Publications by authors named "Ranawaka A P M Perera"

60 Publications

Immunogenicity of standard, high-dose, MF59-adjuvanted, and recombinant-HA seasonal influenza vaccination in older adults.

NPJ Vaccines 2021 Feb 16;6(1):25. Epub 2021 Feb 16.

HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong SAR, China.

The vaccine efficacy of standard-dose seasonal inactivated influenza vaccines (S-IIV) can be improved by the use of vaccines with higher antigen content or adjuvants. We conducted a randomized controlled trial in older adults to compare cellular and antibody responses of S-IIV versus enhanced vaccines (eIIV): MF59-adjuvanted (A-eIIV), high-dose (H-eIIV), and recombinant-hemagglutinin (HA) (R-eIIV). All vaccines induced comparable H3-HA-specific IgG and elevated antibody-dependent cellular cytotoxicity (ADCC) activity at day 30 post vaccination. H3-HA-specific ADCC responses were greatest following H-eIIV. Only A-eIIV increased H3-HA-IgG avidity, HA-stalk IgG and ADCC activity. eIIVs also increased polyfunctional CD4+ and CD8+ T cell responses, while cellular immune responses were skewed toward single-cytokine-producing T cells among S-IIV subjects. Our study provides further immunological evidence for the preferential use of eIIVs in older adults as each vaccine platform had an advantage over the standard-dose vaccine in terms of NK cell activation, HA-stalk antibodies, and T cell responses.
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http://dx.doi.org/10.1038/s41541-021-00289-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886864PMC
February 2021

Cross-reactive Antibody Response between SARS-CoV-2 and SARS-CoV Infections.

Cell Rep 2020 06 18;31(9):107725. Epub 2020 May 18.

HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address:

The World Health Organization has declared the ongoing outbreak of COVID-19, which is caused by a novel coronavirus SARS-CoV-2, a pandemic. There is currently a lack of knowledge about the antibody response elicited from SARS-CoV-2 infection. One major immunological question concerns antigenic differences between SARS-CoV-2 and SARS-CoV. We address this question by analyzing plasma from patients infected by SARS-CoV-2 or SARS-CoV and from infected or immunized mice. Our results show that, although cross-reactivity in antibody binding to the spike protein is common, cross-neutralization of the live viruses may be rare, indicating the presence of a non-neutralizing antibody response to conserved epitopes in the spike. Whether such low or non-neutralizing antibody response leads to antibody-dependent disease enhancement needs to be addressed in the future. Overall, this study not only addresses a fundamental question regarding antigenicity differences between SARS-CoV-2 and SARS-CoV but also has implications for immunogen design and vaccine development.
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http://dx.doi.org/10.1016/j.celrep.2020.107725DOI Listing
June 2020

Neutralizing antibody titres in SARS-CoV-2 infections.

Nat Commun 2021 01 4;12(1):63. Epub 2021 Jan 4.

School of Public Health, The University of Hong Kong, Special Administrative Region of Hong Kong, Hong Kong, China.

The SARS-CoV-2 pandemic poses the greatest global public health challenge in a century. Neutralizing antibody is a correlate of protection and data on kinetics of virus neutralizing antibody responses are needed. We tested 293 sera from an observational cohort of 195 reverse transcription polymerase chain reaction (RT-PCR) confirmed SARS-CoV-2 infections collected from 0 to 209 days after onset of symptoms. Of 115 sera collected ≥61 days after onset of illness tested using plaque reduction neutralization (PRNT) assays, 99.1% remained seropositive for both 90% (PRNT) and 50% (PRNT) neutralization endpoints. We estimate that it takes at least 372, 416 and 133 days for PRNT titres to drop to the detection limit of a titre of 1:10 for severe, mild and asymptomatic patients, respectively. At day 90 after onset of symptoms (or initial RT-PCR detection in asymptomatic infections), it took 69, 87 and 31 days for PRNT antibody titres to decrease by half (T) in severe, mild and asymptomatic infections, respectively. Patients with severe disease had higher peak PRNT and PRNT antibody titres than patients with mild or asymptomatic infections. Age did not appear to compromise antibody responses, even after accounting for severity. We conclude that SARS-CoV-2 infection elicits robust neutralizing antibody titres in most individuals.
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http://dx.doi.org/10.1038/s41467-020-20247-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782739PMC
January 2021

Tropism of SARS-CoV-2, SARS-CoV and influenza virus in canine tissue explants.

J Infect Dis 2021 Jan 4. Epub 2021 Jan 4.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

Background: Human spillovers of SARS-CoV-2 to dogs and the emergence of a highly contagious avian-origin H3N2 canine influenza virus have raised concerns towards the role of dogs in the spread of SARS-CoV-2 and their susceptibility to existing human and avian influenza viruses which might result in further reassortment.

Methods: We systematically studied the replication kinetics of SARS-CoV-2, SARS-CoV, influenza A viruses of H1, H3, H5, H7 and H9 subtypes and influenza B viruses of Yamagata-like and Victoria-like lineages in ex-vivo canine nasal cavity (NC), soft palate (SP), trachea (T) and lung (L) tissue explant cultures and examined ACE2 and sialic acid (SA) receptor distribution in these tissues.

