Yves here. Even with having been attentive to Covid studies and news, KLG’s overview contains quite a few information nuggets that were new to me. For instance, the UK quickly started taking blood samples of ~100,000 patients every 5-6 weeks in what it called the REACT survey to assess, among other things, prevalence of Covid (recall it can be asymptomatic) and whether it was mutating. Commentator were looking at the decline in antibody levels over time among the infected as a proxy for how long immunity lasted. However, KLG describes below that antibody levels “do not correlate with protection from infection.” So the lay and even the professional press has misreported this issue.
KLG also explains, long form, why using only the spike protein may not have been the best approach for a vaccine. Note that KLG also stresses the lack of durable immunity to coronaviruses and what that implies for disease prevention and treatment. This is not even remotely new news; we stressed that from the very outset. Yet he points out how that basic issue has been bizarrely ignored in public health responses.
KLG’s introduction:
COVID-19 did not appear out of nowhere. SARS (2002) and MERS (2013) were first, but the original serious coronavirus disease was caused by Infectious Bronchitis Virus in chickens. The biomedical responses to COVID-19 did not fully take into account previous knowledge of coronavirus disease, especially that durable immunity to coronaviruses is basically a unicorn. Hindsight is often 20:20, but had the scientific and political establishments paid more attention to the known pathobiology of coronavirus disease over the past five years than the bright shiny prospect of vaccines, our collective responses might have been more effective. Perhaps they will improve next time. And there will be a next time.
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
COVID-19 (agent of disease: SARS-CoV-2) did not appear ex nihilo in late 2019. It was presaged by the outbreak of SARS (Severe Acute Respiratory Syndrome) in 2002 and by MERS (Middle East Respiratory Syndrome) ten years later. SARS (SARS-CoV) spread from Guangdong to Singapore and Toronto by early 2003 but was contained by rapid and effective public health measures. Nevertheless, 774 patients in a population of 8,098 reported cases died (9.6%). The death rate for MERS (MERS-CoV), which is not as transmissible as SARS, was ~34% in a population of about 2,600. The death rate for COVID-19 is much lower than for either SARS or MERS, but the current pandemic has killed more than 20 million people worldwide. All three diseases are caused by coronaviruses, which have been recognized as viral pathogens in vertebrates since 1949 and probably earlier.
What follows is an attempt to put COVID-19 in context based on a focused consideration of a coronavirus literature that has become quite large (and intractable) in the past five years. My priors are that the only way to address a scientific problem correctly is to go back to the beginnings so that the foundation of current research is as strong as possible. In my experience in biomedical science, this is the only way to make significant discoveries, small or large. Otherwise, the scientist is only placing bricks on a pile with little thought for how they fit together. [1] This essai is only that, and attempt, and I expect more complete coverage to emerge in the next few years from several perspectives, scientific and political.
We begin with the response to SARS from the perspective of an expert on coronavirus disease in poultry. The first coronavirus disease in vertebrates is caused by what is now known as Infectious Bronchitis Virus (IBV): Severe acute respiratory syndrome vaccine development: experiences of vaccination against avian infectious bronchitis coronavirus (D. Cavanagh, 2003; Institute of Animal Health, currently the Pirbright Institute). Until SARS, human coronaviruses caused only mild upper respiratory tract infections. This paper is representative of several published after the SARS outbreak that addressed how previous experience with the IBV should be useful in dealing with serious coronavirus disease in humans. This review is especially relevant because it concentrates on vaccines against coronavirus disease, and the primary response to COVID-19 has been vaccination.
Coronaviruses have been placed into four taxonomic groups:
- Group 1: Human coronavirus 229E, Feline infectious peritonitis virus
- Group 2: Human coronavirus OC43, Murine hepatic coronavirus
- Group 3: Infectious bronchitis virus (IBV)
- Group 4: SARS-CoV, SARS-CoV-2, MERS-CoV
These viruses are divergent and some cause more serious disease than others. The most well studied coronavirus prior to the SARS outbreak of 2002-2003 was IBV, primarily because it presents a very serious problem in chicken production in Concentrated Animal Feeding Operations (CAFOs). CAFO-based poultry production began in the 1950s in the United States.
IBV pathobiology has much to teach us about coronavirus disease and the role of vaccines in industrial chicken production. These lessons include:
- The best practice is to vaccinate newly hatched broilers on Day 1.
- Protection against disease lasts a short time, and this may require re-vaccination for chickens that are grown longer than 4-6 weeks before slaughter.
- Spike protein (the viral envelope protein that looks like the “crown” in electron micrographs of coronaviruses) may be used as the immunogen for vaccines, but minor divergence in IBV spike variants yields poor cross protection. As a reminder, the exterior spike protein segment is the expression construct in the SARS-CoV-2 mRNA vaccines.
