71 results on '"Nason MC"'
Search Results
2. COVID-19 vaccine trials should seek worthwhile efficacy
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Krause, Philip, primary, Fleming, Thomas R, additional, Longini, Ira, additional, Henao-Restrepo, Ana Maria, additional, Peto, Richard, additional, Dean, NE, additional, Halloran, ME, additional, Huang, Y, additional, Fleming, TR, additional, Gilbert, PB, additional, DeGruttola, V, additional, Janes, HE, additional, Krause, PR, additional, Longini, IM, additional, Nason, MC, additional, Peto, R, additional, Smith, PG, additional, Riveros, AX, additional, Gsell, PS, additional, and Henao-Restrepo, AM, additional
- Published
- 2020
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3. P14-10. Comparable immunogenicity of VRC DNA and rAd5 HIV-1 vaccines delivered by intramuscular, subcutaneous and intradermal routes in healthy adults (VRC 011)
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Ledgerwood, JE, primary, Novik, L, additional, Enama, ME, additional, Gordon, IJ, additional, Holman, LA, additional, Nason, MC, additional, Bailer, RT, additional, Roederer, M, additional, Koup, RA, additional, Mascola, JR, additional, Nabel, GJ, additional, and Graham, BS, additional
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- 2009
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4. Mucosal adenovirus vaccine boosting elicits IgA and durably prevents XBB.1.16 infection in nonhuman primates.
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Gagne M, Flynn BJ, Andrew SF, Marquez J, Flebbe DR, Mychalowych A, Lamb E, Davis-Gardner ME, Burnett MR, Serebryannyy LA, Lin BC, Ziff ZE, Maule E, Carroll R, Naisan M, Jethmalani Y, Pessaint L, Todd JM, Doria-Rose NA, Case JB, Dmitriev IP, Kashentseva EA, Ying B, Dodson A, Kouneski K, O'Dell S, Wali B, Ellis M, Godbole S, Laboune F, Henry AR, Teng IT, Wang D, Wang L, Zhou Q, Zouantchangadou S, Van Ry A, Lewis MG, Andersen H, Kwong PD, Curiel DT, Roederer M, Nason MC, Foulds KE, Suthar MS, Diamond MS, Douek DC, and Seder RA
- Abstract
A mucosal route of vaccination could prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication at the site of infection and limit transmission. We compared protection against heterologous XBB.1.16 challenge in nonhuman primates (NHPs) ~5 months following intramuscular boosting with bivalent mRNA encoding WA1 and BA.5 spike proteins or mucosal boosting with a WA1-BA.5 bivalent chimpanzee adenoviral-vectored vaccine delivered by intranasal or aerosol device. NHPs boosted by either mucosal route had minimal virus replication in the nose and lungs, respectively. By contrast, protection by intramuscular mRNA was limited to the lower airways. The mucosally delivered vaccine elicited durable airway IgG and IgA responses and, unlike the intramuscular mRNA vaccine, induced spike-specific B cells in the lungs. IgG, IgA and T cell responses correlated with protection in the lungs, whereas mucosal IgA alone correlated with upper airway protection. This study highlights differential mucosal and serum correlates of protection and how mucosal vaccines can durably prevent infection against SARS-CoV-2., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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5. Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways.
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Gagne M, Flynn BJ, Honeycutt CC, Flebbe DR, Andrew SF, Provost SJ, McCormick L, Van Ry A, McCarthy E, Todd JM, Bao S, Teng IT, Marciano S, Rudich Y, Li C, Jain S, Wali B, Pessaint L, Dodson A, Cook A, Lewis MG, Andersen H, Zahradník J, Suthar MS, Nason MC, Foulds KE, Kwong PD, Roederer M, Schreiber G, Seder RA, and Douek DC
- Subjects
- Animals, Humans, Male, Chlorocebus aethiops, COVID-19 Drug Treatment, Disease Models, Animal, Macaca mulatta, Spike Glycoprotein, Coronavirus metabolism, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, Vero Cells, Angiotensin-Converting Enzyme 2 antagonists & inhibitors, Antiviral Agents pharmacology, COVID-19 virology, COVID-19 immunology, COVID-19 prevention & control, SARS-CoV-2 drug effects, SARS-CoV-2 physiology, SARS-CoV-2 immunology, Virus Replication drug effects
- Abstract
SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta-the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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6. Aotus nancymaae model predicts human immune response to the placental malaria vaccine candidate VAR2CSA.
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Doritchamou J, Nielsen MA, Chêne A, Viebig NK, Lambert LE, Sander AF, Semblat JP, Hundt S, Orr-Gonzalez S, Janitzek CM, Spiegel AJ, Clemmensen SB, Thomas ML 3rd, Nason MC, Snow-Smith M, Barnafo EK, Shiloach J, Chen BB, Nadakal S, Highsmith K, Ouahes T, Conteh S, Sharma A, Torano H, Butler B, Reiter K, Rausch KM, Scaria PV, Anderson C, Narum DL, Salanti A, Fried M, Theander TG, Gamain B, and Duffy PE
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- Animals, Humans, Female, Pregnancy, Placenta parasitology, Plasmodium falciparum, Antigens, Protozoan, Antibodies, Protozoan, Aotidae, Immunity, Malaria Vaccines, Malaria, Falciparum prevention & control, Malaria, Falciparum parasitology, Malaria prevention & control
- Abstract
Placental malaria vaccines (PMVs) are being developed to prevent severe sequelae of placental malaria (PM) in pregnant women and their offspring. The leading candidate vaccine antigen VAR2CSA mediates parasite binding to placental receptor chondroitin sulfate A (CSA). Despite promising results in small animal studies, recent human trials of the first two PMV candidates (PAMVAC and PRIMVAC) generated limited cross-reactivity and cross-inhibitory activity to heterologous parasites. Here we immunized Aotus nancymaae monkeys with three PMV candidates (PAMVAC, PRIMVAC and ID1-ID2a_M1010) adjuvanted with Alhydrogel, and exploited the model to investigate boosting of functional vaccine responses during PM episodes as well as with nanoparticle antigens. PMV candidates induced high levels of antigen-specific IgG with significant cross-reactivity across PMV antigens by enzyme-linked immunosorbent assay. Conversely, PMV antibodies recognized native VAR2CSA and blocked CSA adhesion of only homologous parasites and not of heterologous parasites. PM episodes did not significantly boost VAR2CSA antibody levels or serum functional activity; nanoparticle and monomer antigens alike boosted serum reactivity but not functional activities. Overall, PMV candidates induced functional antibodies with limited heterologous activity in Aotus monkeys, similar to responses reported in humans. The Aotus model appears suitable for preclinical downselection of PMV candidates and assessment of antibody boosting by PM episodes., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2023
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7. Durable immunity to SARS-CoV-2 in both lower and upper airways achieved with a gorilla adenovirus (GRAd) S-2P vaccine in non-human primates.
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Moliva JI, Andrew SF, Flynn BJ, Wagner DA, Foulds KE, Gagne M, Flebbe DR, Lamb E, Provost S, Marquez J, Mychalowych A, Lorag CG, Honeycutt CC, Burnett MR, McCormick L, Henry AR, Godbole S, Davis-Gardner ME, Minai M, Bock KW, Nagata BM, Todd JM, McCarthy E, Dodson A, Kouneski K, Cook A, Pessaint L, Ry AV, Valentin D, Young S, Littman Y, Boon ACM, Suthar MS, Lewis MG, Andersen H, Alves DA, Woodward R, Leuzzi A, Vitelli A, Colloca S, Folgori A, Raggiolli A, Capone S, Nason MC, Douek DC, Roederer M, Seder RA, and Sullivan NJ
- Abstract
SARS-CoV-2 continues to pose a global threat, and current vaccines, while effective against severe illness, fall short in preventing transmission. To address this challenge, there's a need for vaccines that induce mucosal immunity and can rapidly control the virus. In this study, we demonstrate that a single immunization with a novel gorilla adenovirus-based vaccine (GRAd) carrying the pre-fusion stabilized Spike protein (S-2P) in non-human primates provided protective immunity for over one year against the BA.5 variant of SARS-CoV-2. A prime-boost regimen using GRAd followed by adjuvanted S-2P (GRAd+S-2P) accelerated viral clearance in both the lower and upper airways. GRAd delivered via aerosol (GRAd(AE)+S-2P) modestly improved protection compared to its matched intramuscular regimen, but showed dramatically superior boosting by mRNA and, importantly, total virus clearance in the upper airway by day 4 post infection. GrAd vaccination regimens elicited robust and durable systemic and mucosal antibody responses to multiple SARS-CoV-2 variants, but only GRAd(AE)+S-2P generated long-lasting T cell responses in the lung. This research underscores the flexibility of the GRAd vaccine platform to provide durable immunity against SARS-CoV-2 in both the lower and upper airways., Competing Interests: Declaration of interests M.R., N.J.S., and D.C.D. are inventors on U.S. Patent Application No. 63/147,419 entitled “Antibodies Targeting the Spike Protein of Coronaviruses”. L.P., A.V.R., D.V., A.C., A.D., M.G.L., and H.A. are employees of Bioqual, Inc. A.L., A.V., S.Co., A.F., A.R., and S.Ca. are employees of ReiThera Srl. S.Co. and A.F. are shareholders of Keires AG. A.V., S.Co. and A.R. are named inventors of the Patent Application No. 20183515.4 entitled “Gorilla Adenovirus Nucleic Acid- and Amino Acid-Sequences, Vectors Containing Same, and Uses Thereof”. The other authors declare no competing interests.
- Published
- 2023
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8. Mucosal Adenoviral-vectored Vaccine Boosting Durably Prevents XBB.1.16 Infection in Nonhuman Primates.
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Gagne M, Flynn BJ, Andrew SF, Flebbe DR, Mychalowych A, Lamb E, Davis-Gardner ME, Burnett MR, Serebryannyy LA, Lin BC, Pessaint L, Todd JM, Ziff ZE, Maule E, Carroll R, Naisan M, Jethmalani Y, Case JB, Dmitriev IP, Kashentseva EA, Ying B, Dodson A, Kouneski K, Doria-Rose NA, O'Dell S, Godbole S, Laboune F, Henry AR, Marquez J, Teng IT, Wang L, Zhou Q, Wali B, Ellis M, Zouantchangadou S, Ry AV, Lewis MG, Andersen H, Kwong PD, Curiel DT, Foulds KE, Nason MC, Suthar MS, Roederer M, Diamond MS, Douek DC, and Seder RA
- Abstract
Waning immunity and continued virus evolution have limited the durability of protection from symptomatic infection mediated by intramuscularly (IM)-delivered mRNA vaccines against COVID-19 although protection from severe disease remains high. Mucosal vaccination has been proposed as a strategy to increase protection at the site of SARS-CoV-2 infection by enhancing airway immunity, potentially reducing rates of infection and transmission. Here, we compared protection against XBB.1.16 virus challenge 5 months following IM or mucosal boosting in non-human primates (NHP) that had previously received a two-dose mRNA-1273 primary vaccine regimen. The mucosal boost was composed of a bivalent chimpanzee adenoviral-vectored vaccine encoding for both SARS-CoV-2 WA1 and BA.5 spike proteins (ChAd-SARS-CoV-2-S) and delivered either by an intranasal mist or an inhaled aerosol. An additional group of animals was boosted by the IM route with bivalent WA1/BA.5 spike-matched mRNA (mRNA-1273.222) as a benchmark control. NHP were challenged in the upper and lower airways 18 weeks after boosting with XBB.1.16, a heterologous Omicron lineage strain. Cohorts boosted with ChAd-SARS-CoV-2-S by an aerosolized or intranasal route had low to undetectable virus replication as assessed by levels of subgenomic SARS-CoV-2 RNA in the lungs and nose, respectively. In contrast, animals that received the mRNA-1273.222 boost by the IM route showed minimal protection against virus replication in the upper airway but substantial reduction of virus RNA levels in the lower airway. Immune analysis showed that the mucosal vaccines elicited more durable antibody and T cell responses than the IM vaccine. Protection elicited by the aerosolized vaccine was associated with mucosal IgG and IgA responses, whereas protection elicited by intranasal delivery was mediated primarily by mucosal IgA. Thus, durable immunity and effective protection against a highly transmissible heterologous variant in both the upper and lower airways can be achieved by mucosal delivery of a virus-vectored vaccine. Our study provides a template for the development of mucosal vaccines that limit infection and transmission against respiratory pathogens.