Results: There was limited productive replication of SARS-CoV-2 in canine NC and SARS-CoV in canine NC, SP and L with unexpectedly high ACE2 levels in canine NC and SP. Meanwhile, the canine tissues were susceptible to a wide range of human and avian influenza viruses, which matched with the abundance of both human and avian SA receptors.

Conclusions: Existence of suitable receptors and tropism for the same tissue foster virus adaptation and reassortment. Continuous surveillance in dog populations should be conducted given the plenty of chances for spillover during outbreaks.
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http://dx.doi.org/10.1093/infdis/jiab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799041PMC
January 2021

Development and Assessment of a Pooled Serum as Candidate Standard to Measure Influenza A Virus Group 1 Hemagglutinin Stalk-Reactive Antibodies.

Vaccines (Basel) 2020 Nov 9;8(4). Epub 2020 Nov 9.

Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1124, New York, NY 10029, USA.

The stalk domain of the hemagglutinin has been identified as a target for induction of protective antibody responses due to its high degree of conservation among numerous influenza subtypes and strains. However, current assays to measure stalk-based immunity are not standardized. Hence, harmonization of assay readouts would help to compare experiments conducted in different laboratories and increase confidence in results. Here, serum samples from healthy individuals ( = 110) were screened using a chimeric cH6/1 hemagglutinin enzyme-linked immunosorbent assay (ELISA) that measures stalk-reactive antibodies. We identified samples with moderate to high IgG anti-stalk antibody levels. Likewise, screening of the samples using the mini-hemagglutinin (HA) headless construct #4900 and analysis of the correlation between the two assays confirmed the presence and specificity of anti-stalk antibodies. Additionally, samples were characterized by a cH6/1N5 virus-based neutralization assay, an antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and competition ELISAs, using the stalk-reactive monoclonal antibodies KB2 (mouse) and CR9114 (human). A "pooled serum" (PS) consisting of a mixture of selected serum samples was generated. The PS exhibited high levels of stalk-reactive antibodies, had a cH6/1N5-based neutralization titer of 320, and contained high levels of stalk-specific antibodies with ADCC activity. The PS, along with blinded samples of varying anti-stalk antibody titers, was distributed to multiple collaborators worldwide in a pilot collaborative study. The samples were subjected to different assays available in the different laboratories, to measure either binding or functional properties of the stalk-reactive antibodies contained in the serum. Results from binding and neutralization assays were analyzed to determine whether use of the PS as a standard could lead to better agreement between laboratories. The work presented here points the way towards the development of a serum standard for antibodies to the HA stalk domain of phylogenetic group 1.
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http://dx.doi.org/10.3390/vaccines8040666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712758PMC
November 2020

Variation by lineage in serum antibody responses to influenza B virus infections.

PLoS One 2020 9;15(11):e0241693. Epub 2020 Nov 9.

World Health Organization Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, The University of Hong Kong, Hong Kong, China.

Two lineages of influenza B virus currently co-circulate and have distinct antigenicity, termed Victoria and Yamagata after the B/Victoria/2/87 and B/Yamagata/16/88 strains, respectively. We analyzed antibody titer dynamics following PCR-confirmed influenza B virus infection in a longitudinal community-based cohort study conducted in Hong Kong from 2009-2014 to assess patterns in changes in antibody titers to B/Victoria and B/Yamagata viruses following infections with each lineage. Among 62 PCR-confirmed cases, almost half had undetectable hemagglutination inhibition (HAI) antibody titers to the lineage of infection both pre-infection and post-infection. Among those infected with influenza B/Victoria who showed an HAI titer response after infection, we found strong rises to the lineage of infection, positive but smaller cross-lineage HAI titer boosts, a small dependence of HAI titer boosts on pre-infection titers, and a shorter half-life of HAI titers in adults. Our study is limited by the low HAI sensitivity for non-ether-treated IBV antigen and the incapacity of performing other assays with higher sensitivity, as well as the mismatch between the B/Yamagata lineage circulating strain and the assay strain in one of the study seasons.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241693PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652285PMC
January 2021

Evaluation of a SARS-CoV-2 Surrogate Virus Neutralization Test for Detection of Antibody in Human, Canine, Cat, and Hamster Sera.

J Clin Microbiol 2021 01 21;59(2). Epub 2021 Jan 21.

School of Public Health, The University of Hong Kong, Pok Fu Lam, Hong Kong Special Administrative Region, China

Surrogate neutralization assays for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that can be done without biosafety level 3 containment and in multiple species are desirable. We evaluate a recently developed surrogate virus neutralization test (sVNT) in comparison to 90% plaque reduction neutralization tests (PRNT) in human, canine, cat, and hamster sera. With PRNT as the reference, sVNT had sensitivity of 98.9% and specificity of 98.8%. Using a panel of immune sera corresponding to other coronaviruses, we confirm the lack of cross-reactivity to other coronaviruses in SARS-CoV-2 sVNT and PRNT, except for cross-reactivity to SARS-CoV-1 in sVNT.
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http://dx.doi.org/10.1128/JCM.02504-20DOI Listing
January 2021

Serologic Responses in Healthy Adult with SARS-CoV-2 Reinfection, Hong Kong, August 2020.

