Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-30 (of 36 Records) |
Query Trace: Bandyopadhyay K[original query] |
---|
Safety and immunogenicity of shorter interval schedules of the novel oral poliovirus vaccine type 2 in infants: a phase 3, randomised, controlled, non-inferiority study in the Dominican Republic
Rivera Mejía L , Peña Méndez L , Bandyopadhyay AS , Gast C , Mazara S , Rodriguez K , Rosario N , Zhang Y , Mainou BA , Jimeno J , Aguirre G , Rüttimann R . Lancet Infect Dis 2023 BACKGROUND: The novel oral poliovirus vaccine type 2 (nOPV2) is now authorised by a WHO emergency use listing and widely distributed to interrupt outbreaks of circulating vaccine-derived poliovirus type 2. As protection of vulnerable populations, particularly young infants, could be facilitated by shorter intervals between the two recommended doses, we aimed to assess safety and non-inferiority of immunogenicity of nOPV2 in 1-week, 2-week, and 4-week schedules. METHODS: In this phase 3, open-label, randomised trial, healthy, full-term, infants aged 6-8 weeks from a hospital or a clinic in the Dominican Republic were randomly allocated (1:1:1 ratio) using a pre-prepared, computer-generated randomisation schedule to three groups to receive two doses of nOPV2 immunisations with a 1-week interval (group A), 2-week interval (group B), or 4-week interval (group C). The nOPV2 vaccine was given at a 0·1 mL dose and contained at least 10(5) 50% cell culture infective dose. Neutralising antibodies against poliovirus types 1, 2, and 3 were measured before each immunisation and 4 weeks after the second dose. The primary outcome was the type 2 seroconversion rate 28 days after the second dose, and the non-inferiority margin was defined as a lower bound 95% CI of greater than -10%. Safety and reactogenicity were assessed through diary cards completed by the parent or guardian. The trial is registered with ClinicalTrials.gov, NCT05033561. FINDINGS: We enrolled 905 infants between Dec 16, 2021, and March 28, 2022. 872 infants were included in the per-protocol analyses: 289 in group A, 293 in group B, and 290 in group C. Type 2 seroconversion rates were 87·5% (95% CI 83·2 to 91·1) in group A (253 of 289 participants), 91·8% (88·1 to 94·7) in group B (269 of 293 participants), and 95·5% (92·5 to 97·6) in group C (277 of 290 participants). Non-inferiority was shown for group B compared with group C (difference in rates -3·7; 95% CI -7·9 to 0·3), but not for group A compared with group C (-8·0; -12·7 to -3·6). 4 weeks after the second nOPV2 dose, type 2 neutralising antibodies increased in all three groups such that over 95% of each group was seroprotected against polio type 2, although final geometric mean titres tended to be highest with longer intervals between doses. Immunisation with nOPV2 was well tolerated with no causal association to vaccination of any severe or serious adverse event; one death from septic shock during the study was unrelated to the vaccine. INTERPRETATION: Two nOPV2 doses administered 1 week or 2 weeks apart from age 6 weeks to 8 weeks were safe and immunogenic. Immune responses after a 2-week interval were non-inferior to those after the standard 4-week interval, but marked responses after a 1-week interval suggest that schedules with an over 1-week interval can be used to provide flexibility to campaigns to improve coverage and hasten protection during circulating vaccine-derived poliovirus type 2 outbreaks. FUNDING: Bill & Melinda Gates Foundation. |
Notes from the field: Circulating vaccine-derived poliovirus type 2 emergences linked to novel oral poliovirus vaccine type 2 use - six African countries, 2021-2023
Davlantes E , Jorba J , Henderson E , Bullard K , Deka MA , Kfutwah A , Martin J , Bessaud M , Shulman LM , Hawes K , Diop OM , Bandyopadhyay AS , Zipursky S , Burns CC . MMWR Morb Mortal Wkly Rep 2023 72 (38) 1041-1042 Circulating vaccine-derived poliovirus (cVDPV) outbreaks can occur when oral poliovirus vaccine strains (most often, Sabin monovalent oral poliovirus vaccine type 2 [mOPV2]) undergo prolonged circulation in undervaccinated populations, resulting in genetic reversion to neurovirulence. A novel type 2 oral poliovirus vaccine (nOPV2) has been developed, which has been shown in clinical trials to be less likely than mOPV2 to revert to paralytic variants and to have limited genetic modifications in initial field use (1–4). Approximately 700 million doses of nOPV2 have been administered worldwide in response to outbreaks of cVDPV type 2 (cVDPV2). cVDPV2 detections originating from nOPV2 use from initial rollout during March 2021–September 7, 2023, are described in this report. |
Evaluation of the safety, immunogenicity, and faecal shedding of novel oral polio vaccine type 2 in healthy newborn infants in Bangladesh: a randomised, controlled, phase 2 clinical trial.
Zaman K , Bandyopadhyay AS , Hoque M , Gast C , Yunus M , Jamil KM , Mainou BA , Konopka-Anstadt JL , Hendley WS , Vincent A , Clemens R , Clemens SAC , Ross AG , Clemens JD , Tritama E . Lancet 2022 401 (10371) 131-139 BACKGROUND: Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive newborn infants. METHODS: In this randomised, double-blind, controlled, phase 2 trial we enrolled newborn infants at the Matlab Health Research Centre, Chandpur, Bangladesh. We included infants who were healthy and were a single birth after at least 37 weeks' gestation. Infants were randomly assigned (2:1) to receive either two doses of nOPV2 or placebo, administered at age 0-3 days and at 4 weeks. Exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture. The primary safety outcome was safety and tolerability after one and two doses of nOPV2, given 4 weeks apart in poliovirus vaccine-naive newborn infants and the primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus, measured 28 days after the first and second vaccinations with nOPV2. Study staff recorded solicited and unsolicited adverse events after each dose during daily home visits for 7 days. Poliovirus neutralising antibody responses were measured in sera drawn at birth and at age 4 weeks and 8 weeks. This study is registered on ClinicalTrials.gov, NCT04693286. FINDINGS: Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to receive nOPV2 (n=220 [67%]) or placebo (n=110 [33%]). nOPV2 was well tolerated; 154 (70%) of 220 newborn infants in the nOPV2 group and 78 (71%) of 110 in the placebo group had solicited adverse events, which were all mild or moderate in severity. Severe unsolicited adverse events in 11 (5%) vaccine recipients and five (5%) placebo recipients were considered unrelated to vaccination. 306 (93%) of 330 infants had seroprotective maternal antibodies against type 2 poliovirus at birth, decreasing to 58 (56%) of 104 in the placebo group at 8 weeks. In the nOPV2 group 196 (90%) of 217 infants seroconverted by week 8 after two doses, when 214 (99%) had seroprotective antibodies. INTERPRETATION: nOPV2 was well tolerated and immunogenic in newborn infants, with two doses, at birth and 4 weeks, resulting in almost 99% of infants having protective neutralising antibodies. FUNDING: Bill & Melinda Gates Foundation. |
Genetic and phenotypic stability of poliovirus shed from infants who received novel type 2 or Sabin type 2 oral poliovirus vaccines in Panama: an analysis of two clinical trials.