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- 2023
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9. RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways.
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Gagne M, Flynn BJ, Honeycutt CC, Flebbe DR, Andrew SF, Provost SJ, McCormick L, Van Ry A, McCarthy E, Todd JM, Bao S, Teng IT, Marciano S, Rudich Y, Li C, Pessaint L, Dodson A, Cook A, Lewis MG, Andersen H, Zahradník J, Nason MC, Foulds KE, Kwong PD, Roederer M, Schreiber G, Seder RA, and Douek DC
- Abstract
SARS-CoV-2 has the capacity to evolve mutations to escape vaccine-and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool. Here, we challenged rhesus macaques with SARS-CoV-2 Delta and simultaneously treated them with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment gave equivalent protection in upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 did not block the development of memory responses to Delta and did not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.
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- 2023
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10. Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial.
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Casazza JP, Cale EM, Narpala S, Yamshchikov GV, Coates EE, Hendel CS, Novik L, Holman LA, Widge AT, Apte P, Gordon I, Gaudinski MR, Conan-Cibotti M, Lin BC, Nason MC, Trofymenko O, Telscher S, Plummer SH, Wycuff D, Adams WC, Pandey JP, McDermott A, Roederer M, Sukienik AN, O'Dell S, Gall JG, Flach B, Terry TL, Choe M, Shi W, Chen X, Kaltovich F, Saunders KO, Stein JA, Doria-Rose NA, Schwartz RM, Balazs AB, Baltimore D, Nabel GJ, Koup RA, Graham BS, Ledgerwood JE, and Mascola JR
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- Adult, Antibodies, Neutralizing, Broadly Neutralizing Antibodies, Dependovirus genetics, HIV Antibodies, Humans, HIV Infections drug therapy, HIV-1
- Abstract
Adeno-associated viral vector-mediated transfer of DNA coding for broadly neutralizing anti-HIV antibodies (bnAbs) offers an alternative to attempting to induce protection by vaccination or by repeated infusions of bnAbs. In this study, we administered a recombinant bicistronic adeno-associated virus (AAV8) vector coding for both the light and heavy chains of the potent broadly neutralizing HIV-1 antibody VRC07 (AAV8-VRC07) to eight adults living with HIV. All participants remained on effective anti-retroviral therapy (viral load (VL) <50 copies per milliliter) throughout this phase 1, dose-escalation clinical trial ( NCT03374202 ). AAV8-VRC07 was given at doses of 5 × 10
10 , 5 × 1011 and 2.5 × 1012 vector genomes per kilogram by intramuscular (IM) injection. Primary endpoints of this study were to assess the safety and tolerability of AAV8-VRC07; to determine the pharmacokinetics and immunogenicity of in vivo VRC07 production; and to describe the immune response directed against AAV8-VRC07 vector and its products. Secondary endpoints were to assess the clinical effects of AAV8-VRC07 on CD4 T cell count and VL and to assess the persistence of VRC07 produced in participants. In this cohort, IM injection of AAV8-VRC07 was safe and well tolerated. No clinically significant change in CD4 T cell count or VL occurred during the 1-3 years of follow-up reported here. In participants who received AAV8-VRC07, concentrations of VRC07 were increased 6 weeks (P = 0.008) and 52 weeks (P = 0.016) after IM injection of the product. All eight individuals produced measurable amounts of serum VRC07, with maximal VRC07 concentrations >1 µg ml-1 in three individuals. In four individuals, VRC07 serum concentrations remained stable near maximal concentration for up to 3 years of follow-up. In exploratory analyses, neutralizing activity of in vivo produced VRC07 was similar to that of in vitro produced VRC07. Three of eight participants showed a non-idiotypic anti-drug antibody (ADA) response directed against the Fab portion of VRC07. This ADA response appeared to decrease the production of serum VRC07 in two of these three participants. These data represent a proof of concept that adeno-associated viral vectors can durably produce biologically active, difficult-to-induce bnAbs in vivo, which could add valuable new tools to the fight against infectious diseases., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)- Published
- 2022
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11. mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.
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Gagne M, Moliva JI, Foulds KE, Andrew SF, Flynn BJ, Werner AP, Wagner DA, Teng IT, Lin BC, Moore C, Jean-Baptiste N, Carroll R, Foster SL, Patel M, Ellis M, Edara VV, Maldonado NV, Minai M, McCormick L, Honeycutt CC, Nagata BM, Bock KW, Dulan CNM, Cordon J, Flebbe DR, Todd JM, McCarthy E, Pessaint L, Van Ry A, Narvaez B, Valentin D, Cook A, Dodson A, Steingrebe K, Nurmukhambetova ST, Godbole S, Henry AR, Laboune F, Roberts-Torres J, Lorang CG, Amin S, Trost J, Naisan M, Basappa M, Willis J, Wang L, Shi W, Doria-Rose NA, Zhang Y, Yang ES, Leung K, O'Dell S, Schmidt SD, Olia AS, Liu C, Harris DR, Chuang GY, Stewart-Jones G, Renzi I, Lai YT, Malinowski A, Wu K, Mascola JR, Carfi A, Kwong PD, Edwards DK, Lewis MG, Andersen H, Corbett KS, Nason MC, McDermott AB, Suthar MS, Moore IN, Roederer M, Sullivan NJ, Douek DC, and Seder RA
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Animals, Antibodies, Neutralizing, Antibodies, Viral, Macaca, RNA, Messenger, COVID-19 prevention & control, SARS-CoV-2
- Abstract
SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID
50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost., Competing Interests: Declaration of interests K.S.C. is an inventor on U.S. Patent no. 10,960,070 B2 and International Patent Application no. WO/2018/081318 entitled “Prefusion Coronavirus Spike Proteins and Their Use.” K.S.C. is an inventor on U.S. Patent Application no. 62/972,886 entitled “2019-nCoV Vaccine.” A.R.H., L.W., W.S., Y.Z., E.S.Y., J.R.M., P.D.K., M.R., N.J.S., and D.C.D. are inventors on U.S. Patent Application no. 63/147,419 entitled “Antibodies Targeting the Spike Protein of Coronaviruses.” L.P., A.V.R., B.N., D.V., A. Cook, A.D., K.S., H.A., and M.G.L. are employees of Bioqual. K.S.C., L.W., W.S., and Y.Z. are inventors on multiple U.S. Patent Applications entitled “Anti-Coronavirus Antibodies and Methods of Use.” G.-Y.C., G.S.-J., I.R., Y.-T.L., A.M., K.W., A. Carfi, and D.K.E. are employees of Moderna. M.S.S. serves on the scientific board of advisors for Moderna and Ocugen. The other authors declare no competing interests., (Published by Elsevier Inc.)- Published
- 2022
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12. Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques coincides with anamnestic antibody response in the lung.
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Gagne M, Corbett KS, Flynn BJ, Foulds KE, Wagner DA, Andrew SF, Todd JM, Honeycutt CC, McCormick L, Nurmukhambetova ST, Davis-Gardner ME, Pessaint L, Bock KW, Nagata BM, Minai M, Werner AP, Moliva JI, Tucker C, Lorang CG, Zhao B, McCarthy E, Cook A, Dodson A, Teng IT, Mudvari P, Roberts-Torres J, Laboune F, Wang L, Goode A, Kar S, Boyoglu-Barnum S, Yang ES, Shi W, Ploquin A, Doria-Rose N, Carfi A, Mascola JR, Boritz EA, Edwards DK, Andersen H, Lewis MG, Suthar MS, Graham BS, Roederer M, Moore IN, Nason MC, Sullivan NJ, Douek DC, and Seder RA
- Abstract
mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. Here, we immunized rhesus macaques and assessed immune responses over 1 year in blood and upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID
50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody-binding titers also decreased in bronchoalveolar lavage (BAL). Four days after Delta challenge, the virus was unculturable in BAL, and subgenomic RNA declined by ∼3-log10 compared with control animals. In nasal swabs, sgRNA was reduced by 1-log10 , and the virus remained culturable. Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost., Competing Interests: Declaration of interests K.S.C. and B.S.G. are inventors on US patent no. 10,960,070 B2 and International patent application no. WO/2018/081318 entitled “Prefusion Coronavirus Spike Proteins and Their Use”. K.S.C. and B.S.G. are inventors on US patent application no. 62/972,886 entitled “2019-nCoV Vaccine”. L.W., E.S.Y., W.S., J.R.M., M.R., N.J.S. and D.C.D are inventors on US patent application no. 63/147,419 entitled “Antibodies Targeting the Spike Protein of Coronaviruses”. L.P., A. Cook, A.D., A.G., S.K., H.A., and M.G.L. are employees of Bioqual. K.S.C., L.W., W.S., and B.S.G are inventors on multiple US patent applications entitled “Anti-Coronavirus Antibodies and Methods of Use”. A. Carfi and D.K.E. are employees of Moderna. M.S.S. serves on the scientific board of advisors for Moderna. The other authors declare no competing interests., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2022
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13. Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine.
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Falsey AR, Sobieszczyk ME, Hirsch I, Sproule S, Robb ML, Corey L, Neuzil KM, Hahn W, Hunt J, Mulligan MJ, McEvoy C, DeJesus E, Hassman M, Little SJ, Pahud BA, Durbin A, Pickrell P, Daar ES, Bush L, Solis J, Carr QO, Oyedele T, Buchbinder S, Cowden J, Vargas SL, Guerreros Benavides A, Call R, Keefer MC, Kirkpatrick BD, Pullman J, Tong T, Brewinski Isaacs M, Benkeser D, Janes HE, Nason MC, Green JA, Kelly EJ, Maaske J, Mueller N, Shoemaker K, Takas T, Marshall RP, Pangalos MN, Villafana T, and Gonzalez-Lopez A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 epidemiology, Chile epidemiology, Double-Blind Method, Female, Humans, Immunogenicity, Vaccine, Male, Middle Aged, Peru epidemiology, SARS-CoV-2 immunology, Spike Glycoprotein, Coronavirus immunology, United States epidemiology, Young Adult, COVID-19 prevention & control, ChAdOx1 nCoV-19 adverse effects, Vaccine Efficacy
- Abstract
Background: The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known., Methods: In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru., Results: A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose., Conclusions: AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.)., (Copyright © 2021 Massachusetts Medical Society.)
- Published
- 2021
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14. Protection against SARS-CoV-2 Beta variant in mRNA-1273 vaccine-boosted nonhuman primates.
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Corbett KS, Gagne M, Wagner DA, O' Connell S, Narpala SR, Flebbe DR, Andrew SF, Davis RL, Flynn B, Johnston TS, Stringham CD, Lai L, Valentin D, Van Ry A, Flinchbaugh Z, Werner AP, Moliva JI, Sriparna M, O'Dell S, Schmidt SD, Tucker C, Choi A, Koch M, Bock KW, Minai M, Nagata BM, Alvarado GS, Henry AR, Laboune F, Schramm CA, Zhang Y, Yang ES, Wang L, Choe M, Boyoglu-Barnum S, Wei S, Lamb E, Nurmukhambetova ST, Provost SJ, Donaldson MM, Marquez J, Todd JM, Cook A, Dodson A, Pekosz A, Boritz E, Ploquin A, Doria-Rose N, Pessaint L, Andersen H, Foulds KE, Misasi J, Wu K, Carfi A, Nason MC, Mascola J, Moore IN, Edwards DK, Lewis MG, Suthar MS, Roederer M, McDermott A, Douek DC, Sullivan NJ, Graham BS, and Seder RA
- Subjects
- 2019-nCoV Vaccine mRNA-1273 administration & dosage, Animals, Antibodies, Neutralizing blood, Antibodies, Viral analysis, Antibodies, Viral blood, Bronchoalveolar Lavage Fluid immunology, Bronchoalveolar Lavage Fluid virology, COVID-19 immunology, COVID-19 virology, COVID-19 Vaccines administration & dosage, Immunity, Mucosal, Immunization, Secondary, Macaca mulatta, Memory B Cells immunology, Nose immunology, Nose virology, RNA, Viral analysis, SARS-CoV-2 genetics, SARS-CoV-2 isolation & purification, SARS-CoV-2 physiology, T Follicular Helper Cells immunology, Th1 Cells immunology, Virus Replication, 2019-nCoV Vaccine mRNA-1273 immunology, COVID-19 prevention & control, COVID-19 Vaccines immunology, Immunogenicity, Vaccine, SARS-CoV-2 immunology, Vaccine Efficacy
- Abstract
Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous mRNA-1273 or heterologous mRNA-1273.β, which encompasses the spike sequence of the B.1.351 Beta variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may be required to sustain immunity and protection.
