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8/13/2021 How to Deal with Opposition to Vaccination: Lessons from Addressing Climate Change DenialRead NowI came across an interview that journalist Bill Moyers did with Christian climate scientist Katherine Hayhoe back in 2014. The topic of their conversation is about the particular situation of Evangelical Christians in the United States as it relates to denial of climate change, but I believe the interview is remarkable because of the broader applicability of Dr. Hayhoe’s ideas as to why denial of many issues has been embraced by various communities and what can be done about it. You can watch the interview in the video above, but I will provide a recap of the major points of the interview. Dr. Hayhoe’s argument is that climate change is a hot button issue for many people because they feel it threatens all that they hold dear. However, what people reject about climate change is not so much the science but the solutions. Climate change is something that affects the community, and as such, efforts to deal with climate change require large numbers of people to work together, which means that the government has to be involved. But opposition to government is deeply rooted in the American psyche, and any legislation to limit what people can do or use is viewed with mistrust. Thus, climate change has become a casualty of much larger societal issues. This has been compounded by the fact that people have been lied to by those in whom they deposited their trust. On the one hand, the leaders who many of these people trust because they share their values, have told them that climate change is a hoax, or that it’s real but it’s not a big deal and nothing has to be done about it. Or in the absence of clear leaders, political and media personalities who don’t like the solutions to climate change have stepped in. And because these individuals say the same things that people believe with regards to many other issues, the people put their trust in them. On the other hand, the spokespeople for the opposite point of view have often been scientists who do not share the values of the communities they are addressing. People will not believe messengers whom they do not trust because they perceive them as not sharing their values. The remedy to this situation will not come from more information and more science, but rather from dealing with who we are as humans and how we function politically. Dr. Hayhoe says that, although caring about the climate is consistent with who people are as Christians, we have increasingly confounded our politics with out faith. Instead of allowing faith to determine our attitudes to political and social issues, we are allowing our political party to dictate our attitude towards issues that are clearly consistent with who we are. Finally, Dr. Hayhoe says that everyone has a list of things they care about such as the health of their kids, job security, the cost of living, faith etc., and climate change should not be viewed as one more thing to put on the list that competes with the others because climate change is already affecting the top things on everyone’s list. Climate change is affecting the things most people care about, love, and hold dear.  There are other aspects to the interview, but the ones I’ve mentioned above are those that I think are more generalizable to other situations where misinformation and social dynamics are getting in the way of people accepting and acting on a reality. One possible such situation is COVID-19 vaccine denial.
Despite overwhelming evidence that the COVID-19 vaccines are safe, effective, and necessary, there is a certain proportion of the population of the United States that refuses to accept the vaccine. In parallels with climate change deniers, the sector of the population opposed to vaccination tends to be conservative and distrusting of government. In another parallel to climate change denial, this group of people tends to listen to media that reinforce their fears feeding them misinformation about vaccines. At the same time, this group of people is distrusting of what scientists say about vaccines, and especially of those scientists associated with the government. Like the evangelicals who have allowed their politics to replace their faith in guiding them with regards to climate change, the vaccine deniers have allowed their politics to replace their common sense and instinct of self-preservation when it comes to vaccines. And like climate change deniers, vaccine deniers have a list of things they hold dear and care about, and COVID-19 has probably affected every single item on the top of their lists, from the health of people they admire, acquaintances, friends, and family, to the impact on the economy. Dr. Hayhoe advocates finding trusted messengers within the evangelical community (people who are like them, such as she is) to spread the message that we need to act on climate change. This is indeed a strategy that is currently being pursued in the case of vaccine denial. The government is trying to recruit media personalities and local respected leaders to talk in favor of vaccination. But I think we can go about finding these trusted messengers in an additional way which relies on another parallel between COVID-19 and climate change. Much like climate change, COVID-19 affects everyone, and there is a growing list of vaccines deniers, who have been seriously ill or died due to the virus. The people who listened to these vaccine deniers have now been knocked back to their senses in the most brutal of ways. And I think that their stories should be used to snap vaccine deniers from the stranglehold that their politics have on their common sense and instinct of self-preservation. And unlike climate change, there is no ambiguity as to the cause of the harm. If someone loses their property, a friend, or a loved one to rising sea levels or a fire or a hurricane, they can always be told that there is no direct proof that climate change caused it. But if someone dies due to COVID-19, that reality cannot be denied. So, find out who are those vaccine deniers that were harmed by COVID-19 and seek out their audiences, their acquaintances, their friends, and their families, and ask them to tell their story to those in their communities and to champion vaccination. Every serious vaccine-preventable COVID-19 illness or death among the community of vaccine deniers is a tragedy. But the silver lining is that these illnesses and deaths will generate a group of people willing to open their minds to vaccination and promote it. I think these people have an important role to play in stopping vaccine denial. Image from pixabay by Gerd Altmann is free for commercial use and was modified from the original.
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 COVID-19 Vaccine Those opposed to vaccines (antivaxxers) are fond of quoting government figures to argue that there have been many adverse events due to COVID vaccines. They then proceed to state that because the government figures underreport these adverse events this means that the problem is much, much, worse. They also argue that there is a conspiracy to keep this information from the American public, and they demand that COVID vaccination should stop.
