Yves here. KLG puts on his yellow waders to assess a paper by Anthony Fauci and Gregory Folkers that more than a little seeks to ‘splain the official Covid response.
By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health
I had not intended to come back to this subject so soon, since I wrote about this only two weeks ago with COVID-19 in Context: A Retrospective Review on February 28, 2025 and before that in A Tale of Two Pandemics on December 18, 2024. But as a practicing scientist, although not as active in the laboratory as in the past, I cannot help but review my work in real time. There are always other scientists out there somewhere with similar thoughts, plans, and actions. “COVID-19 in Context” discussed the current pandemic from the perspective of what scientists have known about pathogenic coronaviruses since the 1950s and probably before. “A Tale of Two Pandemics,” which came first, compared responses to HIV/AIDS beginning in the early 1980’s and COVID-19 over the past five years.
I began working on both of those essays in September 2024. Thus, I missed something published in late November in the journal Clinical Infectious Diseases, which is sponsored by the Infectious Diseases Society of America and published by Oxford University Press. The paper is entitled Human Immunodeficiency Virus/AIDS and Coronavirus Disease 19: Shared Lessons from 2 Pandemics (paywall, so block quotes are used liberally in what follows). The authors of this paper are one Anthony S. Fauci and Gregory K. Folkers. The second author is the corresponding/primary author. After retiring from his position as Director of the National Institute of Allergy and Infectious Diseases (NIAID), Dr. Anthony Fauci joined the faculty of the School of Medicine and the McCourt School of Public Health at Georgetown University in Washington, DC. Gregory K. Folkers was formerly Chief of Staff to the NIAID Director.
My immediate reaction to finding this paper was that I had been scooped and didn’t know it, and in the process I may have misled my readers. Getting scooped is every scientist’s recurring nightmare. But usually there are enough differences between two approaches to any given problem that the work of both research groups complement one another. Sometimes they contradict each other. In my view both are relevant here. In what follows, we will proceed through the eight common lessons from Fauci and Folkers (F&F) that HIV/AIDS and COVID-19 have taught us. And just as important for the practice of biomedical research, we will cover what they have not taught us.
Lesson 1: Expect the Unexpected. F&F begin by pointing out that in the 1970s, much of the medical establishment considered infectious disease a problem that had been solved. With vaccines, antibiotics, and robust public health measures widely observed, infectious diseases were soon to be a thing of the past. This was pure hubris, as AIDS taught us an object lesson beginning in the middle of 1981. In the past 40+ years more than 42 million people have died of AIDS. So much for the end of infectious disease. And then in late 2019:
This “once in a lifetime” experience with HIV/AIDS turned out to be not so unique. In 2019, the unexpected again struck the global…SARS-CoV-2. This novel coronavirus has a high efficiency of transmission; the pathogenic capacity to kill large numbers of people, particularly, but not exclusively, the vulnerable such as the elderly and those with underlying conditions; and the ability to rapidly evolve into multiple variants that evade the protection from vaccinations and prior infection. As with HIV, the extraordinary diversity and mutability of SARS-CoV-2 and the immune-evading capacity of new viral variants has posed unexpected challenges for developing a durably protective vaccine. With SARS-CoV-2, a high percentage (at least 50%) of transmissions occur from an asymptomatic or presymptomatic person to an uninfected person, another unexpected (and perhaps unique) characteristic of the virus. Moreover, it became apparent as the COVID-19 pandemic evolved over months and years that transmission occurs mostly through the air and that an alarming number of people with SARS-CoV-2 infection develop postacute sequelae of COVID-19 termed “long COVID”.
It is true HIV was essentially novel in 1981. At the time, only two human retroviruses had been well described: Human T-Lymphotrophic Virus-1 (HTLV-1) and HTLV-2. Both viruses were discovered in the laboratory of Robert C. Gallo, who was active in the search for the cause of AIDS. [1] HTLV-1 causes adult T-cell lymphoma in ~5% of carriers, while HTLV-2 does not cause any specific disease but has been associated with mycosis fungoides. On the other hand, infection with HIV had the grimmest of prognoses until highly active anti-retroviral therapy (HAART, now called ART) was developed in the mid-1990s, more than fourteen years after the beginning of the AIDS pandemic.
However, there was nothing novel about SARS-CoV-2 in 2019. SARS-CoV was known to be the cause of the SARS outbreak of 2002 and MERS-CoV for the outbreak of MERS in 2013. Both of these viruses were contained but caused fatal illnesses with much higher death rates than COVID-19. More than 20 million people have died of COVID-19 in the past five years. It should also be noted that airborne transmission was likely from the beginning of COVID-19 but this fact was not acknowledged as rapidly as it should have been. Instead, we had a year or more of handwashing hygiene theatre, not that handwashing is unimportant in dampening the spread of an infectious disease.
