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The global experience with COVID-19 holds important lessons for preparing for, and responding to, future emergences of pathogens with pandemic potential.

Anti–SARS-CoV-2 antibodies have been used in health care and clinical settings to prevent and treat COVID-19. The National Institutes of Health convened a virtual summit on 15 June 2021 to summarize existing knowledge and to identify key unanswered scientific questions to catalyze future development of these antibodies., 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.

Severe COVID-19 is characterized by a prothrombotic state associated with thrombocytopenia, with microvascular thrombosis being almost invariably present in the lung and other organs at postmortem examination. We evaluated the presence of antibodies to platelet factor 4 (PF4)–polyanion complexes using a clinically validated immunoassay in 100 hospitalized patients with COVID-19 with moderate or severe disease (World Health Organization score, 4 to 10), 25 patients with acute COVID-19 visiting the emergency department, and 65 convalescent individuals. Anti-PF4 antibodies were detected in 95 of 100 hospitalized patients with COVID-19 (95.0%) irrespective of prior heparin treatment, with a mean optical density value of 0.871 ± 0.405 SD (range, 0.177 to 2.706). In contrast, patients hospitalized for severe acute respiratory disease unrelated to COVID-19 had markedly lower levels of the antibodies. In a high proportion of patients with COVID-19, levels of all three immunoglobulin (Ig) isotypes tested (IgG, IgM, and IgA) were simultaneously elevated. Antibody levels were higher in male than in female patients and higher in African Americans and Hispanics than in White patients. Anti-PF4 antibody levels were correlated with the maximum disease severity score and with significant reductions in circulating platelet counts during hospitalization. In individuals convalescent from COVID-19, the antibody levels returned to near-normal values. Sera from patients with COVID-19 induced higher levels of platelet activation than did sera from healthy blood donors, but the results were not correlated with the levels of anti-PF4 antibodies. These results demonstrate that the vast majority of patients with severe COVID-19 develop anti-PF4 antibodies, which may play a role in the clinical complications of COVID-19.

SUMMARYSARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a two-month period, we evaluated antibody and B-cell responses to a third dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies, and memory B cells. Spike-specific B-cell responses from recent infection were elevated at pre-boost but comparatively less so at 60 days post-boost compared to uninfected individuals, and these differences were linked to baseline frequencies of CD27lo B cells. Day 60 to baseline ratio of BCR signaling measured by phosphorylation of Syk was inversely correlated to days between infection and vaccination. Thus, B-cell responses to booster vaccines are impeded by recent infection.

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?

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.

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.

Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) emerged 20 years ago, presaging a series of subsequent infectious disease epidemics of international concern. The recent emergence of SARS-CoV-2 has underscored the importance of targeted preparedness research to enable rapid countermeasure development during a crisis. In December 2021 the National Institute of Allergy and Infectious Diseases (NIAID), building upon the successful strategies developed during the SARS-CoV-2 response and to prepare for future pandemics, published a pandemic preparedness plan that outlined a research strategy focused on priority pathogens, technology platforms, and prototype pathogens. To accelerate the discovery, development, and evaluation of medical countermeasures against new or previously unknown pathogens of pandemic potential, we present here a strategy of research directed at select prototype pathogens. In this manner, leveraging a prototype pathogen approach may serve as a powerful cornerstone in biomedical research preparedness to protect public health from newly emerging and reemerging infectious diseases.

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.

Acute HIV infection is characterized by rapid viral seeding of immunologic inductive sites in the gut followed by the severe depletion of gut CD4(+) T cells. Trafficking of α(4)β(7)-expressing lymphocytes to the gut is mediated by MAdCAM, the natural ligand of α(4)β(7) that is expressed on gut endothelial cells. MAdCAM signaling through α(4)β(7) costimulates CD4(+) T cells and promotes HIV replication. Similar to MAdCAM, the V2 domain of the gp120 HIV envelope protein binds to α(4)β(7). In this study, we report that gp120 V2 shares with MAdCAM the capacity to signal through α(4)β(7) resulting in CD4(+) T cell activation and proliferation. As with MAdCAM-mediated costimulation, cellular activation induced by gp120 V2 is inhibited by anti-α(4)β(7) monoclonal antibodies (mAbs). It is also inhibited by anti-V2 domain antibodies including nonneutralizing mAbs that recognize an epitope in V2 that has been linked to reduced risk of acquisition in the RV144 vaccine trial. The capacity of the V2 domain of gp120 to mediate signaling through α(4)β(7) likely impacts early events in HIV infection. The capacity of nonneutralizing V2 antibodies to block this activity reveals a previously unrecognized mechanism whereby such antibodies might impact HIV transmission and pathogenesis.