Wahid R , Mercer LD , De Leon T , DeAntonio R , Sáez-Llorens X , Macadam A , Chumakov K , Strating J , Koel B , Konopka-Anstadt JL , Oberste MS , Burns CC , Andino R , Tritama E , Bandyopadhyay AS , Aguirre G , Rüttimann R , Gast C , Konz JO . Lancet Microbe 2022 3 (12) e912-e921 BACKGROUND: Sabin strains used in oral poliovirus vaccines (OPV) can revert to virulence and, in rare instances, cause disease or generate vaccine-derived strains leading to outbreaks in areas of low immunisation coverage. A novel OPV2 (nOPV2) was designed to stabilise the viral genome against reversion and reduce recombination events that might lead to virulent strains. In this study, we evaluated the genetic and phenotypic stability of shed poliovirus following administration of one dose of monovalent OPV2 (mOPV2) or nOPV2 to infants aged 18-22 weeks. METHODS: In two similarly designed clinical trials (NCT02521974 and NCT03554798) conducted in Panama, infants aged 18-22-weeks, after immunisation with three doses of bivalent OPV (types 1 and 3) and one dose of inactivated poliovirus vaccine, were administered one or two doses of mOPV2 or nOPV2. In this analysis of two clinical trials, faecally shed polioviruses following one dose of mOPV2 or nOPV2 were isolated from stools meeting predetermined criteria related to sample timing and viral presence and quantity and assessed for nucleotide polymorphisms using next-generation sequencing. A transgenic mouse neurovirulence test was adapted to assess the effect of the possible phenotypic reversion of shed mOPV2 and nOPV2 with a logistic regression model. FINDINGS: Of the 91 eligible samples, 86 were able to be sequenced, with 72 evaluated in the transgenic mouse assay. Sabin-2 poliovirus reverts rapidly at nucleotide 481, the primary attenuation site in domain V of the 5' untranslated region of the genome. There was no evidence of neurovirulence-increasing polymorphisms in domain V of shed nOPV2. Reversion of shed Sabin-2 virus corresponded with unadjusted paralysis rates of 47·6% at the 4 log(10) 50% cell culture infectious dose (CCID(50)) and 76·7% at the 5 log(10) CCID(50) inoculum levels, with rates of 2·8% for 4 log(10) CCID(50) and 11·8% for 5 log(10) CCID(50) observed for shed nOPV2 samples. The estimated adjusted odds ratio at 4·5 log(10) of 0·007 (95% CI 0·002-0·023; p<0·0001) indicates significantly reduced odds of mouse paralysis from virus obtained from nOPV2 recipients compared with mOPV2 recipients. INTERPRETATION: The data indicate increased genetic stability of domain V of nOPV2 relative to mOPV2, with significantly lower neurovirulence of shed nOPV2 virus compared with shed mOPV2. While this vaccine is currently being deployed under an emergency use listing, the data on the genetic stability of nOPV2 will support further regulatory and policy decision-making regarding use of nOPV2 in outbreak responses. FUNDING: Bill & Melinda Gates Foundation. |
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. |
Genetic characterization of novel oral polio vaccine type 2 viruses during initial use phase under emergency use listing - worldwide, March-October 2021
Martin J , Burns CC , Jorba J , Shulman LM , Macadam A , Klapsa D , Majumdar M , Bullows J , Frolov A , Mate R , Bujaki E , Castro CJ , Bullard K , Konz J , Hawes K , Gauld J , Blake IM , Mercer LD , Kurji F , Voorman A , Diop OM , Oberste MS , Modlin J , Macklin G , Eisenhawer M , Bandyopadhyay AS , Zipursky S . MMWR Morb Mortal Wkly Rep 2022 71 (24) 786-790 The emergence and international spread of neurovirulent circulating vaccine-derived polioviruses (cVDPVs) across multiple countries in Africa and Asia in recent years pose a major challenge to the goal of eradicating all forms of polioviruses. Approximately 90% of all cVDPV outbreaks are caused by the type 2 strain of the Sabin vaccine, an oral live, attenuated vaccine; cVDPV outbreaks typically occur in areas of persistently low immunization coverage (1). A novel type 2 oral poliovirus vaccine (nOPV2), produced by genetic modification of the type 2 Sabin vaccine virus genome (2), was developed and evaluated through phase I and phase II clinical trials during 2017-2019. nOPV2 was demonstrated to be safe and well-tolerated, have noninferior immunogenicity, and have superior genetic stability compared with Sabin monovalent type 2 (as measured by preservation of the primary attenuation site [domain V in the 5' noncoding region] and significantly lower neurovirulence of fecally shed vaccine virus in transgenic mice) (3-5). These findings indicate that nOPV2 could be an important tool in reducing the risk for generating vaccine-derived polioviruses (VDPVs) and the risk for vaccine-associated paralytic poliomyelitis cases. Based on the favorable preclinical and clinical data, and the public health emergency of international concern generated by ongoing endemic wild poliovirus transmission and cVDPV type 2 outbreaks, the World Health Organization authorized nOPV2 for use under the Emergency Use Listing (EUL) pathway in November 2020, allowing for its first use for outbreak response in March 2021 (6). As required by the EUL process, among other EUL obligations, an extensive plan was developed and deployed for obtaining and monitoring nOPV2 isolates detected during acute flaccid paralysis (AFP) surveillance, environmental surveillance, adverse events after immunization surveillance, and targeted surveillance for adverse events of special interest (i.e., prespecified events that have the potential to be causally associated with the vaccine product), during outbreak response, as well as through planned field studies. Under this monitoring framework, data generated from whole-genome sequencing of nOPV2 isolates, alongside other virologic data for isolates from AFP and environmental surveillance systems, are reviewed by the genetic characterization subgroup of an nOPV working group of the Global Polio Eradication Initiative. Global nOPV2 genomic surveillance during March-October 2021 confirmed genetic stability of the primary attenuating site. Sequence data generated through this unprecedented global effort confirm the genetic stability of nOPV2 relative to Sabin 2 and suggest that nOPV2 will be an important tool in the eradication of poliomyelitis. nOPV2 surveillance should continue for the duration of the EUL. |
Evaluating stability of attenuated Sabin and two novel type 2 oral poliovirus vaccines in children.