Emerg Infect Dis 2020 12 22;26(12):3076-3078. Epub 2020 Oct 22.

In March 2020, mild signs and symptoms of coronavirus disease developed in a healthy 33-year-old man in Hong Kong. His first infection did not produce virus neutralizing antibodies. In August, he had asymptomatic reinfection, suggesting that persons without a robust neutralizing antibody response might be at risk for reinfection.
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http://dx.doi.org/10.3201/eid2612.203833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706979PMC
December 2020

T-cell responses to MERS coronavirus infection in people with occupational exposure to dromedary camels in Nigeria: an observational cohort study.

Lancet Infect Dis 2021 03 6;21(3):385-395. Epub 2020 Oct 6.

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; Guangzhou Eighth People's Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address:

Background: Middle East respiratory syndrome (MERS) remains of global public health concern. Dromedary camels are the source of zoonotic infection. Over 70% of MERS coronavirus (MERS-CoV)-infected dromedaries are found in Africa but no zoonotic disease has been reported in Africa. We aimed to understand whether individuals with exposure to dromedaries in Africa had been infected by MERS-CoV.

Methods: Workers slaughtering dromedaries in an abattoir in Kano, Nigeria, were compared with abattoir workers without direct dromedary contact, non-abattoir workers from Kano, and controls from Guangzhou, China. Exposure to dromedaries was ascertained using a questionnaire. Serum and peripheral blood mononuclear cells (PBMCs) were tested for MERS-CoV specific neutralising antibody and T-cell responses.

Findings: None of the participants from Nigeria or Guangdong were MERS-CoV seropositive. 18 (30%) of 61 abattoir workers with exposure to dromedaries, but none of 20 abattoir workers without exposure (p=0·0042), ten non-abattoir workers or 24 controls from Guangzhou (p=0·0002) had evidence of MERS-CoV-specific CD4 or CD8 T cells in PBMC. T-cell responses to other endemic human coronaviruses (229E, OC43, HKU-1, and NL-63) were observed in all groups with no association with dromedary exposure. Drinking both unpasteurised camel milk and camel urine was significantly and negatively associated with T-cell positivity (odds ratio 0·07, 95% CI 0·01-0·54).

Interpretation: Zoonotic infection of dromedary-exposed individuals is taking place in Nigeria and suggests that the extent of MERS-CoV infections in Africa is underestimated. MERS-CoV could therefore adapt to human transmission in Africa rather than the Arabian Peninsula, where attention is currently focused.

Funding: The National Science and Technology Major Project, National Institutes of Health.
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http://dx.doi.org/10.1016/S1473-3099(20)30599-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538089PMC
March 2021

SARS-CoV-2 in Quarantined Domestic Cats from COVID-19 Households or Close Contacts, Hong Kong, China.

Emerg Infect Dis 2020 12 16;26(12):3071-3074. Epub 2020 Sep 16.

We tested 50 cats from coronavirus disease households or close contacts in Hong Kong, China, for severe acute respiratory syndrome coronavirus 2 RNA in respiratory and fecal samples. We found 6 cases of apparent human-to-feline transmission involving healthy cats. Virus genomes sequenced from 1 cat and its owner were identical.
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http://dx.doi.org/10.3201/eid2612.202786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706951PMC
December 2020

Author Correction: ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection.

Nat Immunol 2020 10;21(10):1302

HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41590-020-0788-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450682PMC
October 2020

ORF8 and ORF3b antibodies are accurate serological markers of early and late SARS-CoV-2 infection.

Nat Immunol 2020 10 17;21(10):1293-1301. Epub 2020 Aug 17.

HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

The SARS-CoV-2 virus emerged in December 2019 and has caused a worldwide pandemic due to the lack of any pre-existing immunity. Accurate serology testing is urgently needed to help diagnose infection, determine past exposure of populations and assess the response to a future vaccine. The landscape of antibody responses to SARS-CoV-2 is unknown. In this study, we utilized the luciferase immunoprecipitation system to assess the antibody responses to 15 different SARS-CoV-2 antigens in patients with COVID-19. We identified new targets of the immune response to SARS-CoV-2 and show that nucleocapsid, open reading frame (ORF)8 and ORF3b elicit the strongest specific antibody responses. ORF8 and ORF3b antibodies, taken together as a cluster of points, identified 96.5% of COVID-19 samples at early and late time points of disease with 99.5% specificity. Our findings could be used to develop second-generation diagnostic tests to improve serological assays for COVID-19 and are important in understanding pathogenicity.
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http://dx.doi.org/10.1038/s41590-020-0773-7DOI Listing
October 2020

Systems biological assessment of immunity to mild versus severe COVID-19 infection in humans.

Science 2020 09 11;369(6508):1210-1220. Epub 2020 Aug 11.

Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.