What are antivaxxers talking about? What are these government figures? Are they quoting them correctly? What do the numbers mean? By the time vaccines are allowed to be used on the US population, they have gone through multiple clinical trials and other evaluations that have certified they are safe. But this vaccine safety is based on data gathered from at most a few tens of thousands of people. Therefore, it is understood that when vaccines are applied to a population of tens or hundreds of millions there may be some low frequency adverse events that may have not been detected in the clinical trials with a smaller group of people. To account for this, the government in 1990 created a federal database called VAERS (Vaccine Adverse Event Reporting System) that is meant to act as an early warning system to detect possible safety problems with vaccines. However, VAERS is a passive reporting system. This means that anyone can file a VAERS report regardless of its nature, and that report is entered into the database and cannot be removed without the permission of the person who reported it. Although knowingly filing a false VAERS report is a violation of Federal law, if you are convinced that the adverse event you are describing, no matter how outlandish, is tied to a vaccine, it will be incorporated into the database. For example, Dr. James Laidter mentioned in the neurodiversity weblog that back in 2005 he entered a VAERS report claiming that an influenza vaccine had turned him into the incredible Hulk, and the claim was accepted into the database. However, due to its unusual nature, a VAERS representative did contact him, and after an amicable discussion about the limitations of VAERS, the representative requested his permission to remove the claim to which he agreed. If he had not agreed to that, the claim would have remained in the database. Another example, Kevin Leitch writing for the Left Brain Right Brain science blog mentions that he submitted a VAERS report claiming that a vaccine had turned his baby girl into Wonder Woman, and he is not even a US resident! However, even when considering reasonable adverse events, it must be understood that VAERS reports do not stablish that there is a link between the adverse events reported and vaccination. Each day thousands of people develop a health problem and/or die in the United States in a manner unrelated to vaccines. If any of these people received a vaccine around the time they developed the health problem or died, they could be reported to VAERS thus constituting a false positive. The experts understand that the VAERS database has a high number of these false positives, and they use the database as a very preliminary step to perform more research, gather more data, and establish for sure whether a given event being reported is a real adverse event due to vaccines or not. These experts know that quoting numbers directly from the VAERS system is meaningless insofar as learning anything about the safety of vaccines is concerned. But this is exactly what antivaxxers do! And while some antivaxxers may be ignorant about the nature of VAERS, many of the leading antivaxxer influencers know the shortcomings of VAERS and nevertheless choose to continue reporting or quoting the raw numbers to advance their platforms and promote their agendas. Antivaxxers are also prone to saying that VAERS vastly underestimates the number of vaccine adverse events by as much as 99%, so in some of their alarmist literature they suggest that VAERS numbers should be increased by large multiples. However, although reporting to VAERS of non-serious adverse events such as soreness at the injection site is indeed very low, estimates of the sensitivity of VAERS to serious adverse events, while variable, is much higher than antivaxxers would like us to think. For example, for anaphylaxis due to seven different vaccines, estimates of VAERS reporting sensitivity ranged from 13% to 76%, while for Guillain-Barre Syndrome after three different vaccines the sensitivity ranged from 12% to 64%. Despite its shortcomings, the VAERS system has been useful for detecting rare side effects of the COVID-19 vaccines. For example, an elevated risk of myocarditis and pericarditis has been detected in males 12-29 years of age who have received mostly two doses of the Moderna or Pfizer mRNA COVID-19 vaccines. This is a treatable disease that involves inflammation of the heart or its surrounding membranes. The CDC convened a meeting of experts (the Advisory Committee on Immunization Practices: ACIP) to analyze these cases. The analysis involved weighing any harm caused by the vaccine against its benefits. The committee concluded that the benefits of vaccination outweighed the risks. However, now that we know that this age group is at an elevated risk of myocarditis/pericarditis, vaccine providers and healthcare professionals have been alerted to this side effect and its treatment. This is the way VAERS and science are supposed to work. Rare adverse events of a vaccine are detected, and the risk/benefit is determined after a thorough evaluation of the data available. Then a rational course of action is pursued to achieve the greatest benefit with the least harm. The irresponsible use of VAERS by antivaxxers’s to concoct alarmist articles and memes promotes vaccine hesitancy which in turn prolongs the pandemic, leading to more hospitalizations and deaths and may give rise to new variants of the virus that are more resistant to the vaccine. Photo of the Pfizer-BioNTech vaccine from Max Pixel is in the public domain.  I have written extensively on hydroxychloroquine (HQ) in my blog. Now that the interest of society has shifted towards the COVID-19 vaccines, it’s time to do a recap of the issues I addressed related to HQ and provide a final update. 4/25/2020 President Trump advocated HQ and one his advisers criticized Dr. Fauci for questioning its effectiveness. The French doctor Didier Raoult claimed a 99.3% success rate in treating COVID-19 patients with HQ, and accounts of patients treated with HQ experiencing dramatic recoveries (Lazarus-like coming back from the dead effects) were appearing in the news. In my post, I warmed against accepting these isolated “dramatic effects” reports as a measure of a drug effectiveness, stated that the only measure of a drug’s effectiveness is clinical trials, and explained why. 6/19/2020
I addressed the claim made by some doctors that HQ is 100% effective against COVID-19, and I explained not only why it is highly unlikely, but also that this is a regular claim made by charlatans. I also explain that the best clinical trials conducted so far had not found evidence that HQ worked. 7/3/2020 I debunked the misinformation that Dr. Fauci is aligned with powerful pharmaceutical interests to hamper the adoption of HQ as a life saving drug, and that Dr. Fauci already knew HQ worked more than 15 years ago. I also addressed the issue of the articles claiming that HQ did not work and was harmful. I argued that the fact that these articles were published in medical journals and then retracted is not a conspiracy but rather indicate that science worked the way it should. I also debunked the notion that countries that had embraced the use of HQ were doing better. 7/25/2020 I decried the politization of HQ and the notion that it is “the president’s drug”, and I outlined the evidence at the time against HQ which indicated it’s not effective against COVID-19. 8/8/2020 I debunked in more detail the conspiracy that Fauci knew about HQ being effective, and I proceeded to explain a bold hypothesis that explains why HQ alone does not work against COVID-19. 8/20/2020 I debunked the notions that high doses of HQ were used in some clinical trials to make HQ fail, or that pharmaceutical companies want to eliminate HQ because it’s a cheap alternative to their expensive drugs. Since some HQ proponents were then arguing that HQ only works with zinc (the zinc hypothesis), I pointed out that this contradicted their cheering of studies where HQ allegedly worked alone (which it shouldn’t have if it only works with zinc). 9/12/2020 I examined the difference between doctors and scientists and debunked the notions that “doctors know best” and that “we don’t need randomized trials”. I also described the important role of the scientific establishment in science. 9/18/2020 I explained why observational trials cannot provide the final evidence that HQ works, and I pointed out that even the authors of the studies that the pro-HQ folk cite in favor of HQ state that randomized trials are needed. 10/16/2020 Despite the evidence which indicated that HQ did not work alone or with antibiotics, some HQ proponents still supported the hypothesis that HQ worked as long as you combined it with zinc. In this post I explained the evidence against HQ alone or with zinc. I also explained why it is important to remain objective and not fall in love with your hypotheses. 