Last data update: May 06, 2024. (Total: 46732 publications since 2009)
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Query Trace: Ortiz JR[original query] |
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Value profile for respiratory syncytial virus vaccines and monoclonal antibodies
Fleming JA , Baral R , Higgins D , Khan S , Kochar S , Li Y , Ortiz JR , Cherian T , Feikin D , Jit M , Karron RA , Limaye RJ , Marshall C , Munywoki PK , Nair H , Newhouse LC , Nyawanda BO , Pecenka C , Regan K , Srikantiah P , Wittenauer R , Zar HJ , Sparrow E . Vaccine 2023 41 Suppl 2 S7-S40 Respiratory syncytial virus (RSV) is the predominant cause of acute lower respiratory infection (ALRI) in young children worldwide, yet no licensed RSV vaccine exists to help prevent the millions of illnesses and hospitalizations and tens of thousands of young lives taken each year. Monoclonal antibody (mAb) prophylaxis exists for prevention of RSV in a small subset of very high-risk infants and young children, but the only currently licensed product is impractical, requiring multiple doses and expensive for the low-income settings where the RSV disease burden is greatest. A robust candidate pipeline exists to one day prevent RSV disease in infant and pediatric populations, and it focuses on two promising passive immunization approaches appropriate for low-income contexts: maternal RSV vaccines and long-acting infant mAbs. Licensure of one or more candidates is feasible over the next one to three years and, depending on final product characteristics, current economic models suggest both approaches are likely to be cost-effective. Strong coordination between maternal and child health programs and the Expanded Program on Immunization will be needed for effective, efficient, and equitable delivery of either intervention. This 'Vaccine Value Profile' (VVP) for RSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations, and in collaboration with stakeholders from the WHO headquarters. All contributors have extensive expertise on various elements of the RSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information. |
Evaluation of post-introduction COVID-19 vaccine effectiveness: Summary of interim guidance of the World Health Organization.
Patel MK , Bergeri I , Bresee JS , Cowling BJ , Crowcroft NS , Fahmy K , Hirve S , Kang G , Katz MA , Lanata CF , L'Azou Jackson M , Joshi S , Lipsitch M , Mwenda JM , Nogareda F , Orenstein WA , Ortiz JR , Pebody R , Schrag SJ , Smith PG , Srikantiah P , Subissi L , Valenciano M , Vaughn DW , Verani JR , Wilder-Smith A , Feikin DR . Vaccine 2021 39 (30) 4013-4024 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. |
Estimates of inactivated influenza vaccine effectiveness among children in Senegal: results from two consecutive cluster-randomized controlled trials in 2010 and 2011
Niang MN , Sugimoto JD , Diallo A , Diarra B , Ortiz JR , Lewis KDC , Lafond KE , Halloran ME , Widdowson MA , Neuzil KM , Victor JC . Clin Infect Dis 2020 72 (12) e959-e969 BACKGROUND: We report results of Years 2 and 3 of consecutive cluster-randomized controlled trials of trivalent inactivated influenza vaccine (IIV3) in Senegal. METHODS: We cluster-randomized (1:1) 20 villages to annual vaccination with IIV3 or inactivated poliovirus vaccine (IPV) of age-eligible residents (6 months - 10 years). The primary outcome was total vaccine effectiveness against laboratory-confirmed influenza illness (LCI) among age-eligible children (modified-intention-to-treat population [mITT]). Secondary outcomes were indirect (herd protection) and population (overall community) vaccine effectiveness. RESULTS: We vaccinated 74% of 12,408 age-eligible children in Year 2 (June 2010-April 11) and 74% of 11,988 age-eligible children in Year 3 (April 2011-December 2011) with study vaccines. Annual cumulative incidence of LCI was 4.7 (Year 2) and 4.2 (Year 3) per 100 mITT child vaccinees of IPV villages. In Year 2, IIV3 matched circulating influenza strains. The total effectiveness was 52.8% (95% CI: 32.3%-67.0%), and the population effectiveness was 36.0% (95% CI: 10.2%-54.4%) against LCI caused by any influenza strain. The indirect effectiveness against LCI by A/H3N2 was 56.4% (95% CI: 39.0%-68.9%). In Year 3, 74% of influenza detections were vaccine-mismatched to circulating B/Yamagata and 24% were vaccine-matched to circulating A/H3N2. The Year 3 total effectiveness against LCI was -14.5% (95% CI: -81.2%-27.6%). Vaccine effectiveness varied by type/subtype of influenza in both years. CONCLUSION: IIV3 was variably effective against influenza illness in Senegalese children, with total and indirect vaccine effectiveness present during the year when all circulating strains matched the IIV3 formulation. |
Immunogenicity of seasonal inactivated influenza and inactivated polio vaccines among children in Senegal: Results from a cluster-randomized trial