Coronavirus disease 2019 (COVID-19) represents a global crisis, yet major knowledge gaps remain about human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed immune responses in 76 COVID-19 patients and 69 healthy individuals from Hong Kong and Atlanta, Georgia, United States. In the peripheral blood mononuclear cells (PBMCs) of COVID-19 patients, we observed reduced expression of human leukocyte antigen class DR (HLA-DR) and proinflammatory cytokines by myeloid cells as well as impaired mammalian target of rapamycin (mTOR) signaling and interferon-α (IFN-α) production by plasmacytoid dendritic cells. By contrast, we detected enhanced plasma levels of inflammatory mediators-including EN-RAGE, TNFSF14, and oncostatin M-which correlated with disease severity and increased bacterial products in plasma. Single-cell transcriptomics revealed a lack of type I IFNs, reduced HLA-DR in the myeloid cells of patients with severe COVID-19, and transient expression of IFN-stimulated genes. This was consistent with bulk PBMC transcriptomics and transient, low IFN-α levels in plasma during infection. These results reveal mechanisms and potential therapeutic targets for COVID-19.
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http://dx.doi.org/10.1126/science.abc6261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665312PMC
September 2020

SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease.

Emerg Infect Dis 2020 11 4;26(11):2701-2704. Epub 2020 Aug 4.

We investigated 68 respiratory specimens from 35 coronavirus disease patients in Hong Kong, of whom 32 had mild disease. We found that severe acute respiratory syndrome coronavirus 2 and subgenomic RNA were rarely detectable beyond 8 days after onset of illness. However, virus RNA was detectable for many weeks by reverse transcription PCR.
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http://dx.doi.org/10.3201/eid2611.203219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588524PMC
November 2020

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections.

bioRxiv 2020 Mar 17. Epub 2020 Mar 17.

HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

The World Health Organization has recently declared the ongoing outbreak of COVID-19, which is caused by a novel coronavirus SARS-CoV-2, as pandemic. There is currently a lack of knowledge in the antibody response elicited from SARS-CoV-2 infection. One major immunological question is concerning the antigenic differences between SARS-CoV-2 and SARS-CoV. We address this question by using plasma from patients infected by SARS-CoV-2 or SARS-CoV, and plasma obtained from infected or immunized mice. Our results show that while cross-reactivity in antibody binding to the spike protein is common, cross-neutralization of the live viruses is rare, indicating the presence of non-neutralizing antibody response to conserved epitopes in the spike. Whether these non-neutralizing antibody responses will lead to antibody-dependent disease enhancement needs to be addressed in the future. Overall, this study not only addresses a fundamental question regarding the antigenicity differences between SARS-CoV-2 and SARS-CoV, but also has important implications in vaccine.
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http://dx.doi.org/10.1101/2020.03.15.993097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239046PMC
March 2020

Harnessing the potential of blood donation archives for influenza surveillance and control.

PLoS One 2020 29;15(5):e0233605. Epub 2020 May 29.

School of Public Health, WHO Collaborating Center for Infectious Disease Epidemiology and Control, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Many blood donation services around the globe maintain large archives of serum and/or plasma specimens of blood donations which could potentially be used for serologic surveillance and risk assessment of influenza. Harnessing this potential requires robust evidence that the outcomes of influenza serology in plasma, which is rarely used, is consistent with that in serum, which is the conventional choice of specimens for influenza serology. We harvested EDTA-plasma specimens from the blood donation archives of Hong Kong Red Cross Transfusion Services, where EDTA is the type of anticoagulant used for plasma collection, compared their antibody titers and responses to that in serum. Influenza A/H1N1/California/7/2009 and A/H3N2/Victoria/208/2009 were the test strains. Our results showed that antibody titers in 609 matched serum/EDTA-plasma specimens (i.e. obtained from the same donor at the same time) had good agreement inferred by Intraclass Correlation Coefficient, the value of which was 0.82 (95% CI: 0.77-0.86) for hemagglutination inhibition assay and 0.95 (95% CI: 0.93-0.96) for microneutralization assay; seroconversion rates (based on hemagglutination inhibition titers) during the 2010 and 2011 influenza seasons in Hong Kong inferred from paired EDTA-plasma were similar to that inferred from paired sera. Our study provided the proof-of-concept that blood donation archives could be leveraged as a valuable source of longitudinal blood specimens for the surveillance, control and risk assessment of both pandemic and seasonal influenza.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233605PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259782PMC
August 2020

Cross-reactive Antibody Response between SARS-CoV-2 and SARS-CoV Infections.

Cell Rep 2020 06 18;31(9):107725. Epub 2020 May 18.

HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address:

The World Health Organization has declared the ongoing outbreak of COVID-19, which is caused by a novel coronavirus SARS-CoV-2, a pandemic. There is currently a lack of knowledge about the antibody response elicited from SARS-CoV-2 infection. One major immunological question concerns antigenic differences between SARS-CoV-2 and SARS-CoV. We address this question by analyzing plasma from patients infected by SARS-CoV-2 or SARS-CoV and from infected or immunized mice. Our results show that, although cross-reactivity in antibody binding to the spike protein is common, cross-neutralization of the live viruses may be rare, indicating the presence of a non-neutralizing antibody response to conserved epitopes in the spike. Whether such low or non-neutralizing antibody response leads to antibody-dependent disease enhancement needs to be addressed in the future. Overall, this study not only addresses a fundamental question regarding antigenicity differences between SARS-CoV-2 and SARS-CoV but also has implications for immunogen design and vaccine development.
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http://dx.doi.org/10.1016/j.celrep.2020.107725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231734PMC
June 2020

Pathogenesis and transmission of SARS-CoV-2 in golden hamsters.

