Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-30 (of 30 Records) |
Query Trace: Neuzil KM[original query] |
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Prevalence of Salmonella in stool during the Vaccine Impact on Diarrhea in Africa (VIDA) Study, 2015-2018
Kasumba IN , Powell H , Omore R , Hossain MJ , Sow SO , Ochieng JB , Badji H , Verani JR , Widdowson MA , Sen S , Nasrin S , Permala-Booth J , Jones JA , Roose A , Nasrin D , Sugerman CE , Juma J , Awuor A , Jones JCM , Doh S , Okoi C , Zaman SMA , Antonio M , Hunsperger E , Onyango C , Platts-Mills J , Liu J , Houpt E , Neuzil KM , Kotloff KL , Tennant SM . Clin Infect Dis 2023 76 S87-s96 BACKGROUND: Non-typhoidal Salmonella (NTS) is a common cause of gastroenteritis in young children, with limited data on NTS serovars and antimicrobial resistance in Africa. METHODS: We determined the prevalence of Salmonella spp. and frequency of antimicrobial resistance among serovars identified in stools of 0-59 month-old children with moderate-to-severe diarrhea (MSD) and controls enrolled in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in The Gambia, Mali, and Kenya in 2015-2018, and compared with data from the Global Enteric Multicenter Study (GEMS; 2007-2010) and the GEMS-1A study (2011). Salmonella spp. was detected by quantitative real-time PCR (qPCR) and culture-based methods. Identification of serovars was determined by microbiological methods. RESULTS: By qPCR, the prevalence of Salmonella spp. among MSD cases was 4.0%, 1.6%, and 1.9% and among controls was 4.6%, 2.4%, and 1.6% in The Gambia, Mali, and Kenya, respectively, during VIDA. We observed year-to-year variation in serovar distribution and variation between sites. In Kenya, Salmonella enterica serovar Typhimurium decreased (78.1% to 23.1%; P < .001) among cases and controls from 2007 to 2018, whereas serogroup O:8 increased (8.7% to 38.5%; P = .04). In The Gambia, serogroup O:7 decreased from 2007 to 2018 (36.3% to 0%; P = .001) but S. enterica serovar Enteritidis increased during VIDA (2015 to 2018; 5.9% to 50%; P = .002). Only 4 Salmonella spp. were isolated in Mali during all 3 studies. Multidrug resistance was 33.9% in Kenya and 0.8% in The Gambia across all 3 studies. Ceftriaxone resistance was only observed in Kenya (2.3%); NTS isolates were susceptible to ciprofloxacin at all sites. CONCLUSIONS: Understanding variability in serovar distribution will be important for the future deployment of vaccines against salmonellosis in Africa. |
Histo-Blood Group Antigen Null Phenotypes Associated With a Decreased Risk of Clinical Rotavirus Vaccine Failure Among Children <2 Years of Age Participating in the Vaccine Impact on Diarrhea in Africa (VIDA) Study in Kenya, Mali, and the Gambia
Schwartz LM , Oshinsky J , Reymann M , Esona MD , Bowen MD , Jahangir Hossain M , Zaman SMA , Jones JCM , Antonio M , Badji H , Sarwar G , Sow SO , Sanogo D , Keita AM , Tamboura B , Traoré A , Onwuchekwa U , Omore R , Verani JR , Awuor AO , Ochieng JB , Juma J , Ogwel B , Parashar UD , Tate JE , Kasumba IN , Tennant SM , Neuzil KM , Rowhani-Rahbar A , Elizabeth Halloran M , Atmar RL , Pasetti MF , Kotloff KL . Clin Infect Dis 2023 76 S153-s161 BACKGROUND: Previously studied risk factors for rotavirus vaccine failure have not fully explained reduced rotavirus vaccine effectiveness in low-income settings. We assessed the relationship between histo-blood group antigen (HBGA) phenotypes and clinical rotavirus vaccine failure among children <2 years of age participating in the Vaccine Impact on Diarrhea in Africa Study in 3 sub-Saharan African countries. METHODS: Saliva was collected and tested for HBGA phenotype in children who received rotavirus vaccine. The association between secretor and Lewis phenotypes and rotavirus vaccine failure was examined overall and by infecting rotavirus genotype using conditional logistic regression in 218 rotavirus-positive cases with moderate-to-severe diarrhea and 297 matched healthy controls. RESULTS: Both nonsecretor and Lewis-negative phenotypes (null phenotypes) were associated with decreased rotavirus vaccine failure across all sites (matched odds ratio, 0.30 [95% confidence interval: 0.16-0.56] or 0.39 [0.25-0.62], respectively]. A similar decrease in risk against rotavirus vaccine failure among null HBGA phenotypes was observed for cases with P[8] and P[4] infection and their matched controls. While we found no statistically significant association between null HBGA phenotypes and vaccine failure among P[6] infections, the matched odds ratio point estimate for Lewis-negative individuals was >4. CONCLUSIONS: Our study demonstrated a significant relationship between null HBGA phenotypes and decreased rotavirus vaccine failure in a population with P[8] as the most common infecting genotype. Further studies are needed in populations with a large burden of P[6] rotavirus diarrhea to understand the role of host genetics in reduced rotavirus vaccine effectiveness. |