Niang M , Deming ME , Goudiaby D , Diop OM , Dia N , Diallo A , Ortiz JR , Diop D , Lewis KDC , Lafond KE , Widdowson MA , Victor JC , Neuzil KM . Vaccine 2020 38 (47) 7526-7532 Data on influenza vaccine immunogenicity in children are limited from tropical developing countries. We recently reported significant, moderate effectiveness of a trivalent inactivated influenza vaccine (IIV) in a controlled, cluster-randomized trial in children in rural Senegal during 2009, a year of H3N2 vaccine mismatch (NCT00893906). We report immunogenicity of IIV3 and inactivated polio vaccine (IPV) from that trial. We evaluated hemagglutination inhibition (HAI) and polio antibody titers in response to vaccination of three age groups (6 through 35 months, 3 through 5 years, and 6 through 8 years). As all children were IIV naïve, each received two vaccine doses, although titers were assessed after only the first dose for subjects aged 6 through 8 years. Seroconversion rates (4-fold titer rise or increase from <1:10 to ≥1:40) were 74-87% for A/H1N1, 76-87% for A/H3N2, and 54-79% for B/Yamagata. Seroprotection rates (HAI titer ≥ 1:40) were 79-88% for A/H1N1, 88-96% for A/H3N2, and 52-74% for B/Yamagata. IIV responses were lowest in the youngest age group, and they were comparable between ages 3 through 5 years after two doses and 6 through 8 years after one dose. We found that baseline seropositivity (HAI titer ≥ 1:10) was an effect modifier of IIV response. Using a seroprotective titer (HAI titer ≥ 1:160) recommended for IIV evaluation in children, we found that among subjects who were seropositive at baseline, 69% achieved seroprotection for both A/H1N1 and A/H3N2, while among those who were seronegative at baseline, seroprotection was achieved in 11% for A/H1N1 and 22% for A/H3N2. The IPV group had high baseline polio antibody seropositivity and appropriate responses to vaccination. Our data emphasize the importance of a two-dose IIV3 series in vaccine naïve children. IIV and IPV vaccines were immunogenic in Senegalese children. |
Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting
Driscoll AJ , Arshad SH , Bont L , Brunwasser SM , Cherian T , Englund JA , Fell DB , Hammitt LL , Hartert TV , Innis BL , Karron RA , Langley GE , Mulholland EK , Munywoki PK , Nair H , Ortiz JR , Savitz DA , Scheltema NM , Simoes EAF , Smith PG , Were F , Zar HJ , Feikin DR . Vaccine 2020 38 (11) 2435-2448 Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) and hospitalization in infants and children globally. Many observational studies have found an association between RSV LRTI in early life and subsequent respiratory morbidity, including recurrent wheeze of early childhood (RWEC) and asthma. Conversely, two randomized placebo-controlled trials of efficacious anti-RSV monoclonal antibodies (mAbs) in heterogenous infant populations found no difference in physician-diagnosed RWEC or asthma by treatment group. If a causal association exists and RSV vaccines and mAbs can prevent a substantial fraction of RWEC/asthma, the full public health value of these interventions would markedly increase. The primary alternative interpretation of the observational data is that RSV LRTI in early life is a marker of an underlying predisposition for the development of RWEC and asthma. If this is the case, RSV vaccines and mAbs would not necessarily be expected to impact these outcomes. To evaluate whether the available evidence supports a causal association between RSV LRTI and RWEC/asthma and to provide guidance for future studies, the World Health Organization convened a meeting of subject matter experts on February 12-13, 2019 in Geneva, Switzerland. After discussing relevant background information and reviewing the current epidemiologic evidence, the group determined that: (i) the evidence is inconclusive in establishing a causal association between RSV LRTI and RWEC/asthma, (ii) the evidence does not establish that RSV mAbs (and, by extension, future vaccines) will have a substantial effect on these outcomes and (iii) regardless of the association with long-term childhood respiratory morbidity, severe acute RSV disease in young children poses a substantial public health burden and should continue to be the primary consideration for policy-setting bodies deliberating on RSV vaccine and mAb recommendations. Nonetheless, the group recognized the public health importance of resolving this question and suggested good practice guidelines for future studies. |
Immunogenicity and viral shedding of Russian-backbone, seasonal, trivalent, live, attenuated influenza vaccine in a phase II, randomized, placebo-controlled trial among preschool-aged children in urban Bangladesh
Lewis KDC , Ortiz JR , Rahman MZ , Levine MZ , Rudenko L , Wright PF , Katz JM , Dally L , Rahman M , Isakova-Sivak I , Ilyushina NA , Matyushenko V , Fry AM , Lindstrom SE , Bresee JS , Brooks WA , Neuzil KM . Clin Infect Dis 2019 69 (5) 777-785 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. |
Introduction of new vaccines for immunization in pregnancy - Programmatic, regulatory, safety and ethical considerations
Kochhar S , Edwards KM , Ropero Alvarez AM , Moro PL , Ortiz JR . Vaccine 2019 37 (25) 3267-3277 Immunizing pregnant women is a promising strategy to reduce infectious disease-related morbidity and mortality in pregnant women and their infants. Important pre-requisites for the successful introduction of new vaccines for immunization in pregnancy include political commitment and adequate financial resources: trained, committed and sufficient numbers of healthcare workers to deliver the vaccines; close integration of immunization programs with antenatal care and Maternal and Child Health services; adequate access to antenatal care by pregnant women in the country (especially in low and middle-income countries (LMIC)); and a high proportion of births occurring in health facilities (to ensure maternal and neonatal follow-up can be done). The framework needed to advance a vaccine program from product licensure to successful country-level implementation includes establishing and organizing evidence for anticipated vaccine program impact, developing supportive policies, and translating policies into local action. International and national coordination efforts, proactive planning from conception to implementation of the programs (including country-level policy making, planning, and implementation, regulatory guidance, pharmacovigilance) and country-specific and cultural factors must be taken into account during the vaccines introduction. |
