Anthony S. Fauci

NOV 2024FauciClinical Infectious Diseases

HIV/AIDS and COVID-19: Shared Lessons From 2 Pandemics

The global experiences with the human immunodeficiency virus (HIV)/AIDS and coronavirus disease 2019 (COVID-19) pandemics hold important lessons for preparing for, and responding to, future outbreaks of emerging or reemerging infectious diseases. Scores of infectious diseases have emerged or reemerged over the past 4 decades, and future outbreaks are inevitable. The next emerging pathogen likely will again come from unanticipated sources and pose puzzles in terms of microbiology, transmission, natural history, pathogenesis, and epidemiology, and will present challenges to developing countermeasures such as diagnostics, therapeutics, and vaccines. Although dozens of lessons could be addressed, 8 selected lessons common to HIV/AIDS and COVID-19 are addressed here. Consideration of the commonality of lessons learned from HIV/AIDS and COVID-19, the 2 most devastating pandemics over the past half century, will help us-and those who follow us-to minimize the impact of future outbreaks and prevent them from becoming global pandemics.

OCT 2023FauciScience Translational Medicine

What keeps me up at night

The lessons of COVID-19 must be heeded if the world is to be prepared for the next emergent pathogen with pandemic potential.

Increased neutralization potency and breadth elicited by a SARS-CoV-2 mRNA vaccine forming virus-like particles

mRNA developed neutralizing antibodies effective against different variants of concern. These data demonstrate that the Gag/VLP mRNA platform can be successfully applied to vaccines against different agents for the prevention of infectious diseases of global relevance.

Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report

On November 7th and 8th, 2022, The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), The Coalition for Epidemic Preparedness Innovation (CEPI), The Bill & Melinda Gates Foundation (BMGF), The Biomedical Advanced Research and Development Authority (BARDA), and the Wellcome Trust hosted a virtual workshop entitled “Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities.” During the workshop, researchers and vaccine developers from around the world discussed the potential of mucosal vaccines to block SARS-CoV-2 transmission and reviewed the status of SARS-CoV-2 mucosal vaccine research. Here, we summarize key challenges and opportunities in basic, translational, and clinical research that were highlighted during the meeting. We also provide recommendations to advance the field and accelerate the development of mucosal vaccines for SARS-CoV-2.

APR 2023FauciThe Journal of Infectious Diseases

Pandemic Preparedness and Response: Lessons From COVID-19

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

MAdCAM-1 costimulation in the presence of retinoic acid and TGF-β promotes HIV infection and differentiation of CD4+ T cells into CCR5+ TRM-like cells

CD4+ tissue resident memory T cells (TRMs) are implicated in the formation of persistent HIV reservoirs that are established during the very early stages of infection. The tissue-specific factors that direct T cells to establish tissue residency are not well defined, nor are the factors that establish viral latency. We report that costimulation via MAdCAM-1 and retinoic acid (RA), two constituents of gut tissues, together with TGF-β, promote the differentiation of CD4+ T cells into a distinct subset α4β7+CD69+CD103+ TRM-like cells. Among the costimulatory ligands we evaluated, MAdCAM-1 was unique in its capacity to upregulate both CCR5 and CCR9. MAdCAM-1 costimulation rendered cells susceptible to HIV infection. Differentiation of TRM-like cells was reduced by MAdCAM-1 antagonists developed to treat inflammatory bowel diseases. These finding provide a framework to better understand the contribution of CD4+ TRMs to persistent viral reservoirs and HIV pathogenesis.

FEB 2023CollinsScience

The NIH-led research response to COVID-19

Investment, collaboration, and coordination have been key.

