BACKGROUND: Although healthcare personnel (HCP) are targeted for influenza vaccination they typically underutilize vaccines especially in low- and middle-income countries. We explored knowledge, attitudes, and practices of HCP about seasonal influenza vaccines (SIV) to identify factors associated with and modifiable barriers to SIV uptake. METHODS: We pooled individual-level data from cross-sectional surveys about SIV conducted among health workers in 12 low- and middle- income countries during 2018-2020 (i.e., Albania, Armenia, Cote d'Ivoire, Kenya, Kyrgyzstan, Lao PDR, Lebanon, Morocco, North Macedonia, Tunisia, Tajikistan, and Uganda). Eleven countries used a standard protocol and questionnaire based on the Health Belief Model to measure perceptions of susceptibility and severity of influenza disease, benefits of, barriers to, and motivators for vaccination. We analyzed attitudes and perceptions among HCP, including acceptance of vaccine for themselves and willingness to recommend vaccines to patients, grouped by the presence/absence of a national influenza vaccination program. Models were adjusted for geographic region. RESULTS: Our analysis included 10,281 HCP from 12 countries representing four of the six World Health Organization regions: African, Eastern Mediterranean, European, and Western Pacific. The sample was distributed across low income (LIC) (3,183, 31 %), lower-middle (LMIC) (4,744, 46 %), and upper-middle income (UMIC) (2,354, 23 %) countries. Half (50 %) of the countries included in the analysis reported SIV use among HCP in both the year of and the year preceding data collection while the remainder had no influenza vaccination program for HCP. Seventy-four percent (6,341) of HCP reported that they would be willing to be vaccinated if the vaccine was provided free of charge. HCP in LICs were willing to pay prices for SIV representing a higher percentage of their country's annual health expenditure per capita (6.26 % [interquartile range, IQR: 3.13-12.52]) compared to HCP in LMICs and UMICs. HCP in countries with no SIV program were also willing to pay a higher percentage for SIV (5.01 % [IQR: 2.24-8.34]) compared to HCP in countries with SIV programs.. Most (85 %) HCP in our analysis would recommend vaccines to their patients, and those who would accept vaccines for themselves were 3 times more likely to recommend vaccines to their patients (OR 3.1 [95 % CI 1·8, 5·2]). CONCLUSION: Increasing uptake of SIV among HCP can amplify positive impacts of vaccination by increasing the likelihood that HCP recommend vaccines to their patients. Successful strategies to achieve increased uptake of vaccines include clear guidance from health authorities, interventions based on behavior change models, and access to vaccine free-of-charge.

Increasing opportunities for prevention of infectious diseases by new, effective vaccines and the expansion of global immunization programs across the life course highlight the importance and value of evidence-informed decision-making (EIDM) by National Immunization Technical Advisory Groups (NITAGs). The U.S. Centers for Disease Control and Prevention (CDC) and Task Force for Global Health (TFGH) have developed and made available new tools to support NITAGs in EIDM. These include a toolkit for conducting facilitated training of NITAGs, Secretariats, or work groups on the use of the Evidence to Recommendations (EtR) approach to advise Ministries of Health (MoH) on specific vaccine policies, and an eLearning module on the EtR approach for NITAG members, Secretariat and others. The CDC and TFGH have also supported final development and implementation of the NITAG Maturity Assessment Tool (NMAT) for assessing maturity of NITAG capabilities in seven functional domains. The EtR toolkit and eLearning have been widely promoted in collaboration with the World Health Organization (WHO) Headquarters and Regional Offices through workshops engaging over 30 countries to date, and the NMAT assessment tool used in most countries in 3 WHO regions (Americas, Eastern Mediterranean, African). Important lessons have been learned regarding planning and conducting trainings for multiple countries and additional ways to support countries in applying the EtR approach to complete vaccine recommendations. Priorities for future work include the need to evaluate the impact of EtR training and NMAT assessments, working with partners to expand and adapt these tools for wider use, synergizing with other approaches for NITAG strengthening, and developing the best approaches to empower NITAGs to use the EtR approach.

BACKGROUND: Historically, lack of data on cost-effectiveness of influenza vaccination has been identified as a barrier to vaccine use in low- and middle-income countries. We conducted a systematic review of economic evaluations describing (1) costs of influenza illness; (2) costs of influenza vaccination programs; and (3) vaccination cost-effectiveness from low- and middle-income countries to assess if gaps persist that could hinder global implementation of influenza vaccination programs. METHODS AND FINDINGS: We performed a systematic search in Medline, Embase, Cochrane Library, CINAHL, and Scopus in January 2022 and October 2023 using a combination of the following key words: "influenza" AND "cost" OR "economic." The search included studies with publication years 2012 through 2022. Studies were eligible if they (1) presented original, peer-reviewed findings on cost of illness, cost of vaccination program, or cost-effectiveness of vaccination for seasonal influenza; and (2) included data for at least 1 low- or middle-income country. We abstracted general study characteristics and data specific to each of the 3 study types. Of 54 included studies, 26 presented data on cost-effectiveness, 24 on cost-of-illness, and 5 on program costs. Represented countries were classified as upper-middle income (UMIC; n = 12), lower-middle income (LMIC; n = 7), and low-income (LIC; n = 3). The most evaluated target groups were children (n = 26 studies), older adults (n = 17), and persons with chronic medical conditions (n = 12); fewer studies evaluated pregnant persons (n = 9), healthcare workers (n = 5), and persons in congregate living settings (n = 1). Costs-of-illness were generally higher in UMICs than in LMICs/LICs; however, the highest national economic burden, as a percent of gross domestic product and national health expenditure, was reported from an LIC. Among studies that evaluated the cost-effectiveness of influenza vaccine introduction, most (88%) interpreted at least 1 scenario per target group as either cost-effective or cost-saving, based on thresholds designated in the study. Key limitations of this work included (1) heterogeneity across included studies; (2) restrictiveness of the inclusion criteria used; and (3) potential for missed influenza burden from use of sentinel surveillance systems. CONCLUSIONS: The 54 studies identified in this review suggest an increased momentum to generate economic evidence about influenza illness and vaccination from low- and middle-income countries during 2012 to 2022. However, given that we observed substantial heterogeneity, continued evaluation of the economic burden of influenza illness and costs/cost-effectiveness of influenza vaccination, particularly in LICs and among underrepresented target groups (e.g., healthcare workers and pregnant persons), is needed. Use of standardized methodology could facilitate pooling across settings and knowledge sharing to strengthen global influenza vaccination programs.