- Circulating antibody levels do not correlate with protection from infection.
- The schedules required for protection of chicken “flocks” in CAFOs are not cost-effective, which requires rigorous infection control in large chicken houses that may accommodate tens of thousands of birds. [2]
Thus, based on experience with IBV vaccines (p. 568): “Application of a SARS vaccine is perhaps best limited to a minimal number of targeted individuals who can be monitored, as some vaccinated persons might if infected by SARS coronavirus, might become asymptomatic (shedders) of virus, thereby posing a risk to non-vaccinated people.” This research on IBV shows that coronavirus vaccines can be developed, and they elicit an immune response. However, this immune response does not correlate with protection from disease, nor is the immune response durable. Cavanagh’s conclusions are particularly relevant in 2025. As Cavanagh put prospectively sixteen years before COVID-19:
If there were a resurgence of SARS in humans (SARS-CoV-2 qualifies) one would anticipate that the authorities would rapidly put into operation the various surveillance and control measures that proved successful in early 2003. If vaccines had been developed, vaccination might be included, especially for healthcare workers and contacts in the wider community. Coronaviruses can establish persistent infections (in which the virus can evolve) in at least a portion of their hosts, resulting in chronic asymptomatic shedders, with subsequent problems for containment of th disease. For this and other reasons, a decision to apply a SARS vaccine would not be taken lightly. Notwithstanding, what type if vaccine might be used?
Vaccines based on mRNA were not mentioned twenty years ago. But as noted above, the spike protein may not be the best immunogen to use:
If SARS coronavirus (SARS-CoV-2) were to re-emerge in humans, its S1 protein might not be the same as that of the 2002-2003 outbreak. Research with IBV has indicated that differences of only 5% of S1 protein amino acids can reduce cross protection. Consequently, S1 differences among SARS coronavirus isolates must not be viewed complacently. The finding that IBV N-protein (major structural protein of the infectious virion) plays a beneficial role in immunity suggests that the SARS virus N-protein should not be overlooked in a SARS vaccine development program.
This paper, published in 2003 and based on a strong foundation of coronavirus pathobiology, neatly summarizes the chronicle of a pandemic foretold. It was not a one-off.
Another perspective can be found in SARS: Future Research and Vaccine (2004) by Yu-Lung Lau of the University of Hong Kong, Queen Mary Hospital. Professor Lau notes at the beginning that “SARS is a new infectious disease of the 21st century that has pandemic potential” and that “the high morbidity and mortality of this potentially pandemic infections demands a rapid research response to develop effective antiviral treatment and vaccine.” SARS was stopped by epidemiologic surveillance and infection-control. Note that treatment comes before vaccines in the original recommendations from NIAID (May 2003):
- Clinical research: What is the presentation of the disease and how might it be managed in the clinic?
- Epidemiology: How is the disease transmitted (e.g., fomites, droplets, aerosols) and what non-pharmaceutical interventions will prevent transmission (masks, air filtration)?
- Diagnostics: How is the disease identified in a patient?
- Therapeutics: What pharmaceutical interventions can be used?
- Vaccines: What is the best approach to coronavirus vaccines?
The reason for antivirals first is that with SARS “an initial viral replicative phase of about 10 days is followed by an immunopathological phase…(and)…the immunopathological response is triggered by the viral antigens, hence the most strategic treatment is to stop viral replication at the initial phase of the disease so that peak viral load and the subsequent damage is minimized.” Thus, future research priorities should focus on antiviral drug screening. There is ample scientific precedent for drug targets, including:
- Virus binding to target cells.
- Fusion of the virus membrane with the cell membrane to allow the infectious particle entry into the cell.
- RNA-dependent RNA polymerase inhibitors to prevent replication of the coronavirus genome.
- Protease inhibitors to inhibit maturation of functional virus particles in the infected cell.
These targets form the basis of anti-HIV therapy that has made AIDS a manageable condition for those who are fortunate enough to receive HAART (Highly Active Anti-Retroviral Therapy, now called ART). [3] There is no reason in principle this will not work for coronaviruses. Moreover, it is still very clear that vaccines against coronaviruses remain problematic, in that durable immunity to coronaviruses through previous exposure or vaccines has not been demonstrated consistently in coronavirus diseases. Given what we (should) know about coronavirus pathobiology, an Operation Warp Speed for SARS-CoV-2 antiviral drugs would have been the stronger partner with the rapid development of COVID-19 mRNA vaccines.
