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1.
Drug Resist Updat ; 65: 100882, 2022 Oct 03.
Article in English | MEDLINE | ID: covidwho-2104805

ABSTRACT

WHO-defined SARS-CoV-2 variants of concern (VOC) drive therapeutics and vaccine development. The Omicron VOC is dominating the arena since November 2021, but the number of its sublineages is growing in complexity. Omicron represent a galaxy with a myriad of stars that suddenly rise and expand before collapsing into apparent extinction when a more fit sublineage appears. This has already happened with BA.1, BA.2, and BA.4/5 and is happening with BA.2.75. We review here the current PANGO phylogeny, focusing on sublineages with Spike mutations, and show how frequently xxxxxxxx convergent evolution has occurred in these sublineages. We finally summarize how Omicron evolution has progressively defeated the anti-Spike monoclonal antibodies authorized so far, leaving clinicians to again fall back on COVID19 convalescent plasma from vaccinated donors as the only antibody-based therapy available.

2.
Yonsei Med J ; 63(11): 977-983, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2089803

ABSTRACT

As soon as the first case of the omicron variant of severe acute respiratory syndrome coronavirus 2 was reported in November 2021, it quickly spread worldwide with the emergence of several subvariants. Compared to previous variants, omicron was heavily mutated, especially for those in the Spike (S) protein and its receptor-binding domain. These mutations allowed the viruses to evade immune responses (i.e., previous infections and vaccine-elicited) and increase in transmissibility. Although vaccine effectiveness is decreased for omicron, boosters remain effective for protecting against severe diseases. Also, bivalent vaccines have been developed to increase vaccine effectiveness. Interestingly, although omicron is highly infectious, it has less morbidity and mortality compared to previously identified variants, such as delta. Additionally, the mutations that allow the virus to evade immune responses also allow it to evade many of the monoclonal antibodies developed at the beginning of the pandemic for treatment. Here, we reviewed the omicron variant's epidemiology, genetics, transmissibility, disease severity, and responsiveness to vaccine and treatments.


Subject(s)
COVID-19 , Viral Vaccines , Humans , Antibodies, Viral , SARS-CoV-2/genetics
3.
Front Immunol ; 13: 1004045, 2022.
Article in English | MEDLINE | ID: covidwho-2080154

ABSTRACT

Haemodialysis patients respond poorly to vaccination and continue to be at-risk for severe COVID-19. Therefore, dialysis patients were among the first for which a fourth COVID-19 vaccination was recommended. However, targeted information on how to best maintain immune protection after SARS-CoV-2 vaccinations in at-risk groups for severe COVID-19 remains limited. We provide, to the best of our knowledge, for the first time longitudinal vaccination response data in dialysis patients and controls after a triple BNT162b2 vaccination and in the latter after a subsequent fourth full-dose of mRNA-1273. We analysed systemic and mucosal humoral IgG responses against the receptor-binding domain (RBD) and ACE2-binding inhibition towards variants of concern including Omicron and Delta with multiplex-based immunoassays. In addition, we assessed Spike S1-specific T-cell responses by interferon γ release assay. After triple BNT162b2 vaccination, anti-RBD B.1 IgG and ACE2 binding inhibition reached peak levels in dialysis patients, but remained inferior compared to controls. Whilst we detected B.1-specific ACE2 binding inhibition in 84% of dialysis patients after three BNT162b2 doses, binding inhibition towards the Omicron variant was only detectable in 38% of samples and declining to 16% before the fourth vaccination. By using mRNA-1273 as fourth dose, humoral immunity against all SARS-CoV-2 variants tested was strongly augmented with 80% of dialysis patients having Omicron-specific ACE2 binding inhibition. Modest declines in T-cell responses in dialysis patients and controls after the second vaccination were restored by the third BNT162b2 dose and significantly increased by the fourth vaccination. Our data support current advice for a four-dose COVID-19 immunisation scheme for at-risk individuals such as haemodialysis patients. We conclude that administration of a fourth full-dose of mRNA-1273 as part of a mixed mRNA vaccination scheme to boost immunity and to prevent severe COVID-19 could also be beneficial in other immune impaired individuals. Additionally, strategic application of such mixed vaccine regimens may be an immediate response against SARS-CoV-2 variants with increased immune evasion potential.