Management of diarrhea in young children in Sub-Saharan Africa: Adherence to world health organization recommendations during the Global Enteric Multisite Study (2007-2011) and the Vaccine Impact of Diarrhea in Africa (VIDA) Study (2015-2018)
Deichsel EL , Keita AM , Verani JR , Powell H , Jamka LP , Hossain MJ , Jones JCM , Omore R , Awuor AO , Sow SO , Sanogo D , Tapia MD , Neuzil KM , Kotloff KL . Clin Infect Dis 2023 76 S23-s31 BACKGROUND: Reducing diarrhea-related morbidity and mortality is a global priority, particularly in low-resource settings. We assessed adherence to diarrhea case management indicators in the Global Enteric Multisite Study (GEMS) and Vaccine Impact of Diarrhea in Africa (VIDA) study. METHODS: GEMS (2007-2010) and VIDA (2015-2018) were age-stratified case-control studies of moderate-to-severe diarrhea (MSD) in children aged <5 years. In this case-only analysis, we included children enrolled in The Gambia, Kenya, and Mali. A case with no dehydration received adherent care at home if they were offered more than usual fluids and at least the same as usual to eat. Children with diarrhea and some dehydration are to receive oral rehydration salts (ORS) in the facility. The recommendation for severe dehydration is to receive ORS and intravenous fluids in the facility. Adherent care in the facility included a zinc prescription independent of dehydration severity. RESULTS: For home-based management of children with MSD and no signs of dehydration, 16.6% in GEMS and 15.6% in VIDA were adherent to guidelines. Adherence to guidelines in the facility was likewise low during GEMS (some dehydration, 18.5%; severe dehydration, 5.5%). The adherence to facility-based rehydration and zinc guidelines improved during VIDA to 37.9% of those with some dehydration and 8.0% of children with severe dehydration. CONCLUSIONS: At research sites in The Gambia, Kenya, and Mali, suboptimal adherence to diarrhea case management guidelines for children aged <5 years was observed. Opportunities exist for improvement in case management for children with diarrhea in low-resource settings. |
Prevalence, clinical severity, and seasonality of adenovirus 40/41, astrovirus, sapovirus, and rotavirus among young children with moderate-to-severe diarrhea: Results from the Vaccine Impact on Diarrhea in Africa (VIDA) Study
Keita AM , Doh S , Sow SO , Powell H , Omore R , Jahangir Hossain M , Ogwel B , Ochieng JB , Jones JCM , Zaman SMA , Awuor AO , Juma J , Nasrin D , Liu J , Traoré A , Onwuchekwa U , Badji H , Sarwar G , Antonio M , Houpt ER , Tennant SM , Kasumba IN , Jamka LP , Roose A , Platts-Mills JA , Verani JR , Tate JE , Parashar UD , Neuzil KM , Kotloff KL . Clin Infect Dis 2023 76 S123-s131 BACKGROUND: While rotavirus causes severe diarrheal disease in children aged <5 years, data on other viral causes in sub-Saharan Africa are limited. METHODS: In the Vaccine Impact on Diarrhea in Africa study (2015-2018), we analyzed stool from children aged 0-59 months with moderate-to-severe diarrhea (MSD) and without diarrhea (controls) in Kenya, Mali, and The Gambia using quantitative polymerase chain reaction. We derived the attributable fraction (AFe) based on the association between MSD and the pathogen, accounting for other pathogens, site, and age. A pathogen was attributable if the AFe was ≥0.5.The severity of attributable MSD was defined by a modified Vesikari score (mVS). Monthly cases were plotted against temperature and rainfall to assess seasonality. RESULTS: Among 4840 MSD cases, proportions attributed to rotavirus, adenovirus 40/41, astrovirus, and sapovirus were 12.6%, 2.7%, 2.9%, and 1.9%, respectively. Attributable rotavirus, adenovirus 40/41, and astrovirus MSD cases occurred at all sites, with mVS of 11, 10, and 7, respectively. MSD cases attributable to sapovirus occurred in Kenya, with mVS of 9. Astrovirus and adenovirus 40/41 peaked during the rainy season in The Gambia, while rotavirus peaked during the dry season in Mali and The Gambia. CONCLUSIONS: In sub-Saharan Africa, rotavirus was the most common cause of MSD; adenovirus 40/41, astrovirus, and sapovirus contributed to a lesser extent among children aged <5 years. Rotavirus- and adenovirus 40/41-attributable MSD were most severe. Seasonality varied by pathogen and location. Efforts to increase the coverage of rotavirus vaccines and to improve prevention and treatment for childhood diarrhea should continue. |
