Showing papers in "The Lancet microbe in 2022"

Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis

Abstract: Several SARS-CoV-2 variants of concern have been identified that partly escape serum neutralisation elicited by current vaccines. Studies have also shown that vaccines demonstrate reduced protection against symptomatic infection with SARS-CoV-2 variants. We explored whether in-vitro neutralisation titres remain predictive of vaccine protection from infection with SARS-CoV-2 variants.In this meta-analysis, we analysed published data from 24 identified studies on in-vitro neutralisation and clinical protection to understand the loss of neutralisation to existing SARS-CoV-2 variants of concern. We integrated the results of this analysis into our existing statistical model relating in-vitro neutralisation to protection (parameterised on data from ancestral virus infection) to estimate vaccine efficacy against SARS-CoV-2 variants. We also analysed data on boosting of vaccine responses and use the model to predict the impact of booster vaccination on protection against SARS-CoV-2 variants.The neutralising activity against the ancestral SARS-CoV-2 was highly predictive of neutralisation of variants of concern. Decreases in neutralisation titre to the alpha (1·6-fold), beta (8·8-fold), gamma (3·5-fold), and delta (3·9-fold) variants (compared to the ancestral virus) were not significantly different between different vaccines. Neutralisation remained strongly correlated with protection from symptomatic infection with SARS-CoV-2 variants of concern (rS=0·81, p=0·0005) and the existing model remained predictive of vaccine efficacy against variants of concern once decreases in neutralisation to the variants of concern were incorporated. Modelling of predicted vaccine efficacy against variants over time suggested that protection against symptomatic infection might decrease below 50% within the first year after vaccination for some vaccines. Boosting of previously infected individuals with existing vaccines (which target ancestral virus) is predicted to provide a higher degree of protection from infection with variants of concern than primary vaccination schedules alone.In-vitro neutralisation titres remain a correlate of protection from SARS-CoV-2 variants and modelling of the effects of waning immunity predicts a loss of protection to the variants after vaccination. However, booster vaccination with current vaccines should enable higher neutralisation to SARS-CoV-2 variants than is achieved with primary vaccination, which is predicted to provide robust protection from severe infection outcomes with the current SARS-CoV-2 variants of concern, at least in the medium term.The National Health and Medical Research Council (Australia), the Medical Research Future Fund (Australia), and the Victorian Government.

The emergence of COVID-19 associated mucormycosis: a review of cases from 18 countries

Abstract: Reports of COVID-19-associated mucormycosis have been increasing in frequency since early 2021, particularly among patients with uncontrolled diabetes. Patients with diabetes and hyperglycaemia often have an inflammatory state that could be potentiated by the activation of antiviral immunity to SARS-CoV2, which might favour secondary infections. In this Review, we analysed 80 published and unpublished cases of COVID-19-associated mucormycosis. Uncontrolled diabetes, as well as systemic corticosteroid treatment, were present in most patients with COVID-19-associated mucormycosis, and rhino-orbital cerebral mucormycosis was the most frequent disease. Mortality was high at 49%, which was particularly due to patients with pulmonary or disseminated mucormycosis or cerebral involvement. Furthermore, a substantial proportion of patients who survived had life-changing morbidities (eg, loss of vision in 46% of survivors). Our Review indicates that COVID-19-associated mucormycosis is associated with high morbidity and mortality. Diagnosis of pulmonary mucormycosis is particularly challenging, and might be frequently missed in India.

T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study

Abstract: Previous infection with SARS-CoV-2 affects the immune response to the first dose of the SARS-CoV-2 vaccine. We aimed to compare SARS-CoV-2-specific T-cell and antibody responses in health-care workers with and without previous SARS-CoV-2 infection following a single dose of the BNT162b2 (tozinameran; Pfizer-BioNTech) mRNA vaccine.We sampled health-care workers enrolled in the PITCH study across four hospital sites in the UK (Oxford, Liverpool, Newcastle, and Sheffield). All health-care workers aged 18 years or older consenting to participate in this prospective cohort study were included, with no exclusion criteria applied. Blood samples were collected where possible before vaccination and 28 (±7) days following one or two doses (given 3-4 weeks apart) of the BNT162b2 vaccine. Previous infection was determined by a documented SARS-CoV-2-positive RT-PCR result or the presence of positive anti-SARS-CoV-2 nucleocapsid antibodies. We measured spike-specific IgG antibodies and quantified T-cell responses by interferon-γ enzyme-linked immunospot assay in all participants where samples were available at the time of analysis, comparing SARS-CoV-2-naive individuals to those with previous infection.Between Dec 9, 2020, and Feb 9, 2021, 119 SARS-CoV-2-naive and 145 previously infected health-care workers received one dose, and 25 SARS-CoV-2-naive health-care workers received two doses, of the BNT162b2 vaccine. In previously infected health-care workers, the median time from previous infection to vaccination was 268 days (IQR 232-285). At 28 days (IQR 27-33) after a single dose, the spike-specific T-cell response measured in fresh peripheral blood mononuclear cells (PBMCs) was higher in previously infected (n=76) than in infection-naive (n=45) health-care workers (median 284 [IQR 150-461] vs 55 [IQR 24-132] spot-forming units [SFUs] per 106 PBMCs; p<0·0001). With cryopreserved PBMCs, the T-cell response in previously infected individuals (n=52) after one vaccine dose was equivalent to that of infection-naive individuals (n=19) after receiving two vaccine doses (median 152 [IQR 119-275] vs 162 [104-258] SFUs/106 PBMCs; p=1·00). Anti-spike IgG antibody responses following a single dose in 142 previously infected health-care workers (median 270 373 [IQR 203 461-535 188] antibody units [AU] per mL) were higher than in 111 infection-naive health-care workers following one dose (35 001 [17 099-55 341] AU/mL; p<0·0001) and higher than in 25 infection-naive individuals given two doses (180 904 [108 221-242 467] AU/mL; p<0·0001).A single dose of the BNT162b2 vaccine is likely to provide greater protection against SARS-CoV-2 infection in individuals with previous SARS-CoV-2 infection, than in SARS-CoV-2-naive individuals, including against variants of concern. Future studies should determine the additional benefit of a second dose on the magnitude and durability of immune responses in individuals vaccinated following infection, alongside evaluation of the impact of extending the interval between vaccine doses.UK Department of Health and Social Care, and UK Coronavirus Immunology Consortium.

WHO International Standard for evaluation of the antibody response to COVID-19 vaccines: call for urgent action by the scientific community

Abstract: The first WHO International Standard and International Reference Panel for anti-SARS-CoV-2 immunoglobulin were established by the WHO Expert Committee on Biological Standardization in December, 2020. The WHO International Antibody Standards are intended to serve as global reference reagents, against which national reference preparations or secondary standards can be calibrated. Calibration will facilitate comparison of results of assays (eg, of the neutralising antibody response to candidate COVID-19 vaccines) conducted in different countries. Use of these standards is expected to contribute to better understanding of the immune response, and particularly of the correlates of protection. This Personal View provides some technical details of the WHO Antibody Standards for SARS-CoV-2, focusing specifically on the use of these standards for the evaluation of the immune response to COVID-19 vaccines, rather than other applications (eg, diagnostic or therapeutic). The explanation with regard to why rapid adoption of the standards is crucial is also included, as well as how funders, journals, regulators, and ethics committees could drive adoption in the interest of public health.

Global human monkeypox outbreak: atypical presentation demanding urgent public health action

