clinical trials

Don’t Forget The Drugs: An Update

In these pages last March, I reminded readers to be thankful for the vaccines that prevent COVID-19, but to not forget the antiviral drugs that are being developed that might treat the disease. Both vaccines and antivirals are part of the same quiver of weapons we have to fight the pandemic. In that blog post, I mentioned an experimental drug, molnupiravir that was being developed by Merck and Ridgeback Therapeutics. Well, they just posted an encouraging update. It continues to show success at preventing serious disease when given to high-risk people early after infection. Its only side effects were similar to the placebo, meaning it is very safe. In animal studies, the drug also was effective against different CoV-2 variants, including Delta, and against other coronaviruses including SARS and MERS. Molnupiravir is a “prodrug,” which means that it has no activity on its own; rather it is metabolized after ingestion to an active drug that was developed in the early 2000s to treat hepatitis C.

This is a significant step for being able to easily protect high-risk patients at home. The pill that patients take on their own cuts their risk of hospitalization or death by ~50%. The results were so encouraging that the study was halted after consultation with the FDA. Early termination of studies like this is only done when interim data analyses show such good efficacy of a treatment that it would be unethical to continue enrolling subjects, some of whom would receive placebo, thereby being denied an effective therapy.

The drug slows the spread of the virus in infected people by forcing the enzyme that copies the viral genetic material into making so many mistakes the virus cannot reproduce. That, in turn, reduces the patient’s viral load, shortening the infection and damping the type of over-exuberant immune response (cytokine storm) that causes serious problems in many COVID patients. It was not effective when given to already hospitalized, or advanced, patients. It is on track to be approved by the FDA by the end of the year, and would be the first proven and approved oral antiviral drug for treating COVID-19 (neither ivermectin nor hydroxychloroquine have been proven or approved).

The FDA has already cleared another antiviral drug, remdesivir, for treating COVID-19, but it is only used to treat advanced patients who are already hospitalized (interestingly remdesivir was also originally developed to treat hepatitis C and it is also used to treat Ebola). Several lab-produced monoclonal antibody treatments have also been approved by the FDA for treating mild to moderate COVID-19 and they are more successful than molnupiravir at preventing advanced disease. But both remdesivir and the antibody treatments require an intravenous infusion done in a health care setting, making them more complicated and more expensive than just taking a pill at home, which is a decided advantage of molnupiravir. Finally, one of the more effective approved drugs against COVID-19 is the steroid, dexamethasone, but that is only given to very sick patients since its side effects are significant. Therefore, there is much room in the anti-COVID quiver for effective, simple-to-administer drugs such as molnupiravir. Both Pfizer and Roche also have other antiviral drugs that block viral replication in advanced stages of development. Stay tuned.

As of October 5, 2021, the Milken Institute tracker shows that there are 331 “treatments” for COVID-19 in development worldwide. This effort recently got a $3.2 billion boost from the US Antiviral Program for Pandemics, which is a rejuvenated initiative that was started during the MERS outbreak in 2012, but was tabled after MERS fizzled out. Then there is the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program, also sponsored by NIH. These programs focus on developing non-vaccine therapies designed to treat not prevent the disease and they include studies of medicines currently used to treat other diseases (including ivermectin, which has yet to be proven effective) as well as studies of new drugs.

While the news about molnupiravir is encouraging, health experts are concerned that the news also could increase complacency regarding vaccines in the vax-hesitant. It is important to realize that prevention (vaccination) is almost always preferable to treatment (drugs).

Get the vax.

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Long Term Side Effects Of COVID Vaccines

In his nearly 30 years studying vaccines, Paul Goepfert, M.D., director of the Alabama Vaccine Research Clinic at the University of Alabama at Birmingham, has never seen any vaccine as effective as the three COVID vaccines — the mRNA vaccines from Pfizer and Moderna, and the adenovirus-based vaccine from Johnson & Johnson that are currently available in the US. He refers to the 90 percent reduction in infections, and 94 percent protection against hospitalization the vaccines confer. 

Despite this undeniable success, most Americans who have not been vaccinated report long-term safety as a major concern. Nearly a quarter of respondents in Gallup surveys in March and April 2021 said they wanted to confirm the vaccine was safe before getting the shot. And 26 percent of respondents in a survey of parents with children ages 12-15 by the Kaiser Family Foundation in April 2021 said they wanted to “wait a while to see how the vaccine is working” before deciding to get their child vaccinated. 