Wahid R , Mercer L , Gast C , De Leon T , Sáez-Llorens X , Fix A , Macadam A , Stephens L , Chumakov K , Smits SL , Murreddu M , Konopka-Anstadt JL , Steven Oberste M , Burns CC , Andino R , Bachtiar NS , Tritama E , Bandyopadhyay AS , Aguirre G , Rüttimann R , Konz JO . NPJ Vaccines 2022 7 (1) 19 Novel oral poliovirus vaccine type 2 (nOPV2) is being developed to reduce the rare occurrence of disease and outbreaks associated with the genetic instability of the Sabin vaccine strains. Children aged 1 to 5 years were enrolled in two related clinical studies to assess safety, immunogenicity, shedding rates and properties of the shed virus following vaccination with nOPV2 (two candidates) versus traditional Sabin OPV type 2 (mOPV2). The anticipated pattern of reversion and increased virulence was observed for shed Sabin-2 virus, as assessed using a mouse model of poliovirus neurovirulence. In contrast, there were significantly reduced odds of mouse paralysis for shed virus for both nOPV2 candidates when compared to shed Sabin-2 virus. Next-generation sequencing of shed viral genomes was consistent with and further supportive of the observed neurovirulence associated with shed Sabin-2 virus, as well as the reduced reversion to virulence of shed candidate viruses. While shed Sabin-2 showed anticipated A481G reversion in the primary attenuation site in domain V in the 5' untranslated region to be associated with increased mouse paralysis, the stabilized domain V in the candidate viruses did not show polymorphisms consistent with reversion to neurovirulence. The available data from a key target age group for outbreak response confirm the superior genetic and phenotypic stability of shed nOPV2 strains compared to shed Sabin-2 and suggest that nOPV2 should be associated with less paralytic disease and potentially a lower risk of seeding new outbreaks. |
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. |
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. |
Updated Characterization of Outbreak Response Strategies for 2019-2029: Impacts of Using a Novel Type 2 Oral Poliovirus Vaccine Strain.
Kalkowska DA , Pallansch MA , Wilkinson A , Bandyopadhyay AS , Konopka-Anstadt JL , Burns CC , Oberste MS , Wassilak SGF , Badizadegan K , Thompson KM . Risk Anal 2020 41 (2) 329-348 Delays in achieving the global eradication of wild poliovirus transmission continue to postpone subsequent cessation of all oral poliovirus vaccine (OPV) use. Countries must stop OPV use to end all cases of poliomyelitis, including vaccine-associated paralytic polio (VAPP) and cases caused by vaccine-derived polioviruses (VDPVs). The Global Polio Eradication Initiative (GPEI) coordinated global cessation of all type 2 OPV (OPV2) use in routine immunization in 2016 but did not successfully end the transmission of type 2 VDPVs (VDPV2s), and consequently continues to use type 2 OPV (OPV2) for outbreak response activities. Using an updated global poliovirus transmission and OPV evolution model, we characterize outbreak response options for 2019-2029 related to responding to VDPV2 outbreaks with a genetically stabilized novel OPV (nOPV2) strain or with the currently licensed monovalent OPV2 (mOPV2). Given uncertainties about the properties of nOPV2, we model different assumptions that appear consistent with the evidence on nOPV2 to date. Using nOPV2 to respond to detected cases may reduce the expected VDPV and VAPP cases and the risk of needing to restart OPV2 use in routine immunization compared to mOPV2 use for outbreak response. The actual properties, availability, and use of nOPV2 will determine its effects on type 2 poliovirus transmission in populations. Even with optimal nOPV2 performance, countries and the GPEI would still likely need to restart OPV2 use in routine immunization in OPV-using countries if operational improvements in outbreak response to stop the transmission of cVDPV2s are not implemented effectively. |
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. |
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. |
Evolving epidemiology of poliovirus serotype 2 following withdrawal of the type 2 oral poliovirus vaccine
Macklin GR , O'Reilly KM , Grassly NC , Edmunds WJ , Mach O , Santhana Gopala Krishnan R , Voorman A , Vertefeuille JF , Abdelwahab J , Gumede N , Goel A , Sosler S , Sever J , Bandyopadhyay AS , Pallansch MA , Nandy R , Mkanda P , Diop OM , Sutter RW . Science 2020 368 (6489) 401-405 While there have been no cases of type-2 wild poliovirus for over 20 years, transmission of type-2 vaccine-derived poliovirus (VDPV2) and associated paralytic cases in several continents represent a threat to eradication. The withdrawal of the type-2 component of oral poliovirus vaccine (OPV2) was implemented in April 2016 to stop VDPV2 emergence and secure eradication of all poliovirus type 2. Globally, children born after this date have limited immunity to prevent transmission. Using a statistical model, we estimate the emergence date and source of VDPV2s detected between May 2016 and November 2019. Outbreak response campaigns with monovalent OPV2 are the only available method to induce immunity to prevent transmission. Yet, our analysis shows that using monovalent OPV2 is generating more paralytic VDPV2 outbreaks with the potential for establishing endemic transmission. The novel OPV2 is urgently required, alongside a contingency strategy if this vaccine does not materialize or perform as anticipated. |
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. |
Facility-associated release of polioviruses into communities-risks for the posteradication era
Bandyopadhyay AS , Singh H , Fournier-Caruana J , Modlin JF , Wenger J , Partridge J , Sutter RW , Zaffran MJ . Emerg Infect Dis 2019 25 (7) 1363-1369 The Global Polio Eradication Initiative continues to make progress toward the eradication target. Indigenous wild poliovirus (WPV) type 2 was last detected in 1999, WPV type 3 was last detected in 2012, and over the past 2 years WPV type 1 has been detected only in parts of 2 countries (Afghanistan and Pakistan). Once the eradication of poliomyelitis is achieved, infectious and potentially infectious poliovirus materials retained in laboratories, vaccine production sites, and other storage facilities will continue to pose a risk for poliovirus reintroduction into communities. The recent breach in containment of WPV type 2 in an inactivated poliovirus vaccine manufacturing site in the Netherlands prompted this review, which summarizes information on facility-associated release of polioviruses into communities reported over >8 decades. Successful polio eradication requires the management of poliovirus containment posteradication to prevent the consequences of the reestablishment of poliovirus transmission. |