Forty years of investment in HIV research: progress towards ending the HIV pandemic and preparation for future pandemics

Since the beginning of the HIV pandemic, sustained and substantial investment in biomedical research and community engagement has led to extraordinary progress towards ending the HIV pandemic and laid a foundation for a successful response to emerging pandemics. This year, on World AIDS Day, we review achievements to date and examine how investments in HIV research were leveraged to develop effective treatment and prevention interventions for COVID-19. Neither pandemic is over and much remains to be accomplished; however, it is clear that building on successes will help bring an end to the HIV and COVID-19 pandemics and prepare us to respond to future pandemics. From the earliest elucidation of the HIV replication cycle leading to the identification of targets for therapeutic intervention, the number of FDA-approved antiretroviral (ARV) drugs has grown to more than 30 in eight classes. Effective treatment can be as simple as one pill once a day or two injections every 2 months [1]. Anti-retroviral therapy (ART) not only restores life expectancy to near normal [2], but also eliminates the risk of HIV transmission when consistently used [3]. For those at risk of HIV infection, either daily oral tenofovir-based medication with emtricitabine or an injection of cabotegravir every 2 months can serve as effective pre-exposure prophylaxis [4, 5]. In addition to the small molecule anti-viral approach, the development of broadly neutralizing antibodies (bNAbs) that target highly conserved epitopes on the HIV Env protein portends new strategies for HIV treatment and prevention [6]. Animal studies [7] and clinical trials have demonstrated the anti-viral potency of bNAbs and have provided a road map to explore bNAbs as modalities of treatment and prevention [8], as well as a mechanism to probe neutralizing epitopes for use in an HIV vaccine [9]. Using the structure-based design, stabilized, native envelope trimers, which preserve the conformation of bNAb epitopes, define a set of immunogens for sequential immunization strategies that will be used to drive neutralizing antibody breadth [10]. The use of the newer mRNA vaccine platforms to deliver stabilized trimers will accelerate the iterative evaluation of immunogens. These remarkable scientific milestones resulted from substantial investments in a multitude of research programmes over four decades. Programmes for virology, immunology, drug and vaccine discovery, clinical observational research and clinical trial networks comprised of hundreds of dedicated investigators and research staff around the globe resulted from a deliberate long-term strategy to profoundly impact the HIV pandemic. Successes during the research response to HIV validated the concept of team science. These scientific discoveries could not have been achieved with short-term individual grants alone. Instead, sustained investments in collaborative science and ongoing research enterprises allowed for incremental progress to culminate in significant breakthroughs. The critical role of community engagement was clearly established in the research response to HIV. A successful effort could only have been achieved through the meaningful involvement of persons with HIV (PWH) in research, from planning to implementation. From the early days of the HIV pandemic when advocates stormed the US National Institutes of Health (NIH) to make their priorities known, stakeholder engagement to drive the research agenda has been a cornerstone of the HIV research response. The HIV research enterprise is much improved by the broad involvement of community members on research teams and advisory boards—not only in the United States, but globally, through networks that were established to foster research and care in regions and populations most affected by HIV. These enduring partnerships, research advances and the availability of ART provided the basis for the President's Emergency Plan For AIDS Relief (PEPFAR). The rapid implementation of research advances to benefit PWH in low- and middle-income countries bolstered global cooperation in the fight against HIV. PEPFAR, the Global Fund and other committed organizations provided the knowledge and resources to advance HIV care and treatment, and fostered implementation and operational science enhancing and strengthening the delivery of high-quality, cost-effective care. Expanded access to generic ARVs and molecular diagnostics for the detection of drug resistance and HIV viral load, as well as the adoption of clinical strategies, such as task-shifting, demonstrated the power of capacity building. More recently, the HIV research enterprise has served as a foundation for rapid advances during the COVID-19 pandemic. From virology, structural biology and immunology to community engagement, the research response towards COVID-19 was made possible, in part, by the years of investment in HIV research. Drug discovery strategies originally developed for HIV have informed many of the structure-based drug discovery efforts against SARS-CoV-2, an example of which is the improvement in the design of protease inhibitor molecules. The payoff from investment in HIV research is also evident in how structure-based design propelled the SARS-CoV-2 vaccine field leading to the rapid design and development of COVID vaccines and monoclonal antibodies. The D614 stabilized pre-fusion trimer spike of SARS-CoV-2, which was designed using the technology developed to stabilize HIV envelopes, serves as the basis of four effective COVID vaccines [11]. Additionally, SARS-CoV-2-specific mAbs were screened for binding ability using the stabilized trimer spike, leading to effective mAb treatments for COVID-19 early in the pandemic as well as the only agent authorized for use as preexposure prophylaxis [12]. In the clinical sphere, the research infrastructure built to help curtail the HIV epidemic has been successfully leveraged to address the COVID-19 epidemic. Clinical and research laboratories built for HIV were successfully repurposed to diagnose COVID and identify emerging variants of SARS-CoV-2, such as the Omicron variant. NIH-funded HIV clinical trial networks (ACTG, HPTN, HVTN and INSIGHT) and clinical research sites were engaged to implement phase III vaccine trials as well as phase II/III trials of drugs and anti-SARS-CoV-2 monoclonal antibodies for treatment and prevention. These networks quickly pivoted from HIV to COVID-19 while engaging the expertise of network scientists to expeditiously implement an extraordinary number of trials. Experienced network laboratory scientists repurposed an HIV-neutralizing antibody assay to a COVID-neutralizing assay, which helped to define correlates of protection across all five vaccine efficacy trials [13, 14]. Clinical trialists with HIV experience were consulted by drug companies to inform optimal COVID-19 preventive trial designs. All of this was done while engaging with affected communities to ensure the appropriate populations were being enrolled and their needs addressed [15]. Looking to the future, we must maintain our focus on ending the HIV pandemic by developing safe, durable HIV vaccines and cures, as well as addressing the non-infectious comorbidities seen in PWH. This means maintaining long-term, steady investments in science and infrastructure. Simultaneously, we must retain the ability to quickly pivot and form research collaborations when needed to address public health emergencies. The rapid engagement of the HIV research enterprise, including its community engagement programmes, was essential to the overall agility of the COVID-19 response. As the most important questions and challenges in HIV research continue to evolve, so must the investments be maintained. These investments will pay off in progress against HIV and will also ensure the flexibility to rapidly respond to future pandemics. None of the authors has competing interests. All five authors contributed to the framing of the Viewpoint. The first four authors, SWR, PK, MM and CWD, drafted the Viewpoint. SWR, CWD and ASF edited the Viewpoint. The authors value and recognize the thousands of researchers who over the last 40 years discovered and published the information that has made the global response to the HIV pandemic so impactful. This work would not have been possible without the collaborations, engagement and partnerships between community members and clinical trial participants, researchers, funding organizations, governments and ministries of health and stakeholder organizations whose mission is to treat and prevent HIV as well as come together to define how to treat, vaccinate and prevent SARS-CoV-2 disease. No external support was provided for the preparation of the manuscript.