There are several reasons to not worry about such long term consequences of the vaccines. Vaccines are very temporary medicines, making them different from medicines that people take every day, potentially for years, that can have long term safety issues. Further, decades of vaccine history, plus months of data from more than a billion people around the world who have received the current COVID vaccines starting last December, provide powerful real-life proof that there is little chance that any new dangers will arise more than a couple of weeks following the COVID shot. 

Consider the following:

1. Vaccines are eliminated within hours to a couple of days. Unlike many drugs, which are taken daily and chronically, vaccines are generally one (maybe two)-and-done. Medicines you take every day for months or years can cause side effects that only reveal themselves over time. 

Vaccines are designed to deliver a payload that is quickly eliminated by the body. This is particularly true of the mRNA vaccines as I wrote earlier. mRNA is a very unstable molecule that degrades rapidly (within hours) due to ubiquitous enzymes generally known as RNases. So, after a shot, the vaccine lingers just long enough to stimulate an immune reaction, and then the body’s normal mechanisms eliminate it within hours. The only long term effect after the vaccine is eliminated is the immunological memory it leaves behind.

2. Vaccine side effects, if any, show up within hours to a couple of weeks, never longer: No vaccine has ever shown a side effect that appeared more than two months after injection. This is why the FDA requires only two-months of of followup data after injection for Emergency Use Authorization (or six months as an extra precaution for Full Approval).

That is not to say that there have never been safety issues with vaccines. But in each instance, these issues appeared very soon after vaccination. When the oral polio vaccine was first introduced in the US in 1955, it used a crippled form of the polio virus that in very rare cases, about one in 2.4 million recipients, became activated and caused polio. Cases of vaccine-induced polio occurred between one and four weeks after vaccination, none after one month.

In 1976, it was found that in approximately one in 100,000 patients, a vaccine against swine flu was associated with Guillain-Barré Syndrome, in which the immune system attacks the nerves causing temporary paralysis. These cases occurred in the eight weeks after being vaccinated (in contrast the flu itself causes Guillain-Barré Syndrome 17 times more frequently than the vaccine). Eight-weeks is the longest post-vaccine delay for the appearance of a side effect for any vaccine.

3. Real life experience with COVID vaccines: By the time the COVID vaccines were approved for emergency use in the US in December 2020, we already knew what the short-term side effects were from the clinical trials on tens-of-thousands of people. The side effects seen in these studies, and later confirmed in the real-world experience of vaccinating hundreds of millions of people, were mostly simple tolerability issues, like arm pain, temporary fatigue and headache. These side effects occur a day or two after the vaccine and last 24-36 hrs.

As of June 12, 2021, more than 2.33 billion COVID vaccine doses have been administered worldwide, according to the New York Times vaccinations tracker. And as hundreds of millions of people are vaccinated, we can begin to detect the extremely rare side-effects that would not be seen when only tens of thousands of patients had been vaxed. This has not revealed any side effect occurring after two-four weeks following the shot. Thus, the close scrutiny of these hundreds of millions of vaccine recipients make the COVID vaccines perhaps the most studied vaccine in the history of medicine.

We also now know that a few people receiving the AstraZeneca COVID vaccine experienced a clotting disorder known as thrombotic thrombocytopenia. This occurred in just 79 people among more than 20 million people receiving this vaccine in the UK. A smaller number of cases have occurred with Johnson & Johnson’s vaccine as well. These side effects only happened 1-2 weeks following the shot (and clotting problems occur much more frequently following infection). An even rarer side effect, myocarditis, or inflammation of the heart muscle, has been reported in people receiving Pfizer and Moderna COVID-19 vaccines. This effect was found in about one in a million vaccinated people. None of these cases appeared more than a month after the vaccination.

Finally, on July 12, 2021, the FDA announced that in rare cases (100 reports out of 12.8 million shots given in the US), the J&J vaccine might be associated with Guillan-Barré Syndrome. All of these cases appeared about two weeks after injection.

Bottom line: All of this can be boiled down to this: There are no “long term safety issues” with these or any other vaccine. If you don’t have a side effect 2-8 weeks after the injection, you will not have any further vaccine-related problem down the road.

I challenge anyone to name any vaccine that has had side effects more than a few weeks following the shot.

Therefore, it is mind-boggling that people are avoiding COVID vaccines based on an unwarranted hypothetical concern over long term safety, but they are not at all worried about the reality of COVID mortality and the devastation of “long COVID” symptoms seen in 10% of infected people. That is irrational.