Abstract: Following confirmation of the first case of monkeypox in the UK by the UK Health Security Agency (UKHSA) on May 7, 2022, events have evolved with dizzying rapidity—as of May 21, 2022, 92 laboratory confirmed cases and 28 suspected cases of monkeypox have been reported in 12 non-endemic countries across three WHO regions.1WHOMulti-country monkeypox outbreak in non-endemic countries.https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON385Date: May 21, 2022Date accessed: May 22, 2022Google Scholar Monkeypox is a rare viral illness that is seldom detected outside of Africa. WHO have projected that more cases of monkeypox will be identified as surveillance expands in non-endemic countries.1WHOMulti-country monkeypox outbreak in non-endemic countries.https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON385Date: May 21, 2022Date accessed: May 22, 2022Google Scholar Although uncertain, some have expressed concerns that this outbreak of monkeypox could become the next global pandemic. Complicating the situation is the fact that most cases have occurred in men aged 20–50 years who identify as gay or bisexual or have sex with men and do not have recent travel history to monkeypox endemic countries.1WHOMulti-country monkeypox outbreak in non-endemic countries.https://www.who.int/emergencies/disease-outbreak-news/item/2022-DON385Date: May 21, 2022Date accessed: May 22, 2022Google Scholar Additionally, there does not appear to be links between these cases. So far, the number of infections detected outside of Africa since May 7, 2022, has already exceeded the number detected outside of the continent from 1970 to the current outbreak.2Kozlov M Monkeypox goes global: why scientists are on alert.https://www.nature.com/articles/d41586-022-01421-8Date: May 20, 2022Date accessed: May 22, 2022Google Scholar This unprecedented situation raises the possibility of community spread, with sexual contact being suspected as a factor contributing to transmission. Monkeypox is a re-emerging zoonotic disease caused by a DNA virus that belongs to the orthopoxvirus genus of the Poxviridae family. Since the first human case of monkeypox was diagnosed in the Democratic Republic of the Congo in 1970, the disease has become endemic in several African countries, including Nigeria, Benin, and Liberia.2Kozlov M Monkeypox goes global: why scientists are on alert.https://www.nature.com/articles/d41586-022-01421-8Date: May 20, 2022Date accessed: May 22, 2022Google Scholar Monkeypox is closely related to the variola virus (smallpox virus) and results in a smallpox-like disease.3Bunge EM Hoet B Chen L et al.The changing epidemiology of human monkeypox—a potential threat? A systematic review.PLoS Negl Trop Dis. 2022; 16e0010141Crossref PubMed Scopus (317) Google Scholar Two clades of the monkeypox virus exist: the Congo Basin (central African) clade and the west African clade. Mortality varies between clades, with estimated case fatality rates of 10·6% for the Congo Basin clade and 3·6% for the west African clade.2Kozlov M Monkeypox goes global: why scientists are on alert.https://www.nature.com/articles/d41586-022-01421-8Date: May 20, 2022Date accessed: May 22, 2022Google Scholar Monkeypox usually spreads among monkeys, Gambian pouched rats, and squirrels,4Ihekweazu C Yinka-Ogunleye A Lule S Ibrahim A Importance of epidemiological research of monkeypox: is incidence increasing?.Expert Rev Anti Infect Ther. 2020; 18: 389-392Crossref PubMed Scopus (17) Google Scholar but occasionally jumps to people, causing small outbreaks. In addition to fever, headache, muscle aches, and lymphadenopathy, infection triggers a distinctive rash that often begins on the face and spreads to other parts of the body, including the genitals.5Simpson K Heymann D Brown CS et al.Human monkeypox—after 40 years, an unintended consequence of smallpox eradication.Vaccine. 2020; 38: 5077-5081Crossref PubMed Scopus (93) Google Scholar Monkeypox is generally a mild, self-limiting illness and its established modes of transmission are close contact with infected individuals or contaminated clothes, towels, or furniture and respiratory droplets. The monkeypox virus does not transmit from person to person as readily as SARS-CoV-2 does. However, the current outbreak is exposing gaps in our knowledge of monkeypox. Promisingly, on May 19, 2022, scientists in Portugal reported the first draft genome sequence of monkeypox virus that had been recently detected in Portugal.6Isidro J Borges V Pinto M et al.First draft genome sequence of monkeypox virus associated with the suspected multi-country outbreak, May 2022 (confirmed case in Portugal).https://virological.org/t/first-draft-genome-sequence-of-monkeypox-virus-associated-with-the-suspected-multi-country-outbreak-may-2022-confirmed-case-in-portugal/799Date: May 19, 2022Date accessed: May 21, 2022Google Scholar Preliminary genetic data suggest that the 2022 monkeypox virus belongs to the west African clade, and is most closely related to monkeypox viruses linked to disease spread from Nigeria to the UK, Israel, and Singapore in 2018 and 2019.5Simpson K Heymann D Brown CS et al.Human monkeypox—after 40 years, an unintended consequence of smallpox eradication.Vaccine. 2020; 38: 5077-5081Crossref PubMed Scopus (93) Google Scholar, 6Isidro J Borges V Pinto M et al.First draft genome sequence of monkeypox virus associated with the suspected multi-country outbreak, May 2022 (confirmed case in Portugal).https://virological.org/t/first-draft-genome-sequence-of-monkeypox-virus-associated-with-the-suspected-multi-country-outbreak-may-2022-confirmed-case-in-portugal/799Date: May 19, 2022Date accessed: May 21, 2022Google Scholar, 7Mauldin MR McCollum AM Nakazawa YJ et al.Exportation of monkeypox virus from the African continent.J Infect Dis. 2022; 225: 1367-1376Crossref PubMed Scopus (82) Google Scholar A monkeypox vaccine (Imvamune or Imvanex) developed by a Danish biotechnology firm (Bavarian Nordic) has been approved by US regulators for both monkeypox and smallpox. Evidence from Africa indicates that smallpox vaccination provides 85% protection against monkeypox infection.8UK Health Security AgencyRecommendations for the use of pre and post exposure vaccination during a monkeypox incident. Updated May 2022 v6.6.https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1077678/Recommendations-for-use-of-pre-and-post-exposure-vaccination-during-a-monkeypox-incident.pdfDate: May, 2022Date accessed: May 22, 2022Google Scholar The decline in population-level immunity since the cessation of smallpox vaccination in the 1980s contributed to the 2017–20 monkeypox outbreaks in Nigeria.4Ihekweazu C Yinka-Ogunleye A Lule S Ibrahim A Importance of epidemiological research of monkeypox: is incidence increasing?.Expert Rev Anti Infect Ther. 2020; 18: 389-392Crossref PubMed Scopus (17) Google Scholar On May 19, 2022, tecovirimat (Tpoxx) was approved in the USA, Canada, and Europe for the treatment of human smallpox disease.9Carlson R TPOXX smallpox treatment description for 2022.https://www.precisionvaccinations.com/vaccines/tpoxx-smallpox-treatment#:~:text=Then%20on%20May%2019%2C%202022,13%20kg%20in%20November%202021Date: May 19, 2022Date accessed: May 22, 2022Google Scholar The European Medicines Agency approval for tecovirimat also includes the treatment of monkeypox.10Huet N Monkeypox outbreak: drugmaker SIGA says EU authorities seeking to stockpile its smallpox antiviral.https://www.euronews.com/next/2022/05/20/monkeypox-outbreak-drugmaker-siga-says-eu-authorities-seeking-to-stockpile-its-smallpox-anDate: May 21, 2022Date accessed: May 22, 2022Google Scholar The unique variation in the epidemiology of human monkeypox during this current outbreak underlines several issues. For example, both the absence of prodromal symptoms, such as fever, malaise, and headache, and the presence of herald skin lesions at the point of sexual contact in some patients are strongly suggestive of sexual transmission. Nonetheless, there are concerns that the media's projection of men who have sex with men as the at-risk population for the outbreak might unduly stigmatise this group. Case definitions of monkeypox disease have been updated to account for possible cases that do not have a history of travel to endemic countries. Similarly, new clinical guidelines are being developed by the UKHSA to address important questions, including the use of appropriate personal protective equipment in sexual health clinics and the review of standard operating procedures in laboratories. With several cases of monkeypox now identified in 12 countries, the fear of cross-border transmission is real. Robust public health surveillance and control measures are crucial to address this threat. We declare no competing interests. AO and BE contributed equally to this Comment.

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis

Abstract: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.UNITAID, Wellcome, MRC, BMGF.

SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study

Abstract: The memory immune response is crucial for preventing reinfection or reducing disease severity. However, the robustness and functionality of the humoral and T-cell response to SARS-CoV-2 remains unknown 12 months after initial infection. The aim of this study is to investigate the durability and functionality of the humoral and T-cell response to the original SARS-CoV-2 strain and variants in recovered patients 12 months after infection.In this longitudinal cohort study, we recruited participants who had recovered from COVID-19 and who were discharged from the Wuhan Research Center for Communicable Disease Diagnosis and Treatment at the Chinese Academy of Medical Sciences, Wuhan, China, between Jan 7 and May 29, 2020. Patients received a follow-up visit between Dec 16, 2020, and Jan 27, 2021. We evaluated the presence of IgM, IgA, and IgG antibodies against the SARS-CoV-2 nucleoprotein, Spike protein, and the receptor-binding domain 12 months after initial infection, using ELISA. Neutralising antibodies against the original SARS-CoV-2 strain, and the D614G, beta (B.1.351), and delta (B.1.617.2) variants were analysed using a microneutralisation assay in a subset of plasma samples. We analysed the magnitude and breadth of the SARS-CoV-2-specific memory T-cell responses using the interferon γ (IFNγ) enzyme-linked immune absorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) assay. The antibody response and T-cell response (ie, IFN-γ, interleukin-2 [IL-2], and tumour necrosis factor α [TNFα]) were analysed by age and disease severity. Antibody titres were also analysed according to sequelae symptoms.We enrolled 1096 patients, including 289 (26·4%) patients with moderate initial disease, 734 (67·0%) with severe initial disease, and 73 (6·7%) with critical initial disease. Paired plasma samples were collected from 141 patients during the follow-up visits for the microneutralisation assay. PBMCs were collected from 92 of 141 individuals at the 12-month follow-up visit, of which 80 were analysed by ELISpot and 92 by ICS assay to detect the SARS-CoV-2-specific memory T-cell responses. N-IgG (899 [82·0%]), S-IgG (1043 [95·2%]), RBD-IgG (1032 [94·2%]), and neutralising (115 [81·6%] of 141) antibodies were detectable 12 months after initial infection in most individuals. Neutralising antibodies remained stable 6 and 12 months after initial infection in most individuals younger than 60 years. Multifunctional T-cell responses were detected for all SARS-CoV-2 viral proteins tested. There was no difference in the magnitude of T-cell responses or cytokine profiles in individuals with different symptom severity. Moreover, we evaluated both antibody and T-cell responses to the D614G, beta, and delta viral strains. The degree of reduced in-vitro neutralising antibody responses to the D614G and delta variants, but not to the beta variant, was associated with the neutralising antibody titres after SARS-CoV-2 infection. We also found poor neutralising antibody responses to the beta variant; 83 (72·2%) of 115 patients showed no response at all. Moreover, the neutralising antibody titre reduction of the recovered patient plasma against the delta variant was similar to that of the D614G variant and lower than that of the beta variant. By contrast, T-cell responses were cross-reactive to the beta variant in most individuals. Importantly, T-cell responses could be detected in all individuals who had lost the neutralising antibody response to SARS-CoV-2 12 months after the initial infection.SARS-CoV-2-specific neutralising antibody and T-cell responses were retained 12 months after initial infection. Neutralising antibodies to the D614G, beta, and delta viral strains were reduced compared with those for the original strain, and were diminished in general. Memory T-cell responses to the original strain were not disrupted by new variants. This study suggests that cross-reactive SARS-CoV-2-specific T-cell responses could be particularly important in the protection against severe disease caused by variants of concern whereas neutralising antibody responses seem to reduce over time.Chinese Academy of Medical Sciences, National Natural Science Foundation, and UK Medical Research Council.

WHO international standard for SARS-CoV-2 antibodies to determine markers of protection

Abstract: Several studies have shown that neutralising antibody level is a good biomarker for the correlate of protection against SARS-CoV-2 infection.1–3 However, results from these studies are presented using assays that have not been calibrated using a common reference standard, making it difficult to define the exact level of neutralising antibodies required for protection and to compare with current and future studies. The most recent study4 is the only one we have identified that reports the neutralising antibody level using WHO international units by calibrating their neutralisation assays against the WHO international standard for SARS-CoV-2 immunoglobulin; the international standard was established by the WHO Expert Committee on Biological Standardization as a primary calibrant to harmonise the measurement of anti-SARS-CoV-2 antibodies and was made available in December, 2020 from the WHO Collaborative centre, the National Institute for Biological Standards and Control (NIBSC), UK.