Subject(s)
COVID-19 , Viral Vaccines , Mice , Animals , Humans , Immunity, Humoral , SARS-CoV-2 , 2019-nCoV Vaccine mRNA-1273 , BNT162 Vaccine , COVID-19/prevention & control , Angiotensin-Converting Enzyme 2 , COVID-19 Vaccines , Mice, Inbred BALB C , Vaccination , Immunoglobulin G , Renal Dialysis , RNA, Messenger
4.
Front Immunol ; 13: 961198, 2022.
Article in English | MEDLINE | ID: covidwho-2080141

ABSTRACT

In December 2019, an outbreak emerged of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which leads to coronavirus disease 2019 (COVID-19). The World Health Organisation announced the outbreak a global health emergency on 30 January 2020 and by 11 March 2020 it was declared a pandemic. The spread and severity of the outbreak took a heavy toll and overburdening of the global health system, particularly since there were no available drugs against SARS-CoV-2. With an immediate worldwide effort, communication, and sharing of data, large amounts of funding, researchers and pharmaceutical companies immediately fast-tracked vaccine development in order to prevent severe disease, hospitalizations and death. A number of vaccines were quickly approved for emergency use, and worldwide vaccination rollouts were immediately put in place. However, due to several individuals being hesitant to vaccinations and many poorer countries not having access to vaccines, multiple SARS-CoV-2 variants quickly emerged that were distinct from the original variant. Uncertainties related to the effectiveness of the various vaccines against the new variants as well as vaccine specific-side effects have remained a concern. Despite these uncertainties, fast-track vaccine approval, manufacturing at large scale, and the effective distribution of COVID-19 vaccines remain the topmost priorities around the world. Unprecedented efforts made by vaccine developers/researchers as well as healthcare staff, played a major role in distributing vaccine shots that provided protection and/or reduced disease severity, and deaths, even with the delta and omicron variants. Fortunately, even for those who become infected, vaccination appears to protect against major disease, hospitalisation, and fatality from COVID-19. Herein, we analyse ongoing vaccination studies and vaccine platforms that have saved many deaths from the pandemic.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19 Vaccines , COVID-19/prevention & control , Pharmaceutical Preparations
5.
Biomedicines ; 10(10)2022 Oct 16.
Article in English | MEDLINE | ID: covidwho-2071222

ABSTRACT

The latest SARS-CoV-2 variant of concern (VOC), Omicron (B.1.1.529), has diversified into more than 300 sublineages. With an expanding number of newly emerging sublineages, the mutation profile is also becoming complicated. There exist mutually exclusive and revertant mutations in different sublineages. Omicron sublineages share some common mutations with previous VOCs (Alpha, Beta, Gamma, and Delta), indicating an evolutionary relationship between these VOCs. A diverse mutation profile at the spike-antibody interface, flexibility of the regions harboring mutations, mutation types, and coexisting mutations suggest that SARS-CoV-2's evolution is far from over.

6.
Emerg Microbes Infect ; 11(1): 2359-2370, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2070053

ABSTRACT

Viral vectors are a potent vaccine platform for inducing humoral and T-cell immune responses. Among the various viral vectors, replication-competent ones are less commonly used for coronavirus disease 2019 (COVID-19) vaccine development compared with replication-deficient ones. Here, we show the availability of a smallpox vaccine LC16m8Δ (m8Δ) as a replication-competent viral vector for a COVID-19 vaccine. M8Δ is a genetically stable variant of the licensed and highly effective Japanese smallpox vaccine LC16m8. Here, we generated two m8Δ recombinants: one harbouring a gene cassette encoding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) glycoprotein, named m8Δ-SARS2(P7.5-S)-HA; and one encoding the S protein with a highly polybasic motif at the S1/S2 cleavage site, named m8Δ-SARS2(P7.5-SHN)-HA. M8Δ-SARS2(P7.5-S)-HA induced S-specific antibodies in mice that persisted for at least six weeks after a homologous boost immunization. All eight analysed serum samples displayed neutralizing activity against an S-pseudotyped virus at a level similar to that of serum samples from patients with COVID-19, and more than half (5/8) also had neutralizing activity against the Delta/B.1.617.2 variant of concern. Importantly, most serum samples also neutralized the infectious SARS-CoV-2 Wuhan and Delta/B.1.617.2 strains. In contrast, immunization with m8Δ-SARS2(P7.5-SHN)-HA elicited significantly lower antibody titres, and the induced antibodies had less neutralizing activity. Regarding T-cell immunity, both m8Δ recombinants elicited S-specific multifunctional CD8+ and CD4+ T-cell responses even after just a primary immunization. Thus, m8Δ provides an alternative method for developing a novel COVID-19 vaccine.


