45 results on '"Noe B. Mercado"'
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2. Therapeutic efficacy of an Ad26/MVA vaccine with SIV gp140 protein and vesatolimod in ART-suppressed rhesus macaques
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John D. Ventura, Joseph P. Nkolola, Abishek Chandrashekar, Erica N. Borducchi, Jinyan Liu, Noe B. Mercado, David L. Hope, Victoria M. Giffin, Katherine McMahan, Romas Geleziunas, Jeffrey P. Murry, Yunling Yang, Mark G. Lewis, Maria G. Pau, Frank Wegmann, Hanneke Schuitemaker, Emily J. Fray, Mithra R. Kumar, Janet D. Siliciano, Robert F. Siliciano, Merlin L. Robb, Nelson L. Michael, and Dan H. Barouch
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Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Developing an intervention that results in virologic control following discontinuation of antiretroviral therapy (ART) is a major objective of HIV-1 cure research. In this study, we investigated the therapeutic efficacy of a vaccine consisting of adenovirus serotype 26 (Ad26) and modified vaccinia Ankara (MVA) with or without an SIV Envelope (Env) gp140 protein with alum adjuvant in combination with the TLR7 agonist vesatolimod (GS-9620) in 36 ART-suppressed, SIVmac251-infected rhesus macaques. Ad26/MVA therapeutic vaccination led to robust humoral and cellular immune responses, and the Env protein boost increased antibody responses. Following discontinuation of ART, virologic control was observed in 5/12 animals in each vaccine group, compared with 0/12 animals in the sham control group. These data demonstrate therapeutic efficacy of Ad26/MVA vaccination with vesatolimod but no clear additional benefit of adding an Env protein boost. SIV-specific cellular immune responses correlated with virologic control. Our findings show partial efficacy of therapeutic vaccination following ART discontinuation in SIV-infected rhesus macaques.
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- 2022
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3. SARS-CoV-2 binding and neutralizing antibody levels after Ad26.COV2.S vaccination predict durable protection in rhesus macaques
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Ramon Roozendaal, Laura Solforosi, Daniel J. Stieh, Jan Serroyen, Roel Straetemans, Anna Dari, Muriel Boulton, Frank Wegmann, Sietske K. Rosendahl Huber, Joan E. M. van der Lubbe, Jenny Hendriks, Mathieu Le Gars, Liesbeth Dekking, Dominika N. Czapska-Casey, Nuria Guimera, Sarah Janssen, Sarah Tete, Abishek Chandrashekar, Noe B. Mercado, Jingyou Yu, Wouter Koudstaal, Juan J. Perez-Ruixo, Jerry Sadoff, Dan H. Barouch, Hanneke Schuitemaker, and Roland Zahn
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Science - Abstract
Several COVID-19 vaccines have received emergency approval, but durability of protection is unclear. Here, the authors describe correlates of protection (CoP) for the Ad26.COV2.S vaccine in rhesus macaques and report that CoP predict the protection observed 6 months post vaccination.
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- 2021
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4. Persistence of viral RNA in lymph nodes in ART-suppressed SIV/SHIV-infected Rhesus Macaques
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Anthony M. Cadena, John D. Ventura, Peter Abbink, Erica N. Borducchi, Hubert Tuyishime, Noe B. Mercado, Victoria Walker-Sperling, Mazuba Siamatu, Po-Ting Liu, Abishek Chandrashekar, Joseph P. Nkolola, Katherine McMahan, Nicole Kordana, Venous Hamza, Esther A. Bondzie, Emily Fray, Mithra Kumar, Stephanie Fischinger, Sally A. Shin, Mark G. Lewis, Robert F. Siliciano, Galit Alter, and Dan H. Barouch
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Science - Abstract
The existence of HIV reservoir and ongoing replication despite antiretroviral therapy (ART) represents a barrier for cure efforts. Here, using SIV/SHIV-infected rhesus macaque suppressed with ART for one year, the authors characterize multiple lymphoid and non-lymphoid tissues and show that while the viral reservoir exhibits a wide anatomic heterogeneity, persistent viral transcription is mainly restricted to secondary lymphoid organs.
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- 2021
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5. Origin of rebound virus in chronically SIV-infected Rhesus monkeys following treatment discontinuation
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Po-Ting Liu, Brandon F. Keele, Peter Abbink, Noe B. Mercado, Jinyan Liu, Esther A. Bondzie, Abishek Chandrashekar, Erica N. Borducchi, Joseph Hesselgesser, Michael Mish, Gregory Chin, Elena Bekerman, Romas Geleziunas, and Dan H. Barouch
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Science - Abstract
The origin and nature of rebound HIV-1 virus following antiretroviral therapy (ART) discontinuation still remains unclear. Here, Liu et al. suggest that intact proviral DNA in peripheral blood and lymph node mononuclear cells during ART suppression likely is the source of viral rebound following ART discontinuation.
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- 2020
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6. Increased IL-6 expression precedes reliable viral detection in the rhesus macaque brain during acute SIV infection
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Raja Mohan Gopalakrishnan, Malika Aid, Noe B. Mercado, Caitlin Davis, Shaily Malik, Emma Geiger, Valerie Varner, Rhianna Jones, Steven E. Bosinger, Cesar Piedra-Mora, Amanda J. Martinot, Dan H. Barouch, R. Keith Reeves, and C. Sabrina Tan
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AIDS/HIV ,Neuroscience ,Medicine - Abstract
Knowledge of immune activation in the brain during acute HIV infection is crucial for the prevention and treatment of HIV-associated neurological disorders. We determined regional brain (basal ganglia, thalamus, and frontal cortex) immune and virological profiles at 7 and 14 days post infection (dpi) with SIVmac239 in rhesus macaques. The basal ganglia and thalamus had detectable viruses earlier (7 dpi) than the frontal cortex (14 dpi) and contained higher quantities of viruses than the latter. Increased immune activation of astrocytes and significant infiltration of macrophages in the thalamus at 14 dpi coincided with elevated plasma viral load, and SIV colocalized only within macrophages. RNA signatures of proinflammatory responses, including IL-6, were detected at 7 dpi in microglia and interestingly, preceded reliable detection of virus in tissues and were maintained in the chronically infected macaques. Countering the proinflammatory response, the antiinflammatory response was not detected until increased TGF-β expression was found in perivascular macrophages at 14 dpi. But this response was not detected in chronic infection. Our data provide evidence that the interplay of acute proinflammatory and antiinflammatory responses in the brain likely contributed to the overt neuroinflammation, where the immune activation preceded reliable viral detection.
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- 2021
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7. Reduced SARS-CoV-2 disease outcomes in Syrian hamsters receiving immune sera: Quantitative image analysis in pathologic assessments
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Cesar Piedra-Mora, Sally R. Robinson, Lisa H. Tostanoski, Denise A. E. Dayao, Abishek Chandrashekar, Katherine Bauer, Linda Wrijil, Sarah Ducat, Tammy Hayes, Jingyou Yu, Esther A. Bondzie, Katherine McMahan, Daniel Sellers, Victoria Giffin, David Hope, Felix Nampanya, Noe B. Mercado, Swagata Kar, Hanne Andersen, Saul Tzipori, Dan H. Barouch, and Amanda J. Martinot
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COVID-19 Vaccines ,Mesocricetus ,General Veterinary ,SARS-CoV-2 ,Immune Sera ,COVID-19 ,Macaca mulatta ,Rodent Diseases ,Disease Models, Animal ,Cricetinae ,Immunoglobulin G ,Weight Loss ,Animals ,Humans ,Lung - Abstract
There is a need to standardize pathologic endpoints in animal models of SARS-CoV-2 infection to help benchmark study quality, improve cross-institutional comparison of data, and assess therapeutic efficacy so that potential drugs and vaccines for SARS-CoV-2 can rapidly advance. The Syrian hamster model is a tractable small animal model for COVID-19 that models clinical disease in humans. Using the hamster model, the authors used traditional pathologic assessment with quantitative image analysis to assess disease outcomes in hamsters administered polyclonal immune sera from previously challenged rhesus macaques. The authors then used quantitative image analysis to assess pathologic endpoints across studies performed at different institutions using different tissue processing protocols. The authors detail pathological features of SARS-CoV-2 infection longitudinally and use immunohistochemistry to quantify myeloid cells and T lymphocyte infiltrates during SARS-CoV-2 infection. High-dose immune sera protected hamsters from weight loss and diminished viral replication in tissues and reduced lung lesions. Cumulative pathology scoring correlated with weight loss and was robust in distinguishing IgG efficacy. In formalin-infused lungs, quantitative measurement of percent area affected also correlated with weight loss but was less robust in non-formalin-infused lungs. Longitudinal immunohistochemical assessment of interstitial macrophage infiltrates showed that peak infiltration corresponded to weight loss, yet quantitative assessment of macrophage, neutrophil, and CD3+ T lymphocyte numbers did not distinguish IgG treatment effects. Here, the authors show that quantitative image analysis was a useful adjunct tool for assessing SARS-CoV-2 treatment outcomes in the hamster model.
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- 2022
8. Long-acting capsid inhibitor protects macaques from repeat SHIV challenges
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Samuel J. Vidal, Elena Bekerman, Derek Hansen, Bing Lu, Kelly Wang, Judy Mwangi, William Rowe, Federico Campigotto, Jim Zheng, Darryl Kato, Abishek Chandrashekar, Julia Barrett, Shivani Patel, Huahua Wan, Tochi Anioke, Noe B. Mercado, Joseph P. Nkolola, Melissa J. Ferguson, William J. Rinaldi, Christian Callebaut, Wade Blair, Tomas Cihlar, Romas Geleziunas, Stephen R. Yant, and Dan H. Barouch
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Multidisciplinary ,Retrovirus ,virus diseases ,Drug development ,Article - Abstract
Because no currently available vaccine can prevent HIV infection, pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) is an important tool for combating the HIV pandemic1,2. Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration3. GS-CA1 is a small-molecule HIV capsid inhibitor with picomolar antiviral potency against a broad array of HIV strains, including variants resistant to existing ARVs, and has shown long-acting therapeutic potential in a mouse model of HIV infection4. Here we show that a single subcutaneous administration of GS-CA1 provides long-term protection against repeated rectal simian–human immunodeficiency virus (SHIV) challenges in rhesus macaques. Whereas all control animals became infected after 15 weekly challenges, a single 300 mg kg−1 dose of GS-CA1 provided per-exposure infection risk reduction of 97% for 24 weeks. Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges. GS-CA1 levels greater than twice the rhesus plasma protein-adjusted 95% effective concentration conferred 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans., A single dose of a small-molecule HIV capsid inhibitor provides long-term protection from repeated simian–human immunodeficiency virus challenges in macaques and might serve as a novel strategy for HIV prevention in humans.
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- 2021
9. Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine
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Anthony L. Cook, Xuan He, Jake Yalley-Ogunro, Ralph S. Baric, Stefan O. Mueller, David R. Martinez, Jinyan Liu, Andrew C. Cole, Tori Giffin, Hanne Leth Andersen, Daniel Valentin, Benjamin Petsch, Katherine McMahan, Dan H. Barouch, Noe B. Mercado, Shivani A. Patel, Laurent Pessaint, Renita Brown, Jeanne Muench, Julia Barrett, David L. Hope, Adrianus C. M. Boon, Mark G. Lewis, Abishek Chandrashekar, Owen Sanborn, Makda S. Gebre, Zack Flinchbaugh, Xiaowen Liu, Susanne Rauch, Elyse Teow, Daniel Sellers, Amanda J. Martinot, Nicole Roth, and Jingyou Yu
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Male ,COVID-19 Vaccines ,T cell ,T-Lymphocytes ,Respiratory System ,Antibodies, Viral ,Article ,Immunogenicity, Vaccine ,Antigen ,Memory B Cells ,RNA vaccines ,medicine ,Animals ,Neutralizing antibody ,Memory B cell ,BNT162 Vaccine ,Vaccines, Synthetic ,Multidisciplinary ,biology ,SARS-CoV-2 ,Immunogenicity ,COVID-19 ,Nucleosides ,Viral Load ,Virology ,Antibodies, Neutralizing ,Titer ,Macaca fascicularis ,medicine.anatomical_structure ,biology.protein ,Female ,mRNA Vaccines ,Antibody ,Viral load - Abstract
The CVnCoV (CureVac) mRNA vaccine for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) was recently evaluated in a phase 2b/3 efficacy trial in humans1. CV2CoV is a second-generation mRNA vaccine containing non-modified nucleosides but with optimized non-coding regions and enhanced antigen expression. Here we report the results of a head-to-head comparison of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in non-human primates. We immunized 18 cynomolgus macaques with two doses of 12 μg lipid nanoparticle-formulated CVnCoV or CV2CoV or with sham (n = 6 per group). Compared with CVnCoV, CV2CoV induced substantially higher titres of binding and neutralizing antibodies, memory B cell responses and T cell responses as well as more potent neutralizing antibody responses against SARS-CoV-2 variants, including the Delta variant. Moreover, CV2CoV was found to be comparably immunogenic to the BNT162b2 (Pfizer) vaccine in macaques. Although CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded more robust protection with markedly lower viral loads in the upper and lower respiratory tracts. Binding and neutralizing antibody titres were correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of a non-modified mRNA SARS-CoV-2 vaccine in non-human primates., CV2CoV, a second-generation mRNA COVID-19 vaccine with non-modified nucleosides but optimized non-coding regions, is demonstrated to be effective against SARS-CoV-2 challenge when tested in non-human primates.
