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Background RIV4 and cell-culture based inactivated influenza vaccine (ccIIV4) have not been compared to egg-based IIV4 in healthcare personnel, a population with frequent influenza vaccination that may blunt vaccine immune responses over time. We conducted a randomized trial among healthcare personnel (HCP) aged 18–64 years to compare humoral immune responses to ccIIV4 and RIV4 to IIV4. Methods During the 2018–2019 season, participants were randomized to receive ccIIV4, RIV4, or IIV4 and had serum samples collected prevaccination, 1 and 6 months postvaccination. Serum samples were tested by hemagglutination inhibition (HI) for influenza A/H1N1, B/Yamagata, and B/Victoria and microneutralization (MN) for A/H3N2 against cell-grown vaccine reference viruses. Primary outcomes at 1 month were seroconversion rate (SCR), geometric mean titers (GMT), GMT ratio, and mean fold rise (MFR) in the intention-to-treat population. Results In total, 727 participants were included (283 ccIIV4, 202 RIV4, and 242 IIV4). At 1 month, responses to ccIIV4 were similar to IIV4 by SCR, GMT, GMT ratio, and MFR. RIV4 induced higher SCRs, GMTs, and MFRs than IIV4 against A/H1N1, A/H3N2, and B/Yamagata. The GMT ratio of RIV4 to egg-based vaccines was 1.5 (95% confidence interval [CI] 1.2–1.9) for A/H1N1, 3.0 (95% CI: 2.4–3.7) for A/H3N2, 1.1 (95% CI: .9–1.4) for B/Yamagata, and 1.1 (95% CI: .9–1.3) for B/Victoria. At 6 months, ccIIV4 recipients had similar GMTs to IIV4, whereas RIV4 recipients had higher GMTs against A/H3N2 and B/Yamagata. Conclusions RIV4 resulted in improved antibody responses by HI and MN compared to egg-based vaccines against 3 of 4 cell-grown vaccine strains 1 month postvaccination, suggesting a possible additional benefit from RIV4., In this randomized trial among healthcare personnel comparing antibody responses to cell-culture based and recombinant influenza vaccines (RIV4) versus standard-dose egg-based vaccines, RIV4 recipients had higher antibody responses against 3 cell-grown vaccine strains suggesting a possible additional benefit from RIV4.

Background We conducted a cross-sectional study of pregnant women with acute respiratory illness during delivery hospitalizations during influenza season to describe clinical testing for respiratory viruses and infection prevention practices. Methods Women had nasal swabs tested for influenza and other respiratory viruses. Among 91 enrolled women, 22 (24%) had clinical testing for influenza. Results Based on clinical and study testing combined, 41 of 91 (45%) women had samples positive for respiratory viruses. The most common virus was influenza (17 of 91, 19%); 53% (9 of 17) of influenza virus infections were identified through study testing alone. Only 16% of women were on droplet precautions. Conclusions Peripartum respiratory infections may be underrecognized.

Background Workers critical to emergency response and continuity of essential services during the COVID-19 pandemic are at a disproportionally high risk of SARS-CoV-2 infection. Prospective cohort studies are needed for enhancing the understanding of the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, identifying risk factors, assessing clinical outcomes, and determining the effectiveness of vaccination. Objective The Research on the Epidemiology of SARS-CoV-2 in Essential Response Personnel (RECOVER) prospective cohort study was designed to estimate the incidence of symptomatic and asymptomatic SARS-CoV-2 infections, examine the risk factors for infection and clinical spectrum of illness, and assess the effectiveness of vaccination among essential workers. Methods The RECOVER multisite network was initiated in August 2020 and aims to enroll 3000 health care personnel (HCP), first responders, and other essential and frontline workers (EFWs) at 6 US locations. Data on participant demographics, medical history, and vaccination history are collected at baseline and throughout the study. Active surveillance for the symptoms of COVID-19–like illness (CLI), access of medical care, and symptom duration is performed by text messages, emails, and direct participant or medical record reports. Participants self-collect a mid-turbinate nasal swab weekly, regardless of symptoms, and 2 additional respiratory specimens at the onset of CLI. Blood is collected upon enrollment, every 3 months, approximately 28 days after a reverse transcription polymerase chain reaction (RT-PCR)–confirmed SARS-CoV-2 infection, and 14 to 28 days after a dose of any COVID-19 vaccine. From February 2021, household members of RT-PCR–confirmed participants are self-collecting mid-turbinate nasal swabs daily for 10 days. Results The study observation period began in August 2020 and is expected to continue through spring 2022. There are 2623 actively enrolled RECOVER participants, including 280 participants who have been found to be positive for SARS-CoV-2 by RT-PCR. Enrollment is ongoing at 3 of the 6 study sites. Conclusions Data collected through the cohort are expected to provide important public health information for essential workers at high risk for occupational exposure to SARS-CoV-2 and allow early evaluation of COVID-19 vaccine effectiveness. International Registered Report Identifier (IRRID) DERR1-10.2196/31574