The efficacy and safety of rotavirus vaccines in countries in Africa and Asia with high child mortality
Henschke N , Bergman H , Hungerford D , Cunliffe NA , Grais RF , Kang G , Parashar UD , Wang SA , Neuzil KM . Vaccine 2022 40 (12) 1707-1711 Rotavirus remains a leading cause of diarrhoeal morbidity and mortality in young children and rotavirus vaccines are critical for reducing global disease burden. This report addresses the performance of rotavirus vaccines in countries with high child mortality. We performed a sensitivity analysis as part of a systematic review on rotavirus vaccines to inform development of World Health Organization vaccine recommendations. The efficacy of four prequalified vaccines against severe rotavirus gastroenteritis was similar across high mortality settings in Asia and Africa. Within the first year following vaccination, vaccine efficacy for the four vaccines ranged from 48% to 57% while in the second year, efficacy ranged from 29% to 54%. The four vaccines showed no increase in intussusception risk in these settings. All four vaccines appear to prevent significant numbers of severe rotavirus gastroenteritis episodes with no measurable increase in intussusception risk in high mortality settings in Africa and Asia. |
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. |
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. |
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. |
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. |
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. |
Non-interference of rotavirus vaccine with measles-rubella vaccine at 9 months and improvements in anti-rotavirus immunity: a randomized trial
Zaman K , Fleming JA , Victor JC , Yunus M , Bari TI , Azim T , Rahman M , Mowla SM , Bellini WJ , McNeal M , Icenogle JP , Lopman B , Parashar U , Cortese MM , Steele AD , Neuzil KM . J Infect Dis 2016 BACKGROUND: The burden of rotavirus morbidity and mortality is high in children under 5 years in developing countries and evaluations indicate waning protection from rotavirus immunization in the second year. An additional dose of rotavirus vaccine may enhance the immune response and lengthen the period of protection against disease, however co-administration should not interfere with immune responses to concurrently given vaccines. METHODS: Enrolling 480 9-month old participants from Matlab, Bangladesh, the primary objective was to establish non-inferiority of concomitant administration of measles-rubella (MR) vaccine and a 3rd dose of human monovalent rotavirus vaccine (HRV) [MR+HRV] compared to MR vaccine given alone [MR]. Secondary objectives included non-inferiority of rubella antibody seroconversion and evaluating rotavirus IgA/IgG seroresponses in MR+HRV participants. RESULTS: Two months post-vaccination, 75.3% and 74.3% of MR+HRV and MR group infants, respectively, had seroprotective levels of measles virus antibodies. 100.0% and 99.6%, respectively, showed anti-rubella IgG seroprotection. In the MR+HRV group, pre-vaccination anti-rotavirus IgA and IgG seropositivities (52.7% and 66.3%, respectively) increased to 69.6% and 88.3% post-vaccination. CONCLUSIONS: Vaccine-induced measles and rubella antibody responses are not negatively affected by concomitant administration of HRV. The HRV dose increases anti-rotavirus serum antibody titres and the proportion of infants with detectable anti-rotavirus antibody. |
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. |
Rotavirus vaccines for children in developing countries: understanding the science, maximizing the impact, and sustaining the effort
Neuzil KM , Parashar UD , Steele AD . Vaccine 2012 30 Suppl 1 A1-2 The past 5 years have been a period of extraordinary achievement in the rotavirus field. Countries throughout the world licensed, recommended, and introduced rotavirus vaccines, and the impact on childhood disease in early-adopter countries in the Americas, Europe, and Australia has been dramatic [1]. Since the introduction of rotavirus vaccines in Mexico in 2007, for example, the number of children younger than 5 years of age who die as a result of diarrheal illness each year is half the number as compared to before vaccine introduction. In absolute terms, this effect translates into over 2500 lives saved through rotavirus vaccination in Mexico alone over a three-year period [2]. In the United States, where death from diarrheal disease is rare, routine rotavirus vaccination prevents an estimated 40,000 to 60,000 hospitalizations each year [3]. | For developing