Influenza vaccine effectiveness within prospective cohorts of healthcare personnel in Israel and Peru 2016-2019.

BACKGROUND: There are limited data on influenza vaccine effectiveness (IVE) in preventing laboratory-confirmed influenza illness among healthcare personnel (HCP). METHODS: HCP with direct patient contact working full-time in hospitals were followed during three influenza seasons in Israel (2016-2017 to 2018-2019) and Peru (2016 to 2018). Trivalent influenza vaccines were available at all sites, except during 2018-2019 when Israel used quadrivalent vaccines; vaccination was documented by electronic medical records, vaccine registries, and/or self-report (for vaccinations outside the hospital). Twice-weekly active surveillance identified acute respiratory symptoms or febrile illness (ARFI); self-collected respiratory specimens were tested by real-time reverse transcription polymerase chain reaction (PCR) assay. IVE was 100 × 1-hazard ratio (adjusted for sex, age, occupation, and hospital). RESULTS: Among 5,489 HCP who contributed 10,041 person-seasons, influenza vaccination coverage was 47% in Israel and 32% in Peru. Of 3,056 ARFIs in Israel and 3,538 in Peru, A or B influenza virus infections were identified in 205 (7%) in Israel and 87 (2.5%) in Peru. IVE against all viruses across seasons was 1% (95% confidence interval [CI] = -30%, 25%) in Israel and 12% (95% CI = -61%, 52%) in Peru. CONCLUSION: Estimates of IVE were null using person-time models during six study seasons in Israel and Peru.

Incidence of influenza during pregnancy and association with pregnancy and perinatal outcomes in three middle-income countries: a multisite prospective longitudinal cohort study.

BACKGROUND: Influenza vaccination during pregnancy prevents influenza among women and their infants but remains underused among pregnant women. We aimed to quantify the risk of antenatal influenza and examine its association with perinatal outcomes. METHODS: We did a prospective cohort study in pregnant women in India, Peru, and Thailand. Before the 2017 and 2018 influenza seasons, we enrolled pregnant women aged 18 years or older with expected delivery dates 8 weeks or more after the season started. We contacted women twice weekly until the end of pregnancy to identify illnesses with symptoms of myalgia, cough, runny nose or nasal congestion, sore throat, or difficulty breathing and collected mid-turbinate nasal swabs from symptomatic women for influenza real-time RT-PCR testing. We assessed the association of antenatal influenza with preterm birth, late pregnancy loss (≥13 weeks gestation), small for gestational age (SGA), and birthweight of term singleton infants using Cox proportional hazards models or generalised linear models to adjust for potential confounders. FINDINGS: Between March 13, 2017, and Aug 3, 2018, we enrolled 11 277 women with a median age of 26 years (IQR 23-31) and gestational age of 19 weeks (14-24). 1474 (13%) received influenza vaccines. 310 participants (3%) had influenza (270 [87%] influenza A and 40 [13%] influenza B). Influenza incidences weighted by the population of women of childbearing age in each study country were 88·7 per 10 000 pregnant woman-months (95% CI 68·6 to 114·8) during the 2017 season and 69·6 per 10 000 pregnant woman-months (53·8 to 90·2) during the 2018 season. Antenatal influenza was not associated with preterm birth (adjusted hazard ratio [aHR] 1·4, 95% CI 0·9 to 2·0; p=0·096) or having an SGA infant (adjusted relative risk 1·0, 95% CI 0·8 to 1·3, p=0·97), but was associated with late pregnancy loss (aHR 10·7, 95% CI 4·3 to 27·0; p<0·0001) and reduction in mean birthweight of term, singleton infants (-55·3 g, 95% CI -109·3 to -1·4; p=0·0445). INTERPRETATION: Women had a 0·7-0·9% risk of influenza per month of pregnancy during the influenza season, and antenatal influenza was associated with increased risk for some adverse pregnancy outcomes. These findings support the added value of antenatal influenza vaccination to improve perinatal outcomes. FUNDING: US Centers for Disease Control and Prevention. TRANSLATIONS: For the Thai, Hindi, Marathi and Spanish translations of the abstract see Supplementary Materials section.

