Wonder of wonders, miracle of miracles: the unprecedented speed of COVID-19 science.

Abstract

EditorialWonder of wonders, miracle of miracles: the unprecedented speed of COVID-19 scienceMichael SaagMichael SaagUniversity of Alabama at Birmingham, Birmingham, AlabamaM. Saag ([email protected]).Search for more papers by this authorPublished Online:01 Jun 2022https://doi.org/10.1152/physrev.00010.2022This is the final version - click for previous versionMoreSectionsPDF (558 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat 1. INTRODUCTIONCoronavirus disease 2019 (COVID-19) exploded onto the world stage in late December 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a heretofore unknown pathogen in humans, caused a myriad of clinical presentations ranging from asymptomatic to severe respiratory failure and death. In mid-January 2020, within weeks of the announcement of this new disease out of China, the sequence of this novel human pathogen was released (1). One week after the release of the sequence, development of a prototype vaccine using mRNA technology was created. Of note, mRNA vaccines had never been used previously to treat or prevent any other disease. Within days, preclinical testing of this unique vaccine candidate began at the National Institutes of Health in collaboration with Moderna. In parallel, investigators at BioNTec, a pharmaceutical company in Germany, developed its own prototypic mRNA vaccine, for which they later partnered with Pfizer to conduct clinical development. Other pharmaceutical companies, including AstraZenica, Janssen (Johnson and Johnson), and several others initiated vaccine development programs that resulted in the creation of more traditional protein-based or viral vector-based vaccine constructs. Within 11 months of the conceptual design of the prototypic vaccines, the Pfizer and Moderna mRNA vaccines were granted Early Use Authorization (EUA) approval by the US Food and Drug Administration (FDA) (2, 3). Other vaccines were proven to be safe and effective and were granted EUA approval in the United States (Johnson and Johnson/Janssen) or in other countries around the world (AstraZenica, Sinovax, and Novavax). The cumulative impact of the release of these vaccines in such an unprecedented rapid fashion has saved millions of lives in the United States and around the world. A modern miracle.Simultaneous to the successful development and release of effective vaccines was the rapid creation and release of PCR and antigen testing technologies and novel antiviral treatments against SARS-CoV-2. These treatments included traditional nucleoside (such as remdesivir) (4, 5), protease inhibitor-based compounds (6), and novel monoclonal antibody formulations that target the outer spike protein region of SARS-CoV-2 (7–9). These products, when used early in the course of infection, dramatically shorten the duration and reduce the severity of illness. As the natural history, pathobiology, and clinical manifestations of COVID-19 became better understood, other immunologic therapeutics were tested and deployed as treatment for advanced hypoxemia and respiratory failure. These interventions ranged from corticosteroids to inhibitors of cytokine production and immune activation, including IL-6 and JAK inhibitors (10–13).Epidemiologically, real-time collection of incident cases, hospitalizations, and mortality has enabled targeted and rapid release of advice regarding prevention of transmission based on sound, public health principles. Serial sequencing of the virus from recently diagnosed persons detected variants as they emerged in distinct geographic regions and enabled warning systems to be employed as the novel variants spread around the globe (1, 14, 15).Never in the history of mankind have such monumental scientific discoveries been made and deployed into practice in such a rapid and effective way. All these discoveries were made possible from decades of scientific progress in the fields of virology, immunology, epidemiology, and clinical medicine that preceded the COVID-19 epidemic. Although a wide variety of scientific disciplines established the platform upon which the remarkable response to COVID-19 was based, the study of human immunodeficiency virus (HIV-1) over the last 40 yr laid the groundwork for most of these advances. This paper will review the scientific discoveries that emerged over the four decades of the HIV epidemic and how these advances provided the foundation for the rapid response to SARS-CoV-2 (FIGURE 1).FIGURE 1.Comparative timelines of the HIV pandemic versus the SARS-CoV-2 pandemic in the United States. The HIV timeline is measured in years, while the SARS-CoV-2 timeline is measured in months. The accelerated scientific discoveries of the SARS-CoV-2 pandemic were enabled, in large part, by the experience accumulated throughout the HIV pandemic. ACT-UP, AIDS Coalition to Unleash Power; AIDS, acquired immune deficiency