Four Decades of HIV/AIDS Considering the spectacular scientific advances that have been made over nearly four decades, it is conceivable that with optimal implementation of available prevention str...

Historical data regarding time to viral rebound following analytical treatment interruption (ATI) have been used to determine therapeutic efficacy in HIV cure trials; however, such data were collected from studies conducted a decade or more ago and included participants receiving older antiretroviral therapy (ART) regimens with infrequent virologic monitoring. We conducted a study of 22 HIV-infected participants receiving modern ART to determine the kinetics of plasma viral rebound following ATI. Our data suggest that modern ART does not alter kinetics of viral rebound when compared to previous regimens and that immunologic interventions may be necessary to achieve ART-free virologic remission. Clinical Trials Registration ClinicaTrials.gov identifier: NCT03225118.

This article outlines the significant scientific progress reported in 2019 that has led to the development of new drugs and therapeutic regimens, vaccine candidates, and diagnostics for the prevention and treatment of tuberculosis. In 2020, it will be important to build on this momentum and continue to advance basic and clinical research to develop improved tools and interventions, simultaneously optimizing their implementation in national control programs. To successfully achieve the goal to end tuberculosis within a generation, a concerted, collective, and collaborative effort is required, involving government, academia, industry and civil society at all levels.

Significance In HIV-infected patients on combination antiretroviral therapy (cART), greater than 95% of proviruses in the peripheral blood are “defective.” Historically, these defective proviruses have been thought to be dead-end products with no real pathophysiological significance, as they do not encode replication-competent viruses. Contrary to this view, we have identified cells in tissue culture and from cART-treated patients that harbor defective proviruses and produce viral proteins. Features found in these translationally competent yet defective proviruses suggest that HIV-1 infection results in modification of the CD4+ T cell genome analogous to human endogenous retroviruses. We propose that these defective HIV-1 proviruses are biologically significant, despite being “replication incompetent,” have the potential to elicit immune activation, and may serve as a barrier to HIV-1 cure., HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels

Anthony Fauci on four decades of progress against HIV, and what’s needed for the future. Anthony Fauci on four decades of progress against HIV, and what’s needed for the future.

The 2005 Immunity paper by Kariko 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.

International audience; No abstract available

Research in the Context of a Pandemic Clifford Lane and Anthony Fauci comment on the findings of the RECOVERY trial of dexamethasone to treat Covid-19, noting that scientifically robust and ethical...

SARS-CoV-2 mRNA booster vaccines provide protection from severe disease, eliciting strong immunity that is further boosted by previous infection. However, it is unclear whether these immune responses are affected by the interval between infection and vaccination. Over a 2-month period, we evaluated antibody and B cell responses to a third-dose mRNA vaccine in 66 individuals with different infection histories. Uninfected and post-boost but not previously infected individuals mounted robust ancestral and variant spike-binding and neutralizing antibodies and memory B cells. Spike-specific B cell responses from recent infection (180 days) were elevated at pre-boost but comparatively less so at 60 days post-boost compared with uninfected individuals, and these differences were linked to baseline frequencies of CD27

Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 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-α4β7 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-α4β7 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 α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.

Eastern Equine Encephalitis Virus In the summer and fall of 2019, nine U.S. states reported 36 human cases (14 of them fatal) of EEE, an arthropod-borne viral (arboviral) disease transmitted by mos...

A converging public health crisis is emerging because the opioid epidemic is fueling a surge in infectious diseases, such as human immunodeficiency virus infection with or without AIDS, the viral hepatitides, infective endocarditis, and skin and soft-tissue infections. An integrated strategy is needed to tailor preventive and therapeutic approaches toward infectious diseases in people who misuse and/or are addicted to opioids and to concurrently address the underlying predisposing factor for the infections—opioid use disorder. This commentary highlights the unique and complementary roles that the infectious diseases and substance use disorder communities can play in addressing this crisis of dual public health concerns.