Comparison of SARS-CoV-2 anti-spike receptor binding domain IgG antibody responses after CoronaVac, BNT162b2, ChAdOx1 COVID-19 vaccines, and a single booster dose: a prospective, longitudinal population-based study

Abstract: Vaccination is an efficient strategy to control the COVID-19 pandemic. In north Cyprus, vaccine distribution started with CoronaVac followed by BNT162b2, and ChAdOx1 vaccines. An option to obtain a third booster dose with BNT162b2 or CoronaVac was later offered to people fully inoculated with CoronaVac. There are few simultaneous and comparative real-world antibody data for these three vaccines as well as boosters after CoronaVac vaccination. Our study was aimed at evaluating antibody responses after these vaccination schemes.We did a prospective, longitudinal population-based study to measure SARS-CoV-2 anti-spike receptor binding domain (RBD) IgG concentrations, assessed by assaying blood samples collected, in participants in north Cyprus who had received the BNT162b2, ChAdOx1, or CoronaVac vaccine at 1 month and 3 months after the second dose. Participants were recruited when they voluntarily came to the laboratory for testing after vaccination, solicited from health-care access points, or from the general population. We also evaluated antibody responses 1 month after a booster dose of BNT162b2 or CoronaVac after primary CoronaVac regimen. Demographics, baseline characteristics, vaccination reactions, and percentage of antibody responders were collected by phone interviews or directly from the laboratory summarised by vaccine and age group. Antibody levels were compared between groups over time by parametric and non-parametric methods.Recruitment, follow-up, and data collection was done between March 1 and Sept 30, 2021. BNT162b2 induced the highest seropositivity and anti-spike RBD IgG antibody titres, followed by ChAdOx1, and then by CoronaVac. In addition, the rate of decline of antibodies was fastest with CoronaVac, followed by ChAdOx1, and then by BNT162b2. For the older age group, the rate of seropositivity at 3 months after the second dose was 100% for BNT162b2, 90% for ChAdOx1, and 60% for CoronaVac. In the multivariate repeated measures model, lower antibody titres were also significantly associated with male sex, older age, and time since vaccination. Boosting a two-dose CoronaVac regimen at 6 months with a single BNT162b2 dose led to significantly increased titres of IgG compared with boosting with CoronaVac; for the 60 years and older age group, the geometric mean fold rise in antibody titre after the booster relative to 1 month post-baseline was 7·9 (95% CI 5·8-10·8) in the BNT162b2 boost group versus 2·8 (1·6-5·0) in the CoronaVac group.These longitudinal data can help shape vaccination strategies. Given the low antibody titres and fast decline in the CoronaVac group in individuals 60 years or older, more potent vaccine options could be considered as the primary vaccination or booster dose in these high-risk populations to sustain antibody responses for longer.Crowdfunded in north Cyprus.

WHO's Global Tuberculosis Report 2022

Abstract: On Oct 27, WHO released its Global Tuberculosis Report 2022. The document provides an extensive assessment of the global tuberculosis burden, based on data reported from 202 countries and territories, including over 99% of the global population and of tuberculosis cases. According to the Report, the COVID-19 pandemic is still negatively affecting tuberculosis diagnosis and care—and hence the burden of the disease—and has caused a slowdown, interruption, or reversal of the progress made up to 2019 in combating tuberculosis. An estimated 10·6 million people became ill with tuberculosis in 2021, compared with 10·1 million in 2020, and 1·6 million people died from tuberculosis in 2021 (including 187 000 individuals living with HIV), compared with 1·5 million in 2020 (including 214 000 individuals living with HIV). In addition, the incidence rate of tuberculosis increased by 3·6% in 2021 relative to 2020, suggesting a reversal from the trend of nearly 2% decrease per year during the past two decades. In 2014, the World Health Assembly adopted WHO's End TB Strategy, which counts among its aims an 80% decrease in the tuberculosis incidence by 2030, in accordance with UN Sustainable Development Goal 3, which includes ending the global tuberculosis epidemic. However, as Michel Gasana, (WHO Regional Office for Africa, Brazzaville, Congo [Brazzaville]) pointed out, “We are far from reaching the UN Sustainable Development Goal target of ending the tuberculosis epidemic by 2030.” Gasana told The Lancet Microbe, “Globally, the cumulative reduction in the tuberculosis incidence rate from 2015 to 2021 was 10%. Only the WHO African Region in 2021 reached the 2020 incidence milestone of the End TB Strategy, with a reduction of 22% since 2015.” The burden of drug-resistant tuberculosis also increased by 3% between 2020 and 2021, with 450 000 incident cases of rifampicin-resitant tuberculosis reported in 2021. Russia and other countries in eastern Europe and central Asia reported the highest proportions (>50%) of MDR or rifampicin-resistant tuberculosis among previously treated individuals. In 2021, only 161 746 people (20 000 fewer than in 2019) requiring treatment of MDR or rifampicin-resistant tuberculosis received it. During the COVID-19 pandemic, important tuberculosis services were not offered to many people who needed them. As a result, newly diagnosed tuberculosis cases decreased from 7·1 million in 2019 to 5·8 million in 2020 (a level last observed in 2012). In 2021, the number increased to 6·4 million, but remained below pre-pandemic numbers. This decrease relative to before the COVID-19 pandemic suggests an increase in undiagnosed and untreated tuberculosis cases, initially leading to increased community spread of the infection and tuberculosis deaths, followed by a rise in the number of people developing the disease. “The WHO Global Tuberculosis Report is a stark reminder that tuberculosis is now killing nearly twice as many people as COVID-19 every day,” David Dowdy (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA) told The Lancet Microbe. He added, “The major challenges in fighting tuberculosis are not technical. We have good diagnostic tests, good drugs, and good preventive treatment (though we can always do better). The major challenge to ending tuberculosis is a lack of global political will to mobilise resources to fight tuberculosis in the same way that we have done for diseases like COVID-19.” The 2022 Report also pointed out some gains in tackling tuberculosis. For example, in 2020, the first year of the COVID-19 pandemic, the quality of tuberculosis treatment was maintained, with an 86% success rate; in 2018–22, preventive tuberculosis treatment of individuals living with HIV has exceeded the global target of 6 million; and countries have been increasingly taking up new WHO recommendations and tools leading to improved outcomes. To improve the global tuberculosis situation, experts have recommended some measures. Gasana commented that “[there] is a decline in global spending on essential tuberculosis services from US$6 billion in 2019 to US$5·4 billion in 2021. We need to mobilise additional funds and increase tuberculosis funding to address the impact of COVID-19.” “The reported rise in notified cases calls for an invigorated response to tuberculosis control, which will require both political will on the part of governments and civil society as well as substantial financial investment in tuberculosis diagnosis and treatment throughout the world,” said Megan Murray (Harvard Medical School, Boston, MA, USA). Madhukar Pai (McGill International TB Centre, Montreal, QC, Canada) told The Lancet Microbe, “Right now, improving tuberculosis case detection is urgent. All countries have scaled up molecular testing and genetic sequencing capacity for COVID-19, and this expanded capacity could be used for tuberculosis testing. Also, huge advances have been made in digital health tools, tele-health, and home delivery of medicines. I think all of these could help with the recovery of tuberculosis services.” For the Global Tuberculosis Report 2022 see https://www.who.int/publications/i/item/9789240061729For the End TB Strategy see https://www.who.int/teams/global-tuberculosis-programme/the-end-tb-strategyFor UN Sustainable Development Goals see https://sdgs.un.org/2030agenda For the Global Tuberculosis Report 2022 see https://www.who.int/publications/i/item/9789240061729 For the End TB Strategy see https://www.who.int/teams/global-tuberculosis-programme/the-end-tb-strategy For UN Sustainable Development Goals see https://sdgs.un.org/2030agenda

Air and surface sampling for monkeypox virus in a UK hospital: an observational study

Abstract: An outbreak of monkeypox virus infections in non-endemic countries was recognised on May 12, 2022. As of September 29, more than 67 000 infections have been reported globally, with more than 3400 confirmed cases in the UK by September 26. Monkeypox virus is believed to be predominantly transmitted through direct contact with lesions or infected body fluids, with possible involvement of fomites and large respiratory droplets. A case of monkeypox in a health-care worker in the UK in 2018 was suspected to be due to virus exposure while changing bedding. We aimed to measure the extent of environmental contamination in the isolation rooms of patients with symptomatic monkeypox.We investigated environmental contamination with monkeypox virus from infected patients admitted to isolation rooms at the Royal Free Hospital (London, UK) between May 24 and June 17, 2022. Surface swabs of high-touch areas in five isolation rooms, of the personal protective equipment (PPE) of health-care workers in doffing areas in three rooms, and from air samples collected before and during bedding changes in five rooms were analysed using quantitative PCR to assess monkeypox virus contamination levels. Virus isolation was performed to confirm presence of infectious virus in selected positive samples.We identified widespread surface contamination (56 [93%] of 60 samples were positive) in occupied patient rooms (monkeypox DNA cycle threshold [Ct] values 24·7-37·4), on health-care worker PPE after use (Ct 26·1-35·6), and in PPE doffing areas (Ct 26·3-36·8). Of 20 air samples taken, five (25%) were positive. Three (75%) of four air samples collected before and during a bedding change in one patient's room were positive (Ct 32·7-36·2). Replication-competent virus was identified in two (50%) of four samples selected for viral isolation, including from air samples collected during bedding change.These data show contamination in isolation facilities and potential for suspension of monkeypox virus into the air during specific activities. PPE contamination was observed after clinical contact and changing of bedding. Contamination of hard surfaces in doffing areas supports the importance of cleaning protocols, PPE use, and doffing procedures.None.

The emergence of powerful oral anti-COVID-19 drugs in the post-vaccine era.

Abstract: The quest for effective drugs to treat COVID-19 has been a priority since the outbreak of the disease. The clinical application of remdesivir has been greatly restricted by the need for intravenous administration, as well as unstable concentrations in plasma and variable antiviral activity in different organelles.1 Four neutralising antibodies (bamlanivimab, etesevimab, casirivimab, and imdevimab) have been approved by the United States Food and Drug Administration; however, their high cost and need for intravenous administration render them inaccessible to the public.

Optimising predictive models to prioritise viral discovery in zoonotic reservoirs

Abstract: Despite the global investment in One Health disease surveillance, it remains difficult and costly to identify and monitor the wildlife reservoirs of novel zoonotic viruses. Statistical models can guide sampling target prioritisation, but the predictions from any given model might be highly uncertain; moreover, systematic model validation is rare, and the drivers of model performance are consequently under-documented. Here, we use the bat hosts of betacoronaviruses as a case study for the data-driven process of comparing and validating predictive models of probable reservoir hosts. In early 2020, we generated an ensemble of eight statistical models that predicted host-virus associations and developed priority sampling recommendations for potential bat reservoirs of betacoronaviruses and bridge hosts for SARS-CoV-2. During a time frame of more than a year, we tracked the discovery of 47 new bat hosts of betacoronaviruses, validated the initial predictions, and dynamically updated our analytical pipeline. We found that ecological trait-based models performed well at predicting these novel hosts, whereas network methods consistently performed approximately as well or worse than expected at random. These findings illustrate the importance of ensemble modelling as a buffer against mixed-model quality and highlight the value of including host ecology in predictive models. Our revised models showed an improved performance compared with the initial ensemble, and predicted more than 400 bat species globally that could be undetected betacoronavirus hosts. We show, through systematic validation, that machine learning models can help to optimise wildlife sampling for undiscovered viruses and illustrates how such approaches are best implemented through a dynamic process of prediction, data collection, validation, and updating.

