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1.
Sci Adv ; 8(47): eade4433, 2022 Nov 25.
Article in English | MEDLINE | ID: covidwho-2137357

ABSTRACT

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and waning immunity call for next-generation vaccine strategies. Here, we assessed the immunogenicity and protective efficacy of two SARS-CoV-2 vaccines targeting the WA1/2020 spike protein, Ad26.COV2.S (Ad26) and Spike ferritin Nanoparticle (SpFN), in nonhuman primates, delivered as either a homologous (SpFN/SpFN and Ad26/Ad26) or heterologous (Ad26/SpFN) prime-boost regimen. The Ad26/SpFN regimen elicited the highest CD4 T cell and memory B cell responses, the SpFN/SpFN regimen generated the highest binding and neutralizing antibody responses, and the Ad26/Ad26 regimen generated the most robust CD8 T cell responses. Despite these differences, protective efficacy against SARS-CoV-2 Omicron BA.1 challenge was similar for all three regimens. After challenge, all vaccinated monkeys showed significantly reduced peak and day 4 viral loads in both bronchoalveolar lavage and nasal swabs as compared with sham animals. The efficacy conferred by these three immunologically distinct vaccine regimens suggests that both humoral and cellular immunity contribute to protection against SARS-CoV-2 Omicron challenge.

2.
Health Promot Pract ; : 15248399221133726, 2022 Nov 11.
Article in English | MEDLINE | ID: covidwho-2116822

ABSTRACT

From the onset of the pandemic in the United States, racial disparities in COVID-19 outcomes have been evident. In April 2020, several events prompted a concerned group of colleagues to form the Black Equity Coalition (BEC), a Black-led coalition in Allegheny County, Pennsylvania, which brings together professionals from multiple sectors who aim to ensure an equitable response to the COVID-19 pandemic. Several significant milestones have been achieved, and this article describes the development, functioning, and outcomes of the Coalition in the first 15 months of operation (April 2020-June 2021). COVID-19 was the reason for such an unprecedented effort, but this BEC infrastructure will be needed long after COVID-19 is controlled. In addition to short-term activities and reactive measures to prevent and mitigate COVID-19 in Black populations, the BEC is serving as a crucial link between government, health care stakeholders, and communities to produce long-term systemic change.

3.
Nat Commun ; 13(1): 6309, 2022 Oct 23.
Article in English | MEDLINE | ID: covidwho-2087203

ABSTRACT

Coronavirus vaccines that are highly effective against current and anticipated SARS-CoV-2 variants are needed to control COVID-19. We previously reported a receptor-binding domain (RBD)-sortase A-conjugated ferritin nanoparticle (scNP) vaccine that induced neutralizing antibodies against SARS-CoV-2 and pre-emergent sarbecoviruses and protected non-human primates (NHPs) from SARS-CoV-2 WA-1 infection. Here, we find the RBD-scNP induced neutralizing antibodies in NHPs against pseudoviruses of SARS-CoV and SARS-CoV-2 variants including 614G, Beta, Delta, Omicron BA.1, BA.2, BA.2.12.1, and BA.4/BA.5, and a designed variant with escape mutations, PMS20. Adjuvant studies demonstrate variant neutralization titers are highest with 3M-052-aqueous formulation (AF). Immunization twice with RBD-scNPs protect NHPs from SARS-CoV-2 WA-1, Beta, and Delta variant challenge, and protect mice from challenges of SARS-CoV-2 Beta variant and two other heterologous sarbecoviruses. These results demonstrate the ability of RBD-scNPs to induce broad neutralization of SARS-CoV-2 variants and to protect animals from multiple different SARS-related viruses. Such a vaccine could provide broad immunity to SARS-CoV-2 variants.