10/24/2020 In this final post, I readdressed the conspiracy theory that claimed that the clinical trials of HQ were designed to make it fail. I also examined the accusation that Dr. Fauci’s unwillingness to accept that HQ works was killing people. Update As I have mentioned before, to reach a conclusion regarding the activity of HQ on COVID-19 you need to focus on the studies that allocate patients to treatments at random (randomized studies). There are people that keep pushing the claim that HQ does work based on the total number of studies performed on the drug, which includes the observational (non-randomized) studies which are of lower quality because they are prone to bias. I searched a database for randomized studies of HQ and COVID-19, and only two of the studies I found were positive for the drug (1, 2), whereas 25 other studies were negative (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25). However, whether HQ works or not cannot be established merely by counting the number of pro and con studies. Even among randomized studies, some studies are of lower quality than others. One or two high-quality studies can trump many low-quality studies. In order to evaluate the merits of studies in addressing whether HQ works for COVID-19, scientists perform analyses (studies of studies) where they assess the quality and relevance of the studies. Throughout the COVID-19 pandemic several of these analyses have been performed. I searched the database for these analyses and I found 20 of them, all negative for HQ (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20). The conclusion is inescapable, hydroxychloroquine DOES NOT work for COVID-19. Period, end of the discussion. The breathtaking number of studies conducted on this drug is a testament to its politicization. The sheer amount of manpower and resources devoted to testing HQ was unjustified when a handful of studies would have sufficed. The attacks and lies hurdled against scientists including Dr. Fauci because they refused to accept that HQ works based on the available data was unethical. From Mr. Trump who unwisely promoted the drug to individuals such as the epidemiologist Harvey Risch and Dr. Vladimir Zelenko or groups such as the Front-Line Doctors who all claimed the drug worked even when the best evidence indicated otherwise, this saga has been a lesson on what people should not do with science and in science. Unfortunately, these people have not learned their lesson and still claim to have been right all along. Such is the complexity of the human mind. Image by WHO-openaccess was cropped from a PNG file by Cantons-de-l'Est and is used here under a Creative Commons Attribution-ShareAlike 3.0 IGO license, and was modified to include the name and formula of hydroxychloroquine.  COVID-19 Vaccine As I have written several times, science is a process that involves a lot of back and forth. Scientists have different opinions and exchange arguments. They adopt positions based on the available evidence and change their mind when new evidence comes along. As is expected, this process is ongoing for the COVID-19 vaccines. These vaccines have been found to be safe and effective in clinical trials and in studies conducted afterwards in real-world situations. But all vaccines, as everything, do have small risks. For example, the COVID-19 vaccines can cause an anaphylactic reaction in individuals prone to severe allergies, and this is recognized in vaccination decisions and procedures. Because scientists want vaccines to be as safe as possible, there is an effort to identify other rare side effects of vaccines as well as figuring out how the COVID-19 virus works so more effective and safer vaccines can be made. Most COVID-19 vaccines rely on making the cells at the site of injection produce the viral spike protein, which is the protein that allows the virus to get into the cells and infect them. These spike proteins are anchored to the surface of the cells expressing them and trigger the immune response. Therefore, this protein is an object of ongoing research. Several articles have been published in the scientific literature regarding this protein. In one article, researchers found that the spike protein alone in the absence of the rest of the virus can damage the wall of blood vessels (the endothelium). In a another article researchers found that the spike protein alone or its subunits (the spike protein is made up of two subunits) can disrupt the barrier that protects the brain from blood borne substances (the blood brain barrier). These findings, although preliminary, are important in that COVID-19 displays many symptoms involving the circulatory system and indicate that the spike protein alone could be responsible for them.
The issue we are discussing today arises from another article where researchers were able to measure the spike protein in the circulation of patients who had received the COVID-19 vaccine. A Canadian immunologist, Dr. Byram Bridle, saw the above data and (apparently without consulting with colleagues or the authors of the articles) started claiming that we have made a mistake with the COVID-19 vaccines. He unwisely gave interviews where he claimed that the vaccines make our cells produce the spike protein which is a toxin that leaks to the circulation where it can cause damage in some people. Needless to say the antivaxxer social media pages and websites lit up like a Christmas tree and unleashed upon the internet a torrent of posts and memes proclaiming how unsafe the COVID-19 vaccines are, demanding that vaccinations stop, and bragging about how they had been right all along. I am not going to debunk this in detail, as others have done a very good job of that, but here is the gist of the argument. The method used by the researchers that detected the vaccine spike protein in the blood was 100-1000 times more sensitive than regular methods. The amount of protein they measured is basically the background that you would get from a very, very small fraction of the protein making into the circulation because of, for example, cells dying. These levels are tens of thousands of times lower than the spike protein concentrations reported to be detrimental in the other articles. Additionally, the spike protein generated by the vaccine is different from the spike protein from the virus as it has been engineered to be safer. Many scientists including colleagues of Dr. Bridle and even the authors of the papers claim that he is overinterpreting the data. Finally, if indeed the spike protein alone turns out to be responsible for a sizable portion of the COVID-19 pathology, then that is excellent news because the antibodies produced by the vaccine (unlike natural immunity) are all against the spike protein, so they will likely neutralize this toxicity too. Now let me get to the question I formulated in the title of this post. How can you do science in this environment? Scientific research is no cakewalk. There is a lot of frustration and anxiety involved. There are many defeats and few victories. But finally, when scientists find something worth publishing, how do you think they feel when their results are misinterpreted? Every scientist in the COVID-19 field who deals with the demands of research and the toll it takes on their lives must now consider the possibility that the results of their investigations will be splashed in misleading memes all over the internet by the antivaxxer crowd. This means that they will have to devote some of their limited time to dispelling these ideas by doing interviews, writing articles, or answering e-mails from scores of people. But the worst part is that if scientists find something that may be negative about the COVID-19 vaccine, they may be inclined not to publish it just to avoid being in the center of the media hurricane that will surely form around them. And this is terrible, because we need every piece of information so we can have a more complete picture of the safety and efficacy of the vaccines in order to improve them. Science thrives on an open debate among scientists. In the old days this debate, which involves highly technical information with a lot of detail and nuance, took place mostly within the scientific community. Today the public can gain access to this debate by several means. Although this is a positive development, the preliminary data and tentative ideas that scientists generate as part of this debate, are being misrepresented by many people, sometimes out of ignorance, but most of the time as part of an agenda to generate viral stories to cause confusion and sow doubt. And scientists are stuck in the middle of this. The photo of the COVID-19 vaccine by Lisa Ferdinando (DOD) was taken from the Flickr photostream of the US Secretary of Defense and is used here under an Attribution 2.0 Generic (CC BY 2.0) license. 5/29/2021 COVID-19 Origins: Conventional Thinking, Conspiratorial Thinking, Crazy Thinking, and Bat Crap Crazy ThinkingRead Now I have often railed against conspiracy theories in my blog, but I want to make it clear that I make a distinction between conspiracies and conspiracy theories. There have been many verified conspiracies. The cigarette manufacturing companies conspired to hide the fact that cigarettes were harmful. The Nixon administration conspired to maintain its involvement in the wiretapping of the Democratic headquarters in the Watergate Building a secret. The Catholic Church conspired to hide child abuse by their priests. These conspiracies have been exposed and found to be true by detective work backed by internal documents and testimony from witnesses. Conspiracies do happen, and we must take claims of a conspiracy seriously, but only as long as they are backed by evidence. The argument that COVID-19 originated in a lab was originally branded a conspiracy theory, but evidence has emerged, and arguments have been made that have made it more plausible generating a debate within the scientific community. This debate is guided by what we can call “conventional thinking” following the terminology of the Conspiracy Theory Handbook by Stephan Lewandowsky and John Cook.