Lesson 2: With Pandemics, Political Leadership at the Highest Level is Critical. Indeed, it is. Politicians did not do particularly well with AIDS, which appeared five months into Ronald Reagan’s first term. President Reagan did not address AIDS until 1987, two years after the death from AIDS of his friend Rock Hudson. Politicians eventually got over their reticence and twenty years after the beginning of the AIDS pandemic, George W. Bush established the President’s Emergency Plan for AIDS Relief (PEPFAR). PEPFAR has been a resounding foreign aid success, preventing as many as 25 million deaths from AIDS. Alas, PEPFAR may not survive much longer, as foreign aid is currently in jeopardy. F&F then proceed to note that the political leadership, or lack thereof, was critical in the current pandemic:
President Donald Trump frequently minimized the seriousness of the pandemic, repeatedly claiming that COVID-19 would just “go away.” (The same was said of AIDS.) In the first full year of the pandemic (2020, the last year of his presidency) he failed to use his bully pulpit to encourage people to use available “low-tech” tools such as masks/respirators, better ventilation, and physical distancing to reduce the risk of infection. Trump also gave credence to unproven and potentially dangerous substances for COVID-19 prevention and treatment such as bleach injections, the antimalarial hydroxychloroquine, and the antiparasitic drug ivermectin. Many of his hundreds of communications during the COVID-19 pandemic were missed opportunities for political leadership in promoting policies and practices to mitigate the impact of a raging pandemic.
Again, while there is much to unpack here, it was the scientific establishment that was slow to point out that SARS-CoV-2 is an airborne virus and that masks and respirators are non-pharmaceutical interventions (NPI) that prevent spread of the virus. Equivalent NPI that prevented exchange of bodily fluids were identified immediately during the earliest days of the AIDS epidemic in the United States. This history of masks and COVID-19 may be more complicated that implied by F&F, as shown here and in many other articles. The “bleach injection” canard is just that, although President Trump is quite “good thinking out loud.” [2] As for repurposing drugs based on the clinical judgment and experience of practicing physicians, this is not unusual. As one example, thalidomide is now used to treat lymphoma. In the 1950s it caused a horrific “outbreak” of phocomelia, primarily in Europe. [3] F&F conclude Lesson 2 with:
Moving forward, it is essential that the scientific community – and the public at large – support leaders who pledge to embrace evidence-based decision-making in science and public health, who articulate a vision for improving peoples’ health and well-being and (ideally) have a track record in administering health-related programs.
This could be viewed as unexceptional, except “evidence-based medicine” (EBM) depends on whose evidence and for what purpose. Is the evidence from and for Pfizer, Moderna, Novartis, Novo Nordisk, or Eli Lilly? Does the evidence come from academics who are sponsored by a well-known, well-funded, and highly active libertarian think tank? Or is the evidence from disinterested scientists and intended for the common good? EBM is described in The Illusion of Evidence-Based Medicine, which was discussed here previously.
Lesson 3: Prior Scientific Advances Are the Foundation of Successful Pandemic Preparedness and Response. F&F begin with the famous passage that Isaac Newton wrote in 1675 in a letter to Robert Hooke: “If I have seen further, it is by standing on the shoulders of Giants.” This is, of course, true for all scholars in every discipline. It was especially true for HIV/AIDS. If David Baltimore and Howard Temin had not discovered RNA-dependent DNA polymerase, the reverse transcriptase that copies the RNA genome of HIV prior to its insertion into the host cell genome where it remains in perpetuity, AIDS would have remained a mystery. If Robert Gallo and colleagues had not developed methods to continuously propagate retroviruses in culture, AIDS would have been an impossible problem to solve at the time. A most remarkable section follows from F&F:
As with HIV/AIDS, prior scientific advances underpinned progress against SARS-CoV-2, notably in the rapid development of safe and effective COVID-19 vaccines. Just 11 months from the identification of the genomic sequence of SARS-CoV-2, 2 COVID-19 vaccines received Emergency Use Authorization from the U.S. Food and Drug Administration…Likewise, the structure-based approach to immunogen design that had evolved over decades of research in the hunt for an HIV vaccine underpinned the successful development of the mutationally induced, optimally stabilized spike protein immunogen for the COVID-19 vaccines.
This section touches on one of the most interesting parts of the scientific response to COVID-19. This was addressed in COVID-19 in Context: Rather than HIV/AIDS as the paradigm, the response to COVID-19 should have been based on our extensive knowledge of coronavirus disease in vertebrates. So far, durable immunity to coronaviruses, either through prior infection or vaccination has been unattainable, as stated outright in F&F’s first block quote above.
