Publications by authors named "Theresa Fitzgerald"

25 Publications

  • Page 1 of 1

Characterization of SARS-CoV-2 RNA, Antibodies, and Neutralizing Capacity in Milk Produced by Women with COVID-19.

mBio 2021 02 9;12(1). Epub 2021 Feb 9.

Margaret Ritchie School of Family and Consumer Sciences, University of Idaho, Moscow, Idaho, USA

Whether mother-to-infant SARS-CoV-2 transmission can occur during breastfeeding and, if so, whether the benefits of breastfeeding outweigh this risk during maternal COVID-19 illness remain important questions. Using RT-qPCR, we did not detect SARS-CoV-2 RNA in any milk sample (= 37) collected from 18 women following COVID-19 diagnosis. Although we detected evidence of viral RNA on 8 out of 70 breast skin swabs, only one was considered a conclusive positive result. In contrast, 76% of the milk samples collected from women with COVID-19 contained SARS-CoV-2-specific IgA, and 80% had SARS-CoV-2-specific IgG. In addition, 62% of the milk samples were able to neutralize SARS-CoV-2 infectivity , whereas milk samples collected prior to the COVID-19 pandemic were unable to do so. Taken together, our data do not support mother-to-infant transmission of SARS-CoV-2 via milk. Importantly, milk produced by infected mothers is a beneficial source of anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results support recommendations to continue breastfeeding during mild-to-moderate maternal COVID-19 illness. Results from prior studies assaying human milk for the presence of SARS-CoV-2, the causative virus of COVID-19, have suggested milk may act as a potential vehicle for mother-to-child transmission. Most previous studies are limited because they followed only a few participants, were cross-sectional, and/or failed to report how milk was collected and/or analyzed. As such, considerable uncertainty remains regarding whether human milk is capable of transmitting SARS-CoV-2 from mother to child. Here, we report that repeated milk samples collected from 18 women following COVID-19 diagnosis did not contain SARS-CoV-2 RNA; however, risk of transmission via breast skin should be further evaluated. Importantly, we found that milk produced by infected mothers is a source of anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results support recommendations to continue breastfeeding during mild-to-moderate maternal COVID-19 illness as milk likely provides specific immunologic benefits to infants.
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http://dx.doi.org/10.1128/mBio.03192-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885115PMC
February 2021

Gaps in Serologic Immunity against Contemporary Swine-Origin Influenza A Viruses among Healthy Individuals in the United States.

Viruses 2021 Jan 18;13(1). Epub 2021 Jan 18.

Department of Veterinary Preventive Medicine, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA.

Influenza A Viruses (IAV) in domestic swine (IAV-S) are associated with sporadic zoonotic transmission at the human-animal interface. Previous pandemic IAVs originated from animals, which emphasizes the importance of characterizing human immunity against the increasingly diverse IAV-S. We analyzed serum samples from healthy human donors ( = 153) using hemagglutination-inhibition (HAI) assay to assess existing serologic protection against a panel of contemporary IAV-S isolated from swine in the United States ( = 11). Age-specific seroprotection rates (SPR), which are the proportion of individuals with HAI ≥ 1:40, corresponded with lower or moderate pandemic risk classifications for the multiple IAV-S examined (one H1-δ1, one H1-δ2, three H3-IVA, one H3-IVB, one H3-IVF). Individuals born between 2004 and 2013 had SPRs of 0% for the five classified H3 subtype IAV-S, indicating youth may be particularly predisposed to infection with these viruses. Expansion of existing immunologic gaps over time could increase likelihood of future IAV-S spillover to humans and facilitate subsequent sustained human-to-human transmission resulting in disease outbreaks with pandemic potential.
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http://dx.doi.org/10.3390/v13010127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830885PMC
January 2021

COVID-19 and human milk: SARS-CoV-2, antibodies, and neutralizing capacity.

medRxiv 2020 Sep 18. Epub 2020 Sep 18.

Background: It is not known whether SARS-CoV-2 can be transmitted from mother to infant during breastfeeding, and if so whether the benefits of breastfeeding outweigh this risk. This study was designed to evaluate 1) if SARS-CoV-2 RNA can be detected in milk and on the breast of infected women, 2) concentrations of milk-borne anti-SARS-CoV-2 antibodies, and 3) the capacity of milk to neutralize SARS-CoV-2 infectivity.

Methods: We collected 37 milk samples and 70 breast swabs (before and after breast washing) from 18 women recently diagnosed with COVID-19. Samples were analyzed for SARS-CoV-2 RNA using RT-qPCR. Milk was also analyzed for IgA and IgG specific for the nucleocapsid protein, receptor binding domain (RBD), S2 subunit of the spike protein of SARS-CoV-2, as well as 2 seasonal coronaviruses using ELISA; and for its ability to neutralize SARS-CoV-2.

Results: We did not detect SARS-CoV-2 RNA in any milk sample. In contrast, SARS-CoV-2 RNA was detected on several breast swabs, although only one was considered conclusive. All milk contained SARS-CoV-2-specific IgA and IgG, and levels of anti-RBD IgA correlated with SARS-CoV-2 neutralization. Strong correlations between levels of IgA and IgG to SARS-CoV-2 and seasonal coronaviruses were noted.