SARS-CoV-2 antigen-detecting rapid tests for the delta variant

Abstract: Given the emergence of novel SARS-CoV-2 variants of concern, the performance of available diagnostics for these new variants should be investigated. SARS-CoV-2 antigen rapid diagnostic tests (Ag-RDTs) offer quick, cheap, and laboratory-independent results at the point of care.1,2 Although sensitivity is lower compared with RT-PCR, these tests enable reliable detection of high viral loads associated with the presence of infectious viral particles, making them important public health tools.3,4 However, the majority of Ag-RDT validation studies were done before the emergence of SARS-CoV-2 variants of concern.

Severe breakthrough COVID-19 cases in the SARS-CoV-2 delta (B.1.617.2) variant era.

Abstract: Despite compelling evidence that SARS-CoV-2 vaccines are highly effective in preventing COVID-19 infections, breakthrough cases have been emerging at an increasing rate.1 A retrospective cohort study by Tartof and colleagues2 found that vaccine effectiveness against COVID-19 decreased over time; however, its effectiveness against hospitalisation associated with COVID-19 remained robust, with no apparent reduction in vaccine effectiveness between 1 month (87%) and 5 months (88%) after vaccination with the BNT162b2 vaccine.

The gut mycobiome in health, disease, and clinical applications in association with the gut bacterial microbiome assembly.

Abstract: The gut mycobiome (fungi) is a small but crucial component of the gut microbiome in humans. Intestinal fungi regulate host homoeostasis, pathophysiological and physiological processes, and the assembly of the co-residing gut bacterial microbiome. Over the past decade, accumulating studies have characterised the gut mycobiome in health and several pathological conditions. We review the compositional and functional diversity of the gut mycobiome in healthy populations from birth to adulthood. We describe factors influencing the gut mycobiome and the roles of intestinal fungi-especially Candida and Saccharomyces spp-in diseases and therapies with a particular focus on their synergism with the gut bacterial microbiome and host immunity. Finally, we discuss the underappreciated effects of gut fungi in clinical implications, and highlight future microbiome-based therapies that harness the tripartite relationship among the gut mycobiome, bacterial microbiome, and host immunity, aiming to restore a core gut mycobiome and microbiome and to improve clinical efficacy.

Sotrovimab drives SARS-CoV-2 omicron variant evolution in immunocompromised patients

Abstract: Sotrovimab is a monoclonal antibody used as monotherapy in outpatients at risk of developing severe COVID-19 disease. Indications include patients with respiratory, cardiac, metabolic, and immunosuppression comorbidities. Rockett and colleagues1Rockett R Basile K Maddocks S et al.Resistance mutations in SARS-CoV-2 delta variant after sotrovimab use.N Engl J Med. 2022; 386: 1477-1479Crossref PubMed Scopus (13) Google Scholar have shown that, among 100 patients infected with the delta (B.1.617.2) variant and treated with sotrovimab monotherapy, four were immunocompromised and rapidly developed resistant mutations in the spike protein at positions 337 or 340, or both. These mutations are associated with prolonged excretion and in-vitro resistance.1Rockett R Basile K Maddocks S et al.Resistance mutations in SARS-CoV-2 delta variant after sotrovimab use.N Engl J Med. 2022; 386: 1477-1479Crossref PubMed Scopus (13) Google Scholar, 2Cathcart AL Havenar-Daughton C Lempp FA et al.The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2.bioRxiv. 2022; (published online Feb 18.) (preprint).https://doi.org/10.1101/2021.03.09.434607Google Scholar Given that sotrovimab is one of the few monoclonal antibodies that retains efficacy against the widely circulating omicron BA.1 sublineage, monitoring the prevalence of these mutations is crucial.3Bruel T Hadjadj J Maes P et al.Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies.Nat Med. 2022; (published online March 23.)https://doi.org/10.1038/s41591-022-01792-5Crossref PubMed Scopus (35) Google Scholar As part of routine genomic surveillance at the French National Reference Center for respiratory Viruses at the Hospices Civils de Lyon (Lyon, France) from December, 2021, to March, 2022,4Bal A Simon B Destras G et al.Detection and prevalence of SARS-CoV-2 co-infections during the Omicron variant circulation, France, December 2021–February 2022.medRxiv. 2022; (published online March 27.) (preprint).https://doi.org/10.1101/2022.03.24.22272871Google Scholar we detected mutations in the spike protein at positions 340 and 337 in 24 (0·13%) of 18 882 omicron BA.1 lineages and in one (0·02%) of 4025 omicron BA.2 lineages. These 25 samples corresponded to 18 patients infected with SARS-CoV-2 variants carrying either P337 or E340 mutations (appendix p 5). Clinical data were available for eight patients, all of whom were immunocompromised and had been treated with sotrovimab at 0–10 days after symptoms onset (appendix pp 6–7). For six patients with a follow-up, mutations at positions 337 and 340 were absent before sotrovimab infusion and were detected at low relative frequency or high relative frequency (6–100%) at 5–18 days after sotrovimab infusion. Selection of resistant viral escape variants was associated with persistent SARS-CoV-2 excretion for up to 43 days, except for one patient who cleared their infection after convalescent plasma infusion at day 24 (appendix p 4). These results suggest that sotrovimab can rapidly select mutations at positions 337 and 340 in BA.1 and BA.2 sublineages (although in-vitro findings suggest that neutralisation is not effective against the BA.2 sublineage3Bruel T Hadjadj J Maes P et al.Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies.Nat Med. 2022; (published online March 23.)https://doi.org/10.1038/s41591-022-01792-5Crossref PubMed Scopus (35) Google Scholar). These mutations rarely emerge in the omicron variant (2756 [0·03%] of all 10 042 757 omicron sequences reported on the GISAID database; appendix p 8). Notably, these mutations have been exclusively reported after sotrovimab treatment in immunocompromised patients (by Rockett and colleagues1Rockett R Basile K Maddocks S et al.Resistance mutations in SARS-CoV-2 delta variant after sotrovimab use.N Engl J Med. 2022; 386: 1477-1479Crossref PubMed Scopus (13) Google Scholar and in this Correspondence). As previously reported for patients treated with bamlanivimab,5Destras G Assaad S Bal A et al.Bamlanivimab as monotherapy in two immunocompromised patients with COVID-19.Lancet Microbe. 2021; 2: e424Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar we urge to consider monoclonal antibody as monotherapy in immunocompromised patients as a risk for escape mutant selection that might hamper viral clearance. Immunocompromised patients treated with monoclonal antibodies should benefit from a reinforced virological follow-up, including viral sequencing and viral load assessment. GD, AB, and BS contributed equally. We declare no competing interests. Download .pdf (.93 MB) Help with pdf files Supplementary appendix

The current state of clinical mycology in Africa: a European Confederation of Medical Mycology and International Society for Human and Animal Mycology survey.

