Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
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Query Trace: Weldon W[original query] |
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Initial public health response and interim clinical guidance for the 2019 novel coronavirus outbreak - United States, December 31, 2019-February 4, 2020.
Patel A , Jernigan DB , 2019-nCOV CDC Response Team , Abdirizak Fatuma , Abedi Glen , Aggarwal Sharad , Albina Denise , Allen Elizabeth , Andersen Lauren , Anderson Jade , Anderson Megan , Anderson Tara , Anderson Kayla , Bardossy Ana Cecilia , Barry Vaughn , Beer Karlyn , Bell Michael , Berger Sherri , Bertulfo Joseph , Biggs Holly , Bornemann Jennifer , Bornstein Josh , Bower Willie , Bresee Joseph , Brown Clive , Budd Alicia , Buigut Jennifer , Burke Stephen , Burke Rachel , Burns Erin , Butler Jay , Cantrell Russell , Cardemil Cristina , Cates Jordan , Cetron Marty , Chatham-Stephens Kevin , Chatham-Stevens Kevin , Chea Nora , Christensen Bryan , Chu Victoria , Clarke Kevin , Cleveland Angela , Cohen Nicole , Cohen Max , Cohn Amanda , Collins Jennifer , Conners Erin , Curns Aaron , Dahl Rebecca , Daley Walter , Dasari Vishal , Davlantes Elizabeth , Dawson Patrick , Delaney Lisa , Donahue Matthew , Dowell Chad , Dyal Jonathan , Edens William , Eidex Rachel , Epstein Lauren , Evans Mary , Fagan Ryan , Farris Kevin , Feldstein Leora , Fox LeAnne , Frank Mark , Freeman Brandi , Fry Alicia , Fuller James , Galang Romeo , Gerber Sue , Gokhale Runa , Goldstein Sue , Gorman Sue , Gregg William , Greim William , Grube Steven , Hall Aron , Haynes Amber , Hill Sherrasa , Hornsby-Myers Jennifer , Hunter Jennifer , Ionta Christopher , Isenhour Cheryl , Jacobs Max , Jacobs Slifka Kara , Jernigan Daniel , Jhung Michael , Jones-Wormley Jamie , Kambhampati Anita , Kamili Shifaq , Kennedy Pamela , Kent Charlotte , Killerby Marie , Kim Lindsay , Kirking Hannah , Koonin Lisa , Koppaka Ram , Kosmos Christine , Kuhar David , Kuhnert-Tallman Wendi , Kujawski Stephanie , Kumar Archana , Landon Alexander , Lee Leslie , Leung Jessica , Lindstrom Stephen , Link-Gelles Ruth , Lively Joana , Lu Xiaoyan , Lynch Brian , Malapati Lakshmi , Mandel Samantha , Manns Brian , Marano Nina , Marlow Mariel , Marston Barbara , McClung Nancy , McClure Liz , McDonald Emily , McGovern Oliva , Messonnier Nancy , Midgley Claire , Moulia Danielle , Murray Janna , Noelte Kate , Noonan-Smith Michelle , Nordlund Kristen , Norton Emily , Oliver Sara , Pallansch Mark , Parashar Umesh , Patel Anita , Patel Manisha , Pettrone Kristen , Pierce Taran , Pietz Harald , Pillai Satish , Radonovich Lewis , Reagan-Steiner Sarah , Reel Amy , Reese Heather , Rha Brian , Ricks Philip , Rolfes Melissa , Roohi Shahrokh , Roper Lauren , Rotz Lisa , Routh Janell , Sakthivel Senthil Kumar Sarmiento Luisa , Schindelar Jessica , Schneider Eileen , Schuchat Anne , Scott Sarah , Shetty Varun , Shockey Caitlin , Shugart Jill , Stenger Mark , Stuckey Matthew , Sunshine Brittany , Sykes Tamara , Trapp Jonathan , Uyeki Timothy , Vahey Grace , Valderrama Amy , Villanueva Julie , Walker Tunicia , Wallace Megan , Wang Lijuan , Watson John , Weber Angie , Weinbaum Cindy , Weldon William , Westnedge Caroline , Whitaker Brett , Whitaker Michael , Williams Alcia , Williams Holly , Willams Ian , Wong Karen , Xie Amy , Yousef Anna . Am J Transplant 2020 20 (3) 889-895 This article summarizes what is currently known about the 2019 novel coronavirus and offers interim guidance. |
Poliovirus immunity among children aged 6-11 and 36-48 months in 14 polio high-risk provinces of Afghanistan: A health-facility-based study
Soofi SB , Martinez M , Farag NH , Hendley WS , Ehrhardt D , Ahmed I , Hussain I , Weldon W , Kassem AM . Vaccines (Basel) 2022 10 (10) Afghanistan is one of two countries where wild poliovirus (WPV) type 1 remains endemic. We conducted a facility-based cross-sectional survey of antipoliovirus antibodies in children in 14 provinces of Afghanistan. The provinces were selected based on programmatic priorities for polio eradication. Children aged 6-11 and 36-48 months attending outpatient clinics were enrolled in the study. We collected venous blood, isolated serum, and conducted neutralization assays to detect poliovirus neutralizing antibodies. A total of 2086 children from the 14 provinces were enrolled. Among the enrolled children, 44.3% were girls; the median age in the 6-11-month group was 9.4 months, and in the 36-48-month group, it was 41.8 months. The most common spoken language was Pashtu (70.8%). Eighty-two percent of children were fully immunized against all the diseases in the vaccination schedule of Afghanistan. In the children aged 6-11 months, seroprevalence to poliovirus type 1 (PV1) was 96.5% and seroprevalence to poliovirus type 3 (PV3) was 93%; in children aged 36-48 months, seroprevalence to PV1 was 99.5% and to PV3 was 98%. Antipoliovirus antibody prevalence for poliovirus type 2 (PV2) was 70.5% in the younger group compared with 90.9% in the older children. Children from Herat and Laghman provinces had almost 100% seroprevalence to PV1, and other provinces also had high prevalence, ranging from 92.0% to 99.0%. A similar finding was seen for antibodies against PV3, ranging from 88% to 100% by province. On the contrary, antibodies to PV2 were low, ranging from 53% for children in the Khost province to around 89% in Kunduz. There was a cluster of 18 seronegative children in the Nuristan province. Overall, the polio eradication program of Afghanistan has been successful in achieving high seroprevalence of poliovirus neutralizing antibodies in the parts of the country included in this study. |
Co-administration of oral cholera vaccine with oral polio vaccine among Bangladeshi young children: A randomized controlled open label trial to assess interference
Islam MT , Date K , Khan AI , Bhuiyan TR , Khan ZH , Ahmed S , Hossain M , Khaton F , Zaman K , McMillan NAJ , Anand A , An Q , Zhang C , Weldon WC , Yu A , Luby S , Qadri F . Clin Infect Dis 2022 76 (2) 263-270 BACKGROUND: Cholera remains a public health threat for low- and middle-income countries, particularly in Asia and Africa. ShancholTM, an inactivated oral cholera vaccine (OCV) is currently in use globally. OCV and oral poliovirus vaccines (OPV) could be administered concomitantly but the immunogenicity and safety of coadministration among children aged 1-3 years is unknown. METHOD: We undertook an open-label, randomized, controlled, inequality trial in Dhaka city, Bangladesh. Healthy children aged 1-3 years were randomly assigned to one of the three groups: bivalent OPV (bOPV)-alone, OCV-alone, or combined bOPV+OCV and received vaccines on the day of enrollment and 28 days later. Blood samples were collected on the day of enrollment, day 28, and day 56. Serum poliovirus neutralizing antibodies and vibriocidal antibodies against V. cholerae O1 were assessed using microneutralization assays. RESULTS: A total of 579 children aged 13 years were recruited, 193 children per group. More than 90% of the children completed visits at day 56. Few adverse events following immunization were recorded and were equivalent among study arms. On day 28, 60% (90% Confidence interval, 53%-67%) and 54% (46%-61%) of participants with co-administration of bOPV+OCV responded to polioviruses type 1 and 3 respectively, compared to 55% (47%-62%) and 46% (38%-53%) in the bOPV-only group. Additionally, >50% of participants showed a 4-fold increase in vibriocidal antibody titre responses on day 28, comparable to the responses observed in OCV-only arm. CONCLUSIONS: Co-administration of bOPV and OCV is safe and effective in children aged 1-3 years and can be cost-beneficial. |
Fecal shedding of two novel live attenuated oral poliovirus type 2 vaccines candidates by healthy bOPV/IPV-vaccinated infants: two randomized clinical trials.