Conclusions: Our data do not support maternal-to-child transmission of SARS-CoV-2 via milk; however, risk of transmission via breast skin should be further evaluated. Importantly, milk produced by infected mothers is a source of anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results support recommendations to continue breastfeeding during mild-to-moderate maternal COVID-19 illness.
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http://dx.doi.org/10.1101/2020.09.16.20196071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523143PMC
September 2020

Characterizing Emerging Canine H3 Influenza Viruses.

PLoS Pathog 2020 04 14;16(4):e1008409. Epub 2020 Apr 14.

Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned.
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http://dx.doi.org/10.1371/journal.ppat.1008409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182277PMC
April 2020

Monoclonal Antibody Responses after Recombinant Hemagglutinin Vaccine versus Subunit Inactivated Influenza Virus Vaccine: a Comparative Study.

J Virol 2019 11 15;93(21). Epub 2019 Oct 15.

Department of Medicine, Section of Rheumatology, The University of Chicago, Chicago, Illinois, USA

Vaccination is the best measure of protection against influenza virus infection. Vaccine-induced antibody responses target mainly the hemagglutinin (HA) surface glycoprotein, composed of the head and the stalk domains. Recently two novel vaccine platforms have been developed for seasonal influenza vaccination: a recombinant HA vaccine produced in insect cells (Flublok) and Flucelvax, prepared from virions produced in mammalian cells. In order to compare the fine specificity of the antibodies induced by these two novel vaccine platforms, we characterized 42 Flublok-induced monoclonal antibodies (MAbs) and 38 Flucelvax-induced MAbs for avidity, cross-reactivity, and any selectivity toward the head versus the stalk domain. These studies revealed that Flublok induced a greater proportion of MAbs targeting epitopes near the receptor-binding domain on HA head (hemagglutinin inhibition-positive MAbs) than Flucelvax, while the two vaccines induced similar low frequencies of stalk-reactive MAbs. Finally, mice immunized with Flublok and Flucelvax also induced similar frequencies of stalk-reactive antibody-secreting cells, showing that HA head immunodominance is independent of immune memory bias. Collectively, our results suggest that these vaccine formulations are similarly immunogenic but differ in the preferences of the elicited antibodies toward the receptor-binding domain on the HA head. There are ongoing efforts to increase the efficacy of influenza vaccines and to promote production strategies that can rapidly respond to newly emerging viruses. It is important to understand if current alternative seasonal vaccines, such as Flublok and Flucelvax, that use alternate production strategies can induce protective influenza-specific antibodies and to evaluate what type of epitopes are targeted by distinct vaccine formulations.
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http://dx.doi.org/10.1128/JVI.01150-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803255PMC
November 2019

Population Serologic Immunity to Human and Avian H2N2 Viruses in the United States and Hong Kong for Pandemic Risk Assessment.

J Infect Dis 2018 08;218(7):1054-1060

School of Public Health, The University of Hong Kong.

Background: Influenza A pandemics cause significant mortality and morbidity. H2N2 viruses have caused a prior pandemic, and are circulating in avian reservoirs. The age-related frequency of current population immunity to H2 viruses was evaluated.

Methods: Hemagglutinin inhibition (HAI) assays against historical human and recent avian influenza A(H2N2) viruses were performed across age groups in Rochester, New York, and Hong Kong, China. The impact of existing cross-reactive HAI immunity on the effective reproduction number was modeled.

Results: One hundred fifty individual sera from Rochester and 295 from Hong Kong were included. Eighty-five percent of patients born in Rochester and Hong Kong before 1968 had HAI titers ≥1:40 against A/Singapore/1/57, and >50% had titers ≥1:40 against A/Berkeley/1/68. The frequency of titers ≥1:40 to avian H2N2 A/mallard/England/727/06 and A/mallard/Netherlands/14/07 in subjects born before 1957 was 62% and 24%, respectively. There were no H2 HAI titers >1:40 in individuals born after 1968. These levels of seroprevalence reduce the initial reproduction number of A/Singapore/1/1957 or A/Berkeley/1/68 by 15%-20%. A basic reproduction number (R0) of the emerging transmissible virus <1.2 predicts a preventable pandemic.

Conclusions: Population immunity to H2 viruses is insufficient to block epidemic spread of H2 virus. An H2N2 pandemic would have lower impact in those born before 1968.
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http://dx.doi.org/10.1093/infdis/jiy291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107991PMC
August 2018

Directed selection of influenza virus produces antigenic variants that match circulating human virus isolates and escape from vaccine-mediated immune protection.

Immunology 2016 06 30;148(2):160-73. Epub 2016 Mar 30.

David Smith Center for Immunology and Vaccine Biology, Department of Microbiology and Immunology, New York Influenza Center of Excellence at the University of Rochester Medical Center, Rochester, NY, USA.