Anti-PF4 antibodies associated with disease severity in COVID-19

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.

Lessons from the pandemic: Responding to emerging zoonotic viral diseases—a Keystone Symposia report

The COVID-19 pandemic caught the world largely unprepared, including scientific and policy communities. On April 10-13, 2022, researchers across academia, industry, government, and nonprofit organizations met at the Keystone symposium "Lessons from the Pandemic: Responding to Emerging Zoonotic Viral Diseases" to discuss the successes and challenges of the COVID-19 pandemic and what lessons can be applied moving forward. Speakers focused on experiences not only from the COVID-19 pandemic but also from outbreaks of other pathogens, including the Ebola virus, Lassa virus, and Nipah virus. A general consensus was that investments made during the COVID-19 pandemic in infrastructure, collaborations, laboratory and manufacturing capacity, diagnostics, clinical trial networks, and regulatory enhancements-notably, in low-to-middle income countries-must be maintained and strengthened to enable quick, concerted responses to future threats, especially to zoonotic pathogens.

SEP 2022CanonicaAllergy

Legends of allergy and immunology: Lorenzo Moretta—Unfolding the mysteries of NK cells and much more

Recent SARS-CoV-2 infection abrogates antibody and B-cell responses to booster vaccination

SUMMARY 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 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 CD27 lo 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.