Gast C , Bandyopadhyay AS , Sáez-Llorens X , De Leon T , DeAntonio R , Jimeno J , Aguirre G , McDuffie LM , Coffee E , Mathis DL , Oberste MS , Weldon WC , Konopka-Anstadt JL , Modlin J , Bachtiar NS , Fix A , Konz J , Clemens R , Costa Clemens SA , Rüttimann R . J Infect Dis 2022 226 (5) 852-861 BACKGROUND: Primary intestinal immunity through viral replication of live oral vaccine is key to interrupt poliovirus transmission. We assessed viral fecal shedding from infants administered Sabin monovalent poliovirus type 2 vaccine (mOPV2) or low and high doses of 2 novel OPV2 (nOPV2) vaccine candidates. METHODS: In 2 randomized clinical trials in Panama, a control mOPV2 study (October 2015 to April 2016) and nOPV2 study (September 2018 to October 2019), 18-week-old infants vaccinated with bivalent oral poliovirus vaccine/inactivated poliovirus vaccine received 1 or 2 study vaccinations 28 days apart. Stools were assessed for poliovirus RNA by polymerase chain reaction (PCR) and live virus by culture for 28 days postvaccination. RESULTS: Shedding data were available from 621 initially reverse-transcription PCR-negative infants (91 mOPV2, 265 nOPV2-c1, 265 nOPV2-c2 recipients). Seven days after dose 1, 64.3% of mOPV2 recipients and 31.3%-48.5% of nOPV2 recipients across groups shed infectious type 2 virus. Respective rates 7 days after dose 2 decreased to 33.3% and 12.9%-22.7%, showing induction of intestinal immunity. Shedding of both nOPV2 candidates ceased at similar or faster rates than mOPV2. CONCLUSIONS: Viral shedding of either nOPV candidate was similar or decreased relative to mOPV2, and all vaccines showed indications that the vaccine virus was replicating sufficiently to induce primary intestinal mucosal immunity. |
Intradermal administration of fractional doses of the inactivated poliovirus vaccine in a campaign: a pragmatic, open-label, non-inferiority trial in The Gambia
Bashorun AO , Badjie Hydara M , Adigweme I , Umesi A , Danso B , Johnson N , Sambou NA , Fofana S , Kanu FJ , Jeyaseelan V , Verma H , Weldon WC , Oberste MS , Sutter RW , Jeffries D , Wathuo M , Mach O , Clarke E . Lancet Glob Health 2022 10 (2) e257-e268 BACKGROUND: A rapid increase in circulating vaccine-derived poliovirus type 2 outbreaks, and the need to reserve inactivated poliovirus vaccine (IPV) for routine immunisation, has increased the value of fractional dose IPV (fIPV) as a measure to prevent acute flaccid paralysis. However, the intradermal route of administration has been viewed as prohibitive to outbreak response campaigns. We aimed to establish the immunogenicity and safety of administering intradermal fIPV with a disposable syringe jet injector (DSJI) or an intradermal adaptor (IDA) compared with standard administration with a BCG needle and syringe (N&S). METHODS: This pragmatic, non-inferiority trial was undertaken in a campaign setting in communities in The Gambia. Children aged 4-59 months without contraindication to vaccination were eligible. Children were not individually randomly assigned; instead, the vaccination teams were randomly assigned (1:1:1) to one of three administration methods. Parents and the field team were not masked, but laboratory personnel were masked. Baseline demographic and anthropometric data were collected from the participants. Public health officers experienced at intradermal immunisation, and nurses without experience, had 2 h of training on each of the administration methods before the campaign. Participants were vaccinated using the administration method in use by the vaccination team in their community. Poliovirus serum neutralising antibodies (SNA) were measured in children aged 24-59 months before and 4 weeks after vaccination. Adverse events and data on injection quality were collected from all participants. The primary outcome was the type 2 immune response rate (seroconversion in seronegative [SNA titre <8] children plus a 4-fold titre rise in seropositive children). Adjusted differences in the immune response between the DSJI or IDA group versus the N&S group were calculated with 97·5% CIs. A margin of -10% was used to define the non-inferiority of DSJI or IDA compared to N&S. Immunogenicity analysis was done per protocol. The trial is registered with ClinicalTrials.govNCT02967783 and has been completed. FINDINGS: Between Oct 28 and Dec 29, 2016, 3189 children aged 4-59 months were recruited, of whom 3170 were eligible. Over 3 days, 2720 children were vaccinated (N&S, 917; IDA, 874; and DSJI, 929). Among 992 children aged 25-59 months with a baseline SNA available, 90·1% (95% CI 86·1-92·9; 281/312) of those vaccinated using the DSJI had an immune response to type 2 compared with 93·8% (90·6-95·8; 331/353) of those vaccinated with N&S and 96·6% (94·0-98·0; 316/327) of those vaccinated with IDA. All (53/53) type 2 seronegative children seroconverted. For polio type 2, non-inferiority was shown for both the IDA (adjusted difference 0·7% [97·5% CI -3·3 to 4·7], unadjusted difference 2·9% [-0·9 to 6·8]) and DSJI (adjusted difference -3·3% [-8·3 to 1·5], unadjusted difference -3·7% [-8·7 to 1·1]) compared with N&S. Non-inferiority was shown for type 1 and 3 for the IDA and DSJI. Neither injection quality nor the training and experience of the vaccinators had an effect on immune response. No safety concerns were reported. INTERPRETATION: In a campaign, intradermal fIPV is safe and generates consistent immune responses that are not dependent on vaccinator experience or injection quality when administered using an N&S, DSJI, or IDA. Countries facing vaccine-derived poliovirus type 2 outbreaks should consider fIPV campaigns to boost population immunity and prevent cases of acute flaccid paralysis. FUNDING: World Health Organization and the Medical Research Council. |
Poliovirus immunity among adults in the Democratic Republic of the Congo: a cross-sectional serosurvey
Alfonso VH , Voorman A , Hoff NA , Weldon WC , Gerber S , Gadoth A , Halbrook M , Goldsmith A , Mukadi P , Doshi RH , Ngoie-Mwamba G , Fuller TL , Okitolonda-Wemakoy E , Muyembe-Tamfum JJ , Rimoin AW . BMC Infect Dis 2022 22 (1) 30 BACKGROUND: Vaccination efforts to eradicate polio currently focus on children under 5 years of age, among whom most cases of poliomyelitis still occur. However, in the Democratic Republic of the Congo (DRC), an outbreak of wild poliovirus type 1 occurred in 2010-2011 in which 16% of cases occurred among adults; in a related outbreak in the neighboring Republic of Congo, 75% of cases occurred among the same adult age-group. Given that infected adults may transmit poliovirus, this study was designed to assess adult immunity against polioviruses. METHODS: We assessed poliovirus seroprevalence using dried blood spots from 5,526 adults aged 15-59 years from the 2013-2014 Demographic and Health Survey in the DRC. RESULTS: Among adults in the DRC, 74%, 72%, and 57% were seropositive for neutralizing antibodies for poliovirus types 1, 2, and 3, respectively. For all three serotypes, seroprevalence tended to be higher among older age groups, those living in households with more children, and among women. CONCLUSIONS: Protection against poliovirus is generally low among adults in the DRC, particularly for type 3 poliovirus. The lack of acquired immunity in adults suggests a potentially limited poliovirus circulation over the lifetime of those surveyed (spanning 1954 through 2014) and transmission of vaccine-derived poliovirus in this age group while underscoring the risk of these outbreaks among adults in the DRC. |
Assessment of genetic changes and neurovirulence of shed Sabin and novel type 2 oral polio vaccine viruses.