Nature 2020 07 14;583(7818):834-838. Epub 2020 May 14.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus with high nucleotide identity to SARS-CoV and to SARS-related coronaviruses that have been detected in horseshoe bats, has spread across the world and had a global effect on healthcare systems and economies. A suitable small animal model is needed to support the development of vaccines and therapies. Here we report the pathogenesis and transmissibility of SARS-CoV-2 in golden (Syrian) hamsters (Mesocricetus auratus). Immunohistochemistry assay demonstrated the presence of viral antigens in nasal mucosa, bronchial epithelial cells and areas of lung consolidation on days 2 and 5 after inoculation with SARS-CoV-2, followed by rapid viral clearance and pneumocyte hyperplasia at 7 days after inoculation. We also found viral antigens in epithelial cells of the duodenum, and detected viral RNA in faeces. Notably, SARS-CoV-2 was transmitted efficiently from inoculated hamsters to naive hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was not as efficient. Although viral RNA was continuously detected in the nasal washes of inoculated hamsters for 14 days, the communicable period was short and correlated with the detection of infectious virus but not viral RNA. Inoculated and naturally infected hamsters showed apparent weight loss on days 6-7 post-inoculation or post-contact; all hamsters returned to their original weight within 14 days and developed neutralizing antibodies. Our results suggest that features associated with SARS-CoV-2 infection in golden hamsters resemble those found in humans with mild SARS-CoV-2 infections.
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http://dx.doi.org/10.1038/s41586-020-2342-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394720PMC
July 2020

Infection of dogs with SARS-CoV-2.

Nature 2020 10 14;586(7831):776-778. Epub 2020 May 14.

School of Public Health, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first detected in Wuhan in December 2019 and caused coronavirus disease 2019 (COVID-19). In 2003, the closely related SARS-CoV had been detected in domestic cats and a dog. However, little is known about the susceptibility of domestic pet mammals to SARS-CoV-2. Here, using PCR with reverse transcription, serology, sequencing the viral genome and virus isolation, we show that 2 out of 15 dogs from households with confirmed human cases of COVID-19 in Hong Kong were found to be infected with SARS-CoV-2. SARS-CoV-2 RNA was detected in five nasal swabs collected over a 13-day period from a 17-year-old neutered male Pomeranian. A 2.5-year-old male German shepherd was positive for SARS-CoV-2 RNA on two occasions and virus was isolated from nasal and oral swabs. Antibody responses were detected in both dogs using plaque-reduction-neutralization assays. Viral genetic sequences of viruses from the two dogs were identical to the virus detected in the respective human cases. The dogs remained asymptomatic during quarantine. The evidence suggests that these are instances of human-to-animal transmission of SARS-CoV-2. It is unclear whether infected dogs can transmit the virus to other animals or back to humans.
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http://dx.doi.org/10.1038/s41586-020-2334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606701PMC
October 2020

Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults.

J Infect Dis 2020 09;222(8):1383-1391

Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: We analyzed data from a randomized controlled trial on the reactogenicity of 3 enhanced influenza vaccines compared with standard-dose (SD) inactivated influenza vaccine.

Methods: We enrolled community-dwelling older adults in Hong Kong, and we randomly allocated them to receive 2017-2018 northern hemisphere formulations of SD vaccine (FluQuadri; Sanofi Pasteur), MF59-adjuvanted vaccine (FLUAD; Seqirus), high-dose (HD) vaccine (Fluzone High-Dose; Sanofi Pasteur), or recombinant hemagglutinin vaccine (Flublok; Sanofi Pasteur). Local and systemic reactions were evaluated at days 1, 3, 7, and 14 after vaccination.

Results: Reported reactions were generally mild and short-lived. Systemic reactions occurred in similar proportions of participants by vaccine. Some local reactions were slightly more frequently reported among recipients of the MF59-adjuvanted and HD vaccines than among SD vaccine recipients. Participants reporting feverishness 1 day after vaccination had mean fold rises in postvaccination hemagglutination inhibition titers that were 1.85-fold higher (95% confidence interval, 1.01-3.38) for A(H1N1) than in those who did not report feverishness.

Conclusions: Some acute local reactions were more frequent after vaccination with MF59-adjuvanted and HD influenza vaccines, compared with SD inactivated influenza vaccine, whereas systemic symptoms occurred at similar frequencies in all groups. The association between feverishness and immunogenicity should be further investigated in a larger population.

Clinical Trials Registration: NCT03330132.
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http://dx.doi.org/10.1093/infdis/jiaa255DOI Listing
September 2020

Tropism, replication competence, and innate immune responses of the coronavirus SARS-CoV-2 in human respiratory tract and conjunctiva: an analysis in ex-vivo and in-vitro cultures.