Abstract: Africa, although not unique in this context, is a favourable environment for fungal infections, given the high burden of risk factors. An online survey was developed asking about laboratory infrastructure and antifungal drug availability. We received 40 responses (24·4% response rate) of 164 researchers contacted from 21 African countries. Only five institutions (12·5%) of 40 located in Cameroon, Kenya, Nigeria, Sudan, and Uganda potentially fulfilled the minimum laboratory requirements for European Confederation of Medical Mycology Excellence Centre blue status. Difficulties included low access to susceptibility testing for both yeasts and moulds (available in only 30% of institutions) and Aspergillus spp antigen detection (available in only 47·5% of institutions as an in-house or outsourced test), as well as access to mould-active antifungal drugs such as amphotericin B deoxycholate (available for 52·5% of institutions), itraconazole (52·5%), voriconazole (35·0%), and posaconazole (5·0%). United and targeted efforts are crucial to face the growing challenges in clinical mycology. Africa, although not unique in this context, is a favourable environment for fungal infections, given the high burden of risk factors. An online survey was developed asking about laboratory infrastructure and antifungal drug availability. We received 40 responses (24·4% response rate) of 164 researchers contacted from 21 African countries. Only five institutions (12·5%) of 40 located in Cameroon, Kenya, Nigeria, Sudan, and Uganda potentially fulfilled the minimum laboratory requirements for European Confederation of Medical Mycology Excellence Centre blue status. Difficulties included low access to susceptibility testing for both yeasts and moulds (available in only 30% of institutions) and Aspergillus spp antigen detection (available in only 47·5% of institutions as an in-house or outsourced test), as well as access to mould-active antifungal drugs such as amphotericin B deoxycholate (available for 52·5% of institutions), itraconazole (52·5%), voriconazole (35·0%), and posaconazole (5·0%). United and targeted efforts are crucial to face the growing challenges in clinical mycology. IntroductionApproximately a fifth of the world's people live in Africa, a continent with a propitious environment for fungal infections. The continent is marked by social and health inequalities, with a national health insurance scheme absent in most countries. Additionally, a large proportion of its population live in rural settings and are exposed to environmental factors that increase the risk for fungal diseases.1Oxford Poverty and Human Development InitiativeUnited Nations Development ProgrammeCharting pathways out of multidimensional poverty: achieving the SDGs.http://hdr.undp.org/sites/default/files/2020_mpi_report_en.pdfDate: 2020Date accessed: January 15, 2021Google Scholar Africa has the largest population living with HIV, AIDS, and tuberculosis globally, which are major risk factors for fungal infections.2United Nations Development ProgrammeHuman Development Report 2019.http://hdr.undp.org/sites/default/files/hdr2019.pdfDate: 2019Date accessed: January 15, 2021Google Scholar, 3WHOTuberculose (TB).https://www.afro.who.int/health-topics/tuberculosis-tbDate accessed: March 23, 2021Google Scholar Meanwhile, access to treatment for these three conditions is still low in many countries, and has become even worse with the COVID-19 pandemic.4Dada DA Aku E David KB COVID-19 pandemic and antiretrovirals (ARV) availability in Nigeria: recommendations to prevent shortages.Pan Afr Med J. 2020; 35: 149PubMed Google Scholar, 5UNAIDSCOVID-19 could affect the availability and cost of antiretroviral medicines, but the risks can be mitigated.https://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2020/june/20200622_availability-and-cost-of-antiretroviral-medicinesDate: June 22, 2020Date accessed: March 23, 2021Google Scholar, 6Nargesi S Bongomin F Hedayati MT The impact of COVID-19 pandemic on AIDS-related mycoses and fungal neglected tropical diseases: why should we worry?.PLoS Negl Trop Dis. 2021; 15e0009092Crossref PubMed Scopus (7) Google Scholar This problem is mainly attributed to poorly funded and overburdened health systems in many African countries;7Oladele RO Osaigbovo II Ayanlowo OO et al.The role of medical mycology societies in combating invasive fungal infections in low- and middle-income countries: a Nigerian model.Mycoses. 2019; 62: 16-21Crossref PubMed Scopus (7) Google Scholar, 8Oladele RO Akase IE Fahal AH et al.Bridging the knowledge gap on mycoses in Africa: setting up a Pan-African Mycology Working Group.Mycoses. 2020; 63: 244-249Crossref PubMed Scopus (11) Google Scholar thus dealing with the probably high burden of fungal infections is a challenge.Despite the global importance of superficial and invasive mycoses, there is still little information regarding the epidemiology of fungal infections in some areas of the world, including in Africa.9Global Action Fund for Fungal InfectionsHidden crisis: how 150 people die every hour from fungal infection while the world turns a blind eye.https://www.gaffi.org/wp-content/uploads/GAFFI-Final-Brochure-Aug-2017-pages.pdfDate: August, 2017Date accessed: March 23, 2021Google Scholar Medical mycology has made important advances, but non-specific signs and symptoms and the rapid progression of fungal disease in immunocompromised patients continue to present a challenge to clinicians and laboratories.10Cornely OA Lass-Flörl C Lagrou K Arsic-Arsenijevic V Hoenigl M Improving outcome of fungal diseases - guiding experts and patients towards excellence.Mycoses. 2017; 60: 420-425Crossref PubMed Scopus (49) Google Scholar Notable limitations include few resources and investments in clinical mycology and diagnostic resources, as well as difficulties in accessing antifungal therapy. A poor awareness of fungal diseases among health-care professionals and policy makers, as well as the unaffordability of, toxicity of, and little access to antifungal treatment options are some of the challenges facing the continent.11Friedman DZP Schwartz IS Emerging fungal infections: new patients, new patterns, and new pathogens.J Fungi (Basel). 2019; 5: 5Google Scholar, 12Brown GD Denning DW Gow NAR Levitz SM Netea MG White TC Hidden killers: human fungal infections.Sci Transl Med. 2012; 4165rv13Crossref Scopus (2455) Google Scholar, 13Oladele R Otu AA Olubamwo O et al.Evaluation of knowledge and awareness of invasive fungal infections amongst resident doctors in Nigeria.Pan Afr Med J. 2020; 36: 297Crossref PubMed Scopus (7) Google ScholarWith few exceptions (such as testing for cryptococcal antigen), advances within the past 5 years in non-culture-based diagnostics have not reached most low-income and middle-income countries (LMICs). Therefore, it is necessary to assess the present status of the diagnosis of fungal infections in these regions to guide health professionals, patients, and policy makers.12Brown GD Denning DW Gow NAR Levitz SM Netea MG White TC Hidden killers: human fungal infections.Sci Transl Med. 2012; 4165rv13Crossref Scopus (2455) Google Scholar Africa has not yet been comprehensively evaluated for its capability to diagnose and treat fungal diseases. These studies are important not only for epidemiological purposes, but also to guide the appropriate implementation of preventive, diagnostic, and therapeutic measures in medical mycology. Hence, under the umbrella of the European Confederation of Medical Mycology (ECMM) and the International Society for Human and Animal Mycology (ISHAM), we surveyed African institutions to obtain an overview of the current state of mycological laboratory capacities and availability of antifungal treatment in the field of invasive fungal diseases.ProcedureWe designed a cross-sectional survey with 29 questions (appendix pp 1–7) about the profile and size of institutions, antifungal drug availability, laboratory infrastructure, and methods used to identify pathogens and antifungal susceptibility, as well as antigen detection and molecular tests. The survey was open from June 1, 2019, to May 31, 2020, and was released online on the ISHAM and ECMM websites and sent out to their members based in Africa. We contacted 164 African researchers directly by email based on their email address from PubMed publications. Reminders were sent to the authors in cases of non-response.The institutions were classified according to whether the laboratories potentially met the ECMM criteria for blue, silver, gold, or diamond status, or did not meet the criteria. The minimal requirements for the blue status are the identification of relevant yeasts and moulds, susceptibility testing on yeasts and moulds according to standard procedures, and the performance of antigen ELISA for Aspergillus spp (galactomannan) and cryptococcal antigen. The criteria used for the classification of mycology centres are not restricted to the laboratory, but also consider the clinical and epidemiological dimensions, involvement in clinical trials, and in part depend on the type of patients cared for (appendix p 8).14Hoenigl M Gangneux JP Segal E et al.Global guidelines and initiatives from the European Confederation of Medical Mycology to improve patient care and research worldwide: new leadership is about working together.Mycoses. 2018; 61: 885-894Crossref PubMed Scopus (33) Google Scholar This classification procedure was not an accreditation visit or round organised by the ECMM. Instead, we only checked the level at which centres were likely to be accredited if they had formally applied.FindingsWe received 40 responses (24·4% response rate) of the 164 researchers contacted, encompassing 40 different institutions from 21 different countries with all African sub-regions represented (figure 1). Countries with researchers that responded were South Africa (n=8), Nigeria (n=5), Cameroon (n=4), Madagascar (n=3), Uganda (n=3), Malawi (n=2), Algeria (n=1), Botswana (n=1), Burkina Faso (n=1), Democratic Republic of the Congo (n=1), Egypt (n=1), Ethiopia (n=1), Ghana (n=1), Kenya (n=1), Mauritania (n=1), Mauritius (n=1), Namibia (n=1), Senegal (n=1), Sudan (n=1), Togo (n=1), and Tanzania (n=1). Our survey was answered by laboratory professionals (n=22), professors (n=11), attending physicians (n=4), infection control practitioners (n=1), and other professionals who did not fit any of these categories (n=2).Among responders, 29 (72·5%) were from university hospitals or national institutes of research, seven (17·5%) were from public hospitals not related to universities, two (5%) were private hospitals not related to universities, and one (2·5%) was an oncology clinic. One institution (2·5%) was an independent laboratory that served both private and public hospitals. The number of beds per institution ranged from 10 to 2880 (median, 300 beds), the number of adult intensive care unit beds ranged from 6 to 125 (median, 19 beds), and the number of paediatric and neonatal intensive care unit beds ranged from 4 to 300 (median, 20 beds).Institutions served patients living with HIV or AIDS (n=38 [95·0%]), patients with oncological (n=33 [82·5%]) and haematological malignancies (n=35 [87·5%]), patients requiring parenteral nutrition (n=24 [60·0%]), and patients who had received a solid organ transplantation (n=6 [15·0%]) or a haematopoietic stem-cell transplantation (n=4 [10·0%]).Nearly all institutions (n=39 [97·5%]) reported having a microbiology laboratory in place, although one institution outsourced general laboratory services. Focusing specifically on mycological diagnostic tools, three (7·5%) institutions reported no access at all to such services, 14 (35·0%) performed some tests within the institution and outsourced some tests to other laboratories, and 23 (57·5%) always perfomed the tests within the institution.When asked about the most relevant fungi affecting patients in their institutions, most responses were: Candida spp (n=34 [85·0%]), followed by Cryptococcus spp (n=22 [55·0%]), Aspergillus spp (n=16 [40·0%]), Fusarium spp (n=8 [20·0%]), Histoplasma spp (n=5 [12·5%]), and Mucorales (n=4 [10·0%]).When a fungal infection was suspected, 21 (52·5%) institutions reported always performing direct microscopy on clinical specimens, five (12·5%) reported performing it most of the time, seven (17·5%) reported performing it half of the time, five (12·5%) reported performing it rarely, and two (5·0%) reported that direct microscopy was never performed. Although 34 (85·0%) used microscopy to diagnose cryptococcosis, only eight (20·0%) performed a silver stain when pneumocystosis was suspected. Access to fluorescent dyes was also restricted, being available in only nine (22·5%) institutions. India or China ink was available for 31 (77·5%) institutions, followed by potassium hydroxide (n=28 [70·0%]), silver stain (n=28 [70·0%]), Giemsa stain (n=22 [55·0%]), and calcofluor white (n=4 [10·0%]).To identify fungi at the species level, biochemical tests were the most commonly used tools, in 28 (70%) institutions. Automated identification by a VITEK system (an automated system for antibiotic susceptibility testing and microbiology identification; bioMérieux, Marcy-l'Étoile, France) or other commercial methods were accessible in 18 (45·0%) institutions, followed by mounting medium (n=11 [27·5%]), Matrix-Assisted Laser Desorption or Ionization-Time of Flight (MALDI-ToF; n=7 [17·5%]), and DNA sequencing (n=8 [20·0%]). Automated blood culture monitoring was available for 19 institutions (47·5%).Susceptibility testing was available for 25 (62·5%) participants, but only in 12 (30%) institutions was access to susceptibility tests covering both yeasts and moulds available. E-test strips were available in 14 (35·0%) institutions, 14 (35·0%) had access to VITEK, 11 (27·5%) to broth microdilution following Clinical and Laboratory Standards Institute standards, and seven (17·5%) to broth microdilution following European Committee on Antimicrobial Susceptibility Testing standards.When serological testing was considered, antibody detection was mostly available for Aspergillus spp (n=9 [22·5%]), and in ten (25·0%) institutions antibody detection for Aspergillus spp was available at an outsourced laboratory. Anti-Aspergillus IgE was not evaluated in the survey. Candida spp antibody detection was available for five (12·5%) institutions, the same number had access to the test for Candida spp at an outsourced laboratory, Histoplasma spp antibody detection was performed in one institution only (2·5%), and 12 (30%) had access to the test for Histoplasma spp at an outsourced laboratory.The availability of antigen detection tests was low in the study, as illustrated in figure 2. Regarding Histoplasma species, only two (5·0%) centres indicated access to in-house antigen testing, even though 12 (30·0%) had access through an outsourced laboratory. Cryptococcus lateral flow assay was available for 24 (60·0%) institutions, three of which were exclusively through an outsourced laboratory, whereas Cryptococcus latex testing was performed in 16 (40·0%) institutions, and another two (5·0%) had access to the test through an outsourced laboratory. Aspergillus antigen detection (by galactomannan enzyme immunoassay, lateral flow assay, or lateral flow device) was available for 11 (27·5%) institutions locally and for eight (20·0%) exclusively through an outsourced laboratory. 