syndrome; ARV, antiretroviral; AZT, 3′-azidothymidine (zidovudine); CDC, US Center for Disease Control and Prevention; COVID-19, coronavirus disease 2019; EUA, early use authorization; FDA, Food and Drug Administration; HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; HHS, US Department of Health and Human Services; HOPE Act, HIV Organ Policy Equity Act; HOPWA, Housing Opportunities for People with AIDS; IAS-USA, International Antiviral Society-USA; J and J, Johnson and Johnson (pharmaceutical company); NIH, US National Institutes of Health; PEPFAR, President’s Emergency Plan for AIDS Relief; RT, reverse transcriptase; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SFGH, San Francisco General Hospital; WHO, World Health Organization.Download figureDownload PowerPoint2. A TALE OF TWO EPIDEMICSThe symptom complex that would later be named the acquired immunodeficiency syndrome (AIDS) was first described on June 5, 1981 (16). The virus that causes AIDS was not discovered until March 1983 (17–19). A test for HTLV-III (later named HIV) was not licensed by the FDA until May 1985 (20). The first drug to treat HIV was approved by the FDA in August 1987 (21). For reasons described below, there still is no HIV vaccine more than 40 yr after the first description of AIDS (TABLE 1).Table 1. Comparison of the biologic properties of HIV vs. SARS-CoV-2HIVSARS-CoV-2Type of virusRNA (retrovirus)RNA (coronavirus)Size of genome∼9 kb∼30 kbRoute of transmissionSexual, blood, perinatalRespiratoryReplication rateVery highHighGeneration of mutantsVery highLow to moderateTargeted cells for infectionCD4+ cellsRespiratory epithelial cellsDuration of illnessLifelongDays to weeks*Duration of viremiaLifelong2 to 14 daysDrug targetsEntry, reverse transcriptase, protease, integration, capsidPolymerase, proteaseEffective vaccine availableNoYesWorldwide cases†78,000,000482,000,000Worldwide deaths†34,700,0006,200,000*For acute coronavirus disease 2019 (COVID-19), symptoms of postacute sequalae of COVID-19 lasts months to years. †Human immunodeficiency virus (HIV) as of 2021; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as of March 30, 2022.In contrast, COVID-19 was first described in November 2019 and the first vaccines granted EUA approval 1 yr later. The two candidate mRNA vaccines completed randomized clinical trials, enrolling more than 70,000 volunteers in less than 5 mo and finalizing data analysis, and submitted their findings to the US FDA by November 2020. Remarkably, the infrastructure platforms to mass produce the mRNA vaccines, which were developed in parallel to the testing of the products, enabled widespread distribution of the vaccines to millions of individuals within weeks of EUA approval (FIGURE 1).3. HOW DID THIS HAPPEN?The field of virology lagged a couple of decades behind bacteriology. Throughout the 1920s and 1930s, taxonomy for bacteria was established and the principles of bacterial growth and pathogenesis described. The 1940s to 1970s ushered in the era of antibacterial therapy that is still being refined and perfected today. Virology, on the other hand, established its taxonomy in the 1940s to 1970s and the first antiviral therapies, mostly against herpes simplex virus (HSV), were first developed in the 1970s and early 1980s. Intravenous vidarabine, one of the first antiviral agents, was used to successfully treat HSV encephalitis (22). Acyclovir, an orally bioavailable nucleoside analogue, successfully reduced HSV replication, which translated clinically into reduced duration and severity of ulcerative lesions (23). Intravenous acyclovir quickly became the drug of choice for the treatment of HSV encephalitis (24).The pioneering activity with herpes viruses set the stage for the development of HIV drugs. Soon after the discovery of HIV, researchers at the National Cancer Institute screened a number of nucleoside analogues that were developed in the 1960s as anticancer drugs, for activity against HIV (25). One of these agents, 3′-azidothymidine (AZT; zidovudine), demonstrated micromolar inhibitory activity against HIV in vitro. In partnership with Burroughs Wellcome zidovudine was tested in clinical trials. The phase II/III study was stopped early by an independent Data Safety and Monitoring Board owing to a dramatic reduction in mortality among the zidovudine recipients versus placebo (21). Within weeks of the conclusion of this study, the US FDA approved zidovudine for use in patients with advanced HIV infection.Yet, from the perspective of the patient/activist community, the 6-yr delay in establishment of the first effective treatment for HIV was way too long. By 1987, more than 28,000 individuals in the US were diagnosed with HIV, half of whom had died (26). HIV patients, frustrated by the slow progress of drug development as their friends died, created community-based organizations, such as ACT-UP, that demanded increased intensity and active participation (and a place at