Prototype Pathogen Approach for Vaccine and Monoclonal Antibody Development: A Critical Component of the NIAID Plan for Pandemic Preparedness

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.

Early human B cell signatures of the primary antibody response to mRNA vaccination

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.

Prolonged viral suppression with anti-HIV-1 antibody therapy

HIV-1 infection remains a public health problem with no cure. Anti-retroviral therapy (ART) is effective but requires lifelong drug administration owing to a stable reservoir of latent proviruses integrated into the genome of CD4⁺ T cells¹. Immunotherapy with anti-HIV-1 antibodies has the potential to suppress infection and increase the rate of clearance of infected cells²,³. Here we report on a clinical study in which people living with HIV received seven doses of a combination of two broadly neutralizing antibodies over 20 weeks in the presence or absence of ART. Without pre-screening for antibody sensitivity, 76% (13 out of 17) of the volunteers maintained virologic suppression for at least 20 weeks off ART. Post hoc sensitivity analyses were not predictive of the time to viral rebound. Individuals in whom virus remained suppressed for more than 20 weeks showed rebound viraemia after one of the antibodies reached serum concentrations below 10 µg ml⁻¹. Two of the individuals who received all seven antibody doses maintained suppression after one year. Reservoir analysis performed after six months of antibody therapy revealed changes in the size and composition of the intact proviral reservoir. By contrast, there was no measurable decrease in the defective reservoir in the same individuals. These data suggest that antibody administration affects the HIV-1 reservoir, but additional larger and longer studies will be required to define the precise effect of antibody immunotherapy on the reservoir.