countries in Africa and Asia, where the preponderance of rotavirus-related deaths occur, the lack of an evidence base for the efficacy of oral rotavirus vaccines delayed policy decisions on their use. Fortunately, the past 5 years has yielded progress in these countries as well: the large randomized, controlled efficacy trials of currently licensed rotavirus vaccines were completed; the World Health Organization (WHO) recommended global use of the vaccine; and, in 2011, the first GAVI-eligible country in Africa—Sudan—introduced the vaccine [4], [5], [6], [7]. In September 2011, the GAVI Alliance approved rotavirus vaccine funding for 16 new countries, including 12 in Africa. The goal of this special supplement of Vaccine is to bring together a wealth of information on rotavirus and rotavirus vaccines in low-resource countries in order to accelerate vaccine introduction in the remaining countries and guide future research and vaccine development efforts. |
Immunogenicity of the pentavalent rotavirus vaccine in African infants
Armah GE , Breiman RF , Tapia MD , Dallas MJ , Neuzil KM , Binka FN , Sow SO , Ojwando J , Ciarlet M , Steele AD . Vaccine 2012 30 Suppl 1 A86-93 We recently completed a double-blind, placebo-controlled, multicenter Phase III clinical trial of the pentavalent rotavirus vaccine (PRV) in three African countries, Ghana, Kenya, and Mali, from April 2007 to March 2009. The immunogenicity of PRV in African infants is described. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV or placebo at approximately 6, 10, and 14 weeks of age. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed, and HIV-infected infants were not excluded. Immunogenicity of PRV was assessed by measuring serum anti-rotavirus IgA responses, as well as serum neutralization antibody (SNA) to the human rotavirus serotypes G1, G2, G3, G4 and P1A[8] in approximately 150 infants per country. Sera were collected pre-dose 1 (pD1) and approximately 14 days post-dose 3 (PD3) for immunological analysis. For the sero-response rates (≥3-fold rise from pD1 to PD3), the number of subjects evaluable included those with both pD1 and PD3 data available. PRV was immunogenic in African children and significantly reduced severe RVGE in African children through the first two years of life. The pooled anti-rotavirus IgA sero-response rate was 78.3%, with consistent rates in each of the African sites: 73.8% (Kenya), 78.9% (Ghana), and 82.5% (Mali); but generally lower than that reported in Europe and USA. PD3 GMTs (28.2 dilution-units) were 5-10 times lower than those assessed in subjects in clinical trials in developed countries. SNA responses to human rotavirus serotypes G1-G4 and P1A[8] ranged from 6.3% (G3) to 26.5% (G4). PD3 SNA GMTs to G1 and P1A[8] were 4-fold and 3-fold lower respectively, when compared to the corresponding GMTs in subjects who received PRV in similar studies conducted in developed countries. PRV was immunogenic in African infants, and the anti-rotavirus IgA sero-response rates were similar across all three African sites although lower than those observed in Europe and USA. While immune correlates of protection have not been established for rotavirus, the findings are consistent with lower efficacy rates demonstrated during this trial. Further investigation is needed to understand the reason for the lower immunogenicity observed. |
Secondary efficacy endpoints of the pentavalent rotavirus vaccine against gastroenteritis in sub-Saharan Africa
Tapia MD , Armah G , Breiman RF , Dallas MJ , Lewis KD , Sow SO , Rivers SB , Levine MM , Laserson KF , Feikin DR , Victor JC , Ciarlet M , Neuzil KM , Steele AD . Vaccine 2012 30 Suppl 1 A79-85 The efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq((R)), was evaluated in a double-blind, placebo-controlled, multicenter Phase III clinical trial conducted (April 2007-March 2009) in 3 low-income countries in Africa: Ghana, Kenya, and Mali. In total, 5468 infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age; concomitant administration with routine EPI vaccines, including OPV, was allowed. HIV-infected infants were not excluded. The primary endpoint, vaccine efficacy (VE) against severe-rotavirus gastroenteritis (RVGE), as measured by Vesikari scoring system (VSS, score ≥11), from ≥14 days following Dose 3 through a follow-up period of nearly 2 years in the combined 3 African countries, and secondary endpoints by total follow-up period have been previously reported. In this study, we report post hoc subgroup analyses on secondary endpoints of public health importance. VE against RVGE of any severity was 49.2% (95%CI: 29.9, 63.5) through the first year