the table) in guiding AIDS research (27). Protests at the NIH, academic medical centers, and pharmaceutical company offices, infused urgency into studies of HIV pathogenesis and drug discovery that set the stage for the so-called highly active antiretroviral therapy (HAART) era in the mid-1990s.Although the use of AZT and other nucleoside analogue drugs in the late 1980s and early 1990s reduced mortality, the benefits of treatment were short lived. Resistance to the treatments, initially employed as monotherapy, developed in 18–24 mo after initiation of treatment, indicating a need for more potent, durable regimens (28, 29).Detailed study of each coding segment of the 9-kb virus sparked ideas for new drug development. Initially, the simple use of nucleotide reverse transcriptase inhibitors (nRTIs) that caused chain termination via eliminating the 3′-hydroxy group were employed (e.g., 3′-azidothymidine, 2′,3′-dideoxycytidine, and 2′,3′-deoxyinosine). As the structure of the HIV reverse transcriptase (RT) enzyme was revealed, nonnucleoside drugs that directly inhibited the activity of the RT enzyme were developed (30). The leading nonnucleoside reverse transcriptase inhibitors (NNRTIs), nevirapine, delavirdine, and efavirenz, demonstrated potent inhibition of HIV replication. However, the durability of the antiviral efficacy quickly was lost when these drugs were given alone (as monotherapy) owing to the rapid (within days) development of resistance (31). This discovery led to the concept of multidrug regimens, which initially combined a single NNRTI drug with two nRTIs (32).Another set of lead compounds focused on inhibition of the virus’ aspartyl protease gene product, which cleaves nascent viral polypeptides into viable, active proteins that are required for successful viral replication. The protease inhibitor (PI) drugs often had in vitro activity against HIV on the nanomolar level (33). In early clinical trials they reduced HIV viral load levels by 2 log10 copies/ml, and were the most potent activity of any drug class to date (34, 35). The lessons learned through the development of PI agents for HIV were applied to the creation of PI drugs to inhibit SARS-CoV-2.Owing to the high degree of lipid solubility, poor oral bioavailability, and the rapid elimination of the HIV PI drugs by liver enzymes, most notably cytochrome P450 3A4 (CYP 3A4), therapeutic drug levels of the early PI lead compounds could not be achieved or sustained. Ritonavir, one of the first PI agents brought to market, exhibited reasonable potency in vivo but was associated with profound adverse effects when given at therapeutic doses (34). When exploring reasons for toxicity, a surprising finding was made that showed ritonavir was one of the most potent inhibitors of the isoenzyme CYP3A4, along with other key drug processing enzymes CYP2D6 and P-glycopeptide (36, 37). As a result, ritonavir was used as a “boosting” agent for HIV PI agents, a practice adopted for COVID-19 PI drug therapy.Development of quantitative PCR technology allowed, for the first time, the ability to quantify the level of virus in the bloodstream (38, 39). High-level viremia throughout all stages of infection uncovered the driving force of disease progression: unchecked viral replication, producing 1 to 10 billion viruses/day (35). This knowledge, combined with accelerated drug development that led to NNRTIs and protease inhibitors PIs, resulted in near-complete suppression of viral replication when these new agents were used as combination therapy, referred to at that time as highly active antiretroviral therapy (HAART) (40, 41).As these newer treatments were being studied in the early to mid-1990s, the drugs were unavailable to most patients who were not participating in clinical trials. Owing to active monitoring of the performance of newer regimens as they were tested in clinical trials by the HIV activists, the patient community demanded access to the more promising agents as the trials were being conducted. Through active discussions between the activists and the FDA, a so-called “Parallel Track” compassionate use program was established that required the sponsoring pharmaceutical companies to make their investigational drugs available to patients outside of clinical trials prior to formal approval by the FDA (42). In exchange, the pharmaceutical company would be granted more rapid review of their novel regimen (accelerated approval), which was advantageous to the company (longer market life on patent) and the patient community as well. This experience laid the foundation for the Emergency Use Authorization (EUA) process used today (43, 44).The convergence of advanced drug discovery along with routine use of viral load in practice was an inflection point in the AIDS epidemic. HIV infection transitioned from a death sentence to a chronic manageable condition where patients now can live a near-normal life span and do not transmit the virus