Intent to obtain pediatric influenza vaccine among mothers in four middle income countries.

BACKGROUND: Despite a large burden of influenza in middle income countries, pediatric vaccination coverage remains low. The aims of this study were to (1) describe mothers' knowledge and attitudes about influenza illnesses and vaccination, and (2) identify characteristics associated with mothers' intent to vaccinate their child. METHODS: From 2015 to 2017, infants 0-11 months old in Nicaragua, Philippines, Jordan, and Albania were enrolled from community settings and hospitals. Interviewers administered a questionnaire to their mothers. Mothers of infants aged 6-11 months rated their intention (small-to-moderate vs. large chance) to accept pediatric vaccination if it was offered at no-cost. The importance of knowledge, attitudes, and sociodemographic characteristics in predicting influenza vaccination intention was measured as the mean decrease in Gini index when that factor was excluded from 1000 decision trees in a random forest analysis. RESULTS: In total, 1,308 mothers were enrolled from the community setting and 3,286 from the hospital setting. Prevalence of at least some knowledge of influenza illness ranged from 34% in Philippines to 88% in Albania (in the community sample), and between 23% in Philippines to 88% in Jordan (in the hospital sample). In the community sample, most mothers in Albania (69%) and Philippines (58%) would accept the influenza vaccine, and these proportions were higher in the hospital sample for all countries except Albania (48%) (P < 0.0001). Perceived vaccine safety (mean decrease in Gini index = 61) and effectiveness (55), and perceived knowledge of influenza vaccine (45) were the most important predictors of influenza vaccination intention in models that also included country and community versus hospital sample. CONCLUSION: Intent to vaccinate infants aged 6-11 months in four middle income countries was tied primarily to knowledge of the vaccine and perceptions of vaccine safety and effectiveness. These findings were noted among mothers interviewed in the community and mothers of recently hospitalized infants.

Prospective cohort study of influenza vaccine effectiveness among healthcare personnel in Lima, Peru: Estudio Vacuna de Influenza Peru, 2016-2018.

BACKGROUND: The Estudio Vacuna de Influenza Peru (VIP) cohort aims to describe the frequency of influenza virus infection, identify predictors of vaccine acceptance, examine the effects of repeated influenza vaccination on immunogenicity, and evaluate influenza vaccine effectiveness among HCP. METHODS: The VIP cohort prospectively followed HCP in Lima, Peru, during the 2016-2018 influenza seasons; a fourth year is ongoing. Participants contribute blood samples before and after the influenza season and after influenza vaccination (for vaccinees). Weekly surveillance is conducted to identify acute respiratory or febrile illnesses (ARFI). When an ARFI is identified, participants self-collect nasal swabs that are tested for influenza viruses by real-time reverse transcriptase-polymerase chain reaction. Influenza vaccination status and 5-year vaccination history are ascertained. We analyzed recruitment and enrollment results for 2016-2018 and surveillance participation for 2016-2017. RESULTS: In the first 3 years of the cohort, VIP successfully contacted 92% of potential participants, enrolled 76% of eligible HCP, and retained >90% of participants across years. About half of participants are medical assistants (54%), and most provide "hands-on" medical care (76%). Sixty-nine percent and 52% of participants completed surveillance for >70% of weeks in years 1 and 2, respectively. Fewer weeks of completed surveillance was associated with older age (≥50 years), being a medical assistant, self-rated health of fair or poor, and not receiving the influenza vaccine during the current season (P-values < .05). CONCLUSIONS: The VIP cohort provides an opportunity to address knowledge gaps about influenza virus infection, vaccination uptake, effectiveness and immunogenicity among HCP.

Underdetection of laboratory-confirmed influenza-associated hospital admissions among infants: a multicentre, prospective study.