Effectiveness of seasonal influenza vaccination of children in Senegal during a year of vaccine mismatch: a cluster-randomized trial
Diallo A , Diop OM , Diop D , Niang MN , Sugimoto JD , Ortiz JR , Faye EHA , Diarra B , Goudiaby D , Lewis KDC , Emery SL , Zangeneh SZ , Lafond KE , Sokhna C , Halloran ME , Widdowson MA , Neuzil KM , Victor JC . Clin Infect Dis 2019 69 (10) 1780-1788 Background: Population effects of influenza vaccination of children have not been extensively studied, especially in tropical developing countries. In rural Senegal, we assessed the total (primary objective) and indirect effectiveness of inactivated influenza vaccine, trivalent (IIV3). Methods: In this double-blind, cluster-randomized trial, villages were randomly allocated (1:1) for high-coverage vaccination of children aged 6 months through 10 years with 2008-09 northern hemisphere IIV3 or inactivated polio vaccine (IPV). Vaccinees were monitored for serious adverse events. All village residents, vaccinated and unvaccinated, were monitored for signs and symptoms of influenza illness using weekly home visits and surveillance in designated clinics. The primary outcome was all laboratory-confirmed symptomatic influenza. Results: Between May 23 and July 11, 2009, 20 villages were randomized, and 66.5% of age-eligible children were enrolled (3918 in IIV3 villages and 3848 in IPV villages). Follow-up continued until May 28, 2010. Four unrelated serious adverse events were identified. Among vaccinees, total effectiveness against illness caused by seasonal influenza virus (presumed all drifted A/H3N2 based on antigenic characterization data) circulating at high rates among children was 43.6% (95% CI, 18.6% to 60.9%). Indirect effectiveness against seasonal A/H3N2 was 15.4% (95% CI, -22.0% to 41.3%). Total effectiveness against illness caused by pandemic influenza virus (A/H1N1pdm09) was -52.1% (95% CI, -177.2% to 16.6%). Conclusions: IIV3 provided statistically significant, moderate protection to children in Senegal against circulating pre-2010 seasonal influenza strains but not against A/H1N1pdm09 not included in the vaccine. No indirect effects were measured. Further study in low resource populations is warranted. |
The effect of pre-existing immunity on virus detection and immune responses in a phase II randomized trial of a Russian-backbone live attenuated influenza vaccine in Bangladeshi children
Brickley EB , Wright PF , Khalenkov A , Neuzil KM , Ortiz JR , Rudenko L , Levine MZ , Katz JM , Brooks WA . Clin Infect Dis 2018 69 (5) 786-794 Background: In a 2012 phase II clinical trial (NCT01625689), 300 Bangladeshi children aged 24 to 59 months with no prior influenza vaccine exposure were randomized to receive a single dose of intra-nasally administered trivalent Russian-backbone live attenuated influenza vaccine (LAIV) or placebo. Protocol-defined analyses, presented in the companion manuscript, demonstrate decreased viral detection and immunogenicity for A/H1N1pdm09 relative to the A/H3N2 and B strains. This post-hoc analysis of the trial data aims to investigate the LAIV strain differences by testing the hypothesis that pre-existing immunity may influence viral recovery and immune responses after LAIV receipt. Methods: We used logistic regressions to evaluate the relations between markers of pre-existing immunity (i.e., hemagglutination inhibition (HAI), microneutralization, and IgA and IgG antibodies) and LAIV viral recovery in the week post-vaccination. We then tested for potential effect modification by baseline HAI titers (i.e., <10 versus >/=10) and week 1 viral recovery on the LAIV-induced serum and mucosal immune responses measured between days 0 and 21 post-vaccination. Results: Higher levels of pre-existing immunity to influenza A/H3N2 and B were strongly associated with strain-specific prevention of viral shedding upon LAIV receipt. While evidence of LAIV immunogenicity was observed for all three strains, the magnitudes of immune responses were most pronounced in children with no evidence of pre-existing HAI and in those with detectable virus. Conclusion: The results provide evidence for a bidirectional association between viral replication and immunity and underscore the importance of accounting for pre-existing immunity when evaluating virologic and immunologic responses to LAIVs. |
Immunogenicity and safety of MF59-adjuvanted and full-dose unadjuvanted trivalent inactivated influenza vaccines among vaccine-naive children in a randomized clinical trial in rural Senegal