to others once undetectable levels of viremia is achieved and sustained (45).A missing link in the accomplishments of HIV science is the successful development of a vaccine. Soon after the discovery of HIV, Human Health Services Secretary Margaret Heckler declared in 1985, “We will have an effective AIDS vaccine within the next 2 years” (46). We are still waiting; but it is not for lack of effort. Candidate vaccines, ranging from protein constructs, viral vector vaccines, and more recently, use of broadly neutralizing antibodies, have not successfully prevented HIV transmission. A key reason for the difficulty in developing an HIV vaccine is the high degree of genetic variation of HIV (47, 48). With each replication cycle of HIV, an error in transcription is made, resulting in a point mutation within the 9-kb virus. Although many of these errors result in stop codons, which result in nonviable virions, or synonymous mutations, the high number of asynonymous errors creates opportunities for a more fit virus to emerge and evade the immune response. Ultimately, each person with HIV harbors many archived variants that represents a quasispecies within each infected individual (48). The degree of genetic variation, along with the inability of the host immune system to eradicate HIV, makes the development of an HIV vaccine quite difficult. Over the last decade focus has turned to the development of broadly neutralizing antibodies (bNAbs) that are able to inhibit replication of most genetic variants of HIV (49). A current vaccine development strategy includes development of candidate vaccines that can induce the host to produce bNAbs in vivo as a strategy to provide protection against HIV challenge (50).4. FOR SARS-COV-2, THE PAST IS PROLOGUEThe scientific discoveries advanced during the four decades of the HIV epidemic, as well as experience with other coronavirus (SARS-CoV-1) infections, hepatitis C, Zika, and Ebola, established the platform that enabled the rapid advances in responding to the COVID-19 pandemic. The understanding of high-level replication and emergence of variants, especially for RNA viruses, prepared epidemiologists to screen for SARS-CoV-2 variants throughout the pandemic. Intensive study of the nature of coronaviruses following the SARS-CoV-1 epidemic in 2003 and the Middle East respiratory syndrome (MERS) outbreak in 2011 to 2012 created the understanding of the pathogenesis of coronavirus infections, their binding sites, and the nature of transmission (51, 52). Over the last decade, creation of novel beta-coronavirus mRNA vaccine candidates that target the MERS virus led to insights that were rapidly employed in the development of the SARS-CoV-2 specific vaccines (53). Currently, work on creating pancoronavirus mRNA vaccines is well underway (54).Drug development throughout the HIV epidemic laid the groundwork for anti-COVID nucleoside agents, including remdesivir and molnupiravir, and the protease inhibitor nirmatrelvir, which also incorporates the boosting property of ritonavir (6). The use of bNAbs as potential therapies for HIV and other viral infections led to the rapid development of monoclonal antibodies for treatment of COVID-19, including bamlamivimab/etesevimab, casirivimab/imdevimab, sotrovimab, bebtelovimab, and the use of tixagevimab/cilgavimab as primary prophylaxis (7–9, 55).The development of several extraordinarily effective and safe COVID-19 vaccines, however, is the most impactful and remarkable achievement. Years of work on HIV vaccines, including the establishment of standard protocols to asses safety and efficacy, prepared the field for the rapid development of COVID-19 vaccines (56, 57). Establishment of immune correlates of protection with influenza, Varicella-zoster virus (shingles), and human papillomavirus vaccines provided a foundation for assessment of new candidate COVID-19 vaccines in animal models. The urgent need to develop an effective Ebola vaccine during the 2015 outbreak in West Africa sparked the use of the adaptive clinical trial design, which was employed during the development of the COVID-19 vaccines (58). This accelerated vaccine development tremendously, saved months to years of time. Finally, the exploration of mRNA technology as a potential vaccine construct for other viral infections had been under development for more than a decade and was rapidly employed for the Moderna and BioNTec/Pfizer vaccines (59–61).Despite the development of successful therapy, COVID-19 continues to cause substantial morbidity, particularly for those who develop “long COVID-19,” also called postacute sequelae of SARS-CoV-2 [or postacute sequelae of COVID-19 (PASC)] (62, 63). Defined as persistent symptoms of more than 28 days following an acute episode of COVID-19, PASC usually involves lung, heart, gastrointestinal tract, or nervous system, either in one organ system or in a combination of them. Tachycardia, persistent dyspnea, inability to