Lancet Respir Med 2020 07 7;8(7):687-695. Epub 2020 May 7.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Special Administrative Region of Hong Kong, China. Electronic address:

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019, causing a respiratory disease (coronavirus disease 2019, COVID-19) of varying severity in Wuhan, China, and subsequently leading to a pandemic. The transmissibility and pathogenesis of SARS-CoV-2 remain poorly understood. We evaluate its tissue and cellular tropism in human respiratory tract, conjunctiva, and innate immune responses in comparison with other coronavirus and influenza virus to provide insights into COVID-19 pathogenesis.

Methods: We isolated SARS-CoV-2 from a patient with confirmed COVID-19, and compared virus tropism and replication competence with SARS-CoV, Middle East respiratory syndrome-associated coronavirus (MERS-CoV), and 2009 pandemic influenza H1N1 (H1N1pdm) in ex-vivo cultures of human bronchus (n=5) and lung (n=4). We assessed extrapulmonary infection using ex-vivo cultures of human conjunctiva (n=3) and in-vitro cultures of human colorectal adenocarcinoma cell lines. Innate immune responses and angiotensin-converting enzyme 2 expression were investigated in human alveolar epithelial cells and macrophages. In-vitro studies included the highly pathogenic avian influenza H5N1 virus (H5N1) and mock-infected cells as controls.

Findings: SARS-CoV-2 infected ciliated, mucus-secreting, and club cells of bronchial epithelium, type 1 pneumocytes in the lung, and the conjunctival mucosa. In the bronchus, SARS-CoV-2 replication competence was similar to MERS-CoV, and higher than SARS-CoV, but lower than H1N1pdm. In the lung, SARS-CoV-2 replication was similar to SARS-CoV and H1N1pdm, but was lower than MERS-CoV. In conjunctiva, SARS-CoV-2 replication was greater than SARS-CoV. SARS-CoV-2 was a less potent inducer of proinflammatory cytokines than H5N1, H1N1pdm, or MERS-CoV.

Interpretation: The conjunctival epithelium and conducting airways appear to be potential portals of infection for SARS-CoV-2. Both SARS-CoV and SARS-CoV-2 replicated similarly in the alveolar epithelium; SARS-CoV-2 replicated more extensively in the bronchus than SARS-CoV. These findings provide important insights into the transmissibility and pathogenesis of SARS-CoV-2 infection and differences with other respiratory pathogens.

Funding: US National Institute of Allergy and Infectious Diseases, University Grants Committee of Hong Kong Special Administrative Region, China; Health and Medical Research Fund, Food and Health Bureau, Government of Hong Kong Special Administrative Region, China.
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http://dx.doi.org/10.1016/S2213-2600(20)30193-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252187PMC
July 2020

Influenza A Virus Infections in Dromedary Camels, Nigeria and Ethiopia, 2015-2017.

Emerg Infect Dis 2020 01;26(1):173-176

We examined nasal swabs and serum samples acquired from dromedary camels in Nigeria and Ethiopia during 2015-2017 for evidence of influenza virus infection. We detected antibodies against influenza A(H1N1) and A(H3N2) viruses and isolated an influenza A(H1N1)pdm09-like virus from a camel in Nigeria. Influenza surveillance in dromedary camels is needed.
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http://dx.doi.org/10.3201/eid2601.191165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924894PMC
January 2020

Comparative Immunogenicity of Several Enhanced Influenza Vaccine Options for Older Adults: A Randomized, Controlled Trial.

Clin Infect Dis 2020 Oct;71(7):1704-1714

Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: Enhanced influenza vaccines may improve protection for older adults, but comparative immunogenicity data are limited. Our objective was to examine immune responses to enhanced influenza vaccines, compared to standard-dose vaccines, in community-dwelling older adults.

Methods: Community-dwelling older adults aged 65-82 years in Hong Kong were randomly allocated (October 2017-January 2018) to receive 2017-2018 Northern hemisphere formulations of a standard-dose quadrivalent vaccine, MF59-adjuvanted trivalent vaccine, high-dose trivalent vaccine, or recombinant-hemagglutinin (rHA) quadrivalent vaccine. Sera collected from 200 recipients of each vaccine before and at 30-days postvaccination were assessed for antibodies to egg-propagated vaccine strains by hemagglutination inhibition (HAI) and to cell-propagated A/Hong Kong/4801/2014(H3N2) virus by microneutralization (MN). Influenza-specific CD4+ and CD8+ T cell responses were assessed in 20 participants per group.

Results: Mean fold rises (MFR) in HAI titers to egg-propagated A(H1N1) and A(H3N2) and the MFR in MN to cell-propagated A(H3N2) were statistically significantly higher in the enhanced vaccine groups, compared to the standard-dose vaccine. The MFR in MN to cell-propagated A(H3N2) was highest among rHA recipients (4.7), followed by high-dose (3.4) and MF59-adjuvanted (2.9) recipients, compared to standard-dose recipients (2.3). Similarly, the ratio of postvaccination MN titers among rHA recipients to cell-propagated A(H3N2) recipients was 2.57-fold higher than the standard-dose vaccine, which was statistically higher than the high-dose (1.33-fold) and MF59-adjuvanted (1.43-fold) recipient ratios. Enhanced vaccines also resulted in the boosting of T-cell responses.

Conclusions: In this head-to-head comparison, older adults receiving enhanced vaccines showed improved humoral and cell-mediated immune responses, compared to standard-dose vaccine recipients.