Conventional Thinking Several scientists have argued that there is strong evidence that the COVID-19 virus, SARS-Cov-2, arose in the Wuhan Institute of Virology (WIV) and not in a natural manner. Although the details are highly technical, in a nutshell it is argued that there are some aspects of the SARS-COV-2 virus that are unusual as it contains sequences that make it highly contagious for humans. It is also argued that analysis of viral genomes in bats and other animals make it unlikely that the Covid-19 virus arose naturally. Unlike previous coronavirus disease outbreaks, no viruses bearing a close relationship to the SARS-Cov-2 virus have been found around the Wuhan area, and the WIV had samples of large number of bat coronaviruses that they had gathered in trips to several caves a thousand miles away in another Chinese province. It is claimed that the WIV was carrying out gain of function research, which is research performed to make weak viruses more infectious, and that a grant from the NIH may have funded some of this gain of function research. Recently US intelligence has confirmed that some researchers from the WIV were admitted to a hospital with flu-like symptoms before the Covid-19 pandemic started. It is also known that researchers at the WIV were not following safety protocols when collecting the viruses. Thus, there is the possibility that the Covid-19 virus could have been present or even created at the WIV and released accidentally. The critics counter that careful analysis of aspects of the virus’ genetic sequence and makeup compared to other preexisting coronaviruses still leaves open the possibility that the COVID-19 virus arose naturally. They also argue that it is questionable whether the Covid-19 virus shows signs of manipulation or optimization to infect humans as per the most current genetic techniques used in the field of virology. They further point out that some people that have entered caves containing populations of bats have become sick with a Covid-like disease, suggesting that these viruses can infect people directly without need for genetic modification. Finally, they argue that the production of vaccines and drugs against Covid-19 benefited from research at the WIV. With regards to the gain of function funding claims, officials such as Dr. Fauci and the NIH director Dr. Francis Collins deny that the grant money that reached the WIV funded any such research. The above debate is what you get when scientists and other individuals with competing ideas are involved in an exchange regarding complex technical issues. The process of conventional thinking involves skepticism, evaluation of evidence, and coherence. Conventional thinking is not perfect, as it can be distorted by politics, polarization, and emotions, but it is the best method we have at our disposal to generate evidence-based answers to questions. The opposite to conventional thinking is what we will call conspiratorial thinking also following the terminology of the Conspiracy Theory Handbook. Conspiratorial Thinking There are several conspiracy theories regarding the origin of the COVID-19 virus. In general, many of them start with the information I have alluded to above and make the leap to argue not only the “certainty” that the virus was produced at the WIV as a bioweapon with NIH funding, but that the Chinese government released the virus on purpose with the goal of bringing down Donald Trump’s presidency or somehow gaining some global advantage over other countries. While conventional thinking and conspiratorial thinking both rely heavily on evidence, conspiratorial thinking involves overriding suspicion, over-interpretation of the evidence, and often results in contradiction. When properly carried out, conventional thinking uses evidence to find the truth, while conspiratorial thinking often uses evidence to justify a prejudice. Apart from the levels of “conventional thinking” and “conspiratorial thinking” from the Conspiracy Theory Handbook, I also want to suggest two additional levels that lie below it. Crazy Thinking In this level, it is argued not only that China developed and released the virus, but that it did so with the support of the deep state within the US government to not only bring down Trump but to control and track the behavior of people through mask wearing and other measures including the implantation of a microchip using vaccines in coordination with Bill Gates and his foundation. In these claims, Dr. Fauci and other government figures not only knowingly funded the development of COVID-19 by China but also coordinated with pharmaceutical companies to enrich themselves and oppose cheaper effective therapeutic alternatives like hydroxychloroquine. While conspiratorial thinking makes the mistake of overinterpreting evidence or using it in a selective way, at the crazy level people make use of evidence only in the most cursory of ways to lay the foundation for an edifice that they erect based on innuendo, hearsay, rumors, ignorance, fear, bigotry, misinformation, and disinformation. But believe it or not, things can get worse. Bat Crap Crazy Thinking This is the ultimate level of human folly. Here is where you find QAnon, tin foil hatters, flat Earthers and other such fringe. The individuals in this level are so divorced from reality that their claims often run afoul of mainstream crazy. With regards to COVID-19 origins, they make assertions such as that the disease is not produced by a virus but rather by 5G wireless networks, or that it is not a disease at all but a cover up for sex trafficking by a cabal of deep state satanic pedophiles who torture children and drink their blood. They make claims that COVID-19 vaccines are lethal, that the vaccines themselves can cause COVID-19, or that they change people’s DNA. They also argue that the pandemic is a sham, which they call “shamdemic”. The effort to understand the origins of COVID-19 is ongoing, but it is far from perfect. Human passions and folly at several levels may stand in the way of progress towards this goal, but hopefully sane people of goodwill guided by science will get us there. The image by Felton Davis from flickr is used here under an Attribution 2.0 Generic (CC BY 2.0) license.  My First Shot of the COVID-19 Vaccine I got my first shot of the COVID-19 (Moderna) vaccine, and to celebrate this event I thought I would write about the vaccine and how societies in general reacted to vaccines in the past. Before COVID-19 we were spoiled. The massive success of vaccination in eradicating or diminishing disease had made it possible for people to enjoy the luxury of dabbling in antivaxxer pseudoscience and indulging in vaccine hesitancy. Until COVID-19 hit us, many people had not experienced the fear for their loved ones that people had experienced in the times before vaccines were available during epidemics of diseases such as polio. Nowadays few people remember the peace of mind and hope that vaccines brought to humanity. The bliss experienced by people finally rid of the scourge of certain diseases such as smallpox, which periodically decimated entire communities, is difficult to describe today. To give you an idea, let me just present below a translation of a stanza of the poem Oda a La Vacuna (Ode to the Vaccine) by the Venezuelan poet Andres Bello written in 1804 (he mentions Jenner, the discoverer of the smallpox vaccine, and Carlos, the King of Spain who promoted the distribution of the vaccine). “Supreme Providence, the tearful echoes of the disheartened man at last arrived to your abode, and you raised your righteous arm from his neck; admirable and amazing in your resources, you gave the man medicine, wounding the herds with contagious plague; you opened for us new springs of health in the sores, and you stamped upon our flesh a miraculous seal that the black pox respected. Jenner is the one who discovered under the roof of the shepherds such a precious find. He joyfully published to the universe the happy news, and Carlos distributes to earth the gift of heaven.”