Stay tuned:  A multi-post blog series on the “long COVID” or “long haulers” will soon begin in these pages.

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Evidence That Facemasks Prevent COVID-19

As Delta proliferates while the world tries to get back to normal, requirements to wear facemasks in public are also proliferating. The mask mandates are causing no end of consternation in certain segments of the population, which like to claim that there is no evidence that they prevent disease. Their evidence behind this claim is weak and usually boils down to claiming that the virus is similarly prevalent in states with and without mask requirements. For instance, they like to point out that California, with strict mask mandates, has about the same rate of COVID-19 as Florida, which does not have widespread mask mandates.

But, this is not a strong argument. In research, we carefully design studies to compare experimental vs control groups that are as similar as possible in every way except for the variable we wish to test. In other words, we try to isolate the test variable by making all else as equal as possible. This goal for a well-controlled experiment falls apart when comparing California to Florida—they are very different. Differences include age, population and housing density, reliance on public transportation, climate, humidity, and demographics. All of these variables, if not controlled for, will confound the relationship between mask policies and COVID-19 outcomes because each of these variables also affects the spread of disease.

However, comparing counties within a state helps address at least some of these confounding factors since counties within the same state are generally more similar than two different states at opposite ends of the country. Researchers have done just this in Kansas where 21 counties implemented a mask mandate while the others did not. Counties with a mask mandate saw a significant drop in COVID-19 while counties without a mandate saw a 100% increase in new cases during the period of evaluation.

More recently, the ABC Science Collaboration, a partnership between health scientists, K-12 schools and community leaders, in North Carolina collected infection data from >1 million students and staff members between March-June 2021. More than 7000 students and staff caught COVID-19 during that period and contact tracing showed that >40,000 people had close contact with the infected ones. Very few of these close contacts caught the virus and all of them, the infected cases and their close contacts, wore masks. In other words, in schools with mask mandates, there were no outbreaks despite initial COVID infections. And schools are ripe for creating super-spreader outbreaks.

A systematic review and meta-analysis published in The Lancet, examined the efficacy of face masks in reducing the transmission of different coronaviruses (SARS, MERS, and COVID-19). The authors evaluated 39 studies and found that face masks significantly reduced the risk of coronavirus infection compared to no mask wearing.

An article published in the Proceedings of the National Academy of Sciences in January 2021 also reviewed the evidence supporting the use of face masks and similarly concluded that near-universal adoption of non-medical (i.e., cloth) face masks in public could significantly reduce the R0 value of the virus, which is a measure of how well it spreads. In fact, I earlier discussed in these pages a similar finding by British researchers who concluded that widespread mask-wearing could substitute for herd immunity.

There are several other published studies that reach similar conclusions about facemasks. But, perhaps the most comprehensive study was just reported by researchers at Stanford and Yale. It involved a method called cluster randomization where villages in Bangladesh were randomized to get facemasks or not. It involved some 340,000 people in 600 villages. 100 villages received cloth masks and 200 villages received surgical masks. The remaining 300 villages did not receive any intervention to increase mask wearing. The results showed that increased community masking decreased COVID-19 disease in these real-world settings. Surgical masks performed better than cloth masks at reducing COVID-19 disease, though cloth masks were definitely better than no masks.

On a final note, let me reissue my earlier challenge to anti-maskers: If you really think they do not prevent infection, then next time you have surgery, invite the surgical team to throw the masks out when they open you up.

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Vying With Viral Variants

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The back story: There are four known CoV-2 variants in the US that are more transmissible than the parent strain. They are the UK variant, which is 70% more infectious and 60% more deadly than the original strain. There also are Californian and Brazilian variants that are more transmissible, but it is not yet known if they are more deadly. However, in Brazil, their variant is associated with a significant increase in infections and ICU stays for young, healthy, unvaccinated people. Fortunately, the current vaccines seem to be effective at preventing infection with these strains.

More worrisome is the South African variant that is 50% more transmissible. It is worrisome because the AstraZeneca vaccine is not very effective against this variant, and a very recent, but a small study out of Israel suggests that the Pfizer vax might have reduced efficacy against the S. African variant. It is not yet known if this strain causes more serious disease. These findings provide evidence that mutation can produce new viral strains that can evade the immune response to the viral spike protein.