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- 2021
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15. Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in nonhuman primates is coincident with an anamnestic antibody response in the lower airway.
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Gagne M, Corbett KS, Flynn BJ, Foulds KE, Wagner DA, Andrew SF, Todd JM, Honeycutt CC, McCormick L, Nurmukhambetova ST, Davis-Gardner ME, Pessaint L, Bock KW, Nagata BM, Minai M, Werner AP, Moliva JI, Tucker C, Lorang CG, Zhao B, McCarthy E, Cook A, Dodson A, Mudvari P, Roberts-Torres J, Laboune F, Wang L, Goode A, Kar S, Boyoglu-Barnum S, Yang ES, Shi W, Ploquin A, Doria-Rose N, Carfi A, Mascola JR, Boritz EA, Edwards DK, Andersen H, Lewis MG, Suthar MS, Graham BS, Roederer M, Moore IN, Nason MC, Sullivan NJ, Douek DC, and Seder RA
- Abstract
mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. We immunized rhesus macaques at weeks 0 and 4 and assessed immune responses over one year in blood, upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID
50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody binding titers also decreased in bronchoalveolar lavage (BAL). Four days after challenge, virus was unculturable in BAL and subgenomic RNA declined ∼3-log10 compared to control animals. In nasal swabs, sgRNA declined 1-log10 and virus remained culturable. Anamnestic antibody responses (590-fold increase) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.- Published
- 2021
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16. Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial.
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Ruckwardt TJ, Morabito KM, Phung E, Crank MC, Costner PJ, Holman LA, Chang LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Lin B, Bailer R, Chen M, Ortega-Villa AM, Nguyen T, Kumar A, Schwartz RM, Kueltzo LA, Stein JA, Carlton K, Gall JG, Nason MC, Mascola JR, Chen G, and Graham BS
- Subjects
- Adolescent, Adult, Antibodies, Neutralizing, Antibodies, Viral, Double-Blind Method, Humans, Infant, Middle Aged, Respiratory Syncytial Viruses, Vaccines, Subunit adverse effects, Young Adult, Respiratory Syncytial Virus Vaccines adverse effects
- Abstract
Background: Multiple active vaccination approaches have proven ineffective in reducing the substantial morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and older adults (aged ≥65 years). A vaccine conferring a substantial and sustainable boost in neutralising activity is required to protect against severe RSV disease. To that end, we evaluated the safety and immunogenicity of DS-Cav1, a prefusion F subunit vaccine., Methods: In this randomised, open-label, phase 1 clinical trial, the stabilised prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults aged 18-50 years at a single US site. Participants were assigned to receive escalating doses of either 50 μg, 150 μg, or 500 μg DS-Cav1 at weeks 0 and 12, and were randomly allocated in a 1:1 ratio within each dose group to receive the vaccine with or without aluminium hydroxide (AlOH) adjuvant. After 71 participants had been randomised, the protocol was amended to allow some participants to receive a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose within 28 days following each injection. Neutralising activity and RSV F-binding antibodies were evaluated from week 0 to week 44 as secondary and exploratory objectives. Safety was assessed in all participants who received at least one vaccine dose; secondary and exploratory immunogenicity analysis included all participants with available data at a given visit. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting., Findings: Between Feb 21, 2017, and Nov 29, 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 μg (n=30, of which n=15 with AlOH), 150 μg (n=35, of which n=15 with AlOH), or 500 μg (n=30, of which n=15 with AlOH) doses. DS-Cav1 was safe and well tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralising activity and binding antibodies by 4 weeks after a single vaccination (p<0·0001 for F-binding and neutralising antibodies). In analyses of exploratory endpoints at week 44, pre-F-binding IgG and neutralising activity were significantly increased compared with baseline in all groups. At week 44, RSV A neutralising activity was 3·1 fold above baseline in the 50 μg group, 3·8 fold in the 150 μg group, and 4·5 fold in the 500 μg group (p<0·0001). RSV B neutralising activity was 2·8 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 3·7 fold in the 500 μg group (p<0·0001). Pre-F-binding IgG remained significantly 3·2 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 4·0 fold in the 500 μg group (p<0·0001). Pre-F-binding serum IgA remained 4·1 fold above baseline in the 50 μg group, 4·3 fold in the 150 μg group, and 4·8 fold in the 500 μg group (p<0·0001). Although a higher vaccine dose or second immunisation elicited a transient advantage compared with lower doses or a single immunisation, neither significantly impacted long-term neutralisation. There was no long-term effect of dose, number of vaccinations, or adjuvant on neutralising activity., Interpretation: In this phase 1 study, DS-Cav1 vaccination was safe and well tolerated. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks. A single low-dose of pre-F immunisation of antigen-experienced individuals might confer protection that extends throughout an entire RSV season., Funding: The National Institutes of Allergy and Infectious Diseases., Competing Interests: Declaration of interests MC and BSG are inventors on patents for the stabilisation of the RSV F protein. The other authors declared no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
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17. mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates.
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Corbett KS, Werner AP, Connell SO, Gagne M, Lai L, Moliva JI, Flynn B, Choi A, Koch M, Foulds KE, Andrew SF, Flebbe DR, Lamb E, Nurmukhambetova ST, Provost SJ, Bock KW, Minai M, Nagata BM, Ry AV, Flinchbaugh Z, Johnston TS, Mokhtari EB, Mudvari P, Henry AR, Laboune F, Chang B, Porto M, Wear J, Alvarado GS, Boyoglu-Barnum S, Todd JM, Bart B, Cook A, Dodson A, Pessaint L, Steingrebe K, Elbashir S, Sriparna M, Pekosz A, Andersen H, Wu K, Edwards DK, Kar S, Lewis MG, Boritz E, Moore IN, Carfi A, Suthar MS, McDermott A, Roederer M, Nason MC, Sullivan NJ, Douek DC, Graham BS, and Seder RA
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 virology, Cell Line, Chlorocebus aethiops, Female, Humans, Macaca mulatta, Male, Mesocricetus, Primates virology, RNA, Viral immunology, Spike Glycoprotein, Coronavirus immunology, Vaccination methods, Vero Cells, Viral Load methods, COVID-19 immunology, COVID-19 Vaccines immunology, Primates immunology, SARS-CoV-2 immunology
- Abstract
B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log
10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)- Published
- 2021
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18. Durability of mRNA-1273 vaccine-induced antibodies against SARS-CoV-2 variants.
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Pegu A, O'Connell SE, Schmidt SD, O'Dell S, Talana CA, Lai L, Albert J, Anderson E, Bennett H, Corbett KS, Flach B, Jackson L, Leav B, Ledgerwood JE, Luke CJ, Makowski M, Nason MC, Roberts PC, Roederer M, Rebolledo PA, Rostad CA, Rouphael NG, Shi W, Wang L, Widge AT, Yang ES, Beigel JH, Graham BS, Mascola JR, Suthar MS, McDermott AB, Doria-Rose NA, Arega J, Beigel JH, Buchanan W, Elsafy M, Hoang B, Lampley R, Kolhekar A, Koo H, Luke C, Makhene M, Nayak S, Pikaart-Tautges R, Roberts PC, Russell J, Sindall E, Albert J, Kunwar P, Makowski M, Anderson EJ, Bechnak A, Bower M, Camacho-Gonzalez AF, Collins M, Drobeniuc A, Edara VV, Edupuganti S, Floyd K, Gibson T, Ackerley CMG, Johnson B, Kamidani S, Kao C, Kelley C, Lai L, Macenczak H, McCullough MP, Peters E, Phadke VK, Rebolledo PA, Rostad CA, Rouphael N, Scherer E, Sherman A, Stephens K, Suthar MS, Teherani M, Traenkner J, Winston J, Yildirim I, Barr L, Benoit J, Carste B, Choe J, Dunstan M, Erolin R, Ffitch J, Fields C, Jackson LA, Kiniry E, Lasicka S, Lee S, Nguyen M, Pimienta S, Suyehira J, Witte M, Bennett H, Altaras NE, Carfi A, Hurley M, Leav B, Pajon R, Sun W, Zaks T, Coler RN, Larsen SE, Neuzil KM, Lindesmith LC, Martinez DR, Munt J, Mallory M, Edwards C, Baric RS, Berkowitz NM, Boritz EA, Carlton K, Corbett KS, Costner P, Creanga A, Doria-Rose NA, Douek DC, Flach B, Gaudinski M, Gordon I, Graham BS, Holman L, Ledgerwood JE, Leung K, Lin BC, Louder MK, Mascola JR, McDermott AB, Morabito KM, Novik L, O'Connell S, O'Dell S, Padilla M, Pegu A, Schmidt SD, Shi W, Swanson PA 2nd, Talana CA, Wang L, Widge AT, Yang ES, Zhang Y, Chappell JD, Denison MR, Hughes T, Lu X, Pruijssers AJ, Stevens LJ, Posavad CM, Gale M Jr, Menachery V, and Shi PY
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Adolescent, Adult, Aged, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage, Cross Reactions, Humans, Immune Evasion, Immunization, Secondary, Immunogenicity, Vaccine, Middle Aged, Time Factors, Young Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 Vaccines immunology, SARS-CoV-2 immunology
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations may diminish vaccine-induced protective immune responses, particularly as antibody titers wane over time. Here, we assess the effect of SARS-CoV-2 variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), and B.1.617.2 (Delta) on binding, neutralizing, and angiotensin-converting enzyme 2 (ACE2)–competing antibodies elicited by the messenger RNA (mRNA) vaccine mRNA-1273 over 7 months. Cross-reactive neutralizing responses were rare after a single dose. At the peak of response to the second vaccine dose, all individuals had responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of the mRNA-1273 vaccine. Across all assays, B.1.351 had the lowest antibody recognition. These data complement ongoing studies to inform the potential need for additional boost vaccinations.
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- 2021
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19. Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates.
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Corbett KS, Nason MC, Flach B, Gagne M, O'Connell S, Johnston TS, Shah SN, Edara VV, Floyd K, Lai L, McDanal C, Francica JR, Flynn B, Wu K, Choi A, Koch M, Abiona OM, Werner AP, Moliva JI, Andrew SF, Donaldson MM, Fintzi J, Flebbe DR, Lamb E, Noe AT, Nurmukhambetova ST, Provost SJ, Cook A, Dodson A, Faudree A, Greenhouse J, Kar S, Pessaint L, Porto M, Steingrebe K, Valentin D, Zouantcha S, Bock KW, Minai M, Nagata BM, van de Wetering R, Boyoglu-Barnum S, Leung K, Shi W, Yang ES, Zhang Y, Todd JM, Wang L, Alvarado GS, Andersen H, Foulds KE, Edwards DK, Mascola JR, Moore IN, Lewis MG, Carfi A, Montefiori D, Suthar MS, McDermott A, Roederer M, Sullivan NJ, Douek DC, Graham BS, and Seder RA
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Antibody Affinity, Bronchoalveolar Lavage Fluid immunology, Bronchoalveolar Lavage Fluid virology, CD4-Positive T-Lymphocytes immunology, COVID-19 immunology, COVID-19 virology, Female, Immunization Schedule, Immunization, Passive, Immunization, Secondary, Immunoglobulin G immunology, Immunologic Memory, Lung immunology, Lung virology, Macaca mulatta, Male, Mesocricetus, Nasal Mucosa immunology, Nasal Mucosa virology, SARS-CoV-2 physiology, Spike Glycoprotein, Coronavirus immunology, Vaccination, Vaccine Potency, Virus Replication, Antibodies, Neutralizing blood, Antibodies, Viral blood, COVID-19 prevention & control, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines immunology, Immunogenicity, Vaccine, SARS-CoV-2 immunology
- Abstract
Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 μg of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti–S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273–induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine–induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.
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- 2021
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20. The mechanistic analysis of founder virus data in challenge models.