Although many individuals today are too far gone down the rabbit hole of antivaxxer irrationality to be redeemed, now that science has delivered for humanity an effective vaccine against COVID-19 in record time, I hope that many people will regain a measure of gratefulness and respect for vaccines and for scientists. The COVID-19 vaccine has an amazing history involving failure, tragedy, perseverance, and triumph that is worth reading about. This vaccine was made possible by a remarkable confluence of several technologies produced by numerous discoveries in basic and applied science. Others have already reported in depth on these stories, so here I will provide a summary of the most salient points with references. A couple of decades ago, the scientific establishment was skeptical of the concept on which the Moderna and Pfizer vaccines are based: using mRNA to direct the production of a viral protein and generate an immune response. This was mostly due to the fact that the mRNA triggered an immune response against itself that interfered with its effectiveness. A Hungarian born scientist in the United States, Dr. Katalin Karikó, spent many years fighting against this skepticism and paying dearly for it in terms of stress, remuneration, and career advancement. Finally in 2005, Dr. Karikó and a collaborator, Dr. Drew Weissman, succeeded in modifying the molecule to make it more stable. Two emerging biotech companies, Moderna (founded in 2010) and BioNTech (founded in 2008) licensed the technology from Karikó and Weissman and began working on a series of applications for the modified mRNA. When the COVID-19 pandemic broke out, they were ready to hit the ground running with the technology. In 1966, a trial of a vaccine against a virus called respiratory syncytial virus (RSV) went horribly wrong. The vaccine not only was unsuccessful in protecting immunized children, but it actually worsened their response to the virus with 21 children being hospitalized and 2 dying. Dr. Barney Graham, an American virologist, devoted his career to finding out what had happened. Finally, he and his colleagues figured out that the protein the viruses use to fuse with human cells changes shape in the process. Antibodies against the pre-fusion protein were effective against the virus, whereas antibodies against the post-fusion form were not and actually made things worse. Dr. Graham and his colleagues applied this knowledge to develop a vaccine against a type of coronavirus that appeared back in 2012 called Middle East Respiratory Syndrome (MERS) which could not be tested because the disease did not reach epidemic levels. However, by 2017 they had figured out how to develop a vaccine against coronaviruses in general. Graham teamed up with Moderna to incorporate his research into the design of mRNA vaccines. When the COVID-19 pandemic began, Graham’s research and experience with coronaviruses allowed Moderna and other companies to design a vaccine for the right form of the protein. A seldom mentioned issue is that the mRNA in the vaccines is a large and fragile molecule that is easily degraded once inside the body and which does not cross cell membranes. The reason the vaccine mRNA is effective, is that the molecule is packed into vesicles called lipid nanoparticles (LNPs) which protect the molecule and allow its efficient delivery into cells. When Moderna and BioNTech began their work to find the right LNPs to deliver their vaccine mRNA, they benefited from the experience of decades of hit and miss research conducted by multiple labs that painstakingly combined different lipid components, tweaked their proportions, and tested them in cell, animal, and humans studies for effectiveness and toxicity. When the pandemic started, both companies had already produced working LNPs to deliver mRNA. And finally, there are multiple discoveries that resulted in technologies that made possible the day to day practical and theoretical work of scientists. Among these are the advances in genetic sequencing technology, which allowed the quick elucidation of the genome of the virus, and the advances in computing and bioinformatics, which allowed the visualization and analysis of sequences and molecular structures, and the quick sharing of information among scientists worldwide. A lot of things have improved in our societies since Andres Bello published his poem back in 1804. Science has spearheaded a revolution that has increased human lifespan and quality of life, and vaccines such as the COVID-19 vaccine have been an essential part of this process. Sadly, one of the things that has changed for the worst is that today poetry is no longer an art cultivated by the younger generations which consider it something old fashioned. But I am grateful for this gift that science has given to us, and I hope somebody considers composing an ode to the COVID-19 vaccine! The photograph is property of the author and can only be sued with permission.  COVID-19 Vaccine We have begun to detect early signs that COVID-19 vaccination is having a dramatic effect in reducing the number of new cases and deaths. This data comes from studies performed in nursing homes where the vaccine was made available first. Despite this good news, there is a substantial amount of misinformation about the COVID-19 vaccine that is stoking doubt among people that would otherwise elect to be vaccinated. In this post I will address some of these claims.
Vaccine development is a process that takes a decade or more. The COVID-19 vaccines were developed in a year (Operation Warp Speed), so they were rushed, therefore there is no way they can be safe. This claim reveals a misunderstanding of what Operation Warp Speed did. This vaccine development operation was not fast because they cut corners. There are several reasons vaccine development was fast, but one of the most important ones was that the government funded multiple stages of the vaccine development process at once. For example, the vaccine was produced at the same time the clinical trials were ongoing. A pharmaceutical company normally waits for the results of the trials before producing the vaccine, because if the trial fails, then it would lose all the investment in producing a vaccine that wouldn’t be approved. In Operation Warp Speed it was the government that assumed this economic risk, and this accelerated the pace of vaccine production. No corners were cut in the development process. The vaccines were tested in regular clinical trials and they were found to be effective and safe. The coronavirus is a new virus and the Moderna and Pfizer messenger RNA (mRNA) vaccines are a new technology. There is no way that a new technology can be applied to a new virus and result in a safe vaccine in such a short time. This claim ignores the history of both the involvement of scientists with coronaviruses and the history of the development of the mRNA technology. Scientists had been researching coronaviruses such as SARS (2003) and MERS (2012) for many years. By studying these and other viruses they discovered how the proteins in the surface of the virus change when attacking a cell, and they figured out how to make antibodies to the right proteins to avoid problems that can compromise a vaccine. The mRNA technology they used had also been researched for decades and had reached its full potential by the time COVID-19 came around. Finally the Johnson and Johnson vaccine is also as effective and safe as the others and is not based on mRNA technology. The mRNA vaccines will change your DNA, and can give you COVID-19. This is not how mRNA works. DNA produces mRNA, and mRNA carries the instructions for the production of proteins. However, mRNA cannot go back to DNA and alter it. If I asked you whether you are concerned that while you are walking on the sidewalk the concrete under your feet will turn into quicksand and swallow you up, you would probably reply that is silly because it’s not in the nature of concrete to do that. Similarly, it is not in the nature of mRNA to alter DNA. The SARS-Cov-2 virus that produces COVID-19 has a total of 29 proteins. The vaccines contain an mRNA molecule that carries the information to produce ONLY ONE viral protein (the spike protein that the virus uses to enter the cells). The body then produces antibodies against this protein, and the mRNA is degraded after a few hours. The mRNA does not carry the information to produce the rest of the proteins of the virus, thus it is impossible for the mRNA vaccine to give you COVID-19. They tell us that after we get vaccinated, we still need to wear a mask and social distance, so why get vaccinated at all? It is not known if the vaccine can prevent you from being infected with the virus. What we know is that the vaccine will help you fight the virus and protect you against moderate and severe COVID-19 disease. However, scientists don’t know if vaccinated people are still capable of carrying the virus and transmitting it to other people. Thus, scientists are just being careful and recommending that vaccinated people still use masks and social distance while in the presence of others that may not yet be vaccinated until they can answer this question. The COVID-19 vaccines have side effects and have caused severe allergic reactions. The side effects of the COVID-19 vaccines are an indication that the immune system is working. These side effects, such as pain at the site of injection, fatigue, headache, and muscle pain, normally last 24 hours and are an acceptable tradeoff for gaining immunity against a disease that can potentially be lethal or debilitating to you and others you may transmit it to. In rare cases an allergic reaction to the vaccine has been documented which mostly occurs within 30 minutes of vaccination and can be treated by the medical personnel administering the vaccine. This is why it is recommended that people who have a history of allergic reactions should consult with their doctors before getting the vaccine. The COVID-19 vaccines have caused several deaths. This piece of misinformation is straight out of the antivaxxer playbook, and it is based on claims that people who died or had a problem after receiving a vaccine died or had the problem because of the vaccine. In a population of millions of individuals, thousands of people naturally die or have health issues every day. If millions of people get a vaccine, some of them will naturally die or have health issues around the time they received the vaccine, but in a manner unrelated to the vaccine. In other words: correlation does not imply causation. So far the alleged vaccine deaths that have been investigated have not been linked to the vaccine. More than 500,000 American have died as a result of COVID-19 and tens of thousands have been left with long-lasting side effects. All this could have been avoided if we had had a vaccine for the disease at the begining. Well, now we have 3 vaccines against the disease (not counting the Russian, Indian, and Chinese vaccines). There are still tens of millions of people in the US who have not yet had COVID-19, and therefore there is potential for additional morbidity and mortality from the disease. It is important for everyone to get vaccinated to protect both themselves and those around them, so please don’t fall for the vaccine misinformation. Get vaccinated. The photo of the COVID-19 vaccine by Lisa Ferdinando (DOD) was taken from the Flickr photostream of the US Secretary of Defense and is used here under an Attribution 2.0 Generic (CC BY 2.0) license.  The statistics are grim. More than 235,000 Americans are dead. We are entering the dark winter of the second pandemic wave. And it seems the best strategy the government has been able to muster is “live with the virus”, which is a de facto herd immunity approach of sorts, but without the discipline and thought that was put into it by the Swedes (although even that didn’t go that well). So in this dire situation what can we do, apart from wearing a mask, social distancing, washing our hands, and avoiding crowded places? There is one more thing we can do which is in fact the one thing we have always done in in the face of tragedy: tell jokes!