BACKGROUND: Since influenza often presents non-specifically in infancy, we aimed to assess the extent to which existing respiratory surveillance platforms might underestimate the frequency of severe influenza disease among infants. METHODS: The Influenza and Respiratory Syncytial Virus in Infants (IRIS) study was a prospective observational study done at four hospitals in Albania, Jordan, Nicaragua, and the Philippines. We included acutely ill infants aged younger than 1 year admitted to hospital within 10 days or less of illness onset during two influenza seasons (2015-16 and 2016-17) in Albania, Jordan, and Nicaragua, and over a continuous 34 week period (2015-16) in the Philippines. We assessed the frequency of influenza virus infections by real-time RT-PCR (rRT-PCR) and serology. The main study outcome was seroconversion, defined as convalescent antibody titres more than or equal to four-fold higher than acute sera antibody titres, and convalescent antibody titres of 40 or higher. Seroconverison was confirmed by haemagglutination inhibition assay for influenza A viruses, and by hemagglutination inhibition assay and microneutralisation for influenza B viruses. FINDINGS: Between June 27, 2015, and April 21, 2017, 3634 acutely ill infants were enrolled, of whom 1943 were enrolled during influenza seasons and had complete acute-convalescent pairs and thus were included in the final analytical sample. Of the 1943 infants, 94 (5%) were influenza-positive by both rRT-PCR and serology, 58 (3%) were positive by rRT-PCR-only, and 102 (5%) were positive by serology only. Seroconversion to at least one of the influenza A or B viruses was observed among 196 (77%) of 254 influenza-positive infants. Of the 254 infants with influenza virus, 84 (33%) only had non-respiratory clinical discharge diagnoses (eg, sepsis, febrile seizures, dehydration, or other non-respiratory viral illness). A focus on respiratory diagnoses and rRT-PCR-confirmed influenza underdetects influenza-associated hospital admissions among infants by a factor of 2·6 (95% CI 2·0-3·6). Findings were unchanged when syndromic severe acute respiratory infection criteria were applied instead of clinical diagnosis. INTERPRETATION: If the true incidence of laboratory-confirmed influenza-associated hospital admissions among infants is at least twice that of previous estimates, this substantially increases the global burden of severe influenza and expands our estimates of the preventive value of maternal and infant influenza vaccination programmes. FUNDING: US Centers for Disease Control and Prevention.

The Pregnancy and Influenza Multinational Epidemiologic (PRIME) study: a prospective cohort study of the impact of influenza during pregnancy among women in middle-income countries.

BACKGROUND: The World Health Organization identifies pregnant women as at high-risk for severe influenza, but influenza vaccines are underutilized among pregnant women. Data on influenza burden during pregnancy are largely limited to high-income countries and data on the impact of influenza on birth and perinatal outcomes are scarce. METHODS/DESIGN: This prospective, longitudinal cohort study of pregnant women in middle-income countries is designed to address three primary objectives: 1) to evaluate the effect of laboratory-confirmed influenza during pregnancy on pregnancy and perinatal outcomes; 2) to estimate the incidences of all-cause acute respiratory illness and laboratory-confirmed influenza during pregnancy; and 3) to examine the clinical spectrum of illness associated with influenza viruses. Through a multi-country network approach, three sites aim to enroll cohorts of 1500-3000 pregnant women just before local influenza seasons. Women aged ≥ 18 years with expected delivery dates ≥ 8 weeks after the start of the influenza season are eligible. Women are followed throughout pregnancy through twice weekly surveillance for influenza symptoms (≥ 1 of myalgia, cough, runny nose, sore throat, or difficulty breathing) and have mid-turbinate nasal swabs collected for influenza virus testing during illness episodes. Primary outcomes include relative risk of preterm birth and mean birth weight among term singleton infants of women with and without reverse transcription polymerase chain reaction-confirmed influenza during pregnancy. Gestational age is determined by ultrasound at < 28 weeks gestation and birth weight is measured by digital scales using standardized methods. Sites are primarily urban in Bangkok, Thailand; Lima, Peru; and Nagpur, India. All sites recruit from antenatal clinics at referral hospitals and conduct surveillance using telephone calls, messaging applications, or home visits. Nasal swabs are self-collected by participants in Thailand and by study staff in Peru and India. During the first year (2017), sites enrolled participants during March-May in Peru and May-July in India and Thailand; 4779 women were enrolled. DISCUSSION: This study aims to generate evidence of the impact of influenza during pregnancy to inform decisions by Ministries of Health, healthcare providers, and pregnant women in middle-income countries about the value of influenza vaccination during pregnancy.