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Ortega-Villa AM, Nason MC, and Follmann D
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- Animals, Likelihood Functions, Models, Statistical, Poisson Distribution, Simian Acquired Immunodeficiency Syndrome, Simian Immunodeficiency Virus
- Abstract
Repeated low-dose challenge studies provide valuable information when evaluating candidate vaccines since they resemble the typical exposure of natural transmission and inform on the number of exposures prior to infection. Traditionally, the number of challenges to infection has been used as the outcome. This work uses the number of infecting viruses, or founder viruses at the time of infection, to more efficiently characterize a vaccine's mechanism of action. The vaccine mechanisms of action we consider are a Null mechanism (the vaccine offers no protection), a Leaky mechanism in which the number of founder viruses is reduced by some factor in vaccinated subjects, the All-or-None mechanism in which the vaccine randomly provides either complete protection or no protection in vaccinated subjects, and a Combination mechanism with both Leaky and All-or-None components. We consider two discrete marked survival models where the number of founder viruses follows a Poisson distribution with either a fixed mean parameter (Poisson model), or a random mean parameter that follows a Gamma distribution (negative binomial model). We estimate the models using maximum likelihood and derive likelihood ratio testing procedures that are accurate for small samples with boundary parameters. We illustrate the performance of these methodologies with a data example of simian immunodeficiency virus on nonhuman primates and a simulation study., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)
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- 2021
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21. Protection against SARS-CoV-2 Beta Variant in mRNA-1273 Boosted Nonhuman Primates.
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Corbett KS, Gagne M, Wagner DA, Connell SO, Narpala SR, Flebbe DR, Andrew SF, Davis RL, Flynn B, Johnston TS, Stringham C, Lai L, Valentin D, Van Ry A, Flinchbaugh Z, Werner AP, Moliva JI, Sriparna M, O'Dell S, Schmidt SD, Tucker C, Choi A, Koch M, Bock KW, Minai M, Nagata BM, Alvarado GS, Henry AR, Laboune F, Schramm CA, Zhang Y, Wang L, Choe M, Boyoglu-Barnum S, Shi W, Lamb E, Nurmukhambetova ST, Provost SJ, Donaldson MM, Marquez J, Todd JM, Cook A, Dodson A, Pekosz A, Boritz E, Ploquin A, Doria-Rose N, Pessaint L, Andersen H, Foulds KE, Misasi J, Wu K, Carfi A, Nason MC, Mascola J, Moore IN, Edwards DK, Lewis MG, Suthar MS, Roederer M, McDermott A, Douek DC, Sullivan NJ, Graham BS, and Seder RA
- Abstract
Neutralizing antibody responses gradually wane after vaccination with mRNA-1273 against several variants of concern (VOC), and additional boost vaccinations may be required to sustain immunity and protection. Here, we evaluated the immune responses in nonhuman primates that received 100 µg of mRNA-1273 vaccine at 0 and 4 weeks and were boosted at week 29 with mRNA-1273 (homologous) or mRNA-1273.β (heterologous), which encompasses the spike sequence of the B.1.351 (beta or β) variant. Reciprocal ID
50 pseudovirus neutralizing antibody geometric mean titers (GMT) against live SARS-CoV-2 D614G and the β variant, were 4700 and 765, respectively, at week 6, the peak of primary response, and 644 and 553, respectively, at a 5-month post-vaccination memory time point. Two weeks following homologous or heterologous boost β-specific reciprocal ID50 GMT were 5000 and 3000, respectively. At week 38, animals were challenged in the upper and lower airway with the β variant. Two days post-challenge, viral replication was low to undetectable in both BAL and nasal swabs in most of the boosted animals. These data show that boosting with the homologous mRNA-1273 vaccine six months after primary immunization provides up to a 20-fold increase in neutralizing antibody responses across all VOC, which may be required to sustain high-level protection against severe disease, especially for at-risk populations., One-Sentence Summary: mRNA-1273 boosted nonhuman primates have increased immune responses and are protected against SARS-CoV-2 beta infection.- Published
- 2021
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22. Developing Treatment Guidelines During a Pandemic Health Crisis: Lessons Learned From COVID-19.
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Kuriakose S, Singh K, Pau AK, Daar E, Gandhi R, Tebas P, Evans L, Gulick RM, Lane HC, Masur H, Aberg JA, Adimora AA, Baker J, Kreuziger LB, Bedimo R, Belperio PS, Cantrill SV, Coopersmith CM, Davis SL, Dzierba AL, Gallagher JJ, Glidden DV, Grund B, Hardy EJ, Hinkson C, Hughes BL, Johnson S, Keller MJ, Kim AY, Lennox JL, Levy MM, Li JZ, Martin GS, Naggie S, Pavia AT, Seam N, Simpson SQ, Swindells S, Tien P, Waghmare AA, Wilson KC, Yazdany J, Zachariah P, Campbell DM, Harrison C, Burgess T, Francis J, Sheikh V, Uyeki TM, Walker R, Brooks JT, Ortiz LB, Davey RT Jr, Doepel LK, Eisinger RW, Han A, Higgs ES, Nason MC, Crew P, Lerner AM, Lund C, and Worthington C
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- Advisory Committees, COVID-19 epidemiology, Child, Data Interpretation, Statistical, Drug Approval, Evidence-Based Medicine, Female, Humans, Interprofessional Relations, National Institutes of Health (U.S.), Pregnancy, SARS-CoV-2, Stakeholder Participation, United States, COVID-19 Drug Treatment, COVID-19 therapy, Pandemics, Practice Guidelines as Topic
- Abstract
The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.
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- 2021
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23. Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates.
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Corbett KS, Werner AP, O' Connell S, Gagne M, Lai L, Moliva JI, Flynn B, Choi A, Koch M, Foulds KE, Andrew SF, Flebbe DR, Lamb E, Nurmukhambetova ST, Provost SJ, Bock KW, Minai M, Nagata BM, Van Ry A, Flinchbaugh Z, Johnston TS, Mokhtari EB, Mudvari P, Henry AR, Laboune F, Chang B, Porto M, Wear J, Alvarado GS, Boyoglu-Barnum S, Todd JM, Bart B, Cook A, Dodson A, Pessaint L, Steingrebe K, Elbashir S, Andersen H, Wu K, Edwards DK, Kar S, Lewis MG, Bortiz E, Moore IN, Carfi A, Suthar MS, McDermott A, Roederer M, Nason MC, Sullivan NJ, Douek DC, Graham BS, and Seder RA
- Abstract
Background: Vaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351., Methods: Nonhuman primates received 30 or 100 µg of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 µg at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge., Results: Eight weeks post-boost, 100 µg x2 of mRNA-1273 induced reciprocal ID
50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 µg x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 µg. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 µg x2 of mRNA-1273, and there was a ∼2-log reduction in sgRNA in NHP that received two doses of 30 µg compared to controls. In nasal swabs, there was a 1-log10 reduction observed in the 100 µg x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge., Conclusions: Immunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.- Published
- 2021
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24. Immune Correlates of Protection by mRNA-1273 Immunization against SARS-CoV-2 Infection in Nonhuman Primates.
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Corbett KS, Nason MC, Flach B, Gagne M, O' Connell S, Johnston TS, Shah SN, Edara VV, Floyd K, Lai L, McDanal C, Francica JR, Flynn B, Wu K, Choi A, Koch M, Abiona OM, Werner AP, Alvarado GS, Andrew SF, Donaldson MM, Fintzi J, Flebbe DR, Lamb E, Noe AT, Nurmukhambetova ST, Provost SJ, Cook A, Dodson A, Faudree A, Greenhouse J, Kar S, Pessaint L, Porto M, Steingrebe K, Valentin D, Zouantcha S, Bock KW, Minai M, Nagata BM, Moliva JI, van de Wetering R, Boyoglu-Barnum S, Leung K, Shi W, Yang ES, Zhang Y, Todd JM, Wang L, Andersen H, Foulds KE, Edwards DK, Mascola JR, Moore IN, Lewis MG, Carfi A, Montefiori D, Suthar MS, McDermott A, Sullivan NJ, Roederer M, Douek DC, Graham BS, and Seder RA
- Abstract
Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. The nonhuman primate (NHP) model of SARS-CoV-2 infection replicates key features of human infection and may be used to define immune correlates of protection following vaccination. Here, NHP received either no vaccine or doses ranging from 0.3 - 100 μg of mRNA-1273, a mRNA vaccine encoding the prefusion-stabilized SARS-CoV-2 spike (S-2P) protein encapsulated in a lipid nanoparticle. mRNA-1273 vaccination elicited robust circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs following SARS-CoV-2 challenge in vaccinated animals and was most strongly correlated with levels of anti-S antibody binding and neutralizing activity. Consistent with antibodies being a correlate of protection, passive transfer of vaccine-induced IgG to naïve hamsters was sufficient to mediate protection. Taken together, these data show that mRNA-1273 vaccine-induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP., One-Sentence Summary: mRNA-1273 vaccine-induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP.
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- 2021
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25. Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates.
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Corbett KS, Flynn B, Foulds KE, Francica JR, Boyoglu-Barnum S, Werner AP, Flach B, O'Connell S, Bock KW, Minai M, Nagata BM, Andersen H, Martinez DR, Noe AT, Douek N, Donaldson MM, Nji NN, Alvarado GS, Edwards DK, Flebbe DR, Lamb E, Doria-Rose NA, Lin BC, Louder MK, O'Dell S, Schmidt SD, Phung E, Chang LA, Yap C, Todd JM, Pessaint L, Van Ry A, Browne S, Greenhouse J, Putman-Taylor T, Strasbaugh A, Campbell TA, Cook A, Dodson A, Steingrebe K, Shi W, Zhang Y, Abiona OM, Wang L, Pegu A, Yang ES, Leung K, Zhou T, Teng IT, Widge A, Gordon I, Novik L, Gillespie RA, Loomis RJ, Moliva JI, Stewart-Jones G, Himansu S, Kong WP, Nason MC, Morabito KM, Ruckwardt TJ, Ledgerwood JE, Gaudinski MR, Kwong PD, Mascola JR, Carfi A, Lewis MG, Baric RS, McDermott A, Moore IN, Sullivan NJ, Roederer M, Seder RA, and Graham BS
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Animals, Antibodies, Neutralizing blood, Antibodies, Viral blood, Betacoronavirus physiology, CD4 Antigens, COVID-19, COVID-19 Vaccines, Coronavirus Infections pathology, Coronavirus Infections therapy, Disease Models, Animal, Dose-Response Relationship, Immunologic, Immunization, Passive, Lung pathology, Lung virology, Macaca mulatta, Pneumonia, Viral pathology, Pneumonia, Viral therapy, SARS-CoV-2, Spike Glycoprotein, Coronavirus, T-Lymphocytes immunology, Viral Load, Viral Vaccines administration & dosage, Virus Replication, COVID-19 Serotherapy, Betacoronavirus immunology, Coronavirus Infections immunology, Coronavirus Infections prevention & control, Pandemics prevention & control, Pneumonia, Viral immunology, Pneumonia, Viral prevention & control, Viral Vaccines immunology
- Abstract
Background: Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates., Methods: Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens., Results: The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID
50 ) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)-biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group., Conclusions: Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.)., (Copyright © 2020 Massachusetts Medical Society.)- Published
- 2020
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26. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness.