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- 2021
10. Protective efficacy of Ad26.COV2.S against SARS-CoV-2 B.1.351 in macaques
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Lisa H. Tostanoski, David R. Martinez, Laurent Pessaint, Deandre Bueno-Wilkerson, Felix Nampanya, Jinyan Liu, Abishek Chandrashekar, Daniel Valentin, Frank Wegmann, Katherine McMahan, Anthony L. Cook, Mark G. Lewis, Hanne Leth Andersen, Noe B. Mercado, Victoria M. Giffin, Ralph S. Baric, Renita Brown, Huahua Wan, Sarah Gardner, Caroline Atyeo, Roland Zahn, Galit Alter, Daniel Sellers, Amanda J. Martinot, Zack Flinchbaugh, Tochi Anioke, Shivani A. Patel, Aiquan Chang, Jingyou Yu, Tammy Hayes, Dan H. Barouch, Hanneke Schuitemaker, Owen Sanborn, David L. Hope, Joseph P. Nkolola, Catherine Jacob-Dolan, Esther A. Bondzie, Katherine Bauer, and Elyse Teow
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Male ,0301 basic medicine ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,T-Lymphocytes ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Nose ,Antibodies, Viral ,Virus Replication ,Article ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,medicine ,Animals ,030212 general & internal medicine ,Vaccines ,Immunity, Cellular ,Multidisciplinary ,Ad26COVS1 ,biology ,medicine.diagnostic_test ,SARS-CoV-2 ,COVID-19 ,Antibodies, Neutralizing ,Macaca mulatta ,Virology ,Immunity, Humoral ,030104 developmental biology ,Bronchoalveolar lavage ,Viral replication ,biology.protein ,Female ,Antibody ,Bronchoalveolar Lavage Fluid ,CD8 - Abstract
The emergence of SARS-CoV-2 variants that partially evade neutralizing antibodies poses a threat to the efficacy of current COVID-19 vaccines1,2. The Ad26.COV2.S vaccine expresses a stabilized spike protein from the WA1/2020 strain of SARS-CoV-2, and has recently demonstrated protective efficacy against symptomatic COVID-19 in humans in several geographical regions—including in South Africa, where 95% of sequenced viruses in cases of COVID-19 were the B.1.351 variant3. Here we show that Ad26.COV2.S elicits humoral and cellular immune responses that cross-react with the B.1.351 variant and protects against B.1.351 challenge in rhesus macaques. Ad26.COV2.S induced lower binding and neutralizing antibodies against B.1.351 as compared to WA1/2020, but elicited comparable CD8 and CD4 T cell responses against the WA1/2020, B.1.351, B.1.1.7, P.1 and CAL.20C variants. B.1.351 infection of control rhesus macaques resulted in higher levels of virus replication in bronchoalveolar lavage and nasal swabs than did WA1/2020 infection. Ad26.COV2.S provided robust protection against both WA1/2020 and B.1.351, although we observed higher levels of virus in vaccinated macaques after B.1.351 challenge. These data demonstrate that Ad26.COV2.S provided robust protection against B.1.351 challenge in rhesus macaques. Our findings have important implications for vaccine control of SARS-CoV-2 variants of concern., SARS-CoV-2 challenge of rhesus macaques demonstrates that the Ad26.COV2.S vaccine induces robust protection against both the WA1/2020 isolate and the B.1.351 variant of concern.
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- 2021
11. Correlates of Protection Against SARS-CoV-2 in Rhesus Macaques
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Lisa H. Tostanoski, Alex Van Ry, Alex Lee Zhu, Elyse Teow, Abishek Chandrashekar, Shivani A. Patel, Jinyan Liu, Lauren Peter, Anthony L. Cook, Jake Yalley-Ogunro, Galit Alter, Dan H. Barouch, Mark G. Lewis, Carolin Loos, Gabriel Dagotto, Jingyou Yu, Makda S. Gebre, Mehtap Cabus, Felix Nampanya, Zhenfeng Li, Renita Brown, Douglas A. Lauffenburger, Catherine Jacob-Dolan, Esther A. Bondzie, Kelvin Blade, Laurent Pessaint, Noe B. Mercado, Hanne Andersen, Katherine McMahan, and Caroline Atyeo
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0301 basic medicine ,Male ,Adoptive cell transfer ,Cellular immunity ,viruses ,Context (language use) ,CD8-Positive T-Lymphocytes ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Medicine ,Animals ,030212 general & internal medicine ,skin and connective tissue diseases ,COVID-19 Serotherapy ,Multidisciplinary ,Innate immune system ,biology ,business.industry ,SARS-CoV-2 ,fungi ,Immunization, Passive ,virus diseases ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,Viral Load ,Adoptive Transfer ,Macaca mulatta ,body regions ,Disease Models, Animal ,030104 developmental biology ,Immunization ,Immunoglobulin G ,Immunology ,biology.protein ,Regression Analysis ,Female ,Antibody ,business - Abstract
Recent studies have reported the protective efficacy of both natural1 and vaccine-induced2–7 immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8+ T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents. Adoptive transfer of purified IgG from convalescent macaques protects naive macaques against SARS-CoV-2 infection, and cellular immune responses contribute to protection against rechallenge with SARS-CoV-2.
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- 2020
12. Origin of rebound virus in chronically SIV-infected Rhesus monkeys following treatment discontinuation
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Peter Abbink, Jinyan Liu, Mish Michael R, Po-Ting Liu, Noe B. Mercado, Dan H. Barouch, Joseph Hesselgesser, Elena Bekerman, Erica N. Borducchi, Brandon F. Keele, Abishek Chandrashekar, Gregory Chin, Esther A. Bondzie, and Romas Geleziunas
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CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Viral rebound ,viruses ,Simian Acquired Immunodeficiency Syndrome ,General Physics and Astronomy ,HIV Infections ,Virus Replication ,law.invention ,0302 clinical medicine ,Retrovirus ,law ,lcsh:Science ,Lymph node ,Multidisciplinary ,biology ,RNA sequencing ,Viral Load ,Provirus ,Virus Latency ,medicine.anatomical_structure ,Anti-Retroviral Agents ,Recombinant DNA ,Female ,Simian Immunodeficiency Virus ,Patient Dropouts ,Science ,Peripheral blood mononuclear cell ,Article ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Viral reservoirs ,03 medical and health sciences ,medicine ,Animals ,Humans ,business.industry ,General Chemistry ,biology.organism_classification ,Macaca mulatta ,Virology ,Discontinuation ,030104 developmental biology ,HIV-1 ,lcsh:Q ,business ,030217 neurology & neurosurgery - Abstract
Viral rebound following antiretroviral therapy (ART) discontinuation in HIV-1-infected individuals is believed to originate from a small pool of CD4+ T cells harboring replication-competent provirus. However, the origin and nature of the rebound virus has remained unclear. Recent studies have suggested that rebound virus does not originate directly from individual latent proviruses but rather from recombination events involving multiple proviruses. Here we evaluate the origin of rebound virus in 16 ART-suppressed, chronically SIV-infected rhesus monkeys following ART discontinuation. We sequence viral RNA and viral DNA in these animals prior to ART initiation, during ART suppression, and following viral rebound, and we compare rebound viral RNA after ART discontinuation with near full-length viral DNA from peripheral blood and lymph node mononuclear cells (PBMC and LNMC) during ART suppression. Sequences of initial rebound viruses closely match viral DNA sequences in PBMC and LNMC during ART suppression. Recombinant viruses are rare in the initial rebound virus populations but arise quickly within 2–4 weeks after viral rebound. These data suggest that intact proviral DNA in PBMC and LNMC during ART suppression is likely the direct origin of viral rebound in chronically SIV-infected rhesus monkeys following ART discontinuation., The origin and nature of rebound HIV-1 virus following antiretroviral therapy (ART) discontinuation still remains unclear. Here, Liu et al. suggest that intact proviral DNA in peripheral blood and lymph node mononuclear cells during ART suppression likely is the source of viral rebound following ART discontinuation.
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- 2020
13. SARS-CoV-2 receptor binding domain displayed on HBsAg virus-like particles elicits protective immunity in macaques
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Neil C. Dalvie, Lisa H. Tostanoski, Sergio A. Rodriguez-Aponte, Kawaljit Kaur, Sakshi Bajoria, Ozan S. Kumru, Amanda J. Martinot, Abishek Chandrashekar, Katherine McMahan, Noe B. Mercado, Jingyou Yu, Aiquan Chang, Victoria M. Giffin, Felix Nampanya, Shivani Patel, Lesley Bowman, Christopher A. Naranjo, Dongsoo Yun, Zach Flinchbaugh, Laurent Pessaint, Renita Brown, Jason Velasco, Elyse Teow, Anthony Cook, Hanne Andersen, Mark G. Lewis, Danielle L. Camp, Judith Maxwell Silverman, Gaurav S. Nagar, Harish D. Rao, Rakesh R. Lothe, Rahul Chandrasekharan, Meghraj P. Rajurkar, Umesh S. Shaligram, Harry Kleanthous, Sangeeta B. Joshi, David B. Volkin, Sumi Biswas, J. Christopher Love, and Dan H. Barouch
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Multidisciplinary - 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.
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- 2022
14. Ad26 vaccine protects against SARS-CoV-2 severe clinical disease in hamsters
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John S. Burke, Noe B. Mercado, Jingyou Yu, Dan H. Barouch, Komlan Tevi, Vaneesha Ali, Shant H. Mahrokhian, Felix Nampanya, Sarah Ducat, Carly E. Starke, Ramya Nityanandam, Lisa H. Tostanoski, Blake M. Hauser, Linda M. Wrijil, Makda S. Gebre, Kathleen Busman-Sahay, Stephanie Fischinger, Dalia Benetiene, Stephen Bondoc, Maciel Porto, Cesar Piedra-Mora, Chi N. Chan, Jacob D. Estes, Jared Feldman, Frank Wegmann, Hanneke Schuitemaker, Douglas A. Lauffenburger, Mark G. Lewis, Roland Zahn, Gabriel Dagotto, Zijin Lin, Katherine McMahan, Caroline Atyeo, Laurent Pessaint, Timothy M. Caradonna, Galit Alter, Carolin Loos, Michael Nekorchuk, Catherine Jacob-Dolan, Esther A. Bondzie, Jerome Custers, Aaron G. Schmidt, Amanda J. Martinot, and Hanne Leth Andersen
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0301 basic medicine ,Male ,Letter ,COVID-19 Vaccines ,viruses ,Genetic Vectors ,Severity of Illness Index ,General Biochemistry, Genetics and Molecular Biology ,Adenoviridae ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Cricetinae ,medicine ,Animals ,Humans ,Vector (molecular biology) ,Neutralizing antibody ,skin and connective tissue diseases ,Vaccines ,Vaccines, Synthetic ,biology ,Mesocricetus ,business.industry ,SARS-CoV-2 ,fungi ,virus diseases ,COVID-19 ,General Medicine ,Viral Load ,medicine.disease ,Antibodies, Neutralizing ,respiratory tract diseases ,Pneumonia ,Disease Models, Animal ,030104 developmental biology ,Respiratory failure ,Immunization ,Viral replication ,Immunology ,Spike Glycoprotein, Coronavirus ,biology.protein ,Female ,business ,Viral load ,030217 neurology & neurosurgery - Abstract
Coronavirus disease 2019 (COVID-19) in humans is often a clinically mild illness, but some individuals develop severe pneumonia, respiratory failure and death1–4. Studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in hamsters5–7 and nonhuman primates8–10 have generally reported mild clinical disease, and preclinical SARS-CoV-2 vaccine studies have demonstrated reduction of viral replication in the upper and lower respiratory tracts in nonhuman primates11–13. Here we show that high-dose intranasal SARS-CoV-2 infection in hamsters results in severe clinical disease, including high levels of virus replication in tissues, extensive pneumonia, weight loss and mortality in a subset of animals. A single immunization with an adenovirus serotype 26 vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein elicited binding and neutralizing antibody responses and protected against SARS-CoV-2-induced weight loss, pneumonia and mortality. These data demonstrate vaccine protection against SARS-CoV-2 clinical disease. This model should prove useful for preclinical studies of SARS-CoV-2 vaccines, therapeutics and pathogenesis., A single immunization with an adenovirus vector-based vaccine expressing a stabilized SARS-CoV-2 spike protein induces protection against SARS-CoV-2-induced weight loss, pneumonia and mortality in hamsters.