Wahid R , Mercer L , Macadam A , Carlyle S , Stephens L , Martin J , Chumakov K , Laassri M , Petrovskaya S , Smits SL , Stittelaar KJ , Gast C , Weldon WC , Konopka-Anstadt JL , Oberste MS , Van Damme P , De Coster I , Rüttimann R , Bandyopadhyay A , Konz J . NPJ Vaccines 2021 6 (1) 94 Sabin-strain oral polio vaccines (OPV) can, in rare instances, cause disease in recipients and susceptible contacts or evolve to become circulating vaccine-derived strains with the potential to cause outbreaks. Two novel type 2 OPV (nOPV2) candidates were designed to stabilize the genome against the rapid reversion that is observed following vaccination with Sabin OPV type 2 (mOPV2). Next-generation sequencing and a modified transgenic mouse neurovirulence test were applied to shed nOPV2 viruses from phase 1 and 2 studies and shed mOPV2 from a phase 4 study. The shed mOPV2 rapidly reverted in the primary attenuation site (domain V) and increased in virulence. In contrast, the shed nOPV2 viruses showed no evidence of reversion in domain V and limited or no increase in neurovirulence in mice. Based on these results and prior published data on safety, immunogenicity, and shedding, the nOPV2 viruses are promising alternatives to mOPV2 for outbreak responses. |
Neutralizing Ljungan virus antibodies in children with newly diagnosed type 1 diabetes
Lundstig A , McDonald SL , Maziarz M , Weldon WC , Vaziri-Sani F , Lernmark Å , Nilsson AL . J Gen Virol 2021 102 (5) Ljungan virus (LV), a Parechovirus of the Picornavirus family, first isolated from a bank vole at the Ljungan river in Sweden, has been implicated in the risk for autoimmune type 1 diabetes. An assay for neutralizing Ljungan virus antibodies (NLVA) was developed using the original 87-012 LV isolate. The goal was to determine NLVA titres in incident 0-18 years old newly diagnosed type 1 diabetes patients (n=67) and school children controls (n=292) from Jämtland county in Sweden. NLVA were found in 41 of 67 (61 %) patients compared to 127 of 292 (44 %) controls (P=0.009). In the type 1 diabetes patients, NLVA titres were associated with autoantibodies to glutamic acid decarboxylase (GADA) (P=0.023), but not to autoantibodies against insulin (IAA) or islet antigen-2 (IA-2A). The NLVA assay should prove useful for further investigations to determine levels of LV antibodies in patients and future studies to determine a possible role of LV in autoimmune type 1 diabetes. |
Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in children and infants: two clinical trials.
Sáez-Llorens X , Bandyopadhyay AS , Gast C , Leon T , DeAntonio R , Jimeno J , Caballero MI , Aguirre G , Oberste MS , Weldon WC , Konopka-Anstadt JL , Modlin J , Bachtiar NS , Fix A , Konz J , Clemens R , Costa Clemens SA , Rüttimann R . Lancet 2020 397 (10268) 27-38 BACKGROUND: Continued emergence and spread of circulating vaccine-derived type 2 polioviruses and vaccine-associated paralytic poliomyelitis from Sabin oral poliovirus vaccines (OPVs) has stimulated development of two novel type 2 OPV candidates (OPV2-c1 and OPV2-c2) designed to have similar immunogenicity, improved genetic stability, and less potential to reacquire neurovirulence. We aimed to assess safety and immunogenicity of the two novel OPV candidates compared with a monovalent Sabin OPV in children and infants. METHODS: We did two single-centre, multi-site, partly-masked, randomised trials in healthy cohorts of children (aged 1-4 years) and infants (aged 18-22 weeks) in Panama: a control phase 4 study with monovalent Sabin OPV2 before global cessation of monovalent OPV2 use, and a phase 2 study with low and high doses of two novel OPV2 candidates. All participants received one OPV2 vaccination and subsets received two doses 28 days apart. Parents reported solicited and unsolicited adverse events. Type 2 poliovirus neutralising antibodies were measured at days 0, 7, 28, and 56, and stool viral shedding was assessed up to 28 days post-vaccination. Primary objectives were to assess safety in all participants and non-inferiority of novel OPV2 day 28 seroprotection versus monovalent OPV2 in infants (non-inferiority margin 10%). These studies were registered with ClinicalTrials.gov, NCT02521974 and NCT03554798. FINDINGS: The control study took place between Oct 23, 2015, and April 29, 2016, and the subsequent phase 2 study between Sept 19, 2018, and Sept 30, 2019. 150 children (50 in the control study and 100 of 129 assessed for eligibility in the novel OPV2 study) and 684 infants (110 of 114 assessed for eligibility in the control study and 574 of 684 assessed for eligibility in the novel OPV2 study) were enrolled and received at least one study vaccination. Vaccinations were safe and well tolerated with no causally associated serious adverse events or important medical events in any group. Solicited and unsolicited adverse events were overwhelmingly mild or moderate irrespective of vaccine or dose. Nearly all children were seroprotected at baseline, indicating high baseline immunity. In children, the seroprotection rate 28 days after one dose was 100% for monovalent OPV2 and both novel OPV2 candidates. In infants at day 28, 91 (94% [95% CI 87-98]) of 97 were seroprotected after receiving monovalent OPV2, 134 (94% [88-97]) of 143 after high-dose novel OPV2-c1, 122 (93% [87-97]) of 131 after low-dose novel OPV2-c1, 138 (95% [90-98]) of 146 after high-dose novel OPV2-c2, and 115 (91% [84-95]) of 127 after low-dose novel OPV2-c2. Non-inferiority was shown for low-dose and high-dose novel OPV2-c1 and high-dose novel OPV2-c2 despite monovalent OPV2 recipients having higher baseline immunity. INTERPRETATION: Both novel OPV2 candidates were safe, well tolerated, and immunogenic in children and infants. Novel OPV2 could be an important addition to our resources against poliovirus given the current epidemiological situation. FUNDING: Fighting Infectious Diseases in Emerging Countries and Bill & Melinda Gates Foundation. |
Safety and immunogenicity of two novel type 2 oral poliovirus vaccine candidates compared with a monovalent type 2 oral poliovirus vaccine in healthy adults: two clinical trials.
De Coster I , Leroux-Roels I , Bandyopadhyay AS , Gast C , Withanage K , Steenackers K , De Smedt P , Aerssens A , Leroux-Roels G , Oberste MS , Konopka-Anstadt JL , Weldon WC , Fix A , Konz J , Wahid R , Modlin J , Clemens R , Costa Clemens SA , Bachtiar NS , Van Damme P . Lancet 2020 397 (10268) 39-50 BACKGROUND: Two novel type 2 oral poliovirus vaccine (OPV2) candidates, novel OPV2-c1 and novel OPV2-c2, designed to be more genetically stable than the licensed Sabin monovalent OPV2, have been developed to respond to ongoing polio outbreaks due to circulating vaccine-derived type 2 polioviruses. METHODS: We did two randomised studies at two centres in Belgium. The first was a phase 4 historical control study of monovalent OPV2 in Antwerp, done before global withdrawal of OPV2, and the second was a phase 2 study in Antwerp and Ghent with novel OPV2-c1 and novel OPV2-c2. Eligible participants were healthy adults aged 18-50 years with documented history of at least three polio vaccinations, including OPV in the phase 4 study and either OPV or inactivated poliovirus vaccine (IPV) in the novel OPV2 phase 2 study, with no dose within 12 months of study start. In the historical control trial, participants were randomly assigned to either one dose or two doses of monovalent OPV2. In the novel OPV2 trial, participants with previous OPV vaccinations were randomly assigned to either one or two doses of novel OPV2-c1 or to one or two doses of novel OPV2-c2. IPV-vaccinated participants were randomly assigned to receive two doses of either novel OPV2-c1, novel OPV2-c2, or placebo. Vaccine administrators were unmasked to treatment; medical staff performing safety and reactogenicity assessments or blood draws for immunogenicity assessments were masked. Participants received the first vaccine dose on day 0, and a second dose on day 28 if assigned to receive a second dose. Primary objectives were assessments and comparisons of safety up to 28 days after each dose, including solicited adverse events and serious adverse events, and immunogenicity (seroprotection rates on day 28 after the first vaccine dose) between monovalent OPV2 and the two novel OPV2 candidates. Primary immunogenicity analyses were done in the per-protocol population. Safety was assessed in the total vaccinated