of life and 30.5% (95%CI: 16.7, 42.2) through the complete follow-up period. VE against severe-gastroenteritis of any etiology was 21.5% (95%CI: <0, 38.4) through the first year of life and 10.6% (95%CI: <0, 24.9) through the complete follow-up period. Through the complete follow-up period, VE against severe-RVGE caused by (i) vaccine-contained G and P types (G1-G4, P1A[8]), (ii) non-vaccine G types (G8, G9, G10), and (iii) non-vaccine P types (P1B[4], P2A[6]) was 34.0% (95%CI:11.2, 51.2), 81.8% (95%CI:16.5, 98.0) and 40.7% (95%CI:8.4, 62.1), respectively. There was a trend towards higher VE with higher disease severity, although in some cases the numbers were small. In African countries with high under-5 mortality rates, PRV significantly reduced RVGE through nearly 2 years of follow-up; more modest reductions were observed against gastroenteritis of any etiology. PRV provides protection against severe-RVGE caused by diverse rotavirus genotypes, including those not contained in the vaccine. |
Efficacy of pentavalent rotavirus vaccine in a high HIV prevalence population in Kenya
Feikin DR , Laserson KF , Ojwando J , Nyambane G , Ssempijja V , Audi A , Nyakundi D , Oyieko J , Dallas MJ , Ciarlet M , Neuzil KM , Breiman RF . Vaccine 2012 30 Suppl 1 A52-60 BACKGROUND: Rotavirus gastroenteritis (RVGE) is a leading cause of death in African children. The efficacy of pentavalent rotavirus vaccine (PRV) against severe RVGE evaluated in Ghana, Kenya, and Mali in a randomized, double-blind, placebo-controlled trial, showed a combined regional efficacy of 39.3% (95% confidence interval [CI]: 19.1,54.7) in nearly 2 years of follow-up. This report concentrates on the Kenya findings. METHODS: Infants received 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age. HIV testing was offered to all participants. Data on illness symptoms and signs were collected upon presentation to healthcare facilities, where stools were collected, and analyzed by rotavirus-specific enzyme-linked immunosorbent assay. The primary endpoint was severe RVGE (Vesikari score≥11), occurring ≥14 days following the third dose. At monthly home visits, symptoms of illnesses during the past 2 weeks were solicited and limited physical exams were performed; dehydration was defined by WHO's Integrated Management of Childhood Illness. FINDINGS: Vaccine efficacy (VE) against severe RVGE through nearly 2 years of follow-up among 1308 Kenyan children was 63.9% (95% CI: -5.9,89.8). Through the first year of life, VE against severe RVGE was 83.4% (95% CI: 25.5,98.2). From home visits, VE against all-cause gastroenteritis with severe dehydration was 34.4% (95% CI: 5.3,54.6) through the first year and 29.7% (95% CI: 2.5,49.3) through the entire follow-up period. The reduction in incidence of gastroenteritis with severe dehydration in the community during the first year of life (19.0 cases/100 person-years) was almost six times greater than the reduction in severe RVGE presenting to the clinic (3.3/100 person-years). Oral rehydration solution use was lower among PRV recipients (VE 23.1%, 95% CI: 8.8,35.1). An estimated 41% of gastroenteritis with severe dehydration in the first year reported at home was rotavirus-related. CONCLUSIONS: PRV significantly reduced severe RVGE in Kenya. The impact of PRV might be greatest in rural Africa in protecting the many children who develop severe gastroenteritis and cannot access health facilities. |
Analyses of health outcomes from the 5 sites participating in the Africa and Asia clinical efficacy trials of the oral pentavalent rotavirus vaccine
Breiman RF , Zaman K , Armah G , Sow SO , Anh DD , Victor JC , Hille D , Ciarlet M , Neuzil KM . Vaccine 2012 30 Suppl 1 A24-9 BACKGROUND: Efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq((R)), against severe rotavirus gastroenteritis (RVGE) was evaluated in two double-blind, placebo-controlled, multicenter Phase III clinical trials conducted in GAVI-eligible countries in Africa (Ghana, Kenya, and Mali) and in Asia (Bangladesh and Vietnam) from March 2007 through March 2009. The findings from each continent have been analyzed and presented separately, according to a single identical protocol. Ad hoc analyses combining data from the five sites were performed to further assess the impact of PRV. METHODS: 6674 infants (4705 infants from Africa and 1969 infants from Asia), randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6-, 10-, and 14-weeks of age according to each country's EPI schedule, were included in the per protocol efficacy analysis. Breastfeeding and concomitant administration of EPI vaccines, including OPV, were allowed. Episodes of