think clearly (“brain fog”), loss of smell or taste, persistent diarrhea, headache, vertigo, and myocarditis are among the more common presentations. Often the symptoms abate after several months, but prolonged symptomatology is common. The cause of PASC remains elusive, and therefore, treatments are mostly directed at symptom alleviation.Taken together, the development of COVID-19 testing, treatment, and vaccine technologies and the rapid implementation of these innovations in such a rapid and efficient fashion are miraculous. The lives saved are in the tens of millions worldwide (64, 65). Without the innovative research conducted over the last four decades those lives would have been lost. The platform created by these advances enabled the successes of the COVID-19 research effort is noteworthy and should be celebrated.On a more somber note, there is one tradition of excellence that emerged in the HIV research era that has not yet translated into the COVID-19 research portfolio: The role of community activists.27During the first decade of the AIDS epidemic, patients and their families and friends became angry at the lack of attention from governments and the slow progress of research as tens of thousands of individuals worldwide died (66). They organized, protested, occupied offices at NIH and pharmaceutical companies, and demanded that the search for life-saving medications intensify and accelerate. Overtime, their efforts were rewarded with a seat at the table within research organizations, academia, and on advisory boards at pharmaceutical companies. This catalyzed the explosion of new therapies used in novel ways, ultimately transforming HIV infection from a near-certain death sentence to a chronic manageable condition with near-normal life expectancy.By contrast, the activities of many COVID-19 activists have undermined scientific discovery, sewn doubt regarding the veracity of the scientific method, and created confusion among the public through the release and promotion of misinformation, disinformation, and outright falsehoods on social media outlets and talk radio. Unlike the AIDS activists who celebrated the science and pushed the field forward, many of these COVID-19 activists promote therapies that have minimal or no efficacy, especially when compared to monoclonal antibodies, nirmatrelvir/ritonavir, and molnupiravir, and espouse antivaccination rhetoric on social media (67). This has contributed to 35% to 40% of the population in the United States choosing not to be vaccinated. Unvaccinated persons make up more than 80% of hospitalized patients and result in more than a 20-fold increase in death (68). Since the widespread release of vaccination, most of the deaths due to COVID-19 are preventable (64, 65). An outcome that is antithetical to the efforts of activists in the AIDS era.The most pernicious and destructive activity, however, is the “assassination of the Trusted Voice.” Throughout the COVID-19 crisis public health leaders, who normally are sought to provide guidance to the public regarding the best ways forward during Public Health emergencies in order to minimize sickness, death, and the impact on the healthcare delivery system, are maligned via social media and attacked personally, often in the form of serious threats on their lives and the well-being of members of their family (69). The societal cost of these activities are difficult to calculate precisely, but are enormous.As the COVID-19 pandemic transforms into an endemic state, an analysis of the role COVID-19 activists have played in creating harm should be performed. Simultaneously, efforts should be directed at rehabilitating Public Health in providing guidance to the population during future crises.In the meantime, the science that began decades ago in the battle against HIV and other viral diseases and formed the platform upon which the remarkable success of the development of COVID-19 prevention, vaccines, and therapeutics should be celebrated. Communication of this story to the public can be a catalyst for the reestablishment of trust in our Public Health System and its leaders.GRANTSM.S. is supported by National Institute of Allergy and Infectious Diseases Grant P30-AI027767.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.AUTHOR CONTRIBUTIONSM.S. conceived and designed research; M.S. performed experiments; M.S. analyzed data; M.S. interpreted results of experiments; M.S. prepared figures; M.S. drafted manuscript; M.S. edited and revised manuscript; M.S. approved final version of manuscript.REFERENCES1. Wang C, Liu Z, Chen Z, Huang X, Xu M, He T, Zhang Z. The establishment of reference sequence for SARS-CoV-2 and variation analysis. J Med Virol 92: 667–674, 2020. doi:10.1002/jmv.25762. Crossref | PubMed | Google Scholar2. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, et al.. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. 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