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. |
Impact of maternal antibody on the immunogenicity of inactivated polio vaccine in infants immunized with bivalent oral polio vaccine: Implications for the polio eradication endgame
Gaensbauer JT , Gast C , Bandyopadhyay AS , O'Ryan M , Saez-Llorens X , Rivera L , Lopez-Medina E , Melgar M , Weldon WC , Oberste MS , Ruttimann R , Clemens R , Asturias EJ . Clin Infect Dis 2018 67 S57-s65 Background: Quantifying interference of maternal antibodies with immune responses to varying dose schedules of inactivated polio vaccine (IPV) is important for the polio endgame as IPV replaces oral polio vaccine (OPV). Methods: Type 2 poliovirus humoral and intestinal responses were analyzed using pre-IPV type 2 seropositivity as proxy for maternal antibodies from 2 trials in Latin America. Infants received 1 or 2 doses of IPV in sequential IPV-bivalent oral polio vaccine (bOPV) or mixed bOPV-IPV schedules. Results: Among infants vaccinated with bOPV at age 6, 10, and 14 weeks of age and IPV at 14 weeks, those with type 2 pre-IPV seropositivity had lower seroprotection rates than seronegative infants at 4 weeks (92.7% vs 83.8%; difference, 8.9% [95% confidence interval, 0.6%-19.9%]; n = 260) and 22 weeks (82.7% vs 60.4%; difference, 22.3 [12.8%-32.4%]; n = 481) post-IPV. A second IPV at age 36 weeks resulted in 100% seroprotection in both groups. Among infants vaccinated with 1 IPV at age 8 weeks followed by 2 doses of bOPV, pre-IPV type 2-seropositive infants had lower seroprotection at age 28 weeks than those who were seronegative (93.0% vs 73.9%; difference, 19.6% [95% confidence interval, 7.3%-29.4%]; n = 168). A second dose of IPV at 16 weeks achieved >97% seroprotection at age 24 or 28 weeks, regardless of pre-IPV status. Poliovirus shedding after challenge with monovalent OPV, serotype 2, was higher in pre-IPV seropositive infants given sequential IPV-bOPV. No differences were observed in the mixed bOPV-IPV schedule. Conclusions: The presence of maternal antibody is associated with lower type 2 post-IPV seroprotection rates among infants who receive a single dose of IPV. This impact persists until late in infancy and is overcome by a second IPV dose. |
Intestinal immunity to poliovirus following sequential trivalent inactivated polio vaccine/bivalent oral polio vaccine and trivalent inactivated polio vaccine-only immunization schedules: Analysis of an open-label, randomized, controlled trial in Chilean infants
Brickley EB , Wieland-Alter W , Connor RI , Ackerman ME , Boesch AW , Arita M , Weldon WC , O'Ryan MG , Bandyopadhyay AS , Wright PF . Clin Infect Dis 2018 67 S42-s50 Background: Identifying polio vaccine regimens that can elicit robust intestinal mucosal immunity and interrupt viral transmission is a key priority of the polio endgame. Methods: In a 2013 Chilean clinical trial (NCT01841671) of trivalent inactivated polio vaccine (IPV) and bivalent oral polio vaccine (bOPV; targeting types 1 and 3), infants were randomized to receive IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV at 8, 16, and 24 weeks of age and challenged with monovalent oral polio vaccine type 2 (mOPV2) at 28 weeks. Using fecal samples collected from 152 participants, we investigated the extent to which IPV-bOPV and IPV-only immunization schedules induced intestinal neutralizing activity and immunoglobulin A against polio types 1 and 2. Results: Overall, 37% of infants in the IPV-bOPV groups and 26% in the IPV-only arm had detectable type 2-specific stool neutralization after the primary vaccine series. In contrast, 1 challenge dose of mOPV2 induced brisk intestinal immune responses in all vaccine groups, and significant rises in type 2-specific stool neutralization titers (P < .0001) and immunoglobulin A concentrations (P < 0.0001) were measured 2 weeks after the challenge. In subsidiary analyses, duration of breastfeeding also appeared to be associated with the magnitude of polio-specific mucosal immune parameters measured in infant fecal samples. Conclusions: Taken together, these results underscore the concept that mucosal and systemic immune responses to polio are separate in their induction, functionality, and potential impacts on transmission and, specifically, provide evidence that primary vaccine regimens lacking homologous live vaccine components are likely to induce only modest, type-specific intestinal immunity. |
Effectiveness of practices to support appropriate laboratory test utilization: A laboratory medicine best practices systematic review and meta-analysis
Rubinstein M , Hirsch R , Bandyopadhyay K , Madison B , Taylor T , Ranne A , Linville M , Donaldson K , Lacbawan F , Cornish N . Am J Clin Pathol 2018 149 (3) 197-221 Objectives: To evaluate the effectiveness of practices used to support appropriate clinical laboratory test utilization. Methods: This review followed the Centers for Disease Control and Prevention (CDC) Laboratory Medicine Best Practices A6 cycle method. Eligible studies assessed one of the following practices for effect on outcomes relating to over- or underutilization: computerized provider order entry (CPOE), clinical decision support systems/tools (CDSS/CDST), education, feedback, test review, reflex testing, laboratory test utilization (LTU) teams, and any combination of these practices. Eligible outcomes included intermediate, systems outcomes (eg, number of tests ordered/performed and cost of tests), as well as patient-related outcomes (eg, length of hospital stay, readmission rates, morbidity, and mortality). Results: Eighty-three studies met inclusion criteria. Fifty-one of these studies could be meta-analyzed. Strength of evidence ratings for each practice ranged from high to insufficient. Conclusion: Practice recommendations are made for CPOE (specifically, modifications to existing CPOE), reflex testing, and combined practices. No recommendation for or against could be made for CDSS/CDST, education, feedback, test review, and LTU. Findings from this review serve to inform guidance for future studies. |