Diallo A , Victor JC , Feser J , Ortiz JR , Kanesa-Thasan N , Ndiaye M , Diarra B , Cheikh S , Diene D , Ndiaye T , Ndiaye A , Lafond KE , Widdowson MA , Neuzil KM . Vaccine 2018 36 (43) 6424-6432 INTRODUCTION: Effective, programmatically suitable influenza vaccines are needed for low-resource countries. MATERIALS AND METHODS: This phase II, placebo-controlled, randomized safety and immunogenicity trial (NCT01819155) was conducted in Senegal using the 2012-2013 Northern Hemisphere trivalent influenza vaccine (TIV) formulation. Participants were allocated in a 2:2:1 ratio to receive TIV (full-dose for all age groups), adjuvanted TIV (aTIV), or placebo. Participants were stratified into age groups: 6-11, 12-35, and 36-71months. All participants were vaccine-naive and received two doses of study vaccine 4weeks apart. The two independent primary objectives were to estimate the immunogenicity of TIV and of aTIV as the proportion of children with a hemagglutination inhibition (HI) antibody titer of >/=1:40 to each vaccine strain at 28days post-dose two. Safety was evaluated by solicited local and systemic reactions, unsolicited adverse events, and serious adverse events. RESULTS: 296 children received TIV, aTIV, or placebo, and 235 were included in the final analysis. After two doses, children aged 6-11, 12-35, and 36-71months receiving TIV had HI titers >/=1:40 against A/H1N1 (73.1%, 94.1%, and 97.0%), A/H3N2 (96.2%, 100.0%, and 100.0%), and B (80.8%, 97.1%, and 97.0%), respectively. After two doses, 100% children aged 6-11, 12-35, and 36-71months receiving aTIV had >/=1:40 titers against A/H1N1, A/H3N2, and B. After a single dose, the aTIV response was comparable to or greater than the TIV response for all vaccine strains. TIV and aTIV reactogenicity were similar, except for mild elevation in temperature (37.5-38.4 degrees C) which occurred more frequently in aTIV than TIV after each vaccine dose. TIV and aTIV had similarly increased pain/tenderness at the injection site compared to placebo. CONCLUSIONS: Both aTIV and full-dose TIV were well-tolerated and immunogenic in children aged 6-71months. These vaccines may play a role in programmatically suitable strategies to prevent influenza in low-resource settings. |
Revision of clinical case definitions: influenza-like illness and severe acute respiratory infection
Fitzner J , Qasmieh S , Mounts AW , Alexander B , Besselaar T , Briand S , Brown C , Clark S , Dueger E , Gross D , Hauge S , Hirve S , Jorgensen P , Katz MA , Mafi A , Malik M , McCarron M , Meerhoff T , Mori Y , Mott J , Olivera Mtdc , Ortiz JR , Palekar R , Rebelo-de-Andrade H , Soetens L , Yahaya AA , Zhang W , Vandemaele K . Bull World Health Organ 2018 96 (2) 122-128 The formulation of accurate clinical case definitions is an integral part of an effective process of public health surveillance. Although such definitions should, ideally, be based on a standardized and fixed collection of defining criteria, they often require revision to reflect new knowledge of the condition involved and improvements in diagnostic testing. Optimal case definitions also need to have a balance of sensitivity and specificity that reflects their intended use. After the 2009-2010 H1N1 influenza pandemic, the World Health Organization (WHO) initiated a technical consultation on global influenza surveillance. This prompted improvements in the sensitivity and specificity of the case definition for influenza - i.e. a respiratory disease that lacks uniquely defining symptomology. The revision process not only modified the definition of influenza-like illness, to include a simplified list of the criteria shown to be most predictive of influenza infection, but also clarified the language used for the definition, to enhance interpretability. To capture severe cases of influenza that required hospitalization, a new case definition was also developed for severe acute respiratory infection in all age groups. The new definitions have been found to capture more cases without compromising specificity. Despite the challenge still posed in the clinical separation of influenza from other respiratory infections, the global use of the new WHO case definitions should help determine global trends in the characteristics and transmission of influenza viruses and the associated disease burden. |
Report on WHO meeting on immunization in older adults: Geneva, Switzerland, 22-23 March 2017
Teresa Aguado M , Barratt J , Beard JR , Blomberg BB , Chen WH , Hickling J , Hyde TB , Jit M , Jones R , Poland GA , Friede M , Ortiz JR . Vaccine 2018 36 (7) 921-931 Many industrialized countries have implemented routine immunization policies for older adults, but similar strategies have not been widely implemented in low- and middle-income countries (LMICs). In March 2017, the World Health Organization (WHO) convened a meeting to identify policies and activities to promote access to vaccination of older adults, specifically in LMICs. Participants included academic and industry researchers, funders, civil society organizations, implementers of global health interventions, and stakeholders from developing countries with adult immunization needs. These experts reviewed vaccine performance in older adults, the anticipated impact of adult vaccination programs, and the challenges and opportunities of building or strengthening an adult and older adult immunization platforms. Key conclusions of the meeting were that there is a need for discussion of new opportunities for vaccination of all adults as well as for vaccination of older adults, as reflected in the recent shift by WHO to a life-course approach to immunization; that immunization in adults should be viewed in the context of a much broader model based on an individual's abilities rather than chronological age; and that immunization beyond infancy is a global priority that can be successfully integrated with other interventions to promote healthy ageing. As WHO is looking ahead to a global Decade of Healthy Ageing starting in 2020, it will seek to define a roadmap for interdisciplinary collaborations to integrate immunization with improving access to preventive and other healthcare interventions for adults worldwide. |
