Yves here. KLG volunteered that a good intro could be: “What scientists say and what the people hear are sometimes different things.” And the misunderstanding lies primarily with the scientists. Consider: what do you think the widely-touted 95% efficacy of the mRNA vaccines against wild type Covid means?
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
For the past several months I have been reading some of the relevant literature on how we have dealt with vaccines as the primary response to COVID-19. By “we” I mean all of us, including the scientific and medical communities plus our political leaders our fellow citizens, mostly in the so-called Global North.
The most relevant questions appear to be
(1) Are the SARS-CoV-2 vaccines are our best approach to COVID-19? and
(2) Are they effective?
What do the “authorities” say in response to these questions and how have the “people” have reacted to COVID-19? A recently published paper (and its cited references) addresses this topic from a perspective that in my view explains where we are, if not necessarily where we are going, with COVID-19. A complementary paper on “science, conflict, and misinformation” will be discussed in the next contribution in this series.
The first paper is a very clear “Invited Commentary” entitled “Understanding and Improving Vaccine Effectiveness Estimates in the Age of Widespread Background Immunity: A Step Toward Improved Science Communication,” by Edward Nirenberg and Eli N. Perencevich in the journal Clinical Infectious Diseases (Oxford/Infectious Diseases Society of America and HIV Medicine Association, est. 1979), who describe their objectives in a short abstract:
Medical decision making and scientific communication around coronavirus disease 2019 (COVID-19) vaccines and booster doses requires proper understanding of how vaccine effectiveness estimates are determined and the potential biases inherent in current estimates. The importance of background immunity from prior infection is reviewed along with ideas for improving the vaccine effectiveness estimates.
A number of the problems with the general approach to the COVID-19 pandemic are implied in these two sentences, but no one should argue with their following introductory statement that “the costs of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in terms of lives, quality of life, economic hardship, and heartache are immeasurably vast.”  Followed by:
“Despite this, the circumstances of the pandemic have produced extraordinary advances in vaccinology”…with the mRNA vaccines showing exceptionally high vaccine effectiveness (VE) against symptomatic COVID-19(~95%) and severe COVID-19 (~100%).” Yes, but the “current SARS-CoV-2 variants have contributed to declines in VE prompting the use of booster doses (which) exceed 2-dose efficacy against the Delta variant and greatly enhance protection against Omicron as well; boosters have furthermore proved particularly critical for high-risk patients. Despite this, recovery of 95% effectiveness against symptomatic infection has proved elusive. The facile explanation is that the pace of evolution of SARS-CoV-2 is faster than our innovation, regulatory apparatuses, and immune system—yet this is incomplete and, indeed, may not even be the main reason for such findings.” (emphasis added)
The extraordinary advances in vaccinology referred to present us with a conundrum. Yes, mRNA vaccines are novel and technically ingenious. But they have also been obvious since Francis Crick proposed the Central Dogma of Molecular Biology in the late 1950s (DNA makes RNA makes Protein, with minor modifications to account for retroviruses that store a DNA copy of their RNA genome in the host’s DNA; e.g., HIV) and the development of modern molecular biology in the 1960s and 1970s.
Thirty years later Robert Malone (1989) was first author on the first paper, as far as I know, to show that mRNA could be introduced into animal cells and direct production of its cognate protein.  Still, the Pfizer/BioNTech and Moderna mRNA vaccines were the first two such vaccines to be approved for use in humans, another 30 years later. Technical mastery of simple principles can be difficult in biomedicine.
The question, however, is whether these mRNA vaccines are effective? Yes, at the beginning of our current regime of COVID-19 vaccines, they showed “high effectiveness (VE of 95% against symptomatic COVID-19 and 100% against severe outcomes)”. Subsequent declines in VE led to the introduction of booster doses, which also enhanced protection against Delta and Omicron variants. But VE returns to 95% have remained elusive. The common-sense answer, which seems be most likely, to this disappointing result is that rapid virus evolution of SARS-CoV-2 outruns the vaccines based on the spike protein. And this brings us to the definition of VE, vaccine effectiveness.