BACKGROUNDInformation is limited on messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection or attenuating disease when administered in real-world conditions.METHODSProspective cohorts of 3,975 healthcare personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing during December 14 2020—April 10 2021. Self-collected mid-turbinate nasal swabs were tested by qualitative and quantitative reverse-transcription–polymerase-chain-reaction (RT-PCR). VE was calculated as 100%×(1−hazard ratio); adjusted VE was calculated using vaccination propensity weights and adjustments for site, occupation, and local virus circulation.RESULTSSARS-CoV-2 was detected in 204 (5.1%) participants; 16 were partially (≥14 days post-dose-1 to 13 days after dose-2) or fully (≥14 days post-dose-2) vaccinated, and 156 were unvaccinated; 32 with indeterminate status (CONCLUSIONSAuthorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infections when administered in real-world conditions and attenuated viral RNA load, febrile symptoms, and illness duration among those with breakthrough infection despite vaccination.

Background Information is limited regarding the effectiveness of the two-dose messenger RNA (mRNA) vaccines BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna) in preventing infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in attenuating coronavirus disease 2019 (Covid-19) when administered in real-world conditions. Methods We conducted a prospective cohort study involving 3975 health care personnel, first responders, and other essential and frontline workers. From December 14, 2020, to April 10, 2021, the participants completed weekly SARS-CoV-2 testing by providing mid-turbinate nasal swabs for qualitative and quantitative reverse-transcriptase–polymerase-chain-reaction (RT-PCR) analysis. The formula for calculating vaccine effectiveness was 100%×(1−hazard ratio for SARS-CoV-2 infection in vaccinated vs. unvaccinated participants), with adjustments for the propensity to be vaccinated, study site, occupation, and local viral circulation. Results SARS-CoV-2 was detected in 204 participants (5%), of whom 5 were fully vaccinated (≥14 days after dose 2), 11 partially vaccinated (≥14 days after dose 1 and

Background The World Health Organization (WHO) recommends case definitions for influenza surveillance that are also used in public health research, although their performance has not been assessed in many risk groups, including pregnant women in whom influenza may manifest differently. We evaluated the performance of symptom-based definitions to detect influenza in a cohort of pregnant women in India, Peru, and Thailand. Methods In 2017 and 2018, we contacted 11 277 pregnant women twice weekly during the influenza season to identify illnesses with new or worsened cough, runny nose, sore throat, difficulty breathing, or myalgia and collected data on other symptoms and nasal swabs for influenza real-time reverse transcription–polymerase chain reaction (rRT-PCR) testing. We calculated sensitivity, specificity, positive-predictive value, and negative-predictive value of each symptom predictor, WHO respiratory illness case definitions, and a de novo definition derived from results of multivariable modeling. Results Of 5444 eligible illness episodes among 3965 participants, 310 (6%) were positive for influenza. In a multivariable model, measured fever ≥38°C (adjusted odds ratio [95% confidence interval], 4.6 [3.1–6.8]), myalgia (3.0 [2.2–4.0]), cough (2.7 [1.9–3.9]), and chills (1.6 [1.1–2.4]) were independently associated with influenza illness. A definition based on these 4 (measured fever, cough, chills, or myalgia) was 95% sensitive and 27% specific. The WHO influenza-like illness (ILI) definition was 16% sensitive and 98% specific. Conclusions The current WHO ILI case definition was highly specific but had low sensitivity. The intended use of case definitions should be considered when evaluating the tradeoff between sensitivity and specificity.