___Key messages___ The Commission recommends five priority investments to achieve a tuberculosis-free world within a generation. These investments are designed to fulfil the mandate of the UN High Level Meeting on tuberculosis. In addition, they answer the question of how countries with high-burden tuberculosis and their development partners should target their future investments to ensure that ending tuberculosis is achievable. __Invest first to ensure that high quality rapid diagnostics and treatment are provided to all individuals receiving care for tuberculosis, wherever they seek care__ This priority includes rapid drug susceptibility testing and second-line treatment for resistant forms of tuberculosis. Achieving universal, high-quality person-centred and family-centred care—including sustained improvement in the performance of private sector providers—usually should be the top policy and budget priority. __Reach people and populations at high risk for tuberculosis (such as household and other close contacts of people with tuberculosis, and people with HIV) and bring them into care__ Active case-finding and treatment in high-risk populations demands adequate resources to reach and care for these populations. At the same time, reaching certain high-risk populations, such as people co-infected with tuberculosis and HIV, for tuberculosis preventive therapy is essential to achieve epidemiologic control. Once high-risk populations have access to affordable, high-quality diagnostic, treatment and preventive services, invest in identifying tuberculosis cases in the general population, primarily by strengthening the capacity to deliver health services and move toward universal health coverage. __Increase investment to accelerate tuberculosis research and development and bring new diagnostics, therapeutic strategies, and vaccines to clinical practice to quickly end the pandemic__ Strong advocacy with science ministries and research-oriented pharmaceutical companies is crucial, including ministries and companies in middle-income countries, to highlight the importance of investing in new tools. Financing the early uptake of new products will provide important confidence signals to product developers. __Make investment in tuberculosis programmes a shared responsibility, increasing development assistance for tuberculosis according to the financial needs of individual low-income and middle-income countries__ As countries successfully mobilise more domestic resources towards tuberculosis programmes, external assistance to middle-income countries should address the following priorities: reduce the spread of drug-resistant tuberculosis in all affected low-income and middle-income countries; facilitate market-shaping activities to enable access to high quality drugs and diagnostics for high-burden countries; and finance tuberculosis research and development, including product development as well as population, policy, and implementation research that will provide lessons and international sharing of best practices. __Hold countries and key stakeholders accountable for progress made towards ending tuberculosis__ Accountability entails establishing independent, multisectoral processes, such as national tuberculosis report cards, to ensure that all stakeholders carry out their responsibilities to contribute to ending the pandemic. Accountability mechanisms should not only assess progress, but also guarantee that Heads of Governments, national tuberculosis programmes, and even regional and site-level clinics, as well as key non-governmental organisations, take the necessary corrective actions to remove obstacles to ending tuberculosis.

Therapeutic strategies for achieving sustained virologic remission are being explored in human immunodeficiency virus (HIV)–infected individuals who began antiretroviral therapy (ART) during the early phase of infection. In the evaluation of such therapies, clinical protocols should include analytical treatment interruption (ATI); however, the immunologic and virologic impact of ATI in individuals who initiated ART early has not been fully delineated. We demonstrate that ATI causes neither expansion of HIV reservoirs nor immunologic abnormalities following reinitiation of ART. Our findings support the use of ATI to determine whether sustained virologic remission has been achieved in clinical trials of individuals who initiated ART early during HIV infection.

Purpose of review Trafficking of lymphocytes into and between gut inductive and effector sites of the gut tissues is regulated by integrin α4β7. Recent findings that describe the central role of α4β7 CD4 T cells in HIV pathogenesis, and the possibility of targeting these cells to prevent or treat HIV infection will be reviewed. Recent findings Recent reports indicate that the frequency of α4β7 CD4 T cells is directly correlated with the risk of HIV acquisition and CD4 T-cell decline post infection. MAdCAM -mediated signaling through α4β7, in the presence of retinoic acid, supports viral replication in recently activated naive CD4 T cells. Treatment of HIV-infected patients with vedolizumab, an α4β7 antagonist, is well tolerated, and reduces the size and number of lymphoid aggregates in gut associated lymphoid tissues. Summary Integrin α4β7 underlies one of the principal mechanisms that CD4 T cells employ to traffic to the gut. It also defines a subset of cells that play a significant role in HIV transmission and pathogenesis. Understanding how α4β7 facilitates gut homing may provide insight into key aspects of HIV transmission, pathogenesis, and the formation of viral reservoirs. Targeting α4β7 may have utility in the prevention and treatment of HIV infection.

Broadly neutralizing antibodies (bNAbs) represent a promising alternative to antiretroviral drugs for HIV-1 prevention and treatment. Selected antibodies to the CD4-binding site bolster envelope trimer binding via quaternary contacts. Here, we rationally engraft a new paratope, i.e., the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bNAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface is delineated by solving the crystal structure of two FR3 loop-chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, chimeric antibodies display lower autoreactivity and prolonged in vivo half-life in huFcRn mice and rhesus macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality for disease prevention and treatment., Quaternary contacts mediated by an extended heavy-chain framework region 3 (FR3) have been shown to improve binding to HIV envelope and virus neutralization for a few antibodies. Here, Liu et al. engraft such an FR3 loop onto several potent broadly neutralizing antibodies, resulting in improved neutralization activity and pharmacokinetics.

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.

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

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.