As a technical term VE is a measure of relative risk reduction rather than absolute risk reduction. This is explained well by Nirenberg and Perenevich, but relative risk remains a fuzzy concept to the nonscientist as well as many scientists. When taught to medical students, it goes something like this: If exposure to a toxic chemical compound results in disease rate of 2-in-10,000 while 1-in-10,000 among those not exposed get the disease, avoidance of the toxin results in a 50% decrease in chances of getting sick. But the absolute risk is 0.02% (1/5,000) versus 0.01% (1/10,000). This is a stark example with an absolute risk reduction of 0.01% (0.02 – 0.01 = 0.01) but the principle is the same. VE can decline because those who have been infected with SARS-CoV-2 have some residual immunity to the virus, but the vaccine(s) may still work well. But do they, in the common understanding?
Thus, this complex epidemiology “raises questions about how to best describe vaccine effectiveness…(B)ecause vaccine effectiveness is only appropriately defined in terms of relative risk reduction, percentage changes can be misleading in the magnitude of their effect.” 
For example, the decline from 95% VE to 90% VE may seem to be just 5%…but this is a doubling of risk from a 20-fold reduction to a 10-fold reduction. Therefore, it is likely prudent to state explicitly the fold-reduction in risk, as this is more intuitive and reflective of real-world conditions.
Yes, and one could also note that the 20-fold reduction roughly corresponds to a p-value of 0.05. This is the generally accepted value for “statistical significance,” which requires a p-value of 0.05 or less.  The most important question of “Vaccine, yes or no?” is whether the risks of taking the vaccine outweigh its benefits. Is a 20-fold reduction in risk of the disease worth the possible risks of the vaccine itself? A 10-fold risk reduction? That all depends on the reasonably expected and observed side effects of the vaccine.
This paper considers vaccine effectiveness as “a problem of scientific communication.” This is undoubtedly a most important lesson here and it is presented very well. VE for the two COVID-19 mRNA vaccines was originally estimated to be 95% to 100%, depending on measured outcomes.
Yet still, more than one million Americans have died of COVID-19 over the past 40 months, and this is very likely an underestimate. Several hundred die every week, long after widespread vaccination. Life expectancy has returned to its level in 1996, with the US showing greater declines than other so-called developed countries. A reasonable response to this is, “Then what do 95% and 100% mean?” As Nirenberg and Perencevich conclude (reformatted to facilitate discussion):
- We still face a significant public health dilemma in that in an epoch where nearly everyone should have had at least 3 doses of COVID-19 vaccine, too many have received none.
- The misperceptions of vaccine effectiveness driven by incomplete understanding of what vaccine effectiveness calculations currently estimate is directly harmful to the wellbeing of the unvaccinated and the general population.
- More precise communication and metrics of vaccine effectiveness that honestly reflect the value of vaccination is imperative.
- Our current vaccines are imperfect, and we look forward to seeing what improvements may occur with the next generation; however, it is undeniable that they are extremely effective against some of the most feared outcomes of COVID-19, and they are our most important tool for addressing its threat.
As a matter of scientific communication, if this is perceived to be the communication of the science of COVID-19 to the public at large, this requires some unpacking.
Point 1: Even granting that three doses of the current vaccines should have been received by all who can take them, what is the public supposed to think about experimental mRNA vaccines that prevent neither COVID-19 illness nor its transmission? Operation Warp Speed was necessary given the urgency of the pandemic.
But people have the reasonable expectation that vaccines will prevent the disease and/or its transmission.
As an example I have covered before, the Salk polio vaccine prevented poliomyelitis and its transmission. Even though it was new in 1955, it was not experimental. Based on my reading, communication about “vaccine effectiveness” was not paramount 68 years ago, even after a manufacturing error resulted in several hundred cases of polio. The cause of that localized catastrophe was identified immediately and transparently, and then corrected. Vaccinations resumed after a brief pause and by 1957 cases of polio were down by 90% compared to those reported in 1952. By 1961 cases were down by 97%. 430,000 children were vaccinated in Denmark with the Salk vaccine, and not one child contracted polio. The oral Sabin vaccine supplanted the Salk vaccine in the early-1960s and polio virtually disappeared where vaccination was widespread (details are from a recent biography of Jonas Salk).