Importance Data about the risk of SARS-CoV-2 infection among children compared with adults are needed to inform COVID-19 risk communication and prevention strategies, including COVID-19 vaccination policies for children. Objective To compare incidence rates and clinical characteristics of SARS-CoV-2 infection among adults and children and estimated household infection risks within a prospective household cohort. Design, Setting, and Participants Households with at least 1 child aged 0 to 17 years in selected counties in Utah and New York City, New York, were eligible for enrollment. From September 2020 through April 2021, participants self-collected midturbinate nasal swabs for reverse transcription–polymerase chain reaction testing for SARS-CoV-2 and responded to symptom questionnaires each week. Participants also self-collected additional respiratory specimens with onset of COVID-19–like illness. For children unable to self-collect respiratory specimens, an adult caregiver collected the specimens. Main Outcomes and Measures The primary outcome was incident cases of any SARS-CoV-2 infection, including asymptomatic and symptomatic infections. Additional measures were the asymptomatic fraction of infection calculated by dividing incidence rates of asymptomatic infection by rates of any infection, clinical characteristics of infection, and household infection risks. Primary outcomes were compared by participant age group. Results A total of 1236 participants in 310 households participated in surveillance, including 176 participants (14%) who were aged 0 to 4 years, 313 (25%) aged 5 to 11 years, 163 (13%) aged 12 to 17 years, and 584 (47%) 18 years or older. Overall incidence rates of SARS-CoV-2 infection were 3.8 (95% CI, 2.4-5.9) and 7.7 (95% CI, 4.1-14.5) per 1000 person-weeks among the Utah and New York City cohorts, respectively. Site-adjusted incidence rates per 1000 person-weeks were similar by age group: 6.3 (95% CI, 3.6-11.0) for children 0 to 4 years, 4.4 (95% CI, 2.5-7.5) for children 5 to 11 years, 6.0 (95% CI, 3.0-11.7) for children 12 to 17 years, and 5.1 (95% CI, 3.3-7.8) for adults (≥18 years). The asymptomatic fractions of infection by age group were 52%, 50%, 45%, and 12% among individuals aged 0 to 4 years, 5 to 11 years, 12 to 17 years, and 18 years or older, respectively. Among 40 households with 1 or more SARS-CoV-2 infections, the mean risk of SARS-CoV-2 infection among all enrolled household members was 52% (range, 11%-100%), with higher risks in New York City compared with Utah (80% [95% CI, 64%-91%] vs 44% [95% CI, 36%-53%];P Conclusions and Relevance In this study, children had similar incidence rates of SARS-CoV-2 infection compared with adults, but a larger proportion of infections among children were asymptomatic.

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.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.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.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.

Summary 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.

Background Respiratory syncytial virus (RSV) is the most commonly identified viral pathogen among young children with acute lower respiratory tract infection. Understanding global RSV epidemiology and risk factors for severe illness in low- and middle-income settings is critical as new vaccine candidates become available. Methods We prospectively enrolled infants aged < 1 year hospitalized with any acute illness from sites in Albania, Jordan, Nicaragua and Philippines during 2015–2017. Standardized parental interviews and medical record review were conducted. Respiratory specimens collected during enrollment were tested for RSV using rRT–PCR. RSV A or B subgroup was determined using a CDC-developed rRT–PCR assay. Very severe RSV illness was defined as requiring ICU admission or supplemental oxygen. Factors potentially associated with severity were assessed using individual logistic regression models to adjust for age and study site. Results Overall, 1,129 (31%) of 3634 enrolled infants had RSV infection. The median age of RSV-positive infants was 2.7 (range: < 1 to 11.9) months, 665 (59%) were male, and 63 (6%) had ≥1 underlying medical condition. RSV subgroup was determined for 1,028 (91%); RSV A and B co-circulated at all sites with alternating predominance by study year (figure). 583 (52%) infants had very severe RSV illness, which was significantly associated with younger age (median: 2.0 vs. 4.3 months; P < 0.01), study site (aOR: Jordan 5.0, Albania 2.9, Philippines 1.2, Nicaragua reference; P < 0.01), birth by cesarean section (aOR: 1.4; 95% CI [CI] 1.0–1.8; P = 0.03), having received ICU care after birth (aOR: 1.6; CI 1.0–2.4; P = 0.03), chronic heart or respiratory tract disease (aOR: 1.9; CI 1.0–3.4; P = 0.04), and a low weight-for-age Z score (aOR: 1.8; CI 1.3–2.7; P < 0.01). RSV subgroup was not associated with severity (aOR: 1.0; CI: 0.7–1.3; P = 0.72). Conclusion RSV was associated with a substantial proportion of acute illness among hospitalized infants in middle-income countries. Subgroups co-circulated across sites and study years with varying predominance and resulted in similar illness severity. Significant comorbidities were uncommon, but factors including younger age, low weight-for-age and chronic heart or respiratory tract disease were associated with more severe illness. Disclosures All authors: No reported disclosures.