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- 2020
15. Single-Shot Ad26 Vaccine Protects Against SARS-CoV-2 in Rhesus Macaques
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Roland Zahn, Mark J. G. Bakkers, Ralph S. Baric, Laurent Pessaint, Timothy M. Caradonna, Galit Alter, Ted Kwaks, John S. Burke, Mathai Mammen, Jingyou Yu, Johan Van Hoof, Bing Chen, Marinela Kirilova, Alex Van Ry, Joseph P. Nkolola, Lisa H. Tostanoski, Johannes P. M. Langedijk, Shivani A. Patel, Shant H. Mahrokhian, Carolin Loos, Kelvin Blade, Makda S. Gebre, Lauren Peter, Katherine McMahan, Douglas A. Lauffenburger, Caroline Atyeo, Rinke Bos, Felix Nampanya, Zhenfeng Li, John D. Ventura, Noe B. Mercado, David R. Martinez, Renita Brown, Catherine Jacob-Dolan, Esther A. Bondzie, Amanda Strasbaugh, Blake M. Hauser, Huahua Wan, Elyse Teow, Hanne Andersen, Jinyan Liu, Frank Wegmann, Jerome Custers, Mark G. Lewis, Ramya Nityanandam, Anthony L. Cook, Danielle van Manen, Aaron G. Schmidt, Stephanie Fischinger, Mehtap Cabus, Gabriel Dagotto, Lucy Rutten, Lori F. Maxfield, Zijin Lin, Sietske K. Rosendahl Huber, Hanneke Schuitemaker, Paul Stoffels, Abishek Chandrashekar, Dan H. Barouch, Jared Feldman, David Zuijdgeest, Xuan He, Serge Zouantchangadou, Kaylee Verrington, Yongfei Cai, Emily Hoffman, Jort Vellinga, and R. Keith Reeves
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0301 basic medicine ,Male ,COVID-19 Vaccines ,viruses ,Pneumonia, Viral ,Article ,03 medical and health sciences ,Betacoronavirus ,0302 clinical medicine ,Immunity ,Medicine ,Animals ,030212 general & internal medicine ,Vector (molecular biology) ,Neutralizing antibody ,Pandemics ,Immunity, Cellular ,Multidisciplinary ,biology ,business.industry ,SARS-CoV-2 ,Immunogenicity ,Viral Vaccine ,Vaccination ,virus diseases ,COVID-19 ,Viral Vaccines ,Viral Load ,Virology ,Macaca mulatta ,Immunity, Humoral ,Disease Models, Animal ,030104 developmental biology ,Immunization ,biology.protein ,Female ,Antibody ,business ,Coronavirus Infections - Abstract
A safe and effective vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be required to end the coronavirus disease 2019 (COVID-19) pandemic1-8. For global deployment and pandemic control, a vaccine that requires only a single immunization would be optimal. Here we show the immunogenicity and protective efficacy of a single dose of adenovirus serotype 26 (Ad26) vector-based vaccines expressing the SARS-CoV-2 spike (S) protein in non-human primates. Fifty-two rhesus macaques (Macaca mulatta) were immunized with Ad26 vectors that encoded S variants or sham control, and then challenged with SARS-CoV-2 by the intranasal and intratracheal routes9,10. The optimal Ad26 vaccine induced robust neutralizing antibody responses and provided complete or near-complete protection in bronchoalveolar lavage and nasal swabs after SARS-CoV-2 challenge. Titres of vaccine-elicited neutralizing antibodies correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate robust single-shot vaccine protection against SARS-CoV-2 in non-human primates. The optimal Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in clinical trials.
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- 2020
16. Therapeutic efficacy of combined active and passive immunization in ART-suppressed, SHIV-infected rhesus macaques
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Victoria E. K. Walker-Sperling, Noe B. Mercado, Abishek Chandrashekar, Erica N. Borducchi, Jinyan Liu, Joseph P. Nkolola, Mark Lewis, Jeffrey P. Murry, Yunling Yang, Romas Geleziunas, Merlin L. Robb, Nelson L. Michael, Maria G. Pau, Frank Wegmann, Hanneke Schuitemaker, Emily J. Fray, Mithra R. Kumar, Janet D. Siliciano, Robert F. Siliciano, and Dan H. Barouch
- Subjects
Multidisciplinary ,Toll-Like Receptor 7 ,HIV-1 ,Immunization, Passive ,Simian Acquired Immunodeficiency Syndrome ,General Physics and Astronomy ,Animals ,HIV Infections ,Simian Immunodeficiency Virus ,General Chemistry ,Viral Load ,Macaca mulatta ,General Biochemistry, Genetics and Molecular Biology - Abstract
The latent viral reservoir is the critical barrier for developing an HIV-1 cure. Previous studies have shown that therapeutic vaccination or broadly neutralizing antibody (bNAb) administration, together with a Toll-like receptor 7 (TLR7) agonist, enhanced virologic control or delayed viral rebound, respectively, following discontinuation of antiretroviral therapy (ART) in SIV- or SHIV-infected rhesus macaques. Here we show that the combination of active and passive immunization with vesatolimod may lead to higher rates of post-ART virologic control compared to either approach alone. Therapeutic Ad26/MVA vaccination and PGT121 administration together with TLR7 stimulation with vesatolimod resulted in 70% post-ART virologic control in SHIV-SF162P3-infected rhesus macaques. These data suggest the potential of combining active and passive immunization targeting different immunologic mechanisms as an HIV-1 cure strategy.
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- 2021
17. Immunity Elicited by Natural Infection or Ad26.COV2.S Vaccination Protects Hamsters Against SARS-CoV-2 Variants of Concern
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Florian Krammer, Brittany Spence, Roland Zahn, Tochi Anioke, Amanda J. Martinot, David L. Hope, Maciel Porto, Katherine Bauer, Dan H. Barouch, Linda M. Wrijil, Cesar Piedra-Mora, Swagata Kar, Frank Wegmann, Catherine Jacob-Dolan, Esther A. Bondzie, Lisa H. Tostanoski, Shant H. Mahrokhian, Jingyou Yu, Mark G. Lewis, Aiquan Chang, Hanneke Schuitemaker, Hanne Leth Andersen, Laurent Pessaint, Noe B. Mercado, Victoria M. Giffin, Andrew Faudree, Fatima Amanat, Huahua Wan, Katherine McMahan, and Joseph Piegols
- Subjects
2019-20 coronavirus outbreak ,COVID-19 Vaccines ,Coronavirus disease 2019 (COVID-19) ,Ad26COVS1 ,business.industry ,SARS-CoV-2 ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Vaccination ,virus diseases ,COVID-19 ,General Medicine ,Virology ,Article ,Immunity ,Cricetinae ,Medicine ,Animals ,Humans ,business - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern have emerged and may pose a threat to both the efficacy of vaccines based on the original WA1/2020 strain as well as to natural immunity induced by infection with earlier SARS-CoV-2 variants. We sought to explore unanswered questions of how mutations in the spike of circulating SARS-CoV-2 variants, which have been shown to partially evade neutralizing antibodies, impact natural and vaccine-induced immunity. We adapted a Syrian hamster model of moderate to severe clinical disease for two variant strains of SARS-CoV-2: B.1.1.7 (α variant) and B.1.351 (β variant). We then assessed the protective efficacy conferred by either natural immunity from WA1/2020 infection or by vaccination with a single dose of the adenovirus serotype 26 vaccine Ad26.COV2.S. Primary infection with the WA1/2020 strain provided potent protection against weight loss and viral replication in lungs following re-challenge with WA1/2020, B.1.1.7, or B.1.351 14 days later. Ad26.COV2.S induced cross-reactive binding and neutralizing antibodies that were reduced against the B.1.351 strain compared with WA1/2020, but nevertheless still provided robust protection against B.1.351 challenge, as measured by weight loss and pathology scoring in the lungs. Taken together, these data support hamsters as a pre-clinical model to study protection against emerging variants of SARS-CoV-2 conferred by prior infection or vaccination.
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- 2021
18. Protective Efficacy of Gastrointestinal SARS-CoV-2 Delivery against Intranasal and Intratracheal SARS-CoV-2 Challenge in Rhesus Macaques
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Caroline Subra, Natalie D. Collins, Christian Hofer, Jinyan Liu, Elyse Teow, Noe B. Mercado, Victoria M. Giffin, Laurent Pessaint, Hanne Andersen, Erica K. Barkei, Tochi Anioke, Jingyou Yu, Hannah A.D. King, Donald S. Burke, Dan H. Barouch, Anthony L. Cook, Julia Barrett, Kayvon Modjarrad, Diane Bolton, Katherine McMahan, David L. Hope, Jason Velasco, Huahua Wan, Sarah Gardner, Daniel Sellers, Nelson L. Michael, Alex Van Ry, Mark G. Lewis, Felix Nampanya, Abishek Chandrashekar, and Aiquan Chang
- Subjects
Male ,COVID-19 Vaccines ,viruses ,Immunology ,Administration, Oral ,Vaccine Efficacy ,Antibodies, Viral ,Microbiology ,Route of administration ,Oral administration ,Virology ,medicine ,Animals ,Respiratory system ,skin and connective tissue diseases ,Gastrointestinal tract ,biology ,medicine.diagnostic_test ,business.industry ,Immunogenicity ,fungi ,COVID-19 ,respiratory system ,Antibodies, Neutralizing ,Macaca mulatta ,respiratory tract diseases ,Bronchoalveolar lavage ,Viral replication ,Insect Science ,biology.protein ,Nasal administration ,Female ,Antibody ,business ,Viral load - Abstract
Live oral vaccines have been explored for their protective efficacy against respiratory viruses, particularly for adenovirus serotypes 4 and 7. The potential of a live oral vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), however, remains unclear. In this study, we assessed the immunogenicity of live SARS-CoV-2 delivered to the gastrointestinal tract in rhesus macaques and its protective efficacy against intranasal and intratracheal SARS-CoV-2 challenge. Post-pyloric administration of SARS-CoV-2 by esophagogastroduodenoscopy resulted in limited virus replication in the gastrointestinal tract and minimal to no induction of mucosal antibody titers in rectal swabs, nasal swabs, and bronchoalveolar lavage. Low levels of serum neutralizing antibodies were induced and correlated with modestly diminished viral loads in nasal swabs and bronchoalveolar lavage following intranasal and intratracheal SARS-CoV-2 challenge. Overall, our data show that post-pyloric inoculation of live SARS-CoV-2 is weakly immunogenic and confers partial protection against respiratory SARS-CoV-2 challenge in rhesus macaques.ImportanceSARS-CoV-2 remains a global threat, despite the rapid deployment but limited coverage of multiple vaccines. Alternative vaccine strategies that have favorable manufacturing timelines, greater ease of distribution and improved coverage may offer significant public health benefits, especially in resource-limited settings. Live oral vaccines have the potential to address some of these limitations; however no studies have yet been conducted to assess the immunogenicity and protective efficacy of a live oral vaccine against SARS-CoV-2. Here we report that oral administration of live SARS-CoV-2 in non-human primates may offer prophylactic benefits, but that formulation and route of administration will require further optimization.
- Published
- 2021
19. Increased IL-6 expression precedes reliable viral detection in the rhesus macaque brain during acute SIV infection
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Dan H. Barouch, Shaily Malik, C Sabrina Tan, Amanda J. Martinot, Steven E. Bosinger, Malika Aid, Cesar Piedra-Mora, Valerie Varner, Noe B. Mercado, Rhianna Jones, Emma Geiger, Caitlin Davis, R. Keith Reeves, and Raja Mohan Gopalakrishnan
- Subjects
viruses ,animal diseases ,Adaptive immunity ,Simian Acquired Immunodeficiency Syndrome ,Biology ,Virus ,Proinflammatory cytokine ,AIDS/HIV ,Immune system ,Basal ganglia ,medicine ,Animals ,Neuroinflammation ,Microglia ,Interleukin-6 ,Macrophages ,virus diseases ,General Medicine ,Acquired immune system ,Macaca mulatta ,Disease Models, Animal ,Chronic infection ,medicine.anatomical_structure ,Acute Disease ,Immunology ,Cytokines ,Research Article ,Neuroscience - Abstract
Knowledge of immune activation in the brain during acute HIV infection is crucial for the prevention and treatment of HIV-associated neurological disorders. We determined regional brain (basal ganglia, thalamus, and frontal cortex) immune and virological profiles at 7 and 14 days post infection (dpi) with SIVmac239 in rhesus macaques. The basal ganglia and thalamus had detectable viruses earlier (7 dpi) than the frontal cortex (14 dpi) and contained higher quantities of viruses than the latter. Increased immune activation of astrocytes and significant infiltration of macrophages in the thalamus at 14 dpi coincided with elevated plasma viral load, and SIV colocalized only within macrophages. RNA signatures of proinflammatory responses, including IL-6, were detected at 7 dpi in microglia and interestingly, preceded reliable detection of virus in tissues and were maintained in the chronically infected macaques. Countering the proinflammatory response, the antiinflammatory response was not detected until increased TGF-β expression was found in perivascular macrophages at 14 dpi. But this response was not detected in chronic infection. Our data provide evidence that the interplay of acute proinflammatory and antiinflammatory responses in the brain likely contributed to the overt neuroinflammation, where the immune activation preceded reliable viral detection.