16 (40·0%) of all institutions that answered the survey did not have access to antigen testing even through outsourced laboratories.Figure 2Antigen detection availability in African institutionsShow full captionLFA=lateral flow assay. LFD=lateral flow device.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Access to fungal molecular diagnostics was even more restricted, as shown in table 1. For example, in-house molecular tests for Pneumocystis spp were available for seven (17·5%) institutions, and six (15·0%) had access to these methods through an outsourced laboratory.Table 1Molecular test (of any sort) availability in-house and at outsourced laboratories according to the fungal pathogenNumber of institutions with molecular tests available in-houseNumber of institutions with molecular tests performed at outsourced laboratoriesTotalCandida spp8 (20·0%)7 (17·5%)15 (37·5%)Aspergillus spp5 (12·5%)7 (17·5%)12 (30·0%)Pneumocystis spp7 (17·5%)6 (15·0%)13 (32·5%)Other fungi5 (12·5%)6 (15·0%)11 (27·5%)Data shown as n (%). Percentages calculated out of 40 responses. Open table in a new tab Only five (12·5%) institutions fulfilled the minimum laboratory requirements for blue status according to ECMM criteria. These five institutions were located in Cameroon, Kenya, Nigeria, Sudan, and Uganda. Seven (17·5%) other institutions fulfilled three of four blue status criteria, whereas 16 (40%) fulfilled two, 11 (27·5%) institutions fulfilled one criterion, and only one (2·5%) institution did not fulfil any of the criteria. Although South Africa is the only African country with a surveillance system for fungal infections and a national mycology reference laboratory,8Oladele RO Akase IE Fahal AH et al.Bridging the knowledge gap on mycoses in Africa: setting up a Pan-African Mycology Working Group.Mycoses. 2020; 63: 244-249Crossref PubMed Scopus (11) Google Scholar none of the responders from this country performed an antigen ELISA for Aspergillus spp or equivalent assays instead.The availability of antifungal therapy in Africa is detailed in table 2. Therapeutic drug monitoring (TDM) was available for itraconazole in seven (17·5%) institutions in house and in two (5%) institutions at an outsourced laboratory. Regarding TDM for other antifungal agents, voriconazole was available in four (10·0%) institutions, posaconazole in one (2·5%) institution, and 5-flucytosine in three (7·5%) centres in total, both in-house and outsourced.Table 2Antifungal drug availability in AfricaNumber of institutions with antifungal drug availability in Africa (n=40)Fluconazole36 (90·0%)Isavuconazole1 (2·5%)Itraconazole21 (52·5%)Posaconazole2 (5·0%)Voriconazole14 (35·0%)Amphotericin B deoxycholate21 (52·5%)Liposomal amphotericin B7 (17·5%)Amphotericin B lipid complex4 (10·0%)Other lipid formulations of amphotericin B4 (10·0%)Anidulafungin2 (5·0%)Caspofungin acetate8 (20·0%)Micafungin sodium9 (22·5%)5-flucytosine11 (27·5%)Terbinafine25 (62·5%)Data shown as n (%). Percentages calculated out of 40 responses. Open table in a new tab DiscussionWe report for the first time the availability of diagnostic tools and capacity for treatment of fungal infections in Africa. Other investigators have indicated some of the African laboratories' strengths and weaknesses, but they usually focused on specific African sub-regions (sub-Saharan Africa mainly) and diseases, such as HIV or AIDS.15Alemnji GA Zeh C Yao K Fonjungo PN Strengthening national health laboratories in sub-Saharan Africa: a decade of remarkable progress.Trop Med Int Health. 2014; 19: 450-458Crossref PubMed Scopus (54) Google Scholar, 16Gray IP Carter JY An evaluation of clinical laboratory services in sub-Saharan Africa. Ex africa semper aliquid novi?.Clin Chim Acta. 1997; 267: 103-128Crossref PubMed Scopus (16) Google Scholar, 17Zhang HL Omondi MW Musyoka AM et al.Challenges of maintaining good clinical laboratory practices in low-resource settings: a health program evaluation framework case study from east Africa.Am J Clin Pathol. 2016; 146: 199-206Crossref PubMed Scopus (16) Google Scholar, 18Eduful SK, Ocansey BK, Dadzie EA, et al. The current state of medical mycology laboratory practice in Ghana: preliminary data from a FIKI Ghana and GMMG survey. The 7th Laboratory Professionals Annual Meeting of the Celebrate LAB West Africa, Accra, Ghana; April 21–22, 2021.Google Scholar Our survey included institutions with distinct profiles (such as university hospitals and public and private hospitals with different numbers of beds) and from different sub-regions of Africa.The low numbers of responders might reflect the fact that there are few mycologists on the continent. Even though the sample in this survey was a convenience sample, it did provide a snapshot from the entire continent. Only three (7·5%) institutions, located in Ethiopia (n=1), Nigeria (n=1), and Togo (n=1), reported no access to mycological diagnosis. However, we should highlight that some countries are not represented in our sample and might have an even more vulnerable situation when it comes to the diagnosis and treatment of fungal infections, mainly if we consider those countries with a lower human development index, lower gross national income per person, and worse indicators related to multidimensional poverty, than the countries included here.1Oxford Poverty and Human Development InitiativeUnited Nations Development ProgrammeCharting pathways out of multidimensional poverty: achieving the SDGs.http://hdr.undp.org/sites/default/files/2020_mpi_report_en.pdfDate: 2020Date accessed: January 15, 2021Google Scholar, 2United Nations Development ProgrammeHuman Development Report 2019.http://hdr.undp.org/sites/default/files/hdr2019.pdfDate: 2019Date accessed: January 15, 2021Google Scholar Nevertheless, the high prevalence of university hospitals and national centres of research (72·5%) among responders might overestimate the available resources. In Africa, challenges posed by fungal infection are huge and diverse. The burden of fungal infection, both cutaneous and invasive, is high, and is well documented in many studies.19Ocansey BK Pesewu GA Codjoe FS Osei-Djarbeng S Feglo PK Denning DW Estimated burden of serious fungal infections in Ghana.J Fungi (Basel). 2019; 5 (11): 38Crossref Scopus (13) Google Scholar, 20Badiane AS Ndiaye D Denning DW Burden of fungal infections in Senegal.Mycoses. 2015; 58: 63-69Crossref PubMed Scopus (22) Google Scholar, 21Chekiri-Talbi M Denning DW Burden of fungal infections in Algeria.Eur J Clin Microbiol Infect Dis. 2017; 36: 999-1004Crossref PubMed Scopus (19) Google Scholar, 22Faini D Maokola W Furrer H et al.Burden of serious fungal infections in Tanzania.Mycoses. 2015; 58: 70-79Crossref PubMed Scopus (28) Google Scholar, 23Guto JA Bii CC Denning DW Estimated burden of fungal infections in Kenya.J Infect Dev Ctries. 2016; 10: 777-784Crossref PubMed Scopus (19) Google Scholar, 24Koffi D Bonouman IV Toure AO et al.Estimates of serious fungal infection burden in Côte d'Ivoire and country health profile.J Mycol Med. 2021; 31101086Crossref PubMed Scopus (5) Google Scholar, 25Kwizera R Musaazi J Meya DB et al.Burden of fungal asthma in Africa: a systematic review and meta-analysis.PLoS One. 2019; 14e0216568Crossref PubMed Scopus (33) Google Scholar, 26Mandengue CE Denning DW The burden of serious fungal infections in Cameroon.J Fungi (Basel). 2018; 4: 1-9Google Scholar, 27Oladele RO Denning DW Burden of serious fungal infection in Nigeria.West Afr J Med. 2014; 33: 107-114PubMed Google Scholar, 28Parkes-Ratanshi R Achan B Kwizera R Kambugu A Meya D Denning DW Cryptococcal disease and the burden of other fungal diseases in Uganda; where are the knowledge gaps and how can we fill them?.Mycoses. 2015; 58: 85-93Crossref PubMed Scopus (31) Google Scholar, 29Rajasingham R Smith RM Park BJ et al.Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis.Lancet Infect Dis. 2017; 17: 873-881Summary Full Text Full Text PDF PubMed Scopus (1008) Google Scholar, 30Zaki SM Denning DW Serious fungal infections in Egypt.Eur J Clin Microbiol Infect Dis. 2017; 36: 971-974Crossref PubMed Scopus (19) Google Scholar Deaths due to cryptococcal disease, which are associated with HIV infection, exceed 200 000 per year.29Rajasingham R Smith RM Park BJ et al.Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis.Lancet Infect Dis. 2017; 17: 873-881Summary Full Text Full Text PDF PubMed Scopus (1008) Google Scholar, 31Nyazika TK Tatuene JK Kenfak-Foguena A et al.Epidemiology and aetiologies of cryptococcal meningitis in Africa, 1950-2017: protocol for a systematic review.BMJ Open. 2018; 8e020654Crossref PubMed Scopus (16) Google Scholar A study evaluating non-culture-based methods, performed with inpatients in South Africa, showed that one in ten inpatients had evidence of an invasive mycosis (including cryptococcosis, pneumocystosis, and histoplasmosis).32van Schalkwyk E Mhlanga M Maphanga TG et al.Screening for invasive fungal disease using non-culture-based assays among inpatients with advanced HIV disease at a large academic hospital in South Africa.Mycoses. 2020; 63: 478-487Crossref PubMed Scopus (4) Google Scholar Additionally, a high incidence of co-infection with tuberculosis was observed, complicating the diagnosis and management of these patients, particularly because of drug–drug interactions. The authors of this previous study estimated that 60% of invasive fungal diseases were missed,32van Schalkwyk E Mhlanga M Maphanga TG et al.Screening for invasive fungal disease using non-culture-based assays among inpatients with advanced HIV disease at a large academic hospital in South Africa.Mycoses. 2020; 63: 478-487Crossref PubMed Scopus (4) Google Scholar corroborating the urgent need for improving diagnostic capacities in this region.Few studies assessing mycological practices around the world have been performed,33Lasseter G McNulty CAM Palmer M Yoxall H Kibbler C Developing best practice for fungal specimen submission--fungal audit of general practice.Mycoses. 2012; 55: 476-482Crossref PubMed Scopus (3) Google Scholar, 34Schelenz S Owens K Guy R et al.National mycology laboratory diagnostic capacity for invasive fungal diseases in 2017: evidence of sub-optimal practice.J Infect. 2019; 79: 167-173Summary Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 35Morris AJ Arthur IH Kidd SE et al.Mycological testing of clinical samples in Australasian pathology laboratories: wide diversity and room for improvement.Pathology. 2016; 48: 531-534Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 36Rosner ER Reiss E Warren NG Shadomy HJ Lipman HB Evaluation of the status of laboratory practices and the need for continuing education in medical mycology.Am J Clin Pathol. 2002; 118: 278-286Crossref PubMed Scopus (16) Google Scholar, 37Schelenz S Barnes RA Kibbler CC Jones BL Denning DW Standards of care for patients with invasive fungal infections within the United Kingdom: a national audit.J Infect. 2009; 58: 145-153Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar and fewer so in LMICs.18Eduful SK, Ocansey BK, Dadzie EA, et al. The current state of medical mycology laboratory practice in Ghana: preliminary data from a FIKI Ghana and GMMG survey. The 7th Laboratory Professionals Annual Meeting of the Celebrate LAB West Africa, Accra, Ghana; April 21–22, 2021.Google Scholar, 38Falci DR Pasqualotto AC Clinical mycology in Latin America and the Caribbean: a snapshot of diagnostic and therapeutic capabilities.Mycoses. 2019; 62: 368-373Crossref PubMed Scopus (17) Google Scholar, 39Chindamporn A Chakrabarti A Li R et al.Survey of laboratory practices for diagnosis of fungal infection in seven Asian countries: an Asia Fungal Working Group (AFWG) initiative.Med Mycol. 2018; 56: 416-425Crossref PubMed Scopus (54) Google Scholar Sufficient numbers of responders are a challenge in this type of approach: the sample size was also a limitation for Falci and Pasqualotto38Falci DR Pasqualotto AC Clinical mycology in Latin America and the Caribbean: a snapshot of diagnostic and therapeutic capabilities.Mycoses. 2019; 62: 368-373Crossref PubMed Scopus (17) Google Scholar (129 responses from 14 countries [96 from Brazil, nine from Mexico, five from Colombia, three from Uruguay, three from Guatemala, two from Argentina, two from Chile, two from Paraguay, two from Venezuela, one from Barbados, one from Ecuador, one from Honduras, one from Peru, and one from French Guiana], of which 74% were from one country only) and Chindamporn and colleagues39Chindamporn A Chakrabarti A Li R et al.Survey of laboratory practices for diagnosis of fungal infection in seven Asian countries: an Asia Fungal Working Group (AFWG) initiative.Med Mycol. 2018; 56: 416-425Crossref PubMed Scopus (54) Google Scholar (241 laboratories from seven countries answered the survey out of nearly 900 who were directly contacted, a response rate of approximately 26%). Despite this, data from these snapshots are interesting tools to be used for the advocacy of laboratory capacity improvements. Our data can be combined with those from these previous papers, indicating that there is an unequivocal absence of adequate diagnostic tools to manage fungal disease burden in these regions (Asia, Africa, and Latin America).In many mycoses, choosing the most appropriate therapy and accurately identifying the causative fungal species is crucial. One example is Candida auris, a multidrug resistant pathogen that was retrospectively identified in 2009 in South Africa and in 2011 in Kenya.40Adam RD Revathi G Okinda N et al.Analysis of Candida auris fungemia at a single facility in Kenya.Int J Infect Dis. 2019; 85: 182-187Summary Full Text Full Text PDF PubMed Scopus (24) Google Scholar, 41Magobo RE Corcoran C Seetharam S Govender NP Candida auris-associated candidemia, South Africa.Emerg Infect Dis. 2014; 20: 1250-1251Crossref PubMed Scopus (11) Google Scholar Nevertheless, few laboratories reported having the capacity to correctly identify C auris, which includes modern technology such as MALDI-To