Thus, the overwhelming emphasis on vaccines for COVID-19 has been puzzling from a scientific perspective. Not only should biomedical scientists and those working in BioMedicine (Big Pharma/Big Medicine) know the scientific foundations of coronavirus pathobiology, it is becoming increasingly clear that immune pathology is also associated with SARS-CoV-2 infection. Of course, this was well understood for SARS-CoV when Yu-Lung Lao published his review:
Since immune response might play a role in SARS pathogenesis, one must be cautious of the possibility of enhancement of the disease in immunized subjects. This has indeed occurred for an experimental vaccine directed against feline infectious peritonitis virus, which is a coronavirus. Therefore, caution has been urged on developing SARS vaccines.
Research is beginning to show that T-cell exhaustion and long-term immune system damage follows SARS-CoV-2 infection, especially in people with long Covid. Moreover, the proper testing of candidate SARS and by extension SARS-CoV-2 vaccines would require an animal model that reproduces severe coronavirus disease in humans. During the initial research on a SARS vaccine, macaques were used after being used to confirm Koch’s final postulate that SARS-CoV is the etiologic agent of SARS. [4] However, these monkeys did not always recapitulate the disease state in humans. Early research on the COVID-19 mRNA vaccines used rhesus macaques as the experimental nonhuman primate.
Where do we go from here? None of the foregoing is meant to cast aspersions, but it must be noted that the current COVID-19 vaccines are a rushed and unlikely technical fix for a problem that did not necessarily have to exist. COVID-19 is the third serious coronavirus outbreak since 2002. As has been noted by many, there was every reason to expect another coronavirus outbreak, one that could be worse than SARS or MERS. So far, SARS-CoV-2 is the agent of a worldwide pandemic, and new mutations that make the virus more transmissible and/or virulent have been identified. Given the apparent unpredictability of the course of a coronavirus infection (the sniffles of a common cold, enduring widespread and long-term organ damage, death) there is no good reason that coronaviruses have not remained a continuing commitment in biomedical research since the original SARS outbreak.
But the research establishment clearly did not respond as needed. This is illustrated in the following figure, which is a simple measure (based on entries in PubMed) of SARS, MERS, and COVID-19 research since the original SARS outbreak. As expected, there was a peak in SARS research papers in 2003 and 2004, followed by a decline to a relatively low baseline for such a serious disease>The same was true for MERS beginning in 2013.
The publication spike beginning in 2019 coincides with COVID-19 (“SARS” as in SARS-CoV-2 would have been included in most research papers on COVID-19). Given the clinical course of SARS and MERS, these two coronavirus diseases should have received more attention. Continued research on viral pathobiology using appropriate model systems, especially on antivirals for human coronaviruses, should have been a high priority of the World Health Organization and the United States National Institutes of Health and similar organizations in other countries with strong biomedical research infrastructures. Alas, this was the road not taken.
The COVID publication spike could represent an attempt by the research establishment to “catch up” as an adjunct of Operation Warp Speed, but it is almost certainly due to changes in the business of scientific publication in the open access era of pro forma peer review in a pay-to-publish environment in which numbers of papers trump content for those evaluating so-called productivity. Note that the scale of the y-axis in Panel A is 1/100th of Panel B. That 454,000 legitimate COVID papers have been published in the past five years is inconceivable. In comparison, as of 23 February 2025, there are 184,856 HIV/AIDS papers in PubMed over the past 43 years.
Where does this leave us? COVID-19 has not disappeared (4,934 deaths in through February 15 in 2025), and the current season has been one of the worst for respiratory infections in a years. Vaccines against SARS-CoV-2 moderate the course of disease in some patients. But they do not prevent the disease or its transmission, contrary what was said by politicians during the height of the pandemic. One year ago a paper appeared in Cell Host and Microbe entitled Rethinking next-generation vaccines for coronaviruses, influenzaviruses, and other respiratory viruses (the authors are well known and certainly understand infectious disease). A very good article of its kind, the Abstract/Summary is worth quoting in full:
Viruses that replicate in the human respiratory mucosa without infecting systemically, including influenza A, SARS-CoV-2, endemic coronaviruses, RSV, and many other “common cold” viruses, cause significant mortality and morbidity and are important public health concerns. Because these viruses generally do not elicit complete and durable protective immunity by themselves, they have not to date been effectively controlled by licensed or experimental vaccines. In this review, we examine challenges that have impeded development of effective mucosal respiratory vaccines, emphasizing that all of these viruses replicate extremely rapidly in the surface epithelium and are quickly transmitted to other hosts, within a narrow window of time before adaptive immune responses are fully marshaled. We discuss possible approaches to developing next-generation vaccines against these viruses, in consideration of several variables such as vaccine antigen configuration, dose and adjuventation, route and timing of vaccination, vaccine boosting, adjunctive therapies, and options for public health vaccination polices. (emphasis added)
Yes, it has been known for a long time that these agents of the common cold, influenza, SARS, MERS, and COVID-19 are poor targets for vaccines because durable immunity to these pathogens is difficult to establish, either through infection or vaccination. Yet, the goal remains: Develop a vaccine! Perhaps an intranasal killed- or attenuated-virus vaccine will work. Eventually.