- Published
- 2021
20. Defining the determinants of protection against SARS-CoV-2 infection and viral control in a dose-down Ad26.CoV2.S vaccine study in nonhuman primates
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Daniel Y. Zhu, Matthew J. Gorman, Dansu Yuan, Jingyou Yu, Noe B. Mercado, Katherine McMahan, Erica N. Borducchi, Michelle Lifton, Jinyan Liu, Felix Nampanya, Shivani Patel, Lauren Peter, Lisa H. Tostanoski, Laurent Pessaint, Alex Van Ry, Brad Finneyfrock, Jason Velasco, Elyse Teow, Renita Brown, Anthony Cook, Hanne Andersen, Mark G. Lewis, Douglas A. Lauffenburger, Dan H. Barouch, and Galit Alter
- Subjects
Primates ,COVID-19 Vaccines ,General Immunology and Microbiology ,Ad26COVS1 ,SARS-CoV-2 ,General Neuroscience ,COVID-19 ,Receptors, Fc ,Antibodies, Viral ,Antibodies, Neutralizing ,General Biochemistry, Genetics and Molecular Biology ,Spike Glycoprotein, Coronavirus ,Animals ,Humans ,General Agricultural and Biological Sciences - 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.
- Published
- 2021
21. Prior infection with SARS-CoV-2 WA1/2020 partially protects rhesus macaques against reinfection with B.1.1.7 and B.1.351 variants
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Mark G. Lewis, Laurent Pessaint, Tochi Anioke, Lisa H. Tostanoski, Anthony L. Cook, Aiquan Chang, Daniel Valentin, Dan H. Barouch, Abishek Chandrashekar, Katherine McMahan, Owen Sanborn, Lauren Wattay, Hanne Leth Andersen, Jingyou Yu, Shelby L. O’Connor, Deandre Bueno-Wilkerson, Felix Nampanya, David L. Hope, Noe B. Mercado, Victoria M. Giffin, Huahua Wan, Sarah Gardner, Jinyan Liu, Maria Grazia Ferrari, Catherine Jacob-Dolan, John J. Baczenas, Daniel Sellers, Renita Brown, Benjamin Espina, Amanda J. Martinot, Elyse Teow, and Shivani A. Patel
- Subjects
2019-20 coronavirus outbreak ,biology ,Coronavirus disease 2019 (COVID-19) ,business.industry ,SARS-CoV-2 ,viruses ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,virus diseases ,COVID-19 ,General Medicine ,Evasion (ethics) ,Antibodies, Viral ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,Transmissibility (vibration) ,Reinfection ,biology.protein ,Medicine ,Animals ,Humans ,Antibody ,business ,Re infection - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that result in increased transmissibility and partial evasion of neutralizing antibodies have recently emerged. Whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against rechallenge with these SARS-CoV-2 variants remains a critical unresolved question. In this study, we show that natural immunity induced by the WA1/2020 strain leads to partial but incomplete protection against the SARS-CoV-2 variants B.1.1.7 (alpha) and B.1.351 (beta) in rhesus macaques. We challenged rhesus macaques with B.1.1.7 and B.1.351 and showed that infection with these variants resulted in high viral replication in the upper and lower respiratory tract. We then infected rhesus macaques with the WA1/2020 strain and rechallenged them on day 35 with the WA1/2020, B.1.1.7, or B.1.351 variants. Natural immunity to WA1/2020 led to robust protection against rechallenge with WA1/2020 but only partial protection against rechallenge with B.1.351. An intermediate degree of protection was observed in rhesus macaques against rechallenge with B.1.1.7. These data demonstrate partial but incomplete protective efficacy of natural immunity induced by WA1/2020 against SARS-CoV-2 variants of concern. Our findings have important implications for both vaccination and public health strategies in the context of emerging SARS-CoV-2 variants of concern.
- Published
- 2021
22. A modular protein subunit vaccine candidate produced in yeast confers protection against SARS-CoV-2 in non-human primates
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Sangeeta B. Joshi, Jingyou Yu, Lisa H. Tostanoski, Christopher A Naranjo, Amanda J. Martinot, J. Christopher Love, Sumi Biswas, Jason Velasco, Judith M. Silverman, Harry Kleanthous, Neil C. Dalvie, Elyse Teow, Kawaljit Kaur, Felix Nampanya, Dongsoo Yun, Sergio A. Rodriguez-Aponte, Shivani A. Patel, David B. Volkin, Sakshi Bajoria, Lesley Bowman, Anthony L. Cook, Mark G. Lewis, Aiquan Chang, Dan H. Barouch, Abishek Chandrashekar, Ozan S. Kumru, Danielle L Camp, Zach Flinchbaugh, Renita Brown, Katherine McMahan, Laurent Pessaint, Hanne Leth Andersen, Noe B. Mercado, and Victoria M. Giffin
- Subjects
Protein subunit ,medicine.medical_treatment ,Cold storage ,Biology ,Virology ,Article ,Yeast ,Titer ,Immunity ,biology.protein ,medicine ,Antibody ,Viral load ,Adjuvant - Abstract
Vaccines against SARS-CoV-2 have been distributed at massive scale in developed countries, and have been effective at preventing COVID-19. Access to vaccines is limited, however, in low- and middle-income countries (LMICs) due to insufficient supply, high costs, and cold storage requirements. New vaccines that can be produced in existing manufacturing facilities in LMICs, can be manufactured at low cost, and use widely available, proven, safe adjuvants like alum, would improve global immunity against SARS-CoV-2. One such protein subunit vaccine is produced by the Serum Institute of India Pvt. Ltd. and is currently in clinical testing. Two protein components, the SARS-CoV-2 receptor binding domain (RBD) and hepatitis B surface antigen virus-like particles (VLPs), are each produced in yeast, which would enable a low-cost, high-volume manufacturing process. Here, we describe the design and preclinical testing of the RBD-VLP vaccine in cynomolgus macaques. We observed titers of neutralizing antibodies (>104) above the range of protection for other licensed vaccines in non-human primates. Interestingly, addition of a second adjuvant (CpG1018) appeared to improve the cellular response while reducing the humoral response. We challenged animals with SARS-CoV-2, and observed a ~3.4 and ~2.9 log10reduction in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, compared to sham controls. These results inform the design and formulation of current clinical COVID-19 vaccine candidates like the one described here, and future designs of RBD-based vaccines against variants of SARS-CoV-2 or other betacoronaviruses.
- Published
- 2021
23. Impact of prior Dengue immunity on Zika vaccine protection in rhesus macaques and mice
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John D. Ventura, Abishek Chandrashekar, Peter Abbink, Noe B. Mercado, Rafael De La Barrera, Kenneth H. Eckels, Nelson L. Michael, Erica N. Borducchi, Michael P. Busch, Zhenfeng Li, Dan H. Barouch, Kayvon Modjarrad, and Rafael A. Larocca
- Subjects
RNA viruses ,viruses ,Monkeys ,Antibodies, Viral ,Pathology and Laboratory Medicine ,Dengue fever ,Zika virus ,Mice ,0302 clinical medicine ,Medical Conditions ,Medicine and Health Sciences ,Medicine ,Public and Occupational Health ,Biology (General) ,Mammals ,0303 health sciences ,Vaccines ,Attenuated vaccine ,biology ,Zika Virus Infection ,Viral Vaccine ,Eukaryota ,virus diseases ,Animal Models ,Vaccination and Immunization ,Vaccination ,Infectious Diseases ,Experimental Organism Systems ,Medical Microbiology ,Viral Pathogens ,Viruses ,Vertebrates ,Antibody ,Pathogens ,Macaque ,Research Article ,Primates ,Infectious Disease Control ,QH301-705.5 ,030231 tropical medicine ,Immunology ,Dengue Vaccines ,Mouse Models ,Cross Reactions ,Research and Analysis Methods ,Microbiology ,03 medical and health sciences ,Model Organisms ,Immunity ,Virology ,Old World monkeys ,Genetics ,Animals ,Humans ,Molecular Biology ,Microbial Pathogens ,030304 developmental biology ,Biology and life sciences ,Flaviviruses ,business.industry ,Organisms ,Viral Vaccines ,Zika Virus ,Dengue Virus ,biochemical phenomena, metabolism, and nutrition ,RC581-607 ,medicine.disease ,biology.organism_classification ,Antibodies, Neutralizing ,Macaca mulatta ,Immunization ,Amniotes ,biology.protein ,Animal Studies ,Parasitology ,Preventive Medicine ,Immunologic diseases. Allergy ,business ,Zoology - Abstract
Pre-existing immunity to flaviviruses can influence the outcome of subsequent flavivirus infections. Therefore, it is critical to determine whether baseline DENV immunity may influence subsequent ZIKV infection and the protective efficacy of ZIKV vaccines. In this study, we investigated the impact of pre-existing DENV immunity induced by vaccination on ZIKV infection and the protective efficacy of an inactivated ZIKV vaccine. Rhesus macaques and mice inoculated with a live attenuated DENV vaccine developed neutralizing antibodies (NAbs) to multiple DENV serotypes but no cross-reactive NAbs responses to ZIKV. Animals with baseline DENV NAbs did not exhibit enhanced ZIKV infection and showed no overall reduction in ZIKV vaccine protection. Moreover, passive transfer of purified DENV-specific IgG from convalescent human donors did not augment ZIKV infection in STAT2 -/- and BALB/c mice. In summary, these results suggest that baseline DENV immunity induced by vaccination does not significantly enhance ZIKV infection or impair the protective efficacy of candidate ZIKV vaccines in these models. These data can help inform immunization strategies in regions of the world with multiple circulating pathogenic flaviviruses., Author summary Whether the induction of anti-Dengue immunity by vaccination affects the protective efficacy of Zika virus (ZIKV) vaccines is an important consideration for public health programs aimed at controlling Dengue and Zika transmission. Here, we report the impact of previous anti-Dengue virus (DENV) immunity elicited by both live-attenuated tetravalent (TDENV-LAV) or single-serotype inactivated DENV vaccination on subsequent ZIKV vaccine efficacy in both rhesus macaques and mice. In macaques and mice, prior anti-DENV vaccination did not generate cross-reactive neutralizing antibodies against ZIKV. Previous immunization with TDENV-LAV showed no significant enhancement of ZIKV infection or reduced the protective efficacy of a subsequent immunization with candidate ZIKV vaccines. In addition, ZIKV viral loads were not enhanced following ZIKV challenge of STAT2 -/- mice previously passively transferred with anti-DENV IgG. These results suggest that prior immunization with DENV vaccines have a minimal impact on ZIKV disease enhancement and do not impact the overall protective efficacy of subsequent ZIKV immunization in both macaques and mice.