Serum neutralisation of the SARS-CoV-2 omicron sublineage BA.2

Abstract: The rapidly emerging SARS-CoV-2 omicron variant is associated with high transmissibility, compromised serum neutralising activity, and reduced vaccine effectiveness.1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar, 3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar BA.1 is the dominant omicron sublineage, making up more than 97% of omicron variant sequences worldwide in November and December, 2021, whereas BA.2 and BA.3 were rare.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar Hence, early studies of the omicron variant were mainly based on the BA.1 sublineage. Since early January, 2022, there has been a sudden upsurge of BA.2 in Europe and Asia, accounting for 15·6% of omicron variant sequences detected at the end of January, 2022.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar In view of the increasing epidemiological importance, there is an urgent need to assess the serum neutralising activity against BA.2, which correlates with vaccine effectiveness.We measured the serum neutralising antibody (NAb) activity against BA.1 and BA.2 with a live virus NAb assay,1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar and report the results here. We tested serum specimens collected from individuals who had received three doses of COVID-19 vaccine (three-dose vaccinated; n=21; appendix p 4),4Khong K-W Liu D Leung K-Y et al.Antibody response of combination of BNT162b2 and CoronaVac platforms of COVID-19 vaccines against omicron variant.Vaccines (Basel). 2022; 10: 160Crossref PubMed Scopus (19) Google Scholar patients who had COVID-19 in 2020 who received one dose of the Pfizer-BioNTech BNT162b2 vaccine after recovery (pre-variant of concern [VOC] convalescent, one-dose vaccinated; n=15),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar patients who had COVID-19 in 2020 but had not been vaccinated (pre-VOC convalescent, non-vaccinated; n=9),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar and patients recently infected by the omicron sublineage BA.2 (omicron BA.2 convalescent; n=10; appendix p 4). Overall (n=55), the geometric mean NAb titre (GMT) against BA.2 was 1·68 (CI 1·63–1·73) times higher than against BA.1 (73·2 against BA.2 vs 43·7 against BA.1; p<0·0001; appendix p 2). Subgroup analysis showed that the GMT against BA.2 was 2·0 times higher (95% CI 1·99–2·01) than the GMT against BA.1 in the pre-VOC convalescent, one-dose vaccinated group (422·2 against BA.2 vs 211·1 against BA.1; p=0·0005), 2·3 times higher (95% CI 2·12-2·56) in the pre-VOC convalescent, non-vaccinated group (29·4 against BA.2 vs 12·6 against BA.1; p=0·0078), and 2·0 times higher (95% CI 1·63–2·50) in the omicron BA.2 convalescent group (32·5 against BA.2 vs 16·3 against BA.1; p=0·031). However, the difference between BA.2 and BA.1 in the three-dose vaccinated group was not statistically significant (p=0·14).To better understand the difference between BA.2 and BA.1, we calculated the ratio of BA.2 NAb titre to BA.1 NAb titre in each individual. All individuals in the pre-VOC convalescent, one-dose vaccinated group; the pre-VOC convalescent, non-vaccinated group; and the omicron BA.2 convalescent group had equal or higher NAb titres for BA.2 than BA.1. However, four (19%) of 21 individuals in the three-dose vaccinated group had a lower NAb titre for BA.2 than BA.1. The BA.2-to-BA.1 NAb titre ratio in the three-dose vaccinated group was numerically lower than in other groups, but was only significantly lower than in the pre-VOC convalescent, non-vaccinated group (p=0·041; appendix p 3).Our data indicate that the immune escape from BA.2 is not as severe as from BA.1, suggesting that other viral or host factors are driving the rapid spread of BA.2. Since NAb titres correlate with vaccine effectiveness, our data suggest that currently available vaccines might be more effective against BA.2 than BA.1. This study was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 13–265 and UW 21–214) and the Hospital Authority Kowloon West Cluster (KW/EX-20–038[144–26]). Written informed consent was obtained from all study participants. The rapidly emerging SARS-CoV-2 omicron variant is associated with high transmissibility, compromised serum neutralising activity, and reduced vaccine effectiveness.1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar, 3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar BA.1 is the dominant omicron sublineage, making up more than 97% of omicron variant sequences worldwide in November and December, 2021, whereas BA.2 and BA.3 were rare.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar Hence, early studies of the omicron variant were mainly based on the BA.1 sublineage. Since early January, 2022, there has been a sudden upsurge of BA.2 in Europe and Asia, accounting for 15·6% of omicron variant sequences detected at the end of January, 2022.3WHOCOVID-19 weekly epidemiological update.https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-february-2022Date: Feb 8, 2022Date accessed: February 12, 2022Google Scholar In view of the increasing epidemiological importance, there is an urgent need to assess the serum neutralising activity against BA.2, which correlates with vaccine effectiveness. We measured the serum neutralising antibody (NAb) activity against BA.1 and BA.2 with a live virus NAb assay,1Lu L Mok BW Chen LL et al.Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients.Clin Infect Dis. 2021; (published online Dec 16.)https://doi.org/10.1093/cid/ciab1041Crossref Scopus (113) Google Scholar, 2Chen LL Chua GT Lu L et al.Omicron variant susceptibility to neutralizing antibodies induced in children by natural SARS-CoV-2 infection or COVID-19 vaccine.Emerg Microbes Infect. 2022; 11: 543-547Crossref PubMed Scopus (23) Google Scholar and report the results here. We tested serum specimens collected from individuals who had received three doses of COVID-19 vaccine (three-dose vaccinated; n=21; appendix p 4),4Khong K-W Liu D Leung K-Y et al.Antibody response of combination of BNT162b2 and CoronaVac platforms of COVID-19 vaccines against omicron variant.Vaccines (Basel). 2022; 10: 160Crossref PubMed Scopus (19) Google Scholar patients who had COVID-19 in 2020 who received one dose of the Pfizer-BioNTech BNT162b2 vaccine after recovery (pre-variant of concern [VOC] convalescent, one-dose vaccinated; n=15),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar patients who had COVID-19 in 2020 but had not been vaccinated (pre-VOC convalescent, non-vaccinated; n=9),5Lu L Chen LL Zhang RR et al.Boosting of serum neutralizing activity against the omicron variant among recovered COVID-19 patients by BNT162b2 and Coronavac vaccines.SSRN. 2022; (published online Feb 8.) (preprint).https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4029746Google Scholar and patients recently infected by the omicron sublineage BA.2 (omicron BA.2 convalescent; n=10; appendix p 4). Overall (n=55), the geometric mean NAb titre (GMT) against BA.2 was 1·68 (CI 1·63–1·73) times higher than against BA.1 (73·2 against BA.2 vs 43·7 against BA.1; p<0·0001; appendix p 2). Subgroup analysis showed that the GMT against BA.2 was 2·0 times higher (95% CI 1·99–2·01) than the GMT against BA.1 in the pre-VOC convalescent, one-dose vaccinated group (422·2 against BA.2 vs 211·1 against BA.1; p=0·0005), 2·3 times higher (95% CI 2·12-2·56) in the pre-VOC convalescent, non-vaccinated group (29·4 against BA.2 vs 12·6 against BA.1; p=0·0078), and 2·0 times higher (95% CI 1·63–2·50) in the omicron BA.2 convalescent group (32·5 against BA.2 vs 16·3 against BA.1; p=0·031). However, the difference between BA.2 and BA.1 in the three-dose vaccinated group was not statistically significant (p=0·14). To better understand the difference between BA.2 and BA.1, we calculated the ratio of BA.2 NAb titre to BA.1 NAb titre in each individual. All individuals in the pre-VOC convalescent, one-dose vaccinated group; the pre-VOC convalescent, non-vaccinated group; and the omicron BA.2 convalescent group had equal or higher NAb titres for BA.2 than BA.1. However, four (19%) of 21 individuals in the three-dose vaccinated group had a lower NAb titre for BA.2 than BA.1. The BA.2-to-BA.1 NAb titre ratio in the three-dose vaccinated group was numerically lower than in other groups, but was only significantly lower than in the pre-VOC convalescent, non-vaccinated group (p=0·041; appendix p 3). Our data indicate that the immune escape from BA.2 is not as severe as from BA.1, suggesting that other viral or host factors are driving the rapid spread of BA.2. Since NAb titres correlate with vaccine effectiveness, our data suggest that currently available vaccines might be more effective against BA.2 than BA.1. This study was approved by the institutional review board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 13–265 and UW 21–214) and the Hospital Authority Kowloon West Cluster (KW/EX-20–038[144–26]). Written informed consent was obtained from all study participants. We declare no competing interests. L-LC and AW-HC contributed equally. This work was supported by Health and Medical Research Fund, the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (ref no. COVID190124 and COVID1903010 [Project 1]), the Emergency Collaborative Project (EKPG22-01) of Guangzhou Laboratory, and donations from Richard Yu and Carol Yu, Shaw Foundation Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, Lee Wan Keung Charity Foundation, Hong Kong Sanatorium and Hospital, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie and George Ho Charitable Foundation, Kai Chong Tong, Tse Kam Ming Laurence, Foo Oi Foundation, Betty Hing-Chu Lee, and Ping Cham So. The funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all data in the study and had final responsibility for the decision to submit for publication. L-LC and KK-WT directly accessed and verified the underlying data. Data are available from the corresponding author upon reasonable request. Supplementary Material Download .pdf (.57 MB) Help with pdf files Supplementary appendix Download .pdf (.57 MB) Help with pdf files Supplementary appendix