The Concept of Classical Herd Immunity May Not Apply to COVID-19

There has been speculation about when in the coronavirus disease 2019 (COVID-19) pandemic we will be able to live with the virus in a manner that does not disrupt most peoples’ lives. Much of this discussion has focused on herd immunity thresholds (Box 1). As commonly understood [1–7], herd immunity thresholds are reached when a sufficient proportion of the population is vaccinated or has recovered from natural infection with a pathogen such that its community circulation is reduced below the level of significant public health threat. For example, this threshold has been met with polio and measles circulation in the United States. A herd immunity threshold is the proportion of a population with immunity against a communicable disease agent (resulting from innate immunity, natural infection, or vaccination) above which transmission of the agent is largely prevented, except for sporadic outbreaks in undervaccinated or otherwise incompletely protected subsets of individuals. However, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is so different from polio and measles that classical herd immunity may not readily apply to it. Important differences include the phenotypic stability of polio and measles viruses, and their ability to elicit long-term protective immunity, compared to SARS-CoV-2. For these and other reasons, controlling COVID-19 by increasing herd immunity may be an elusive goal. Conceptualizations of herd immunity thresholds evolved gradually before the microbiology era. By about 1700, a few diseases such as smallpox and measles had been distinguished based on pathognomonic signs and symptoms. The 1720 European and colonial introduction of smallpox inoculation [8] clarified that both natural infection and inoculation protected against infection and reinfection. At the population level, widespread use of smallpox inoculation in human cohorts prevented or limited epidemics, including inoculation of soldiers during the American Revolutionary War [9] and of enslaved people on US plantations. Such early observations of “herd protection” led scientists of the late 19th century to propose that smallpox could be eradicated, a goal finally realized in 1978. Around 1807, a crucial observation—seemingly unrelated to immune protection—was made. In cities and large towns, childhood measles was documented to occur in regular cycles. Comparing one city to another, cycle intervals varied from as short as 2 to 3 years, to as long as 6 to 7 years, with different cities having their own characteristic intervals. Longer cycles were seen in towns and smaller cities, whereas shorter cycles were more common in large, crowded cities with high birthrates. Contemporary data, such as those in Britain’s mortality registry or from comparative examination of early 19th century measles cyclicity in 20 international cities, could not explain this phenomenon [10, 11]. After 1876, the new sciences of microbiology, immunology, and epidemiology began to clear up the mystery: measles and some other epidemic infections of early childhood elicited long-term protective immunity that reduced or prevented epidemics, until such time as cumulative births resulted in sufficiently large cohorts of susceptible children to support new waves of transmission. Among the first direct observational studies of this phenomenon was a 1904–1907 report of measles outbreaks in British primary schools. Classroom measles epidemics occurred when fewer than 70% of children were immune, and tended to end or be prevented when classroom immunity reached 85% [12]. In short, measurable rules about epidemic disease transmission were related to population cohort immune status. Such rules initially had no name. The terms “herd immunity” and “herd immunity threshold” emerged when American veterinary researchers began using them during World War I [13]. The terminology was soon adopted by British statistician-epidemiologists studying herd immunity in laboratory animals, hoping to identify human disease-control variables [14–20]. But as experimental and human observational research progressed, such hopes were soon dashed. Numerous variables greatly affected herd immunity thresholds, including differences among diseases and hosts, transmission modes (eg, respiratory, enteric), duration and completeness of immunity, crowding and population movement, and small pockets of nonimmune persons (religious groups or other unvaccinated groups), among other factors. These variables interacted in complex ways to result in herd immunity thresholds that were situation specific and often significantly altered by small changes in key variables. For example, in mathematical studies, even small changes in population density had large effects on herd immunity thresholds. Herd immunity theory seemed useful as a general concept but was inadequate in important real-world situations. Over the past 70 years, herd immunity threshold concepts have been repeatedly questioned amid attempts to control, to geographically eliminate, or to eradicate infectious diseases [3, 6]. With influenza, for example, the inadequacy or limited durability of immunity after vaccination or infection, and the continual antigenic drifting and occasional pandemic-producing antigenic shifting, has foiled attainment of strong herd immunity threshold effects. Moreover, small numbers of unvaccinated individuals make completely protective herd immunity difficult even for the most phenotypically stable disease agents [21]. For example, long after the 1960s to 1970s, when measles and polio in the United States seemingly had been controlled by mass vaccination and school-exclusion policies, disease importations from abroad continued to cause localized outbreaks [22]. These outbreaks occurred even