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Corbett KS, Edwards DK, Leist SR, Abiona OM, Boyoglu-Barnum S, Gillespie RA, Himansu S, Schäfer A, Ziwawo CT, DiPiazza AT, Dinnon KH, Elbashir SM, Shaw CA, Woods A, Fritch EJ, Martinez DR, Bock KW, Minai M, Nagata BM, Hutchinson GB, Wu K, Henry C, Bahl K, Garcia-Dominguez D, Ma L, Renzi I, Kong WP, Schmidt SD, Wang L, Zhang Y, Phung E, Chang LA, Loomis RJ, Altaras NE, Narayanan E, Metkar M, Presnyak V, Liu C, Louder MK, Shi W, Leung K, Yang ES, West A, Gully KL, Stevens LJ, Wang N, Wrapp D, Doria-Rose NA, Stewart-Jones G, Bennett H, Alvarado GS, Nason MC, Ruckwardt TJ, McLellan JS, Denison MR, Chappell JD, Moore IN, Morabito KM, Mascola JR, Baric RS, Carfi A, and Graham BS
- Subjects
- 2019-nCoV Vaccine mRNA-1273, Animals, Antibodies, Neutralizing immunology, Betacoronavirus genetics, CD8-Positive T-Lymphocytes immunology, COVID-19, COVID-19 Vaccines, Clinical Trials, Phase III as Topic, Coronavirus Infections genetics, Coronavirus Infections virology, Female, Lung immunology, Lung virology, Mice, Mutation, Nose immunology, Nose virology, Pneumonia, Viral virology, RNA, Messenger genetics, RNA, Viral genetics, SARS-CoV-2, Th1 Cells immunology, Toll-Like Receptor 4 agonists, Toll-Like Receptor 4 immunology, Viral Vaccines chemistry, Viral Vaccines genetics, Betacoronavirus immunology, Coronavirus Infections immunology, Coronavirus Infections prevention & control, Pandemics prevention & control, Pneumonia, Viral immunology, Pneumonia, Viral prevention & control, Viral Vaccines immunology
- Abstract
A vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is needed to control the coronavirus disease 2019 (COVID-19) global pandemic. Structural studies have led to the development of mutations that stabilize Betacoronavirus spike proteins in the prefusion state, improving their expression and increasing immunogenicity
1 . This principle has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation. Here we show that mRNA-1273 induces potent neutralizing antibody responses to both wild-type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology. mRNA-1273 is currently in a phase III trial to evaluate its efficacy.- Published
- 2020
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27. Prospective International Study of Incidence and Predictors of Immune Reconstitution Inflammatory Syndrome and Death in People Living With Human Immunodeficiency Virus and Severe Lymphopenia.
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Sereti I, Sheikh V, Shaffer D, Phanuphak N, Gabriel E, Wang J, Nason MC, Roby G, Ngeno H, Kirui F, Pau A, Mican JM, Rupert A, Bishop R, Agan B, Chomchey N, Teeratakulpisarn N, Tansuphaswadikul S, Langat D, Kosgei J, French M, Ananworanich J, and Sawe F
- Subjects
- Adult, CD4 Lymphocyte Count, Female, HIV, Humans, Incidence, Kenya, Male, Prospective Studies, Thailand, HIV Infections complications, HIV Infections drug therapy, Immune Reconstitution Inflammatory Syndrome epidemiology, Lymphopenia epidemiology
- Abstract
Background: Patients living with human immunodeficiency virus (PLWH) with low CD4 counts are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death at antiretroviral therapy (ART) initiation., Methods: We investigated the clinical impact of IRIS in PLWH and CD4 counts <100 cells/μL starting ART in an international, prospective study in the United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We assessed associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48 with Cox models., Results: We enrolled 506 participants (39.3% were women). Median age was 37 years, and CD4 count was 29 cells/μL. Within 6 months of ART, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at baseline were at higher IRIS risk (hazard ratio [HR], 1.2; P = .004). IRIS was independently associated with increased risk of death after adjustment for known risk factors (HR, 3.2; P = .031). Being female (P = .004) and having a lower body mass index (BMI; P = .003), higher white blood cell count (P = .005), and higher D-dimer levels (P = .044) were also significantly associated with increased risk of death. Decision-tree analysis identified hemoglobin <8.5 g/dL as predictive of IRIS and C-reactive protein (CRP) >106 μg/mL and BMI <15.6 kg/m2 as predictive of death., Conclusions: For PLWH with severe immunosuppression initiating ART, baseline low BMI and hemoglobin and high CRP and D-dimer levels may be clinically useful predictors of IRIS and death risk., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)
- Published
- 2020
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28. Distinct neutralizing antibody correlates of protection among related Zika virus vaccines identify a role for antibody quality.
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Maciejewski S, Ruckwardt TJ, Morabito KM, Foreman BM, Burgomaster KE, Gordon DN, Pelc RS, DeMaso CR, Ko SY, Fisher BE, Yang ES, Nair D, Foulds KE, Todd JP, Kong WP, Roy V, Aleshnick M, Speer SD, Bourne N, Barrett AD, Nason MC, Roederer M, Gaudinski MR, Chen GL, Dowd KA, Ledgerwood JE, Alter G, Mascola JR, Graham BS, and Pierson TC
- Subjects
- Animals, Antibodies, Neutralizing, Antibodies, Viral, Mice, Viral Vaccines, Zika Virus, Zika Virus Infection prevention & control
- Abstract
The emergence of Zika virus (ZIKV) in the Americas stimulated the development of multiple ZIKV vaccine candidates. We previously developed two related DNA vaccine candidates encoding ZIKV structural proteins that were immunogenic in animal models and humans. We sought to identify neutralizing antibody (NAb) properties induced by each vaccine that correlated with protection in nonhuman primates (NHPs). Despite eliciting equivalent NAb titers in NHPs, these vaccines were not equally protective. The transfer of equivalent titers of vaccine-elicited NAb into AG129 mice also revealed nonequivalent protection, indicating qualitative differences among antibodies (Abs) elicited by these vaccines. Both vaccines elicited Abs with similar binding titers against envelope protein monomers and those incorporated into virus-like particles, as well as a comparable capacity to orchestrate phagocytosis. Functional analysis of vaccine-elicited NAbs from NHPs and humans revealed a capacity to neutralize the structurally mature form of the ZIKV virion that varied in magnitude among vaccine candidates. Conversely, sensitivity to the virion maturation state was not a characteristic of NAbs induced by natural or experimental infection. Passive transfer experiments in mice revealed that neutralization of mature ZIKV virions more accurately predicts protection from ZIKV infection. These findings demonstrate that NAb correlates of protection may differ among vaccine antigens when assayed using standard neutralization platforms and suggest that measurements of Ab quality, including the capacity to neutralize mature virions, will be critical for defining correlates of ZIKV vaccine-induced immunity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
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29. Characteristic and quantifiable COVID-19-like abnormalities in CT- and PET/CT-imaged lungs of SARS-CoV-2-infected crab-eating macaques ( Macaca fascicularis ).
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Finch CL, Crozier I, Lee JH, Byrum R, Cooper TK, Liang J, Sharer K, Solomon J, Sayre PJ, Kocher G, Bartos C, Aiosa NM, Castro M, Larson PA, Adams R, Beitzel B, Di Paola N, Kugelman JR, Kurtz JR, Burdette T, Nason MC, Feuerstein IM, Palacios G, St Claire MC, Lackemeyer MG, Johnson RF, Braun KM, Ramuta MD, Wada J, Schmaljohn CS, Friedrich TC, O'Connor DH, and Kuhn JH
- Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing an exponentially increasing number of coronavirus disease 19 (COVID-19) cases globally. Prioritization of medical countermeasures for evaluation in randomized clinical trials is critically hindered by the lack of COVID-19 animal models that enable accurate, quantifiable, and reproducible measurement of COVID-19 pulmonary disease free from observer bias. We first used serial computed tomography (CT) to demonstrate that bilateral intrabronchial instillation of SARS-CoV-2 into crab-eating macaques ( Macaca fascicularis ) results in mild-to-moderate lung abnormalities qualitatively characteristic of subclinical or mild-to-moderate COVID-19 (e.g., ground-glass opacities with or without reticulation, paving, or alveolar consolidation, peri-bronchial thickening, linear opacities) at typical locations (peripheral>central, posterior and dependent, bilateral, multi-lobar). We then used positron emission tomography (PET) analysis to demonstrate increased FDG uptake in the CT-defined lung abnormalities and regional lymph nodes. PET/CT imaging findings appeared in all macaques as early as 2 days post-exposure, variably progressed, and subsequently resolved by 6-12 days post-exposure. Finally, we applied operator-independent, semi-automatic quantification of the volume and radiodensity of CT abnormalities as a possible primary endpoint for immediate and objective efficacy testing of candidate medical countermeasures., Competing Interests: Competing interest declaration. The authors declare no competing interests.
- Published
- 2020
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30. Creating a Framework for Conducting Randomized Clinical Trials during Disease Outbreaks.
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Dean NE, Gsell PS, Brookmeyer R, Crawford FW, Donnelly CA, Ellenberg SS, Fleming TR, Halloran ME, Horby P, Jaki T, Krause PR, Longini IM, Mulangu S, Muyembe-Tamfum JJ, Nason MC, Smith PG, Wang R, Henao-Restrepo AM, and De Gruttola V
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- Cooperative Behavior, Humans, Research Design, Clinical Protocols, Disease Outbreaks, Publishing standards, Randomized Controlled Trials as Topic methods
- Published
- 2020
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31. A proof of concept for structure-based vaccine design targeting RSV in humans.
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Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Kumar A, Chang LA, Moin SM, Hill JP, DiPiazza AT, Schwartz RM, Kueltzo L, Cooper JW, Chen P, Stein JA, Carlton K, Gall JG, Nason MC, Kwong PD, Chen GL, Mascola JR, McLellan JS, Ledgerwood JE, and Graham BS
- Subjects
- Adolescent, Adult, Antibodies, Neutralizing blood, Antibodies, Viral blood, Epitope Mapping, Humans, Middle Aged, Young Adult, Immunogenicity, Vaccine, Respiratory Syncytial Virus Infections prevention & control, Respiratory Syncytial Virus Vaccines chemistry, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Virus, Human immunology, Viral Fusion Proteins chemistry, Viral Fusion Proteins immunology
- Abstract
Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2019
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32. Antibody Lineages with Vaccine-Induced Antigen-Binding Hotspots Develop Broad HIV Neutralization.
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Kong R, Duan H, Sheng Z, Xu K, Acharya P, Chen X, Cheng C, Dingens AS, Gorman J, Sastry M, Shen CH, Zhang B, Zhou T, Chuang GY, Chao CW, Gu Y, Jafari AJ, Louder MK, O'Dell S, Rowshan AP, Viox EG, Wang Y, Choi CW, Corcoran MM, Corrigan AR, Dandey VP, Eng ET, Geng H, Foulds KE, Guo Y, Kwon YD, Lin B, Liu K, Mason RD, Nason MC, Ohr TY, Ou L, Rawi R, Sarfo EK, Schön A, Todd JP, Wang S, Wei H, Wu W, Mullikin JC, Bailer RT, Doria-Rose NA, Karlsson Hedestam GB, Scorpio DG, Overbaugh J, Bloom JD, Carragher B, Potter CS, Shapiro L, Kwong PD, and Mascola JR
- Subjects
- Amino Acid Sequence, Animals, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing classification, B-Lymphocytes cytology, B-Lymphocytes metabolism, Crystallography, X-Ray, Female, HEK293 Cells, HIV Antibodies chemistry, HIV Antibodies classification, HIV-1 metabolism, Humans, Macaca mulatta, Male, Peptides chemistry, Protein Structure, Tertiary, env Gene Products, Human Immunodeficiency Virus chemistry, env Gene Products, Human Immunodeficiency Virus immunology, env Gene Products, Human Immunodeficiency Virus metabolism, AIDS Vaccines immunology, Antibodies, Neutralizing immunology, HIV Antibodies immunology, Peptides immunology
- Abstract
The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization., (Published by Elsevier Inc.)
- Published
- 2019
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33. Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies.
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Duan H, Chen X, Boyington JC, Cheng C, Zhang Y, Jafari AJ, Stephens T, Tsybovsky Y, Kalyuzhniy O, Zhao P, Menis S, Nason MC, Normandin E, Mukhamedova M, DeKosky BJ, Wells L, Schief WR, Tian M, Alt FW, Kwong PD, and Mascola JR
- Subjects
- AIDS Vaccines immunology, Animals, Antibodies, Monoclonal immunology, Broadly Neutralizing Antibodies, Cell Line, Female, Gene Knock-In Techniques, HIV Envelope Protein gp120 immunology, HIV Infections immunology, HIV Infections prevention & control, Humans, Immunoglobulin Heavy Chains immunology, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Polysaccharides chemistry, Antibodies, Neutralizing immunology, Binding Sites, Antibody immunology, CD4 Antigens immunology, HIV Antibodies immunology, HIV-1 immunology
- Abstract
An important class of HIV-1 broadly neutralizing antibodies, termed the VRC01 class, targets the conserved CD4-binding site (CD4bs) of the envelope glycoprotein (Env). An engineered Env outer domain (OD) eOD-GT8 60-mer nanoparticle has been developed as a priming immunogen for eliciting VRC01-class precursors and is planned for clinical trials. However, a substantial portion of eOD-GT8-elicited antibodies target non-CD4bs epitopes, potentially limiting its efficacy. We introduced N-linked glycans into non-CD4bs surfaces of eOD-GT8 to mask irrelevant epitopes and evaluated these mutants in a mouse model that expressed diverse immunoglobulin heavy chains containing human IGHV1-2
∗ 02, the germline VRC01 VH segment. Compared to the parental eOD-GT8, a mutant with five added glycans stimulated significantly higher proportions of CD4bs-specific serum responses and CD4bs-specific immunoglobulin G+ B cells including VRC01-class precursors. These results demonstrate that glycan masking can limit elicitation of off-target antibodies and focus immune responses to the CD4bs, a major target of HIV-1 vaccine design., (Published by Elsevier Inc.)- Published
- 2018
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34. Lymph Node Activation by PET/CT Following Vaccination With Licensed Vaccines for Human Papillomaviruses.