Subject(s)
COVID-19 , Smallpox Vaccine , Viral Vaccines , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Mice , SARS-CoV-2/genetics , Smallpox Vaccine/genetics , Spike Glycoprotein, Coronavirus/genetics
7.
Vaccine ; 40(47): 6864-6872, 2022 Nov 08.
Article in English | MEDLINE | ID: covidwho-2069777

ABSTRACT

BACKGROUND: In the face of rapid emerging variants of concern (VOCs) with potential of evading immunity from Beta to Omicron and uneven distribution of different vaccine brands, a mix-match strategy has been considered to enhance immunity. However, whether increasing immunogenicity using such a mix-match can lead to high clinical efficacy, particularly when facing Omicron pandemic, still remains elusive without using the traditional phase 3 trial. The aim of this study is to demonstrate how to evaluate correlates of protection (CoP) of the mix-match vaccination. METHODS: Data on neutralizing antibody (NtAb) titers and clinical efficacy against Wuhan or D614G strains of homologous ChAdOx1 nCov-19 or mRNA-1273 and heterologous vaccination were extracted from previous studies for demonstration. The reductions in NtAb titers of homologous vaccination against Beta, Delta, and Omicron variants were obtained from literatures. A Bayesian inversion method was used to derive CoP from homologous to mix-match vaccine. Findings The predicted efficacy of ChAdOx1 nCov-19 and mRNA-1273 for Wuhan or D614G strains was 93 % (89 %-97 %). Given 8 âˆ¼ 11-fold, 2 âˆ¼ 5.5-fold, and 32.5 âˆ¼ 36-fold reduction of NtAb for Beta, Delta, and Omicron variants compared with D614G, the corresponding predictive efficacy of the mix-match ranged from 75.63 % to 73.87 %, 84.87 % to 81.25 %, and 0.067 % to 0.059 %, respectively. Interpretations While ChAdOx1 nCov-19 and mRNA-1273 used for demonstrating how to timely evaluate CoP for the mix-match vaccine still provides clinical efficacy against Beta and Delta VOCs but it appears ineffective for Omicron variants, which highlights the urgent need for next generation vaccine against Omicron variant.


Subject(s)
COVID-19 , Influenza Vaccines , Humans , COVID-19 Vaccines , COVID-19/prevention & control , Antibodies, Viral , Bayes Theorem , ChAdOx1 nCoV-19 , SARS-CoV-2 , Antibodies, Neutralizing , Vaccination
8.
J Clin Virol ; 157: 105321, 2022 Oct 18.
Article in English | MEDLINE | ID: covidwho-2069294

ABSTRACT

BACKGROUND: The NVX-CoV2373-vaccine has recently been licensed, although knowledge on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to mRNA-regimens is limited. METHODS: In this observational study, 66 individuals were recruited to compare immunogenicity and reactogenicity of NVX-CoV2373 with BNT162b2 or mRNA-1273. Vaccine-induced antibodies were analyzed using ELISA and neutralization assays, specific CD4 and CD8 T-cells were characterized based on intracellular cytokine staining using flow-cytometry after antigen-specific stimulation with parental spike or VOCs. RESULTS: Two doses of NVX-CoV2373 strongly induced anti-spike IgG, although IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (p = 0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. The protein-based vaccine failed to induce any spike-specific CD8 T-cells which were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals, although their levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFα and IL-2 (p = 0.0007). Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T-cells equally recognized all tested VOCs from Alpha to Omicron. In individuals with a history of infection, one dose of NVX-CoV2373 had similar immunogenicity as two doses in non-infected individuals. The vaccine was overall well tolerated. CONCLUSION: NVX-CoV2373 strongly induced spike-specific antibodies and CD4 T-cells, albeit at lower levels as mRNA-regimens. Cross-reactivity of CD4 T-cells towards the parental strain and all tested VOCs may hold promise to protect from severe disease.