with nationwide immunity levels above ostensible herd immunity thresholds, as enclaves of undervaccinated populations provided vulnerable targets for pathogen reemergences [21, 22]. Time and again, human movement and other human behaviors have circumvented physical barriers between the infectious and the susceptible. Even global smallpox eradication had to contend with repeated outbreaks and cases among unvaccinated individuals [3] throughout the decade leading to the very last natural case in 1978. For many common respiratory viruses such as influenza and respiratory syncytial virus, the barriers to achieving herd immunity are even greater than with measles, polio, and smallpox. These barriers include asymptomatic transmission, incomplete or short-duration protective immunity, and viral immune escape [23]. Indeed, for many such respiratory viruses, including SARS-CoV-2, immunity is itself a fluid concept, ranging from complete and durable (long-lasting) immunity that fully protects against infections, to immunity that protects against severe disease but does not prevent reinfection and onward transmission. There are significant obstacles to achieving complete herd immunity with COVID-19. Classical herd immunity, leading to disease eradication or elimination, almost certainly is an unattainable goal. As noted, mass vaccination and aggressive public health approaches have struggled to control other (seemingly more controllable) respiratory infectious diseases, such as smallpox, measles, and rubella, all caused by viruses with limited phenotypic evolution. Controlling SARS-CoV-2 and its cycles of new variants presents a much more formidable challenge [23]. Like influenza, SARS-CoV-2 mutates continually into new variants that can escape immunity derived from infections and vaccines. It also can be transmitted asymptomatically and without pathognomonic signs, impeding public health control. SARS-CoV-2 appears not to substantially engage the systemic immune system, as do viruses such as smallpox, measles, and rubella that consistently have a pronounced viremic phase. Moreover, neither infection nor vaccination appears to induce prolonged protection against SARS-CoV-2 in many or most people. Finally, the public health community has encountered substantial resistance to efforts to control the spread of SARS-CoV-2 by vaccination, mask wearing, and other interventions. If vaccine- or infection-induced immunity to SARS-CoV-2 indeed proves to be short-lived, or if escape mutants continue to emerge, viral spread may continue indefinitely, albeit hopefully at a low endemic level. This notably has occurred with the 1918 pandemic influenza virus, whose viral descendants still are causing seasonal outbreaks and occasional pandemics 104 years later (pandemic H2N2 in 1957, H3N2 in 1968, and H1N1 in 2009) [24], and which we have been unable, after more than 80 years of trying, to fully control with vaccines. Such factors probably make SARS-CoV-2 impossible to eradicate (only one human virus—smallpox—has ever been eradicated), difficult to eliminate over long periods within large geographic areas, and difficult to satisfactorily control even with good vaccines. Thus, COVID-19 is likely to be with us, even if at a very low level of endemic community spread and with lower severity, for the foreseeable future. Like influenza, any level of herd protection against SARS-CoV-2 potentially can be overcome by ever-changing levels of immunity among countless subpopulations, by human movement, crowding, changes in social or prevention behaviors, by demographics, by vaccination levels, by variations in durability of infection- or vaccine-induced immunity, and by evolution of viral variants, among many other variables. But encouragingly, after more than 2 years of viral circulation, and more than a year of vaccines with boosters, we now have a high degree of background population immunity to SARS-CoV-2, as well as medical countermeasures such as antiviral drugs and monoclonal antibodies to prevent progression of disease, and widely available diagnostic tests. With these interventions we can aspire to, and very likely will succeed in achieving, substantial control of community spread without the disruptions of society caused by COVID-19 over the past 2 years. We no longer need the elusive concept of herd immunity as an aspirational goal: COVID-19 control is already within our grasp. Looking forward, more broadly protective vaccines could play important roles in controlling SARS-CoV-2 and its inevitable variants. Developing “universal” coronavirus vaccines (or at least universal SARS-CoV-2 vaccines that elicit durable and broadly protective immunity against multiple SARS-CoV-2 variants) is an important goal for the immediate future [23]. Meanwhile, optimal COVID-19 control will require both classic, nonpharmacologic public health approaches and vaccination of many more people globally with the SARS-CoV-2–specific vaccines we already have, with booster shots, and with updates to vaccine antigens if needed. Living with COVID-19 is best considered not as reaching a numerical threshold of immunity, but as optimizing population protection without prohibitive restrictions on our daily lives. Effective tools for prevention and control of COVID-19 (vaccines, prevention measures) are available; if utilized, the road back to normality is achievable even without achieving classical herd immunity. Authors. D. M. M. is Senior Scientific Advisor to the Director of the National Institute of Allergy and Infectious Diseases (NIAID); G. K. F. is Chief of Staff to the Director, NIAID; and A. S. F. is Director, NIAID. Financial support. This work was supported by the Office of the Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health. Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