Subject(s)
COVID-19 , Nanoparticles , SARS Virus , Viral Vaccines , Mice , Animals , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Mice, Inbred BALB C , COVID-19/prevention & control , Antibodies, Neutralizing/chemistry , Ferritins
4.
Sci Immunol ; 7(77): eabq7647, 2022 Nov 18.
Article in English | MEDLINE | ID: covidwho-1986327

ABSTRACT

Spike-specific neutralizing antibodies (NAbs) are generally considered key correlates of vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recently, robust vaccine prevention of severe disease with SARS-CoV-2 variants that largely escape NAb responses has been reported, suggesting a role for other immune parameters for virologic control. However, direct data demonstrating a role of CD8+ T cells in vaccine protection have not yet been reported. In this study, we show that vaccine-elicited CD8+ T cells contribute substantially to virologic control after SARS-CoV-2 challenge in rhesus macaques. We vaccinated 30 macaques with a single immunization of the adenovirus vector-based vaccine Ad26.COV2.S or sham and then challenged them with 5 × 105 median tissue culture infectious dose SARS-CoV-2 B.1.617.2 (Delta) by the intranasal and intratracheal routes. All vaccinated animals were infected by this high-dose challenge but showed rapid virologic control in nasal swabs and bronchoalveolar lavage by day 4 after challenge. However, administration of an anti-CD8α- or anti-CD8ß-depleting monoclonal antibody in vaccinated animals before SARS-CoV-2 challenge resulted in higher levels of peak and day 4 virus in both the upper and lower respiratory tracts. These data demonstrate that CD8+ T cells contribute substantially to vaccine protection against SARS-CoV-2 replication in macaques.


Subject(s)
COVID-19 , Viral Vaccines , Animals , Humans , SARS-CoV-2 , CD8-Positive T-Lymphocytes , Macaca mulatta , Ad26COVS1 , COVID-19/prevention & control
5.
HEM/ONC Today ; 23(10):1-15, 2022.
Article in English | ProQuest Central | ID: covidwho-1970631

ABSTRACT

A study of U.S. Health Care Cost Institute and American Cancer Society data, published in April in The American Surgeon, showed increases not only in diagnoses of lung/bronchus (0.29%), pancreatic (1.46%), breast (2.89%), colorectal (19.72%) and prostate cancer (144.5%) in 2020 (P < .01 for all), but also in the total number of deaths due to colorectal, pancreatic, breast and prostate cancers from 2019 to 2021. A study of visits to Moores Cancer Center at University of California, San Diego Health in 2019 vs. 2020 showed a numeric increase in the percentage of patients with colorectal cancer who presented with stage IV disease (6.7% [n = 3] vs. 19.5% [n = 8];OR = 0.3;95% CI, 0.05-1.37) and a numeric decrease in the number who presented with stage I disease (17.8% [n = 8] vs. 14.6% [n = 6];OR = 1.26;95% CI, 0.34-4.88). Specifically, three established Cancer Intervention and Surveillance Modeling Network breast cancer models projected 950 cumulative excess breast cancer deaths associated with decreased screening, 1,314 associated with delayed diagnosis of symptomatic cases and 151 associated with decreased use of chemotherapy in women with hormone receptor-positive, earlystage disease. [...]we observed a decrease of approximately 50% in screenings as patients who were supposed to come to the hospital for screening did not out of fear," Villena-Vargas said during an interview with Healio ;HemOnc Today.

6.
PLoS Biol ; 20(5): e3001609, 2022 05.
Article in English | MEDLINE | ID: covidwho-1962969

ABSTRACT

Despite the rapid creation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccines, the precise correlates of immunity against severe Coronavirus Disease 2019 (COVID-19) are still unknown. Neutralizing antibodies represent a robust surrogate of protection in early Phase III studies, but vaccines provide protection prior to the evolution of neutralization, vaccines provide protection against variants that evade neutralization, and vaccines continue to provide protection against disease severity in the setting of waning neutralizing titers. Thus, in this study, using an Ad26.CoV2.S dose-down approach in nonhuman primates (NHPs), the role of neutralization, Fc effector function, and T-cell immunity were collectively probed against infection as well as against viral control. While dosing-down minimally impacted neutralizing and binding antibody titers, Fc receptor binding and functional antibody levels were induced in a highly dose-dependent manner. Neutralizing antibody and Fc receptor binding titers, but minimally T cells, were linked to the prevention of transmission. Conversely, Fc receptor binding/function and T cells were linked to antiviral control, with a minimal role for neutralization. These data point to dichotomous roles of neutralization and T-cell function in protection against transmission and disease severity and a continuous role for Fc effector function as a correlate of immunity key to halting and controlling SARS-CoV-2 and emerging variants.