9.
Indian J Med Microbiol ; 2022 Oct 13.
Article in English | MEDLINE | ID: covidwho-2069140

ABSTRACT

PURPOSE: Despite COVID vaccination with ChAdOx1 ncov-19 (COVISHIELD®) (ChAdOx1 ncov-19) a large number of healthcare workers (HCWs) were getting infected in wave-2 of the pandemic in a cancer hospital of India. It was important therefore to determine the genotypes responsible for vaccine breakthrough infections. METHODS & OBJECTIVES: Retrospective observational study of HCWs. Whole genome sequencing of SARS CoV-2 using Illumina NovaSeq was done. Mutations from both waves were compared to identify genomic correlates of transmissibility and vaccine breakthrough infections. RESULTS: Vaccine breakthrough infections were seen in 127 HCWs out of 1806 fully vaccinated staff (7.03%). Median number of HCWs infected per day in wave-1 was 0.92 versus 3.25 in wave-2. Majority of wave-1 samples belonged to B.1 and B.1.1 lineage. Variant of concern- Delta variant (90%), and variant of interest- Kappa variant (10%), was seen in only wave-2 samples. Total mutation observed in wave-2 samples (median â€‹= â€‹44) was 1.8 times than wave-1 sample (median â€‹= â€‹24). Spike protein in wave-2 samples had 13 non-synonymous mutation as compared to 8 seen in wave-1 samples. E484Q-vaccine escape mutant was detected in five samples of wave-2; T478K - highly infectious mutation was seen in 31 samples of wave-2. We identified a novelcoding disruptive in-frame deletion (c.467_472delAGTTCA, p. Glu156_Arg158delinsGly) in the Spike protein. This mutation was seen only in wave-2 (78%, n â€‹= â€‹39) samples. CONCLUSION: The circulating virus strains in wave-2 infections demonstrated a greater degree of infectivity. There was a significant change in the genotypes observed in wave-1 and wave-2 infections along with almost twice the number of mutations. We noted that vaccine breakthrough infections (although mostly mild).

10.
Cell Host Microbe ; 2022 Oct 18.
Article in English | MEDLINE | ID: covidwho-2068781

ABSTRACT

SARS-CoV-2 spread in humans results in continuous emergence of new variants, highlighting the need for vaccines with broad-spectrum antigenic coverage. Using inter-lineage chimera and mutation-patch strategies, we engineered a recombinant monomeric spike variant (STFK1628x) that contains key regions and residues across multiple SAR-CoV-2 variants. STFK1628x demonstrated high immunogenicity and mutually complementary antigenicity to its prototypic form (STFK). In hamsters, a bivalent vaccine composed of STFK and STFK1628x elicited high titers of broad-spectrum neutralizing antibodies to 19 circulating SARS-CoV-2 variants, including Omicron sublineages BA.1, BA.1.1, BA.2, BA.2.12.1, BA.2.75, and BA.4/5. Furthermore, this vaccine conferred robust protection against intranasal challenges by either SARS-CoV-2 ancestral strain or immune-evasive Beta and Omicron BA.1. Strikingly, vaccination with the bivalent vaccine in hamsters effectively blocked within-cage virus transmission of ancestral SARS-CoV-2, Beta variant, and Omicron BA.1 to unvaccinated sentinels. Thus, our study provided insight and antigen candidates for the development of next-generation COVID-19 vaccines.

11.
Elife ; 112022 08 09.
Article in English | MEDLINE | ID: covidwho-2067161

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) have been key drivers of new coronavirus disease 2019 (COVID-19) pandemic waves. To better understand variant epidemiologic characteristics, here we apply a model-inference system to reconstruct SARS-CoV-2 transmission dynamics in South Africa, a country that has experienced three VOC pandemic waves (i.e. Beta, Delta, and Omicron BA.1) by February 2022. We estimate key epidemiologic quantities in each of the nine South African provinces during March 2020 to February 2022, while accounting for changing detection rates, infection seasonality, nonpharmaceutical interventions, and vaccination. Model validation shows that estimated underlying infection rates and key parameters (e.g. infection-detection rate and infection-fatality risk) are in line with independent epidemiological data and investigations. In addition, retrospective predictions capture pandemic trajectories beyond the model training period. These detailed, validated model-inference estimates thus enable quantification of both the immune erosion potential and transmissibility of three major SARS-CoV-2 VOCs, that is, Beta, Delta, and Omicron BA.1. These findings help elucidate changing COVID-19 dynamics and inform future public health planning.