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- 2021
24. Lack of therapeutic efficacy of an antibody to α 4 β 7 in SIVmac251-infected rhesus macaques
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Edward T. Moseley, Abishek Chandrashekar, Brandon F. Keele, Aaron J. Belli, Keith A. Reimann, Katherine McMahan, Rebecca Peterson, Esther A. Bondzie, Romas Geleziunas, Peter Abbink, Joseph P. Nkolola, Arshi Agarwal, Hubert Tuyishime, Mark G. Lewis, Noe B. Mercado, Dan H. Barouch, and Erica N. Borducchi
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0301 basic medicine ,Viral rebound ,Multidisciplinary ,biology ,business.industry ,Human immunodeficiency virus (HIV) ,Simian immunodeficiency virus ,medicine.disease_cause ,Virology ,Antiretroviral therapy ,Discontinuation ,03 medical and health sciences ,Chronic infection ,030104 developmental biology ,0302 clinical medicine ,030220 oncology & carcinogenesis ,medicine ,biology.protein ,Antibody ,business ,Viral load - Abstract
An antibody is not the antidote An HIV therapeutic that would give long-term remission without sustained antiretroviral therapy (ART) is a long-term goal. Byrareddy et al. [ Science 354 , 197 (2016)] reported that treating simian immunodeficiency virus (SIV)–positive macaques with an antibody against integrin α 4 β 7 during and after ART results in sustained virologic control after stopping all treatment. Three studies in this issue question the reproducibility of that result. Di Mascio et al. sequenced the virus used in the 2016 study and found that it was a variant with a stop codon in the nef gene rather than a wild-type virus. Abbink et al. used the same antibody for α 4 β 7 as before but tested control of a more commonly used pathogenic virus. Iwamato et al. used the same nef -stop virus as in the earlier paper but combined the antibody against the integrin with an antibody against the SIV envelope glycoprotein, which also blocks viral binding of the integrin. None of these three new studies found that treating with the antibody had any effect on virologic control after stopping ART treatment. Science , this issue p. 1025 , p. 1029 , p. 1033
- Published
- 2019
25. Antibody and TLR7 Agonist Delay Viral Rebound in SHIV-Infected Monkeys
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David Jetton, Joseph Hesselgesser, Erica N. Borducchi, Mark G. Lewis, Dan H. Barouch, Galit Alter, Peter Abbink, Edward T. Moseley, Lauren Peter, Elena Bekerman, Jinyan Liu, Joseph P. Nkolola, Noe B. Mercado, Wen-Han Yu, Abishek Chandrashekar, Thomas Broge, Romas Geleziunas, Katherine McMahan, Anthony M. Cadena, Stephanie Fischinger, and Wenjun Li
- Subjects
Male ,0301 basic medicine ,Agonist ,Adoptive cell transfer ,Anti-HIV Agents ,medicine.drug_class ,CD8 Antigens ,viruses ,Simian Acquired Immunodeficiency Syndrome ,HIV Antibodies ,Antibodies, Viral ,Virus ,Article ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Animals ,Humans ,Medicine ,030212 general & internal medicine ,Immunity, Cellular ,Multidisciplinary ,biology ,business.industry ,Pteridines ,TLR7 ,Viral Load ,Adoptive Transfer ,Antibodies, Neutralizing ,Macaca mulatta ,Virology ,Immunity, Innate ,3. Good health ,Discontinuation ,030104 developmental biology ,Toll-Like Receptor 7 ,DNA, Viral ,HIV-1 ,biology.protein ,Female ,Simian Immunodeficiency Virus ,Antibody ,business ,Viral load - Abstract
The latent viral reservoir is the critical barrier for the development of a cure for HIV-1 infection. Previous studies have shown direct antiviral activity of potent HIV-1 Env-specific broadly neutralizing antibodies (bNAbs) administered when antiretroviral therapy (ART) was discontinued, but it remains unclear whether bNAbs can target the viral reservoir during ART. Here we show that administration of the V3 glycan-dependent bNAb PGT121 together with the Toll-like receptor 7 (TLR7) agonist vesatolimod (GS-9620) during ART delayed viral rebound following discontinuation of ART in simian-human immunodeficiency virus (SHIV)-SF162P3-infected rhesus monkeys in which ART was initiated during early acute infection. Moreover, in the subset of monkeys that were treated with both PGT121 and GS-9620 and that did not show viral rebound after discontinuation of ART, adoptive transfer studies and CD8-depletion studies also did not reveal virus. These data demonstrate the potential of bNAb administration together with innate immune stimulation as a possible strategy for targeting the viral reservoir.
- Published
- 2018
26. Comparison of Subgenomic and Total RNA in SARS-CoV-2-Challenged Rhesus Macaques
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Gabriel Dagotto, Yixuan J. Hou, Ralph S. Baric, Joseph P. Nkolola, Robert H. Carnahan, David R. Martinez, Noe B. Mercado, James E. Crowe, and Dan H. Barouch
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RNase P ,medicine.drug_class ,viruses ,Immunology ,Biology ,Monoclonal antibody ,Microbiology ,Virus ,03 medical and health sciences ,0302 clinical medicine ,Virology ,Vaccines and Antiviral Agents ,medicine ,030212 general & internal medicine ,Guide RNA ,030304 developmental biology ,Subgenomic mRNA ,0303 health sciences ,subgenomic RNA ,SARS-CoV-2 ,Nucleoprotein ,viral load ,Reverse transcription polymerase chain reaction ,genomic RNA ,Insect Science ,Respiratory virus ,non-human primates - Abstract
Developing therapeutic and prophylactic countermeasures for the SARS-CoV-2 virus is a public health priority. During challenge studies, respiratory viruses are delivered and sampled from the same anatomical location., Respiratory virus challenge studies involve administration of the challenge virus and sampling to assess for protection in the same anatomical locations. It can therefore be difficult to differentiate actively replicating virus from input challenge virus. For SARS-CoV-2, specific monitoring of actively replicating virus is critical for investigating the protective and therapeutic efficacy of vaccines, monoclonal antibodies, and antiviral drugs. We adapted a SARS-CoV-2 subgenomic RNA (sgRNA) RT-PCR assay to differentiate productive infection from inactivated or neutralized virus. Subgenomic RNAs are generated after cell entry and are poorly incorporated into mature virions, and thus may provide a marker for actively replicating virus. We show envelope (E) sgRNA was degraded by RNase in infected cell lysates, while genomic RNA (gRNA) was protected, presumably due to packaging into virions. To investigate the capacity of the sgRNA assay to distinguish input challenge virus from actively replicating virus in vivo, we compared the E sgRNA assay to a standard nucleoprotein (N) or E total (both gRNA and sgRNA) RNA in convalescent rhesus macaques and in antibody-treated rhesus macaques after experimental SARS-CoV-2 challenge. In both studies, the E sgRNA assay was negative, suggesting protective efficacy, whereas the N and E total RNA assays remained positive. These data suggest the potential utility of sgRNA to monitor actively replicating virus in prophylactic and therapeutic SARS-CoV-2 studies. IMPORTANCE Developing therapeutic and prophylactic countermeasures for the SARS-CoV-2 virus is a public health priority. During challenge studies, respiratory viruses are delivered and sampled from the same anatomical location. It is therefore important to distinguish actively replicating virus from input challenge virus. The most common assay for detecting SARS-CoV-2 virus, reverse transcription PCR (RT-PCR) targeting nucleocapsid total RNA, cannot distinguish neutralized input virus from replicating virus. In this study, we assess SARS-CoV-2 subgenomic RNA as a potential measure of replicating virus in rhesus macaques.
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- 2021
27. SARS-CoV-2 binding and neutralizing antibody levels after Ad26.COV2.S vaccination predict durable protection in rhesus macaques
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Nuria Guimera, Liesbeth Dekking, Sarah Tete, Dominika N. Czapska-Casey, Juan J. Perez-Ruixo, Joan E.M. van der Lubbe, Jan Serroyen, Jenny Hendriks, Roel Straetemans, Daniel J. Stieh, Wouter Koudstaal, Hanneke Schuitemaker, Dan H. Barouch, Roland Zahn, Frank Wegmann, Jingyou Yu, Sietske K. Rosendahl Huber, Mathieu Le Gars, Anna Dari, Jerry Sadoff, Abishek Chandrashekar, Laura Solforosi, Noe B. Mercado, Ramon Roozendaal, Sarah Janssen, and Muriel Boulton
- Subjects
Male ,COVID-19 Vaccines ,Science ,General Physics and Astronomy ,Nose ,Antibodies, Viral ,Virus Replication ,Predictive markers ,General Biochemistry, Genetics and Molecular Biology ,Article ,Immunity ,Medicine ,Animals ,Humans ,Neutralizing antibody ,Lung ,Vaccines ,Multidisciplinary ,biology ,Ad26COVS1 ,business.industry ,SARS-CoV-2 ,Immunogenicity ,Vaccination ,Antibody titer ,COVID-19 ,General Chemistry ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,Immunity, Humoral ,HEK293 Cells ,Logistic Models ,Immunization ,Viral replication ,Viral infection ,Spike Glycoprotein, Coronavirus ,biology.protein ,Female ,Antibody ,business - Abstract
Several COVID-19 vaccines have recently gained authorization for emergency use. Limited knowledge on duration of immunity and efficacy of these vaccines is currently available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short-lived, and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection. In this work, we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike protein in rhesus macaques and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We show that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of Spike-binding and neutralizing antibodies, indicating that Ad26.COV2.S could confer durable protection in humans and immunological correlates of protection may enable the prediction of durability of protection., Several COVID-19 vaccines have received emergency approval, but durability of protection is unclear. Here, the authors describe correlates of protection (CoP) for the Ad26.COV2.S vaccine in rhesus macaques and report that CoP predict the protection observed 6 months post vaccination.
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- 2021
28. Low-dose Ad26.COV2.S protection against SARS-CoV-2 challenge in rhesus macaques
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Leslie van der Fits, Shivani A. Patel, Frank Wegmann, Sietske K. Rosendahl Huber, Katherine McMahan, Marjolein van Heerden, Jingyou Yu, Sarah Ducat, Cesar Piedra-Mora, Elyse Teow, Roland Zahn, Renita Brown, Brad Finneyfrock, Michelle A. Lifton, Laurent Pessaint, Dan H. Barouch, Erica N. Borducchi, Anthony L. Cook, Jason Velasco, Lauren Peter, Abishek Chandrashekar, Hanne Leth Andersen, Felix Nampanya, Noe B. Mercado, Mark G. Lewis, Ronnie Chamanza, Amanda J. Martinot, Xuan He, Lisa H. Tostanoski, Hanneke Schuitemaker, Alex Van Ry, Sidney Beecy, and Jinyan Liu
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Male ,COVID-19 Vaccines ,Biology ,Antibodies, Viral ,General Biochemistry, Genetics and Molecular Biology ,Article ,Adenoviridae ,03 medical and health sciences ,0302 clinical medicine ,Immunogenicity, Vaccine ,medicine ,Animals ,Neutralizing antibody ,030304 developmental biology ,0303 health sciences ,B-Lymphocytes ,medicine.diagnostic_test ,business.industry ,SARS-CoV-2 ,Immunogenicity ,Vaccination ,COVID-19 ,Viral Vaccines ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,Viral Breakthrough ,Titer ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Immunization ,Immunology ,Humoral immunity ,Spike Glycoprotein, Coronavirus ,biology.protein ,Nasal administration ,Female ,business ,Immunologic Memory ,030217 neurology & neurosurgery ,Respiratory tract - Abstract
We previously reported that a single immunization with an adenovirus serotype 26 (Ad26) vector-based vaccine expressing an optimized SARS-CoV-2 spike (Ad26.COV2.S) protected rhesus macaques against SARS-CoV-2 challenge. To evaluate reduced doses of Ad26.COV2.S, 30 rhesus macaques were immunized once with 1x1011, 5x1010, 1.125x1010, or 2x109 vp Ad26.COV2.S or sham and were challenged with SARS-CoV-2. Vaccine doses as low as 2x109 vp provided robust protection in bronchoalveolar lavage, whereas doses of 1.125x1010 vp were required for protection in nasal swabs. Activated memory B cells and binding or neutralizing antibody titers following vaccination correlated with protective efficacy. At suboptimal vaccine doses, viral breakthrough was observed but did not show enhancement of disease. These data demonstrate that a single immunization with relatively low dose of Ad26.COV2.S effectively protected against SARS-CoV-2 challenge in rhesus macaques, although a higher vaccine dose may be required for protection in the upper respiratory tract., Evaluation of a reduced dosage of the single-shot Ad26.COV2.S reveals protection across different tissues protects against SARS-CoV-2 challenge and enhancement of disease. A higher dosage may be needed for protection in the upper respiratory tract.
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- 2021
29. SARS-CoV-2 binding and neutralizing antibody levels after vaccination with Ad26.COV2.S predict durable protection in rhesus macaques
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Sarah Tete, Liesbeth Dekking, Noe B. Mercado, Wouter Koudstaal, Hanneke Schuitemaker, Jan Serroyen, Laura Solforosi, Joan E.M. van der Lubbe, Sietske K. Rosendahl Huber, Dominika N. Czapska-Casey, Frank Wegmann, Jenny Hendriks, Mathieu Le Gars, Daniel J. Stieh, Nuria Guimera, Ramon Roozendaal, Jerry Sadoff, Jingyou Yu, Roland Zahn, Abishek Chandrashekar, Roel Straetemans, Dan H. Barouch, and Sarah Janssen
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biology ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Immunogenicity ,Antibody titer ,Virology ,Vaccination ,Immunization ,Immunity ,biology.protein ,Medicine ,Antibody ,business ,Neutralizing antibody - Abstract
The first COVID-19 vaccines have recently gained authorization for emergency use.1,2 At this moment, limited knowledge on duration of immunity and efficacy of these vaccines is available. Data on other coronaviruses after natural infection suggest that immunity to SARS-CoV-2 might be short lived,3,4 and preliminary evidence indicates waning antibody titers following SARS-CoV-2 infection.5 Here we model the relationship between immunogenicity and protective efficacy of a series of Ad26 vectors encoding stabilized variants of the SARS-CoV-2 Spike (S) protein in rhesus macaques6,7,8 and validate the analyses by challenging macaques 6 months after immunization with the Ad26.COV2.S vaccine candidate that has been selected for clinical development. We find that Ad26.COV2.S confers durable protection against replication of SARS-CoV-2 in the lungs that is predicted by the levels of S-binding and neutralizing antibodies. These results suggest that Ad26.COV2.S could confer durable protection in humans and that immunological correlates of protection may enable the prediction of durability of protection.