Clinical Trials Registration: NCT03330132.
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http://dx.doi.org/10.1093/cid/ciz1034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289658PMC
October 2020

Maternal Antibodies Against Influenza in Cord Blood and Protection Against Laboratory-Confirmed Influenza in Infants.

Clin Infect Dis 2020 Oct;71(7):1741-1748

Department of Pediatrics and Adolescent Medicine, Queen Mary Hospital and Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Background: Studies that correlate maternal antibodies with protection from influenza A or B virus infection in young infants in areas with prolonged influenza circulation are lacking.

Methods: We conducted a prospective, observational study to evaluate the effects of maternally transferred antibodies against influenza A and B viruses against laboratory-confirmed influenza in a cohort born over 24 months. Cord blood samples were retrieved at birth and infants were actively followed for the first 6 months of life. Nasal swabs were collected and tested for influenza A and B by reverse transcriptase-polymerase chain reaction whenever an illness episode was identified. Cord blood samples were tested by the hemagglutination inhibition (HAI) assay to viruses that circulated during the follow-up period.

Results: 1162 infants were born to 1140 recruited women: 1092 (94%) infants completed 6 months of follow-up. Proportions of cord blood with HAI antibody titers ≥40 against A(H1N1), A(H3N2), B/Victoria, and B/Yamagata were 31%, 24%, 31%, and 54%, respectively. Only 4% of women had maternal influenza vaccination. Cord blood antigen-specific HAI titers ≥40 were found to correlate with protection from infection only for influenza B/Yamagata. No influenza B virus infection occurred in infants ≤60 days old. Proportional hazards analysis showed that a cord blood HAI titer of 40 was associated with 83% (95% confidence interval, 44-95%) reduction in the risk of influenza B/Yamagata infections compared with a cord blood titer <10.

Conclusions: We documented that maternal immunity against influenza B/Yamagata was conferred to infants within the first 6 months of life.
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http://dx.doi.org/10.1093/cid/ciz1058DOI Listing
October 2020

Diversity of Dromedary Camel Coronavirus HKU23 in African Camels Revealed Multiple Recombination Events among Closely Related Betacoronaviruses of the Subgenus Embecovirus.

J Virol 2019 12 13;93(23). Epub 2019 Nov 13.

School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, Republic of China

Genetic recombination has frequently been observed in coronaviruses. Here, we sequenced multiple complete genomes of dromedary camel coronavirus HKU23 (DcCoV-HKU23) from Nigeria, Morocco, and Ethiopia and identified several genomic positions indicative of cross-species virus recombination events among other betacoronaviruses of the subgenus Embecovirus (clade A beta-CoVs). Recombinant fragments of a rabbit coronavirus (RbCoV-HKU14) were identified at the hemagglutinin esterase gene position. Homolog fragments of a rodent CoV were also observed at 8.9-kDa open reading frame 4a at the 3' end of the spike gene. The patterns of recombination differed geographically across the African region, highlighting a mosaic structure of DcCoV-HKU23 genomes circulating in dromedaries. Our results highlighted active recombination of coronaviruses circulating in dromedaries and are also relevant to the emergence and evolution of other betacoronaviruses, including Middle East respiratory syndrome coronavirus (MERS-CoV). Genetic recombination is often demonstrated in coronaviruses and can result in host range expansion or alteration in tissue tropism. Here, we showed interspecies events of recombination of an endemic dromedary camel coronavirus, HKU23, with other clade A betacoronaviruses. Our results supported the possibility that the zoonotic pathogen MERS-CoV, which also cocirculates in the same camel species, may have undergone similar recombination events facilitating its emergence or may do so in its future evolution.
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http://dx.doi.org/10.1128/JVI.01236-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854494PMC
December 2019

Transmissibility of MERS-CoV Infection in Closed Setting, Riyadh, Saudi Arabia, 2015.

Emerg Infect Dis 2019 10 17;25(10):1802-1809. Epub 2019 Oct 17.

To investigate a cluster of Middle East respiratory syndrome (MERS) cases in a women-only dormitory in Riyadh, Saudi Arabia, in October 2015, we collected epidemiologic information, nasopharyngeal/oropharyngeal swab samples, and blood samples from 828 residents during November 2015 and December 2015-January 2016. We found confirmed infection for 19 (8 by reverse transcription PCR and 11 by serologic testing). Infection attack rates varied (2.7%-32.3%) by dormitory building. No deaths occurred. Independent risk factors for infection were direct contact with a confirmed case-patient and sharing a room with a confirmed case-patient; a protective factor was having an air conditioner in the bedroom. For 9 women from whom a second serum sample was collected, antibodies remained detectable at titers >1:20 by pseudoparticle neutralization tests (n = 8) and 90% plaque-reduction neutralization tests (n = 2). In closed high-contact settings, MERS coronavirus was highly infectious and pathogenicity was relatively low.
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http://dx.doi.org/10.3201/eid2510.190130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759265PMC
October 2019

The Effect of Influenza Vaccination History on Changes in Hemagglutination Inhibition Titers After Receipt of the 2015-2016 Influenza Vaccine in Older Adults in Hong Kong.