Point 2. As for communication about the technical definition of vaccine effectiveness, in my view the problem is not that people do not understand how VE is calculated.
Rather, what they do understand is that the COVID mRNA vaccines do not prevent disease or its transmission very well despite originally hearing and understanding something like this: “If I get this vaccine, there is a 95% chance I will not get COVID-19 and a near-100% chance that I will not die if I am exposed and get sick.”
The messages coming from CDC, NIH, FDA, and the biomedical research community have been muddled from the start of the pandemic. There is no need to return to this here, but it has been distressing to hear scientists state, “Well, no. The vaccines do not prevent disease but that was never the goal. The vaccines were always intended to prevent the worst outcomes when, not if, you get infected with the virus.” This is a rationalization after the fact. People have been asked repeatedly to “trust the science.” But the science has not come through as it did for polio, smallpox, and the childhood diseases of those of us of a certain age, which in my case included rubeola (“two-week measles” at the age of 6, spent in a dark room with no television), rubella (German, “three-day measles”), chicken pox, and mumps.
Despite the continuing undercurrent of discontent about vaccines, some of which may be attributed to mixed, if not fleeting, results with COVID-19 vaccines, most of us view vaccinations (MMR, DTaP, etc.) as essential and effective public health measures. This also includes recent vaccines against such pathogens as chicken pox and human papilloma viruses (HPV), which will reduce the burden of shingles and cervical/oropharyngeal cancer in generations to come.
Finally, what was never communicated to the public was that these mRNA vaccines are experimental in every way that matters. A necessary experiment under the circumstances, but an experiment nevertheless, on a very large population. This does not mean, however, that the molecular, cellular, and technical details of the production of the vaccines are experimental. These are standard in every molecular biology research laboratory.
Point 3. Yes, people must be told what to expect from these vaccines. And that should include the chances they will be infected by the virus and the fold-protection to be expected after vaccination. The likelihood of serious adverse events must also be included in these communications. This has been apparently, but perhaps not inexplicably, suppressed during COVID-19.
Point 4. All vaccines are imperfect, but few (if any?) vaccines have been so widely used under an Emergency Use Authorization. As for the next generation of SARS-CoV-2 vaccines, one can only hope that different strategies result in different results.
The experiment with these mRNA vaccines was successful, but the outcomes are uncertain at best: The current vaccines prevent neither infection nor transmission of SARS-CoV-2, and now we know that.
COVID-19 is manifestly not a pandemic of the unvaccinated, even if the vaccines have prevented the worst outcomes among many of those infected with the virus. Nor has it been communicated effectively how boosters targeting strains of the virus that have supplanted the original “wild type” are likely to work. 
Moreover, it has been known for a long time that lasting immunity to coronaviruses is generally not achieved in vertebrates after infection, but this seems not to have been widely recognized or communicated in public discussion of COVID-19. This implies that herd immunity is unlikely to accompany endemic COVID-19, which is an obvious conclusion reached early in the pandemic by coronavirus virologists.
So, where do we go from here regarding the pandemic? Based on the results of mass vaccination with the current mRNA vaccines, it can be argued that “they are (not) our most important tool for addressing” the many threats of COVID-19.
Without going into the relevant immunology, intranasal vaccines that prevent infection of the nasal mucosa should be expected to work better than the mRNA vaccines. Early versions have not been particularly successful, but this would seem to be another serious effort requiring Operation Warp Speed 2. Vaccines have been sought for HIV for forty years but have remained elusive. Different virus, different biology but antiviral drugs have proven to be highly effective against AIDS, which has become a manageable chronic condition in most people infected with HIV. These patients maintain low-to-unmeasurable levels of virus during HAART (highly active antiretroviral therapy; triple therapy) which came into widespread use (in the Global North) by 1996.