Back when the Spanish Flu killed half a million Americans in 1918, people lightened the somber mood enveloping the country by composing poems and coming up with witticisms. One of my favorites is a children’s jump rope rhyme: I had a little bird, Its name was Enza. I opened the window And in flew Enza! COVID-19 has been no exception to the unwillingness of the human spirit to suppress a laugh when confronted with misfortune. Today we will go over a few of the jokes spawned by this pandemic dealing with things ranging from quarantine, social distancing, masks, and vaccines to 2020, Zoom, alcohol, and the government’s response to the virus. Social Distancing After weeks of staying indoors eating and drinking, the COVID-19 curve may be flattening, but the buttons of my shirt have started social distancing from each other! Person #1: He’s a natural. Staying inside, social distancing, and cleaning himself are practically second nature to him. Person #2: Whom are you talking about? Person #1: My cat. Social distancing guideline in Leon County, Florida: “This is a reminder that during COVID 19, please remember to keep at least 1 large alligator between you and everyone else at all times.” COVID-19 The World Health Organization (WHO) announced that scientists have finally figured out that dogs cannot catch COVID-19, so all dogs previously held in quarantine can be released. The WHO let the dogs out. During COVID-19, an epidemiologist, an infectious disease expert, and an ICU doctor walk into a bar…just kidding, they know better. Remember the times when we used to eat the cake after someone had blown on it to snuff the candles? Reopening feels so good and liberating. No more lockdowns, social distancing, or masks! I went to the bar and ate and drank and sang with my buddies. My only complaint is that they must have changed the food because I couldn’t taste anything. COVID-19 Scientists: If we provide the American people with the facts, they will all do what is sensible. Climate Scientists: Ha, Ha, Ha… Face Masks Never in my wildest dreams would I have thought that it would be considered OK to walk into a bank wearing a mask and ask the teller for money. One dog to another: Why are they wearing muzzles? Americans: I have to cover my face. I can’t interact with people, and I am told to stay at home. This is terrible! Women in Islamic Countries: First time? Saying that wearing a mask during the pandemic is living in fear is like saying that using oven mittens means you’re afraid of the oven. Pssst, Hey, the government has placed hidden cameras with facial recognition software everywhere. The only way to prevent them from tracking you is to wear face masks. Pass it on! COVID-19 Vaccine Some people fear that the COVID-19 vaccine will have a microchip that will allow the government to track them, and all these people own smart phones. I have received the Russian coronavirus vaccine, and I have had no problemы. Я think что vaccine подействует на всех, кто ее получит. Using Zoom Today I attended a Zoom conference wearing my work pajamas. Due to COVID-19, they had the first remote trial via Zoom. It’s seems that things will be settled out of court. I told a joke during my Zoom meeting, but people didn’t find it remotely funny. I thought the year 2020 would fly by, but I didn’t know it would Zoom. The Government (or Lack Thereof) The 16 people of the White House Coronavirus Task Force got up on a tightly packed stage and recommended avoiding social gatherings of more than 10 people. Q: How is COVID-19 like a disaster movie? A: Every disaster movie starts with the government ignoring the scientists. Person #1: I just received a very detailed, thorough, and thoughtful plan to deal with the virus. Person#2: Did you get it from the government? Person #1: No, from the owner of my gym. Who do you believe? The guy who spent his life studying viruses, or the guy who wonders out loud during a press conference whether the virus inside the body can be treated with bleach or ultraviolet light? Whenever you think that no one listens to you, and feel irrelevant and useless, just remember that somewhere Dr. Fauci is trying to advise the government about COVID-19. Quarantine and Working from Home Q: What type of jokes do people tell during quarantine? A: Inside jokes! Thirteen years from now, the babies born during the coronavirus baby boom will be known as the quaranteens. People who are bored during quarantine have no imagination. For example, I’ve found out that while one bag of rice that I purchased had 10,537 grains, another had 10,339. This is your pilot speaking. Due to the COVID-19 pandemic I’m working remotely from home today. Quarantine is getting on my nerves. Today I swear I heard my dog say to me, “See? This is why I chew the furniture”. Son: Dad, why is my sister named “Paris”? Father: Because your mom and I conceived her in Paris. Son: Oh, OK, thanks Dad. Father: No problem, Quarantine. I ran out of toilet paper during quarantine, so I started using lettuce leaves. Today was the tip of the iceberg, tomorrow romaines to be seen. I was once told that I would never accomplish anything by lying in bed all day, but look at me now. I’m flattening the curve and saving the world! My heart goes out to all those husbands that told their wives, “I’ll do it when I have the time”. Quarantine is getting on my nerves. Today I had to ask my husband to blink a little more quietly. Now everyone wants to know what introverts do for fun. If this quarantine goes on too long it will be very hard to go back to a society where we are required to wear pants and bras. Beer and Spirits What do you know? I tried to make my own hand sanitizer and it came out a margarita! Even people really into booze were astonished to find out their hands were consuming more alcohol than their mouths! Person #1: I thought you said you were sick, but here you are drinking beer. Person #2: Well, that’s not what I meant when I said “I have a case of Corona”. I got small supporting role in a movie they are going to make about COVID-19. I’m going to be a Corona Extra. Your quarantine alcoholic name is your first name followed by your last name. Customer: I’ll take a Corona minus the virus, ha, ha, ha. Bartender: Year 2020 It’s as if Camus, Kafka, Beckett, Ionesco, Vonnegut, Orwell, and Brecht all got drunk together, wrote a play, and entitled it “2020”. Optimist: The glass is half full with beer. Pessimist: The glass is half empty of beer. 2020: That’s pee. Man, what a year 2020 has been! Just yesterday the Pentagon confirmed that UFOs exist, Elvis was cloned, and the moon landing was faked, and it barely made the news! 13 says, “I’m the worst number!” 666 says, “No, I’m the worst number!” 2020 says, “Bitches, please.” Image from ph used under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication license.  