Influenza vaccination does not provide 100% protection from infection, partly due to antigenic drift of the haemagglutinin (HA) protein. Low serum antibody titres increase the risk of infection. To determine whether there were additional correlates of risk, we examined the relationship between human serum immunity and antigenic variation in seasonal H3N2 influenza viruses. Seasonal H3N2 vaccine strains grown in the presence of heterogeneous human or mono-specific ferret antisera selected variants with mutations in the HA antigenic sites. Surprisingly, circulating strains infecting human subjects in the same seasons displayed mutations in the same positions, although only in one case did the change correspond to the same amino acid. Serum antibody titres were lower against both the in vitro selected and clinical isolates compared with the vaccine strains, suggesting that the mutations are relevant to vaccine failure. Antibody titres were also significantly lower in sera from infected subjects than in non-infected subjects, suggesting relatively poor responses to vaccination in the infected subjects. Collectively, the data suggest that risk from influenza infection is a result of poor response to vaccination, as well as encounter with drifted seasonal influenza virus antigenic variants. The results also show that directed selection under human immune pressure could reveal antigenic variants relevant to real-world drifted viruses, helping in annual vaccine re-formulation.
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http://dx.doi.org/10.1111/imm.12594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863573PMC
June 2016

Evaluation of the Safety and Immunogenicity of a Candidate Pandemic Live Attenuated Influenza Vaccine (pLAIV) Against Influenza A(H7N9).

J Infect Dis 2016 Mar 9;213(6):922-9. Epub 2015 Dec 9.

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda.

Background: We evaluated a candidate A/Anhui/2013(H7N9) pandemic live attenuated influenza vaccine (pLAIV) in healthy adults, and assessed the ability of 1 or 2 doses to induce immune memory.

Methods: Healthy subjects in 2 age groups (18-49 years and 50-70 years) with undetectable hemagglutination-inhibiting (HAI) antibody to H7N9 were enrolled. Younger subjects received either 1 or 2 intranasal doses of 10(7.0) fluorescent focus units of A/Anhui/1/2013 pLAIV, while older subjects received a single dose. All subjects received a single 30-µg dose of unadjuvanted, antigenically matched A/Shanghai2/2013(H7N9) pandemic inactivated influenza vaccine (pIIV) 12 weeks after their first dose of pLAIV.

Results: Both vaccines were well tolerated. Serum HAI antibody responses were detected in 0 of 32 younger subjects and 1 of 17 older subjects after 1 dose of pLAIV and in 2 of 16 younger subjects after a second dose. Strong serum antibody responses were detected after a single subsequent dose of pIIV that was broadly reactive against H7 influenza viruses.

Conclusions: An A(H7N9) pLAIV candidate was safe in both age groups. Priming with pLAIV resulted in responses to subsequent pIIV that exceeded those seen in naive subjects in previous reports. The A(H7N9) pLAIV induces strong immune memory that can be demonstrated by exposure to subsequent antigenic challenge.

Clinical Trials Registration: NCT01995695 and NCT02274545.
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http://dx.doi.org/10.1093/infdis/jiv526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760421PMC
March 2016

High-Affinity H7 Head and Stalk Domain-Specific Antibody Responses to an Inactivated Influenza H7N7 Vaccine After Priming With Live Attenuated Influenza Vaccine.

J Infect Dis 2015 Oct 2;212(8):1270-8. Epub 2015 Apr 2.

David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology.

Recent studies have shown that live attenuated influenza vaccines (LAIVs) expressing avian influenza virus hemagglutinins (HAs) prime for strong protective antibody responses to an inactivated influenza vaccine (IIV) containing the HA. To better understand this priming effect, we compared H7 HA head and stalk domain-specific B-cell responses in H7N7 LAIV-primed subjects and non-H7-primed controls after a single dose of H7N7 IIV. As previously reported, H7N7 LAIV-primed subjects but not control subjects generated strong hemagglutination-inhibiting and neutralizing antibody responses to the H7N7 IIV. Here, we found that the quantity, epitope diversity, and affinity of H7 head-specific antibodies increased rapidly in only H7N7 LAIV-primed subjects after receipt of the IIV. However, all cohorts generated a vigorous, high-affinity, stalk-specific antibody response. Consistent increases in circulating memory B-cell frequencies after receipt of the IIV reflected the specificity of high-affinity antibody production. Our findings emphasize the value of LAIVs as a vehicle for prepandemic vaccination.
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http://dx.doi.org/10.1093/infdis/jiv210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577047PMC
October 2015

Diversifying Selection Analysis Predicts Antigenic Evolution of 2009 Pandemic H1N1 Influenza A Virus in Humans.

J Virol 2015 May 4;89(10):5427-40. Epub 2015 Mar 4.