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Coates EE, Costner PJ, Nason MC, Herrin DM, Conant S, Herscovitch P, Sarwar UN, Holman L, Mitchell J, Yamshchikov G, Koup RA, Graham BS, Millo CM, and Ledgerwood JE
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- Adolescent, Adult, Female, Humans, Papillomaviridae, Vaccination, Young Adult, Human Papillomavirus Recombinant Vaccine Quadrivalent, Types 6, 11, 16, 18 immunology, Lymph Nodes diagnostic imaging, Lymph Nodes metabolism, Papillomavirus Vaccines immunology, Positron Emission Tomography Computed Tomography
- Abstract
Background: While PET using F-FDG is most commonly used for imaging malignant tumors, vaccination is known to cause transient inflammation of lymph nodes inducing positive findings on F-FDG PET scans. The pattern, magnitude, and duration of lymph node activation following vaccination have not been clearly defined. Furthermore, the addition of adjuvants to vaccines can further enhance the immune response. The presented study was designed to define lymph node activation following administration of the Food and Drug Administration-licensed human papillomavirus vaccines, Cervarix and Gardasil, which contain similar antigens with different adjuvants., Methods: Twenty-seven women aged 18 to 25 years were randomized to receive either Cervarix or Gardasil in the clinical trial VRC 900. Fifteen subjects participated in the PET/CT portion of the trial and received scans of lymph node activation at prevaccination and "1 week" (8-14 days) and "1 month" (23-36 days) after the first or third vaccination., Results: PET/CT scans revealed that all vaccine recipients had ipsilateral axillary lymph node activity. Three of 4 Cervarix recipients also showed contralateral lymph node activity 1 month after the first vaccination. For both Cervarix and Gardasil, the SUV activity resolved over time, with activity extended up to day 37 after the first and third vaccinations., Conclusions: Following intramuscular vaccination, there were no major differences between duration of uptake and intensity of SUV between Cervarix and Gardasil recipients in ipsilateral axillary lymph nodes. Contralateral node activation was detected up to 1 month after the first vaccination in Cervarix recipients only, possibly reflecting differences in vaccine adjuvant formulation.
- Published
- 2017
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35. Attenuated PfSPZ Vaccine induces strain-transcending T cells and durable protection against heterologous controlled human malaria infection.
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Lyke KE, Ishizuka AS, Berry AA, Chakravarty S, DeZure A, Enama ME, James ER, Billingsley PF, Gunasekera A, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, Kc N, Murshedkar T, Mendoza FH, Gordon IJ, Zephir KL, Holman LA, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Berkowitz NM, Flynn BJ, Nason MC, Garver LS, Laurens MB, Plowe CV, Richie TL, Graham BS, Roederer M, Sim BK, Ledgerwood JE, Hoffman SL, and Seder RA
- Subjects
- Adolescent, Adult, Female, Healthy Volunteers, Humans, Malaria Vaccines adverse effects, Malaria Vaccines immunology, Malaria, Falciparum immunology, Malaria, Falciparum parasitology, Male, Middle Aged, Plasmodium falciparum pathogenicity, Sporozoites immunology, Sporozoites pathogenicity, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes parasitology, Vaccines, Attenuated adverse effects, Vaccines, Attenuated immunology, Malaria Vaccines administration & dosage, Malaria, Falciparum prevention & control, Plasmodium falciparum drug effects, Vaccines, Attenuated administration & dosage
- Abstract
A live-attenuated malaria vaccine, Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 10
5 PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls ( P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.- Published
- 2017
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36. Accelerating Vaccine Development During the 2013-2016 West African Ebola Virus Disease Outbreak.
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Higgs ES, Dubey SA, Coller BAG, Simon JK, Bollinger L, Sorenson RA, Wilson B, Nason MC, and Hensley LE
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- Africa, Western epidemiology, Disease Outbreaks, Hemorrhagic Fever, Ebola transmission, Humans, Biomedical Research statistics & numerical data, Ebola Vaccines supply & distribution, Hemorrhagic Fever, Ebola epidemiology, Hemorrhagic Fever, Ebola prevention & control
- Abstract
The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak. Despite these hurdles, the global health community succeeded in accelerating Ebola virus vaccine development, in a 5-month interval initiating phase I trials in humans in September 2014 and initiating phase II/III trails in February 2015. Each of the three Ebola virus disease-affected countries, Sierra Leone, Guinea, and Liberia, conducted a phase II/III Ebola virus vaccine trial. Only one of these trials evaluating recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein demonstrated vaccine efficacy using an innovative mobile ring vaccination trial design based on a ring vaccination strategy responsible for eradicating smallpox that reached areas of new outbreaks. Thoughtful and intensive community engagement in each country enabled the critical community partnership and acceptance of the phase II/III in each country. Due to the delayed clinical trial initiation, relative to the epidemiologic peak of the outbreak in the three countries, vaccine interventions may or may not have played a major role in bringing the epidemic under control. Having demonstrated that clinical trials can be performed during a large outbreak, the global research community can now build on the experience to implement trials more rapidly and efficiently in future outbreaks. Incorporating clinical research needs into planning for future health emergencies and understanding what kind of trial designs is needed for reliable results in an epidemic of limited duration should improve global response to future infectious disease outbreaks.
- Published
- 2017
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37. Safety and Immunogenicity of a rAd35-EnvA Prototype HIV-1 Vaccine in Combination with rAd5-EnvA in Healthy Adults (VRC 012).
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Crank MC, Wilson EM, Novik L, Enama ME, Hendel CS, Gu W, Nason MC, Bailer RT, Nabel GJ, McDermott AB, Mascola JR, Koup RA, Ledgerwood JE, and Graham BS
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- AIDS Vaccines genetics, Adenoviridae genetics, Adolescent, Adult, Antibody Formation immunology, Female, Genetic Vectors, HIV Infections immunology, HIV Infections virology, HIV-1 drug effects, HIV-1 immunology, HIV-1 pathogenicity, Humans, Immunization, Secondary, Male, Middle Aged, Vaccines, DNA administration & dosage, Vaccines, DNA genetics, Vaccines, DNA immunology, Young Adult, env Gene Products, Human Immunodeficiency Virus administration & dosage, env Gene Products, Human Immunodeficiency Virus genetics, AIDS Vaccines administration & dosage, Antibodies, Viral immunology, HIV Infections genetics, HIV Infections prevention & control, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
Background: VRC 012 was a Phase I study of a prototype recombinant adenoviral-vector serotype-35 (rAd35) HIV vaccine, the precursor to two recently published clinical trials, HVTN 077 and 083. On the basis of prior evaluation of multiclade rAd5 HIV vaccines, Envelope A (EnvA) was selected as the standard antigen for a series of prototype HIV vaccines to compare various vaccine platforms. In addition, prior studies of rAd5-vectored vaccines suggested pre-existing human immunity may be a confounding factor in vaccine efficacy. rAd35 is less seroprevalent across human populations and was chosen for testing alone and in combination with a rAd5-EnvA vaccine in the present two-part phase I study., Methods: First, five subjects each received a single injection of 109, 1010, or 1011 particle units (PU) of rAd35-EnvA in an open-label, dose-escalation study. Next, 20 Ad5/Ad35-seronegative subjects were randomized to blinded, heterologous prime-boost schedules combining rAd5-EnvA and rAd35-EnvA with a three month interval. rAd35-EnvA was given at 1010 or 1011 PU to ten subjects each; all rAd5-EnvA injections were 1010 PU. EnvA-specific immunogenicity was assessed four weeks post-injection. Solicited reactogenicity and clinical safety were followed after each injection., Results: Vaccinations were well tolerated at all dosages. Antibody responses measured by ELISA were detected at 4 weeks in 30% and 50% of subjects after single doses of 1010 or 1011 PU rAd35, respectively, and in 89% after a single rAd5-EnvA 1010 PU injection. EnvA-specific IFN-γ ELISpot responses were detected at four weeks in 0%, 70%, and 50% of subjects after the respective rAd35-EnvA dosages compared to 89% of subjects after rAd5. T cell responses were higher after a single rAd5-EnvA 1010 PU injection than after a single rAd35-EnvA 1010 PU injection, and humoral responses were low after a single dose of either vector. Of those completing the vaccine schedule, 100% of rAd5-EnvA recipients and 90% of rAd35-EnvA recipients had both T cell and humoral responses after boosting with the heterologous vector. ELISpot response magnitude was similar in both regimens and comparable to a single dose of rAd5. A trend toward more robust CD8 T cell responses using rAd5-EnvA prime and rAd35-EnvA boost was observed. Humoral response magnitude was also similar after either heterologous regimen, but was several fold higher than after a single dose of rAd5. Adverse events (AEs) related to study vaccines were in general mild and limited to one episode of hematuria, Grade two. Activated partial thromboplastin time (aPTT) AEs were consistent with an in vitro effect on the laboratory assay for aPTT due to a transient induction of anti-phospholipid antibody, a phenomenon that has been reported in other adenoviral vector vaccine trials., Conclusions: Limitations of the rAd vaccine vectors, including the complex interactions among pre-existing adenoviral immunity and vaccine-induced immune responses, have prompted investigators to include less seroprevalent vectors such as rAd35-EnvA in prime-boost regimens. The rAd35-EnvA vaccine described here was well tolerated and immunogenic. While it effectively primed and boosted antibody responses when given in a reciprocal prime-boost regimen with rAd5-EnvA using a three-month interval, it did not significantly improve the frequency or magnitude of T cell responses above a single dose of rAd5. The humoral and cellular immunogenicity data reported here may inform future vaccine and study design., Trial Registration: ClinicalTrials.gov NCT00479999., Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: Dr. Gary Nabel is currently employed by Sanofi; however, his involvement in the planning of the clinical trial and any significant input on the manuscript were completed while he was employed at the Vaccine Research Center, NIAID, NIH. Dr. Nabel is named on patent applications for the vaccine concepts employed in the manuscript. The identification numbers for these patents are as follows: E-275-2000, 60/225,097; E-335-2003, 60/503,508; E-173-2004, 60/561,341. There are no further patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.
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- 2016
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38. Rapid development of a DNA vaccine for Zika virus.
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Dowd KA, Ko SY, Morabito KM, Yang ES, Pelc RS, DeMaso CR, Castilho LR, Abbink P, Boyd M, Nityanandam R, Gordon DN, Gallagher JR, Chen X, Todd JP, Tsybovsky Y, Harris A, Huang YS, Higgs S, Vanlandingham DL, Andersen H, Lewis MG, De La Barrera R, Eckels KH, Jarman RG, Nason MC, Barouch DH, Roederer M, Kong WP, Mascola JR, Pierson TC, and Graham BS
- Subjects
- Animals, Antibodies, Neutralizing blood, Antibodies, Neutralizing immunology, Female, Macaca mulatta, Male, Mice, Vaccination, Viral Envelope Proteins genetics, Viral Load immunology, Viremia immunology, Viremia prevention & control, Zika Virus genetics, Zika Virus Infection virology, Immunogenicity, Vaccine, Vaccines, DNA immunology, Viral Envelope Proteins immunology, Viral Vaccines immunology, Zika Virus immunology, Zika Virus Infection prevention & control
- Abstract
Zika virus (ZIKV) was identified as a cause of congenital disease during the explosive outbreak in the Americas and Caribbean that began in 2015. Because of the ongoing fetal risk from endemic disease and travel-related exposures, a vaccine to prevent viremia in women of childbearing age and their partners is imperative. We found that vaccination with DNA expressing the premembrane and envelope proteins of ZIKV was immunogenic in mice and nonhuman primates, and protection against viremia after ZIKV challenge correlated with serum neutralizing activity. These data not only indicate that DNA vaccination could be a successful approach to protect against ZIKV infection, but also suggest a protective threshold of vaccine-induced neutralizing activity that prevents viremia after acute infection., (Copyright © 2016, American Association for the Advancement of Science.)