BACKGROUND: During November 2019-October 2021, a pediatric influenza vaccination demonstration project was conducted in four sub-counties in Kenya. The demonstration piloted two different delivery strategies: year-round vaccination and a four-month vaccination campaign. Our objective was to compare the costs of both delivery strategies. METHODS: Cost data were collected using standardized questionnaires and extracted from government and project accounting records. We reported total costs and costs per vaccine dose administered by delivery strategy from the Kenyan government perspective in 2021 US$. Costs were separated into financial costs (monetary expenditures) and economic costs (financial costs plus the value of existing resources). We also separated costs by administrative level (national, regional, county, sub-county, and health facility) and program activity (advocacy and social mobilization; training; distribution, storage, and waste management; service delivery; monitoring; and supervision). RESULTS: The total estimated cost of the pediatric influenza demonstration project was US$ 225,269 (financial) and US$ 326,691 (economic) for the year-round delivery strategy (30,397 vaccine doses administered), compared with US$ 214,753 (financial) and US$ 242,385 (economic) for the campaign strategy (25,404 doses administered). Vaccine purchase represented the largest proportion of costs for both strategies. Excluding vaccine purchase, the cost per dose administered was US$ 1.58 (financial) and US$ 5.84 (economic) for the year-round strategy and US$ 2.89 (financial) and US$ 4.56 (economic) for the campaign strategy. CONCLUSIONS: The financial cost per dose was 83% higher for the campaign strategy than the year-round strategy due to larger expenditures for advocacy and social mobilization, training, and hiring of surge staff for service delivery. However, the economic cost per dose was more comparable for both strategies (year-round 22% higher than campaign), balanced by higher costs of operating equipment and monitoring activities for the year-round strategy. These delivery cost data provide real-world evidence to inform pediatric influenza vaccine introduction in Kenya.

This report updates the 2008 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]). Information on vaccination issues related to the recently identified novel influenza A H1N1 virus will be published later in 2009. The 2009 seasonal influenza recommendations include new and updated information. Highlights of the 2009 recommendations include 1) a recommendation that annual vaccination be administered to all children aged 6 months-18 years for the 2009-10 influenza season; 2) a recommendation that vaccines containing the 2009-10 trivalent vaccine virus strains A/Brisbane/59/2007 (H1N1)-like, A/Brisbane/10/2007 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; and 3) a notice that recommendations for influenza diagnosis and antiviral use will be published before the start of the 2009-10 influenza season. Vaccination efforts should begin as soon as vaccine is available and continue through the influenza season. Approximately 83% of the United States population is specifically recommended for annual vaccination against seasonal influenza; however, <40% of the U.S. population received the 2008-09 influenza vaccine. These recommendations also include a summary of safety data for U.S. licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates or supplements that might be required during the 2009-10 influenza season also can be found at this website. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.

This report updates the 2012 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccines for the prevention and control of seasonal influenza (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2012;61:613-8). Routine annual influenza vaccination is recommended for all persons aged ≥ 6 months. For the 2013-14 influenza season, it is expected that trivalent live attenuated influenza vaccine (LAIV3) will be replaced by a quadrivalent LAIV formulation (LAIV4). Inactivated influenza vaccines (IIVs) will be available in both trivalent (IIV3) and quadrivalent (IIV4) formulations. Vaccine virus strains included in the 2013-14 U.S. trivalent influenza vaccines will be an A/California/7/2009 (H1N1)-like virus, an H3N2 virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011, and a B/Massachusetts/2/2012-like virus. Quadrivalent vaccines will include an additional influenza B virus strain, a B/Brisbane/60/2008-like virus, intended to ensure that both influenza B virus antigenic lineages (Victoria and Yamagata) are included in the vaccine. This report describes recently approved vaccines, including LAIV4, IIV4, trivalent cell culture-based inactivated influenza vaccine (ccIIV3), and trivalent recombinant influenza vaccine (RIV3). No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one product is otherwise appropriate. This information is intended for vaccination providers, immunization program personnel, and public health personnel. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates also will be found at this website. Vaccination and health-care providers should check the CDC influenza website periodically for additional information.

This report updates previous recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of antiviral agents for the prevention and treatment of influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]).This report contains information on treatment and chemoprophylaxis of influenza virus infection and provides a summary of the effectiveness and safety of antiviral treatment medications. Highlights include recommendations for use of 1) early antiviral treatment of suspected or confirmed influenza among persons with severe influenza (e.g., those who have severe, complicated, or progressive illness or who require hospitalization); 2) early antiviral treatment of suspected or confirmed influenza among persons at higher risk for influenza complications; and 3) either oseltamivir or zanamivir for persons with influenza caused by 2009 H1N1 virus, influenza A (H3N2) virus, or influenza B virus or when the influenza virus type or influenza A virus subtype is unknown; 4) antiviral medications among children aged <1 year; 5) local influenza testing and influenza surveillance data, when available, to help guide treatment decisions; and 6) consideration of antiviral treatment for outpatients with confirmed or suspected influenza who do not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset. Additional information is available from CDC's influenza website at http://www.cdc.gov/flu, including any updates or supplements to these recommendations that might be required during the 2010-11 influenza season. Health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information. Recommendations related to the use of vaccines for the prevention of influenza during the 2010-11 influenza season have been published previously (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP], 2010. MMWR 2010;59[No. RR-8]).