Subject(s)
COVID-19 , Ad26COVS1 , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Primates , Receptors, Fc , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
7.
PNAS Nexus ; 1(3): pgac091, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1961140

ABSTRACT

Emergence of SARS-CoV-2 variants and waning of vaccine/infection-induced immunity pose threats to curbing the COVID-19 pandemic. Effective, safe, and convenient booster vaccines are in need. We hypothesized that a variant-modified mucosal booster vaccine might induce local immunity to prevent SARS-CoV-2 infection at the port of entry. The beta-variant is one of the hardest to cross-neutralize. Herein, we assessed the protective efficacy of an intranasal booster composed of beta variant-spike protein S1 with IL-15 and TLR agonists in previously immunized macaques. The macaques were first vaccinated with Wuhan strain S1 with the same adjuvant. A total of 1 year later, negligibly detectable SARS-CoV-2-specific antibody remained. Nevertheless, the booster induced vigorous humoral immunity including serum- and bronchoalveolar lavage (BAL)-IgG, secretory nasal- and BAL-IgA, and neutralizing antibody against the original strain and/or beta variant. Beta-variant S1-specific CD4+ and CD8+ T cell responses were also elicited in PBMC and BAL. Following SARS-CoV-2 beta variant challenge, the vaccinated group demonstrated significant protection against viral replication in the upper and lower respiratory tracts, with almost full protection in the nasal cavity. The fact that one intranasal beta-variant booster administrated 1 year after the first vaccination provoked protective immunity against beta variant infections may inform future SARS-CoV-2 booster design and administration timing.

8.
Science (New York, N.Y.) ; 2022.
Article in English | EuropePMC | ID: covidwho-1939926

ABSTRACT

To combat future SARS-CoV-2 variants and spillovers of SARS-like betacoronaviruses (sarbecoviruses) threatening global health, we designed mosaic nanoparticles presenting randomly-arranged sarbecovirus spike receptor-binding domains (RBDs) to elicit antibodies against epitopes that are conserved and relatively occluded, rather than variable, immunodominant, and exposed. We compared immune responses elicited by mosaic-8 (SARS-CoV-2 and seven animal sarbecoviruses) and homotypic (only SARS-CoV-2) RBD-nanoparticles in mice and macaques, observing stronger responses elicited by mosaic-8 to mismatched (not on nanoparticles) strains including SARS-CoV and animal sarbecoviruses. Mosaic-8 immunization showed equivalent neutralization of SARS-CoV-2 variants including Omicrons and protected from SARS-CoV-2 and SARS-CoV challenges, whereas homotypic SARS-CoV-2 immunization protected only from SARS-CoV-2 challenge. Epitope mapping demonstrated increased targeting of conserved epitopes after mosaic-8 immunization. Together, these results suggest mosaic-8 RBD-nanoparticles could protect against SARS-CoV-2 variants and future sarbecovirus spillovers. Description

9.
Bull Math Biol ; 84(9): 90, 2022 07 20.
Article in English | MEDLINE | ID: covidwho-1942799

ABSTRACT

Understanding the joint impact of vaccination and non-pharmaceutical interventions on COVID-19 development is important for making public health decisions that control the pandemic. Recently, we created a method in forecasting the daily number of confirmed cases of infectious diseases by combining a mechanistic ordinary differential equation (ODE) model for infectious classes and a generalized boosting machine learning model (GBM) for predicting how public health policies and mobility data affect the transmission rate in the ODE model (Wang et al. in Bull Math Biol 84:57, 2022). In this paper, we extend the method to the post-vaccination period, accordingly obtain a retrospective forecast of COVID-19 daily confirmed cases in the US, and identify the relative influence of the policies used as the predictor variables. In particular, our ODE model contains both partially and fully vaccinated compartments and accounts for the breakthrough cases, that is, vaccinated individuals can still get infected. Our results indicate that the inclusion of data on non-pharmaceutical interventions can significantly improve the accuracy of the predictions. With the use of policy data, the model predicts the number of daily infected cases up to 35 days in the future, with an average mean absolute percentage error of [Formula: see text], which is further improved to [Formula: see text] if combined with human mobility data. Moreover, the most influential predictor variables are the policies of restrictions on gatherings, testing and school closing. The modeling approach used in this work can help policymakers design control measures as variant strains threaten public health in the future.