gastroenteritis (GE) in infants who presented to study facilities were captured and scored using the 20-point Vesikari scale. Stool samples were analyzed by rotavirus-specific EIA to detect presence of rotavirus antigen and RT-PCR to determine the G/P genotypes. We assessed efficacy to prevent all-cause GE and RVGE at a variety of cut-off points (score≥11, severe; score≥15, very severe). RESULTS: Vaccine efficacy (VE) against RVGE, regardless of serotype, through the entire follow-up period for any severity, severe (score≥11), and very severe (score≥15) was 33.9%, 95% CI (22.7, 43.5), 42.5%, 95% CI (27.4, 54.6), and 51.2%, 95% CI (26.3, 68.2), respectively. Through the first year of life, VE against severe RVGE was 58.9%, 95% CI (40.0, 72.3) and against all-cause severe GE was 23.0%, 95% CI (5.4, 37.3). VE against severe RVGE caused by non-vaccine G serotypes, G8 and G9, through the entire follow-up period was 87.5%, 95% CI (6.8, 99.7) and 48.0%, 95% CI (-5.5, 75.6), respectively. All G8 strains were associated with P2A[6] (a P-type not contained in PRV), while the majority of the G9 strains were associated with P1A[8] (a P-type contained in PRV). CONCLUSIONS: Combining data from the 5 sites strengthens the precision of VE estimates and reveals rising VE with increased RVGE severity. Extrapolating data from VE against severe GE and RVGE suggest that 39% of severe GE episodes during the first year of life were due to rotavirus, highlighting substantial, potentially preventable, public health burden of RVGE. PRV provides protection against non-vaccine serotypes (G8P2A[6]). |
Safety of the pentavalent rotavirus vaccine (PRV), RotaTeq(R), in Kenya, including among HIV-infected and HIV-exposed infants
Laserson KF , Nyakundi D , Feikin DR , Nyambane G , Cook E , Oyieko J , Ojwando J , Rivers SB , Ciarlet M , Neuzil KM , Breiman RF . Vaccine 2012 30 Suppl 1 A61-70 Two multicenter Phase III trials were conducted in five countries from March 2007 to March 2009 to evaluate the safety and efficacy of the pentavalent rotavirus vaccine (PRV), RotaTeq((R)), in Africa and Asia. In this report, we evaluate the safety of this vaccine, including among HIV-infected and HIV-exposed infants, in Kenya. 1308 Infants were randomized 1:1 to receive 3 doses of PRV/placebo at approximately 6, 10, and 14 weeks of age. HIV counseling and testing were offered to all participants. A positive PCR result indicated HIV infection; the presence of HIV antibody in PCR-negative children indicated HIV exposure without HIV infection. All serious adverse events (SAE) within 14 days of any dose, and vaccine-related SAEs, intussusception, and deaths occurring at any time during the study, were reported ("SAE surveillance"). In addition, 297 participants were followed for 42 days after any dose for any adverse event (AE), regardless of severity ("intensive safety surveillance"). The safety evaluation was stratified by HIV status. SAEs were reported in 20/649 vaccine recipients (3.1%) and 21/643 placebo recipients (3.3%) within 14 days following vaccination (p=0.9). The most common SAE in the vaccinated group was pneumonia (1.7%). No individual SAE was significantly more common among vaccine vs. placebo recipients. Seventy-two deaths were reported, 38 (5.9%) and 34 (5.3%) among vaccine and placebo recipients, respectively (p=0.66). No cases of intussusception were reported. During intensive safety surveillance, 137/147 (93.2%) vaccine recipients and 147/150 (98.0%) placebo recipients experienced one or more AEs (risk ratio=0.95; 95% CI: 0.91-1.0; p=0.05). 88.5% of the infants were tested for HIV infection; 21/581 (3.6%) children in the vaccine group and 17/577 (2.9%) in the placebo group were HIV-infected. Among the 37 HIV-infected infants with full safety follow-up, 5/21 (23.8%) vaccine recipients and 2/16 (12.5%) placebo recipients reported an SAE (p=0.67). In total, 12 deaths occurred among identified HIV-infected infants: 8 (38%) receiving vaccine vs. 4 (23.5%) receiving placebo (RR=1.6, 95% CI: 0.59-4.5). Among the 21 HIV-infected infants in the vaccine group, 2 of 8 deaths were gastroenteritis-related; among the 17 HIV-infected infants in the placebo group, 3 of 4 deaths were gastroenteritis-related. There were no significant differences in serious or non-serious AEs, including vaccine-related SAEs, between the 88 HIV-exposed vaccine recipients vs. the 89 HIV-exposed placebo recipients. PRV appears to be a safe intervention against rotavirus gastroenteritis among infants in Kenya. AEs, including serious AEs, were not associated with receipt of vaccine. Further, SAEs were not significantly more common among HIV-infected or HIV-exposed participants; however, the low number of HIV-infected infants did not provide sufficient power to fully assess safety in HIV- infected vaccine recipients. |