J. Craig Venter Institute, La Jolla, California, USA Department of Pathology, University of California, San Diego, California, USA

Unlabelled: Although a large number of immune epitopes have been identified in the influenza A virus (IAV) hemagglutinin (HA) protein using various experimental systems, it is unclear which are involved in protective immunity to natural infection in humans. We developed a data mining approach analyzing natural H1N1 human isolates to identify HA protein regions that may be targeted by the human immune system and can predict the evolution of IAV. We identified 16 amino acid sites experiencing diversifying selection during the evolution of prepandemic seasonal H1N1 strains and found that 11 sites were located in experimentally determined B-cell/antibody (Ab) epitopes, including three distinct neutralizing Caton epitopes: Sa, Sb, and Ca2 [A. J. Caton, G. G. Brownlee, J. W. Yewdell, and W. Gerhard, Cell 31:417-427, 1982, http://dx.doi.org/10.1016/0092-8674(82)90135-0]. We predicted that these diversified epitope regions would be the targets of mutation as the 2009 H1N1 pandemic (pH1N1) lineage evolves in response to the development of population-level protective immunity in humans. Using a chi-squared goodness-of-fit test, we identified 10 amino acid sites that significantly differed between the pH1N1 isolates and isolates from the recent 2012-2013 and 2013-2014 influenza seasons. Three of these sites were located in the same diversified B-cell/Ab epitope regions as identified in the analysis of prepandemic sequences, including Sa and Sb. As predicted, hemagglutination inhibition (HI) assays using human sera from subjects vaccinated with the initial pH1N1 isolate demonstrated reduced reactivity against 2013-2014 isolates. Taken together, these results suggest that diversifying selection analysis can identify key immune epitopes responsible for protective immunity to influenza virus in humans and thereby predict virus evolution.

Importance: The WHO estimates that approximately 5 to 10% of adults and 20 to 30% of children in the world are infected by influenza virus each year. While an adaptive immune response helps eliminate the virus following acute infection, the virus rapidly evolves to evade the established protective memory immune response, thus allowing for the regular seasonal cycles of influenza virus infection. The analytical approach described here, which combines an analysis of diversifying selection with an integration of immune epitope data, has allowed us to identify antigenic regions that contribute to protective immunity and are therefore the key targets of immune evasion by the virus. This information can be used to determine when sequence variations in seasonal influenza virus strains have affected regions responsible for protective immunity in order to decide when new vaccine formulations are warranted.
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http://dx.doi.org/10.1128/JVI.03636-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4442545PMC
May 2015

Live attenuated H7N7 influenza vaccine primes for a vigorous antibody response to inactivated H7N7 influenza vaccine.

Vaccine 2014 Nov 16;32(50):6798-804. Epub 2014 Oct 16.

Laboratory of Infectious Diseases, National Institutes of Health, Bethesda, MD, United States.

Background: H7 influenza viruses have emerged as potential pandemic threat. We evaluated the safety and immunogenicity of two candidate H7 pandemic live attenuated influenza vaccines (pLAIV) and their ability to prime for responses to an unadjuvanted H7 pandemic inactivated influenza vaccine (pIIV).

Methods: Healthy seronegative adults received two doses of A/Netherlands/219/03 (H7N7) or one dose of A/chicken/British Columbia/CN-6/04 (H7N3) pLAIV all given as 10(7.5) 50% tissue culture infective doses (TCID50) intranasally. A subset of subjects received one 45 μg dose of H7N7 pIIV containing the A/Mallard/Netherlands/12/2000 HA intramuscularly 18-24 months after pLAIV. Viral shedding was assessed by culture and real-time polymerase chain reaction (rRT-PCR), B cell responses following pLAIV were evaluated by ELISPOT and flow cytometry. Serum antibody was assessed by hemagglutination-inhibition (HAI), microneutralization (MN) and ELISA assays after each vaccine.

Results: Serum HAI or MN responses were not detected in any subject following one or two doses of either H7 pLAIV, although some subjects had detectable H7 specific B cells after vaccination. However, 10/13 subjects primed with two doses of H7N7 pLAIV responded to a subsequent dose of the homologous H7N7 pIIV with high titer HAI and MN antibody that cross-reacted with both North American and Eurasian lineage H7 viruses, including H7N9. In contrast, naïve subjects and recipients of a single dose of the mismatched H7N3 pLAIV did not develop HAI or MN antibody after pIIV.

Conclusions: While pLAIVs did not elicit detectable serum MN or HAI antibody, strain-specific pLAIV priming established long term immune memory that was cross-reactive with other H7 influenza strains. Understanding the mechanisms underlying priming by pLAIV may aid in pandemic vaccine development.
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http://dx.doi.org/10.1016/j.vaccine.2014.09.070DOI Listing
November 2014

Maintain the gain: program to sustain performance improvement in environmental cleaning.

Infect Control Hosp Epidemiol 2014 Jul 7;35(7):866-8. Epub 2014 May 7.

Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

Sustaining performance is a difficult and often overlooked aspect of quality improvement and implementation science. Over a 4-year period, we observed that monthly feedback of performance data in face-to-face meetings with frontline personnel was crucial in maintaining environmental-cleaning effectiveness in adult critical care units.
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http://dx.doi.org/10.1086/676873DOI Listing
July 2014

B cell response and hemagglutinin stalk-reactive antibody production in different age cohorts following 2009 H1N1 influenza virus vaccination.

Clin Vaccine Immunol 2013 Jun 10;20(6):867-76. Epub 2013 Apr 10.

David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA.