Subject(s)
COVID-19 , Pandemics , COVID-19/epidemiology , Disease Susceptibility , Humans , Retrospective Studies , SARS-CoV-2 , South Africa/epidemiology , United States
12.
Viruses ; 14(10)2022 09 30.
Article in English | MEDLINE | ID: covidwho-2066552

ABSTRACT

SARS-CoV-2 continues to infect millions of people worldwide. The subvariants arising from the variant-of-concern (VOC) Omicron include BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, and BA.5. All possess multiple mutations in their Spike glycoprotein, notably in its immunogenic receptor-binding domain (RBD), and present enhanced viral transmission. The highly mutated Spike glycoproteins from these subvariants present different degrees of resistance to recognition and cross-neutralisation by plasma from previously infected and/or vaccinated individuals. We have recently shown that the temperature affects the interaction between the Spike and its receptor, the angiotensin converting enzyme 2 (ACE2). The affinity of RBD for ACE2 is significantly increased at lower temperatures. However, whether this is also observed with the Spike of Omicron and sub-lineages is not known. Here we show that, similar to other variants, Spikes from Omicron sub-lineages bind better the ACE2 receptor at lower temperatures. Whether this translates into enhanced transmission during the fall and winter seasons remains to be determined.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Humans , SARS-CoV-2/genetics , Temperature , Spike Glycoprotein, Coronavirus/metabolism , Peptidyl-Dipeptidase A/metabolism , Mutation
13.
Journal of Translational Internal Medicine. ; 2022.
Article in English | EMBASE | ID: covidwho-2065373

ABSTRACT

The pandemic coronavirus disease 2019 (COVID-19) has rapidly spread to all countries worldwide. The emergence of its variants has exacerbated this problem. To date, many variants have been identified across the viral genome;the variants of concern are the focus of attention due to their higher transmissibility and resistance to vaccines, especially the delta variant. The delta variant has become the dominant severe acute respiratory syndrome novel coronavirus (SARS-CoV-2) variant worldwide, causing severe panic as it is highly infectious. A better understanding of these variants may help in the development of possible treatments and save more lives. In this study, we summarize the characteristics of the variants of concern. More importantly, we summarize the results of previous studies on the delta variant. The delta variant has a high transmissibility rate and increases the risk of hospitalization and death. However, it is partially sensitive to vaccines. In addition, nonpharmaceutical interventions are valuable during epidemics. These interventions can be used against the delta variant, but managing this variant should still be taken seriously. Copyright © 2022 Meng Zhang, Yanchao He, Zhijun Jie, published by Sciendo 2022.