Subject(s)
COVID-19 , COVID-19/epidemiology , COVID-19/prevention & control , Humans , Mathematical Concepts , Models, Biological , Public Policy , Retrospective Studies , Vaccination
10.
iScience ; 25(6): 104457, 2022 Jun 17.
Article in English | MEDLINE | ID: covidwho-1867292

ABSTRACT

COVID-19 vaccine efficacy is threatened by emerging SARS-CoV-2 variants of concern (VOC) with the capacity to evade protective neutralizing antibody responses. We recently developed clinical vaccine candidate COH04S1, a synthetic modified vaccinia Ankara vector (sMVA) co-expressing spike and nucleocapsid antigens based on the Wuhan-Hu-1 reference strain that showed potent efficacy to protect against ancestral SARS-CoV-2 in Syrian hamsters and non-human primates and was safe and immunogenic in healthy volunteers. Here, we demonstrate that intramuscular immunization of Syrian hamsters with COH04S1 and an analogous Beta variant-adapted vaccine candidate (COH04S351) elicits potent cross-reactive antibody responses and protects against weight loss, lower respiratory tract infection, and lung pathology following challenge with major SARS-CoV-2 VOC, including Beta and the highly contagious Delta variant. These results demonstrate efficacy of COH04S1 and a variant-adapted vaccine analog to confer cross-protective immunity against SARS-CoV-2 and its emerging VOC, supporting clinical investigation of these sMVA-based COVID-19 vaccine candidates.

11.
Orthop J Sports Med ; 10(4): 23259671221088326, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1854750

ABSTRACT

Background: Chronic Achilles and patellar tendinopathy are a significant burden in physically active populations. High-volume image-guided injection (HVIGI) proposes to strip away associated neovascularity, disrupt painful nerve ingrowth, and facilitate rehabilitation. Purpose: To investigate the efficacy of HVIGI with and without steroid relative to placebo. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 62 participants were recruited between May 25, 2016, and March 5, 2020. Participants were men aged 18 to 55 years with Achilles or patellar tendinopathy of at least 6-month chronicity that had not improved with nonoperative management (including physical therapy and shockwave therapy), with ultrasound evidence of neovascularization, tendon thickening, and echogenic changes. They were assigned to the following groups: control (3 mL of subcutaneous 0.5% bupivacaine), HVIGI (10 mL of 0.5% bupivacaine and 30 mL of normal saline, ultrasound-guided between tendon and underlying fat pad), or HVIGI with steroid (HVIGIwSteroid; 0.25 mL of 100 mg/mL hydrocortisone). Clinicians and assessors were blinded. All participants were supervised through a pain-guided progressive loading program for 6 months postinjection. The main outcome measures were the Victoria Institute of Sport Assessments (VISA) for Achilles and patellar tendinopathy and the visual analog scale (VAS) for pain at 6 months postinjection. Results: The VISA score improved by a mean of 22.8 points (95% CI, 10.4-35.3 points; effect size [ES], 1.51) in the control group (n = 21), 18.6 points (95% CI, 9.1-28.0 points; ES, 1.31) in the HVIGI group (n = 21), and 18.5 points (95% CI, 3.4-33.6 points; ES, 0.88) in the HVIGIwSteroid group (n = 20). VAS pain improved by a mean of 15 points (interquartile range [IQR], -38.75, 8 points; ES, 0.39) in controls, 13 points (IQR,-34.0, 3.75 points; ES, 0.47) in the HVIGI group, and 27 points (IQR,-38.0, -1.0 points; ES, 0.54) in the HVIGIwSteroid group. The main effects were significant for time (P < .001) but not group (P ≥ .48), with no group × time interaction (P = .71). One participant was lost to follow-up from each group, multiple imputation was used for missing data points. No adverse events occurred. Conclusion: Study findings did not demonstrate superiority of HVIGI over control injection. Registration: EU Clinical Trials Register (EudraCT: 2015-003587-36).