Intestinal immune responses to type 2 oral polio vaccine (OPV) challenge in infants previously immunized with bivalent OPV and either high-dose or standard inactivated polio vaccine
Brickley EB , Strauch CB , Wieland-Alter WF , Connor RI , Lin S , Weiner JA , Ackerman ME , Arita M , Oberste MS , Weldon WC , Saez-Llorens X , Bandyopadhyay AS , Wright PF . J Infect Dis 2018 217 (3) 371-380 Background: The impact of inactivated polio vaccines (IPVs) on intestinal mucosal immune responses to live poliovirus is poorly understood. Methods: In a 2014 phase 2 clinical trial, Panamanian infants were immunized at 6, 10, and 14 weeks of age with bivalent oral polio vaccine (bOPV) and randomized to receive either a novel monovalent high-dose type 2-specific IPV (mIPV2HD) or a standard trivalent IPV at 14 weeks. Infants were challenged at 18 weeks with a monovalent type 2 oral polio vaccine (mOPV2). Infants' intestinal immune responses during the 3 weeks following challenge were investigated by measuring poliovirus type-specific neutralization and immunoglobulin (Ig) A, IgA1, IgA2, IgD, IgG, and IgM antibodies in stool samples. Results: Despite mIPV2HD's 4-fold higher type 2 polio D-antigen content and heightened serum neutralization profile, mIPV2HD-immunized infants' intestinal immune responses to mOPV2 challenge were largely indistinguishable from those receiving standard IPV. Mucosal responses were tightly linked to evidence of active infection and, in the 79% of participants who shed virus, robust type 2-specific IgA responses and stool neutralization were observed by 2 weeks after challenge. Conclusions: Enhancing IPV-induced serum neutralization does not substantively improve intestinal mucosal immune responses or limit viral shedding on mOPV2 challenge. Clinical Trials Registration: NCT02111135. |
Effectiveness of laboratory practices to reducing patient misidentification due to specimen labeling errors at the time of specimen collection in healthcare settings: LMBP Systematic Review
Sandhu P , Bandyopadhyay K , Ernst DJ , Hunt W , Taylor TH Jr , Birch R , Krolak J , Geaghan S . J Appl Lab Med 2017 2 (2) 244-258 Background: Specimen labeling errors have long plagued the laboratory industry putting patients at risk of transfusion-related death, medication errors, misdiagnosis, and patient mismanagement. Many interventions have been implemented and deemed to be effective in reducing sample error rates. The objective of this review was to identify and evaluate the effectiveness of laboratory practices/ interventions to develop evidence based recommendations for the best laboratory practices to reduce labeling errors. Content: The standardized LMBP A-6 methods were used to conduct this systematic review. Total evidence included 12 studies published during the time periods of 1980 to September 2015. Combined data from seven studies found that the interventions developed as a result of improved communication and collaboration between the laboratory and clinical staff resulted in substantial decrease in specimen labeling errors (Median relative percent change in labeling errors: -75.86; IQI: -84.77, -58.00). Further data from subset of four studies showed a significant decrease in specimen labeling errors after the institution of the standardized specimen labeling protocols (Median relative percent decrease in specimen labeling errors: -72.45; IQI: -83.25, -46.50). Summary: Based on the evidence included in this review, the interventions that enhance the communication and collaboration between laboratory and healthcare professionals can decrease the specimen identification errors in healthcare settings. However, more research is needed to make the conclusion on the effectiveness of other evaluated practices in this review including training and education of the specimen collection staff, audit and feedback of labeling errors, and implementation of new technology (other than barcoding). |
Exploring the relationship between polio type 2 serum neutralizing antibodies and intestinal immunity using data from two randomized controlled trials of new bOPV-IPV immunization schedules
Bandyopadhyay AS , Asturias EJ , O'Ryan M , Oberste MS , Weldon W , Clemens R , Ruttimann R , Modlin JF , Gast C . Vaccine 2017 35 (52) 7283-7291 BACKGROUND: Inactivated polio vaccine (IPV) is now the only source of routine type 2 protection. The relationship, if any, between vaccine-induced type 2 humoral and intestinal immunity is poorly understood. METHODS: Two clinical trials in five Latin American countries of mixed or sequential bOPV-IPV schedules in 1640 infants provided data on serum neutralizing antibodies (NAb) and intestinal immunity, assessed as viral shedding following oral mOPV2 challenge. Analyses with generalized additive and quantile regression models examined the relationships between prechallenge NAb titers and proportion, duration and titers (magnitude) of viral shedding. RESULTS: We found a statistically significant (p<.0001) but weak relationship between NAb titer at the time of mOPV2 challenge and the Shedding Index Endpoint, the mean log10 stool viral titer over 4 post-challenge assessments. Day 28 post-challenge shedding was 13.4% (8.1%, 18.8%) lower and the Day 21 post-challenge median titer of shed virus was 3.10 log10 (2.21, 3.98) lower for subjects with NAb titers at the ULOQ as compared with LLOQ on day of challenge. Overall, there was a weak but significant negative relationship, with high NAb titers associated with lower rates of viral shedding, an effect supported by subset analysis to elucidate between-country differences. CONCLUSIONS: Taken alone, the weak association between pre-challenge NAb titers following IPV or mixed/sequential bOPV/IPV immunization and differences in intestinal immunity is insufficient to predict polio type 2 intestinal immunity; even very high titers may not preclude viral shedding. Further research is needed to identify predictive markers of intestinal immunity in the context of global OPV cessation and IPV-only immunization. |
Inactivated polio vaccines from three different manufacturers have equivalent safety and immunogenicity when given as 1 or 2 additional doses after bivalent OPV: Results from a randomized controlled trial in Latin America