Evolution of the pediatric influenza vaccination program in the United States
Neuzil KM , Fiore AE , Schieber RA . Pediatrics 2012 129 Suppl 2 S51-3 For many years, the Advisory Committee on Immunization Practices (ACIP) for the Centers for Disease Control and Prevention (CDC) focused its vaccination policy on persons at higher risk for influenza complications (eg, older adults, children and adults with certain high-risk conditions, pregnant women) and their contacts (eg, household contacts, health care personnel). Unfortunately, although vaccination coverage rates varied, they remained low for most adult and pediatric high-risk groups, other than persons aged ≥65 years.1 In conjunction with the recognition that influenza vaccination recommendations for high-risk target populations were not being optimally implemented, the adverse effects of influenza illness on all children was increasingly recognized. This led to the expansion of vaccination recommendations for children, beginning in 2002, when influenza vaccination was “encouraged” for children aged 6 through 23 months, and in 2004, when a full recommendation was issued for this age group.2,3 That recommendation was based largely on studies documenting that these young children had influenza-related hospitalization rates that were comparable to hospitalization rates in older persons with underlying risk conditions who were targeted to receive influenza vaccine.4,–6 Full recommendation was added for other groups who are at risk, such as adults and children with neuromuscular and other conditions that can compromise respiratory function or the handling of respiratory secretions, as data became available.7 |
Rotavirus in Africa: shifting the focus to disease prevention
Neuzil KM , Armah GE , Parashar UD , Steele AD . J Infect Dis 2010 202 Suppl S1-4 On 5 June 2009, the Strategic Advisory Group of Experts on Immunization of the World Health Organization (WHO) recommended that rotavirus vaccines be included in the immunization programs of all countries of the world [1]. This recommendation came 10 years after a previous rotavirus vaccine was withdrawn from the market in the United States because of concerns over its association with intussusception. During that decade, it is estimated that >2 million children have died from rotavirus disease on the African continent alone [2]. This historic policy decision should serve as a catalyst for efforts to ensure that the next decade heralds reductions in deaths due to diarrheal disease, the second leading cause of death among young children in Africa. | The commitment and hard work of literally hundreds of individuals, organizations, and governments over many years contributed to this notable policy decision on rotavirus vaccines. The initial step forward was establishing the burden of rotavirus illness in Africa. The first surveillance studies in the continent, though geographically limited, established rotavirus as an important cause of severe rotavirus gastroenteritis among young African children [3–6]. As rotavirus surveillance expanded, so did the realization that rotavirus infection was an important and ubiquitous disease throughout the continent. In 2008, the WHO reported that, as in the rest of the world, rotavirus was the most common cause of severe diarrheal disease hospitalizations in young children in Africa [7]. Although this surveillance was limited to 4 countries, the consistency of the results among those countries, and with results from other studies in Africa and throughout the world, was striking. |
Global impact of rotavirus vaccines
Tate JE , Patel MM , Steele AD , Gentsch JR , Payne DC , Cortese MM , Nakagomi O , Cunliffe NA , Jiang B , Neuzil KM , de Oliveira LH , Glass RI , Parashar UD . Expert Rev Vaccines 2010 9 (4) 395-407 The WHO has recently recommended the inclusion of rotavirus vaccine in the national immunization programs of all countries. In countries in the Americas, Europe and Australia that have adopted routine childhood immunization against rotavirus, significant reductions in the burden of severe childhood diarrhea have been observed. Besides protecting vaccinated children, disease rates also appear to be reduced in unvaccinated children, suggesting indirect benefits from vaccination (i.e., herd protection). Early clinical trial data from Africa and Asia are promising, and further efforts are needed to optimize the benefits of vaccination in developing countries where vaccines are likely to have their greatest impact. |