The goal is noble, but not at the expense of other approaches that are known to work, including antiviral drugs and non-pharmaceutical inventions. The epistemic closure [5] that led to the overwhelming emphasis of vaccination as the one true solution to COVID-19 was unfortunate but understandable at several levels. The mRNA vaccines were the “hot new thing” in biomedical molecular biology and scientists were enthusiastic about extending this technology to the clinic. That mRNA vaccines had not yet been shown to work against human disease (e.g., Zika virus) was only a technical detail awaiting an inevitable solution. mRNA vaccines were also said to be tunable to new variants in real time, although how vaccinologists could keep up with random variation in SARS-CoV-2 was never explained very well (to my knowledge). And finally, mRNA vaccines were very profitable but possibly not a good business decision, as noted here (paywall) and from a different, more critical perspective, here. It is no accident that Operation Warp Speed was a public-private partnership that favored Big Pharma and Big Medicine.
Finally, that these mRNA vaccines did not work as people have come to expect of vaccines in the prevention of a very serious and seriously disruptive disease has rejuvenated an anti-vaccine movement whose moment has arrived. It will take great effort to avoid this political and scientific Slough of Despond in the coming months and years. More on that in future instalments, but we should also remember that we have also been here before. And that the solution to COVID-19 and other pandemics surely to come will require that biomedical science remember its past while it plans its future.
Notes
[1] To be fair to those pursuing an academic scientific career, well-designed innovative proposals are unlikely to get funded in an environment in which success rates range from 9% to 20%. I am an “n =1” anecdote, but when I attempted to go just beyond current conventional wisdom in a grant application and referred to a fundamental paper published in Science in 1945 by a pioneering cell biologist before cell biology was a discipline, one reviewer was “unimpressed” that a paper so old could be relevant. I note that the first “similar article” at this Novikoff link was The essential role of integrative biomedical sciences in protecting and contributing to the health and well-being of our nation. This is a perfect statement of the role of disinterested biomedical science, especially in the current political climate.
[2] I have visited two CAFOs for industrial pork production. One could not enter the various confinement areas without wearing coveralls and rubber boots and walking through a disinfectant bath. Pigs produce as much or more excreta per individual as humans, so the attached “waste lagoons” are another horrific matter. This is not how livestock should be raised, and those who object to such practices are correct. However, the solution is to go back to a future represented by White Oak Pastures and similar legitimate farms instead of the fever dreams of George Monbiot. The first is sustainable and when extended throughout the Global North it will be affordable as the world gets smaller and economies more local and regional in the coming inconvenient apocalypse. The other, described by Monbiot in Regenesis, is neither sustainable nor affordable. It is most certainly not palatable.
[3] HIV is a retrovirus and inserts its genome into the host cell DNA. Coronaviruses do not do this, but coronavirus infection can persist in the host just as HIV and other viruses (e.g., herpes). The processes of viral entry, genome replication and viral assembly are similar, however, and are good drug targets. Pre-exposure prophylaxis (PrEP) against HIV is also now possible, for those who can afford it.
[4] Koch’s Postulates (strong version): (1) The microorganism must be found in abundance in all organisms suffering from the disease but should not be found in healthy organisms. (2) The microorganism must be isolated from a diseased organism and grown in pure culture. (3) The microorganism (from the pure culture) should cause disease when inoculated into a healthy organism. (4) The microorganism must be re-isolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.
[5] In prose, as one of my favorite teachers might have put it: If a Scientist A knows vaccines and that a vaccine is the cure for disease X, then Scientist A knows how to cure (or prevent) Disease X. That older wisdom is inconsistent with this matters not. Epistemic closure has led biomedical science down other “unproductive” pathways, including the Diet-Heart Hypothesis that led to the demonization of a balanced, omnivore diet and caused an obesity epidemic; and the Amyloid Cascade Hypothesis of Alzheimer’s disease, which has yet to suggest an effective intervention for AD. My first and indispensable mentor in science, an enzymologist of the old school, never transcended his epistemic certitude that only enzymes (proteins) could have catalytic activity and nothing could convince him otherwise, even after Thomas R. Cech and Sidney Altman were awarded a Nobel Prize in Chemistry for their discovery of catalytic RNA. Still, we could do with a few more of those sages from another world.