Whether the COVID-19 vaccines are effective depends on the definition. Yes, they are said to prevent the worst outcomes for some patients, and this should not be minimized. But these experimental vaccines prevent neither the disease nor its transmission. [4] However, prevention is what people have come to expect of vaccines (smallpox, polio, measles, pertussis, diphtheria, tetanus, chickenpox, human papilloma virus, etc.). But this is what our political leaders told us the mRNA vaccines would do. Attempts to finesse the meaning of “effective” in this manner, from the highest levels of science and politics, only increase vaccine hesitancy in a fraught political environment, which unfortunately remains the continuo of our healthcare politics as the second term of President Trump begins.
Lesson 4: Misinformation and Disinformation Are Universal Enemies of Pandemic Control. This section begins with HIV denialism in the person of Peter Duesberg of the University of California – Berkeley, who “claimed that HIV was not the cause (of AIDS),” with what can only be called spurious arguments that were not taken seriously by anyone forty years ago. According to F&F regarding COVID-19:
Misinformation and disinformation have been rampant during the COVID-19 pandemic and were made worse by online platforms that amplify untruths faster than at any other time in history, some of them spread by well-funded bad-faith actors. From a public health standpoint, this has been particularly damaging with hesitancy to accept the safe and highly effective COVID vaccines among certain segments of the population. As with the avoidable AIDS-related loss of life from the lack of availability of antiretroviral drugs in the RSA (Republic of South Africa), lives were unnecessarily lost because of vaccine hesitancy related to COVID vaccines. It has been estimated that in the United States, at least 23,200 deaths could have been prevented among unvaccinated adults during the period from May 2021 and September 2022 had they received a least the primary series of COVID vaccinations.
The internet can be a hive mind filled with misinformation, but there is enough blame to go around here, several times. For example, so-called “bad-faith actors” [5] have come from all sides during the five years of COVID-19. As for vaccine hesitancy causing unnecessary deaths, this is undoubtedly true. However, many Americans had been vaccinated prior to May 2021, including virtually all of my coworkers. Many of these daily companions have subsequently had COVID-19 multiple times. According to CDC during the period cited above, in the fifth COVID-19 spike 21,337 Americans died of (provisional) COVID-19 in the week of January 22, 2022. This certainly is not to diminish the saving of 23,000 lives, but it does place our responses to COVID-19 in context.
Lesson 5: Increased Attention to the Human/Animal Interface is Critical for Pandemic Prevention. Nothing to argue with here, except to note that as long as planet Earth is believed to exist primarily for exploitation by human beings, people will encounter pathogens that otherwise would remain largely unknown.
Lesson 6. Inequities, Health Disparities, Stigma, and Discrimination in Pandemic Settings. Yes, “HIV/AIDS and COVID-19 are compelling examples of the disproportionate disease burden – especially infectious diseases – among underserved populations.” As stated:
During the COVID-19 pandemic, excess mortality among American Indians or Alaskan Natives, Hispanic, and non-Hispanic Black individuals aged 65 years and older far surpassed rates of their non-Hispanic, White counterparts. These disparities were driven by longstanding systemic health and social inequities including discrimination and limited access to healthcare; occupations that disproportionately put poorer populations in essential work that increased their exposure to respiratory-born illnesses; educational, income and wealth gaps, and housing inequities where certain people are forced to live in crowded multigenerational homes where it is difficult to adhere to prevention strategies. They also were driven by a greater prevalence of underlying conditions such as diabetes, hypertension, obesity, and chronic lung and heart disease that predispose a person to an increased severity of COVID-19.
This is all true. For now, we will leave for another time aspects of our political economy such as the nature of “essential work” and why living together as multigenerational families should ever be a problem for any family. However, F&F do address the fundamental problem of healthcare in the United States, where healthcare is something to be paid for by individuals, one way or another, with the result that people with more money get better healthcare. [6] People who are afraid to go to the doctor because the result could be bankruptcy tend to do less well that those without, for now, that fear:
COVID-19 has shown a bright light on how the social determinants of health lead to disparities in incidence and severity of disease. These determinants will not disappear in weeks, months, or even years; however, they will never disappear unless we commit now to the process of addressing them. Among many efforts, policies are needed to ensure universal, affordable, and equitable health coverage.
“Affordable” and “equitable” are doing a lot of work here. Healthcare is a right, not a privilege, and the only way to be fully ready for the next pandemic is to address this without hesitation, fear, or favor. This can be done. Or more correctly, it has been done. The great Aneurin Bevan set up the National Health Service in little more than one year after the Labour government of Clement Atlee took office immediately after World War II, despite opposition from Harley Street physicians and surgeons and Tory politicians. In the United States, the Social Security Amendments of 1965 led to the establishment of Medicare and Medicaid shortly thereafter. In contrast, From passage to implementation, the inferior Affordable Care Act of 2010 required nearly four years.
