidemic. Methods: Serum samples were collected longitudinally in a community-based study. Most participants provided their first serum after the start of circulation of influenza A(H1N1)pdm09 virus in 2009. We developed a Bayesian hierarchical model to correct for nonbracketing sera and estimate the cumulative incidence of infection from the serological data and surveillance data in Hong Kong. Results: We analyzed 4,843 sera from 2,097 unvaccinated participants in the study, collected from April 2009 to December 2010. After accounting for nonbracketing, we estimated that the cumulative incidence of H1N1pdm09 virus infection was 45% (95% credible interval [CI] = 40%, 49%), 17% (95% CI = 13%, 20%), and 11% (95% CI = 6%, 18%) for children ages 0–18 years, adults 19–50 years, and older adults >50 years, respectively. Including all available data substantially increased precision compared with a simpler analysis based only on sera collected at 6-month intervals in a subset of participants. Conclusions: We developed a framework for the analysis of antibody titers that accounted for the timing of sera collection with respect to influenza activity and permitted robust estimation of the cumulative incidence of infection during an epidemic.postprin

Variability in the immunogenicity of inactivated seasonal influenza vaccine in children due to age and recent previous influenza vaccination

Poster Session: VaccinesBackground: Annual receipt of trivalent inactivated influenza (TIV) vaccination is recommended for school-age children in some countries. However, there is little data on the variability of the immunogenicity of influenza vaccination in children and how this is affected by their age and recent influenza vaccination history. Materials and Methods: We used data on children in a Hong Kong community-based study who were randomized to receive TIV before the 2009-2010 influenza season. Antibody titers against seasonal and pandemic A(H1N1), seasonal A(H3N2), and two B influenza viruses (B/Brisbane and B/Florida) were measured by hemagglutination inhibition immediately before and 1 month after vaccination (Cowling et al. Clin Infect Dis. 2012). Multivariate regression models were fitted in a Bayesian framework to characterize the distribution of changes in antibody titers following vaccination and update previous findings by considering the correlation between virus strains (Ng et al. Pediatr Infect Dis J. 2013). Results: In 452 subjects, statistically significant rises in the geometric means of all antibody titers were observed, with those against the virus strains included in the TIV rising by geometric means of 7.95 to 13.36; those against pandemic A(H1N1) and B/Florida rose by 1.47 and 4.21, respectively. Geometric standard deviations were between 3.76 and 8.41 around the geometric means, with pandemic A(H1N1) showing the least variability in rises. The most closely correlated titer increases were those for the two influenza B viruses, while increases in pandemic A(H1N1) titers were unrelated to any other titer. Being vaccinated in either of the two previous years significantly reduced the increase in seasonal A(H1N1) and A(H3N2) antibody titers, while among children not vaccinated in the previous 2 years, those aged > 9 years experienced significantly higher increases in the influenza B titers than those aged 6-8 years. Conclusions: Increases in antibody titers following vaccination can vary depending on age and vaccination history. 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.published_or_final_versio