population-ie, all participants who received at least one dose of their assigned vaccine. The phase 4 control study is registered with EudraCT (2015-003325-33) and the phase 2 novel OPV2 study is registered with EudraCT (2018-001684-22) and ClinicalTrials.gov (NCT04544787). FINDINGS: In the historical control study, between Jan 25 and March 18, 2016, 100 volunteers were enrolled and randomly assigned to receive one or two doses of monovalent OPV2 (n=50 in each group). In the novel OPV2 study, between Oct 15, 2018, and Feb 27, 2019, 200 previously OPV-vaccinated volunteers were assigned to the four groups to receive one or two doses of novel OPV2-c1 or novel OPV2-c2 (n=50 per group); a further 50 participants, previously vaccinated with IPV, were assigned to novel OPV2-c1 (n=17), novel OPV2-c2 (n=16), or placebo (n=17). All participants received the first dose of assigned vaccine or placebo and were included in the total vaccinated population. All vaccines appeared safe; no definitely vaccine-related withdrawals or serious adverse events were reported. After first doses in previously OPV-vaccinated participants, 62 (62%) of 100 monovalent OPV2 recipients, 71 (71%) of 100 recipients of novel OPV2-c1, and 74 (74%) of 100 recipients of novel OPV2-c2 reported solicited systemic adverse events, four (monovalent OPV2), three (novel OPV2-c1), and two (novel OPV2-c2) of which were considered severe. In IPV-vaccinated participants, solicited adverse events occurred in 16 (94%) of 17 who received novel OPV2-c1 (including one severe) and 13 (81%) of 16 who received novel OPV2-c2 (including one severe), compared with 15 (88%) of 17 placebo recipients (including two severe). In previously OPV-vaccinated participants, 286 (97%) of 296 were seropositive at baseline; after one dose, 100% of novel OPV2 vaccinees and 97 (97%) of monovalent OPV2 vaccinees were seropositive. INTERPRETATION: Novel OPV2 candidates were as safe, well tolerated, and immunogenic as monovalent OPV2 in previously OPV-vaccinated and IPV-vaccinated adults. These data supported the further assessment of the vaccine candidates in children and infants. FUNDING: University of Antwerp and Bill & Melinda Gates Foundation. |
Randomized controlled clinical trial of bivalent oral poliovirus vaccine and inactivated poliovirus vaccine in Nigerian children
Tagbo BN , Verma H , Mahmud ZM , Ernest K , Nnani RO , Chukwubike C , Craig KT , Hamisu A , Weldon WC , Oberste SM , Jeyaseelan V , Braka F , Mkanda P , Esangbedo D , Olowu A , Nwaze E , Sutter RW . J Infect Dis 2020 226 (2) 299-307 BACKGROUND: We conducted a trial in Nigeria to assess the immunogenicity of the new bOPV + IPV immunization schedule and gains in type 2 immunity with addition of second dose of IPV. The trial was conducted in August 2016-March 2017 period, well past the tOPV-bOPV switch in April 2016. METHODS: This was an open-label, two-arm, non-inferiority, multi-center, randomized controlled trial. We enrolled 572 infants of age ≤14 days and randomized them into two arms. Arm A received bOPV at birth, 6 and 10 weeks, bOPV+IPV at week 14 and IPV at week 18. Arm B received IPV each at 6, 10, 14 weeks and bOPV at 18 weeks of age. RESULTS: Seroconversion rates for poliovirus types 1 and 3, respectively, were 98.9% (95%CI:96.7-99.8) and 98.1% (95%CI:88.2-94.8) in Arm A, and 89.6% (95%CI:85.4-93.0) and 98.5% (95%CI:96.3-99.6) in Arm B. Type 2 seroconversion with one dose IPV in Arm A was 72.0% (95%CI:66.2-77.3), which increased significantly with addition of second dose to 95.9% (95%CI:92.8-97.9). CONCLUSION: This first trial on the new EPI schedule in a sub-Saharan African country demonstrated excellent immunogenicity against poliovirus types 1 and 3, and substantial/enhanced immunogenicity against poliovirus type 2 after 1 to 2 doses of IPV respectively. |
Safety and immunogenicity of inactivated poliovirus vaccine schedules for the post-eradication era: a randomised open-label, multicentre, phase 3, non-inferiority trial
Bandyopadhyay AS , Gast C , Rivera L , Saez-Llorens X , Oberste MS , Weldon WC , Modlin J , Clemens R , Costa Clemens SA , Jimeno J , Ruttimann R . Lancet Infect Dis 2020 21 (4) 559-568 Background: Following the global eradication of wild poliovirus, countries using live attenuated oral poliovirus vaccines will transition to exclusive use of inactivated poliovirus vaccine (IPV) or fractional doses of IPV (f-IPV; a f-IPV dose is one-fifth of a normal IPV dose), but IPV supply and cost constraints will necessitate dose-sparing strategies. We compared immunisation schedules of f-IPV and IPV to inform the choice of optimal post-eradication schedule. Method(s): This randomised open-label, multicentre, phase 3, non-inferiority trial was done at two centres in Panama and one in the Dominican Republic. Eligible participants were healthy 6-week-old infants with no signs of febrile illness or known allergy to vaccine components. Infants were randomly assigned (1:1:1:1, 1:1:1:2, 2:1:1:1), using computer-generated blocks of four or five until the groups were full, to one of four groups and received: two doses of intradermal f-IPV (administered at 14 and 36 weeks; two f-IPV group); or three doses of intradermal f-IPV (administered at 10, 14, and 36 weeks; three f-IPV group); or two doses of intramuscular IPV (administered at 14 and 36 weeks; two IPV group); or three doses of intramuscular IPV (administered at 10, 14, and 36 weeks; three IPV group). The primary outcome was seroconversion rates based on neutralising antibodies for poliovirus type 1 and type 2 at baseline and at 40 weeks (4 weeks after the second or third vaccinations) in the per-protocol population to allow non-inferiority and eventually superiority comparisons between vaccines and regimens. Three co-primary outcomes concerning poliovirus types 1 and 2 were to determine if seroconversion rates at 40 weeks of age after a two-dose regimen (administered at weeks 14 and 36) of intradermally administered f-IPV were non-inferior to a corresponding two-dose regimen of intramuscular IPV; if seroconversion rates at 40 weeks of age after a two-dose IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose IPV regimen (weeks 10, 14, and 36); and if seroconversion rates after a two-dose f-IPV regimen (weeks 14 and 36) were non-inferior to those after a three-dose f-IPV regimen (weeks 10, 14, and 36). The non-inferiority boundary was set at -10% for the lower bound of the two-sided 95% CI for the seroconversion rate difference. Safety was assessed as serious adverse events and important medical events. This study is registered on ClinicalTrials.gov, NCT03239496. Finding(s): From Oct 23, 2017, to Nov 13, 2018, we enrolled 773 infants (372 [48%] girls) in Panama and the Dominican Republic (two f-IPV group n=217, three f-IPV group n=178, two IPV group n=178, and three IPV group n=200). 686 infants received all scheduled vaccine doses and were included in the per-protocol analysis. We observed non-inferiority for poliovirus type 1 seroconversion rate at 40 weeks for the two f-IPV dose schedule (95.9% [95% CI 92.0-98.2]) versus the two IPV dose schedule (98.7% [95.4-99.8]), and for the three f-IPV dose schedule (98.8% [95.6-99.8]) versus the three IPV dose schedule (100% [97.9-100]). Similarly, poliovirus type 2 seroconversion rate at 40 weeks for the two f-IPV dose schedule (97.9% [94.8-99.4]) versus the two IPV dose schedule (99.4% [96.4-100]), and for the three f-IPV dose schedule (100% [97.7-100]) versus the three IPV dose schedule (100% [97.9-100]) were non-inferior. Seroconversion rate for the two f-IPV regimen was statistically superior 4 weeks after the last vaccine dose in the 14 and 36 week schedule (95.9% [92.0-98.2]) compared with the 10 and 14 week schedule (83.2% [76.5-88.6]; p=0.0062) for poliovirus type 1. Statistical superiority of the 14 and 36 week schedule was also found for poliovirus type 2 (14 and 36 week schedule 97.9% [94.8-99.4] vs 10 and 14 week schedule 83.9% [77.2-89.2]; p=0.0062), and poliovirus type 3 (14 and 36 week schedule 84.5% [78.7-89.3] vs 10 and 14 week schedule 73.3% [65.8-79.9]; p=0.0062). For IPV, a two dose regimen administered at 14 and 36 weeks (99.4% [96.4-100]) was superior a 10 and 14 week schedule (88.9% [83.4-93.1]; p<0.0001) for poliovirus type 2, but not for type 1 (14 and 36 week schedule 98.7% [95.4-99.8] vs 10 and 14 week schedule 95.6% [91.4-98.1]), or type 3 (14 and 36 week schedule 97.4% [93.5-99.3] vs 10 and 14 week schedule 93.9% [89.3-96.9]). There were no related serious adverse events or important medical events reported in any group showing safety was unaffected by administration route or schedule. Interpretation(s): Our observations suggest that adequate immunity against poliovirus type 1 and type 2 is provided by two doses of either IPV or f-IPV at 14 and 36 weeks of age, and broad immunity is provided with three doses of f-IPV, enabling substantial savings in cost and supply. These novel clinical data will inform global polio immunisation policy for the post-eradication era. Funding(s): Bill & Melinda Gates Foundation. |