Report on eighth WHO meeting on development of influenza vaccines that induce broadly protective and long-lasting immune responses: Chicago, USA, 23-24 August 2016
Ortiz JR , Hickling J , Jones R , Donabedian A , Engelhardt OG , Katz JM , Madhi SA , Neuzil KM , Rimmelzwaan GF , Southern J , Spiro DJ , Hombach J . Vaccine 2017 36 (7) 932-938 In August 2016, the World Health Organization (WHO) convened the "Eighth meeting on development of influenza vaccines that induce broadly protective and long-lasting immune responses" to discuss the regulatory requirements and pathways for licensure of next-generation influenza vaccines, and to identify areas where WHO can promote the development of such vaccines. Participants included approximately 120 representatives of academia, the vaccine industry, research and development funders, and regulatory and public health agencies. They reviewed the draft WHO preferred product characteristics (PPCs) of vaccines that could address prioritized unmet public health needs and discussed the challenges facing the development of such vaccines, especially for low- and middle-income countries (LMIC). They defined the data desired by public-health decision makers globally and explored how to support the progression of promising candidates into late-stage clinical trials and for all countries. This report highlights the major discussions of the meeting. |
Data and product needs for influenza immunization programs in low- and middle-income countries: Rationale and main conclusions of the WHO preferred product characteristics for next-generation influenza vaccines
Neuzil KM , Bresee JS , de la Hoz F , Johansen K , Karron RA , Krishnan A , Madhi SA , Mangtani P , Spiro DJ , Ortiz JR . Vaccine 2017 35 (43) 5734-5737 In 2017, WHO convened a working group of global experts to develop the Preferred Product Characteristics (PPC) for Next-Generation Influenza Vaccines. PPCs are intended to encourage innovation in vaccine development. They describe WHO preferences for parameters of vaccines, in particular their indications, target groups, implementation strategies, and clinical data needed for assessment of safety and efficacy. PPCs are shaped by the global unmet public health need in a priority disease area for which WHO encourages vaccine development. These preferences reflect WHO's mandate to promote the development of vaccines with high public health impact and suitability in Low- and Middle-Income Countries (LMIC). The target audience is all entities intending to develop or to achieve widespread adoption of a specific influenza vaccine product in these settings. The working group determined that existing influenza vaccines are not well suited for LMIC use. While many developed country manufactures and research funders prioritize influenza vaccine products for use in adults and the elderly, most LMICs do not have sufficiently strong health systems to deliver vaccines to these groups. Policy makers from LMICs are expected to place higher value on vaccines indicated for prevention of severe illness, however the clinical development of influenza vaccines focuses on demonstrating prevention of any influenza illness. Many influenza vaccine products do not meet WHO standards for programmatic suitability of vaccines, which introduces challenges when vaccines are used in low-resource settings. And finally, current vaccines do not integrate well with routine immunization programs in LMICs, given age of vaccine licensure, arbitrary expiration dates timed for temperate country markets, and the need for year-round immunization in countries with prolonged influenza seasonality. While all interested parties should refer to the full PPC document for details, in this article we highlight data needs for new influenza vaccines to better demonstrate the value proposition in LMICs. |
Influenza epidemiology and immunization during pregnancy: Final report of a World Health Organization working group
Fell DB , Azziz-Baumgartner E , Baker MG , Batra M , Beaute J , Beutels P , Bhat N , Bhutta ZA , Cohen C , De Mucio B , Gessner BD , Gravett MG , Katz MA , Knight M , Lee VJ , Loeb M , Luteijn JM , Marshall H , Nair H , Pottie K , Salam RA , Savitz DA , Serruya SJ , Skidmore B , Ortiz JR . Vaccine 2017 35 (43) 5738-5750 From 2014 to 2017, the World Health Organization convened a working group to evaluate influenza disease burden and vaccine efficacy to inform estimates of maternal influenza immunization program impact. The group evaluated existing systematic reviews and relevant primary studies, and conducted four new systematic reviews. There was strong evidence that maternal influenza immunization prevented influenza illness in pregnant women and their infants, although data on severe illness prevention were lacking. The limited number of studies reporting influenza incidence in pregnant women and infants under six months had highly variable estimates and underrepresented low- and middle-income countries. The evidence that maternal influenza immunization reduces the risk of adverse birth outcomes was conflicting, and many observational studies were subject to substantial bias. The lack of scientific clarity regarding disease burden or magnitude of vaccine efficacy against severe illness poses challenges for robust estimation of the potential impact of maternal influenza immunization programs. |