J Infect Dis 2020 01;221(1):33-41

WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.

Background: Immune responses to influenza vaccination can be weaker in older adults than in other age groups. We hypothesized that antibody responses would be particularly weak among repeat vaccinees when the current and prior season vaccine components are the same.

Methods: An observational study was conducted among 827 older adults (aged ≥75 years) in Hong Kong. Serum samples were collected immediately before and 1 month after receipt of the 2015-2016 quadrivalent inactivated influenza vaccine. We measured antibody titers with the hemagglutination inhibition assay and compared the mean fold rise from prevaccination to postvaccination titers and the proportions with postvaccination titers ≥40 or ≥160.

Results: Participants who reported receipt of vaccination during either of the previous 2 years had a lower mean fold rise against all strains than with those who did not. Mean fold rises for A(H3N2) and B/Yamagata were particularly weak after repeated vaccination with the same vaccine strain, but we did not generally find significant differences in the proportions of participants with postvaccination titers ≥40 and ≥160.

Conclusions: Overall, we found that reduced antibody responses in repeat vaccinees were particularly reduced among older adults who had received vaccination against the same strains in preceding years.
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http://dx.doi.org/10.1093/infdis/jiz327DOI Listing
January 2020

Age-specific differences in the dynamics of protective immunity to influenza.

Nat Commun 2019 04 10;10(1):1660. Epub 2019 Apr 10.

Department of Ecology and Evolution, University of Chicago, 1101 E 57th Street, Chicago, IL, 60637, USA.

Influenza A viruses evolve rapidly to escape host immunity, causing reinfection. The form and duration of protection after each influenza virus infection are poorly understood. We quantify the dynamics of protective immunity by fitting individual-level mechanistic models to longitudinal serology from children and adults. We find that most protection in children but not adults correlates with antibody titers to the hemagglutinin surface protein. Protection against circulating strains wanes to half of peak levels 3.5-7 years after infection in both age groups, and wanes faster against influenza A(H3N2) than A(H1N1)pdm09. Protection against H3N2 lasts longer in adults than in children. Our results suggest that influenza antibody responses shift focus with age from the mutable hemagglutinin head to other epitopes, consistent with the theory of original antigenic sin, and might affect protection. Imprinting, or primary infection with a subtype, has modest to no effect on the risk of non-medically attended infections in adults.
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http://dx.doi.org/10.1038/s41467-019-09652-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458119PMC
April 2019

Serum anti-neuraminidase antibody responses in human influenza A(H1N1)pdm09 virus infections.

Emerg Microbes Infect 2019 ;8(1):404-412

a WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine , The University of Hong Kong , Hong Kong , Hong Kong SAR, People's Republic of China.

Haemagglutination inhibition (HAI) antibody titres are a correlate of protection for influenza virus infection, but several studies have also demonstrated the protective role of anti-neuraminidase (anti-NA) antibodies. However, there is limited data on anti-NA antibody responses in naturally occurring human influenza. We investigated anti-NA antibody responses to pandemic N1 and seasonal N1 in 18 RT-PCR-confirmed patients with naturally acquired pandemic influenza A (H1N1) 2009 disease detected as part of a prospective community study of influenza. There were increases in neuraminidase inhibition (NAI) antibody titres to both pandemic and seasonal N1 antigens, with greater fold increases in those who had low levels of anti-pandemic N1 titres in acute sera. Of 18 patients with pandemic H1N1 infection, fourfold increases in antibody were observed by HAI in 11 (61%) patients, by anti-pandemic N1 inhibition in 13 (72%) or either in 15 of them (83%). Prior seasonal H1N1 virus infections had elicited cross-reactive anti-pandemic N1 antibody titres in some people prior to the emergence of the 2009 pandemic H1N1 virus. Antibody responses to the anti-N1 pandemic 2009 virus and cross-reactive responses to anti-seasonal N1 antibody were seen in influenza A pandemic 2009 infections. NAI antibodies can complement HAI antibody in sero-diagnosis and sero-epidemiology.
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http://dx.doi.org/10.1080/22221751.2019.1572433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455630PMC
August 2019

Indirect protection from vaccinating children against influenza in households.

Nat Commun 2019 01 10;10(1):106. Epub 2019 Jan 10.

Mathematical Modelling of Infectious Diseases Unit, Institut Pasteur, 25-28 Rue du Docteur Roux, 75015, Paris, France.

Vaccination is an important intervention to prevent influenza virus infection, but indirect protection of household members of vaccinees is not fully known. Here, we analyze a cluster household randomized controlled trial, with one child in each household randomized to receive influenza vaccine or placebo, for an influenza B epidemic in Hong Kong. We apply statistical models to estimate household transmission dynamics and quantify the direct and indirect protection of vaccination. Direct vaccine efficacy was 71%. The infection probability of unvaccinated household members in vaccinated households was only 5% lower than in control households, because only 10% of infections are attributed to household transmission. Even when that proportion rises to 30% and all children are vaccinated, we predict that the infection probability for unvaccinated household members would only be reduced by 20%. This suggests that benefits of individual vaccination remain important even when other household members are vaccinated.
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http://dx.doi.org/10.1038/s41467-018-08036-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328591PMC
January 2019