Cytokine biomarkers associated with clinical cases of acute flaccid myelitis
Weldon WC , Zhao K , Jost HA , Hetzler K , Ciomperlik-Patton J , Konopka-Anstadt JL , Oberste MS . J Clin Virol 2020 131 104591 Acute flaccid myelitis (AFM) is a serious neurological illness first recognized in the United States in 2014, with subsequent outbreaks every two years. Following extensive etiologic testing by multiple laboratories of hundreds of specimens collected from patients diagnosed with AFM, no consistent cause of AFM has been identified. However, viruses, including enteroviruses, have been implicated through detection in non-sterile site specimens and antibody studies. Cytokines and chemokines play important roles in the modulation of the innate and adaptive immune response to pathogens. In the current study, we measured levels of cytokines and chemokines in serum and CSF collected from confirmed AFM patients and non-AFM control patients, to identify unique biomarkers as potential hallmarks of AFM pathogenesis. Analysis of ratios of cytokines and chemokines in the CSF compared to the serum indicate that the pro-inflammatory cytokines/chemokines IP-10 and IL-6 were significantly elevated in AFM patients compared to non-AFM patients. These results may provide additional insight into potential etiologies, pathogenic mechanisms, and treatments for AFM. |
A randomized phase 4 study of immunogenicity and safety following monovalent oral type 2 Sabin polio vaccine challenge in IPV-vaccinated children in Lithuania
Bandyopadhyay AS , Gast C , Brickley EB , Ruttimann R , Clemens R , Oberste MS , Weldon WC , Ackerman ME , Connor RI , Wieland-Alter WF , Wright P , Usonis V . J Infect Dis 2020 223 (1) 119-127 BACKGROUND: Understanding immunogenicity and safety of monovalent type-2 oral polio vaccine (mOPV2) in inactivated polio vaccine (IPV)-immunized children is of major importance to inform global policy to control circulating vaccine-derived poliovirus (cVDPV) outbreaks. METHODS: In this open-label, phase 4 study (NCT02582255) in 100 IPV-vaccinated Lithuanian 1-5-year-olds we measured humoral and intestinal type-2 polio neutralizing antibodies before and 28 days after one or two mOPV2 doses given 28 days apart, and stool viral shedding after each dose. Parents recorded solicited adverse events (AE) for 7 days after each dose and unsolicited AEs for 6 weeks postvaccination. RESULTS: After one mOPV2 challenge the type-2 seroprotection rate increased from 98% to 100%. Approximately 28 days after mOPV2 challenge 34 of 68 (50%, 95% CI: 38-62) children were shedding virus; 9 of 37 (24%, 12-41) were shedding 28 days after a second challenge. Before challenge type-2 intestinal immunity was undetectable in IPV-primed children, but 28 of 87 (32%) had intestinal neutralizing titers >/= 32 after one mOPV2 dose. No vaccine-related serious or severe AEs were reported. CONCLUSIONS: High viral excretion following mOPV2 among exclusively IPV-vaccinated children was substantially lower following a subsequent dose, indicating induction of intestinal immunity against type-2 poliovirus. |
Estimating population immunity to poliovirus in Lebanon: Results from a seroprevalence survey, 2016
Mansour Z , Said R , Wannemuehler K , Weldon W , Estephan J , Khachan J , Warrak R , Hendley W , Ehrhardt D , Farag NH . Vaccine 2020 38 (31) 4846-4852 INTRODUCTION: Circulation of poliovirus in neighboring countries and mass population movement places Lebanon at risk of polio and other vaccine-preventable disease outbreaks. Determining population immunity levels is essential for guiding program planning and implementation of targeted supplementary immunization activities (SIAs) in governorates and subpopulations with low seroprevalence. METHODS: A cross-sectional multi-stage cluster survey was conducted during February-December 2016 in all six governorates of Lebanon adapted from the World Health Organization (WHO) recommended Expanded Progamme on Immunization (EPI) methodology. Sera from selected children aged 12-59 months were tested for poliovirus neutralizing antibodies. RESULTS: Of 2,164 children recruited in this study, 1,893 provided sufficient quantity of serum samples for laboratory testing. Seroprevalence for all three poliovirus serotypes was greater than 90% in all six governorates. Poliovirus vaccine coverage with three or more doses, based on vaccination cards or parental recall, ranged between 54.1% for children aged 36-47 months in the North and 83.5% for children aged 48-59 months in Beirut. CONCLUSION: Immunity to polioviruses was high in Lebanon in 2016 following a series of supplementary immunization activities. It is essential to continue strategies that increase vaccination coverage in order to sustain the considerably high immunity levels and prevent reintroduction and transmission of poliovirus. Educating caregivers and training health care workers on the standardized usage of home-based vaccination records is needed to guarantee the accuracy of records on children's vaccination status. |
Immunity and field efficacy of type 2-containing polio vaccines after cessation of trivalent oral polio vaccine: A population-based serological study in Pakistan
Voorman A , Habib MA , Hussain I , Muhammad Safdar R , Ahmed JA , Weldon WC , Ahmed I , Umer M , Partridge J , Soofi SB . Vaccine X 2020 5 100067 Background: In Pakistan and other countries using oral polio vaccine (OPV), immunity to type 2 poliovirus is now maintained by a single dose of inactivated polio vaccine (IPV) in routine immunization, supplemented in outbreak settings by monovalent OPV type 2 (mOPV2) and IPV. While well-studied in clinical trials, population protection against poliovirus type 2 achieved in routine and outbreak settings is generally unknown. Methods: We conducted two phases of a population-based serological survey of 7940 children aged 6-11 months old, between November 2016 and October 2017 from 13 polio high-risk locations in Pakistan. Results: Type 2 seroprevalence was 50% among children born after trivalent OPV (tOPV) withdrawal (April 2016), with heterogeneity across survey areas. Supplementary immunization activities (SIAs) with mOPV2 followed by IPV improved population immunity, varying from 89% in Pishin to 64% in Killa Abdullah, with little observed marginal benefit of subsequent campaigns. In the other high-risk districts surveyed, a single SIA with IPV was conducted and appeared to improve immunity to 57% in Karachi to 84% in Khyber. Conclusions: Our study documents declining population immunity following trivalent OPV withdrawal in Pakistan, and wide heterogeneity in the population impact of supplementary immunization campaigns. Differences between areas, attributable to vaccination campaign coverage, were far more important for type 2 humoral immunity than the number of vaccination campaigns or vaccines used. This emphasizes the importance of immunization campaign coverage for type 2 outbreak response in the final stages of polio eradication. Given the declining type 2 immunity in new birth cohorts it is also recommended that 2 or more doses of IPV should be introduced in the routine immunization program of Pakistan. |
Assessment of immunity to polio among Rohingya children in Cox's Bazar, Bangladesh, 2018: A cross-sectional survey
