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1.
Viruses ; 15(2)2023 01 18.
Article in English | MEDLINE | ID: covidwho-2272025

ABSTRACT

The COVID-19 pandemic remains a global health threat and novel antiviral strategies are urgently needed. SARS-CoV-2 employs the cellular serine protease TMPRSS2 for entry into lung cells, and TMPRSS2 inhibitors are being developed for COVID-19 therapy. However, the SARS-CoV-2 Omicron variant, which currently dominates the pandemic, prefers the endo/lysosomal cysteine protease cathepsin L over TMPRSS2 for cell entry, raising doubts as to whether TMPRSS2 inhibitors would be suitable for the treatment of patients infected with the Omicron variant. Nevertheless, the contribution of TMPRSS2 to the spread of SARS-CoV-2 in the infected host is largely unclear. In this study, we show that the loss of TMPRSS2 strongly reduced the replication of the Beta variant in the nose, trachea and lung of C57BL/6 mice, and protected the animals from weight loss and disease. The infection of mice with the Omicron variant did not cause disease, as expected, but again, TMPRSS2 was essential for efficient viral spread in the upper and lower respiratory tract. These results identify the key role of TMPRSS2 in SARS-CoV-2 Beta and Omicron infection, and highlight TMPRSS2 as an attractive target for antiviral intervention.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Humans , Mice , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Mice, Inbred C57BL , Pandemics , Serine Endopeptidases/genetics
2.
Front Immunol ; 13: 944713, 2022.
Article in English | MEDLINE | ID: covidwho-2141966

ABSTRACT

In late 2021, the omicron variant of SARS Coronavirus 2 (SARS-CoV-2) emerged and replaced the previously dominant delta strain. Effectiveness of COVID-19 vaccines against omicron has been challenging to estimate in clinical studies or is not available for all vaccines or populations of interest. T cell function can be predictive of vaccine longevity and effectiveness against disease, likely in a more robust way than antibody neutralization. In this mini review, we summarize the evidence on T cell immunity against omicron including effects of boosters, homologous versus heterologous regimens, hybrid immunity, memory responses and vaccine product. Overall, T cell reactivity in post-vaccine specimens is largely preserved against omicron, indicating that vaccines utilizing the parental antigen continue to be protective against disease caused by the omicron variant.


Subject(s)
COVID-19 , Viral Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Humans , SARS-CoV-2 , T-Lymphocytes , Vaccination
3.
Sci Rep ; 12(1): 19858, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-2133587

ABSTRACT

SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection against infection. The novel variant of concern (VoC) Omicron BA.1 and its sub-lineages have the largest number of amino acid alterations in its Spike protein to date. Thus, they may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals in particular in those who have only received a primary immunization scheme. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron sub-lineages BA.1, BA.2, BA.2.12.1, BA.3, BA.4/5, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (96-100%) towards the SARS-CoV-2 B.1 isolate, and minor to moderate reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant and its sub-lineages had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron BA.1 and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination, vector-based AZD1222 and Ad26.CoV2.S performed less well with peak responder rates of 48%, 56% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argue for booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based primary immunization scheme.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , Neutralization Tests , Antibodies, Viral , COVID-19 Vaccines , RNA, Messenger , Ad26COVS1 , BNT162 Vaccine , COVID-19/prevention & control , ChAdOx1 nCoV-19 , Vaccination
4.
NPJ Vaccines ; 7(1): 147, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2119433

ABSTRACT

Virus neutralization data using post-vaccination sera are an important tool in informing vaccine use policy decisions, however, they often pose interpretive challenges. We systematically reviewed the pre-print and published literature for neutralization studies against Omicron using sera collected after both primary and booster vaccination. We found a high proportion of post-primary vaccination sera were not responding against Omicron but boosting increased both neutralizing activity and percent of responding sera. We recommend reporting percent of responders alongside neutralization data to portray vaccine neutralization ability more accurately.