Resistome and virulome accretion in an NDM-1-producing ST147 sublineage of Klebsiella pneumoniae associated with an outbreak in Tuscany, Italy: a genotypic and phenotypic characterisation.

Abstract: Carbapenemase-producing Enterobacterales (CPE), particularly those producing metallo-β-lactamases, are among the most challenging antibiotic-resistant pathogens, causing outbreaks of difficult-to-treat nosocomial infections worldwide. Since November 2018, an outbreak of New Delhi metallo-β-lactamases-positive CPE (NDM-CPE) has emerged in Tuscany, Italy. In this study, we aimed to investigate the NDM-CPE associated with the outbreak and characterise the responsible Klebsiella pneumoniae clone.We used whole-genome sequencing and bioinformatic analysis to characterise NDM-CPE isolates that caused bloodstream infections in 53 patients at 11 hospitals in Tuscany and that were collected between Jan 1, 2018, and July 5, 2019 (ie, the early phase of the outbreak and preceding months). The CPE isolates characterised in this study were isolated and identified at the species level and as NDM producers by six diagnostic microbiology laboratories that serve the 11 hospitals. We used comparative genomic analysis, antimicrobial susceptibility testing, plasmid conjugal transfer assays, evaluation of virulence potential in the Galleria mellonella infection model, and serum bactericidal assays to further characterise the clone causing the outbreak.The outbreak was sustained by an ST147 K pneumoniae producing NDM-1, which had a complex resistome that mediated resistance to most antimicrobials (except cefiderocol, the aztreonam-avibactam combination, colistin, and fosfomycin). The clone belonged to a sublineage of probably recent evolution, occurred by the sequential acquisition of an integrative and conjugative element encoding the yersiniabactin siderophore, an FIB(pQil)-type multiresistance plasmid carrying blaNDM-1, and a transferable chimeric plasmid, derived from virulence elements of hypervirulent K pneumoniae, carrying several resistance and virulence determinants. Infection of G mellonella larvae revealed a variable virulence potential. The behaviour in serum bactericidal assays was different from typical hypervirulent K pneumoniae strains, with variable grades of serum resistance apparently associated with mutations in specific chromosomal loci (csrD, pal, and ramR).This description of a sublineage of ST147 K pneumoniae with a complex resistome and virulome that is capable of sustaining a large regional outbreak adds to existing research on the evolutionary trajectories within high-risk clones of K pneumoniae. Global surveillance programmes are warranted to track the dissemination of these lineages, and to prevent and control their spread.Italian Ministry of Health and Department of Experimental and Clinical Medicine, University of Florence.

Human-to-human transmission of Chlamydia psittaci in China, 2020: an epidemiological and aetiological investigation.

Abstract: Chlamydia psittaci can infect a wide range of avian species, occasionally causing psittacosis (also known as parrot fever) in humans. Most human psittacosis cases are associated with close contact with pet birds or poultry. In December, 2020, an outbreak of severe community-acquired pneumonia of unknown aetiology was reported in a hospital in Shandong province, China, and some of the patients' close contacts had respiratory symptoms. Our aims were to determine the causative agent of this epidemic and whether there had been human-to-human transmission.For this epidemiological and aetiological investigation study, we enrolled patients who had community-acquired pneumonia confirmed by chest CT at two local hospitals in Shandong Province in China. We collected sputum, bronchoalveolar lavage fluid, and nasopharyngeal swab samples from participants and detected pathogens by surveying for 22 target respiratory microbes using a commercial assay, followed by metagenomic next-generation sequencing, specific nested PCR, and qPCR tests. We excluded individuals who were C psittaci-negative on both tests. We recruited close contacts of the C psittaci-positive patients, and tested nasopharyngeal swabs from the close contacts and samples from ducks from the processing plant where these patients worked. We then integrated the epidemiological, clinical, and laboratory data to reveal the potential chain of transmission of C psittaci that characterised this outbreak.Between Dec 4 and 29, 2020, we used metagenomic next-generation sequencing and different PCR-based approaches to test 12 inpatients with community-acquired pneumonia, of whom six (50%) were workers at a duck-meat processing plant and two (17%) were unemployed people, who were positive for C psittaci and enrolled in this study. We contacted 61 close contacts of the six patients who worked at the duck-meat processing plant, of whom 61 (100%) were enrolled and tested, and we determined that the community-acquired pneumonia outbreak was caused by C psittaci. Within the outbreak cluster, 17 (77%) of 22 participants had confirmed C psittaci infections and five (23%) of 22 participants were asymptomatic C psittaci carriers. The outbreak had begun with avian-to-human transmission, and was followed by secondary and tertiary human-to-human transmission, which included transmission by several asymptomatic carriers and by health-care workers. In addition, some of the participants with confirmed C psittaci infection had no identified source of infection, which suggested cryptic bacterial transmission.Our study data might represent the first documented report of human-to-human transmission of C psittaci in China. Therefore, C psittaci has the potential to evolve human-to-human transmission via various routes, should be considered an elevated biosecurity and emergent risk, and be included as part of the routine diagnosis globally, especially for high-risk populations.Academic Promotion Programme of Shandong First Medical University, National Science and Technology Major Project, ARC Australian Laureate Fellowship.

Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial

Abstract: Safe and effective vaccines are urgently needed to end the COVID-19 pandemic caused by SARS-CoV-2 infection. We aimed to assess the preliminary safety, tolerability, and immunogenicity of an mRNA vaccine ARCoV, which encodes the SARS-CoV-2 spike protein receptor-binding domain (RBD).This single centre, double-blind, randomised, placebo-controlled, dose-escalation, phase 1 trial of ARCoV was conducted at Shulan (Hangzhou) hospital in Hangzhou, Zhejiang province, China. Healthy adults aged 18-59 years negative for SARS-CoV-2 infection were enrolled and randomly assigned using block randomisation to receive an intramuscular injection of vaccine or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, and 25 μg. The first six participants in each block were sentinels and along with the remaining 18 participants, were randomly assigned to groups (5:1). In block 1 sentinels were given the lowest vaccine dose and after a 4-day observation with confirmed safety analyses, the remaining 18 participants in the same dose group proceeded and sentinels in block 2 were given their first administration on a two-dose schedule, 28 days apart. All participants, investigators, and staff doing laboratory analyses were masked to treatment allocation. Humoral responses were assessed by measuring anti-SARS-CoV-2 RBD IgG using a standardised ELISA and neutralising antibodies using pseudovirus-based and live SARS-CoV-2 neutralisation assays. SARS-CoV-2 RBD-specific T-cell responses, including IFN-γ and IL-2 production, were assessed using an enzyme-linked immunospot (ELISpot) assay. The primary outcome for safety was incidence of adverse events or adverse reactions within 60 min, and at days 7, 14, and 28 after each vaccine dose. The secondary safety outcome was abnormal changes detected by laboratory tests at days 1, 4, 7, and 28 after each vaccine dose. For immunogenicity, the secondary outcome was humoral immune responses: titres of neutralising antibodies to live SARS-CoV-2, neutralising antibodies to pseudovirus, and RBD-specific IgG at baseline and 28 days after first vaccination and at days 7, 15, and 28 after second vaccination. The exploratory outcome was SARS-CoV-2-specific T-cell responses at 7 days after the first vaccination and at days 7 and 15 after the second vaccination. This trial is registered with www.chictr.org.cn (ChiCTR2000039212).Between Oct 30 and Dec 2, 2020, 230 individuals were screened and 120 eligible participants were randomly assigned to receive five-dose levels of ARCoV or a placebo (20 per group). All participants received the first vaccination and 118 received the second dose. No serious adverse events were reported within 56 days after vaccination and the majority of adverse events were mild or moderate. Fever was the most common systemic adverse reaction (one [5%] of 20 in the 5 μg group, 13 [65%] of 20 in the 10 μg group, 17 [85%] of 20 in the 15 μg group, 19 [95%] of 20 in the 20 μg group, 16 [100%] of 16 in the 25 μg group; p<0·0001). The incidence of grade 3 systemic adverse events were none (0%) of 20 in the 5 μg group, three (15%) of 20 in the 10 μg group, six (30%) of 20 in the 15 μg group, seven (35%) of 20 in the 20 μg group, five (31%) of 16 in the 25 μg group, and none (0%) of 20 in the placebo group (p=0·0013). As expected, the majority of fever resolved in the first 2 days after vaccination for all groups. The incidence of solicited systemic adverse events was similar after administration of ARCoV as a first or second vaccination. Humoral immune responses including anti-RBD IgG and neutralising antibodies increased significantly 7 days after the second dose and peaked between 14 and 28 days thereafter. Specific T-cell response peaked between 7 and 14 days after full vaccination. 15 μg induced the highest titre of neutralising antibodies, which was about twofold more than the antibody titre of convalescent patients with COVID-19.ARCoV was safe and well tolerated at all five doses. The acceptable safety profile, together with the induction of strong humoral and cellular immune responses, support further clinical testing of ARCoV at a large scale.National Key Research and Development Project of China, Academy of Medical Sciences China, National Natural Science Foundation China, and Chinese Academy of Medical Sciences.