14.
JMIR Public Health Surveill ; 8(11): e41004, 2022 Nov 11.
Article in English | MEDLINE | ID: covidwho-2065330

ABSTRACT

BACKGROUND: Digital proximity-tracing apps have been deployed in multiple countries to assist with SARS-CoV-2 pandemic mitigation efforts. However, it is unclear how their performance and effectiveness were affected by changing pandemic contexts and new viral variants of concern. OBJECTIVE: The aim of this study is to bridge these knowledge gaps through a countrywide digital proximity-tracing app effectiveness assessment, as guided by the World Health Organization/European Center for Prevention and Disease Control (WHO/ECDC) indicator framework to evaluate the public health effectiveness of digital proximity-tracing solutions. METHODS: We performed a descriptive analysis of the digital proximity-tracing app SwissCovid in Switzerland for 3 different periods where different SARS-CoV-2 variants of concern (ie, Alpha, Delta, and Omicron, respectively) were most prevalent. In our study, we refer to the indicator framework for the evaluation of public health effectiveness of digital proximity-tracing apps of the WHO/ECDC. We applied this framework to compare the performance and effectiveness indicators of the SwissCovid app. RESULTS: Average daily registered SARS-CoV-2 case rates during our assessment period from January 25, 2021, to March 19, 2022, were 20 (Alpha), 54 (Delta), and 350 (Omicron) per 100,000 inhabitants. The percentages of overall entered authentication codes from positive tests into the SwissCovid app were 9.9% (20,273/204,741), 3.9% (14,372/365,846), and 4.6% (72,324/1,581,506) during the Alpha, Delta, and Omicron variant phases, respectively. Following receipt of an exposure notification from the SwissCovid app, 58% (37/64, Alpha), 44% (7/16, Delta), and 73% (27/37, Omicron) of app users sought testing or performed self-tests. Test positivity among these exposure-notified individuals was 19% (7/37) in the Alpha variant phase, 29% (2/7) in the Delta variant phase, and 41% (11/27) in the Omicron variant phase compared to 6.1% (228,103/3,755,205), 12% (413,685/3,443,364), and 41.7% (1,784,951/4,285,549) in the general population, respectively. In addition, 31% (20/64, Alpha), 19% (3/16, Delta), and 30% (11/37, Omicron) of exposure-notified app users reported receiving mandatory quarantine orders by manual contact tracing or through a recommendation by a health care professional. CONCLUSIONS: In constantly evolving pandemic contexts, the effectiveness of digital proximity-tracing apps in contributing to mitigating pandemic spread should be reviewed regularly and adapted based on changing requirements. The WHO/ECDC framework allowed us to assess relevant domains of digital proximity tracing in a holistic and systematic approach. Although the Swisscovid app mostly worked, as reasonably expected, our analysis revealed room for optimizations and further performance improvements. Future implementation of digital proximity-tracing apps should place more emphasis on social, psychological, and organizational aspects to reduce bottlenecks and facilitate their use in pandemic contexts.


Subject(s)
COVID-19 , Mobile Applications , Humans , Pandemics/prevention & control , SARS-CoV-2 , Contact Tracing , Cross-Sectional Studies , Switzerland/epidemiology , COVID-19/epidemiology , COVID-19/prevention & control
15.
American Journal of Transplantation ; 22(Supplement 3):640-641, 2022.
Article in English | EMBASE | ID: covidwho-2063541

ABSTRACT

Purpose: Kidney transplant recipients (KTRs) have diminished immune response and protection after 2-dose mRNA COVID-19 vaccination. It is unknown if additional doses improve neutralization of variants of concern (VOC) in KTRs with prior poor seroresponse. Method(s): Adult KTRs with negative (<0.8 U/mL) or low (<=50 U/ml) anti-RBD Ig (Roche Elecsys anti-SARS-CoV-2-S) after 2-dose mRNA series were given a homologous 3rd dose (D3). Anti-RBD and VOC surrogate neutralization (%ACE2i) were measured 30 days post D3;responses were stratified by baseline anti-RBD. Reactogenicity, serial SARS-CoV-2 swabs, and donor-specific antibody (DSA) were assessed. Result(s): 81 KTRs (50% negative anti-RBD) received D3 (72% BNT162b2, 28% mRNA-1273) at median 167 days post D2 (Table). Median (IQR) anti-RBD increase was 410 (8-2309) U/mL with 69% (40% negative vs 98% low anti-RBD) achieving day 30 anti-RBD >50 U/ml (Fig1a). 22% remained seronegative. Non-response was associated with lower baseline lymphocyte count (median 770 vs 1160 cells/ uL;p=0.05) and IgG (median 779 vs 979 mg/dL;p<0.01), but not demographics, vaccine, or immunosuppressives. Median (IQR) delta variant %ACE2i increased from 6% (3-7) to 10% (4-22) (p<0.001), a 1% (0-5) increase in negative vs 13% (5-25) in low anti-RBD. %ACE2i was linearly associated with anti-RBD >=100 U/ mL (all VOC shown in Fig1b);64% of KTRs with anti-RBD >=250 U/mL had delta %ACE2i >20. There were 3 cases of mild-moderate COVID-19 >=7 days post-D3, with pre-infection anti-RBD <0.4, 22, 76 U/mL and delta %ACE2i 6, 9, and 16, respectively. There was no acute rejection, nor increased or de novo DSA. Conclusion(s): A 3rd mRNA vaccine dose increased anti-RBD and VOC neutralization in KTRs without inducing clinical alloimmunity, yet 45% with negative baseline anti-RBD remained seronegative without delta variant neutralization. Trials are ongoing to test immune response augmentation in this subgroup via temporary immunosuppression reduction or heterologous boosting.