Lopez-Medina E , Melgar M , Gaensbauer JT , Bandyopadhyay AS , Borate BR , Weldon WC , Ruttimann R , Ward J , Clemens R , Asturias EJ . Vaccine 2017 35 (28) 3591-3597 BACKGROUND: Since April 2016 inactivated poliovirus vaccine (IPV) has been the only routine source of polio type 2 protection worldwide. With IPV supply constraints, data on comparability of immunogenicity and safety will be important to optimally utilize available supplies from different manufacturers. METHODS: In this multicenter phase IV study, 900 Latin American infants randomly assigned to six study groups received three doses of bOPV at 6, 10 and 14weeks and either one IPV dose at 14weeks (groups SP-1, GSK-1 and BBio-1) or two IPV doses at 14 and 36weeks (groups SP-2, GSK-2 and BBio-2) from three different manufacturers. Children were challenged with mOPV2 at either 18 (one IPV dose) or 40weeks (two IPV doses) and stools were collected weekly for 4weeks to assess viral shedding. Serum neutralizing antibodies were measured at various time points pre and post vaccination. Serious adverse events and important medical events (SAE and IME) were monitored for 6months after last study vaccine. RESULTS: At week 18, 4weeks after one dose of IPV, overall type 2 seroconversion rates were 80.4%, 80.4% and 73.3% for SP-1, GSK-1 and BBio-1 groups, respectively; and 92.6%, 96.8% and 88.0% in those who were seronegative before IPV administration. At 40weeks, 4weeks after a second IPV dose, type 2 seroconversion rates were ≥99% for any of the three manufacturers. There were no significant differences in fecal shedding index endpoint (SIE) after one or two IPV doses (SP: 2.3 [95% CI: 2.1-2.6]); GSK: 2.2 [1.7-2.5]; BBio 1.8 [1.5-2.3]. All vaccines appeared safe, with no vaccine-related SAE or IME. CONCLUSION: Current WHO prequalified IPV vaccines are safe and induce similar humoral and intestinal immunity after one or two doses. The parent study was registered with ClinicalTrials.gov, number NCT01831050. |
Vaccine-induced mucosal immunity to poliovirus: analysis of cohorts from an open-label, randomised controlled trial in Latin American infants
Wright PF , Connor RI , Wieland-Alter WF , Hoen AG , Boesch AW , Ackerman ME , Oberste MS , Gast C , Brickley EB , Asturias EJ , Ruttimann R , Bandyopadhyay AS . Lancet Infect Dis 2016 16 (12) 1377-1384 BACKGROUND: Identification of mechanisms that limit poliovirus replication is crucial for informing decisions aimed at global polio eradication. Studies of mucosal immunity induced by oral poliovirus (OPV) or inactivated poliovirus (IPV) vaccines and mixed schedules thereof will determine the effectiveness of different vaccine strategies to block virus shedding. We used samples from a clinical trial of different vaccination schedules to measure intestinal immunity as judged by neutralisation of virus and virus-specific IgA in stools. METHODS: In the FIDEC trial, Latin American infants were randomly assigned to nine groups to assess the efficacy of two schedules of bivalent OPV (bOPV) and IPV and challenge with monovalent type 2 OPV, and stools samples were collected. We selected three groups of particular interest-the bOPV control group (serotypes 1 and 3 at 6, 10, and 14 weeks), the trivalent attenuated OPV (tOPV) control group (tOPV at 6, 10, and 14 weeks), and the bOPV-IPV group (bOPV at 6, 10, and 14 weeks plus IPV at 14 weeks). Neutralising activity and poliovirus type-specific IgA were measured in stool after a monovalent OPV type 2 challenge at 18 weeks of age. Mucosal immunity was measured by in-vitro neutralisation of a type 2 polio pseudovirus (PV2). Neutralisation titres and total and poliovirus-type-specific IgG and IgA concentrations in stools were assessed in samples collected before challenge and 2 weeks after challenge from all participants. FINDINGS: 210 infants from Guatemala and Dominican Republic were included in this analysis. Of 38 infants tested for mucosal antibody in the tOPV group, two were shedding virus 1 week after challenge, compared with 59 of 85 infants receiving bOPV (p<0.0001) and 53 of 87 infants receiving bOPV-IPV (p<0.0001). Mucosal type 2 neutralisation and type-specific IgA were noted primarily in response to tOPV. An inverse correlation was noted between virus shedding and both serum type 2 neutralisation at challenge (p<0.0001) and mucosal type 2 neutralisation at challenge (p<0.0001). INTERPRETATION: Mucosal type-2-specific antibodies can be measured in stool and develop in response to receipt of OPV type 2 either in the primary vaccine series or at challenge. These mucosal antibodies influence the amount of virus that is shed in an established infection. FUNDING: Bill & Melinda Gates Foundation. |
Humoral and intestinal immunity induced by new schedules of bivalent oral poliovirus vaccine and one or two doses of inactivated poliovirus vaccine in Latin American infants: an open-label randomised controlled trial
Asturias EJ , Bandyopadhyay AS , Self S , Rivera L , Saez-Llorens X , Lopez E , Melgar M , Gaensbauer JT , Weldon WC , Oberste MS , Borate BR , Gast C , Clemens R , Orenstein W , O'Ryan M , Jimeno J , Clemens SA , Ward J , Ruttimann R . Lancet 2016 388 (10040) 158-69 BACKGROUND: Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV. METHODS: This open-label randomised controlled multicentre trial was part of a larger study. 6-week-old full-term infants due for their first polio vaccinations, who were healthy on physical examination, with no obvious medical conditions and no known chronic medical disorders, were enrolled from four investigational sites in Colombia, Dominican Republic, Guatemala, and Panama. The infants were randomly assigned by permuted block randomisation (through the use of a computer-generated list, block size 36) to nine groups, of which five will be discussed in this report. These five groups were randomly assigned 1:1:1:1 to four permutations of schedule: groups 1 and 2 (control groups) received bOPV at 6, 10, and 14 weeks; group 3 (also a control group, which did not count as a permutation) received tOPV at 6, 10, and 14 weeks; group 4 received bOPV plus one dose of IPV at 14 weeks; and group 5 received bOPV plus two doses of IPV at 14 and 36 weeks. Infants in all groups were challenged with monovalent type 2 vaccine (mOPV2) at 18 weeks (groups 1, 3, and 4) or 40 weeks (groups 2 and 5). The primary objective was to assess the superiority of bOPV-IPV schedules over bOPV alone, as assessed by the primary endpoints of humoral immunity (neutralising antibodies-ie, seroconversion) to all three serotypes and intestinal immunity (faecal viral shedding post-challenge) to