12.
Med (N Y) ; 3(4): 262-268.e4, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1829236

ABSTRACT

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (B.1.1.529) variant has proven to be highly transmissible and has outcompeted the Delta variant in many regions of the world. Early reports have also suggested that Omicron may result in less severe clinical disease in humans. Here, we show that Omicron is less pathogenic than prior SARS-CoV-2 variants in Syrian golden hamsters. Methods: Hamsters were inoculated with either SARS-CoV-2 Omicron or other SARS-CoV-2 variants. Animals were followed for weight loss, and upper and lower respiratory tract tissues were assessed for viral loads and histopathology. Findings: Infection of hamsters with the SARS-CoV-2 WA1/2020, Alpha, Beta, or Delta strains led to 4%-10% weight loss by day 4 and 10%-17% weight loss by day 6. In contrast, infection of hamsters with two different Omicron challenge stocks did not result in any detectable weight loss, even at high challenge doses. Omicron infection led to substantial viral replication in both the upper and lower respiratory tracts but demonstrated lower viral loads in lung parenchyma and reduced pulmonary pathology compared with WA1/2020 infection. Conclusions: These data suggest that the SARS-CoV-2 Omicron variant may result in robust upper respiratory tract infection, but less severe lower respiratory tract clinical disease, compared with prior SARS-CoV-2 variants. Funding: Funding for this study was provided by NIH grant CA260476, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute, and the Musk Foundation.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Cricetinae , SARS-CoV-2/genetics , Virulence , Weight Loss
13.
Journal of Forensic Practice ; 24(2):95-110, 2022.
Article in English | ProQuest Central | ID: covidwho-1794896

ABSTRACT

Purpose>South Wales Police Mental Health (MH) Triage service was initiated to meet the Welsh Government MH priority of early intervention to prevent MH crisis. Community Psychiatric Nurses, based in the control-room, provide advice to police and control room staff on the management of MH-related incidents. The purpose of this paper is to evaluate the first 12 months of operation (January-December 2019).Design/methodology/approach>Service evaluation of the first 12 months of operation (January–December 2019). Data were analysed in relation to: MH incidents;repeat callers;Section (S)136 use/assessment outcomes. Police, health staff and triage service users were interviewed and surveyed to capture their opinions of the service.Findings>Policing areas with high engagement in triage saw reductions in S136 use and estimated opportunity costs saving. Triage was considered a valuable service that promoted cross agency collaborations. De-escalation in cases of mental distress was considered a strength. Access to follow-on services was identified as a challenge.Practical implications>Triage enables a multi-agency response in the management of MH-related incidents. Improving trust between services, with skilled health professionals supporting police decision-making in real time.Originality/value>There is a gap in the research on the impact of police-related MH triage models beyond the use of S136. This project evaluated the quality of the service, its design and the relationship between health, police and partner agencies during the triage process. Multi-agency assessment of follow-up is needed to measure the long-term impact on services and users.

14.
Bull Math Biol ; 84(5): 57, 2022 04 08.
Article in English | MEDLINE | ID: covidwho-1782924

ABSTRACT

Accurate prediction of the number of daily or weekly confirmed cases of COVID-19 is critical to the control of the pandemic. Existing mechanistic models nicely capture the disease dynamics. However, to forecast the future, they require the transmission rate to be known, limiting their prediction power. Typically, a hypothesis is made on the form of the transmission rate with respect to time. Yet the real form is too complex to be mechanistically modeled due to the unknown dynamics of many influential factors. We tackle this problem by using a hypothesis-free machine-learning algorithm to estimate the transmission rate from data on non-pharmaceutical policies, and in turn forecast the confirmed cases using a mechanistic disease model. More specifically, we build a hybrid model consisting of a mechanistic ordinary differential equation (ODE) model and a gradient boosting model (GBM). To calibrate the parameters, we develop an "inverse method" that obtains the transmission rate inversely from the other variables in the ODE model and then feed it into the GBM to connect with the policy data. The resulting model forecasted the number of daily confirmed cases up to 35 days in the future in the USA with an averaged mean absolute percentage error of 27%. It can identify the most informative predictive variables, which can be helpful in designing improved forecasters as well as informing policymakers.


Subject(s)
COVID-19 , COVID-19/epidemiology , COVID-19/prevention & control , Humans , Machine Learning , Mathematical Concepts , Models, Biological , Pandemics/prevention & control
15.
Cell ; 185(9): 1549-1555.e11, 2022 04 28.
Article in English | MEDLINE | ID: covidwho-1748149

ABSTRACT

The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. In this study, we show that the mRNA-based BNT162b2 vaccine and the adenovirus-vector-based Ad26.COV2.S vaccine provide robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in cynomolgus macaques. We vaccinated 30 macaques with homologous and heterologous prime-boost regimens with BNT162b2 and Ad26.COV2.S. Following Omicron challenge, vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs. However, 4 vaccinated animals that had moderate Omicron-neutralizing antibody titers and undetectable Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Moreover, virologic control correlated with both antibody and T cell responses. These data suggest that both humoral and cellular immune responses contribute to vaccine protection against a highly mutated SARS-CoV-2 variant.