This report updates the 2009 recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine for the prevention and control of influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2009;58[No. RR-8] and CDC. Use of influenza A (H1N1) 2009 monovalent vaccine---recommendations of the Advisory Committee on Immunization Practices [ACIP], 2009. MMWR 2009;58:[No. RR-10]). The 2010 influenza recommendations include new and updated information. Highlights of the 2010 recommendations include 1) a recommendation that annual vaccination be administered to all persons aged >or=6 months for the 2010-11 influenza season; 2) a recommendation that children aged 6 months--8 years whose vaccination status is unknown or who have never received seasonal influenza vaccine before (or who received seasonal vaccine for the first time in 2009-10 but received only 1 dose in their first year of vaccination) as well as children who did not receive at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine regardless of previous influenza vaccine history should receive 2 doses of a 2010-11 seasonal influenza vaccine (minimum interval: 4 weeks) during the 2010--11 season; 3) a recommendation that vaccines containing the 2010-11 trivalent vaccine virus strains A/California/7/2009 (H1N1)-like (the same strain as was used for 2009 H1N1 monovalent vaccines), A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens be used; 4) information about Fluzone High-Dose, a newly approved vaccine for persons aged >or=65 years; and 5) information about other standard-dose newly approved influenza vaccines and previously approved vaccines with expanded age indications. Vaccination efforts should begin as soon as the 2010-11 seasonal influenza vaccine is available and continue through the influenza season. These recommendations also include a summary of safety data for U.S.-licensed influenza vaccines. These recommendations and other information are available at CDC's influenza website (http://www.cdc.gov/flu); any updates or supplements that might be required during the 2010-11 influenza season also will be available at this website. Recommendations for influenza diagnosis and antiviral use will be published before the start of the 2010-11 influenza season. Vaccination and health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information.

Introduction: Historically, lack of data on cost-effectiveness of influenza vaccination has been identified as a barrier to vaccine use in low- and middle-income countries. We conducted a systematic review of economic evaluations describing (1) costs of influenza illness, (2) costs of influenza vaccination programs, and (3) vaccination cost-effectiveness from low- and middle-income countries to assess if gaps persist. Method(s): We performed a systematic search in Medline, Embase, Cochrane Library, CINAHL, and Scopus using a combination of the following key words: "influenza" AND "cost" OR "economic." The search included studies with publication years 2012 through 2021. We abstracted general study characteristics and data specific to each of the three areas of review. Result(s): Of 50 included studies, 24 presented data on cost-effectiveness, 23 on cost-of-illness, and four on program costs. Represented countries were classified as upper-middle income (UMIC; n=11), lower-middle income (LMIC; n=7), and low-income (LIC; n=3). The most evaluated target groups were children (n=26 studies), older adults (n=16), and persons with chronic medical conditions (n=12); fewer studies evaluated pregnant persons (n=8), healthcare workers (n=4), and persons in congregate living settings (n=1). Costs-of-illness were generally higher in UMICs than in LMICs/LICs; however, the highest total costs, as a percent of gross domestic product and national health expenditure, were reported from an LIC. Among studies that evaluated the cost-effectiveness of influenza vaccine introduction, most (83%) interpreted at least one scenario per target group as either cost-effective or cost-saving, based on thresholds designated in the study. Conclusion(s): Continued evaluation of the economic burden of influenza illness and costs and cost-effectiveness of influenza vaccination, particularly in low-income countries and among underrepresented target groups (e.g., healthcare workers and pregnant persons), is needed; use of standardized methodology could facilitate pooling across settings. Robust, global economic data are critical to design and maintain sustainable influenza vaccination programs. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

OBJECTIVES: Seasonal influenza vaccines protect against 3 (trivalent influenza vaccine [IIV3]) or 4 (quadrivalent influenza vaccine [IIV4]) viruses. IIV4 costs more than IIV3, and there is a trade-off between incremental cost and protection. This is especially the case in low- and middle-income countries (LMICs) with limited budgets; previous reviews have not identified studies of IIV4-IIV3 comparisons in LMICs. We summarized the literature that compared health and economic outcomes of IIV4 and IIV3, focused on LMICs. METHODS: We systematically searched 5 databases for articles published before October 6, 2021, that modeled health or economic effects of IIV4 versus IIV3. We abstracted data and compared findings among countries and models. RESULTS: Thirty-eight studies fit our selection criteria; 10 included LMICs. Most studies (N = 31) reported that IIV4 was cost-saving or cost-effective compared with IIV3; we observed no difference in health or economic outcomes between LMICs and other countries. Based on cost differences of influenza vaccines, only one study compared coverage of IIV3 with IIV4 and reported that the maximum IIV4 price that would still yield greater public health impact than IIV3 was 13% to 22% higher than IIV3. CONCLUSIONS: When vaccination coverage with IIV4 and IIV3 is the same, IIV4 tends to be not only more effective but more cost-effective than IIV3, even with relatively high price differences between vaccine types. Alternatively, where funding is limited as in most LMICs, higher vaccine coverage can be achieved with IIV3 than IIV4, which could result in more favorable health and economic outcomes.