serotype 2, analysed in the per-protocol population. Serious and medically important adverse events were monitored for up to 6 months after the study vaccination. This study is registered with ClinicalTrials.gov, number NCT01831050, and has been completed. FINDINGS: Between May 20, 2013, and Aug 15, 2013, 940 eligible infants were enrolled and randomly assigned to the five treatment groups (210 to group 1, 210 to group 2, 100 to group 3, 210 to group 4, and 210 to group 5). One infant in group 1 was not vaccinated because their parents withdrew consent after enrolment and randomisation, so 939 infants actually received the vaccinations. Three doses of bOPV or tOPV elicited type 1 and 3 seroconversion rates of at least 97.7%. Type 2 seroconversion occurred in 19 of 198 infants (9.6%, 95% CI 6.2-14.5) in the bOPV-only groups, 86 of 88 (97.7%, 92.1-99.4) in the tOPV-only group (p<0.0001 vs bOPV-only), and 156 of 194 (80.4%, 74.3-85.4) infants in the bOPV-one dose of IPV group (p<0.0001 vs bOPV-only). A further 20 of 193 (10%) infants in the latter group seroconverted 1 week after mOPV2 challenge, resulting in around 98% of infants being seropositive against type 2. After a bOPV-two IPV schedule, all 193 infants (100%, 98.0-100; p<0.0001 vs bOPV-only) seroconverted to type 2. IPV induced small but significant decreases in a composite serotype 2 viral shedding index after mOPV2 challenge. 21 serious adverse events were reported in 20 patients during the study, including two that were judged to be possibly related to the vaccines. Most of the serious adverse events (18 [86%] of 21) and 24 (80%) of the 30 important medical events reported were infections and infestations. No deaths occurred during the study. INTERPRETATION: bOPV provided humoral protection similar to tOPV against polio serotypes 1 and 3. After one or two IPV doses in addition to bOPV, 80% and 100% of infants seroconverted, respectively, and the vaccination induced a degree of intestinal immunity against type 2 poliovirus. FUNDING: Bill & Melinda Gates Foundation. |
Immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine in infants: a comparative, observer-blind, randomised, controlled trial
Saez-Llorens X , Clemens R , Leroux-Roels G , Jimeno J , Clemens SA , Weldon WC , Oberste MS , Molina N , Bandyopadhyay AS . Lancet Infect Dis 2015 16 (3) 321-30 BACKGROUND: Following the proposed worldwide switch from trivalent oral poliovirus vaccine (tOPV) to bivalent types 1 and 3 OPV (bOPV) in 2016, inactivated poliovirus vaccine (IPV) will be the only source of protection against poliovirus type 2. With most countries opting for one dose of IPV in routine immunisation schedules during this transition because of cost and manufacturing constraints, optimisation of protection against all poliovirus types will be a priority of the global eradication programme. We assessed the immunogenicity and safety of a novel monovalent high-dose inactivated poliovirus type 2 vaccine (mIPV2HD) in infants. METHODS: This observer-blind, comparative, randomised controlled trial was done in a single centre in Panama. We enrolled healthy infants who had not received any previous vaccination against poliovirus. Infants were randomly assigned (1:1) by computer-generated randomisation sequence to receive a single dose of either mIPV2HD or standard trivalent IPV given concurrently with a third dose of bOPV at 14 weeks of age. At 18 weeks, all infants were challenged with one dose of monovalent type 2 OPV (mOPV2). Primary endpoints were seroconversion and median antibody titres to type 2 poliovirus 4 weeks after vaccination with mIPV2HD or IPV; and safety (as determined by the proportion and nature of serious adverse events and important medical events for 8 weeks after vaccination). The primary immunogenicity analyses included all participants for whom a post-vaccination blood sample was available. All randomised participants were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02111135. FINDINGS: Between April 14 and May 9, 2014, 233 children were enrolled and randomly assigned to receive mIPV2HD (117 infants) or IPV (116 infants). 4 weeks after vaccination with mIPV2HD or IPV, seroconversion to poliovirus type 2 was recorded in 107 (93.0%, 95% CI 86.8-96.9) of 115 infants in the mIPV2HD group compared with 86 (74.8%, 65.8-82.4) of 115 infants in the IPV group (difference between groups 18.3%, 95% CI 5.0-31.1; p<0.0001), and median antibody titres against poliovirus type 2 were 181 (95% CI 72.0-362.0) in the mIPV2HD group and 36 (18.0-113.8) in the IPV group (difference between groups 98.8, 95% CI 60.7-136.9; p<0.0001). Serious adverse events were reported for six (5%) of 117 infants in the mIPV2HD group and seven (6%) of 116 infants in the IPV group during the 8-week period after vaccination; none were related to vaccination. No important medical events were reported. INTERPRETATION: Our findings lend support to the use of mIPV2HD as an option for stockpiling for outbreak response or primary protection in selected areas at risk for emergence of poliovirus type 2 during the next phase of the polio eradication plan. FUNDING: Bill & Melinda Gates Foundation. |
Impact of prompt influenza antiviral treatment on extended care needs after influenza hospitalization among community-dwelling older adults
Chaves SS , Perez A , Miller L , Bennett NM , Bandyopadhyay A , Farley MM , Fowler B , Hancock EB , Kirley PD , Lynfield R , Ryan P , Morin C , Schaffner W , Sharangpani R , Lindegren ML , Tengelsen L , Thomas A , Hill MB , Bradley KK , Oni O , Meek J , Zansky S , Widdowson MA , Finelli L . Clin Infect Dis 2015 61 (12) 1807-14 BACKGROUND: Patients hospitalized with influenza may require extended care upon discharge. We aimed to explore predictors for extended care needs and the potential mitigating effect of antiviral treatment among community-dwelling adults aged ≥65 years hospitalized with influenza. METHODS: We used laboratory-confirmed influenza hospitalizations from 3 influenza seasons. Extended care was defined as new placement in a skilled nursing home/long-term/rehabilitation facility upon hospital discharge. We focused on those treated with antiviral agents to explore the effect of early treatment on extended care and hospital length of stay (LOS) using logistic regression and competing risk survival analysis, accounting for time from illness onset to hospitalization. Treatment was categorized as early (≤4 days) and late (>4 days) in reference to date of illness onset. RESULTS: Among 6,593 community-dwelling adults aged ≥65 years hospitalized for influenza, 18% required extended care at discharge. Need for care increased with age and neurologic disorders, ICU admission, and pneumonia were predictors of care needs. Early treatment reduced the odds of extended care after hospital discharge for those hospitalized ≤2 or >2 days from illness onset (adjusted odds ratio [aOR] 0.38; 95% confidence interval [CI] 0.17, 0.85, and aOR 0.75; 95% CI 0.56, 0.97 respectively). Early treatment was also independently associated with reduction in LOS for those hospitalized ≤2 days from illness onset (adjusted hazard ratio [aHR] 1.81; 95% CI 1.43, 2.30) or >2 days (aHR 1.30; 95% CI 1.20, 1.40). CONCLUSIONS: Prompt antiviral treatment decreases the impact of influenza on older adults through shorten hospitalization and reduced extended care needs. |
