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1.
Proc Natl Acad Sci U S A ; 119(28): e2204607119, 2022 Jul 12.
Article in English | MEDLINE | ID: mdl-35759653

ABSTRACT

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

2.
Nature ; 606(7913): 375-381, 2022 06.
Article in English | MEDLINE | ID: mdl-35650437

ABSTRACT

Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.


Subject(s)
Anti-HIV Agents , Antibodies, Neutralizing , HIV Antibodies , HIV Infections , HIV-1 , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Anti-HIV Agents/immunology , Anti-HIV Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/immunology , Antibodies, Neutralizing/therapeutic use , Broadly Neutralizing Antibodies/administration & dosage , Broadly Neutralizing Antibodies/adverse effects , Broadly Neutralizing Antibodies/immunology , Broadly Neutralizing Antibodies/therapeutic use , Double-Blind Method , HIV Antibodies/administration & dosage , HIV Antibodies/adverse effects , HIV Antibodies/immunology , HIV Antibodies/therapeutic use , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/virology , HIV-1/drug effects , HIV-1/immunology , HIV-1/isolation & purification , Humans , Viral Load/drug effects , Viremia/drug therapy , Viremia/immunology , Viremia/virology
3.
J Infect Dis ; 2022 Mar 31.
Article in English | MEDLINE | ID: mdl-35356987
5.
Nat Med ; 27(12): 2234-2245, 2021 12.
Article in English | MEDLINE | ID: mdl-34887575

ABSTRACT

The development of a protective vaccine remains a top priority for the control of the HIV/AIDS pandemic. Here, we show that a messenger RNA (mRNA) vaccine co-expressing membrane-anchored HIV-1 envelope (Env) and simian immunodeficiency virus (SIV) Gag proteins to generate virus-like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macaques. In mice, immunization with co-formulated env and gag mRNAs was superior to env mRNA alone in inducing neutralizing antibodies. Macaques were primed with a transmitted-founder clade-B env mRNA lacking the N276 glycan, followed by multiple booster immunizations with glycan-repaired autologous and subsequently bivalent heterologous envs (clades A and C). This regimen was highly immunogenic and elicited neutralizing antibodies against the most prevalent (tier-2) HIV-1 strains accompanied by robust anti-Env CD4+ T cell responses. Vaccinated animals had a 79% per-exposure risk reduction upon repeated low-dose mucosal challenges with heterologous tier-2 simian-human immunodeficiency virus (SHIV AD8). Thus, the multiclade env-gag VLP mRNA platform represents a promising approach for the development of an HIV-1 vaccine.


Subject(s)
Antibodies, Neutralizing/immunology , Genes, env , Genes, gag , HIV Antibodies/biosynthesis , HIV-1/immunology , Simian Acquired Immunodeficiency Syndrome/prevention & control , Vaccines, Synthetic/immunology , /immunology , Animals , HIV Antibodies/immunology , Immunization, Secondary , Macaca mulatta , Risk Factors , Simian Acquired Immunodeficiency Syndrome/immunology , Vaccines, Synthetic/administration & dosage , /administration & dosage
7.
Immunity ; 54(12): 2676-2680, 2021 12 14.
Article in English | MEDLINE | ID: mdl-34739870

ABSTRACT

The 2005 Immunity paper by Karikó et al. has been hailed as a cornerstone insight that directly led to the design and delivery of the mRNA vaccines against COVID-19. We asked experts in pathogen sensing, vaccine development, and public health to provide their perspective on the study and its implications.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/physiology , /immunology , Animals , History, 21st Century , Humans , RNA, Messenger/immunology , World Health Organization
8.
Ann Intern Med ; 175(1): 119-126, 2022 01.
Article in English | MEDLINE | ID: mdl-34724404

ABSTRACT

As the fourth wave of the SARS-CoV-2 pandemic encircles the globe, there remains an urgent challenge to identify safe and effective treatment and prevention strategies that can be implemented in a range of health care and clinical settings. Substantial advances have been made in the use of anti-SARS-CoV-2 antibodies to mitigate the morbidity and mortality associated with COVID-19. On 15 June 2021, the National Institutes of Health, in collaboration with the U.S. Food and Drug Administration, convened a virtual summit to summarize existing knowledge on anti-SARS-CoV-2 antibodies and to identify key unanswered scientific questions to further catalyze the clinical development and implementation of antibodies.