There is a good rationale to expect that triple therapy for SARS-CoV-2 will work as well as it has for HIV/AIDS, a result that Operation Warp Speed 3 could produce. And of course, non-pharmaceutical interventions also work and should not be ignored, even as masks fall into desuetude despite the likelihood that even mild COVID-19 can lead to cognitive deficits, news report here  and the underlying paper here.
Finally, I would like to close with the suggestion that our mRNA vaccines are a hurried, but very lucrative for Big Pharma, technical fix for a problem that does 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 crisis, one that could be worse than SARS or MERS in either transmissibility or course of disease. Given the apparent unpredictability of the illness associated with a coronavirus infection (the sniffles of a common cold, enduring widespread organ damage, long covid, cognitive impairment, death) there is no good reason that coronaviruses have not been a “hot topic” in biomedical research for the past 20 years.
But according to the PubMed database maintained by NIH/National Library of Medicine, for the 70 years from January 1949 through September 2019, there are 15,208 hits using “coronavirus” as the query. A search from 1 October 2019 through 10 April 2023 returns 346,883 papers using “Covid” as the query (the search is case-insensitive). Too little, too late despite the total.
Please forgive me for repeating myself, but the deluge of Covid papers reveals more about the current business of scientific publishing and the imperatives of academic and scientific entrepreneurship than the actual science of coronaviruses and COVID-19. If we are to meet the challenge of COVID-19, and any number of other emerging diseases that are just as predictable based on what we already know about the world and our outsized place in it, we must do better at every level. We can begin with communicating effectively in the vernacular about the causes, agents, and consequences of potential pandemic diseases and our approaches to them. 
Acknowledgment: Thank you to Lambert for alerting me to this paper, which focused my thoughts on this post and the next topic in this series.
 Many continue to argue with this statement. One can still read and hear that “COVID-19 is no worse than the common cold,” that “the young and healthy are not at risk,” and that “the pandemic is a thing of the past.” Nevertheless, millions have died from SARS-CoV-2 infections, and many are afflicted with long COVID. As many as 1 in 4 convalescent mild COVID-19 patients have persistent cognitive deficits (see Note 6). Thus, the consequences of COVID-19 have been dire, as also shown by the steep decline in life expectancy in the US over the past few years. What the future holds is still very much an open question for a pandemic that has been declared “over.”
 I remember this result well because the kind of protein produced in this experiment was the focus of my first research position, long before the era of recombinant DNA and gene cloning. This paper in Proceedings of the National Academy of Sciences was “high impact.” It also seems to be the foundation of Dr. Robert Malone’s claim to be the inventor of mRNA vaccines, but I have not looked carefully into this.
 Which is how marketing by Big Pharma and its attendant science works.
 Whether conventional, frequentist statistics are all that useful is another matter altogether, and I say this as a confirmed Bayesian. I hope to elaborate on this in a future post, depending on the final results of current research with several colleagues, on the utility of high stakes standardized tests as measures of academic potential. This practice depends on conventional statistical analysis that in my view willfully confuses statistical significance with predictive utility.
 The primary “selling point” of mRNA vaccines is that they are readily “tunable” as new strains of a pathogen evolve. Indeed, experimental mRNA constructs are “tuned” in a matter of days in well supported molecular biology laboratories, but these are intended for use in experimental models such as cultured cells and perhaps mice, not human patients. The latter require thorough evaluation of safety and effectiveness that should go further than the Emergency Use Authorization (EUA) under which the current mRNA vaccines were approved if the promise of rapid vaccine response is to be sustainable. Whether this is possible is not entirely known with rapidly evolving viruses such as SARS-CoV-2.
 From this report: In one study, researchers in Brazil found people who had mild COVID-19 symptoms showed “persistent cognitive impairment” months post-infection, where some were complaining of bumping into things or not being able to park the car due to altered depth perception and visual processing. “Everybody was worried about severe COVID, but the number of people with mild COVID is four times higher,” says Marco Romano-Silva, of the Federal University of Minas Gerais in Brazil and senior author of the study published in June in Molecular Psychiatry.
 This appeared in my email as I was finishing this post. I do not endorse this particular meeting but the topics are on point and The Scientist is a very good “free” source of science news.