The Conspiracy Theory that Went Bust Some of the proponents of the drug hydroxychloroquine (HCQ) have put forward a conspiracy theory to explain the negative results for the drug in some clinical trials. They claim that the scientists running the trials have sold out to pharmaceutical companies and designed the trials in such a way as to make HCQ fail the trials. The alleged reason for doing this is to favor more expensive alternatives such as the drug remdesevir from Gilead Sciences and vaccines or antibodies made by other companies. This convoluted conspiracy theory has grown to encompass a worldwide network of scientists that have sold out in this fashion and to even involve organizations such as the Gates Foundation and the World Health Organization that are also allegedly colluding with the pharmaceutical companies. This vast network of colluding scientists from different countries using different sources of funding and engaging in behavior contrary to the principles of the organizations for which they work, is not only very unlikely but the most basic tenets of the conspiracy theory are not even coherent. I have mentioned before that the same trial that found that HCQ was not effective against COVID-19 (the Recovery trial), also found that dexamethasone was effective in advanced cases of the disease. Steroids like dexamethasone are cheap generic drugs. Why would scientists colluding with pharmaceutical companies design the trials to torpedo one cheap drug (HCQ) but not another one (dexamethasone)? But there is more. Recently the results of the Solidarity trial sponsored by the World Health Organization (WHO) were published. It was already known that the trial had not found HCQ to be effective and this fanned the conspiracy theory, but another result of the trial was that remdesivir was not effective too! Why would the WHO betray their pharma overlords by trashing their drug? The answer is that the WHO didn’t because there was no one to betray. The vast majority of scientists involved in this research are honest individuals who are genuinely interested in finding whether these drugs work against a terrible disease. These scientists designed and performed clinical trials to the best of their abilities to obtain answers. This is how science is supposed to work. No ulterior motives, no deceit, and no conspiracy: just the facts, the evidence, and the truth.  Dr. Anthony Fauci The Accusation that Fell Flat The attacks on Dr. Anthony Fauci continue due to his resistance to accept that hydroxychloroquine works. Dr. Fauci has stated: “The point that I think is important, because we all want to keep an open mind, any and all of the randomized placebo-controlled trials, which is the gold standard of determining if something is effective, none of them had shown any efficacy by hydroxychloroquine. Having said that, I will state, when I do see a randomized placebo-controlled trial that looks at any aspect of hydroxychloroquine, either early study, middle study, or late, if that randomized placebo-controlled trial shows efficacy, I would be the first one to admit it and to promote it. But I have not seen yet a randomized placebo-controlled trial that’s done that. And in fact, every randomized placebo-controlled trial that has looked at it, has shown no efficacy. So, I just have to go with the data. I don’t have any horse in the game one way or the other, I just look at the data.” This is the comment we would expect from a scientist like Dr. Fauci, Just show him a well-designed study that shows that HCQ is effective and he will change his mind. Makes sense right? But no, HCQ proponents will have none of it. They claim the evidence for HCQ is overwhelming (it isn’t), but it is being suppressed by a massive disinformation campaign (which is really an attempt by responsible organizations and individuals to counter misinformation about HCQ). And they have found another way to attack Dr. Fauci. They claim that the lack of acceptance of the effectiveness of HCQ by Fauci is killing people! The Yale epidemiologist Harvey Risch and others have stated that back in the 1980s Dr. Fauci refused to issue guidelines for physicians to consider the prophylactic use of an antibiotic (Bactrim) to prevent an opportunistic infection (pneumocystis pneumonia) in AIDS patients because he considered there was not enough data, and this led to the preventable deaths of 17,000 people. They claim that Fauci is doing this again with HCQ and that people who could be saved are dying. This new accusation has reached a fevered pitch with claims that Dr. Fauci is a mass murderer. The notorious HCQ proponent Vladimir Zelenko is circulating a petition to the White House to bring several individuals including Dr. Fauci to justice for “Crimes Against Humanity / Mass Murder”. There are several things that have to be understood by Fauci’s critics. The first is that, as I have explained before, the job of doctors is to save their patients and improve their lives, and doctors have the freedom to treat patients as they see fit. On the other hand, the job of scientists like Fauci is to try to figure out what works and what doesn’t based on the evidence. During times when a disease ravages society, the use of many drugs that may or may not work is often proposed. These drugs can be prescribed by doctors, but they should not be endorsed by scientists. There is a scientific discussion that has to take place and the evidence has to be generated and/or evaluated. Dr. Fauci cannot endorse a drug for which the evidence is deficient. In any case Dr. Fauci himself has stated that he had no authority to issue guidelines, but he offered to help with carrying out a clinical trial. The second thing is that Fauci is not the type of callous person that he is made out to be by HCQ proponents. Just consider that their accusations are remarkably similar to those levied upon Fauci by the notorious AIDS activist Larry Kramer back in the 1980s who besides calling him a murderer also said Fauci was a Nazi who should be put in front of a firing squad. Larry Kramer eventually befriended Fauci and he and other AIDS activists worked together with Fauci to make improvements to the clinical trial system which has saved many lives and given patients more control over the process. And finally, just consider Fauci’s achievements. Apart from what I mentioned above regarding the modification of the clinical trials system, Fauci has not only made many scientific contributions that have advanced our knowledge of disease as well as developing effective therapies against diseases, but he has been among the architects of major programs such as PEPFAR (President's Emergency Plan for AIDS Relief) which has saved the lives of 18 million (!) people in Africa. In recognition for his work in creating the PEPFAR program, President George W. Bush awarded him the Presidential Medal of Freedom in 2008. Fortunately, this accusation by HCQ proponents that Fauci is a murderer has fallen flat. The vast majority of people understand that Dr. Fauci is an exceptional individual both as a scientist and as a person. The vast majority of people also understand that those levying these accusations against Fauci have now pushed themselves further into a fringe and lost all credibility. The image of Dr. Fauci ny NIAID is used here under an Attribution 2.0 Generic (CC BY 2.0) license. The conspiracy sign by Nick Youngson from Picpedia.Org (used here under a Creative Commons 3 - CC BY-SA 3.0 license), the public domain image of hydroxychloroquine by Fvasconcellos, and the public domain coronavirus image by Alissa Eckert, MS; Dan Higgins, MAM, from the CDC's Public Health Image Library were modified and merged.