Subject(s)
Antibodies, Monoclonal/therapeutic use , COVID-19/prevention & control , COVID-19/therapy , SARS-CoV-2/immunology , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/immunology , COVID-19/immunology , Humans , Immunization, Passive/adverse effects , National Institutes of Health (U.S.) , United States , United States Food and Drug Administration
9.
Nat Med ; 27(11): 1893-1898, 2021 11.
Article in English | MEDLINE | ID: mdl-34711975

ABSTRACT

Certain infected individuals suppress human immunodeficiency virus (HIV) in the absence of anti-retroviral therapy (ART). Elucidating the underlying mechanism(s) is of high interest. Here we present two contrasting case reports of HIV-infected individuals who controlled plasma viremia for extended periods after undergoing analytical treatment interruption (ATI). In Participant 04, who experienced viral blips and initiated undisclosed self-administration of suboptimal ART detected shortly before day 1,250, phylogenetic analyses of plasma HIV env sequences suggested continuous viral evolution and/or reactivation of pre-existing viral reservoirs over time. Antiviral CD8+ T cell activities were higher in Participant 04 than in Participant 30. In contrast, Participant 30 exhibited potent plasma-IgG-mediated neutralization activity against autologous virus that became ineffective when he experienced sudden plasma viral rebound 1,434 d after ATI due to HIV superinfection. Our data provide insight into distinct mechanisms of post-treatment interruption control and highlight the importance of frequent monitoring of undisclosed use of ART and superinfection during the ATI phase.


Subject(s)
Anti-HIV Agents/therapeutic use , Antibodies, Viral/blood , CD8-Positive T-Lymphocytes/immunology , HIV Infections/drug therapy , HIV-1/immunology , Patient Compliance , Adult , Antibodies, Neutralizing/blood , CD4 Lymphocyte Count , HIV Infections/immunology , Humans , Immunoglobulin G/blood , Male , Middle Aged , Viral Load/immunology , Viremia/drug therapy , Viremia/immunology , Virus Activation/genetics , env Gene Products, Human Immunodeficiency Virus/blood , env Gene Products, Human Immunodeficiency Virus/genetics
10.
China CDC Wkly ; 2(39): 764-766, 2020 Sep 25.
Article in English | MEDLINE | ID: mdl-34594757
11.
Sci Transl Med ; 13(607)2021 08 18.
Article in English | MEDLINE | ID: mdl-34408080

ABSTRACT

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4ß7 with an anti-α4ß7 monoclonal antibody (Rh-α4ß7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4ß7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4ß7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4ß7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4ß7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.


Subject(s)
HIV Infections , HIV-1 , Simian Acquired Immunodeficiency Syndrome , Simian Immunodeficiency Virus , Animals , Antibodies, Neutralizing , Antibodies, Viral , Broadly Neutralizing Antibodies , HIV Antibodies , HIV Infections/drug therapy , Integrins , Macaca mulatta , Simian Acquired Immunodeficiency Syndrome/drug therapy
12.
medRxiv ; 2021 Jul 07.
Article in English | MEDLINE | ID: mdl-34268520

ABSTRACT

SARS-CoV-2 mRNA vaccines are highly effective, although weak antibody responses are seen in some individuals with correlates of immunity that remain poorly understood. Here we longitudinally dissected antibody, plasmablast, and memory B cell (MBC) responses to the two-dose Moderna mRNA vaccine in SARS-CoV-2-uninfected adults. Robust, coordinated IgA and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses, but earlier and more intensely after dose two. Distinct antigen-specific MBC populations also emerged post-vaccination with varying kinetics. We identified antigen non-specific pre-vaccination MBC and post-vaccination plasmablasts after dose one and their spike-specific counterparts early after dose two that correlated with subsequent antibody levels. These baseline and response signatures can thus provide early indicators of serological efficacy and explain response variability in the population.