NOV 2021FauciJournal of the International AIDS Society

Fitting a vaccine into the HIV prevention landscape

The development of highly effective treatment and prevention strategies for HIV has been a significant scientific achievement over the past 25 years. Although progress has been made in the global access of antiretroviral treatment (ART), the UNAIDS 2020 global targets were not achieved because of structural and individual barriers. Therefore, the global targets are being revised for the 2025–2030 timeframe [1]. In this article, we will discuss the current state of HIV treatment and prevention and describe the research agenda that will help advance the next generation of strategies. In the context of this rapidly evolving prevention and treatment landscape, the levels of efficacy expected from an HIV vaccine increase. While using some of the lessons learned from SARS-CoV-2 vaccines, we will also point out that a safe, efficacious and durable HIV vaccine is achievable and remains a worthy goal. As of June 2020, global ART coverage was estimated at 26 million people living with HIV (PLWH), two-thirds of the universal treatment target. Current estimates of adherence suggest that 59% of PLWH are virus-free worldwide and thus can expect relatively normal life spans [2]. Furthermore, global endorsement of “undetectable equals untransmissible”, also known as U = U, makes ART the most potent and widely used preventive approach today [3]. The first longacting injectable ART regimen delivered via monthly injection has been approved by regulatory authorities. Additional long-acting formulations are in development, including several containing broadly neutralizing antibodies (bNAbs) that could potentially extend the injection time from once every 6 months to once a year. Simplified delivery of long-acting combinations will result in both greater population coverage and durable virologic suppression. Furthermore, greater population coverage with these potent, durable regimens will boost the role of treatment as prevention in helping to control the global HIV pandemic. With these significant periods of time between doses, long-acting ART may well soon become a preferred option for treatment of PLWH. Except for barrier methods and adult medical male circumcision, all successful HIV prevention methods rely on antiretroviral drugs [4,5]. The hypothesis has been that if there is a sufficient concentration of drug blocking HIV replication in the exposed tissues, then virus cannot establish infection, allowing the individual to remain HIV-free. Studies of different drug regimens of oral pre-exposure prophylaxis (PrEP) have shown that with adherence, protection from acquisition of HIV is remarkably high, greater than 95% and consistent across populations [6]. However, with only approximately a million PrEP users in 70 countries, the full impact of this powerful preventive tool is far from being fully achieved [6]. A major challenge facing PrEP-based HIV prevention has been the lack of sustained use by individuals who would gain the most benefit from the intervention. In studies comparing methods to improve PrEP rollout, high PrEP uptake and initiation was achieved at onset, but was then followed by significant levels of PrEP discontinuation [7]. One strategy to address adherence challenges has been the development of long-acting PrEP. In 2020, PrEP trials of an injectable drug, administered every 8 weeks, demonstrated superior efficacy compared to the standard daily oral PrEP among atrisk women and men. This significant achievement will soon lead to drug approval and implementation [8,9]. As with therapy, new agents for PrEP are moving forward in the evaluation process that could increase the amount of time between doses to once or twice a year. This could lead to increased adherence, with significant improvements in effectiveness and less burden on the health system, compared to daily pills. In addition to antivirals, bNAbs are being explored as prevention modalities. The recently completed Antibody Mediated Prevention (AMP) trials demonstrated that the protection from infection is governed by the sensitivity of the virus to the bNAbs [10]. In addition to advancing important options for treatment and prevention of HIV infection, bNAbs also serve as a window into the levels of activity a future HIV vaccine will need to be able to trigger [11]. New medications for HIV treatment are also being evaluated for HIV prevention. Based upon the properties of each new drug, a variety of dosing options are under consideration – from weekly to once or twice a year, delivered by pill or injection. Currently, biomedical HIV prevention modalities

Blocking α ₄ β ₇ integrin delays viral rebound in SHIV SF162P3 -infected macaques treated with anti-HIV broadly neutralizing antibodies

Broadly neutralizing antibodies and an anti-α4β7 monoclonal antibody prolong viral load control in SHIVSF162P3-infected macaques. Integrin blockade may contribute to HIV control Blocking integrin α4β7 has been shown to have immunomodulatory effects. In a new study, Frank et al. investigated how blocking integrin α4β7 in macaques infected with a simian-human immunodeficiency virus and treated with anti-HIV broadly neutralizing antibodies (bNAbs) could modulate viral load. Their results suggested that the combination of α4β7 blockade and bNAbs may have controlled the virus better and longer than treatment with bNAbs alone. These findings need to be recapitulated in larger studies with a focus on determining the mechanisms and the duration of virologic control, before they can be translated into clinical settings. 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.

Pre-vaccination and early B cell signatures predict antibody response to SARS-CoV-2 mRNA vaccine

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.

Report of the National Institutes of Health SARS-CoV-2 Antiviral Therapeutics Summit

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.