Lesson 7: Community Activism and Engagement Are Critical in Pandemic Responses. Community activists certainly made a difference forty years ago during the early days of the HIV, as rules for clinical trials of possible drugs were modified. This has been covered especially well in Choose Your Medicine Freedom of Therapeutic Choice in America (2021) by Lewis A. Grossman. COVID-19 advocates helped push through funding for research on long COVID: Researching COVID to Enhance Recovery – Treating Long Covid (RECOVER-TLC). Nevertheless, it would be better to prevent COVID-19 in the first place, since that is the only way to prevent long COVID.
Lesson 8: Emerging Infections Diseases are a Perpetual Challenge. Here F&F recapitulate their opening:
Although the infectious diseases community and the entire medical community were stunned by the unexpected appearance of a brand-new pandemic disease in HIV/AIDS, only to be followed almost 40 years later by another pandemic caused by a novel pathogen, history should have warned us that this would happen. From before recorded history, civilizations have been devasted and shaped by the appearance of emergent infectious diseases, from the plague of Athens (etiology unknown) in 426 BC to the bubonic plague (Yersinia pestis) in the 14th century, to the pandemic influenza of 1918, among others.
My response remains the same. Yes, HIV/AIDS was a shock, but previous work on obscure viruses that may cause lymphoma made a rapid response possible. Even then, it took fifteen years for AIDS to become treatable with anti-retroviral therapy. An HIV vaccine remains just over the horizon, at best. But the injectable anti-HIV drug lenacapavir has shown near-100% efficacy in preventing AIDS. This truly is reason to celebrate the result and the science, that is if the drug is made available as a right rather than a privilege that comes with the ability to pay the asking price for it.
COVID-19 may have been a surprise, but the very recent history of SARS and MERS did warn us this could happen again. Had biomedical research funding on SARS and MERS been continued at a sufficient level, especially on infection/transmission and antivirals that treat coronavirus disease, things could have been different. Operation Warp Speed should have addressed COVID-19 prevention (ventilation and air filtration as analogs to behavioral changes that were quickly shown to prevent the transmission of HIV) and treatment of SARS-CoV-2 in the form of a highly active anti-coronavirus therapy (HAACT). The latter could have followed the path developed with HIV, in which a drugs interfering with separate stages of the virus life cycle are used to stop viral replication.
Finally, in my view the response to COVID-19 by the scientific and political establishments missed what had been staring us in the face since the SARS and MERS outbreaks of 2002 and 2013, while at the same time misinterpreting what HIV/AIDS had to teach us about an effective response to a lethal pandemic virus. The only way to do better in the future is to simply do better at supporting research. But that will require an open-ended approach to supporting potentially pressing questions such as coronavirus diseases, while at the same time providing ample support to ask simple questions about the natural world. The latter is what made biomedical research so productive during the second half of the twentieth century. Directed research is useful but not as effective as naïvely expected. The engineering ideal in biology is productive only in the very long term, if then. After the current mishegoss ends, if it does, perhaps we can return to science for the sake of science. If we do this, Mother Nature will still bite at times but the result could be much less damaging.
Notes
[1] An early name given for the AIDS virus by Robert Gallo was HTLV-3. The two scientists who were awarded a Nobel Prize for the discovery of HIV called it LAV (Lymphadenopathy Virus) in their early research.
[2] Snopes on bleach injection. This accusation has as much credibility as Elon Musk railing that Social Security benefits are provided to Americans who are long dead, but I can attest that many acquaintances fell for that without a second thought.
[3] Thalidomide did less damage in the United States thanks to the work of Frances Oldham Kelsey, a pharmacologist at the Food and Drug Administration.
[4] mRNA vaccines are experimental, but there is nothing experimental about mRNA vaccine technology, which has been “in the air” since Dr. Robert Malone did not invent mRNA vaccines in 1989 when he showed that mammalian cells could be transfected with an exogenous mRNA and then produce the protein product of that mRNA. In fairness to Dr. Malone, his paper was a signal advance in modern molecular biology and it was recognized as such at the time.
[5] Too much information in this PNAS paper but the controversy surrounding the Proximal Origins paper in Nature Medicine is not reassuring. Ditto for gain-of-function research on pathogenic viruses. And unlike forty years ago with HIV/AIDS, solid information about the origins of COVID-19, the effectiveness and hazards of the vaccines, and effective non-pharmaceutical interventions has been unusually difficult to obtain. In any case, the origin of SARS-CoV-2 is immaterial to how we should continue to respond to the pandemic.
[6] Personal example: I recently had major outpatient surgery (recovery went well). Early on the morning of the event, I unexpectedly was required to pay a substantial sum before proceeding. Arrangements “would have been made” if I had been unable to pay, but the resulting stress of the looming bill considerably larger than the proverbial $400 emergency that most Americans cannot afford would not have been healthy.