16.
American Journal of Transplantation ; 22(Supplement 3):872-873, 2022.
Article in English | EMBASE | ID: covidwho-2063469

ABSTRACT

Purpose: Humoral response to COVID-19 vaccines is attenuated in many solid organ transplant recipients (SOTRs), necessitating additional primary and booster vaccinations. The omicron variant demonstrates substantial immune evasion, and it is not known if boosters increase neutralizing capacity versus omicron among SOTRs. We therefore investigated SOTR antibody response and neutralization versus variants of concern (VOC) including omicron to a 4th vaccine dose (D4). Method(s): Within a national, prospective observational cohort, 25 SOTRs underwent anti-SARS-CoV-2 spike and receptor binding domain (RBD) IgG testing using the Meso Scale Discovery platform before and 2-4 weeks after D4. Surrogate neutralization (%ACE2 inhibition [%ACE2i], range 0-100% with >20% correlating with live virus neutralization), was measured versus full spike proteins of the ancestral ("vaccine") strain and 5 VOCs including delta and omicron. Change in IgG level and %ACE2i were compared using paired Wilcoxon rank-sum testing. Result(s): Demographics are outlined in Table 1, including median (IQR) age 59 (45- 55) years, 64% kidney recipients, and D4 receipt (60% Moderna, 40% Pfizer) median (IQR) 93 days (28-134) post D3. Two participants had SARS-CoV-2 exposure per anti-nucleocapsid testing, including one incident infection. Overall, anti-RBD (92%- >100%) and anti-spike (84%->92%) seropositivity increased after D4, as did median (IQR) anti-spike IgG 42.3 (4.9-134.2)->228.9 (115.4-655.8) WHO binding antibody units (p<0.05). Median (IQR) %ACE2i significantly increased after D4 vs the vaccine strain 5.8% (0-16.8)->20.6% (5.8-45.9) and delta variant 9.1% (4.9-12.8)->17.1% (10.3-31.7) (both p<0.001). In contrast, no SOTR showed neutralization vs omicron before or after D4: median (IQR) %ACE2i 4.1% (0-6.9)->0.5% (0-5.7) (p=0.11). Conclusion(s): Although a 4th vaccine dose increased anti-spike IgG and neutralizing capacity vs some VOC, there was no omicron variant neutralization among SOTRs. SOTRs may remain at high risk for SARS-CoV-2 infection despite boosting, thus additional protective interventions should be urgently explored. (Figure Presented).

17.
American Journal of Transplantation ; 22(Supplement 3):638, 2022.
Article in English | EMBASE | ID: covidwho-2063446

ABSTRACT

Purpose: Prior studies suggest that two doses of mRNA vaccine in SOTR may result in lower antibody and T-cell responses relative to levels seen following natural SARS-CoV-2 infection. In this study, we evaluated whether three doses of mRNA-1273 vaccine result in immune responses more comparable to, or greater than, natural infection. Method(s): Serum was collected 4-6 weeks from symptom onset in n=74 SOTR recovered from SARS-CoV-2 infection, and in n=60 SOTR receiving a third dose of mRNA-1273. Disease severity in the infection cohort ranged from mild to severe, but no deaths were reported. Vaccinated SOTR all had negative anti-nucleoprotein antibody results to confirm absence of infection. SARS-CoV-2 serology was assessed using an anti-spike (S) receptor binding domain (RBD) immunoassay (Roche). Neutralizing antibodies (nAb) were assessed using a commercial surrogate virus neutralization test (SVNT) targeting wildtype (WT), alpha, beta and delta strains (GenScript). A subset of participants underwent spike-specific T-cell testing (infection n=50, three doses n=34). PBMCs were stimulated overnight with overlapping peptides and frequencies of S-specific polyfunctional CD4+ and CD8+ T-cells (expressing IFN-gamma and IL-2) were measured by intracellular cytokine staining. Mann Whitney U, and Chi-square tests were used for statistical comparisons;significance was defined at p<0.05. Result(s): Anti-S RBD antibodies in SOTR recovered from infection were similar to levels in those receiving three doses of mRNA-1273 (median U/mL [IQR]: 73.5 [14.9-240.1] vs. 313.8 [313.8-2191.0];p=0.17). Relative to SOTR recovered from infection, the proportion of SOTR positive for nAb after three doses of vaccine was significantly lower. This was true for WT (93.2% vs. 60.0%, p<0.0001) and all variants tested - alpha: 90.5% vs. 56.7%, p<0.0001;beta: 67.6% vs. 50%, p=0.039;and delta: 85.1% vs. 55%, p=0.0001. Spike-specific polyfunctional CD4+ T-cell frequencies were similar between infection and three doses of vaccine (median cell frequency [IQR]: 241.7 [50-539.7] vs. 432.4 [50-1226];p>0.05). Spike-specific polyfunctional CD8+ T-cells were uncommonly detected following infection or vaccination. Vaccinated participants were significantly older than infected SOTR (p<0.001), and some differences in type of transplant were found between groups. However, sex and type of immunosuppressive medications were similar between infected and vaccinated SOTR cohorts (p>0.05). Conclusion(s): Three doses of mRNA vaccine may be required to optimize binding antibody, and to a lesser extent, CD4+ T-cell immunity, to levels similar to natural infection. However, nAb responses to wild-type virus and variants of concern were highest in SOTR recovered from infection when compared to vaccinated patients. These data provide further evidence of impaired SARS-CoV-2 vaccine responses in SOTR.