Estivariz CF , Bennett SD , Lickness JS , Feldstein LR , Weldon WC , Leidman E , Ehlman DC , Khan MFH , Adhikari JM , Hasan M , Billah MM , Oberste MS , Alamgir ASM , Flora MD . PLoS Med 2020 17 (3) e1003070 BACKGROUND: We performed a cross-sectional survey in April-May 2018 among Rohingya in Cox's Bazar, Bangladesh, to assess polio immunity and inform vaccination strategies. METHODS AND FINDINGS: Rohingya children aged 1-6 years (younger group) and 7-14 years (older group) were selected using multi-stage cluster sampling in makeshift settlements and simple random sampling in Nayapara registered camp. Surveyors asked parents/caregivers if the child received any oral poliovirus vaccine (OPV) in Myanmar and, for younger children, if the child received vaccine in any of the 5 campaigns delivering bivalent OPV (serotypes 1 and 3) conducted during September 2017-April 2018 in Cox's Bazar. Dried blood spot (DBS) specimens were tested for neutralizing antibodies to poliovirus types 1, 2, and 3 in 580 younger and 297 older children. Titers >/= 1:8 were considered protective. Among 632 children (335 aged 1-6 years, 297 aged 7-14 years) enrolled in the study in makeshift settlements, 51% were male and 89% had arrived after August 9, 2017. Among 245 children (all aged 1-6 years) enrolled in the study in Nayapara, 54% were male and 10% had arrived after August 9, 2017. Among younger children, 74% in makeshift settlements and 92% in Nayapara received >3 bivalent OPV doses in campaigns. Type 1 seroprevalence was 85% (95% CI 80%-89%) among younger children and 91% (95% CI 86%-95%) among older children in makeshift settlements, and 92% (88%-95%) among younger children in Nayapara. Type 2 seroprevalence was lower among younger children than older children in makeshift settlements (74% [95% CI 68%-79%] versus 97% [95% CI 94%-99%], p < 0.001), and was 69% (95% CI 63%-74%) among younger children in Nayapara. Type 3 seroprevalence was below 75% for both age groups and areas. The limitations of this study are unknown routine immunization history and poor retention of vaccination cards. CONCLUSIONS: Younger Rohingya children had immunity gaps to all 3 polio serotypes and should be targeted by future campaigns and catch-up routine immunization. DBS collection can enhance the reliability of assessments of outbreak risk and vaccination strategy impact in emergency settings. |
Neutralization capacity of highly divergent type 2 vaccine-derived polioviruses from immunodeficient patients
McDonald SL , Weldon WC , Wei L , Chen Q , Shaw J , Zhao K , Jorba J , Kew OM , Pallansch MA , Burns CC , Oberste MS . Vaccine 2020 38 (14) 3042-3049 The use of the oral poliovirus vaccine (OPV) in developing countries has reduced the incidence of poliomyelitis by >99% since 1988 and is the primary tool for global polio eradication. Spontaneous reversions of the vaccine virus to a neurovirulent form can impede this effort. In persons with primary B-cell immunodeficiencies, exposure to OPV can result in chronic infection, mutation, and excretion of immunodeficiency-associated vaccine-derived polioviruses, (iVDPVs). These iVDPVs may have the potential for transmission in a susceptible population and cause paralysis. The extent to which sera from OPV recipients are able to neutralize iVDPVs with varying degrees of antigenic site substitutions is investigated here. We tested sera from a population immunized with a combination vaccine schedule (both OPV and inactivated polio vaccine) against a panel of iVDPVs and found that increases in amino acid substitution in the P1 capsid protein resulted in a decrease in the neutralizing capacity of the sera. This study underscores the importance of maintaining high vaccine coverage in areas of OPV use as well as active surveillance of those known to be immunocompromised. |
First Case of 2019 Novel Coronavirus in the United States.
Holshue ML , DeBolt C , Lindquist S , Lofy KH , Wiesman J , Bruce H , Spitters C , Ericson K , Wilkerson S , Tural A , Diaz G , Cohn A , Fox L , Patel A , Gerber SI , Kim L , Tong S , Lu X , Lindstrom S , Pallansch MA , Weldon WC , Biggs HM , Uyeki TM , Pillai SK . N Engl J Med 2020 382 (10) 929-936 An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient's initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection. |
Thin silk fibroin films as a dried format for temperature stabilization of inactivated polio vaccine
Stinson JA , Palmer CR , Miller DP , Li AB , Lightner K , Jost H , Weldon WC , Oberste MS , Kluge JA , Kosuda KM . Vaccine 2020 38 (7) 1652-1660 Current inactivated polio vaccine (IPV) products are sensitive to both freezing and elevated temperatures and therefore must be shipped and stored between 2 degrees C and 8 degrees C, a requirement that imposes financial and logistical challenges for global distribution. As such, there is a critical need for a robust, thermally stable IPV to support global polio eradication and post-eradication immunization needs. Here, we present the development of air-dried thin films for temperature stabilization of IPV using the biomaterial silk fibroin. Thin-film product compositions were optimized for physical properties as well as poliovirus D-antigen recovery and were tested under accelerated and real-time stability storage conditions. Silk fibroin IPV films maintained 70% D-antigen potency after storage for nearly three years at room temperature, and greater than 50% potency for IPV-2 and IPV-3 serotypes at 45 degrees C for one year. The immunogenicity of silk fibroin IPV films after 2-week storage at 45 degrees C was assessed in Wistar rats and the stressed films generated equivalent neutralizing antibody responses to commercial vaccine for IPV-1 and IPV-2. However, the absence of IPV-3 responses warrants further investigation into the specificity of ELISA for intact IPV-3 D-antigen. By demonstrating immunogenicity post-storage, we offer the air-dried silk film format as a means to increase IPV vaccine access through innovative delivery systems such as microneedles. |
Antifungal triazole posaconazole targets an early stage of the parechovirus A3 life cycle.
Rhoden E , Ng TFF , Campagnoli R , Nix WA , Konopka-Anstadt J , Selvarangan R , Briesach L , Oberste MS , Weldon WC . Antimicrob Agents Chemother 2019 64 (3) Viruses in species Parechovirus A (Picornaviridae) are associated with a wide variety of clinical manifestations. Parechovirus A3 (PeV-A3) is known to cause sepsis-like illness, meningitis, and encephalitis in infants and young children. To date, no specific therapies are available to treat PeV-A3-infected children. We had previously identified two FDA-cleared antifungal drugs, itraconazole (ITC) and posaconazole (POS) with potent and specific antiviral activity against PeV-A3. Time-of-addition and synchronized infection assays revealed that POS targets an early stage of the PeV-A3 life cycle. POS exerts an antiviral effect, evidenced by a reduction in viral titer following the addition of POS to Vero-P cells before infection, coaddition of POS and PeV-A3 to Vero-P cells, incubation of POS and PeV-A3 prior to Vero-P infection, and at attachment. POS exerts less of an effect on virus entry. A PeV-A3 ELISA inhibition experiment, using an anti-PeV-A3 monoclonal antibody (mAb), suggested that POS binds directly to the PeV-A3 capsid. POS-resistant PeV-A3 strains developed by serial passage in the presence of POS, acquired substitutions in multiple regions of the genome, including the capsid. Reverse genetics confirmed substitutions in capsid proteins VP0, VP3, VP1 and nonstructural proteins 2A and 3A. Single mutants VP0_K66R, VP0_A124T, VP3_N88S, VP1_Y224C, 2A_S788L and 3A_T1I were respectively 4-, 9-, 12-, 34-, 51-, and 119-fold more resistant to POS than its susceptible prototype strain. Our studies demonstrate that POS may be a valuable tool in developing an antiviral therapy for PeV-A3. |
Acute flaccid myelitis in the United States: 2015-2017
Ayers T , Lopez A , Lee A , Kambhampati A , Nix WA , Henderson E , Rogers S , Weldon WC , Oberste MS , Sejvar J , Hopkins SE , Pallansch MA , Routh JA , Patel M . Pediatrics 2019 144 (5) BACKGROUND: Acute flaccid myelitis (AFM) is a neurologic condition characterized by flaccid limb weakness. After a large number of reports of AFM in 2014, the Centers for Disease Control and Prevention began standardized surveillance in the United States to characterize the disease burden and explore potential etiologies and epidemiologic associations. METHODS: Persons meeting the clinical case criteria of acute flaccid limb weakness from January 1, 2015, through December 31, 2017, were classified as confirmed (spinal cord gray matter lesions on MRI) or probable (white blood cell count >5 cells per mm(3) in cerebrospinal fluid [CSF]). We describe clinical, radiologic, laboratory, and epidemiologic findings of pediatric patients (age </=21 years) confirmed with AFM. RESULTS: Of 305 children reported from 43 states, 193 were confirmed and 25 were probable. Of confirmed patients, 61% were male, with a median age of 6 years (range: 3 months to 21 years; interquartile range: 3 to 10 years). An antecedent respiratory or febrile illness was reported in 79% with a median of 5 days (interquartile range: 2 to 7 days) before limb weakness. Among 153 sterile-site specimens (CSF and serum) submitted to the Centers for Disease Control and Prevention, coxsackievirus A16 was detected in CSF and serum of one case patient and enterovirus D68 was detected in serum of another. Of 167 nonsterile site (respiratory and stool) specimens, 28% tested positive for enterovirus or rhinovirus. CONCLUSIONS: AFM surveillance data suggest a viral etiology, including enteroviruses. Further study is ongoing to better characterize the etiology, pathogenesis, and risk factors of this rare condition. |