Efficacy of a Russian-backbone live attenuated influenza vaccine among children in Senegal: A randomised, double-blind, placebo-controlled trial
Victor JC , Lewis KD , Diallo A , Niang MN , Diarra B , Dia N , Ortiz JR , Widdowson MA , Feser J , Hoagland R , Emery SL , Lafond KE , Neuzil KM . Lancet Glob Health 2016 4 (12) e955-e965 BACKGROUND: Live attenuated influenza vaccines have been shown to significantly reduce influenza in diverse populations of children, but no efficacy studies have been done in resource-poor tropical settings. In Senegal, we assessed the efficacy and safety of a live attenuated influenza vaccine based on Russian-derived master donor viruses and licensed as a single dose. METHODS: In this double-blind, placebo-controlled, parallel group, single-centre trial done near Niakhar, Senegal, generally healthy children aged 2-5 years were randomly allocated (2:1) to receive a single intranasal dose of masked trivalent live attenuated influenza vaccine or placebo. The allocation sequence was computer-generated by PATH with block sizes of three. The manufacturer provided vaccine and placebo in coded vials to preserve blinding. Participants were monitored through the predictable influenza season in Senegal for adverse events and signs and symptoms of influenza using weekly home visits and surveillance in clinics. The primary outcome was symptomatic laboratory-confirmed influenza caused by any strain and occurring from 15 days post-vaccination to the end of the study. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT01854632. FINDINGS: Between May 23, and July 1, 2013, 1761 children were randomly assigned, 1174 to receive live attenuated influenza vaccine and 587 to receive placebo. The per-protocol set included 1173 vaccinees and 584 placebo recipients followed up to Dec 20, 2013. Symptomatic influenza was laboratory-confirmed in 210 (18%) of 1173 recipients of live attenuated influenza vaccine and 105 (18%) of placebo recipients, giving a vaccine efficacy of 0.0% (95% CI -26.4 to 20.9). Adverse events were balanced between the study groups. Two girls who had received live attenuated influenza vaccine died, one due to anasarca 12 days postvaccination and one due to malnutrition 70 days postvaccination. INTERPRETATION: Live attenuated influenza vaccine was well tolerated in young children in Senegal, but did not provide protection against influenza. Further study in such populations, which might experience extended periods of influenza circulation, is warranted. FUNDING: US Centers for Disease Control and Prevention and Bill & Melinda Gates Foundation. |
Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: a randomised, double-blind, placebo-controlled trial
Brooks WA , Zaman K , Lewis KD , Ortiz JR , Goswami D , Feser J , Sharmeen AT , Nahar K , Rahman M , Rahman MZ , Barin B , Yunus M , Fry AM , Bresee J , Azim T , Neuzil KM . Lancet Glob Health 2016 4 (12) e946-e954 BACKGROUND: The rates of influenza illness and associated complications are high among children in Bangladesh. We assessed the clinical efficacy and safety of a Russian-backbone live attenuated influenza vaccine (LAIV) at two field sites in Bangladesh. METHODS: Between Feb 27 and April 9, 2013, children aged 2-4 years in urban Kamalapur and rural Matlab, Bangladesh, were randomly assigned in a 2:1 ratio, according to a computer-generated schedule, to receive one intranasal dose of LAIV or placebo. After vaccination, we monitored children in weekly home visits until Dec 31, 2013, with study clinic surveillance for influenza illness. The primary outcome was symptomatic, laboratory-confirmed influenza illness due to vaccine-matched strains. Analysis was per protocol. The trial is registered with ClinicalTrials.gov, number NCT01797029. FINDINGS: Of 1761 children enrolled, 1174 received LAIV and 587 received placebo. Laboratory-confirmed influenza illness due to vaccine-matched strains was seen in 93 (15.8%) children in the placebo group and 79 (6.7%) in the LAIV group. Vaccine efficacy of LAIV for vaccine-matched strains was 57.5% (95% CI 43.6-68.0). The vaccine was well tolerated, and adverse events were balanced between the groups. The most frequent adverse events were tachypnoea (n=86 in the LAIV group and n=54 in the placebo group), cough (n=73 and n=43), and runny nose (n=68 and n=39), most of which were mild. INTERPRETATION: This single-dose Russian-backbone LAIV was safe and efficacious at preventing symptomatic laboratory-confirmed influenza illness due to vaccine-matched strains. LAIV programmes might reduce the burden of influenza illness in Bangladesh. FUNDING: The Bill & Melinda Gates Foundation. |
Influenza pneumonia surveillance among hospitalized adults may underestimate the burden of severe influenza disease