Subject(s)
Ad26COVS1/immunology , BNT162 Vaccine/immunology , COVID-19 , Macaca , SARS-CoV-2 , Ad26COVS1/administration & dosage , Animals , Antibodies, Neutralizing , Antibodies, Viral , BNT162 Vaccine/administration & dosage , COVID-19/immunology , COVID-19/prevention & control , T-Lymphocytes/immunology
16.
Sci Adv ; 8(11): eabl6015, 2022 Mar 18.
Article in English | MEDLINE | ID: covidwho-1745843

ABSTRACT

Authorized vaccines against SARS-CoV-2 remain less available in low- and middle-income countries due to insufficient supply, high costs, and storage requirements. Global immunity could still benefit from new vaccines using widely available, safe adjuvants, such as alum and protein subunits, suited to low-cost production in existing manufacturing facilities. Here, a clinical-stage vaccine candidate comprising a SARS-CoV-2 receptor binding domain-hepatitis B surface antigen virus-like particle elicited protective immunity in cynomolgus macaques. Titers of neutralizing antibodies (>104) induced by this candidate were above the range of protection for other licensed vaccines in nonhuman primates. Including CpG 1018 did not significantly improve the immunological responses. Vaccinated animals challenged with SARS-CoV-2 showed reduced median viral loads in bronchoalveolar lavage (~3.4 log10) and nasal mucosa (~2.9 log10) versus sham controls. These data support the potential benefit of this design for a low-cost modular vaccine platform for SARS-CoV-2 and other variants of concern or betacoronaviruses.

17.
Med (N Y) ; 3(3): 188-203.e4, 2022 Mar 11.
Article in English | MEDLINE | ID: covidwho-1740045

ABSTRACT

BACKGROUND: Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention or therapy. The pre-exposure prophylactic efficacy of neutralizing antibodies that are engineered with mutations to extend their persistence in human serum and the neutralizing antibody titer in serum required for protection against SARS-CoV-2 infection remain poorly characterized. METHODS: The Fc region of two neutralizing mAbs (COV2-2130 and COV2-2381) targeting non-overlapping epitopes on the receptor binding domain of SARS-CoV-2 spike protein was engineered to extend their persistence in humans and reduce interactions with Fc gamma receptors. We assessed protection by individual antibodies or a combination of the two antibodies (designated ADM03820) given prophylactically by an intravenous or intramuscular route in a non-human primate (NHP) model of SARS-CoV-2 infection. FINDINGS: Passive transfer of individual mAbs or ADM03820 conferred virological protection in the NHP respiratory tract in a dose-dependent manner, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro. We defined a protective serum-neutralizing antibody titer and concentration in NHPs for passively transferred human antibodies that acted by direct viral neutralization. CONCLUSIONS: In summary, we demonstrate that neutralizing antibodies with extended half-life and lacking Fc-mediated effector functions are efficient for pre-exposure prophylaxis of SARS-CoV-2 infection in NHPs. These results support clinical development of ADM03820 for COVID-19 prevention. FUNDING: This research was supported by a contract from the JPEO-CBRND (W911QY-20-9-003, 20-05); the Joint Sciences and Technology Office and Joint Program Executive Office (MCDC-16-01-002 JSTO, JPEO); a DARPA grant (HR0011-18-2-0001); an NIH grant (R01 AI157155); and the 2019 Future Insight Prize from Merck KGaA.


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antibodies, Monoclonal , Antibodies, Neutralizing/therapeutic use , COVID-19/prevention & control , Humans , Macaca , Spike Glycoprotein, Coronavirus
18.
PLoS Pathog ; 17(9): e1009701, 2021 09.
Article in English | MEDLINE | ID: covidwho-1701737