Inactivated poliovirus vaccine given alone or in a sequential schedule with bivalent oral poliovirus vaccine in Chilean infants: a randomised, controlled, open-label, phase 4, non-inferiority study
O'Ryan M , Bandyopadhyay AS , Villena R , Espinoza M , Novoa J , Weldon WC , Oberste MS , Self S , Borate BR , Asturias EJ , Clemens R , Orenstein W , Jimeno J , Ruttimann R , Costa Clemens SA . Lancet Infect Dis 2015 15 (11) 1273-82 BACKGROUND: Bivalent oral poliovirus vaccine (bOPV; types 1 and 3) is expected to replace trivalent OPV (tOPV) globally by April, 2016, preceded by the introduction of at least one dose of inactivated poliovirus vaccine (IPV) in routine immunisation programmes to eliminate vaccine-associated or vaccine-derived poliomyelitis from serotype 2 poliovirus. Because data are needed on sequential IPV-bOPV schedules, we assessed the immunogenicity of two different IPV-bOPV schedules compared with an all-IPV schedule in infants. METHODS: We did a randomised, controlled, open-label, non-inferiority trial with healthy, full-term (>2.5 kg birthweight) infants aged 8 weeks (+/- 7 days) at six well-child clinics in Santiago, Chile. We used supplied lists to randomly assign infants (1:1:1) to receive three polio vaccinations (IPV by injection or bOPV as oral drops) at age 8, 16, and 24 weeks in one of three sequential schedules: IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV. We did the randomisation with blocks of 12 stratified by study site. All analyses were done in a masked manner. Co-primary outcomes were non-inferiority of the bOPV-containing schedules compared with the all-IPV schedule for seroconversion (within a 10% margin) and antibody titres (within two-thirds log2 titres) to poliovirus serotypes 1 and 3 at age 28 weeks, analysed in the per-protocol population. Secondary outcomes were seroconversion and titres to serotype 2 and faecal shedding for 4 weeks after a monovalent OPV type 2 challenge at age 28 weeks. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01841671, and is closed to new participants. FINDINGS: Between April 25 and August 1, 2013, we assigned 570 infants to treatment: 190 to IPV-bOPV-bOPV, 192 to IPV-IPV-bOPV, and 188 to IPV-IPV-IPV. 564 (99%) were vaccinated and included in the intention-to-treat cohort, and 537 (94%) in the per-protocol analyses. In the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, the proportions of children with seroconversion to type 1 poliovirus were 166 (98.8%) of 168, 95% CI 95.8-99.7; 178 (100%), 97.9-100.0; and 175 (100%), 97.9-100.0. Proportions with seroconvsion to type 3 poliovirus were 163 (98.2%) of 166, 94.8-99.4; 177 (100%), 97.9-100.0, and 172 (98.9%) of 174, 95.9-99.7. Non-inferiority was thus shown for the bOPV-containing schedules compared with the all-IPV schedule, with no significant differences between groups. In the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, the proportions of children with seroprotective antibody titres to type 1 poliovirus were 168 (98.8%) of 170, 95% CI 95.8-99.7; 181 (100%), 97.9-100.0; and 177 (100%), 97.9-100.0. Proportions to type 3 poliovirus were 166 (98.2%) of 169, 94.9-99.4; 180 (100%), 97.9-100.0; and 174 (98.9%) of 176, 96.0-99.7. Non-inferiority comparisons could not be done for this outcome because median titres for the groups receiving OPV were greater than the assay's upper limit of detection (log2 titres >10.5). The proportions of children seroconverting to type 2 poliovirus in the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, were 130 (77.4%) of 168, 95% CI 70.5-83.0; 169 (96.0%) of 176, 92.0-98.0; and 175 (100%), 97.8-100. IPV-bOPV schedules resulted in almost a 0.3 log reduction of type 2 faecal shedding compared with the IPV-only schedule. No participants died during the trial; 81 serious adverse events were reported, of which one was thought to be possibly vaccine-related (intestinal intussusception). INTERPRETATION: Seroconversion rates against polioviruses types 1 and 3 were non-inferior in sequential schedules containing IPV and bOPV, compared with an all-IPV schedule, and proportions of infants with protective antibodies were high after all three schedules. One or two doses of bOPV after IPV boosted intestinal immunity for poliovirus type 2, suggesting possible cross protection. Additionally, there was evidence of humoral priming for type 2 from one dose of IPV. Our findings could give policy makers flexibility when choosing a vaccination schedule, especially when trying to eliminate vaccine-associated and vaccine-derived poliomyelitis. FUNDING: Bill & Melinda Gates Foundation. |
Comparing clinical characteristics between hospitalized adults with laboratory-confirmed influenza A and B virus infection
Su S , Chaves SS , Perez A , D'Mello T , Kirley PD , Yousey-Hindes K , Farley MM , Harris M , Sharangpani R , Lynfield R , Morin C , Hancock EB , Zansky S , Hollick GE , Fowler B , McDonald-Hamm C , Thomas A , Horan V , Lindegren ML , Schaffner W , Price A , Bandyopadhyay A , Fry AM . Clin Infect Dis 2014 59 (2) 252-5 We challenge the notion that influenza B virus infection is milder than influenza A virus infection by finding similar clinical characteristics and outcomes between adults hospitalized with these two types of influenza. Among patients treated with oseltamivir, length of stay and mortality did not differ by type of virus infection. |
- Page last reviewed:Feb 1, 2024
- Page last updated:May 13, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure