Binding and avidity signatures of polyclonal sera from individuals with different exposure histories to SARS-CoV-2 infection, vaccination, and Omicron breakthrough infections.

BACKGROUND: The number of exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to vaccination antigens impact the magnitude and avidity of the polyclonal response. METHODS: We studied binding and avidity of different antibody isotypes to the spike, the receptor binding domain (RBD), and the nucleoprotein (NP) of wild type (WT) and BA.1 SARS-CoV-2 in convalescent, mRNA vaccinated, mRNA boosted, hybrid immune individuals, and in individuals with breakthrough cases during the peak of the BA.1 wave. RESULTS: We found an increase in spike binding antibodies and antibody avidity with increasing number of exposures to infection and/or vaccination. Nucleoprotein antibodies were detectible in convalescent individuals and a proportion of breakthrough cases, but displayed low avidity. Omicron breakthrough infections elicited high levels of cross-reactive antibodies between WT and BA.1 antigens in vaccinated individuals without prior infection directed against the spike and receptor binding domain (RBDs). The magnitude of the antibody response and avidity correlated with neutralizing activity against WT virus. CONCLUSIONS: The magnitude and quality of the antibody response increased with the number of antigen exposures, including breakthrough infections. However, cross-reactivity of the antibody response after BA.1 breakthroughs, was impacted by the number of prior antigenic exposures.

Detection of SARS-CoV-2 Antibodies in Immunoglobulin Products.

BACKGROUND: For patients with primary antibody deficiency, the first line of therapy is replacement with immunoglobulin (Ig) products. Prior to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, Ig products did not contain antibodies with specificity for this virus, and there have been limited data on the antibodies present in the Ig products in current use. OBJECTIVE: To quantitatively examine SARS-CoV-2 antibodies in current Ig products. METHODS: We examined 142 unique lots of 11 different Ig products intended for intravenous and/or subcutaneous delivery for IgG-binding activities against recombinant SARS-CoV-2 receptor binding domain, spike, and nucleocapsid proteins by enzyme-linked immunosorbent assays. In addition, to assess functionality, 48 of these unique lots were assessed for their ability to inhibit the variants SARS-CoV-2 Ancestral, Alpha, Beta, Delta, and Omicron spike binding to angiotensin-converting enzyme 2 (ACE2). RESULTS: Significantly increased antibody values were observed for products manufactured after the year 2020 (expiration dates 2023-2024), as compared with Ig products before 2020 (prepandemic). Sixty percent and 85% of the Ig products with expiration dates of 2023 and 2024 were positive for antibody to SARS-CoV-2 proteins, respectively. The area under the curve values were significantly higher in products with later expiration dates. Later dates of expiration were also strongly correlated with inhibition of ACE2-binding activity; however, a decline in inhibition activity was observed with later variants. CONCLUSIONS: Overall, more recent Ig products (expiration dates 2023-2025) contained significantly higher binding and inhibition activities against SARS-CoV-2 proteins, compared with earlier, or prepandemic products. Normal donor SARS-CoV-2 antibodies are capable of inhibiting ACE2-binding activities and may provide a therapeutic benefit for patients who do not make a robust vaccine response.

2019-NCoV: What every neurologist should know?

The 2019 novel Corona Virus pandemic beginning from Wuhan, China primarily affects the respiratory tract but its has impacted clinical practice across a range of specialities including neurology. We review the bearing of the 2019 NCoV infection on neurological practice. Neurological manifestations are less common than respiratory manifestations, yet conspicuous, affecting nearly over a third of hospitalized individuals. These may be classified in to early – headache, dizziness, hyposmia and hypogeusia and late – encephalopathy. Rarely but surely, a very small proportion of infected individuals might present with stroke. Certain neurological conditions, including cerebrovascular disease in both China and Italy and dementia in Italy predispose to infection and more severe manifestations, requiring intensive care unit admission. There is no convincing evidence that the manifestations, course and outcome of various neurological disorders is impacted by 2019 nCoV infection. Concerns of an increased risk of febrile seizures offset by a reduced frequency of infection in the paediatric age group. Individuals with multiple sclerosis might potentially experience both true and pseudorelapses. Besides a direct effect, 2019 nCoV has tremendously affected neurological care by disrupting the continuity of care and the availability of neurological medicines worldwide. Neurologists should respond to this challenge by developing and sustaining innovative methods of providing care as well as alerting the society at large to adopt measures to contain the spread of 2019 nCoV.