Ortiz JR , Neuzil KM , Cooke CR , Neradilek MB , Goss CH , Shay DK . PLoS One 2014 9 (11) e113903 BACKGROUND: Studies seeking to estimate the burden of influenza among hospitalized adults often use case definitions that require presence of pneumonia. The goal of this study was to assess the extent to which restricting influenza testing to adults hospitalized with pneumonia could underestimate the total burden of hospitalized influenza disease. METHODS: We conducted a modelling study using the complete State Inpatient Databases from Arizona, California, and Washington and regional influenza surveillance data acquired from CDC from January 2003 through March 2009. The exposures of interest were positive laboratory tests for influenza A (H1N1), influenza A (H3N2), and influenza B from two contiguous US Federal Regions encompassing the study area. We identified the two outcomes of interest by ICD-9-CM code: respiratory and circulatory hospitalizations, as well as critical illness hospitalizations (acute respiratory failure, severe sepsis, and in-hospital death). We linked the hospitalization datasets with the virus surveillance datasets by geographic region and month of hospitalization. We used negative binomial regression models to estimate the number of influenza-associated events for the outcomes of interest. We sub-categorized these events to include all outcomes with or without pneumonia diagnosis codes. RESULTS: We estimated that there were 80,834 (95% CI 29,214-174,033) influenza-associated respiratory and circulatory hospitalizations and 26,760 (95% CI 14,541-47,464) influenza-associated critical illness hospitalizations. When a pneumonia diagnosis was excluded, the estimated number of influenza-associated respiratory and circulatory hospitalizations was 24,816 (95% CI 6,342-92,624). The estimated number of influenza-associated critical illness hospitalizations was 8,213 (95% CI 3,764-20,799). Around 30% of both influenza-associated respiratory and circulatory hospitalizations, as well as influenza-associated critical illness hospitalizations did not have pneumonia diagnosis codes. CONCLUSIONS: Surveillance studies which only consider hospitalizations that include a diagnosis of pneumonia may underestimate the total burden of influenza hospitalizations. |
The burden of influenza-associated critical illness hospitalizations
Ortiz JR , Neuzil KM , Shay DK , Rue TC , Neradilek MB , Zhou H , Seymour CW , Hooper LG , Cheng PY , Goss CH , Cooke CR . Crit Care Med 2014 42 (11) 2325-32 OBJECTIVE: Influenza is the most common vaccine-preventable disease in the United States; however, little is known about the burden of critical illness due to influenza virus infection. Our primary objective was to estimate the proportion of all critical illness hospitalizations that are attributable to seasonal influenza. DESIGN: Retrospective cohort study. SETTING: Arizona, California, and Washington from January 2003 to March 2009. PATIENTS: All adults hospitalized with critical illness, defined by International Classification of Diseases, 9th Edition, Clinical Modification diagnosis and procedure codes for acute respiratory failure, severe sepsis, or in-hospital death. MEASUREMENTS AND MAIN RESULTS: We combined the complete hospitalization discharge databases for three U.S. states, regional influenza virus surveillance, and state census data. Using negative binomial regression models, we estimated the incidence rates of adult influenza-associated critical illness hospitalizations and compared them with all-cause event rates. We also compared modeled outcomes to International Classification of Diseases, 9th Edition, Clinical Modification-coded influenza hospitalizations to assess potential underrecognition of severe influenza disease. During the study period, we estimated that 26,760 influenza-associated critical illness hospitalizations (95% CI, 14,541, 47,464) occurred. The population-based incidence estimate for influenza-associated critical illness was 12.0 per 100,000 person-years (95% CI, 6.6, 21.6) or 1.3% of all critical illness hospitalizations (95% CI, 0.7%, 2.3%). During the influenza season, 3.4% of all critical illness hospitalizations (95% CI, 1.9%, 5.8%) were attributable to influenza. There were only 2,612 critical illness hospitalizations with International Classification of Diseases, 9th Edition, Clinical Modification-coded influenza diagnoses, suggesting influenza is either undiagnosed or undercoded in a substantial proportion of critical illness. CONCLUSIONS: Extrapolating our data to the 2010 U.S. population, we estimate that about 28,000 adults are hospitalized for influenza-associated critical illness annually. Influenza in many of these critically ill patients may be undiagnosed. Critical care physicians should have a high index of suspicion for influenza in the ICU, particularly when influenza is known to be circulating in their communities. |
Characterizing wild bird contact and seropositivity to highly pathogenic avian influenza A (H5N1) virus in Alaskan residents
Reed C , Bruden D , Byrd KK , Veguilla V , Bruce M , Hurlburt D , Wang D , Holiday C , Hancock K , Ortiz JR , Klejka J , Katz JM , Uyeki TM . Influenza Other Respir Viruses 2014 8 (5) 516-23 BACKGROUND: Highly pathogenic avian influenza A (HPAI) H5N1 viruses have infected poultry and wild birds on three continents with more than 600 reported human cases (59% mortality) since 2003. Wild aquatic birds are the natural reservoir for avian influenza A viruses, and migratory birds have been documented with HPAI H5N1 virus infection. Since 2005, clade 2.2 HPAI H5N1 viruses have spread from Asia to many countries. OBJECTIVES: We conducted a cross-sectional seroepidemiological survey in Anchorage and western Alaska to identify possible behaviors associated with migratory bird exposure and measure seropositivity to HPAI H5N1. METHODS: We enrolled rural subsistence bird hunters and their families, urban sport hunters, wildlife biologists, and a comparison group without bird contact. We interviewed participants regarding their exposures to wild birds and collected blood to perform serologic testing for antibodies against a clade 2.2 HPAI H5N1 virus strain. RESULTS: Hunters and wildlife biologists reported exposures to wild migratory birds that may confer risk of infection with avian influenza A viruses, although none of the 916 participants had evidence of seropositivity to HPAI H5N1. CONCLUSIONS: We characterized wild bird contact among Alaskans and behaviors that may influence risk of infection with avian influenza A viruses. Such knowledge can inform surveillance and risk communication surrounding HPAI H5N1 and other influenza viruses in a population with exposure to wild birds at a crossroads of intercontinental migratory flyways. |