Estimating population immunity to poliovirus in Jordan's high-risk areas
Farag NH , Wannemuehler K , Weldon W , Arbaji A , Belbaisi A , Khuri-Bulos N , Ehrhardt D , Surour MR , ElhajQasem NS , Al-Abdallat MM . Hum Vaccin Immunother 2019 16 (3) 548-553 A community-based serosurvey was conducted among children ages 6-59 to assess population immunity in Jordan's high-risk areas following the Middle East polio outbreak response. The survey was a two-stage cluster-quota sample with high risk areas as the primary sampling units. High-risk areas included border and hard-to-reach areas, and areas with a high proportion of refugees, mobile communities and/or low coverage during previous immunization campaigns. Population immunity to poliovirus was high overall. In high-risk areas, Type 1 seroprevalence = 98% (95% CI = 96, 99), Type 2= 98 (95% CI = 96, 99) and Type 3= 96 (95% CI = 94, 98). Seroprevalence was higher in the refugee camps: Type 1 seroprevalence = 99.6 (95% CI = 97.9, 100); Type 2: 99.6 (95% CI = 97.9, 99.9), and Type 3: 100 (95% CI = 100,100). The vigilance that the Jordan Ministry of Health has placed on locating and vaccinating high-risk populations has been successful in maintaining high population immunity and averting polio outbreaks despite the influx of refugees from Syria. |
Poliopolis: pushing boundaries of scientific innovations for disease eradication
Van Damme P , Coster I , Bandyopadhyay AS , Suykens L , Rudelsheim P , Neels P , Oberste MS , Weldon WC , Clemens R , Revets H . Future Microbiol 2019 14 1321-1330 Although global polio eradication is within reach, sustained eradication of all polioviruses requires cessation of oral poliovirus vaccine use to mitigate against vaccine-derived poliovirus circulation and vaccine-associated paralytic poliomyelitis. The first step in this direction was the WHO-recommended global withdrawal of live attenuated type 2 Sabin poliovirus from routine immunisation in May 2016, with future use restricted to outbreak response, and handling controlled by strict containment provisions (GAPIII). This creates unique challenges for development and testing of novel type 2 poliovirus vaccines. We describe the creation of a novel purpose-built containment facility, Poliopolis, to study new monovalent OPV2 vaccine candidates in healthy adult volunteers, which may be a model for future endeavors in vaccine development for emergency use. |
The safety and immunogenicity of two novel live attenuated monovalent (serotype 2) oral poliovirus vaccines in healthy adults: a double-blind, single-centre phase 1 study
Van Damme P , De Coster I , Bandyopadhyay AS , Revets H , Withanage K , De Smedt P , Suykens L , Oberste MS , Weldon WC , Costa-Clemens SA , Clemens R , Modlin J , Weiner AJ , Macadam AJ , Andino R , Kew OM , Konopka-Anstadt JL , Burns CC , Konz J , Wahid R , Gast C . Lancet 2019 394 (10193) 148-158 BACKGROUND: Use of oral live-attenuated polio vaccines (OPV), and injected inactivated polio vaccines (IPV) has almost achieved global eradication of wild polio viruses. To address the goals of achieving and maintaining global eradication and minimising the risk of outbreaks of vaccine-derived polioviruses, we tested novel monovalent oral type-2 poliovirus (OPV2) vaccine candidates that are genetically more stable than existing OPVs, with a lower risk of reversion to neurovirulence. Our study represents the first in-human testing of these two novel OPV2 candidates. We aimed to evaluate the safety and immunogenicity of these vaccines, the presence and extent of faecal shedding, and the neurovirulence of shed virus. METHODS: In this double-blind, single-centre phase 1 trial, we isolated participants in a purpose-built containment facility at the University of Antwerp Hospital (Antwerp, Belgium), to minimise the risk of environmental release of the novel OPV2 candidates. Participants, who were recruited by local advertising, were adults (aged 18-50 years) in good health who had previously been vaccinated with IPV, and who would not have any contact with immunosuppressed or unvaccinated people for the duration of faecal shedding at the end of the study. The first participant randomly chose an envelope containing the name of a vaccine candidate, and this determined their allocation; the next 14 participants to be enrolled in the study were sequentially allocated to this group and received the same vaccine. The subsequent 15 participants enrolled after this group were allocated to receive the other vaccine. Participants and the study staff were masked to vaccine groups until the end of the study period. Participants each received a single dose of one vaccine candidate (candidate 1, S2/cre5/S15domV/rec1/hifi3; or candidate 2, S2/S15domV/CpG40), and they were monitored for adverse events, immune responses, and faecal shedding of the vaccine virus for 28 days. Shed virus isolates were tested for the genetic stability of attenuation. The primary outcomes were the incidence and type of serious and severe adverse events, the proportion of participants showing viral shedding in their stools, the time to cessation of viral shedding, the cell culture infective dose of shed virus in virus-positive stools, and a combined index of the prevalence, duration, and quantity of viral shedding in all participants. This study is registered with EudraCT, number 2017-000908-21 and ClinicalTrials.gov, number NCT03430349. FINDINGS: Between May 22 and Aug 22, 2017, 48 volunteers were screened, of whom 15 (31%) volunteers were excluded for reasons relating to the inclusion or exclusion criteria, three (6%) volunteers were not treated because of restrictions to the number of participants in each group, and 30 (63%) volunteers were sequentially allocated to groups (15 participants per group). Both novel OPV2 candidates were immunogenic and increased the median blood titre of serum neutralising antibodies; all participants were seroprotected after vaccination. Both candidates had acceptable tolerability, and no serious adverse events occurred during the study. However, severe events were reported in six (40%) participants receiving candidate 1 (eight events) and nine (60%) participants receiving candidate 2 (12 events); most of these events were increased blood creatinine phosphokinase but were not accompanied by clinical signs or symptoms. Vaccine virus was detected in the stools of 15 (100%) participants receiving vaccine candidate 1 and 13 (87%) participants receiving vaccine candidate 2. Vaccine poliovirus shedding stopped at a median of 23 days (IQR 15-36) after candidate 1 administration and 12 days (1-23) after candidate 2 administration. Total shedding, described by the estimated median shedding index (50% cell culture infective dose/g), was observed to be greater with candidate 1 than candidate 2 across all participants (2.8 [95% CI 1.8-3.5] vs 1.0 [0.7-1.6]). Reversion to neurovirulence, assessed as paralysis of transgenic mice, was low in isolates from those vaccinated with both candidates, and sequencing of shed virus indicated that there was no loss of attenuation in domain V of the 5'-untranslated region, the primary site of reversion in Sabin OPV. INTERPRETATION: We found that the novel OPV2 candidates were safe and immunogenic in IPV-immunised adults, and our data support the further development of these vaccines to potentially be used for maintaining global eradication of neurovirulent type-2 polioviruses. FUNDING: Bill & Melinda Gates Foundation. |
Extended delivery of vaccines to the skin improves immune responses.