Association of influenza vaccination during pregnancy with birth outcomes in Nicaragua.

BACKGROUND: Studies have shown that influenza vaccination during pregnancy reduces the risk of influenza disease in pregnant women and their offspring. Some have proposed that maternal vaccination may also have beneficial effects on birth outcomes. In 2014, we conducted an observational study to test this hypothesis using data from two large hospitals in Managua, Nicaragua. METHODS: We conducted a retrospective cohort study to evaluate associations between influenza vaccination and birth outcomes. We carried out interviews and reviewed medical records post-partum to collect data on demographics, influenza vaccination during pregnancy, birth outcomes and other risk factors associated with adverse neonatal outcomes. We used influenza surveillance data to adjust for timing of influenza circulation. We assessed self-reports of influenza vaccination status by further reviewing medical records of those who self-reported but did not have readily available evidence of vaccination status. We performed multiple logistic regression (MLR) and propensity score matching (PSM). RESULTS: A total of 3268 women were included in the final analysis. Of these, 55% had received influenza vaccination in 2014. Overall, we did not observe statistically significant associations between influenza vaccination and birth outcomes after adjusting for risk factors, with either MLR or PSM. With PSM, after adjusting for risk factors, we observed protective associations between influenza vaccination in the second and third trimester and preterm birth (aOR: 0.87; 95% confidence interval (CI): 0.75-0.99 and aOR: 0.66; 95% CI: 0.45-0.96, respectively) and between influenza vaccination in the second trimester and low birth weight (aOR: 0.80; 95% CI: 0.64-0.97). CONCLUSIONS: We found evidence to support an association between influenza vaccination and birth outcomes by trimester of receipt with data from an urban population in Nicaragua. The study had significant selection and recall biases. Prospective studies are needed to minimize these biases.

Influenza and respiratory syncytial virus in infants study (IRIS) of hospitalized and non-ill infants aged <1 year in four countries: study design and methods.

BACKGROUND: This multi-country prospective study of infants aged <1 year aims to assess the frequency of influenza virus and respiratory syncytial virus (RSV) infections associated with hospitalizations, to describe clinical features and antibody response to infection, and to examine predictors of very severe disease requiring intensive care. METHODS/DESIGN: We are enrolling a hospital-based cohort and a sample of non-ill infants in four countries (Albania, Jordan, Nicaragua, and the Philippines) using a common protocol. We are currently starting year 2 of a 2- to 3-year study and will enroll approximately 3,000 infants hospitalized for any acute illness (respiratory or non-respiratory) during periods of local influenza and/or RSV circulation. After informed consent and within 24 h of admission, we collect blood and respiratory specimens and conduct an interview to assess socio-demographic characteristics, medical history, and symptoms of acute illness (onset ≤10 days). Vital signs, interventions, and medications are documented daily through medical record abstraction. A follow-up health assessment and collection of convalescent blood occurs 3-5 weeks after enrollment. Influenza and RSV infection is confirmed by singleplex real time reverse transcriptase polymerase chain reaction (rRT-PCR) assays. Serologic conversion will be assessed comparing acute and convalescent sera using hemagglutination inhibition assay for influenza antibodies and enzyme-linked immunosorbent assay (ELISA) for RSV. Concurrent with hospital-based enrollment, respiratory specimens are also being collected (and tested by rRT-PCR) from approximately 1,400 non-ill infants aged <1 year during routine medical or preventive care. DISCUSSION: The Influenza and RSV in Infants Study (IRIS) promises to expand our knowledge of the frequency, clinical features, and antibody profiles of serious influenza and RSV disease among infants aged <1 year, quantify the proportion of infections that may be missed by traditional surveillance, and inform decisions about the potential value of existing and new vaccines and other prevention and treatment strategies.