5.
Vaccines (Basel) ; 10(10)2022 Oct 20.
Article in English | MEDLINE | ID: covidwho-2082017

ABSTRACT

BACKGROUND: The emergence of the Omicron variant (B.1.1.529), which correlated with dramatic losses in cross-neutralization capacity of post-vaccination sera, raised concerns about the effectiveness of COVID-19 vaccines against infection and disease. Several clinically relevant sub-variants subsequently emerged rapidly. METHODS: We evaluated published and pre-print studies reporting sub-variant specific reductions in cross-neutralization compared to the prototype strain of SARS-CoV-2 and between sub-variants. Median fold-reduction across studies was calculated by sub-variant and vaccine platform. RESULTS: Among 178 studies with post-vaccination data, after primary vaccination the sub-variant specific fold-reduction in neutralization capacity compared to the prototype antigen varied widely, from median 4.2-fold for BA.3 to 40.1-fold for BA.2.75; in boosted participants fold-reduction was similar for most sub-variants (5.3-fold to 7.0-fold); however, a more pronounced fold-change was observed for sub-variants related to BA.4 and BA.5 (10.4-fold to 14.2-fold). Relative to BA.1, the other Omicron sub-variants had similar neutralization capacity post-primary vaccination (range median 0.8-fold to 1.1-fold) and post-booster (0.9-fold to 1.4-fold) except for BA.4/5-related sub-variants which was higher (2.1-fold to 2.7-fold). Omicron sub-variant-specific responder rates were low post-primary vaccination (range median 28.0% to 65.9%) compared to the prototype (median 100%) but improved post-booster (range median 73.3% to 100%). CONCLUSIONS: Fold-reductions in neutralization titers were comparable post-booster except for sub-variants related to BA.4 and BA.5, which had higher fold-reduction. Assessment after primary vaccination was not possible because of overall poor neutralization responses causing extreme heterogeneity. Considering large fold-decreases in neutralization titers relative to the parental strain for all Omicron sub-variants, vaccine effectiveness is very likely to be reduced against all Omicron sub-variants, and probably more so against variants related to BA.4 or BA.5.

6.
Frontiers in immunology ; 13, 2022.
Article in English | EuropePMC | ID: covidwho-1998874

ABSTRACT

In late 2021, the omicron variant of SARS Coronavirus 2 (SARS-CoV-2) emerged and replaced the previously dominant delta strain. Effectiveness of COVID-19 vaccines against omicron has been challenging to estimate in clinical studies or is not available for all vaccines or populations of interest. T cell function can be predictive of vaccine longevity and effectiveness against disease, likely in a more robust way than antibody neutralization. In this mini review, we summarize the evidence on T cell immunity against omicron including effects of boosters, homologous versus heterologous regimens, hybrid immunity, memory responses and vaccine product. Overall, T cell reactivity in post-vaccine specimens is largely preserved against omicron, indicating that vaccines utilizing the parental antigen continue to be protective against disease caused by the omicron variant.

7.
Clin Infect Dis ; 75(Supplement_1): S61-S71, 2022 Aug 15.
Article in English | MEDLINE | ID: covidwho-1992145

ABSTRACT

BACKGROUND: Male sex and old age are risk factors for severe coronavirus disease 2019, but the intersection of sex and aging on antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines has not been characterized. METHODS: Plasma samples were collected from older adults (aged 75-98 years) before and after 3 doses of SARS-CoV-2 mRNA vaccination, and from younger adults (aged 18-74 years) post-dose 2, for comparison. Antibody binding to SARS-CoV-2 antigens (spike protein [S], S receptor-binding domain, and nucleocapsid), functional activity against S, and live-virus neutralization were measured against the vaccine virus and the Alpha, Delta, and Omicron variants of concern (VOCs). RESULTS: Vaccination induced greater antibody titers in older females than in older males, with both age and frailty associated with reduced antibody responses in males but not females. Responses declined significantly in the 6 months after the second dose. The third dose restored functional antibody responses and eliminated disparities caused by sex, age, and frailty in older adults. Responses to the VOCs, particularly the Omicron variant, were significantly reduced relative to the vaccine virus, with older males having lower titers to the VOCs than older females. Older adults had lower responses to the vaccine and VOC viruses than younger adults, with greater disparities in males than in females. CONCLUSIONS: Older and frail males may be more vulnerable to breakthrough infections owing to low antibody responses before receipt of a third vaccine dose. Promoting third dose coverage in older adults, especially males, is crucial to protecting this vulnerable population.