Predictors for reactogenicity and humoral immunity to SARS-CoV-2 following infection and mRNA vaccination: A regularized, mixed-effects modelling approach.

Introduction: The influence of pre-existing humoral immunity, inter-individual demographic factors, and vaccine-associated reactogenicity on immunogenicity following COVID vaccination remains poorly understood. Methods: Ten-fold cross-validated least absolute shrinkage and selection operator (LASSO) and linear mixed effects models were used to evaluate symptoms experienced by COVID+ participants during natural infection and following SARS-CoV-2 mRNA vaccination along with demographics as predictors for antibody (AB) responses to recombinant spike protein in a longitudinal cohort study. Results: In previously infected individuals (n=33), AB were more durable and robust following primary vaccination when compared to natural infection alone. Higher AB were associated with experiencing dyspnea during natural infection, as was the total number of symptoms reported during the COVID-19 disease course. Both local and systemic symptoms following 1st and 2nd dose (n=49 and 48, respectively) of SARS-CoV-2 mRNA vaccines were predictive of higher AB after vaccination. Lastly, there was a significant temporal relationship between AB and days since infection or vaccination, suggesting that vaccination in COVID+ individuals is associated with a more robust immune response. Discussion: Experiencing systemic and local symptoms post-vaccine was suggestive of higher AB, which may confer greater protection.

Mucormycosis, past and present: a comprehensive review.

Mucormycosis is an emerging opportunistic angioinvasive fungal infection. Predisposing factors such as diabetes, neutropenia, long-term corticosteroid therapy, solid organ transplantation and immunosuppression contribute to its occurrence. This disease was not of significant concern prior to the COVID-19 pandemic, but gained prominence due to infections in COVID-19 patients. Mucormycosis needs special attention and coordinated efforts of the scientific community and medical professionals to reduce morbidity and mortality. Here we present an overview of the epidemiology and prevalence of mucormycosis in the pre- and post-COVID-19 eras, the factors that contributed to the abrupt increase in COVID-19-associated mucormycosis (CAM), the actions taken by the regulatory agencies (including Code Mucor and CAM registry), the existing diagnostic tools and CAM management strategies.

The devastating effects of the COVID-19 pandemic have been further enhanced by various secondary illnesses, particularly opportunistic fungal infections such as mucormycosis. Mucormycosis or 'black fungus' primarily affects people with weakened immunity, those with medical conditions such as diabetes or cancer and those who use medications that reduce the body's capacity to resist infections and disease. The infection starts in the sinuses or the lungs after breathing in spores of the black fungus from the air. In just 2 months between 5 May and 12 July 2021, this uncommon but fatal fungal illness was responsible for 41,512 cases and 3554 fatalities in India alone. The government of India declared a mucormycosis epidemic in May 2021. The majority of such cases occurred during active SARS-CoV-2 outbreaks in India in 2021. Black fungus took over while the host defenses were compromised and the globe was preoccupied tackling the COVID-19 pandemic. Steroids prescribed in amounts and time spans that far exceeded WHO recommendations to manage severe COVID-19 cases, potentially weakened patients' immune systems, and raised blood sugar levels making them vulnerable to fungal invasion. Early diagnosis and treatment are the keys to a patient's survival. Simple means such as maintaining hygienic conditions, avoiding contact with an infected person, judiciously using steroid medications and antibiotics and properly managing high blood sugar can help protect an individual from black-fungus infection.

Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody against antigenically distinct Omicron subvariants.

The rapid evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identified S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) that was derived from an individual previously infected with WT SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrated broad cross-neutralization of all dominant variants, including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1/XBB). Furthermore, S728-1157 protected hamsters against in vivo challenges with WT, Delta, and BA.1 viruses. Structural analysis showed that this antibody targets a class 1/RBS-A epitope in the receptor binding domain via multiple hydrophobic and polar interactions with its heavy chain complementarity determining region 3 (CDR-H3), in addition to common motifs in CDR-H1/CDR-H2 of class 1/RBS-A antibodies. Importantly, this epitope was more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared with diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential and may inform target-driven vaccine designs against future SARS-CoV-2 variants.

Impact of COVID-19 on Guillain-Barre Syndrome in India: A Multicenter Ambispective Cohort Study.

Introduction/Aims: Studies conducted during the coronavirus disease 2019 (COVID-19) pandemic have reported varied data regarding the incidence of Guillain-Barre syndrome (GBS). The present study investigated demographic and clinical features, management, and outcomes of patients with GBS during a specified period of the COVID-19 pandemic, and compared these features to those of GBS in the previous year. Methods: A multicenter, ambispective cohort study including 26 centers across India was conducted. Data from a pre-COVID-19 period (March 1 to August 31, 2019) were collected retrospectively and collected ambispectively for a specified COVID-19 period (March 1 to August 31, 2020). The study was registered with the Clinical Trial Registry India (CTRI/2020/11/029143). Results: Data from 555 patients were included for analysis: pre-COVID-19 (n = 334) and COVID-19 (n = 221). Males were more commonly affected during both periods (male:female, 2:1). Gastroenteritis was the most frequent antecedent event in 2019 (17.4%), whereas fever was the most common event in 2020 (10.7%). Paraparesis (21.3% versus [vs.] 9.3%, P = 0.001) and sensory involvement (51.1% vs. 41.3%; P = 0.023) were more common during COVID-19 in 2020, whereas back pain (26.3% vs. 18.4%; P = 0.032) and bowel symptoms (20.7% vs. 13.7%; P = 0.024) were more frequent in the pre-COVID period. There was no difference in clinical outcomes between the two groups in terms of GBS disability score at discharge and 3 months after discharge. Independent predictors of disability in the pre-COVID period included areflexia/hyporeflexia, the requirementfor intubation, and time to bulbar weakness; in the COVID-19 period, independent predictors included time from onset to admission, intubation, and intubation requirement. The mortality rate was 2.3% during the entire study period (13/555 cases). Discussion: Results of this study revealed an overall reduction in the frequency of GBS during the pandemic. The lockdown likely reduced the risk for antecedent infections due to social distancing and improved hygiene, which may have resulted in the reduction of the frequency of GBS.

An inactivated NDV-HXP-S COVID-19 vaccine elicits a higher proportion of neutralizing antibodies in humans than mRNA vaccination.

NDV-HXP-S is a recombinant Newcastle disease virus-based vaccine against SARS-CoV-2, which expresses an optimized (HexaPro) spike protein on its surface. The vaccine can be produced in embryonated chicken eggs using the same process as that used for the production of the vast majority of influenza virus vaccines. Here, we performed a secondary analysis of the antibody responses after vaccination with inactivated NDV-HXP-S in a phase 1 clinical study in Thailand. The SARS-CoV-2 neutralizing and spike protein binding activity of NDV-HXP-S postvaccination serum samples was compared to that of samples from mRNA BNT162b2 (Pfizer) vaccinees. Neutralizing activity of sera from NDV-HXP-S vaccinees was comparable to that of BNT162b2 vaccinees, whereas spike protein binding activity of the NDV-HXP-S vaccinee samples was lower than that of sera obtained from mRNA vaccinees. This led us to calculate ratios between binding and neutralizing antibody titers. Samples from NDV-HXP-S vaccinees had binding to neutralizing activity ratios that were lower than those of BNT162b2 sera, suggesting that NDV-HXP-S vaccination elicits a high proportion of neutralizing antibodies and low non-neutralizing antibody titers. Further analysis showed that, in contrast to mRNA vaccination, which induces strong antibody titers to the receptor binding domain (RBD), the N-terminal domain, and the S2 domain, NDV-HXP-S vaccination induced an RBD-focused antibody response with little reactivity to S2. This finding may explain the high proportion of neutralizing antibodies. In conclusion, vaccination with inactivated NDV-HXP-S induces a high proportion of neutralizing antibodies and absolute neutralizing antibody titers that are comparable to those elicited by mRNA vaccination.

Identification of Pyrazole Derivatives of Usnic Acid as Novel Inhibitor of SARS-CoV-2 Main Protease Through Virtual Screening Approaches.

The infection produced by the SARS-CoV-2 virus remains a significant health crisis worldwide. The lack of specific medications for COVID-19 necessitates a concerted effort to find the much-desired therapies for this condition. The main protease (Mpro) of SARS-CoV-2 is a promising target, vital for virus replication and transcription. In this study, fifty pyrazole derivatives were tested for their pharmacokinetics and drugability, resulting in eight hit compounds. Subsequent molecular docking simulations on SARS-CoV-2 main protease afforded two lead compounds with strong affinity at the active site. Additionally, the molecular dynamics (MD) simulations of lead compounds (17 and 39), along with binding free energy calculations, were accomplished to validate the stability of the docked complexes and the binding poses achieved in docking experiments. Based on these findings, compound 17 and 39, with their favorable projected pharmacokinetics and pharmacological characteristics, are the proposed potential antiviral candidates which require further investigation to be used as anti-SARS-CoV-2 medication.

A cluster-randomized trial comparing home-based primary health care and usual clinic care for epilepsy in a resource-limited country.

OBJECTIVE: To ascertain whether home-based care with community and primary healthcare workers' support improves adherence to antiseizure medications, seizure control, and quality of life over routine clinic-based care in community samples of people with epilepsy in a resource-poor country. METHODS: Participants included consenting individuals with active epilepsy identified in a population survey in impoverished communities. The intervention included antiseizure medication provision, adherence reinforcement and epilepsy self- and stigma management guidance provided by a primary health care-equivalent worker. We compared the intervention group to a routine clinic-based care group in a cluster-randomized trial lasting 24 months. The primary outcome was antiseizure medication adherence, appraised from monthly pill counts. Seizure outcomes were assessed by monthly seizure aggregates and time to first seizure and impact by the Personal Impact of Epilepsy scale. RESULTS: Enrolment began on September 25, 2017 and was complete by July 24, 2018. Twenty-four clusters, each comprising ten people with epilepsy, were randomized to either home- or clinic-care. Home-care recipients were more likely to have used up their monthly-dispensed epilepsy medicine stock (regression coefficient: 0.585; 95% confidence intervals, 0.289-0.881; P = 0.001) and had fewer seizures (regression coefficient: -2.060; 95%CI, -3.335 to -0.785; P = 0.002). More people from clinic-care (n = 44; 37%) than home-care (n = 23; 19%) exited the trial (P = 0.003). The time to first seizure, adverse effects and the personal impact of epilepsy were similar in the two arms. SIGNIFICANCE: Home care for epilepsy compared to clinic care in resource-limited communities improves medication adherence and seizure outcomes and reduces the secondary epilepsy treatment gap.

In Silico Screening of Plant-Derived Anti-virals from Shorea hemsleyana (King) King ex Foxw Against SARS CoV-2 Main Protease

Shorea hemsleyana (King) King ex Foxw is used to treat various ailments in humans. Numerous biological activities have been reported previously. The current study sought to identify S. hemsleyana phyto-derived anti-viral compounds against the SARS-CoV-2 main protease to gain insight into the molecular interactions. In the present research, nine compounds obtained from the PubChem database are examined via molecular docking. Docking experiments were conducted using the AutoDock Vina tool. The Swiss ADME and DruLito servers were used for drug-like predictions. Our research shows that the phytoconstituents of S. hemsleyana, namely, Hemsleyanol-A and Hemsleyanoside-A, may act against SARS CoV-2 main protease with the binding affinity of - 7.6 and - 6.8 kcal/mol respectively, which were further validated by molecular dynamics (MD) simulations and end-state binding energy calculations. These phytocompounds could be used in contemporary strategies to develop effective medicines from natural sources. The identified substances are potential anti-viral agents. However, in vitro studies are necessary to assess their effectiveness against SARS-CoV-2.

Discovery and intranasal administration of a SARS-CoV-2 broadly acting neutralizing antibody with activity against multiple Omicron subvariants.

BACKGROUND: The continual emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern, in particular the newly emerged Omicron (B.1.1.529) variant and its BA.X lineages, has rendered ineffective a number of previously FDA emergency use authorized SARS-CoV-2 neutralizing antibody therapies. Furthermore, those approved antibodies with neutralizing activity against Omicron BA.1 are reportedly ineffective against the subset of Omicron subvariants that contain a R346K substitution, BA.1.1, and the more recently emergent BA.2, demonstrating the continued need for discovery and characterization of candidate therapeutic antibodies with the breadth and potency of neutralizing activity required to treat newly diagnosed COVID-19 linked to recently emerged variants of concern. METHODS: Following a campaign of antibody discovery based on the vaccination of Harbor H2L2 mice with defined SARS-CoV-2 spike domains, we have characterized the activity of a large collection of spike-binding antibodies and identified a lead neutralizing human IgG1 LALA antibody, STI-9167. FINDINGS: STI-9167 has potent, broad-spectrum neutralizing activity against the current SARS-COV-2 variants of concern and retained activity against each of the tested Omicron subvariants in both pseudotype and live virus neutralization assays. Furthermore, STI-9167 nAb administered intranasally or intravenously provided protection against weight loss and reduced virus lung titers to levels below the limit of quantitation in Omicron-infected K18-hACE2 transgenic mice. CONCLUSIONS: With this established activity profile, a cGMP cell line has been developed and used to produce cGMP drug product intended for intravenous or intranasal use in human clinical trials. FUNDING: Funded by CRIPT (no. 75N93021R00014), DARPA (HR0011-19-2-0020), and NCI Seronet (U54CA260560).

mRNA-1273 but not BNT162b2 induces antibodies against polyethylene glycol (PEG) contained in mRNA-based vaccine formulations.

Two messenger RNA (mRNA)-based vaccines are widely used globally to prevent coronavirus disease 2019 (COVID-19). Both vaccine formulations contain PEGylated lipids in their composition, in the form of polyethylene glycol [PEG] 2000 dimyristoyl glycerol for mRNA-1273, and 2 [(polyethylene glycol)-2000]-N,N-ditetradecylacetamide for BNT162b2. It is known that some PEGylated drugs and products for human use which contain PEG are capable of eliciting immune responses that lead to to detectable PEG-specific antibodies in serum. In this study, we determined if any of the components of mRNA-1273 or BNT162b2 formulations elicited PEG-specific antibody responses in serum by enzyme linked immunosorbent assay (ELISA). We detected an increase in the reactivity to mRNA vaccine formulations in mRNA-1273 but not BNT162b2 vaccinees' sera in a prime-boost dependent manner. Furthermore, we observed the same pattern of reactivity against irrelevant lipid nanoparticles from an influenza virus mRNA formulation and found that the reactivity of such antibodies correlated well with antibody levels against high and low molecular weight PEG. Using sera from participants selected based on the vaccine-associated side effects experienced after vaccination, including delayed onset, injection site or severe allergic reactions, we found no obvious association between PEG antibodies and adverse reactions. Overall, our data shows a differential induction of anti-PEG antibodies by mRNA-1273 and BNT162b2. The clinical relevance of PEG reactive antibodies induced by administration of the mRNA-1273 vaccine, and the potential interaction of these antibodies with other PEGylated drugs remains to be explored.

Maternal COVID-19 Vaccine May Reduce the Risk of MIS-C in Infants: A Narrative Review.

COVID-19 infection in the pediatric population usually leads to a mild illness; however, a rare but serious complication of MIS-C has been seen in children. MIS-C usually presents 2-4 weeks after COVID-19 infection or exposure, and rare reports have been documented in neonates. Vaccinations for COVID-19 have been approved for children aged 6 months and above in the United States, and recent reports suggest significantly low prevalence and risk of complications of Multi-organ Inflammatory Syndrome (MIS-C) in vaccinated children compared to unvaccinated children. Vaccinations for COVID-19 are safe and recommended during pregnancy and prevent severe maternal morbidity and adverse birth outcomes. Evidence from other vaccine-preventable diseases suggests that through passive transplacental antibody transfer, maternal vaccinations are protective against infections in infants during the first 6 months of life. Various studies have demonstrated that maternal COVID-19 vaccination is associated with the presence of anti-spike protein antibodies in infants, persisting even at 6 months of age. Further, completion of a 2-dose primary mRNA COVID-19 vaccination series during pregnancy is associated with reduced risk for COVID-19-associated hospitalization among infants aged 6 months or less. Therefore, it can be hypothesized that maternal COVID-19 vaccination can reduce the risk of and severity of MIS-C in infants. In this article, we review the literature to support this hypothesis.

SARS-CoV-19-associated Rhino-orbital and cerebral mucormycosis: clinical and radiological presentations.

We describe presenting clinical and imaging manifestations of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-associated Rhino-oculo-cerebral mucormycosis (ROCM) in a hospital setting during the second wave of SARS-CoV-2 pandemic in India. Data on the presenting manifestations were collected from 1 March to 31 May 2021. Associations between clinical and imaging findings were explored, specifically: (1) the presence or absence of orbital pain and infiltration of a superior orbital fissure on imaging; (2) the presence of unilateral facial nerve palsy and pterygopalatine fossa infiltration and geniculate ganglion signal on contrast magnetic resonance imaging, and (3) vision loss and optic nerve findings on imaging. Orbital pain was reported by 6/36 subjects. A fixed, frozen eye with proptosis and congestion was documented in 26 (72%), complete vision loss in 23 (64%), and a unilateral lower motor neuron facial nerve palsy in 18 (50%). No association was found between the presence of orbital pain and superior orbital fissure infiltration on imaging. The ipsilateral geniculate ganglion was found to enhance more profoundly in 7/11 subjects with facial palsy and available magnetic resonance (MR) imaging, and the ipsilateral pterygopalatine fossa was found infiltrated in 14. Among 23 subjects with complete loss of vision, 9 (39%) demonstrated long-segment bright signal in the posterior optic nerve on diffusion MR images. We conclude that orbital pain might be absent in SARS-CoV-2-associated ROCM. Facial nerve palsy is more common than previously appreciated and ischemic lesions of the posterior portion of the optic nerve underlie complete vision loss.

Unique clinical and radiological manifestations identified in the outbreak of Rhino-oculo-cerebral mucormycosis (ROCM) during the second epidemic wave of coronavirus disease 2019 (COVID-19) infection included the common occurrence of facial paralysis, frequent absence of ocular pain, and long segments of optic nerve damage.

SARS-CoV-2 vaccination induces mucosal antibody responses in previously infected individuals.

Immune responses at the respiratory mucosal interface are critical to prevent respiratory infections but it is unclear to what extent antigen specific mucosal secretory IgA (SIgA) antibodies are induced by mRNA vaccination in humans. Here we analyze paired serum and saliva samples from patients with and without prior coronavirus disease 2019 (COVID-19) at multiple time points pre and post severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccination. Our results suggest mucosal SIgA responses induced by mRNA vaccination are impacted by pre-existing immunity. Indeed, vaccination induced a minimal mucosal SIgA response in individuals without pre-exposure to SARS-CoV-2 while SIgA induction after vaccination was more efficient in patients with a history of COVID-19.

SARS-CoV-2 Spike-Binding Antibody Longevity and Protection from Reinfection with Antigenically Similar SARS-CoV-2 Variants.