The 2009 pandemic H1N1 (pH1N1) influenza virus carried a swine-origin hemagglutinin (HA) that was closely related to the HAs of pre-1947 H1N1 viruses but highly divergent from the HAs of recently circulating H1N1 strains. Consequently, prior exposure to pH1N1-like viruses was mostly limited to individuals over the age of about 60 years. We related age and associated differences in immune history to the B cell response to an inactivated monovalent pH1N1 vaccine given intramuscularly to subjects in three age cohorts: 18 to 32 years, 60 to 69 years, and ≥70 years. The day 0 pH1N1-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers were generally higher in the older cohorts, consistent with greater prevaccination exposure to pH1N1-like viruses. Most subjects in each cohort responded well to vaccination, with early formation of circulating virus-specific antibody (Ab)-secreting cells and ≥4-fold increases in HAI and MN titers. However, the response was strongest in the 18- to 32-year cohort. Circulating levels of HA stalk-reactive Abs were increased after vaccination, especially in the 18- to 32-year cohort, raising the possibility of elevated levels of cross-reactive neutralizing Abs. In the young cohort, an increase in MN activity against the seasonal influenza virus A/Brisbane/59/07 after vaccination was generally associated with an increase in the anti-Brisbane/59/07 HAI titer, suggesting an effect mediated primarily by HA head-reactive rather than stalk-reactive Abs. Our findings support recent proposals that immunization with a relatively novel HA favors the induction of Abs against conserved epitopes. They also emphasize the need to clarify how the level of circulating stalk-reactive Abs relates to resistance to influenza.
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http://dx.doi.org/10.1128/CVI.00735-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3675965PMC
June 2013

CD4+ T-cell expansion predicts neutralizing antibody responses to monovalent, inactivated 2009 pandemic influenza A(H1N1) virus subtype H1N1 vaccine.

J Infect Dis 2013 Jan 12;207(2):297-305. Epub 2012 Nov 12.

Department of Pediatrics, Department of Pediatrics, Division of Infectious Diseases, University of Rochester Medical Center, Rochester, NY 14642, USA.

Background: The ability of influenza vaccines to elicit CD4(+) T cells and the relationship between induction of CD4(+) T cells and vaccine-induced neutralizing antibody responses has been controversial. The emergence of swine-origin 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) provided a unique opportunity to examine responses to an influenza vaccine composed of both novel and previously encountered antigens and to probe the relationship between B-cell and T-cell responses to vaccination.

Methods: We tracked CD4(+) T-cell and antibody responses of human subjects vaccinated with monovalent subunit A(H1N1)pdm09 vaccine. The specificity and magnitude of the CD4(+) T-cell response was evaluated using cytokine enzyme-linked immunosorbent spot assays in conjugation with peptide pools representing distinct influenza virus proteins.

Results: Our studies revealed that vaccination induced readily detectable CD4(+) T cells specific for conserved portions of hemagglutinin (HA) and the internal viral proteins. Interestingly, expansion of HA-specific CD4(+) T cells was most tightly correlated with the antibody response.

Conclusions: These results indicate that CD4(+) T-cell expansion may be a limiting factor in development of neutralizing antibody responses to pandemic influenza vaccines and suggest that approaches to facilitate CD4(+) T-cell recruitment may increase the neutralizing antibody produced in response to vaccines against novel influenza strains.
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http://dx.doi.org/10.1093/infdis/jis684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3532833PMC
January 2013

Antigenic and immunogenic properties of recombinant hemagglutinin proteins from H1N1 A/Brisbane/59/07 and B/Florida/04/06 when produced in various protein expression systems.

Vaccine 2012 Jun 15;30(31):4606-16. Epub 2012 May 15.

New York Influenza Center of Excellence, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center, 601 Elmwood Avenue, Box 609, Rochester, NY 14642, USA. felix

Antibodies directed against the influenza hemagglutinin (HA) protein largely mediate virus neutralization and confer protection against infection. Consequently, many studies and assays of influenza vaccines are focused on HA-specific immune responses. Recombinant HA (rHA) proteins can be produced in a number of protein expression and cell culture systems. These range from baculovirus infection of insect cell cultures, to transient transfection of plants, to stably transfected human cell lines. Furthermore, the rHA proteins may contain genetic modifications, such as histidine tags or trimerization domains, intended to ease purification or enhance protein stability. However, no systematic study of these different forms of the HA protein have been conducted. It is not clear which, if any, of these different protein expression systems or structural modifications improve or diminish the biological behavior of the proteins as immunogens or antigens in immune assays. Therefore we set out to perform systematic evaluation of rHA produced in different proteins expression systems and with varied modifications. Five rHA proteins based on recent strains of seasonal influenza A and five based on influenza B HA were kindly provided by the Biodefense and Emerging Infections Reagent Repository (BEIR). These proteins were evaluated in a combination of biochemical and structural assays, in vitro humoral and cellular immune assays, and in an animal vaccination model. Marked differences in the behavior of the individual proteins was evident suggesting that they are not equal when being used to detect an immune response. They were, nevertheless, similar at eliciting neutralizing antibody responses.
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http://dx.doi.org/10.1016/j.vaccine.2012.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379008PMC
June 2012

Immunogenicity of an inactivated monovalent 2009 influenza A (H1N1) vaccine in patients who have cancer.