One of the things you learn as a scientist is to be skeptical of stories. By stories I mean narratives that scientists have put together to try to explain certain observations, to explain how some things work, or to suggest new ways of doing things that may be more effective than the old approaches. And the way you learn to be skeptical of stories is through the experience of witnessing countless numbers of them crash and burn over the years. We scientists try to discover reality, but the problem is that reality is often more complicated and nuanced than we can imagine. The English biologist Thomas Huxley once encapsulated this in his famous dictum: The great tragedy of Science—the slaying of a beautiful hypothesis by an ugly fact.  Because scientists are human, they tend to fall in love with their ideas and bring to the front in their arguments all the evidence that suggests those ideas are true while overlooking evidence that indicates the opposite. But thankfully these biases are countered by experience. As a scientist, I have lost track of how many times I thought I understood how things worked only to have my ideas disproved by the next experiment. As a scientist, I have also lost track of the number of times I became enamored of a beautiful idea proposed by a scientist only to read later that another scientist had performed an experiment that refuted it. After years of being exposed to this process, you tend to be wary of anything new that sounds too good, and this experience is a fundamental part of the development of a skeptical scientific mindset. I remarked before that one of the problems we have in science communication is that now people without training as scientists have access to information intended only for experts. The vast majority of these people do not have the experience I outlined above. As a result of this, I am witnessing many of these individuals become infatuated by unverified hypotheses to the point of aggressively defending them in social media and arguing that these hypotheses have been proven to be true by what is nothing but substandard evidence. A case in point is the hypothesis that hydroxychloroquine (HCQ) and/or its combination with zinc is effective against COVID-19. Hydroxychloroquine (HCQ)
HCQ and its parent compound chloroquine (CQ) have been used for decades against malaria. But the original interest in using HCQ against COVID-19 was generated as a result of studies that indicated CQ had antiviral activity against various viruses including SARS-Cov, a virus related to SARS-Cov-2 which produces COVID-19. More recent studies found that HCQ does indeed have antiviral activity against SARS-Cov-2. Unfortunately, this antiviral activity was evaluated in cultured green monkey kidney (Vero-E6) cells. When HCQ was tested in human airway cells or animal models, no such activity was found. Thus the initial rationale that got scientists interested in using HCQ against COVID-19 has evaporated. If we knew at the start of the pandemic what we now know about HCQ’s lack of antiviral activity against SARS-Cov-2, HCQ would never have been tested against COVID-19. This lack of antiviral activity probably explains why HCQ has not been found to be effective against COVID-19 in the best designed trials (1, 2, 3, 4, 5, 6, 7, 8, 9). Nevertheless, HCQ proponents claim that other effects of HCQ such as its anti-inflammatory actions can produce a protective effect against COVID-19. HCQ does indeed have well-documented anti-inflammatory action in diseases such as lupus or rheumatoid arthritis. However, the onset of this action is slow taking several weeks to months for patients to begin to see improvements, with the full effects taking as much as a year or more. In comparison, the time frame of HCQ treatment in COVID-19 is a couple of weeks at most. And in case you are wondering, studies indicate that patients with lupus or rheumatoid arthritis who were taking HCQ were not protected from COVID-19. There is some evidence that in patients with COVID-19 treated with HCQ there is a faster onset of anti-inflammatory action, but it is not clear why HCQ would be better than other anti-inflammatory agents or why the anti-inflammatory properties of HCQ did not make a difference in the best designed trials. Zinc and HCQ Another hypothesis for a possible HCQ action against COVID-19 involves the trace element, zinc. HCQ proponents claim that HCQ taken with zinc is a very effective therapeutic for COVID-19. Zinc has been found to have antiviral action in cell culture because it inhibits the enzyme necessary for the replication of the virus’ genetic material. Additionally, zinc deficiency compromises normal immune function and there is some evidence that zinc deficiency results in a worse COVID-19 outcome. So giving zinc to people with COVID-19 seems like a good idea to correct any zinc deficiency. In fact one of the treatments that the president received when he was infected with COVID-19 was zinc supplements (but not HCQ). So you may ask, if a COVID-19 patient is receiving zinc, why also coadminister HCQ? Some HCQ proponents argue that in physiological conditions zinc is a charged molecule that has trouble getting across cell membranes, and HCQ in a cell culture study was found to act like a zinc ionophore. This means it increases zinc uptake into cells. Therefore the claim is that you administer HCQ with zinc to “help” zinc get inside the cells where it can inhibit the virus. In this view, it is zinc that has the antiviral action while HCQ only helps it get into cells. The issue with this notion is that zinc has no problems getting across cell membranes. There are zinc transporters in the membranes of cells that can let zinc in (and out) just fine. In fact, 99.9% of the zinc in the body is inside the cells. Regardless, HCQ proponents argue that HCQ is necessary to drive the uptake of an excess amount of zinc to produce antiviral effects. In the cell culture study mentioned above (and bearing in mind that these are cell culture results with all of their caveats), a concentration of 10 micromolar HCQ outside the cells increased intracellular zinc slightly above two times the normal amount. Whether this is enough to antagonize viral replication is an open question. However, the majority of the intracellular zinc was targeted to a compartment called a lysosome (which is where HCQ accumulates). The problem is that viral replication takes place elsewhere in the cell (the cytosol). How can zinc trapped in the lysosome affect extralysosomal viral replication? And increasing the HCQ concentration outside the cell to push in more zinc is problematic. In humans, HCQ plasma concentrations greater than 15 micromolar are associated with mortality (reference: download pdf). An additional complicating factor is that the majority of the zinc both inside and outside the cells is not free. It is bound to proteins. Zinc is used as a signaling molecule by cells and if its levels are allowed to increase in an uncontrolled fashion, they can be toxic. Cells control their internal free zinc levels and try to keep them as low as possible. I am greatly skeptical about the effectiveness of HCQ against COVID-19, because I consider that the best evidence we have indicates it doesn’t work. I am also skeptical about the zinc story. There are too many questions and a lot of it remains unproven. The effect of zinc alone may be to correct a deficiency as opposed to a pharmacological effect, and HCQ may have no role in the process. But as I have stated before, I want to save lives, not be right. If HCQ alone is found to work against COVID-19 in some specific dose modality or temporal dosing regimen, then that’s great. If zinc combined with HCQ is better than HCQ alone, then that’s great too. But we need well-designed clinical trials to prove this (which excludes observational studies). In the meantime we will all be best served if we maintain a reasonable level of skepticism. My message to HCQ proponents is: Avoid falling in love with the story. Heart image by Mozilla used here under a Creative Commons Attribution 4.0 International (CC BY 4.0) license was modified from to include the words of hydroxychloroquine and zinc with the heart on a white background. |
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