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- 2021
30. Publisher Correction: Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques
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Lisa H. Tostanoski, Anthony L. Cook, Lori F. Maxfield, Hanneke Schuitemaker, Joseph P. Nkolola, Marinela Kirilova, Hanne Leth Andersen, John S. Burke, Jerome Custers, Kelvin Blade, Lauren Peter, Mathai Mammen, Ramya Nityanandam, Renita Brown, Frank Wegmann, Bing Chen, Jingyou Yu, Aaron G. Schmidt, Mehtap Cabus, Katherine McMahan, Shant H. Mahrokhian, John D. Ventura, Makda S. Gebre, Noe B. Mercado, Lucy Rutten, Roland Zahn, Jared Feldman, Alex Van Ry, Catherine Jacob-Dolan, Ralph S. Baric, Jinyan Liu, Esther A. Bondzie, Amanda Strasbaugh, Laurent Pessaint, Timothy M. Caradonna, Stephanie Fischinger, Elyse Teow, R. Keith Reeves, Douglas A. Lauffenburger, Mark J. G. Bakkers, Danielle van Manen, Mark G. Lewis, Kaylee Verrington, Rinke Bos, Huahua Wan, Emily Hoffman, Gabriel Dagotto, Caroline Atyeo, Shivani A. Patel, Ted Kwaks, Galit Alter, Blake M. Hauser, Jort Vellinga, Carolin Loos, Johan Van Hoof, Felix Nampanya, Zhenfeng Li, Dan H. Barouch, David Zuijdgeest, Zijin Lin, Johannes P. M. Langedijk, David R. Martinez, Sietske K. Rosendahl Huber, Yongfei Cai, Paul Stoffels, Xuan He, Serge Zouantchangadou, and Abishek Chandrashekar
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2019-20 coronavirus outbreak ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Single shot ,Biology ,Virology - Published
- 2021
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31. Feasibility and safety of ultrasound-guided minimally invasive autopsy in COVID-19 patients
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Kathleen Busman-Sahay, Makda S. Gebre, Olga R. Brook, Jonathan L. Hecht, Kimberly G. Piper, Sarah Ducat, Jacob D. Estes, Dan H. Barouch, Carly E. Starke, Linda M. Wrijil, Noe B. Mercado, and Amanda J. Martinot
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Male ,medicine.medical_specialty ,Percutaneous ,Biopsy ,Urology ,Spleen ,Autopsy ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Interventional Radiology ,Humans ,Medicine ,Radiology, Nuclear Medicine and imaging ,Ultrasonography, Interventional ,Aged ,Aged, 80 and over ,Kidney ,Lung ,medicine.diagnostic_test ,Radiological and Ultrasound Technology ,SARS-CoV-2 ,business.industry ,Gastroenterology ,COVID-19 ,Histology ,Middle Aged ,medicine.anatomical_structure ,Radiology Nuclear Medicine and imaging ,030220 oncology & carcinogenesis ,Feasibility Studies ,Female ,Radiology ,business ,Viral load - Abstract
Objectives To determine the feasibility and safety of ultrasound-guided minimally invasive autopsy in COVID-19 patients. Methods 60 patients who expired between 04/22/2020–05/06/2020 due to COVID-19 were considered for inclusion in the study, based on availability of study staff. Minimally invasive ultrasound-guided autopsy was performed with 14G core biopsies through a 13G coaxial needle. The protocol required 20 cores of the liver, 30 of lung, 12 of spleen, 20 of heart, 20 of kidney, 4 of breast, 4 of testis, 2 of skeletal muscle, and 4 of fat with total of 112 cores per patient. Quality of the samples was evaluated by number, size, histology, immunohistochemistry, and in situ hybridization for COVID-19 and PCR-measured viral loads for SARS-CoV-2. Results Five (5/60, 8%) patients were included. All approached families gave their consent for the minimally invasive autopsy. All organs for biopsy were successfully targeted with ultrasound guidance obtaining all required samples, apart from 2 patients where renal samples were not obtained due to atrophic kidneys. The number, size, and weight of the tissue cores met expectation of the research group and tissue histology quality was excellent. Pathology findings were concordant with previously reported autopsy findings for COVID-19. Highest SARS-CoV-2 viral load was detected in the lung, liver, and spleen that had small to moderate amount, and low viral load in was detected in the heart in 2/5 (40%). No virus was detected in the kidney (0/3, 0%). Conclusions Ultrasound-guided percutaneous post-mortem core biopsies can safely provide adequate tissue. Highest SARS-CoV-2 viral load was seen in the lung, followed by liver and spleen with small amount in the myocardium. Electronic supplementary material The online version of this article (10.1007/s00261-020-02753-7) contains supplementary material, which is available to authorized users.
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- 2020
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32. SARS-CoV-2 infection protects against rechallenge in rhesus macaques
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Makda S. Gebre, John S. Burke, Peter K. Sorger, Mark G. Lewis, Gabriel Dagotto, Caroline Atyeo, Roland Zahn, Brad Finneyfrock, Xuan He, Laurent Pessaint, Jacob D. Estes, Galit Alter, Linda M. Wrijil, Aaron G. Schmidt, David R. Martinez, Margaret Terry, Abishek Chandrashekar, Jingyou Yu, Kathleen Busman-Sahay, Michael Nekorchuk, Lisa H. Tostanoski, Anthony Cook, Renita Brown, Catherine Jacob-Dolan, Michelle A. Lifton, Dan H. Barouch, Esther A. Bondzie, Zoltan Maliga, Noe B. Mercado, Frank Wegmann, Hanne Andersen, Zhenfeng Li, Matthew D. Slein, Sarah Ducat, Alex Van Ry, Kelvin Blade, Jack Greenhouse, Peter Abbink, Shant H. Mahrokhian, Lauren Peter, Lori F. Maxfield, Stephanie Fischinger, Ralph S. Baric, Nicole Kordana, Andrew D. Miller, Amanda J. Martinot, Joseph P. Nkolola, Katherine McMahan, Jason Velasco, Elyse Teow, Tammy Taylor, Jinyan Liu, and Ramya Nityanandam
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Male ,0301 basic medicine ,viruses ,Antibodies, Viral ,Virus Replication ,0302 clinical medicine ,Recurrence ,Lung ,Research Articles ,Immunity, Cellular ,Multidisciplinary ,biology ,medicine.diagnostic_test ,Viral Load ,Rhesus macaque ,030220 oncology & carcinogenesis ,Viral pneumonia ,Spike Glycoprotein, Coronavirus ,Female ,Antibody ,Coronavirus Infections ,Bronchoalveolar Lavage Fluid ,Viral load ,Research Article ,Pneumonia, Viral ,Immunology ,Betacoronavirus ,03 medical and health sciences ,Immune system ,Immunity ,Virology ,medicine ,Animals ,Pandemics ,SARS-CoV-2 ,business.industry ,R-Articles ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,biology.organism_classification ,Antibodies, Neutralizing ,Macaca mulatta ,Immunity, Humoral ,respiratory tract diseases ,Disease Models, Animal ,Nasal Mucosa ,Pneumonia ,030104 developmental biology ,Bronchoalveolar lavage ,biology.protein ,Lung Diseases, Interstitial ,business ,Immunologic Memory - Abstract
An understanding of protective immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for vaccine and public health strategies aimed at ending the global coronavirus disease 2019 (COVID-19) pandemic. A key unanswered question is whether infection with SARS-CoV-2 results in protective immunity against reexposure. We developed a rhesus macaque model of SARS-CoV-2 infection and observed that macaques had high viral loads in the upper and lower respiratory tract, humoral and cellular immune responses, and pathologic evidence of viral pneumonia. After the initial viral clearance, animals were rechallenged with SARS-CoV-2 and showed 5 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa compared with after the primary infection. Anamnestic immune responses after rechallenge suggested that protection was mediated by immunologic control. These data show that SARS-CoV-2 infection induced protective immunity against reexposure in nonhuman primates.
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- 2020
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33. DNA vaccine protection against SARS-CoV-2 in rhesus macaques
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Mark G. Lewis, Gabriel Dagotto, Frank Wegmann, Joseph P. Nkolola, Yuezhou Chen, Marinela Kirilova, Yongfei Cai, Jason Velasco, Catherine Jacob-Dolan, Shant H. Mahrokhian, John D. Ventura, Nicole Kordana, Esther A. Bondzie, Lisa H. Tostanoski, Felipe J.N. Lelis, Lauren Peter, Roland Zahn, Lori F. Maxfield, Elyse Teow, Makda S. Gebre, Laurent Pessaint, Jinyan Liu, Matthew D. Slein, Adam Zuiani, Ralph S. Baric, David R. Martinez, Bing Chen, John S. Burke, Alan Dodson, Duane R. Wesemann, Jingyou Yu, Xuan He, Brad Finneyfrock, Renita Brown, Alex Van Ry, Dan H. Barouch, Galit Alter, Katherine McMahan, Caroline Atyeo, Anthony Cook, Huahua Wan, Stephanie Fischinger, Aaron G. Schmidt, Kelvin Blade, Meghan Travers, Carolin Loos, Felix Nampanya, Zhenfeng Li, Ramya Nityanandam, Abishek Chandrashekar, Shaghayegh Habibi, Noe B. Mercado, Hanne Andersen, and Zijin Lin
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Male ,viruses ,Antibodies, Viral ,Immunogenicity, Vaccine ,Vaccines, DNA ,Medicine ,Neutralizing antibody ,Research Articles ,Immunity, Cellular ,Multidisciplinary ,biology ,Immunogenicity ,Viral Vaccine ,Vaccination ,Microbio ,Viral Load ,Spike Glycoprotein, Coronavirus ,Female ,Antibody ,Coronavirus Infections ,Viral load ,Bronchoalveolar Lavage Fluid ,Research Article ,COVID-19 Vaccines ,Pneumonia, Viral ,Immunology ,Immunization, Secondary ,DNA vaccination ,Betacoronavirus ,Adjuvants, Immunologic ,Protein Domains ,Immunity ,Animals ,Humans ,Pandemics ,business.industry ,SARS-CoV-2 ,R-Articles ,COVID-19 ,Viral Vaccines ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,Immunity, Humoral ,Disease Models, Animal ,Nasal Mucosa ,biology.protein ,Mutant Proteins ,business ,Immunologic Memory - Abstract
The global coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made the development of a vaccine a top biomedical priority. In this study, we developed a series of DNA vaccine candidates expressing different forms of the SARS-CoV-2 spike (S) protein and evaluated them in 35 rhesus macaques. Vaccinated animals developed humoral and cellular immune responses, including neutralizing antibody titers at levels comparable to those found in convalescent humans and macaques infected with SARS-CoV-2. After vaccination, all animals were challenged with SARS-CoV-2, and the vaccine encoding the full-length S protein resulted in >3.1 and >3.7 log10 reductions in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, as compared with viral loads in sham controls. Vaccine-elicited neutralizing antibody titers correlated with protective efficacy, suggesting an immune correlate of protection. These data demonstrate vaccine protection against SARS-CoV-2 in nonhuman primates.
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- 2020
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34. Differential Outcomes following Optimization of Simian-Human Immunodeficiency Viruses from Clades AE, B, and C
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George M. Shaw, Esther A. Bondzie, Shant H. Mahrokhian, Zhenfeng Li, Nicole Kordana, Siddhant Gupte, Dan H. Barouch, Noe B. Mercado, Abishek Chandrashekar, Michael S. Seaman, Po-Ting Liu, Hui Li, Venous Hamza, Erica N. Borducchi, Christy L. Lavine, Lawrence J. Tartaglia, Peter Abbink, Sebastien Trott, and Kevin Clyde Pastores
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CD4-Positive T-Lymphocytes ,Male ,Env ,animal diseases ,viruses ,Immunology ,Human immunodeficiency virus (HIV) ,Simian Acquired Immunodeficiency Syndrome ,HIV Infections ,Simian ,medicine.disease_cause ,Virus Replication ,Microbiology ,Virus ,stomatognathic system ,Virology ,medicine ,Animals ,Humans ,Clade ,Infectivity ,biology ,Wild type ,virus diseases ,Gene Products, env ,Simian immunodeficiency virus ,Viral Load ,biology.organism_classification ,Antibodies, Neutralizing ,Macaca mulatta ,SHIV ,Insect Science ,Mutation ,HIV-1 ,Pathogenesis and Immunity ,Female ,Simian Immunodeficiency Virus ,Viral load ,Sequence Analysis ,optimization - Abstract
We sought to enhance the infectivity of three SHIV stocks by optimization of a key residue in human immunodeficiency virus type 1 (HIV-1) Env (Env375). We developed the following three new simian-human immunodeficiency virus (SHIV) stocks: SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH. SHIV-SF162p3S could not be optimized, SHIV-AE16W proved comparable to the parental virus, and SHIV-325cH demonstrated markedly enhanced replicative capacity compared with the parental virus., Simian-human immunodeficiency virus (SHIV) infection of rhesus monkeys is an important preclinical model for human immunodeficiency virus type 1 (HIV-1) vaccines, therapeutics, and cure strategies. SHIVs have been optimized by incorporating HIV-1 Env residue 375 mutations that mimic the bulky or hydrophobic residues typically found in simian immunodeficiency virus (SIV) Env to improve rhesus CD4 binding. We applied this strategy to three SHIV challenge stocks (SHIV-SF162p3, SHIV-AE16, and SHIV-325c) and observed three distinct outcomes. We constructed six Env375 variants (M, H, W, Y, F, and S) for each SHIV, and we performed a pool competition study in rhesus monkeys to define the optimal variant for each SHIV prior to generating large-scale challenge stocks. We identified SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH as the optimal variants. SHIV-SF162p3S could not be improved, as it already contained the optimal Env375 residue. SHIV-AE16W exhibited a similar replicative capacity to the parental SHIV-AE16 stock. In contrast, SHIV-325cH demonstrated a 2.6-log higher peak and 1.6-log higher setpoint viral loads than the parental SHIV-325c stock. These data demonstrate the diversity of potential outcomes following Env375 modification in SHIVs. Moreover, the clade C SHIV-325cH challenge stock may prove useful for evaluating prophylactic or therapeutic interventions against clade C HIV-1. IMPORTANCE We sought to enhance the infectivity of three SHIV stocks by optimization of a key residue in human immunodeficiency virus type 1 (HIV-1) Env (Env375). We developed the following three new simian-human immunodeficiency virus (SHIV) stocks: SHIV-SF162p3S/wild type, SHIV-AE16W, and SHIV-325cH. SHIV-SF162p3S could not be optimized, SHIV-AE16W proved comparable to the parental virus, and SHIV-325cH demonstrated markedly enhanced replicative capacity compared with the parental virus.