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- 2016
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39. Corrigendum: Protection against malaria at 1 year and immune correlates following PfSPZ vaccination.
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Ishizuka AS, Lyke KE, DeZure A, Berry AA, Richie TL, Mendoza FH, Enama ME, Gordon IJ, Chang LJ, Sarwar UN, Zephir KL, Holman LA, James ER, Billingsley PF, Gunasekera A, Chakravarty S, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, K C N, Murshedkar T, DeCederfelt H, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Laurens MB, Plowe CV, Flynn B, Whalen WR, Todd JP, Noor J, Rao S, Sierra-Davidson K, Lynn GM, Epstein JE, Kemp MA, Fahle GA, Mikolajczak SA, Fishbaugher M, Sack BK, Kappe SH, Davidson SA, Garver LS, Björkström NK, Nason MC, Graham BS, Roederer M, Sim BK, Hoffman SL, Ledgerwood JE, and Seder RA
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- 2016
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40. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination.
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Ishizuka AS, Lyke KE, DeZure A, Berry AA, Richie TL, Mendoza FH, Enama ME, Gordon IJ, Chang LJ, Sarwar UN, Zephir KL, Holman LA, James ER, Billingsley PF, Gunasekera A, Chakravarty S, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, K C N, Murshedkar T, DeCederfelt H, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Laurens MB, Plowe CV, Flynn B, Whalen WR, Todd JP, Noor J, Rao S, Sierra-Davidson K, Lynn GM, Epstein JE, Kemp MA, Fahle GA, Mikolajczak SA, Fishbaugher M, Sack BK, Kappe SH, Davidson SA, Garver LS, Björkström NK, Nason MC, Graham BS, Roederer M, Sim BK, Hoffman SL, Ledgerwood JE, and Seder RA
- Subjects
- Administration, Intravenous, Adolescent, Adult, Animals, Enzyme-Linked Immunosorbent Assay, Female, Healthy Volunteers, Humans, Immunoglobulin G immunology, Interferon-gamma immunology, Liver cytology, Macaca mulatta, Malaria Vaccines immunology, Male, Middle Aged, Parasitemia immunology, Sporozoites immunology, T-Lymphocytes immunology, Young Adult, Antibodies, Protozoan immunology, CD8-Positive T-Lymphocytes immunology, Immunogenicity, Vaccine immunology, Liver immunology, Malaria Vaccines therapeutic use, Malaria, Falciparum prevention & control, Parasitemia prevention & control, Plasmodium falciparum immunology
- Abstract
An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.
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- 2016
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41. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges.
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Gautam R, Nishimura Y, Pegu A, Nason MC, Klein F, Gazumyan A, Golijanin J, Buckler-White A, Sadjadpour R, Wang K, Mankoff Z, Schmidt SD, Lifson JD, Mascola JR, Nussenzweig MC, and Martin MA
- Subjects
- AIDS Vaccines administration & dosage, AIDS Vaccines immunology, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal blood, Antibodies, Monoclonal genetics, Antibodies, Monoclonal immunology, Antibodies, Neutralizing administration & dosage, Antibodies, Neutralizing blood, Antibodies, Neutralizing genetics, Antibodies, Neutralizing immunology, Female, HIV Antibodies blood, HIV Antibodies genetics, HIV Infections immunology, HIV Infections prevention & control, HIV Infections transmission, Half-Life, Immunoglobulin Fc Fragments chemistry, Immunoglobulin Fc Fragments genetics, Immunoglobulin Fc Fragments immunology, Macaca mulatta immunology, Macaca mulatta virology, Male, Mutation genetics, Protein Structure, Tertiary, SAIDS Vaccines administration & dosage, SAIDS Vaccines immunology, Simian Acquired Immunodeficiency Syndrome blood, Time Factors, HIV Antibodies administration & dosage, HIV Antibodies immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.
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- 2016
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42. Immunological Signaling During Herpes Simplex Virus-2 and Cytomegalovirus Vaginal Shedding After Initiation of Antiretroviral Treatment.
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Nason MC, Patel EU, Kirkpatrick AR, Prodger JL, Shahabi K, Tobian AA, Gianella S, Kalibbala S, Ssebbowa P, Kaul R, Gray RH, Quinn TC, Serwadda D, Reynolds SJ, and Redd AD
- Abstract
Vaginal proinflammatory cytokine expression during herpes virus reactivation was examined in human immunodeficiency virus-infected women before and after initiation of antiretroviral therapy (ART). Vaginal swabs were screened for levels of cytokines interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, tumor necrosis factor (TNF)-α, and interferon-γ. The relative risk (RR) of herpes simplex virus-2 or cytomegalovirus (CMV) shedding being associated with cytokine levels above the median were estimated. Herpes simplex virus-2 shedding was significantly associated with higher levels of IL-6 (RR = 1.4, P = .003) and TNF-α (RR = 1.3, P = .010), whereas CMV shedding was associated with higher IL-6 (RR = 1.3, P = .006) and IL-2 (RR = 1.4, P = .01). The association of viral shedding with higher IL-6 levels suggests that herpes virus reactivation may be playing a role in immune activation after ART initiation.
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- 2016
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43. Implementation of an Ebola virus disease vaccine clinical trial during the Ebola epidemic in Liberia: Design, procedures, and challenges.
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Kennedy SB, Neaton JD, Lane HC, Kieh MW, Massaquoi MB, Touchette NA, Nason MC, Follmann DA, Boley FK, Johnson MP, Larson G, Kateh FN, and Nyenswah TG
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- Clinical Protocols, Clinical Trials, Phase II as Topic methods, Clinical Trials, Phase III as Topic methods, Double-Blind Method, Follow-Up Studies, Humans, International Cooperation, Liberia, Sample Size, United States, World Health Organization, Ebola Vaccines, Hemorrhagic Fever, Ebola prevention & control, Randomized Controlled Trials as Topic methods, Research Design
- Abstract
The index case of the Ebola virus disease epidemic in West Africa is believed to have originated in Guinea. By June 2014, Guinea, Liberia, and Sierra Leone were in the midst of a full-blown and complex global health emergency. The devastating effects of this Ebola epidemic in West Africa put the global health response in acute focus for urgent international interventions. Accordingly, in October 2014, a World Health Organization high-level meeting endorsed the concept of a phase 2/3 clinical trial in Liberia to study Ebola vaccines. As a follow-up to the global response, in November 2014, the Government of Liberia and the US Government signed an agreement to form a research partnership to investigate Ebola and to assess intervention strategies for treating, controlling, and preventing the disease in Liberia. This agreement led to the establishment of the Joint Liberia-US Partnership for Research on Ebola Virus in Liberia as the beginning of a long-term collaborative partnership in clinical research between the two countries. In this article, we discuss the methodology and related challenges associated with the implementation of the Ebola vaccines clinical trial, based on a double-blinded randomized controlled trial, in Liberia., (© The Author(s) 2016.)
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- 2016
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44. Prefusion F-specific antibodies determine the magnitude of RSV neutralizing activity in human sera.
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Ngwuta JO, Chen M, Modjarrad K, Joyce MG, Kanekiyo M, Kumar A, Yassine HM, Moin SM, Killikelly AM, Chuang GY, Druz A, Georgiev IS, Rundlet EJ, Sastry M, Stewart-Jones GB, Yang Y, Zhang B, Nason MC, Capella C, Peeples ME, Ledgerwood JE, McLellan JS, Kwong PD, and Graham BS
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- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Neutralizing blood, Antibodies, Neutralizing chemistry, Antibodies, Neutralizing isolation & purification, Antibodies, Viral blood, Antibodies, Viral chemistry, Antibodies, Viral isolation & purification, Child, Humans, Middle Aged, Respiratory Syncytial Virus Vaccines immunology, Respiratory Syncytial Viruses chemistry, Viral Fusion Proteins chemistry, Young Adult, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Respiratory Syncytial Viruses immunology, Viral Fusion Proteins immunology
- Abstract
Respiratory syncytial virus (RSV) is estimated to claim more lives among infants <1 year old than any other single pathogen, except malaria, and poses a substantial global health burden. Viral entry is mediated by a type I fusion glycoprotein (F) that transitions from a metastable prefusion (pre-F) to a stable postfusion (post-F) trimer. A highly neutralization-sensitive epitope, antigenic site Ø, is found only on pre-F. We determined what fraction of neutralizing (NT) activity in human sera is dependent on antibodies specific for antigenic site Ø or other antigenic sites on F in healthy subjects from ages 7 to 93 years. Adsorption of individual sera with stabilized pre-F protein removed >90% of NT activity and depleted binding antibodies to both F conformations. In contrast, adsorption with post-F removed ~30% of NT activity, and binding antibodies to pre-F were retained. These findings were consistent across all age groups. Protein competition neutralization assays with pre-F mutants in which sites Ø or II were altered to knock out binding of antibodies to the corresponding sites showed that these sites accounted for ~35 and <10% of NT activity, respectively. Binding competition assays with monoclonal antibodies (mAbs) indicated that the amount of site Ø-specific antibodies correlated with NT activity, whereas the magnitude of binding competed by site II mAbs did not correlate with neutralization. Our results indicate that RSV NT activity in human sera is primarily derived from pre-F-specific antibodies, and therefore, inducing or boosting NT activity by vaccination will be facilitated by using pre-F antigens that preserve site Ø., (Copyright © 2015, American Association for the Advancement of Science.)
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- 2015
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45. HIV-1 fitness cost associated with escape from the VRC01 class of CD4 binding site neutralizing antibodies.
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Lynch RM, Wong P, Tran L, O'Dell S, Nason MC, Li Y, Wu X, and Mascola JR
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- Amino Acid Sequence, Broadly Neutralizing Antibodies, CD4 Antigens immunology, Humans, Mutagenesis, Site-Directed, Neutralization Tests, Sequence Alignment, Sequence Analysis, DNA, Viral Envelope Proteins genetics, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, Genetic Fitness immunology, HIV Antibodies immunology, HIV Infections immunology, HIV-1 immunology, Immune Evasion immunology
- Abstract
Unlabelled: Broadly neutralizing antibodies (bNAbs) have been isolated from selected HIV-1-infected individuals and shown to bind to conserved sites on the envelope glycoprotein (Env). However, circulating plasma virus in these donors is usually resistant to autologous isolated bNAbs, indicating that during chronic infection, HIV-1 can escape from even broadly cross-reactive antibodies. Here, we evaluate if such viral escape is associated with an impairment of viral replication. Antibodies of the VRC01 class target the functionally conserved CD4 binding site and share a structural mode of gp120 recognition that includes mimicry of the CD4 receptor. We examined naturally occurring VRC01-sensitive and -resistant viral strains, as well as their mutated sensitive or resistant variants, and tested point mutations in the backbone of the VRC01-sensitive isolate YU2. In several cases, VRC01 resistance was associated with a reduced efficiency of CD4-mediated viral entry and diminished viral replication. Several mutations, alone or in combination, in the loop D or β23-V5 region of Env conferred a high level of resistance to VRC01 class antibodies, suggesting a preferred escape pathway. We further mapped the VRC01-induced escape pathway in vivo using Envs from donor 45, from whom antibody VRC01 was isolated. Initial escape mutations, including the addition of a key glycan, occurred in loop D and were associated with impaired viral replication; however, compensatory mutations restored full replicative fitness. These data demonstrate that escape from VRC01 class antibodies can diminish viral replicative fitness, but compensatory changes may explain the limited impact of neutralizing antibodies during the course of natural HIV-1 infection., Importance: Some antibodies that arise during natural HIV-1 infection bind to conserved regions on the virus envelope glycoprotein and potently neutralize the majority of diverse HIV-1 strains. The VRC01 class of antibodies blocks the conserved CD4 receptor binding site interaction that is necessary for viral entry, raising the possibility that viral escape from antibody neutralization might exert detrimental effects on viral function. Here, we show that escape from VRC01 class antibodies can be associated with impaired viral entry and replication; however, during the course of natural infection, compensatory mutations restore the ability of the virus to replicate normally., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
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- 2015
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46. Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo.