13.
J Infect Dis ; 224(Supplement_1): S1-S21, 2021 Jul 15.
Article in English | MEDLINE | ID: mdl-34111271

ABSTRACT

The NIH Virtual SARS-CoV-2 Antiviral Summit, held on 6 November 2020, was organized to provide an overview on the status and challenges in developing antiviral therapeutics for coronavirus disease 2019 (COVID-19), including combinations of antivirals. Scientific experts from the public and private sectors convened virtually during a live videocast to discuss severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets for drug discovery as well as the preclinical tools needed to develop and evaluate effective small-molecule antivirals. The goals of the Summit were to review the current state of the science, identify unmet research needs, share insights and lessons learned from treating other infectious diseases, identify opportunities for public-private partnerships, and assist the research community in designing and developing antiviral therapeutics. This report includes an overview of therapeutic approaches, individual panel summaries, and a summary of the discussions and perspectives on the challenges ahead for antiviral development.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , SARS-CoV-2/drug effects , Antiviral Agents/pharmacology , COVID-19/virology , Drug Development , Humans , National Institutes of Health (U.S.) , Peptide Hydrolases/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , United States , Virus Replication/drug effects
14.
Am J Public Health ; 111(7): 1267-1272, 2021 07.
Article in English | MEDLINE | ID: mdl-34111372

ABSTRACT

Both the 1918 influenza pandemic and the 2019‒2021 COVID-19 pandemic are among the most disastrous infectious disease emergences of modern times. In addition to similarities in their clinical, pathological, and epidemiological features, the two pandemics, separated by more than a century, were each met with essentially the same, or very similar, public health responses, and elicited research efforts to control them with vaccines, therapeutics, and other medical approaches. Both pandemics had lasting, if at times invisible, psychosocial effects related to loss and hardship. In considering these two deadly pandemics, we ask: what lessons have we learned over the span of a century, and how are we applying those lessons to the challenges of COVID-19?


Subject(s)
COVID-19/epidemiology , Communicable Disease Control/organization & administration , Influenza, Human/epidemiology , Pandemics/history , COVID-19/history , COVID-19/pathology , History, 20th Century , History, 21st Century , Humans , Influenza, Human/history , Public Health/history
15.
Am J Public Health ; 111(6): 1086-1094, 2021 06.
Article in English | MEDLINE | ID: mdl-33950739

ABSTRACT

Separated by a century, the influenza pandemic of 1918 and the COVID-19 pandemic of 2019-2021 are among the most disastrous infectious disease emergences of modern times. Although caused by unrelated viruses, the two pandemics are nevertheless similar in their clinical, pathological, and epidemiological features, and in the civic, public health, and medical responses to combat them. Comparing and contrasting the two pandemics, we consider what lessons we have learned over the span of a century and how we are applying those lessons to the challenges of COVID-19.


Subject(s)
COVID-19/epidemiology , Influenza, Human/epidemiology , Pandemics/history , SARS-CoV-2/isolation & purification , COVID-19/history , COVID-19/pathology , History, 20th Century , History, 21st Century , Humans , Influenza A virus/isolation & purification , Influenza, Human/history , Influenza, Human/pathology , Public Health
16.
Med (N Y) ; 2(5): 493-497, 2021 05 14.
Article in English | MEDLINE | ID: mdl-33899041

ABSTRACT

Therapeutics for hospitalized COVID-19 patients were identified through a robust research response with several lessons learned: clinical trial data should guide therapeutic use, results should not be extrapolated between disease stages, and robust studies should be designed to give clinically relevant data. These lessons should be applied to the outpatient research response.


Subject(s)
COVID-19 , Humans , SARS-CoV-2
18.
J Infect Dis ; 224(9): 1455-1461, 2021 11 16.
Article in English | MEDLINE | ID: mdl-33825905

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted persons with human immunodeficiency virus (HIV), interfering with critical health services for HIV prevention, treatment, and care. While there are multiple profiles of persons living with HIV and the impact of COVID-19 may differ for each, the severity of COVID-19 in persons with HIV is related strongly to the presence of comorbidities that increase the risk of severe disease in COVID-19 patients in the absence of HIV. An effective response to the juxtaposition of the HIV and COVID-19 pandemics requires a novel coordinated and collaborative global effort of scientists, industry, and community partners to accelerate basic and clinical research, as well as implementation science to operationalize evidence-based interventions expeditiously in real-world settings. Accelerated development and clinical evaluation of prevention and treatment countermeasures are urgently needed to mitigate the juxtaposition of the HIV and COVID-19 pandemics.


Subject(s)
COVID-19/epidemiology , HIV Infections/epidemiology , Pandemics , Acquired Immunodeficiency Syndrome , HIV , Humans , SARS-CoV-2
20.
JAMA ; 325(13): 1261-1262, 2021 04 06.
Article in English | MEDLINE | ID: mdl-33571363
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