Joyce JC , Sella HE , Jost H , Mistilis MJ , Esser ES , Pradhan P , Toy R , Collins ML , Rota PA , Roy K , Skountzou I , Compans RW , Oberste MS , Weldon WC , Norman JJ , Prausnitz MR . J Control Release 2019 304 135-145 Vaccines prevent 2-3 million childhood deaths annually; however, low vaccine efficacy and the resulting need for booster doses create gaps in immunization coverage. In this translational study, we explore the benefits of extended release of licensed vaccine antigens into skin to increase immune responses after a single dose in order to design improved vaccine delivery systems. By administering daily intradermal injections of inactivated polio vaccine according to six different delivery profiles, zeroth-order release over 28days resulted in neutralizing antibody titers equivalent to two bolus vaccinations administered one month apart. Vaccinations following this profile also improved immune responses to tetanus toxoid and subunit influenza vaccine but not a live-attenuated viral vaccine, measles vaccine. Finally, using subunit influenza vaccine, we demonstrated that daily vaccination by microneedle patch induced a potent, balanced humoral immunity with an increased memory response compared to bolus vaccination. We conclude that extended presentation of antigen in skin via intradermal injection or microneedle patch can enhance immune responses and reduce the number of vaccine doses, thereby enabling increased vaccination efficacy. |
Immunogenicity of full and fractional dose of inactivated poliovirus vaccine for use in routine immunisation and outbreak response: an open-label, randomised controlled trial
Snider CJ , Zaman K , Estivariz CF , Yunus M , Weldon WC , Wannemuehler KA , Oberste MS , Pallansch MA , Wassilak SG , Bari TIA , Anand A . Lancet 2019 393 (10191) 2624-2634 BACKGROUND: Intradermal administration of fractional inactivated poliovirus vaccine (fIPV) is a dose-sparing alternative to the intramuscular full dose. We aimed to compare the immunogenicity of two fIPV doses versus one IPV dose for routine immunisation, and also assessed the immunogenicity of an fIPV booster dose for an outbreak response. METHODS: We did an open-label, randomised, controlled, inequality, non-inferiority trial in two clinics in Dhaka, Bangladesh. Healthy infants were randomly assigned at 6 weeks to one of four groups: group A received IPV at age 14 weeks and IPV booster at age 22 weeks; group B received IPV at age 14 weeks and fIPV booster at age 22 weeks; group C received IPV at age 6 weeks and fIPV booster at age 22 weeks; and group D received fIPV at 6 weeks and 14 weeks and fIPV booster at age 22 weeks. IPV was administered by needle-syringe as an intramuscular full dose (0.5 mL), and fIPV was administered intradermally (0.1 mL of the IPV formulation was administered using the 0.1 mL HelmJect auto-disable syringe with a Helms intradermal adapter). Both IPV and fIPV were administered on the outer, upper right thigh of infants. The primary outcome was vaccine response to poliovirus types 1, 2, and 3 at age 22 weeks (routine immunisation) and age 26 weeks (outbreak response). Vaccine response was defined as seroconversion from seronegative (<1:8) at baseline to seropositive (>/=1:8) or four-fold increase in reciprocal antibody titres adjusted for maternal antibody decay and was assessed in the modified intention-to-treat population (infants who received polio vaccines per group assignment and polio antibody titre results to serotypes 1, 2, and 3 at 6, 22, 23, and 26 weeks of age). The non-inferiority margin was 12.5%. This trial is registered with ClinicalTrials.gov, number NCT02847026. FINDINGS: Between Sept 1, 2016 and May 2, 2017, 1076 participants were randomly assigned and included in the modified intention-to-treat analysis: 271 in Group A, 267 in group B, 268 in group C, and 270 in group D. Vaccine response at 22 weeks to two doses of fIPV (group D) was significantly higher (p<0.0001) than to one dose of IPV (groups A and B) for all three poliovirus serotypes: the type 1 response comprised 212 (79% [95% CI 73-83]) versus 305 (57% [53-61]) participants, the type 2 response comprised 173 (64% [58-70]) versus 249 (46% [42-51]) participants, and the type 3 response comprised 196 (73% [67-78]) versus 196 (36% [33-41]) participants. At 26 weeks, the fIPV booster was non-inferior to IPV (group B vs group A) for serotype 1 (-1.12% [90% CI -2.18 to -0.06]), serotype 2 (0.40%, [-2.22 to 1.42]), and serotype 3 (1.51% [-3.23 to -0.21]). Of 129 adverse events, 21 were classified as serious including one death; none were attributed to IPV or fIPV. INTERPRETATION: fIPV appears to be an effective dose-sparing strategy for routine immunisation and outbreak responses. FUNDING: US Centers for Disease Control and Prevention. |
Neutralizing antibody against enterovirus D68 in children and adults before 2014 outbreak, Kansas City, Missouri, USA
Harrison CJ , Weldon WC , Pahud BA , Jackson MA , Oberste MS , Selvarangan R . Emerg Infect Dis 2019 25 (3) 585-588 We evaluated enterovirus D68 seroprevalence in Kansas City, Missouri, USA, from samples obtained during 2012-2013. Neutralizing antibodies against Fermon and the dominant 2014 Missouri isolate were universally detected. Titers increased with age. Widespread circulation of enterovirus D68 occurred before the 2014 outbreak. Research is needed to determine a surrogate of protection. |
Rapid disappearance of poliovirus type 2 immunity in young children following withdrawal of oral poliovirus type 2 containing vaccine in Vietnam
Huyen DTT , Mach O , Trung NT , Thai PQ , Thang HV , Weldon WC , Oberste MS , Jeyaseelan V , Sutter RW , Anh DD . J Infect Dis 2019 220 (3) 386-391 BACKGROUND: Due to global shortage of inactivated poliovirus vaccine and global withdrawal of poliovirus type-2 (PV2) containing oral vaccine in May 2016, Vietnam has not used any PV2-containing vaccine between May 2016-October 2018. We assessed population immunity gap to PV2. METHODS: A cross-sectional survey in children 1-18 months of age was carried out in January 2018: one blood sample was obtained and analysed for the presence of poliovirus neutralizing antibodies. In children with detectable anti-PV2 antibodies, a second blood sample was obtained and analysed four months later to distinguish between passive (maternally-derived) and active (induced by secondary transmission or vaccination) immunity. RESULTS: Analysable sera were obtained from 1,106/1,110 enrolled children. Seroprevalence of PV2 antibodies was 87/368 (23.6%) among 1-7-month-old; 27/471 (5.7%) in the 8-15-month-old; and 19/267 (7.1%) in the 16-18-month-old. Seroprevalence declined with age in the 1-7 month-old group, and in children 8-18 months it remained without significant change by age. Four months later, 11/87 (14%), 9/27 (32%), and 12/19 (37%) remained seropositive in the 1-7, 8-15, and 16-18-month groups, respectively. INTERPRETATION: We found declining immunity to PV2, suggesting that Vietnam is at risk for an outbreak of type 2 vaccine-derived poliovirus in case of importation or new emergence. |
Poliovirus immunity among children under five years-old in accessible areas of Afghanistan, 2013
Hsu CH , Wannemuehler KA , Soofi S , Mashal M , Hussain I , Bhutta ZA , McDuffie L , Weldon W , Farag NH . Vaccine 2019 37 (12) 1577-1583 BACKGROUND: Afghanistan remains among the three countries with endemic wild poliovirus transmission, and high population immunity levels are required to interrupt transmission and prevent outbreaks. Surveillance and vaccination of children in Afghanistan have been challenging due to security issues limiting accessibility in certain areas. METHODS: A serosurvey was conducted in 2013 within accessible enumeration areas (EAs) among children aged <5years using samples collected for a national micronutrient assessment survey to assess poliovirus immunity in Afghanistan. Of 21194 total EAs in Afghanistan, 107 were inaccessible and therefore were excluded from the sampling frame. RESULTS: Population immunity was high overall but varied for the poliovirus serotypes, and was lowest for type 3 (95% [95% CI: 93%, 96%]) compared to type 1 (99% [95% CI:97%, 99%]) and type 2 (98% [95% CI:96%, 99%]). The proportion of the population immune to all three types was 93% (95% CI: 91%, 95%), and the proportion seronegative for all three types was 0.5% (95% CI: 0.2%, 1.7%). CONCLUSION: Except for regional differences in immunity to type 3 virus, there were no other apparent differences in seroprevalence by region or by any of the demographic or nutritional characteristics assessed in this study. The study was not powered to provide provincial level seroprevalence estimates, but Paktika Province, in the South region, had the largest proportion of seronegative specimens for type 1 (4 seronegative of 17 serum specimens compared to 14 seronegative of 673 for the remainder of the areas). Among accessible children in Afghanistan, seroprevalence of antibodies to poliovirus was high, with most seroprevalence reported at 95% or greater. Despite high seroprevalence in areas assessed in this study, the continued detection of poliovirus cases in the South and East regions indicate that overall regional vaccination coverage and performance is not sufficient to stop polio transmission. |
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