Subject(s)
COVID-19 , Frailty , Viral Vaccines , Aged , COVID-19/prevention & control , Humans , Male , SARS-CoV-2/genetics , Vaccines, Synthetic , mRNA Vaccines
8.
Vaccines (Basel) ; 10(6)2022 May 26.
Article in English | MEDLINE | ID: covidwho-1869857

ABSTRACT

Assessing COVID-19 vaccine effectiveness against emerging SARS-CoV-2 variants is crucial for determining future vaccination strategies and other public health strategies. When clinical effectiveness data are unavailable, a common method of assessing vaccine performance is to utilize neutralization assays using post-vaccination sera. Neutralization studies are typically performed across a wide array of settings, populations and vaccination strategies, and using different methodologies. For any comparison and meta-analysis to be meaningful, the design and methodology of the studies used must at minimum address aspects that confer a certain degree of reliability and comparability. We identified and characterized three important categories in which studies differ (cohort details, assay details and data reporting details) and that can affect the overall reliability and/or usefulness of neutralization assay results. We define reliability as a measure of methodological accuracy, proper study setting concerning subjects, samples and viruses, and reporting quality. Each category comprises a set of several relevant key parameters. To each parameter, we assigned a possible impact (ranging from low to high) on overall study reliability depending on its potential to influence the results. We then developed a reliability assessment tool that assesses the aggregate reliability of a study across all parameters. The reliability assessment tool provides explicit selection criteria for inclusion of comparable studies in meta-analyses of neutralization activity of SARS-CoV-2 variants in post-vaccination sera and can also both guide the design of future neutralization studies and serve as a checklist for including important details on key parameters in publications.

9.
Front Immunol ; 12: 720952, 2021.
Article in English | MEDLINE | ID: covidwho-1417084

ABSTRACT

The ongoing COVID-19 pandemic has increased awareness about sex-specific differences in immunity and outcomes following SARS-CoV-2 infection. Strong evidence of a male bias in COVID-19 disease severity is hypothesized to be mediated by sex differential immune responses against SARS-CoV-2. This hypothesis is based on data from other viral infections, including influenza viruses, HIV, hepatitis viruses, and others that have demonstrated sex-specific immunity to viral infections. Although males are more susceptible to most viral infections, females possess immunological features that render them more vulnerable to distinct immune-related disease outcomes. Both sex chromosome complement and related genes as well as sex steroids play important roles in mediating the development of sex differences in immunity to viral infections.


Subject(s)
COVID-19/pathology , Severity of Illness Index , Sex Characteristics , CD4 Lymphocyte Count , CD4-CD8 Ratio , Cytokines/blood , Female , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Male , SARS-CoV-2/immunology , Sex Factors
10.
Emerg Microbes Infect ; 10(1): 1807-1818, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1360311

ABSTRACT

Male sex was repeatedly identified as a risk factor for death and intensive care admission. However, it is yet unclear whether sex hormones are associated with disease severity in COVID-19 patients. In this study, we analysed sex hormone levels (estradiol and testosterone) of male and female COVID-19 patients (n = 50) admitted to an intensive care unit (ICU) in comparison to control non-COVID-19 patients at the ICU (n = 42), non-COVID-19 patients with the most prevalent comorbidity (coronary heart diseases) present within the COVID-19 cohort (n = 39) and healthy individuals (n = 50). We detected significantly elevated estradiol levels in critically ill male COVID-19 patients compared to all control cohorts. Testosterone levels were significantly reduced in critically ill male COVID-19 patients compared to control cohorts. No statistically significant differences in sex hormone levels were detected in critically ill female COVID-19 patients, albeit similar trends towards elevated estradiol levels were observed. Linear regression analysis revealed that among a broad range of cytokines and chemokines analysed, IFN-γ levels are positively associated with estradiol levels in male and female COVID-19 patients. Furthermore, male COVID-19 patients with elevated estradiol levels were more likely to receive ECMO treatment. Thus, we herein identified that disturbance of sex hormone metabolism might present a hallmark in critically ill male COVID-19 patients.


Subject(s)
COVID-19/mortality , COVID-19/pathology , Estradiol/blood , Testosterone/blood , Aged , Aged, 80 and over , COVID-19/blood , Critical Care , Critical Illness , Extracorporeal Membrane Oxygenation , Female , Humans , Hypogonadism/pathology , Intensive Care Units , Interferon-gamma/blood , Male , Middle Aged , Retrospective Studies , Risk Factors , SARS-CoV-2 , Severity of Illness Index , Sex Distribution
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