18.
Cell Mol Immunol ; 19(11): 1279-1289, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2062197

ABSTRACT

The rapid mutation and spread of SARS-CoV-2 variants urge the development of effective mucosal vaccines to provide broad-spectrum protection against the initial infection and thereby curb the transmission potential. Here, we designed a chimeric triple-RBD immunogen, 3Ro-NC, harboring one Delta RBD and two Omicron RBDs within a novel protein scaffold. 3Ro-NC elicits potent and broad RBD-specific neutralizing immunity against SARS-CoV-2 variants of concern. Notably, intranasal immunization with 3Ro-NC plus the mucosal adjuvant KFD (3Ro-NC + KFDi.n) elicits coordinated mucosal IgA and higher neutralizing antibody specificity (closer antigenic distance) against the Omicron variant. In Omicron-challenged human ACE2 transgenic mice, 3Ro-NC + KFDi.n immunization significantly reduces the tissue pathology in the lung and lowers the viral RNA copy numbers in both the lung (85.7-fold) and the nasal turbinate (13.6-fold). Nasal virologic control is highly correlated with RBD-specific secretory IgA antibodies. Our data show that 3Ro-NC plus KFD is a promising mucosal vaccine candidate for protection against SARS-CoV-2 Omicron infection, pathology and transmission potential.


Subject(s)
COVID-19 Vaccines , COVID-19 , Animals , Humans , Mice , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , COVID-19 Vaccines/immunology , Immunity, Mucosal , Administration, Intranasal
19.
J Allergy Clin Immunol Glob ; 2022 Oct 04.
Article in English | MEDLINE | ID: covidwho-2061406

ABSTRACT

Background & Objectives: SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which can range from a mild illness to a severe phenotype characterised by acute respiratory distress, needing mechanical ventilation. Children with combined immunodeficiencies might be unable to mount a sufficient cellular and humoral immune response against Covid-19 and have persistent disease. The authors describe a child with combined immunodeficiency, with favorable post-HSCT course following a haploidentical haematopoietic stem cell transplant in the presence of persistent SARS-CoV-2 infection. Methods & results: A 13-month-old girl with MHC class II deficiency developed persistent pre-HSCT SARS-CoV-2 infection. Faced with a significant challenge of balancing the risk of progressive infection due to incompetent immune system with the danger of inflammatory pneumonitis peri-immune reconstitution post-HSCT, she underwent a maternal (with a recent history of Covid-19 infection) haploidentical haematopoietic stem cell transplant. The patient received Regdanvimab® (post stem cell infusion) and Remdesivir (pre and post stem cell infusion). We noted a gradual increase in the Ct (cycle threshold) values, implying reduction in viral RNA with concomitant expansion in the CD3 lymphocyte subset and clinical/radiological improvement. Conclusions: Combination of adoptive transfer of maternal CD45RO+ memory add-back T-lymphocytes after haploidentical HSCT, use of Regdanvimab® (SARS-CoV-2 neutralising monoclonal antibody) and Remdesivir may have led to the successful outcome in our patient with severe immunodeficiency, undergoing HSCT. Our case highlights the role of novel antiviral strategies (monoclonal antibodies and CD45RO+ memory T-lymphocytes) in contributing to viral clearance in a challenging clinical scenario.

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