Rotavirus vaccines for infants in developing countries in Africa and Asia: considerations from a World Health Organization-sponsored consultation
Steele AD , Patel M , Parashar UD , Victor JC , Aguado T , Neuzil KM . J Infect Dis 2009 200 Suppl 1 S63-9 The World Health Organization (WHO) and its international partners have prioritized the development of rotavirus vaccines for the past 3 decades. In November 2005, the WHO's Strategic Advisory Group of Experts first reviewed the clinical efficacy data from 2 new live attenuated oral rotavirus vaccines, which demonstrated excellent protective efficacy against severe rotavirus disease in regions where they were evaluated. Despite these successes, the WHO has urged the clinical evaluation of these vaccines in populations of Africa and Asia, where most of the deaths due to rotavirus occur, and has emphasized the need for ongoing postlicensure safety monitoring in countries introducing vaccines. Clinical studies in Africa and Asia will soon provide data on the efficacy of both new vaccines in these populations. A WHO international consultative meeting convened to evaluate how to use these imminent data for the future use of rotavirus vaccines in developing countries. In brief, it was agreed that (1) even vaccines with lesser efficacy in developing countries, compared with industrialized countries, would still lead to substantial public health benefits and would be cost-effective in saving lives in Africa and Asia; (2) criteria, such as the WHO mortality strata and local epidemiology of rotavirus infection, would be appropriate measures for extrapolating the clinical data to other regions and countries; and (3) research toward understanding the programmatic limitations of rotavirus vaccine use may help develop strategies to improve vaccine uptake and overall impact. |
Evaluation of rotavirus vaccines in Asia--are there lessons to be learnt?
Mirzayeva R , Steele AD , Parashar UD , Zaman K , Neuzil KM , Nelson EA . Vaccine 2009 27 Suppl 5 F120-9 Rotavirus mortality is highest in the Asia-Pacific region and rotavirus vaccines could have enormous impact here. Yet, live-attenuated orally administered rotavirus vaccines have been evaluated in a small number of immunogenicity studies in some Asian countries, where the immune responses have been documented to be moderate in low-income countries with high diarrhoeal disease burden and mortality, and high in middle-/high-income countries with little reported rotavirus deaths. This review of these rotavirus clinical trials examines the results observed and attempts to draw lessons to inform decision-making, aid design of additional clinical trials and guide vaccine development by local manufacturers. |
2009 influenza A(H1N1) monovalent vaccines for children
Fiore AE , Neuzil KM . JAMA 2009 303 (1) 73-4 The 2009 influenza A(H1N1) virus was first identified 8 months ago,1 but the virus has already had a substantial effect on human health. Influenza activity in the United States has remained higher than normal since May, and measures of severe illness such as hospitalizations and deaths during the summer and fall have been equal to or higher than rates usually observed in a typical winter influenza season in all age groups except older adults.2 Even though influenza activity has decreased in recent weeks in some states, there remains the possibility of continued activity through the traditional winter influenza season and the prospect of normal winter circulation of seasonal influenza viruses. | The 2009 influenza A(H1N1) pandemic highlights the role of children in influenza epidemiology. Serological studies suggested that children had no measurable immunity against H1N1 prior to the outbreak.3 In addition, children have been a primary source of illness in community outbreaks of pandemic influenza, as indicated by the association between outbreaks in schools or summer camps and influenza activity in the community.4 Children also have developed severe influenza A(H1N1)–related complications more frequently than is usually seen for seasonal influenza and reports of pediatric deaths and hospitalizations continue to increase.2 As of December 5, 2009, 224 laboratory-confirmed deaths among children had been reported to the Centers for Disease Control and Prevention, far surpassing any recent influenza season,2 and the actual number of pediatric deaths due to the influenza A(H1N1) virus pandemic is likely to be considerably higher.5 Children have been among the primary groups targeted for the limited amount of vaccine available in most areas.6 |
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