Development of the Respiratory Index of Severity in Children (RISC) score among young children with respiratory infections in South Africa
Reed C , Madhi SA , Klugman KP , Kuwanda L , Ortiz JR , Finelli L , Fry AM . PLoS One 2012 7 (1) e27793 OBJECTIVE: Pneumonia is a leading cause of death in children worldwide. A simple clinical score predicting the probability of death in a young child with lower respiratory tract infection (LRTI) could aid clinicians in case management and provide a standardized severity measure during epidemiologic studies. METHODS: We analyzed 4,148 LRTI hospitalizations in children <24 months enrolled in a pneumococcal conjugate vaccine trial in South Africa from 1998-2001, to develop the Respiratory Index of Severity in Children (RISC). Using clinical data at admission, a multivariable logistic regression model for mortality was developed and statistically evaluated using bootstrap resampling techniques. Points were assigned to risk factors based on their coefficients in the multivariable model. A child's RISC score is the sum of points for each risk factor present. Separate models were developed for HIV-infected and non-infected children. RESULTS: Significant risk factors for HIV-infected and non-infected children included low oxygen saturation, chest indrawing, wheezing, and refusal to feed. The models also included age and HIV clinical classification (for HIV-infected children) or weight-for-age (for non-infected children). RISC scores ranged up to 7 points for HIV-infected or 6 points for non-infected children and correlated with probability of death (0-47%, HIV-infected; 0-14%, non-infected). Final models showed good discrimination (area under the ROC curve) and calibration (goodness-of-fit). CONCLUSION: The RISC score incorporates a simple set of risk factors that accurately discriminate between young children based on their risk of death from LRTI, and may provide an objective means to quantify severity based on the risk of mortality. |
Pandemic influenza in Africa, lessons learned from 1968: a systematic review of the literature
Ortiz JR , Lafond KE , Wong TA , Uyeki TM . Influenza Other Respir Viruses 2011 6 (1) 11-24 BACKGROUND: To help understand the potential impact of the 2009 H1N1 pandemic in Africa, we reviewed published data from Africa of the two previous influenza pandemics. METHODS: We conducted a systematic search of three biomedical databases for articles in any language on 1957 H2N2 or 1968 H3N2 pandemic influenza virus infection in Africa published from January 1950 through August 2008. RESULTS: We identified 1327 potentially relevant articles, and 298 warranted further review. Fourteen studies on 1968 H3N2 influenza met inclusion criteria, while two studies identified describing 1957 H2N2 were excluded for data limitations. Among these 14 studies, community attack rates for symptomatic infection during all 1968 pandemic waves were around 20%. However, the proportion infected in communities ranged from 6% in isolated communities to 100% in enclosed populations. A total of 22-64% of sampled clinic patients and 8-72% of hospitalized patients had evidence of 1968 H3N2 virus infection. After the second pandemic wave, up to 41-75% of persons tested had serological evidence of 1968 H3N2 virus infection. CONCLUSION: The 1968 H3N2 influenza pandemic, generally regarded as mild worldwide, appears to have had a substantial impact upon public health in Africa. Without more epidemiologic data the impact of the 2009 H1N1 pandemic in Africa cannot be assumed to have been mild. Assessment of the burden of 2009 H1N1 virus and future influenza pandemics in Africa should attempt to assess disease impact by a variety of methods, including substudies among specific populations. |
Strategy to enhance influenza surveillance worldwide
Ortiz JR , Sotomayor V , Uez OC , Oliva O , Bettels D , McCarron M , Bresee JS , Mounts AW . Emerg Infect Dis 2009 15 (8) 1271-8 The emergence of a novel strain of influenza virus A (H1N1) in April 2009 focused attention on influenza surveillance capabilities worldwide. In consultations before the 2009 outbreak of influenza subtype H1N1, the World Health Organization had concluded that the world was unprepared to respond to an influenza pandemic, due in part to inadequate global surveillance and response capacity. We describe a sentinel surveillance system that could enhance the quality of influenza epidemiologic and laboratory data and strengthen a country's capacity for seasonal, novel, and pandemic influenza detection and prevention. Such a system would 1) provide data for a better understanding of the epidemiology and extent of seasonal influenza, 2) provide a platform for the study of other acute febrile respiratory illnesses, 3) provide virus isolates for the development of vaccines, 4) inform local pandemic planning and vaccine policy, 5) monitor influenza epidemics and pandemics, and 6) provide infrastructure for an early warning system for outbreaks of new virus subtypes. |
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