ABSTRACT

The speed of development, versatility and efficacy of mRNA-based vaccines have been amply demonstrated in the case of SARS-CoV-2. DNA vaccines represent an important alternative since they induce both humoral and cellular immune responses in animal models and in human trials. We tested the immunogenicity and protective efficacy of DNA-based vaccine regimens expressing different prefusion-stabilized Wuhan-Hu-1 SARS-CoV-2 Spike antigens upon intramuscular injection followed by electroporation in rhesus macaques. Different Spike DNA vaccine regimens induced antibodies that potently neutralized SARS-CoV-2 in vitro and elicited robust T cell responses. The antibodies recognized and potently neutralized a panel of different Spike variants including Alpha, Delta, Epsilon, Eta and A.23.1, but to a lesser extent Beta and Gamma. The DNA-only vaccine regimens were compared to a regimen that included co-immunization of Spike DNA and protein in the same anatomical site, the latter of which showed significant higher antibody responses. All vaccine regimens led to control of SARS-CoV-2 intranasal/intratracheal challenge and absence of virus dissemination to the lower respiratory tract. Vaccine-induced binding and neutralizing antibody titers and antibody-dependent cellular phagocytosis inversely correlated with transient virus levels in the nasal mucosa. Importantly, the Spike DNA+Protein co-immunization regimen induced the highest binding and neutralizing antibodies and showed the strongest control against SARS-CoV-2 challenge in rhesus macaques.


Subject(s)
Macaca mulatta , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA , Animals , COVID-19/immunology , COVID-19/therapy , Cohort Studies , DNA, Viral/immunology , Disease Models, Animal , Female , Immunization, Passive , Leukocytes, Mononuclear/immunology , Mice , RNA, Messenger/analysis , SARS-CoV-2/genetics , T-Lymphocytes/immunology , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology
19.
Sci Transl Med ; 14(638): eabm4996, 2022 03 30.
Article in English | MEDLINE | ID: covidwho-1705843

ABSTRACT

Ad26.COV2.S has demonstrated durability and clinical efficacy against symptomatic COVID-19 in humans. In this study, we report the correlates of durability of humoral and cellular immune responses in 20 rhesus macaques immunized with single-shot Ad26.COV2.S and the immunogenicity of a booster shot at 8 to 10 months after the initial immunization. Ad26.COV2.S elicited durable binding and neutralizing antibodies as well as memory B cells and long-lived bone marrow plasma cells. Innate immune responses and bone marrow plasma cell responses correlated with durable antibody responses. After Ad26.COV2.S boost immunization, binding and neutralizing antibody responses against multiple SARS-CoV-2 variants increased 31- to 69-fold and 23- to 43-fold, respectively, compared with preboost concentrations. Antigen-specific B cell and T cell responses also increased substantially after the boost immunization. Boosting with a modified Ad26.COV2.S.351 vaccine expressing the SARS-CoV-2 spike protein from the beta variant led to largely comparable responses with slightly higher beta- and omicron-specific humoral immune responses. These data demonstrate that a late boost with Ad26.COV2.S or Ad26.COV2.S.351 resulted in a marked increase in humoral and cellular immune responses that were highly cross-reactive across multiple SARS-CoV-2 variants in rhesus macaques.


Subject(s)
Ad26COVS1 , COVID-19 , Immunity, Humoral , Immunization, Secondary , SARS-CoV-2 , Ad26COVS1/immunology , Animals , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Macaca mulatta , Spike Glycoprotein, Coronavirus
20.
NPJ Vaccines ; 7(1): 7, 2022 Jan 21.
Article in English | MEDLINE | ID: covidwho-1641964

ABSTRACT

Second-generation COVID-19 vaccines could contribute to establish protective immunity against SARS-CoV-2 and its emerging variants. We developed COH04S1, a synthetic multiantigen modified vaccinia Ankara-based SARS-CoV-2 vaccine that co-expresses spike and nucleocapsid antigens. Here, we report COH04S1 vaccine efficacy in animal models. We demonstrate that intramuscular or intranasal vaccination of Syrian hamsters with COH04S1 induces robust Th1-biased antigen-specific humoral immunity and cross-neutralizing antibodies (NAb) and protects against weight loss, lower respiratory tract infection, and lung injury following intranasal SARS-CoV-2 challenge. Moreover, we demonstrate that single-dose or two-dose vaccination of non-human primates with COH04S1 induces robust antigen-specific binding antibodies, NAb, and Th1-biased T cells, protects against both upper and lower respiratory tract infection following intranasal/intratracheal SARS-CoV-2 challenge, and triggers potent post-challenge anamnestic antiviral responses. These results demonstrate COH04S1-mediated vaccine protection in animal models through different vaccination routes and dose regimens, complementing ongoing investigation of this multiantigen SARS-CoV-2 vaccine in clinical trials.

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