Oncologist 2012 12;17(1):125-34. Epub 2012 Jan 12.

Division of Hematology and Oncology, Department of Internal Medicine, Maimonides Medical Center, 6300 8 Avenue, Brooklyn, New York 11220, USA.

Background: The immune response of patients who have cancer, who may be receiving immunosuppressive therapy, is generally considered to be decreased. This study aimed to evaluate the immune response of cancer patients to the 2009 influenza A (H1N1) vaccine.

Patients And Methods: We conducted a prospective single site study comparing the immune response after H1N1 vaccination of healthy controls (group A), patients who had solid tumors and were taking myelosuppressive chemotherapy (group B), patients who had solid tumors and were taking nonmyelosuppressive or no treatment (group C), and patients who had hematologic malignancies (group D).

Results: At 2-6 weeks after vaccination, seroconversion was observed in 80.0% of group A (95% confidence interval [CI], 65.0%-89.7%), 72.2% of group B (95% CI, 55.9%-84.3%), 87.0% of group C (95% CI, 72.2%-94.7%), and 75.0% of group D (95% CI, 52.8%-89.2%) (p = NS). The geometric mean titer ratio, that is, geometric mean factor increase in antibody titer after vaccination, was 12.6 (95% CI, 7.9-19.9), 12.7 (95% CI, 7.3-22.1), 23.0 (95% CI, 13.9-38.2), and 12.1 (95% CI, 5.3-27.9) (p = NS), and the seroprotection rates were 95.5% (95% CI, 84.0%-99.6%), 79.0% (95% CI, 63.4%-89.2%), 90.5% (95% CI, 77.4%-96.8%), and 90.0% (95% CI, 71%-98.7%) in the corresponding groups (p = NS). Immune responses were robust regardless of malignancy, or time intervals between the use of myelosuppressive or immunosuppressive medications and vaccination. No participants developed clinical H1N1 infection.

Conclusion: Cancer patients, whether taking myelosuppressive chemotherapy or not, are able to generate an immune response to the H1N1 vaccine similar to that of healthy controls.
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http://dx.doi.org/10.1634/theoncologist.2011-0220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267811PMC
June 2012

Vaccination with drifted variants of avian H5 hemagglutinin protein elicits a broadened antibody response that is protective against challenge with homologous or drifted live H5 influenza virus.

Vaccine 2011 Nov 28;29(48):8888-97. Epub 2011 Sep 28.

New York Influenza Center of Excellence, University of Rochester Medical Center, Rochester, NY, USA.

Substantial H5 influenza HA directed immunity is elicited after vaccination of human subjects who had been previously immunized with a drifted H5 HA variant. We sought to investigate the characteristics of H5 HA specific immune responses in more depth by developing an animal model of H5 HA vaccination using drift variants of recombinant H5 HA proteins. HA proteins derived from influenzas A/Vietnam/1203/04 (Clade 1) and A/Indonesia/05/05 (Clade 2.1) were chosen. The sequence of vaccination consisted of two doses of homologous protein, followed by one additional dose of the homologous or heterologous, drifted HA protein. Each dose of HA was combined with CpG as an adjuvant and was injected subcutaneously. All the animals exhibited a serum IgG antibody response that cross-reacted with both HAs in an ELISA. However, those animals that received the drifted variant exhibited higher reactivity to the heterologous HA. Competitive ELISA of serum from drift-variant recipients showed evidence of antibody focusing towards the drifted HA, suggesting modification of the response towards improved cross-reactivity, though development of neutralizing antibodies was limited. Nevertheless, animals were protected against live-virus challenge, and passive transfer of serum was sufficient to confer protection to otherwise naïve mice, indicating that both neutralizing and non-neutralizing antibodies offer some degree of protection. These findings suggest that pre-vaccination against H5 influenza has the potential to prime immunity against emerging drifted H5 strains, and could also lower the dose requirements of vaccination in the event of a pandemic.
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http://dx.doi.org/10.1016/j.vaccine.2011.09.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202679PMC
November 2011

A biopsychosocial formulation of pain communication.

Psychol Bull 2011 Nov;137(6):910-939

Department of Psychology.

We present a detailed framework for understanding the numerous and complicated interactions among psychological and social determinants of pain through examination of the process of pain communication. The focus is on an improved understanding of immediate dyadic transactions during painful events in the context of broader social phenomena. Fine-grain consideration of social transactions during pain leads to an appreciation of sociobehavioral events affecting both suffering persons as well as caregivers. Our examination considers knowledge from a variety of perspectives, including clinical health psychology, social and developmental processes, evolutionary psychology, communication studies, and behavioral neuroscience.
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http://dx.doi.org/10.1037/a0023876DOI Listing
November 2011

Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI).

Vaccine 2011 Jul 17;29(31):4897-902. Epub 2011 May 17.

VaxInnate Corporation, 3 Cedar Brook Drive, Cranbury, NJ 08512, USA.

Background: Influenza vaccines perform poorly in the elderly with reduced serological response and vaccine efficacy. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in Escherichia coli.