Background The World Health Organization (WHO) recommends case definitions for influenza surveillance that are also used in public health research, though their performance has not been assessed in many risk groups, including pregnant women in whom influenza may manifest differently. Â We evaluated the performance of symptom-based case definitions to detect influenza in a cohort of pregnant women in India, Peru, and Thailand. Methods In 2017, we contacted 4774 pregnant women twice a week during the influenza season to identify illnesses with new or worsened cough, runny nose, sore throat, difficulty breathing or myalgia, and collected data on other symptoms and nasal swabs for influenza rRT–PCR testing. To identify symptom predictors of influenza, we used multivariable logistic regression with forward selection of symptoms significant in univariate analysis after controlling for country, chronic conditions, influenza vaccination, and time from symptom onset to swab collection. We calculated sensitivity and specificity of each symptom, WHO respiratory illness case definitions and a case definition based on significant predictors from the multivariable model. Results Of 2431 eligible illness episodes among 1,716 participants, 142 (5.8%) were positive for influenza. Among individual symptoms, runny nose was most sensitive and measured fever ≥ 38° Celsius was most specific (Figure 1). In a multivariable model, measured fever ≥ 38° Celsius [adjusted odds ratio = 3.8, 95% confidence interval [CI] = 2.0–7.2], cough [2.7, CI 1.6–4.7], chills [2.2, CI 1.2–3.8], and myalgia [1.2, CI 2.2, 5.3] were independently associated with influenza illness. A case definition based on these four (measured fever, cough, chills or myalgia), was 91%-sensitive and 37% specific. Sensitivity and specificity of case definitions varied (Figure 2). Conclusion While a case definition based on one or more of fever, chills, cough or myalgia is highly-sensitive and moderately specific among pregnant women, case definitions requiring measured or subjective fever may miss many influenza cases making them sub-optimal for studies of burden or vaccine efficacy. The intended use of case definitions should be considered when evaluating the tradeoff between sensitivity and specificity. Disclosures All authors: No reported disclosures.

Background The World Health Organization recommends influenza vaccination for pregnant women. However, few data exist on influenza incidence and clinical course among pregnant women in middle-income countries where influenza vaccine use during pregnancy is often limited. We conducted a prospective cohort study of pregnant women to estimate incidences of influenza in Lima, Peru; Bangkok, Thailand; and Nagpur, India. Methods Prior to and early in the 2017 and 2018 influenza seasons, we enrolled pregnant women aged > 18 years with expected delivery dates > 8 weeks after the start of the season. We contacted women twice weekly until end of pregnancy to identify illnesses with myalgia, cough, runny nose, sore throat, or difficulty breathing and collected nasal swabs from symptomatic women for influenza real-time reverse transcription polymerase chain reaction testing. Using 2017 cohort data, we calculated crude incidences per 10,000 pregnancy-months during influenza season by site and trimester and overall incidence weighted for population of women of childbearing age in each country. Results We enrolled 4774 women with a median age of 26 years (interquartile range [IQR] 23–31) and gestational age of 20 weeks (IQR 15–24); 15% received influenza vaccine. Local influenza seasons spanned 4.5–8 months. Overall, 143 participants (3%) had influenza (113 (79%) influenza A and 30 (21%) influenza B). Weighted influenza incidence was 88.7/10,000 pregnancy-months (95% CI 68.6–114.8), though incidences varied up to two-fold by site (Figure 1). Incidences did not differ by pregnancy trimester (Figure 2). Among the 143 influenza episodes, the median duration was 7 days (IQR 5–10), 30% involved fever or chills, 43% disrupted daily activities, 47% prompted medical attention, 4% were associated with hospitalization, and < 1% were treated with antiviral medications. Conclusion Overall, pregnant women had an average risk of influenza of 0.9% per month of pregnancy spent in the influenza season with almost half of illnesses disrupting daily activities and prompting medical attention. Influenza-associated hospitalization was infrequent. These findings provide valuable inputs to estimate illnesses averted by vaccine programs and evaluate their cost–benefit among pregnant women in middle-income countries. Disclosures All authors: No reported disclosures.

Background This multi-country prospective study of infants aged