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Rudicell RS, Kwon YD, Ko SY, Pegu A, Louder MK, Georgiev IS, Wu X, Zhu J, Boyington JC, Chen X, Shi W, Yang ZY, Doria-Rose NA, McKee K, O'Dell S, Schmidt SD, Chuang GY, Druz A, Soto C, Yang Y, Zhang B, Zhou T, Todd JP, Lloyd KE, Eudailey J, Roberts KE, Donald BR, Bailer RT, Ledgerwood J, Mullikin JC, Shapiro L, Koup RA, Graham BS, Nason MC, Connors M, Haynes BF, Rao SS, Roederer M, Kwong PD, Mascola JR, and Nabel GJ
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- Animals, Antibodies, Neutralizing administration & dosage, Antibodies, Neutralizing genetics, HIV Antibodies administration & dosage, HIV Antibodies genetics, HIV-1 genetics, Macaca mulatta, Male, Molecular Sequence Data, Sequence Analysis, DNA, Antibodies, Neutralizing immunology, HIV Antibodies immunology, HIV-1 immunology, Immunization, Passive methods, Simian Acquired Immunodeficiency Syndrome prevention & control
- Abstract
Unlabelled: Over the past 5 years, a new generation of highly potent and broadly neutralizing HIV-1 antibodies has been identified. These antibodies can protect against lentiviral infection in nonhuman primates (NHPs), suggesting that passive antibody transfer would prevent HIV-1 transmission in humans. To increase the protective efficacy of such monoclonal antibodies, we employed next-generation sequencing, computational bioinformatics, and structure-guided design to enhance the neutralization potency and breadth of VRC01, an antibody that targets the CD4 binding site of the HIV-1 envelope. One variant, VRC07-523, was 5- to 8-fold more potent than VRC01, neutralized 96% of viruses tested, and displayed minimal autoreactivity. To compare its protective efficacy to that of VRC01 in vivo, we performed a series of simian-human immunodeficiency virus (SHIV) challenge experiments in nonhuman primates and calculated the doses of VRC07-523 and VRC01 that provide 50% protection (EC50). VRC07-523 prevented infection in NHPs at a 5-fold lower concentration than VRC01. These results suggest that increased neutralization potency in vitro correlates with improved protection against infection in vivo, documenting the improved functional efficacy of VRC07-523 and its potential clinical relevance for protecting against HIV-1 infection in humans., Importance: In the absence of an effective HIV-1 vaccine, alternative strategies are needed to block HIV-1 transmission. Direct administration of HIV-1-neutralizing antibodies may be able to prevent HIV-1 infections in humans. This approach could be especially useful in individuals at high risk for contracting HIV-1 and could be used together with antiretroviral drugs to prevent infection. To optimize the chance of success, such antibodies can be modified to improve their potency, breadth, and in vivo half-life. Here, knowledge of the structure of a potent neutralizing antibody, VRC01, that targets the CD4-binding site of the HIV-1 envelope protein was used to engineer a next-generation antibody with 5- to 8-fold increased potency in vitro. When administered to nonhuman primates, this antibody conferred protection at a 5-fold lower concentration than the original antibody. Our studies demonstrate an important correlation between in vitro assays used to evaluate the therapeutic potential of antibodies and their in vivo effectiveness., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)
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- 2014
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47. Enhanced neonatal Fc receptor function improves protection against primate SHIV infection.
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Ko SY, Pegu A, Rudicell RS, Yang ZY, Joyce MG, Chen X, Wang K, Bao S, Kraemer TD, Rath T, Zeng M, Schmidt SD, Todd JP, Penzak SR, Saunders KO, Nason MC, Haase AT, Rao SS, Blumberg RS, Mascola JR, and Nabel GJ
- Subjects
- Administration, Rectal, Animals, Antibodies, Neutralizing analysis, Antibodies, Neutralizing blood, Antibodies, Neutralizing genetics, Antibodies, Viral analysis, Antibodies, Viral blood, Antibodies, Viral genetics, Antibody Affinity genetics, Antibody Affinity immunology, Antibody-Dependent Cell Cytotoxicity immunology, Binding Sites genetics, CD4 Antigens metabolism, Female, HIV chemistry, HIV immunology, HIV Antibodies analysis, HIV Antibodies blood, HIV Antibodies genetics, HIV Antibodies immunology, HIV Envelope Protein gp160 chemistry, HIV Envelope Protein gp160 immunology, Half-Life, Immunity, Mucosal immunology, Immunization, Passive, Intestinal Mucosa immunology, Macaca mulatta, Male, Mice, Mutagenesis, Site-Directed, Receptors, IgG immunology, Receptors, IgG metabolism, Rectum immunology, Simian Immunodeficiency Virus immunology, Transcytosis, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, HIV Infections immunology, HIV Infections prevention & control, Histocompatibility Antigens Class I immunology, Receptors, Fc immunology, Simian Acquired Immunodeficiency Syndrome immunology, Simian Acquired Immunodeficiency Syndrome prevention & control
- Abstract
To protect against human immunodeficiency virus (HIV-1) infection, broadly neutralizing antibodies (bnAbs) must be active at the portals of viral entry in the gastrointestinal or cervicovaginal tracts. The localization and persistence of antibodies at these sites is influenced by the neonatal Fc receptor (FcRn), whose role in protecting against infection in vivo has not been defined. Here, we show that a bnAb with enhanced FcRn binding has increased gut mucosal tissue localization, which improves protection against lentiviral infection in non-human primates. A bnAb directed to the CD4-binding site of the HIV-1 envelope (Env) protein (denoted VRC01) was modified by site-directed mutagenesis to increase its binding affinity for FcRn. This enhanced FcRn-binding mutant bnAb, denoted VRC01-LS, displayed increased transcytosis across human FcRn-expressing cellular monolayers in vitro while retaining FcγRIIIa binding and function, including antibody-dependent cell-mediated cytotoxicity (ADCC) activity, at levels similar to VRC01 (the wild type). VRC01-LS had a threefold longer serum half-life than VRC01 in non-human primates and persisted in the rectal mucosa even when it was no longer detectable in the serum. Notably, VRC01-LS mediated protection superior to that afforded by VRC01 against intrarectal infection with simian-human immunodeficiency virus (SHIV). These findings suggest that modification of FcRn binding provides a mechanism not only to increase serum half-life but also to enhance mucosal localization that confers immune protection. Mutations that enhance FcRn function could therefore increase the potency and durability of passive immunization strategies to prevent HIV-1 infection.
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- 2014
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48. Homologous boosting with adenoviral serotype 5 HIV vaccine (rAd5) vector can boost antibody responses despite preexisting vector-specific immunity in a randomized phase I clinical trial.
- Author
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Sarwar UN, Novik L, Enama ME, Plummer SA, Koup RA, Nason MC, Bailer RT, McDermott AB, Roederer M, Mascola JR, Ledgerwood JE, and Graham BS
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- Adolescent, Adult, Enzyme-Linked Immunosorbent Assay, Humans, Middle Aged, Young Adult, AIDS Vaccines immunology, Adenoviridae genetics, Genetic Vectors, HIV Antibodies biosynthesis
- Abstract
Background: Needle-free delivery improves the immunogenicity of DNA vaccines but is also associated with more local reactogenicity. Here we report the first comparison of Biojector and needle administration of a candidate rAd5 HIV vaccine., Methods: Thirty-one adults, 18-55 years, 20 naive and 11 prior rAd5 vaccine recipients were randomized to receive single rAd5 vaccine via needle or Biojector IM injection at 1010 PU in a Phase I open label clinical trial. Solicited reactogenicity was collected for 5 days; clinical safety and immunogenicity follow-up was continued for 24 weeks., Results: Overall, injections by either method were well tolerated. There were no serious adverse events. Frequency of any local reactogenicity was 16/16 (100%) for Biojector compared to 11/15 (73%) for needle injections. There was no difference in HIV Env-specific antibody response between Biojector and needle delivery. Env-specific antibody responses were more than 10-fold higher in subjects receiving a booster dose of rAd5 vaccine than after a single dose delivered by either method regardless of interval between prime and boost., Conclusions: Biojector delivery did not improve antibody responses to the rAd5 vaccine compared to needle administration. Homologous boosting with rAd5 gene-based vectors can boost insert-specific antibody responses despite pre-existing vector-specific immunity., Trial Registration: Clinicaltrials.gov NCT00709605 NCT00709605.
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- 2014
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49. Passive transfer of modest titers of potent and broadly neutralizing anti-HIV monoclonal antibodies block SHIV infection in macaques.
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Shingai M, Donau OK, Plishka RJ, Buckler-White A, Mascola JR, Nabel GJ, Nason MC, Montefiori D, Moldt B, Poignard P, Diskin R, Bjorkman PJ, Eckhaus MA, Klein F, Mouquet H, Cetrulo Lorenzi JC, Gazumyan A, Burton DR, Nussenzweig MC, Martin MA, and Nishimura Y
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Neutralizing administration & dosage, DNA Primers genetics, HIV Antibodies administration & dosage, Humans, Macaca mulatta, Mutagenesis, Neutralization Tests, Regression Analysis, Vaccination methods, Antibodies, Monoclonal immunology, Antibodies, Neutralizing immunology, HIV immunology, HIV Antibodies immunology, Lentivirus Infections prevention & control, Simian Immunodeficiency Virus immunology
- Abstract
It is widely appreciated that effective human vaccines directed against viral pathogens elicit neutralizing antibodies (NAbs). The passive transfer of anti-HIV-1 NAbs conferring sterilizing immunity to macaques has been used to determine the plasma neutralization titers, which must be present at the time of exposure, to prevent acquisition of SIV/HIV chimeric virus (SHIV) infections. We administered five recently isolated potent and broadly acting anti-HIV neutralizing monoclonal antibodies (mAbs) to rhesus macaques and challenged them intrarectally 24 h later with either of two different R5-tropic SHIVs. By combining the results obtained from 60 challenged animals, we determined that the protective neutralization titer in plasma preventing virus infection in 50% of the exposed monkeys was relatively modest (∼1:100) and potentially achievable by vaccination.
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- 2014
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50. Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor.
- Author
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Pegu A, Yang ZY, Boyington JC, Wu L, Ko SY, Schmidt SD, McKee K, Kong WP, Shi W, Chen X, Todd JP, Letvin NL, Huang J, Nason MC, Hoxie JA, Kwong PD, Connors M, Rao SS, Mascola JR, and Nabel GJ
- Subjects
- Animals, Antibodies, Neutralizing immunology, CD4 Antigens immunology, Female, HIV Antibodies immunology, HIV Antibodies therapeutic use, Macaca mulatta, Male, Antibodies, Neutralizing therapeutic use, HIV Infections immunology, HIV Infections prevention & control, HIV-1 immunology, env Gene Products, Human Immunodeficiency Virus immunology
- Abstract
HIV-1 infection depends on effective viral entry mediated by the interaction of its envelope (Env) glycoprotein with specific cell surface receptors. Protective antiviral antibodies generated by passive or active immunization must prevent these interactions. Because the HIV-1 Env is highly variable, attention has also focused on blocking the HIV-1 primary cell receptor CD4. We therefore analyzed the in vivo protective efficacy of three potent neutralizing monoclonal antibodies (mAbs) to HIV-1 Env compared to an antibody against the CD4 receptor. Protection was assessed after mucosal challenge of rhesus macaques with simian/HIV (SHIV). Despite its comparable or greater neutralization potency in vitro, the anti-CD4 antibody did not provide effective protection in vivo, whereas the HIV-1-specific mAbs VRC01, 10E8, and PG9, targeting the CD4 binding site, membrane-proximal, and V1V2 glycan Env regions, respectively, conferred complete protection, albeit at different relative potencies. These findings demonstrate the protective efficacy of broadly neutralizing antibodies directed to the HIV-1 Env and suggest that targeting the HIV-1 Env is preferable to the cell surface receptor CD4 for the prevention of HIV-1 transmission., (Copyright © 2014, American Association for the Advancement of Science.)
- Published
- 2014
- Full Text
- View/download PDF
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