The PARIS (Protection Associated with Rapid Immunity to SARS-CoV-2) cohort follows health care workers with and without documented coronavirus disease 2019 (COVID-19) since April 2020. We report our findings regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike-binding antibody stability and protection from infection in the pre-variant era. We analyzed data from 400 health care workers (150 seropositive and 250 seronegative at enrollment) for a median of 84 days. The SARS-CoV-2 spike-binding antibody titers were highly variable with antibody levels decreasing over the first 3 months, followed by a relative stabilization. We found that both more advanced age (>40 years) and female sex were associated with higher antibody levels (1.6-fold and 1.4-fold increases, respectively). Only six percent of the initially seropositive participants "seroreverted." We documented a total of 11 new SARS-CoV-2 infections (10 naive participants and 1 previously infected participant without detectable antibodies; P < 0.01), indicating that spike antibodies limit the risk of reinfection. These observations, however, only apply to SARS-CoV-2 variants antigenically similar to the ancestral SARS-CoV-2 ones. In conclusion, SARS-CoV-2 antibody titers mounted upon infection are stable over several months and provide protection from infection with antigenically similar viruses. IMPORTANCE SARS-CoV-2 is the cause of one of the largest noninfluenza pandemics of this century. This exceptional public health crisis highlights the urgent need for better understanding of the correlates of protection from infection and severe COVID-19. We established the PARIS cohort to determine durability and effectiveness of SARS-CoV-2 immune responses. Here, we report on the kinetics of SARS-CoV-2 spike-binding antibody after SARS-CoV-2 infection as well as reinfection rates using data collected between April 2020 and August 2021. We found that antibody levels stabilized at individual steady state levels after an initial decrease with seroreversion being found in only 6% of the convalescent participants. SARS-CoV-2 infections only occurred in participants without detectable spike-binding antibodies, indicating significant protection from reinfection with antigenically similar viruses. Our data indicate the importance of spike-binding antibody titers in protection prior to vaccination and the wide circulation of antigenically diverse variants of concern.

Characterization of SARS-CoV-2 Spike mutations important for infection of mice and escape from human immune sera.

Due to differences in human and murine angiotensin converting enzyme 2 (ACE-2) receptor, initially available SARS-CoV-2 isolates could not infect mice. Here we show that serial passaging of USA-WA1/2020 strain in mouse lungs results in "mouse-adapted" SARS-CoV-2 (MA-SARS-CoV-2) with mutations in S, M, and N genes, and a twelve-nucleotide insertion in the S gene. MA-SARS-CoV-2 infection causes mild disease, with more pronounced morbidity depending on genetic background and in aged and obese mice. Two mutations in the S gene associated with mouse adaptation (N501Y, H655Y) are present in SARS-CoV-2 variants of concern (VoCs). N501Y in the receptor binding domain of viruses of the B.1.1.7, B.1.351, P.1 and B.1.1.529 lineages (Alpha, Beta, Gamma and Omicron variants) is associated with high transmissibility and allows VoCs to infect wild type mice. We further show that S protein mutations of MA-SARS-CoV-2 do not affect neutralization efficiency by human convalescent and post vaccination sera.

Trivalent NDV-HXP-S Vaccine Protects against Phylogenetically Distant SARS-CoV-2 Variants of Concern in Mice.

Equitable access to vaccines is necessary to limit the global impact of the coronavirus disease 2019 (COVID-19) pandemic and the emergence of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. In previous studies, we described the development of a low-cost vaccine based on a Newcastle Disease virus (NDV) expressing the prefusion-stabilized spike protein from SARS-CoV-2, named NDV-HXP-S. Here, we present the development of next-generation NDV-HXP-S variant vaccines, which express the stabilized spike protein of the Beta, Gamma, and Delta variants of concerns (VOC). Combinations of variant vaccines in bivalent, trivalent, and tetravalent formulations were tested for immunogenicity and protection in mice. We show that the trivalent preparation, composed of the ancestral Wuhan, Beta, and Delta vaccines, substantially increases the levels of protection and of cross-neutralizing antibodies against mismatched, phylogenetically distant variants, including the currently circulating Omicron variant. IMPORTANCE This manuscript describes an extended work on the Newcastle disease virus (NDV)-based vaccine focusing on multivalent formulations of NDV vectors expressing different prefusion-stabilized versions of the spike proteins of different SARS-CoV-2 variants of concern (VOC). We demonstrate here that this low-cost NDV platform can be easily adapted to construct vaccines against SARS-CoV-2 variants. Importantly, we show that the trivalent preparation, composed of the ancestral Wuhan, Beta, and Delta vaccines, substantially increases the levels of protection and of cross-neutralizing antibodies against mismatched, phylogenetically distant variants, including the currently circulating Omicron variant. We believe that these findings will help to guide efforts for pandemic preparedness against new variants in the future.