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- 2019
35. Potently neutralizing and protective human antibodies against SARS-CoV-2
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Taylor Jones, Pavlo Gilchuk, Benjamin K. Mueller, Rachel S. Nargi, Rita E. Chen, Yueh-Ming Loo, Natasha M. Kafai, Broc T. McCune, Larissa B. Thackray, Joseph P. Nkolola, Alexandra Schäfer, Rachel E. Sutton, James Brett Case, Michael S. Diamond, Luke Myers, Andrew Trivette, Elad Binshtein, Emma S. Winkler, Nicole L. Kallewaard, Samuel Day, Swathi Shrihari, Jens Meiler, Shamus P. Keeler, Kuishu Ren, Noe B. Mercado, Lauren E. Williamson, Seth J. Zost, Abishek Chandrashekar, Dan H. Barouch, Robert H. Carnahan, David R. Martinez, Ralph S. Baric, James E. Crowe, Elaine C. Chen, Joseph X. Reidy, Naveenchandra Suryadevara, James J. Steinhardt, Ahmed O. Hassan, Julie M. Fox, Michael J. Holtzman, and Lisa E. Gralinski
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0301 basic medicine ,Male ,medicine.drug_class ,Pneumonia, Viral ,Inflammation ,Biology ,Cross Reactions ,Peptidyl-Dipeptidase A ,Monoclonal antibody ,Antibodies, Viral ,Severe Acute Respiratory Syndrome ,Binding, Competitive ,Virus ,Epitope ,Article ,Cell Line ,03 medical and health sciences ,Betacoronavirus ,Mice ,0302 clinical medicine ,Neutralization Tests ,medicine ,Animals ,Humans ,Pandemics ,Multidisciplinary ,SARS-CoV-2 ,Antibodies, Monoclonal ,COVID-19 ,Middle Aged ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,Disease Models, Animal ,030104 developmental biology ,Severe acute respiratory syndrome-related coronavirus ,Cell culture ,Humoral immunity ,Spike Glycoprotein, Coronavirus ,biology.protein ,Epitopes, B-Lymphocyte ,Female ,Pre-Exposure Prophylaxis ,Angiotensin-Converting Enzyme 2 ,Antibody ,medicine.symptom ,Coronavirus Infections ,Viral load ,030217 neurology & neurosurgery - Abstract
The ongoing pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major threat to global health1 and the medical countermeasures available so far are limited2,3. Moreover, we currently lack a thorough understanding of the mechanisms of humoral immunity to SARS-CoV-24. Here we analyse a large panel of human monoclonal antibodies that target the spike (S) glycoprotein5, and identify several that exhibit potent neutralizing activity and fully block the receptor-binding domain of the S protein (SRBD) from interacting with human angiotensin-converting enzyme 2 (ACE2). Using competition-binding, structural and functional studies, we show that the monoclonal antibodies can be clustered into classes that recognize distinct epitopes on the SRBD, as well as distinct conformational states of the S trimer. Two potently neutralizing monoclonal antibodies, COV2-2196 and COV2-2130, which recognize non-overlapping sites, bound simultaneously to the S protein and neutralized wild-type SARS-CoV-2 virus in a synergistic manner. In two mouse models of SARS-CoV-2 infection, passive transfer of COV2-2196, COV2-2130 or a combination of both of these antibodies protected mice from weight loss and reduced the viral burden and levels of inflammation in the lungs. In addition, passive transfer of either of two of the most potent ACE2-blocking monoclonal antibodies (COV2-2196 or COV2-2381) as monotherapy protected rhesus macaques from SARS-CoV-2 infection. These results identify protective epitopes on the SRBD and provide a structure-based framework for rational vaccine design and the selection of robust immunotherapeutic agents. An analysis identifies human monoclonal antibodies that potently neutralize wild-type SARS-CoV-2 and protect animals from disease, including two that synergize in a cocktail, suggesting that these could be candidates for use as therapeutic agents for the treatment of COVID-19 in humans.
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- 2019
36. Lack of therapeutic efficacy of an antibody to α
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Peter, Abbink, Noe B, Mercado, Joseph P, Nkolola, Rebecca L, Peterson, Hubert, Tuyishime, Katherine, McMahan, Edward T, Moseley, Erica N, Borducchi, Abishek, Chandrashekar, Esther A, Bondzie, Arshi, Agarwal, Aaron J, Belli, Keith A, Reimann, Brandon F, Keele, Romas, Geleziunas, Mark G, Lewis, and Dan H, Barouch
- Subjects
Integrin beta Chains ,viruses ,Integrin alpha4 ,Simian Acquired Immunodeficiency Syndrome ,Antibodies, Monoclonal ,HIV Infections ,Viral Load ,Antibodies, Viral ,Macaca mulatta ,Article ,Anti-Retroviral Agents ,DNA, Viral ,Codon, Terminator ,Animals ,Simian Immunodeficiency Virus ,Viral Regulatory and Accessory Proteins - Abstract
Sustained virologic control of human immunodeficiency virus type 1 (HIV-1) infection following discontinuation of antiretroviral therapy (ART) is a major goal of the HIV-1 cure field. A recent study reported that anti-α(4)β(7) antibody administration induced durable virologic control following ART discontinuation in 100% of rhesus macaques infected with an attenuated strain of simian immunodeficiency virus (SIV) containing a stop codon in nef. We performed similar studies in 50 rhesus macaques infected with wildtype, pathogenic SIVmac251. In animals that initiated ART during either acute or chronic infection, anti-α(4)β(7) antibody infusion had no detectable effect on the viral reservoir or viral rebound following ART discontinuation. These data demonstrate that anti-α(4)β(7) antibody administration did not provide therapeutic efficacy in the model of pathogenic SIVmac251 infection of rhesus macaques.
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- 2019
37. Passive Transfer of Vaccine-Elicited Antibodies Protects against SIV in Rhesus Macaques
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Thomas Broge, Khader Ghneim, Douglas A. Lauffenburger, Lars Hangartner, Wenjun Li, Rafick-Pierre Sekaly, Galit Alter, Caitlyn Linde, Joseph P. Nkolola, Esther A. Bondzie, Katherine R. McKenney, Michael S. Seaman, Todd J. Suscovich, Wen-Han Yu, Venous Hamza, Katherine McMahan, Erica N. Borducchi, Tom Linnekin, Shant H. Mahrokhian, Nicole Kordana, Noe B. Mercado, Abishek Chandrashekar, Rebecca Nedellec, Ashish Sharma, Peter Abbink, Lauren Peter, Dan H. Barouch, Mark G. Lewis, and Massachusetts Institute of Technology. Department of Biological Engineering
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Adoptive cell transfer ,viruses ,Simian Acquired Immunodeficiency Syndrome ,Gene Products, gag ,Gene Products, pol ,Antibodies, Viral ,Article ,General Biochemistry, Genetics and Molecular Biology ,Immunoglobulin G ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Interferon ,medicine ,Animals ,SIV Vaccine ,030304 developmental biology ,AIDS Vaccines ,Antibody-dependent cell-mediated cytotoxicity ,0303 health sciences ,biology ,Immunization, Passive ,SAIDS Vaccines ,Gene Products, env ,virus diseases ,Antibodies, Neutralizing ,Macaca mulatta ,Virology ,Polyclonal antibodies ,Antibody Formation ,HIV-1 ,biology.protein ,Simian Immunodeficiency Virus ,Antibody ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Several HIV-1 and SIV vaccine candidates have shown partial protection against viral challenges in rhesus macaques. However, the protective efficacy of vaccine-elicited polyclonal antibodies has not previously been demonstrated in adoptive transfer studies in nonhuman primates. In this study, we show that passive transfer of purified antibodies from vaccinated macaques can protect naive animals against SIVmac251 challenges. We vaccinated 30 rhesus macaques with Ad26-SIV Env/Gag/Pol and SIV Env gp140 protein vaccines and assessed the induction of antibody responses and a putative protective signature. This signature included multiple antibody functions and correlated with upregulation of interferon pathways in vaccinated animals. Adoptive transfer of purified immunoglobulin G (IgG) from the vaccinated animals with the most robust protective signatures provided partial protection against SIVmac251 challenges in naive recipient rhesus macaques. These data demonstrate the protective efficacy of purified vaccine-elicited antiviral antibodies in this model, even in the absence of virus neutralization., National Institutes of Health (Grants AI060354, AI080289, AI102660, AI124377, AI126603, AI128751, AI129797, OD024917)
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- 2020
38. Vaccine protection against Zika virus from Brazil
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David Jetton, Christine A. Bricault, Ramya Nityanandam, Jean Pierre Schatzmann Peron, Marinela Kirilova, Zhenfeng Li, Paolo Marinho de Andrade Zanotto, Noe B. Mercado, Michael R. Boyd, George H. Neubauer, Peter Abbink, Rafael De La Barrera, Dan H. Barouch, Alexander Badamchi-Zadeh, Kenneth H. Eckels, Joseph P. Nkolola, David Ng’ang’a, Patricia B. Giglio, M. Justin Iampietro, Stephen J. Thomas, Lori F. Maxfield, Richard G. Jarman, Nelson L. Michael, Rafael A. Larocca, Erica N. Borducchi, and Edward T. Moseley
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CD4-Positive T-Lymphocytes ,0301 basic medicine ,viruses ,CD8-Positive T-Lymphocytes ,Antibodies, Viral ,Article ,Virus ,Zika virus ,DNA vaccination ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Viral Envelope Proteins ,Antibody Specificity ,Vaccines, DNA ,Animals ,Humans ,030212 general & internal medicine ,Multidisciplinary ,biology ,Zika Virus Infection ,Viral Vaccine ,Antibody titer ,Viral Vaccines ,Zika Virus ,biology.organism_classification ,Adoptive Transfer ,Antibodies, Neutralizing ,Virology ,3. Good health ,Flavivirus ,030104 developmental biology ,Vaccines, Inactivated ,Immunization ,Immunoglobulin G ,Vaccines, Subunit ,Immunology ,Microcephaly ,biology.protein ,Female ,Antibody ,Brazil ,Gene Deletion - Abstract
Zika virus (ZIKV) is a flavivirus that is responsible for an unprecedented current epidemic in Brazil and the Americas1,2. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans3–8 and mice9–11. The rapid development of a safe and effective ZIKV vaccine is a global health priority1,2, but very little is currently known about ZIKV immunology and mechanisms of immune protection. Here we show that a single immunization of a plasmid DNA vaccine or a purified inactivated virus vaccine provides complete protection in susceptible mice against challenge with a ZIKV outbreak strain from northeast Brazil. This ZIKV strain has recently been shown to cross the placenta and to induce fetal microcephaly and other congenital malformations in mice11. We produced DNA vaccines expressing full-length ZIKV pre-membrane and envelope (prM-Env) as well as a series of deletion mutants. The full-length prM-Env DNA vaccine, but not the deletion mutants, afforded complete protection against ZIKV as measured by absence of detectable viremia following challenge, and protective efficacy correlated with Env-specific antibody titers. Adoptive transfer of purified IgG from vaccinated mice conferred passive protection, and CD4 and CD8 T lymphocyte depletion in vaccinated mice did not abrogate protective efficacy. These data demonstrate that protection against ZIKV challenge can be achieved by single-shot subunit and inactivated virus vaccines in mice and that Env-specific antibody titers represent key immunologic correlates of protection. Our findings suggest that the development of a ZIKV vaccine for humans will likely be readily achievable.