Methods: 120 subjects ≥ 65 years old were enrolled at three clinical centers. VAX125 vaccine was administered at doses of 0.5, 1, 2, 3, 5 or 8 μg delivered i.m. as a single dose vaccination on Day 0 using a dose-escalation with 20 subjects in each dose level. Subjects were followed for adverse events and sera were tested by hemagglutination-inhibition (HAI) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP) and anti-flagellin antibody were also assessed.

Results: The mean age was 71 years. The vaccine was well tolerated at all dose levels, with no more than mild to moderate local or systemic symptoms. The geometric mean titers (GMT) increased in all dose groups. In the 5 μg group the day 14 post-vaccination HAI titer was 1:226 showing a 12-fold increase over baseline. The 8 μg group showed a similar post-vaccination GMT increase (∼ 8-fold). In the combined 5 and 8 μg groups, the seroconversion rate was 75% and the seroprotection rate was 98%.

Conclusions: A 5 μg dose of VAX125 was safe and able to induce a greater than 10-fold increase HAI antibody levels and nearly complete seroprotection in subjects over 65 years old. The use of flagellin to adjuvant influenza vaccines via the TLR5 innate immune pathway appears to be a useful approach to overcome poor immune responses in the elderly. VAX125 is a promising new candidate for prevention of influenza A disease in both young adults and the elderly.
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http://dx.doi.org/10.1016/j.vaccine.2011.05.001DOI Listing
July 2011

Practice guidelines for assessing pain in older persons with dementia residing in long-term care facilities.

Physiother Can 2010 23;62(2):104-13. Epub 2010 Apr 23.

Department of Psychology and Centre on Aging and Health, University of Regina, Regina, Saskatchewan, Canada.

Purpose: Frail patients with dementia most frequently present with musculoskeletal pain and mobility concerns; therefore, physiotherapy interventions for this population are likely to be of great benefit. However, physiotherapists who work with older adults with dementia confront a considerable challenge: the communication impairments that characterize dementia make it difficult to assess pain and determine its source. For an effective physiotherapy programme to be implemented, valid pain assessment is necessary. This paper is intended to provide practice guidelines for pain assessment among older persons with dementia.

Summary Of Key Points: Over the last several years, there has been tremendous research progress in this area. While more research is needed, several promising assessment methodologies are available. These methodologies most often involve the use of observational checklists to record specific pain behaviours.

Recommendations: We encourage the ongoing and regular evidence-based pain assessment of older persons with dementia, using standardized procedures. Without regular and systematic assessment, pain problems will often go undetected in this population. Given the need for systematic pain assessment and intervention for long-term care populations with mobility concerns and muculoskeletal pain problems, we call for increased involvement of physical therapists in long-term care facilities.
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http://dx.doi.org/10.3138/physio.62.2.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871017PMC
August 2011

Safety and immunogenicity of a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125) in healthy young adults.

Vaccine 2010 Dec 20;28(52):8268-74. Epub 2010 Oct 20.

University of Rochester, School of Medicine and Dentistry, 601 Elmwood Ave, Box 689, Rochester, NY 14642, USA.

Background: The need for worldwide seasonal and pandemic vaccine production has increased interest in the development of innovative technologies for influenza vaccine production. We evaluated a novel influenza vaccine consisting of the globular head of the HA1 domain of the A/Solomon Islands/3/2006 (H1N1) influenza virus (VAX125) genetically fused to the TLR5 ligand, flagellin, and produced in E. coli.

Methods: 128 healthy adult subjects 18-49 years old were enrolled in a clinical trial conducted in three stages at a single center. Stage 1 was an open-label, dose escalation study in which the VAX125 vaccine was administered intramuscularly (im) at doses of 0.1 μg, 0.3 μg, 1 μg, 2 μg, 3 μg, 5 μg and 8 μg to groups of 8 subjects each. Stage 2 was a double-blind, placebo-controlled study in which subjects were randomized to receive 1.0 μg and 2.0 μg VAX125 vaccine doses or placebo, with 16 subjects per group. Finally, an additional 24 subjects received a 0.5 μg dose of VAX125 in stage 3, which was a non-randomized, open label study. In all parts subjects were followed for adverse events and sera was tested by hemagglutination-inhibition (HAI) and microneutralization (MN) against egg-grown virus on days 0, 7, 14, and 28. Serum C-reactive protein (CRP), cytokine levels, and anti-flagellin antibody were also assessed.

Results: Vaccine was generally well tolerated and there were no serious adverse events. Pain at the injection site was the most common local adverse event, and was mild or moderate in intensity. Systemic symptoms after vaccination include fatigue and headache, and two subjects, who received either 3 or 8 μg, had moderately severe systemic symptoms accompanied by substantial increases in serum CRP. Serum antibody responses against SI were seen by HAI and MN in most study subjects, with the geometric mean titer of post vaccination antibody increasing in a dose-dependent fashion. Overall, four-fold or greater serum HAI responses were seen in 61 of 96 (64%) subjects who received doses of 0.5 μg or greater, including in 46 of 72 subjects who received doses from 0.5 μg to 2 μg.