BACKGROUND: Using country-specific surveillance data to describe influenza epidemic activity could inform decisions on the timing of influenza vaccination. We analysed surveillance data from African countries to characterise the timing of seasonal influenza epidemics to inform national vaccination strategies. METHODS: We used publicly available sentinel data from African countries reporting to the WHO Global Influenza Surveillance and Response FluNet platform that had 3-10 years of data collected during 2010-19. We calculated a 3-week moving proportion of samples positive for influenza virus and assessed epidemic timing using an aggregate average method. The start and end of each epidemic were defined as the first week when the proportion of positive samples exceeded or went below the annual mean, respectively, for at least 3 consecutive weeks. We categorised countries into five epidemic patterns: northern hemisphere-dominant, with epidemics occurring in October-March; southern hemisphere-dominant, with epidemics occurring in April-September; primarily northern hemisphere with some epidemic activity in southern hemisphere months; primarily southern hemisphere with some epidemic activity in northern hemisphere months; and year-round influenza transmission without a discernible northern hemisphere or southern hemisphere predominance (no clear pattern). FINDINGS: Of the 34 countries reporting data to FluNet, 25 had at least 3 years of data, representing 46% of the countries in Africa and 89% of Africa's population. Study countries reported RT-PCR respiratory virus results for a total of 503 609 specimens (median 12 971 [IQR 9607-20 960] per country-year), of which 74 001 (15%; median 2078 [IQR 1087-3008] per country-year) were positive for influenza viruses. 248 epidemics occurred across 236 country-years of data (median 10 [range 7-10] per country). Six (24%) countries had a northern hemisphere pattern (Algeria, Burkina Faso, Egypt, Morocco, Niger, and Tunisia). Eight (32%) had a primarily northern hemisphere pattern with some southern hemisphere epidemics (Cameroon, Ethiopia, Mali, Mozambique, Nigeria, Senegal, Tanzania, and Togo). Three (12%) had a primarily southern hemisphere pattern with some northern hemisphere epidemics (Ghana, Kenya, and Uganda). Three (12%) had a southern hemisphere pattern (Central African Republic, South Africa, and Zambia). Five (20%) had no clear pattern (Côte d'Ivoire, DR Congo, Madagascar, Mauritius, and Rwanda). INTERPRETATION: Most countries had identifiable influenza epidemic periods that could be used to inform authorities of non-seasonal and seasonal influenza activity, guide vaccine timing, and promote timely interventions. FUNDING: None. TRANSLATIONS: For the Berber, Luganda, Xhosa, Chewa, Yoruba, Igbo, Hausa and Afan Oromo translations of the abstract see Supplementary Materials section.

A network of global respiratory disease surveillance systems and partnerships has been built over decades as a direct response to the persistent threat of seasonal, zoonotic, and pandemic influenza. These efforts have been spearheaded by the World Health Organization, country ministries of health, the US Centers for Disease Control and Prevention, nongovernmental organizations, academic groups, and others. During the COVID-19 pandemic, the US Centers for Disease Control and Prevention worked closely with ministries of health in partner countries and the World Health Organization to leverage influenza surveillance systems and programs to respond to SARS-CoV-2 transmission. Countries used existing surveillance systems for severe acute respiratory infection and influenza-like illness, respiratory virus laboratory resources, pandemic influenza preparedness plans, and ongoing population-based influenza studies to track, study, and respond to SARS-CoV-2 infections. The incorporation of COVID-19 surveillance into existing influenza sentinel surveillance systems can support continued global surveillance for respiratory viruses with pandemic potential.

The US Centers for Disease Control and Prevention (CDC) supports international partners in introducing vaccines, including those against SARS-CoV-2 virus. CDC contributes to the development of global technical tools, guidance, and policy for COVID-19 vaccination and has established its COVID-19 International Vaccine Implementation and Evaluation (CIVIE) program. CIVIE supports ministries of health and their partner organizations in developing or strengthening their national capacities for the planning, implementation, and evaluation of COVID-19 vaccination programs. CIVIE's 7 priority areas for country-specific technical assistance are vaccine policy development, program planning, vaccine confidence and demand, data management and use, workforce development, vaccine safety, and evaluation. We discuss CDC's work on global COVID-19 vaccine implementation, including priorities, challenges, opportunities, and applicable lessons learned from prior experiences with Ebola, influenza, and meningococcal serogroup A conjugate vaccine introductions.

Improved influenza vaccines are urgently needed to reduce the burden of seasonal influenza and to ensure a rapid and effective public-health response to future influenza pandemics. The Influenza Vaccines Research and Development (R&D) Roadmap (IVR) was created, through an extensive international stakeholder engagement process, to promote influenza vaccine R&D. The roadmap covers a 10-year timeframe and is organized into six sections: virology; immunology; vaccinology for seasonal influenza vaccines; vaccinology for universal influenza vaccines; animal and human influenza virus infection models; and policy, finance, and regulation. Each section identifies barriers, gaps, strategic goals, milestones, and additional R&D priorities germane to that area. The roadmap includes 113 specific R&D milestones, 37 of which have been designated high priority by the IVR expert taskforce. This report summarizes the major issues and priority areas of research outlined in the IVR. By identifying the key issues and steps to address them, the roadmap not only encourages research aimed at new solutions, but also provides guidance on the use of innovative tools to drive breakthroughs in influenza vaccine R&D.

BACKGROUND: During the 2009 influenza A(H1N1)pdm09 pandemic, 77 countries received donated monovalent A(H1N1)pdm09 vaccine through the WHO Pandemic Influenza A(H1N1) Vaccine Deployment Initiative. However, 47% did not receive their first shipment until after the first wave of virus circulation, and 8% did not receive their first shipment until after the WHO declared the end of the pandemic. Arguably, these shipments were too late into the pandemic to have a substantial effect on virus transmission or disease burden during the first waves of the pandemic. OBJECTIVES: In order to evaluate the potential benefits of earlier vaccine availability, we estimated the number of illnesses and deaths that could be averted during a 2009-like influenza pandemic under five different vaccine-availability timing scenarios. METHODS: We adapted a model originally developed to estimate annual influenza morbidity and mortality burden averted through US seasonal vaccination and ran it for five vaccine availability timing scenarios in nine low- and middle-income countries that received donated vaccine. RESULTS: Among nine study countries, we estimated that the number of averted cases was 61-216,197 for actual vaccine receipt, increasing to 2,914-283,916 had vaccine been available simultaneously with the United States. CONCLUSIONS: Earlier delivery of vaccines can reduce influenza case counts during a simulated 2009-like pandemic in some low- and middle-income countries. For others, increasing the number of cases and deaths prevented through vaccination may be dependent on factors other than timely initiation of vaccine administration, such as distribution and administration capacity.

Phase 3 randomized-controlled trials have provided promising results of COVID-19 vaccine efficacy, ranging from 50 to 95% against symptomatic disease as the primary endpoints, resulting in emergency use authorization/listing for several vaccines. However, given the short duration of follow-up during the clinical trials, strict eligibility criteria, emerging variants of concern, and the changing epidemiology of the pandemic, many questions still remain unanswered regarding vaccine performance. Post-introduction vaccine effectiveness evaluations can help us to understand the vaccine's effect on reducing infection and disease when used in real-world conditions. They can also address important questions that were either not studied or were incompletely studied in the trials and that will inform evolving vaccine policy, including assessment of the duration of effectiveness; effectiveness in key subpopulations, such as the very old or immunocompromised; against severe disease and death due to COVID-19; against emerging SARS-CoV-2 variants of concern; and with different vaccination schedules, such as number of doses and varying dosing intervals. WHO convened an expert panel to develop interim best practice guidance for COVID-19 vaccine effectiveness evaluations. We present a summary of the interim guidance, including discussion of different study designs, priority outcomes to evaluate, potential biases, existing surveillance platforms that can be used, and recommendations for reporting results.

INTRODUCTION: Despite considerable global burden of influenza, few low- and middle-income countries (LMICs) have national influenza vaccination programs. This report provides a systematic assessment of barriers to and activities that support initiating or expanding influenza vaccination programs from the perspective of in-country public health officials. METHODS: Public health officials in LMICs were sent a web-based survey to provide information on barriers and activities to initiating, expanding, or maintaining national influenza vaccination programs. The survey primarily included Likert-scale questions asking respondents to rank barriers and activities in five categories. RESULTS: Of 109 eligible countries, 62% participated. Barriers to influenza vaccination programs included lack of data on cost-effectiveness of influenza vaccination programs (87%) and on influenza disease burden (84%), competing health priorities (80%), lack of public perceived risk from influenza (79%), need for better risk communication tools (77%), lack of financial support for influenza vaccine programs (75%), a requirement to use only WHO-prequalified vaccines (62%), and young children require two vaccine doses (60%). Activities for advancing influenza vaccination programs included educating healthcare workers (97%) and decision-makers (91%) on the benefits of influenza vaccination, better estimates of influenza disease burden (91%) and cost of influenza vaccination programs (89%), simplifying vaccine introduction by focusing on selected high-risk groups (82%), developing tools to prioritize target populations (80%), improving availability of influenza diagnostic testing (79%), and developing collaborations with neighboring countries for vaccine procurement (74%) and regulatory approval (73%). Responses varied by country region and income status. CONCLUSIONS: Local governments and key international stakeholders can use the results of this survey to improve influenza vaccination programs in LMICs, which is a critical component of global pandemic preparedness for influenza and other pathogens such as coronaviruses. Additionally, strategies to improve global influenza vaccination coverage should be tailored to country income level and geographic location.

BACKGROUND: Influenza illness burden is substantial, particularly among young children, older adults, and those with underlying conditions. Initiatives are underway to develop better global estimates for influenza-associated hospitalizations and deaths. Knowledge gaps remain regarding the role of influenza viruses in severe respiratory disease and hospitalizations among adults, particularly in lower-income settings. METHODS AND FINDINGS: We aggregated published data from a systematic review and unpublished data from surveillance platforms to generate global meta-analytic estimates for the proportion of acute respiratory hospitalizations associated with influenza viruses among adults. We searched 9 online databases (Medline, Embase, CINAHL, Cochrane Library, Scopus, Global Health, LILACS, WHOLIS, and CNKI; 1 January 1996-31 December 2016) to identify observational studies of influenza-associated hospitalizations in adults, and assessed eligible papers for bias using a simplified Newcastle-Ottawa scale for observational data. We applied meta-analytic proportions to global estimates of lower respiratory infections (LRIs) and hospitalizations from the Global Burden of Disease study in adults ≥20 years and by age groups (20-64 years and ≥65 years) to obtain the number of influenza-associated LRI episodes and hospitalizations for 2016. Data from 63 sources showed that influenza was associated with 14.1% (95% CI 12.1%-16.5%) of acute respiratory hospitalizations among all adults, with no significant differences by age group. The 63 data sources represent published observational studies (n = 28) and unpublished surveillance data (n = 35), from all World Health Organization regions (Africa, n = 8; Americas, n = 11; Eastern Mediterranean, n = 7; Europe, n = 8; Southeast Asia, n = 11; Western Pacific, n = 18). Data quality for published data sources was predominantly moderate or high (75%, n = 56/75). We estimate 32,126,000 (95% CI 20,484,000-46,129,000) influenza-associated LRI episodes and 5,678,000 (95% CI 3,205,000-9,432,000) LRI hospitalizations occur each year among adults. While adults <65 years contribute most influenza-associated LRI hospitalizations and episodes (3,464,000 [95% CI 1,885,000-5,978,000] LRI hospitalizations and 31,087,000 [95% CI 19,987,000-44,444,000] LRI episodes), hospitalization rates were highest in those ≥65 years (437/100,000 person-years [95% CI 265-612/100,000 person-years]). For this analysis, published articles were limited in their inclusion of stratified testing data by year and age group. Lack of information regarding influenza vaccination of the study population was also a limitation across both types of data sources. CONCLUSIONS: In this meta-analysis, we estimated that influenza viruses are associated with over 5 million hospitalizations worldwide per year. Inclusion of both published and unpublished findings allowed for increased power to generate stratified estimates, and improved representation from lower-income countries. Together, the available data demonstrate the importance of influenza viruses as a cause of severe disease and hospitalizations in younger and older adults worldwide.

Prior to updating global influenza-associated mortality estimates, the World Health Organization convened a consultation in July 2017 to understand differences in methodology and implications on results of three influenza mortality projects from the United States Centers for Disease Control and Prevention (CDC), the Netherlands Institute for Health Service Research (GLaMOR), and the Institute for Health Metrics and Evaluation (IHME). The expert panel reviewed estimates and discussed differences in data sources, analysis, and modeling assumptions. We performed a comparison analysis of the estimates. Influenza-associated respiratory death counts were comparable between CDC and GLaMOR; IHME estimate was considerably lower. The greatest country-specific influenza-associated mortality rate fold differences between CDC/IHME and between GLaMOR/IHME estimates were among countries in South-East Asia and Eastern Mediterranean region. The data envelope used for the calculation was one of the major differences (CDC and GLaMOR: all respiratory deaths; IHME: low respiratory infection deaths). With the assumption that there is only one cause of death for each death, IHME estimates a fraction of the full influenza-associated respiratory mortality that is measured by the other two groups. Wide variability of parameters was observed. Continued coordination between groups could assist with better understanding of methodological differences and new approaches to estimating influenza deaths globally.

BACKGROUND: National seasonal influenza programs have been recommended as a foundation for pandemic preparedness. During the 2009 pandemic, WHO aimed to increase Member States' equitable access to influenza vaccines through pandemic vaccine donation. METHODS: This analysis explores whether the presence of a seasonal influenza program contributed to more rapid national submission of requirements to receive vaccine during the 2009 influenza pandemic. Data from 2009 influenza vaccine donation, deployment, and surveillance initiatives were collected during May-September 2018 from WHO archival material. Data about the presence of seasonal influenza vaccine programs prior to 2009 were gathered from the WHO-UNICEF Joint Reporting Form. Cox proportional hazards models were used to assess the relationship between presence of a seasonal influenza program and time to submission of a national deployment and vaccination plan and to vaccine delivery. FINDING: Of 97 countries eligible to receive WHO-donated vaccine, 83 (86%) submitted national deployment and vaccination plans and 77 (79%) received vaccine. Countries with a seasonal influenza vaccine program were more likely to submit a national deployment and vaccination plan (hazards ratio [HR] 2.1; 95% confidence interval [CI]. Countries with regulatory delays were less likely to receive vaccine than those without these delays (HR 0.4, 95% CI: 0.2-0.6). INTERPRETATION: During the 2009 pandemic, eligible countries with a seasonal influenza vaccine program weremore ready to receive and use donated vaccines than those without a program. Our findings suggest that robust seasonal influenza vaccine programs increase national familiarity with the management of influenza vaccines and therefore enhance pandemic preparedness. FUNDING: N/A.

BACKGROUND: We evaluated a Russian-backbone, live, attenuated influenza vaccine (LAIV) for immunogenicity and viral shedding in a randomized, placebo-controlled trial among Bangladeshi children. METHODS: Healthy children received a single, intranasal dose of LAIV containing the 2011-2012 recommended formulation or placebo. Nasopharyngeal wash (NPW) specimens were collected on days 0, 2, 4, and 7. Reverse transcription polymerase chain reactions and sequencing identified the influenza virus (vaccine or wild-type). On days 0 and 21, blood specimens were collected to assess immunogenicity using hemagglutination inhibition, microneutralization, and immunoglobulin A (IgA) and G enzyme-linked immunosorbent assays (ELISAs); NPW specimens were also collected to assess mucosal immunogenicity using kinetic IgA ELISA. RESULTS: We enrolled 300 children aged 24 through 59 months in the immunogenicity and viral shedding analyses. Among children receiving LAIV, 45% and 67% shed A/H3N2 and B vaccine strains, respectively. No child shed A/H1N1 vaccine strain. There were significantly higher day 21 geometric mean titers (GMTs) for the LAIV, as compared to the placebo groups, in all immunoassays for A/H3N2 and B (log10 titer P < .0001; GMT Ratio >2.0). Among immunoassays for A/H1N1, only the mucosal IgA GMT was significantly higher than placebo at day 21 (log10 titer P = .0465). CONCLUSIONS: Children vaccinated with LAIV had serum and mucosal antibody responses to A/H3N2 and B, but only a mucosal IgA response to A/H1N1. Many children shed A/H3N2 and B vaccine strains, but none shed A/H1N1. More research is needed to determine the reason for decreased LAIV A/H1N1 immunogenicity and virus shedding. CLINICAL TRIALS REGISTRATION: NCT01625689.

BACKGROUND: The estimated association of maternal influenza vaccination and birth outcomes may be sensitive to methods used to define preterm birth or small-for-gestational age (SGA). METHODS: In a cohort of pregnant women in Lao People's Democratic Republic, we estimated gestational age from: (a) date of last menstrual period (LMP), (b) any prenatal ultrasound, (c) first trimester ultrasound, (d) Ballard Score at delivery, and (e) an algorithm combining LMP and ultrasound. Infants were classified as SGA at birth using a Canadian, global, and equation-based growth reference. We estimated the association of maternal influenza vaccination and birth outcomes, by influenza activity, using multivariable log-binomial regression and Cox proportional hazards regression with vaccination as a time-varying exposure. RESULTS: The frequency of preterm birth in the cohort varied by method to estimate gestational age, from 5% using Ballard Score to 15% using any ultrasound. Using LMP, any ultrasound, or the algorithm, we found statistically significant reductions in preterm birth among vaccinated women during periods of high influenza activity and statistically significant increases in SGA, using a Canadian growth reference. We did not find statistically significant associations with SGA when using global or equation-based growth references. CONCLUSIONS: The association of maternal influenza vaccination and birth outcomes was most affected by the choice of a growth reference used to define SGA at birth. The association with pre-term birth was present and consistent across multiple statistical approaches. Future studies of birth outcomes, specifically SGA, should carefully consider the potential for bias introduced by measurement choice.

Influenza vaccination remains the most effective tool for reducing seasonal influenza disease burden. Few Low and Middle-Income Countries (LMICs) have robust, sustainable annual influenza national vaccination programs. The Partnership for Influenza Vaccine Introduction (PIVI) was developed as a public-private partnership to support LMICs to develop and sustain national vaccination programs through time-limited vaccine donations and technical support. We review the first 5years of experience with PIVI, including the concept, country progress toward sustainability, and lesson learned. Between 2013 and 2018, PIVI worked with Ministries of Health in 17 countries. Eight countries have received donated vaccines and technical support; of these, two have transitioned to sustained national support of influenza vaccination and six are increasing national support of the vaccine programs towards full transition to local vaccine program support by 2023. Nine additional countries have received technical support for building the evidence base for national policy development and/or program evaluation. PIVI has resulted in increased use of vaccines in partner countries, and early countries have demonstrated progress towards sustainability, suggesting that a model of vaccine and technical support can work in LMICs. PIVI expects to add new country partners as current countries transition to self-reliance.

National Immunization Technical Advisory Groups (NITAGs) are multidisciplinary national experts who provide independent, evidence-informed vaccine policy recommendations to national health authorities. An essential NITAG function is to ensure that these decisions are grounded in the best available evidence generated through a systematic, transparent process. However, in many low- and middle-income countries (LMICs), experience with this decision making method is limited. The Task Force for Global Health manages the Partnership for Influenza Vaccine Introduction (PIVI) program in collaboration with the Centers for Disease Control and Prevention, Ministries of Health, corporate partners and others. During 2017, PIVI worked with its country partners and the World Health Organization regional and local offices to assess NITAG strengthening needs and to provide technical assistance in 7 LMIC countries (Laos Peoples Democratic Republic, Mongolia, Vietnam, Armenia, Cote d'Ivoire; Moldova and the Republic of Georgia). Our workshops supported general NITAG capacity building and the evidence-based review process using vaccines of interest to the country. For NITAGs reviewing evidence on seasonal influenza, we developed an influenza resource package to support their review and provide country-relevant information in an easy to use format. Of the seven NITAGs trained, six have applied some of the concepts learnt: revision or development of formal transparent, systematic procedures for their operations; preparation of recommendations on seasonal influenza vaccination using quality-assessed data from systematic searches and local data; and have applied the principles learned for making other new vaccine recommendations. Our experience confirms that LMIC NITAGs are considerably under-resourced without adequate technical support or access to global peer-reviewed literature. Ongoing support from NITAG partners must be secured and creative approaches might be needed to help countries achieve the GVAP 2020 target and support development of sustainable vaccine policies and programs.

BACKGROUND: Rapid reporting of human infections with novel influenza A viruses accelerates detection of viruses with pandemic potential and implementation of an effective public health response. After detection of human infections with influenza A (H3N2) variant (H3N2v) viruses associated with agricultural fairs during August 2016, the Michigan Department of Health and Human Services worked with the US Centers for Disease Control and Prevention (CDC) to identify infections with variant influenza viruses using a text-based illness monitoring system. OBJECTIVE: To enhance detection of influenza infections using text-based monitoring and evaluate the feasibility and acceptability of the system for use in future outbreaks of novel influenza viruses. METHODS: During an outbreak of H3N2v virus infections among agricultural fair attendees, we deployed a text-illness monitoring (TIM) system to conduct active illness surveillance among households of youth who exhibited swine at fairs. We selected all fairs with suspected H3N2v virus infections. For fairs without suspected infections, we selected only those fairs that met predefined criteria. Eligible respondents were identified and recruited through email outreach and/or on-site meetings at fairs. During the fairs and for 10 days after selected fairs, enrolled households received daily, automated text-messages inquiring about illness; reports of illness were investigated by local health departments. To understand the feasibility and acceptability of the system, we monitored enrollment and trends in participation and distributed a Web-based survey to households of exhibitors from five fairs. RESULTS: Among an estimated 500 households with a member who exhibited swine at one of nine selected fairs, representatives of 87 (17.4%) households were enrolled, representing 392 household members. Among fairs that were ongoing when the TIM system was deployed, the number of respondents peaked at 54 on the third day of the fair and then steadily declined throughout the rest of the monitoring period; 19 out of 87 household representatives (22%) responded through the end of the 10-day monitoring period. We detected 2 H3N2v virus infections using the TIM system, which represents 17% (2/12) of all H3N2v virus infections detected during this outbreak in Michigan. Of the 70 survey respondents, 16 (23%) had participated in the TIM system. A total of 73% (11/15) participated because it was recommended by fair coordinators and 80% (12/15) said they would participate again. CONCLUSIONS: Using a text-message system, we monitored for illness among a large number of individuals and households and detected H3N2v virus infections through active surveillance. Text-based illness monitoring systems are useful for detecting novel influenza virus infections when active monitoring is necessary. Participant retention and testing of persons reporting illness are critical elements for system improvement.

Despite global recommendations for influenza vaccination of high-risk, target populations, few low and middle-income countries have national influenza vaccination programs. Between 2012 and 2017, Lao PDR planned and conducted a series of activities to develop its national influenza vaccine program as a part of its overall national immunization program. In this paper, we review the underlying strategic planning for this process, and outline the sequence of activities, research studies, partnerships, and policy decisions that were required to build Laos' influenza vaccine program. The successful development and sustainability of the program in Laos offers lessons for other low and middle-income countries interested in initiating or expanding influenza immunization.

A century after the great influenza pandemic of 1918, influenza remains a major public health threat. Annual epidemics are associated with significant mortality and morbidity globally, leading to an estimated 290,000–650,000 deaths each year [1]. In addition, the ongoing threat of the next pandemic requires significant resources and attention to ensure that communities and governments are prepared to mitigate the health and societal impact that would likely be much larger than the seasonal toll from influenza [2]. Vaccines against influenza have long been used to reduce seasonal disease risk and to reduce illness and spread of pandemic influenza [3], [4], [5], [6]. However, the variable and moderate effectiveness, the limited ability to prevent influenza caused by antigenically dissimilar challenge viruses, and the complex and lengthy process for semiannual vaccine production, highlight the limitations of current vaccines to optimally address both seasonal and pandemic threats [7], [8], [9], [10]. As a result, growing interest in developing improved influenza vaccines has been voiced by public health authorities and other global stakeholders.

The Sierra Leone Trial to Introduce a Vaccine against Ebola (STRIVE), a phase 2/3 trial of investigational rVSVG-ZEBOV-GP vaccine, was conducted during an unprecedented Ebola epidemic. More than 8600 eligible healthcare and frontline response workers were individually randomized to immediate (within 7 days) or deferred (within 18-24 weeks) vaccination and followed for 6 months after vaccination for serious adverse events and Ebola virus infection. Key challenges included limited infrastructure to support trial activities, unreliable electricity, and staff with limited clinical trial experience. Study staff made substantial infrastructure investments, including renovation of enrollment sites, laboratories, and government cold chain facilities, and imported equipment to store and transport vaccine at </=-60oC. STRIVE built capacity by providing didactic and practical research training to >350 staff, which was reinforced with daily review and feedback meetings. The operational challenges of safety follow-up were addressed by issuing mobile telephones to participants, making home visits, and establishing a nurse triage hotline. Before the Ebola outbreak, Sierra Leone had limited infrastructure and staff to conduct clinical trials. Without interfering with the outbreak response, STRIVE responded to an urgent need and helped build this capacity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].

BACKGROUND: Estimates of influenza-associated mortality are important for national and international decision making on public health priorities. Previous estimates of 250 000-500 000 annual influenza deaths are outdated. We updated the estimated number of global annual influenza-associated respiratory deaths using country-specific influenza-associated excess respiratory mortality estimates from 1999-2015. METHODS: We estimated country-specific influenza-associated respiratory excess mortality rates (EMR) for 33 countries using time series log-linear regression models with vital death records and influenza surveillance data. To extrapolate estimates to countries without data, we divided countries into three analytic divisions for three age groups (<65 years, 65-74 years, and >/=75 years) using WHO Global Health Estimate (GHE) respiratory infection mortality rates. We calculated mortality rate ratios (MRR) to account for differences in risk of influenza death across countries by comparing GHE respiratory infection mortality rates from countries without EMR estimates with those with estimates. To calculate death estimates for individual countries within each age-specific analytic division, we multiplied randomly selected mean annual EMRs by the country's MRR and population. Global 95% credible interval (CrI) estimates were obtained from the posterior distribution of the sum of country-specific estimates to represent the range of possible influenza-associated deaths in a season or year. We calculated influenza-associated deaths for children younger than 5 years for 92 countries with high rates of mortality due to respiratory infection using the same methods. FINDINGS: EMR-contributing countries represented 57% of the global population. The estimated mean annual influenza-associated respiratory EMR ranged from 0.1 to 6.4 per 100 000 individuals for people younger than 65 years, 2.9 to 44.0 per 100 000 individuals for people aged between 65 and 74 years, and 17.9 to 223.5 per 100 000 for people older than 75 years. We estimated that 291 243-645 832 seasonal influenza-associated respiratory deaths (4.0-8.8 per 100 000 individuals) occur annually. The highest mortality rates were estimated in sub-Saharan Africa (2.8-16.5 per 100 000 individuals), southeast Asia (3.5-9.2 per 100 000 individuals), and among people aged 75 years or older (51.3-99.4 per 100 000 individuals). For 92 countries, we estimated that among children younger than 5 years, 9243-105 690 influenza-associated respiratory deaths occur annually. INTERPRETATION: These global influenza-associated respiratory mortality estimates are higher than previously reported, suggesting that previous estimates might have underestimated disease burden. The contribution of non-respiratory causes of death to global influenza-associated mortality should be investigated. FUNDING: None.