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- 2016
39. Therapeutic Efficacy of Vectored PGT121 Gene Delivery in HIV-1-Infected Humanized Mice
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Michael R. Boyd, Marinela Kirilova, Vladimir Vrbanac, Peter Abbink, Dan H. Barouch, Po-Ting Liu, Christine A. Bricault, Lawrence J. Tartaglia, Noe B. Mercado, Andrew M. Tager, Ovini Nanayakkara, Rafael A. Larocca, Alexander Badamchi-Zadeh, and Michael S. Seaman
- Subjects
0301 basic medicine ,viruses ,Genetic Vectors ,Immunology ,HIV Infections ,adeno-associated virus ,Gene delivery ,Biology ,medicine.disease_cause ,Microbiology ,Virus ,Adenoviridae ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transduction, Genetic ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,neutralizing antibodies ,Vector (molecular biology) ,Adeno-associated virus ,Mice, Knockout ,Mice, Inbred BALB C ,Genetic Therapy ,3. Good health ,030104 developmental biology ,adenoviruses ,030220 oncology & carcinogenesis ,Insect Science ,PGT121 ,HIV-1 ,biology.protein ,Female ,Antibody ,Viral load ,Antiantibody - Abstract
Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies. However, administration of purified bNAbs poses challenges in resource-poor settings, where the HIV-1 disease burden is greatest. In vivo vector-based production of bNAbs represents an alternative strategy. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121 in wild-type and immunocompromised C57BL/6 mice as well as in HIV-1-infected bone marrow-liver-thymus (BLT) humanized mice. Ad5.PGT121 and AAV1.PGT121 produced functional antibody in vivo . Ad5.PGT121 produced PGT121 rapidly within 6 h, whereas AAV1.PGT121 produced detectable PGT121 in serum by 72 h. Serum PGT121 levels were rapidly reduced by the generation of anti-PGT121 antibodies in immunocompetent mice but were durably maintained in immunocompromised mice. In HIV-1-infected BLT humanized mice, Ad5.PGT121 resulted in a greater reduction of viral loads than did AAV1.PGT121. Ad5.PGT121 also led to more-sustained virologic control than purified PGT121 IgG. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice. Further evaluation of vector delivery of HIV-1 bNAbs is warranted, although approaches to prevent the generation of antiantibody responses may also be required. IMPORTANCE Broadly neutralizing antibodies (bNAbs) are being explored for HIV-1 prevention and cure strategies, but delivery of purified antibodies may prove challenging. We investigated adenovirus serotype 5 (Ad5) and adeno-associated virus serotype 1 (AAV1) vectors to deliver the HIV-1-specific bNAb PGT121. Ad5.PGT121 afforded more rapid, robust, and durable antiviral efficacy than AAV1.PGT121 and purified PGT121 IgG in HIV-1-infected humanized mice.
- Published
- 2018
40. Rapid Cloning of Novel Rhesus Adenoviral Vaccine Vectors
- Author
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Ramya Nityanandam, Eryn Blass, Lawrence J. Tartaglia, Marinela Kirilova, Guoyan Zhao, Erica N. Borducchi, Herbert W. Virgin, David Jetton, Michael R. Boyd, Alexander Badamchi-Zadeh, Dan H. Barouch, Peter Abbink, Menzo J. E. Havenga, Rebecca Peterson, Lori F. Maxfield, Noe B. Mercado, Scott A. Handley, Zhenfeng Li, Malika Aid, Tinaye Mutetwa, Ovini Nanayakkara, and Rafael A. Larocca
- Subjects
0301 basic medicine ,viruses ,030106 microbiology ,Immunology ,Genetic Vectors ,Chimpanzee adenovirus ,rhesus monkey ,Biology ,Microbiology ,Adenoviridae ,03 medical and health sciences ,Mice ,Immunogenicity, Vaccine ,Immunity ,Adenovirus Vaccines ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,Humans ,Vector (molecular biology) ,Cloning, Molecular ,Cloning ,live vector vaccines ,vaccines ,Macaca mulatta ,3. Good health ,Adenovirus vaccine ,Restriction enzyme ,Titer ,030104 developmental biology ,A549 Cells ,adenoviruses ,Insect Science ,biology.protein ,Antibody ,medicine.drug - Abstract
Human and chimpanzee adenovirus vectors are being developed to circumvent preexisting antibodies against common adenovirus vectors such as Ad5. However, baseline immunity to these vectors still exists in human populations. Traditional cloning of new adenovirus vaccine vectors is a long and cumbersome process that takes 2 months or more and that requires rare unique restriction enzyme sites. Here we describe a novel, restriction enzyme-independent method for rapid cloning of new adenovirus vaccine vectors that reduces the total cloning procedure to 1 week. We developed 14 novel adenovirus vectors from rhesus monkeys that can be grown to high titers and that are immunogenic in mice. All vectors grouped with the unusual adenovirus species G and show extremely low seroprevalence in humans. Rapid cloning of novel adenovirus vectors is a promising approach for the development of new vector platforms. Rhesus adenovirus vectors may prove useful for clinical development. IMPORTANCE To overcome baseline immunity to human and chimpanzee adenovirus vectors, we developed 14 novel adenovirus vectors from rhesus monkeys. These vectors are immunogenic in mice and show extremely low seroprevalence in humans. Rhesus adenovirus vectors may prove useful for clinical development.
- Published
- 2017
41. Protection against a mixed SHIV challenge by a broadly neutralizing antibody cocktail
- Author
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Jake A. LeSuer, Noe B. Mercado, Stephen D. Schmidt, John R. Mascola, Dan H. Barouch, James B. Whitney, Megha Kamath, Peter Abbink, Bette T. Korber, Katherine McMahan, Kshitij Wagh, Lawrence J. Tartaglia, Michael S. Seaman, Joseph P. Nkolola, Boris Julg, Po-Ting Liu, Will Fischer, Erica N. Borducchi, Dennis R. Burton, and Shreeya Khatiwada
- Subjects
0301 basic medicine ,Broadly neutralizing antibody ,Simian Acquired Immunodeficiency Syndrome ,Biology ,Epitope ,Article ,03 medical and health sciences ,Epitopes ,Inhibitory Concentration 50 ,Viral sequence ,Inhibitory concentration 50 ,Animals ,Base sequence ,Amino Acid Sequence ,Sequence variation ,Base Sequence ,Gene Products, env ,General Medicine ,Virology ,Antibodies, Neutralizing ,Macaca mulatta ,030104 developmental biology ,Immunology ,biology.protein ,HIV-1 ,Simian Immunodeficiency Virus ,Antibody - Abstract
HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in the majority of HIV-1 infected individuals and can lead to viral escape following bNAb monotherapy in humans. In this study, we show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of pre-existing viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in SHIV-SF162P3-infected rhesus monkeys. We then show that the V3 glycan-dependent antibody PGT121 alone and the V2 glycan-dependent antibody PGDM1400 alone both fail to protect against a mixed challenge with SHIV-SF162P3 and SHIV-325C. In contrast, the combination of both bNAbs provides 100% protection against this mixed SHIV challenge. These data reveal that single bNAbs efficiently select resistant viruses from a diverse challenge swarm to establish infection, demonstrating the importance of bNAb cocktails for HIV-1 prevention.
- Published
- 2017
42. Durability and correlates of vaccine protection against Zika virus in rhesus monkeys
- Author
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Richard G. Jarman, Kittipos Visitsunthorn, Michael R. Boyd, Ramya Nityanandam, Priya Gandhi, Shreeya Khatiwada, Ovini Nanayakkara, Marinela Kirilova, Nelson L. Michael, Kayvon Modjarrad, Rafael A. Larocca, Abishek Chandrashekar, Zhenfeng Li, Kenneth H. Eckels, Peter Abbink, Rafael De La Barrera, Mark G. Lewis, Stephen J. Thomas, David Jetton, Gregory D. Gromowski, Noe B. Mercado, Shanell Mojta, Erica N. Borducchi, Jake A. LeSuer, Dan H. Barouch, and Rebecca Peterson
- Subjects
0301 basic medicine ,DNA vaccination ,Viral vector ,Zika virus ,03 medical and health sciences ,0302 clinical medicine ,Immunity ,Medicine ,Animals ,030212 general & internal medicine ,Neutralizing antibody ,Antigens, Viral ,Mice, Inbred BALB C ,biology ,business.industry ,Zika Virus Infection ,Vaccination ,Viral Vaccines ,General Medicine ,Zika Virus ,biology.organism_classification ,Virology ,Macaca mulatta ,Titer ,030104 developmental biology ,Immunization ,DNA, Viral ,biology.protein ,Female ,business - Abstract
An effective Zika virus (ZIKV) vaccine will require long-term durable protection. Several ZIKV vaccine candidates have demonstrated protective efficacy in nonhuman primates, but these studies have typically involved ZIKV challenge shortly after vaccination at peak immunity. We show that a single immunization with an adenovirus vector–based vaccine, as well as two immunizations with a purified inactivated virus vaccine, afforded robust protection against ZIKV challenge in rhesus monkeys at 1 year after vaccination. In contrast, two immunizations with an optimized DNA vaccine, which provided complete protection at peak immunity, resulted in reduced protective efficacy at 1 year that was associated with declining neutralizing antibody titers to subprotective levels. These data define a microneutralization log titer of 2.0 to 2.1 as the threshold required for durable protection against ZIKV challenge in this model. Moreover, our findings demonstrate that protection against ZIKV challenge in rhesus monkeys is possible for at least 1 year with a single-shot vaccine.
- Published
- 2017
43. Publisher Correction: Antibody and TLR7 agonist delay viral rebound in SHIV-infected monkeys
- Author
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Stephanie Fischinger, David Jetton, Dan H. Barouch, Mark G. Lewis, Katherine McMahan, Jinyan Liu, Galit Alter, Noe B. Mercado, Joseph P. Nkolola, Romas Geleziunas, Wenjun Li, Wen-Han Yu, Edward T. Moseley, Joseph Hesselgesser, Anthony M. Cadena, Erica N. Borducchi, Abishek Chandrashekar, Thomas Broge, Elena Bekerman, Peter Abbink, and Lauren Peter
- Subjects
0301 basic medicine ,Viral rebound ,Agonist ,03 medical and health sciences ,030104 developmental biology ,Multidisciplinary ,biology ,medicine.drug_class ,biology.protein ,medicine ,TLR7 ,Antibody ,Virology - Abstract
In Fig. 4b of this Article, the x-axis labels ‘PGT121’ and ‘GS-9620’ were inadvertently swapped in both graphs. In Fig. 5a, b, ‘TLR7’ should have been ‘GS-9620’. These figures have been corrected online.
- Published
- 2018
44. Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys
- Author
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George H. Neubauer, Dan H. Barouch, Michael R. Boyd, Peter Abbink, Rafael De La Barrera, Mark G. Lewis, Jessica Jimenez, Richard G. Jarman, Christine A. Bricault, David Jetton, Noe B. Mercado, Edward T. Moseley, Jean Pierre Schatzmann Peron, Stephen J. Thomas, Nelson L. Michael, Arshi Agarwal, Crystal Cabral, Mayuri Shetty, Amanda L. Brinkman, Galit Alter, Brad Finneyfrock, Marinela Kirilova, Ramya Nityanandam, Shanell Mojta, Erica N. Borducchi, Kayvon Modjarrad, Rafael A. Larocca, Zhenfeng Li, Katherine Molloy, Benjamin C. Lee, Paolo Marinho de Andrade Zanotto, Abishek Chandrashekar, Patricia B. Giglio, Kathryn E. Stephenson, Ovini Nanayakkara, Johnathan Misamore, David Ng’ang’a, and Kenneth H. Eckels
- Subjects
0301 basic medicine ,Male ,Adoptive cell transfer ,Genetic Vectors ,Immunoglobulins ,medicine.disease_cause ,Antibodies, Viral ,Zika virus ,Adenoviridae ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immunogenicity, Vaccine ,Plasmid dna ,Viral Envelope Proteins ,medicine ,Vaccines, DNA ,Animals ,Humans ,030212 general & internal medicine ,Mice, Inbred BALB C ,Multidisciplinary ,Fetal microcephaly ,biology ,Zika Virus Infection ,Immunogenicity ,Puerto Rico ,Viral Vaccines ,Zika Virus ,Vector vaccine ,biology.organism_classification ,Virology ,Adoptive Transfer ,Macaca mulatta ,030104 developmental biology ,Vaccines, Inactivated ,Immunology ,biology.protein ,Female ,Antibody ,Brazil - Abstract
Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans.
- Published
- 2016
45. Defining the determinants of protection against SARS-CoV-2 infection and viral control in a dose-down Ad26.CoV2.S vaccine study in nonhuman primates.
- Author
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Daniel Y Zhu, Matthew J Gorman, Dansu Yuan, Jingyou Yu, Noe B Mercado, Katherine McMahan, Erica N Borducchi, Michelle Lifton, Jinyan Liu, Felix Nampanya, Shivani Patel, Lauren Peter, Lisa H Tostanoski, Laurent Pessaint, Alex Van Ry, Brad Finneyfrock, Jason Velasco, Elyse Teow, Renita Brown, Anthony Cook, Hanne Andersen, Mark G Lewis, Douglas A Lauffenburger, Dan H Barouch, and Galit Alter
- Subjects
Biology (General) ,QH301-705.5 - 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.
- Published
- 2022
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