Conclusions: The globular head of the influenza HA expressed in a prokaryotic system was able to induce a functional antibody response against native virions. Vigorous responses were seen at relatively low doses of HA antigen suggesting that the addition of flagellin provided a substantial adjuvanting effect. The high levels of immune response at low doses of antigen and the relative ease of production associated with E. coli expression suggests that this approach may represent an effective strategy for enhancing the global influenza vaccine supply.
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http://dx.doi.org/10.1016/j.vaccine.2010.10.009DOI Listing
December 2010

Reconceptualizing the role of fear of falling and balance confidence in fall risk.

J Aging Health 2011 Feb 17;23(1):3-23. Epub 2010 Sep 17.

University of Regina, Saskatchewan, Canada.

Objective: This article aimed to critically examine preexisting conceptualizations of the relationship among fear of falling, falls efficacy, and falls and to offer a new theoretical model incorporating findings from the recent literature.

Method: This is a theoretical article based on a review of preexisting findings pertaining to fear of falling and falls efficacy.

Results: Traditional conceptualizations consider avoidance of activity and deconditioning to be mediators in the relationship between fear of falling and falls, but recent findings suggest that this mediational conceptualization may not be accurate. Moreover, the terms falls efficacy and fear of falling are often used interchangeably in the literature, which is conceptually problematic.

Discussion: We conclude with the presentation and discussion of an alternative predictive model of fear of falling that incorporates important findings from the recent literature.
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http://dx.doi.org/10.1177/0898264310378039DOI Listing
February 2011

Caregiver fear of falling and functional ability among seniors residing in long-term care facilities.

Gerontology 2009 21;55(4):460-7. Epub 2009 May 21.

Department of Psychology and Centre on Aging and Health, University of Regina, Regina, Sask., Canada.

Background: Consistent with fear-avoidance models of falling and pain, past research has demonstrated that, among adults living in the community, excessive fear of falling and fear of pain result in activity restriction and predict functional outcomes including falls (possibly because self-imposed activity restriction, due to fear of pain or falling, can lead to muscular decline and deconditioning). Among seniors with dementia, who rely on others for their care, decisions concerning activity restrictions are made by caregivers. As such, caregivers' fear about the possibility of care recipient falls and pain is important to examine.

Objective: In this investigation of patients with dementia, our goal was to conduct a longitudinal investigation of the relationship between professional caregivers' fears (about the possibility that care recipients will experience falls and pain) with long-term care (LTC) resident functional ability and falls.

Methods: For the purposes of our 3-month longitudinal study, nurses' and special care aides' fears that specific residents might experience pain and falls were examined. Resident functional ability was assessed, based on an established and well-validated caregiver-administered questionnaire, both before and after the 3-month period. Falls and fall-related injuries sustained by residents were recorded.

Results: After controlling for physical risk factors for falling and functional ability at the beginning of the study, caregiver fears that residents might experience pain or falls were found to be predictive of restraint/restriction use. In turn, the use of restraints/restrictions was found to be predictive of future functional ability of residents with dementia (after controlling for functional ability at the beginning of the study) and injurious falls (after controlling for physical risk factors for falling).

Conclusions: This is the first study to apply a modified fear-avoidance model of falls and pain to seniors with dementia who reside in LTC facilities. Our results demonstrate the importance of considering caregiver fears concerning falls and pain, when developing programs designed to optimize the use of physical restrictions (to prevent falls and minimize functional decline) in LTC facilities.
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http://dx.doi.org/10.1159/000221007DOI Listing
November 2009

Effect of silver-coated urinary catheters: efficacy, cost-effectiveness, and antimicrobial resistance.

Am J Infect Control 2004 Dec;32(8):445-50

Department of Internal Medicine, University of Nebraska Medical Center, 984031 Nebraska Medical Center, Omaha, NE 68198, USA.

Background: Urinary tract infections (UTIs) are the most common nosocomial infection experienced by patients in United States hospitals and are responsible for significant morbidity and excess hospital costs. The purpose of this study was to determine the efficacy of a silver alloy, hydrogel-coated, urinary catheter in the prevention of catheter-associated UTI, to assess the cost effectiveness of the coated catheter, and to test for the emergence of silver-resistance in urinary microbial isolates.

Methods: A 2-year prospective surveillance study in 10 patient care units was conducted to determine the rate of catheter-associated UTI. Historic control data was utilized to assess the effect of the coated catheter. A cost-effectiveness analysis was conducted using a range of cost estimates. Silver susceptibility was determined for microbes responsible for catheter-associated UTI.

Results: Data were analyzed using a Poisson regression model. The rate of catheter-associated UTI fell from 6.13/1000 catheter-days during the period 1999-2000 to 2.62/1000 catheter-days during 2001-2002 ( P = .002). Calculated cost savings varied widely. Modest savings were achieved at the realistic lower cost estimates. No silver-resistant microbes were recovered in the susceptibility tests.

Conclusions: The introduction of a silver alloy, hydrogel-coated urinary catheter was associated with a significant decline in nosocomial UTI and cost savings over the range of cost estimates. Silver-resistant urinary pathogens were not recovered from patients experiencing catheter-associated UTI during the study period.
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http://dx.doi.org/10.1016/j.ajic.2004.05.002DOI Listing
December 2004