Two other variants, the so-called New York variant, and a second Brazilian variant have early signs of being more infectious or even being able to reinfect people who previously had COVID-19. Data are still being collected in order to better understand the risk that these variants pose. Stay tuned.

You can follow the variants in the US here.

The bottom line is that the world is in a race to roll out vaccines faster than troubling virus variants can arise. The UK is expected to reach herd immunity​ early next week. Infections there dropped by 60% during March, with deaths dropping more rapidly, indicating that the vaccines are helping prevent severe illness and viral spread. Meanwhile, the US leads the world in total vaccines administered (175 million), with 43% of the adult population having received at least one shot. More than 700 million doses have been administered world-wide.

The major concern is that a too-slow vaccine distribution, such as what has happened in Brazil, will encourage more virulent variants to arise. If we don’t quickly achieve herd immunity across the world, it probably will just be a matter of time before a variant arose that renders the current vaccines useless, and we would have to start over.

What is a world to do? Besides increasing surveillance of viral variants, a couple more prevention initiatives are in the works. One is economic and the other scientific.

Economics of viral mitigation: The economic approach is detailed in an article by the Associated Press Economics Writer, Martin Crutsinger. Basically, the International Monetary Fund (IMF) proposes giving $650 million to support vulnerable countries struggling to deal with a global pandemic. Along with that, the Group of 20 major industrial countries issued a joint statement that announced a six-month moratorium on debt payments by 73 of the world’s poorest countries.

The rationale behind these actions is to ensure that poor countries, where vaccinations are lagging due to lack of resources and infrastructure, can pick up the pace of vaccination. Their lag in rolling out shots is a threat to the whole world, even while wealthy countries are approaching herd immunity. In order to beat the variants, vaccines are needed to quickly create herd immunity and stop viral spread before a variant that can avoid vaccine immunity appears. When countries lag in vaccinations, the virus continues to spread increasing the chance for an immune-avoiding variant to pop up. Such a variant can then spread to countries that are highly vaccinated, starting the pandemic over again because the current vaccines would be ineffective. We would be back at square one.

Science to the rescue: So far, all the vaccines, except one from China, which uses the whole virus, direct the immune response to the viral spike protein that is used to attach to receptors on the surface of cells in your body. The viral variants we are concerned about show mutations in the spike protein that allow them to become more infectious, and in one case, to be less affected by some of the vaccines. In addition to trying to  nip the virus in the bud by quickly building world-wide herd immunity, new vaccine strategies are being developed to quickly respond to newly arising CoV-2 variants, and even to respond to entirely new strains of viruses that will arise in the future.

  • One way to do this is to begin developing booster shots as soon as a coronavirus variant becomes a significant concern. With the new mRNA, and adenovirus vaccine delivery technology, this is eminently possible. It just requires scientists around the world being vigilant for new variants. Pfizer, Moderna, AstraZeneca, and Johnson & Johnson have all said they’re starting work on developing booster shots to the known variants.
  • Last week, the US government announced a pact with CureVac to tackle variants, pairing artificial intelligence to predict future mutations that can be quickly addressed with modern vaccine technology. London-based GlaxoSmithKline is also working with CureVac on mutant-quelling vaccines.
  • Another strategy is to identify viral molecules other than the spike protein that the immune system can recognize. Efforts are underway to test the immunogenicity of what is called the CoV-2 nucleocapsid, or N protein, which wraps itself around the viral RNA. If successful, future vaccines could incorporate both the N and S (or spike) proteins, which would require the virus to mutate both of those genes in order to avoid vaccine-induced immunity, a greatly tougher task for the virus.
  • Researchers at Moderna, Novavax, and the University of Oxford are designing multivalent vaccine strategies to protect against multiple CoV-2 variants with a single shot, and even against new viruses that might emerge in the future. A similar strategy is used with the annual flu vaccine, which usually incorporates four different influenza strains in one shot. It is also used with measles, mumps, and rubella vaccines. Some vaccines against pneumonia target as many as 23 variants of that pathogen.
  • Finally, a wholly new vaccine technology has shown recent success in animal studies. It works by chemically attaching many short viral protein sequences from different CoV-2 variants, and even from completely different coronaviruses, to engineered nanoparticles that are then injected. In mice, this single vaccine induced an antibody response capable of neutralizing many different coronavirus strains. If successful, this could represent a universal vaccine capable of neutralizing CoV-2 and its variants, as well as other coronaviruses such as SARS and MERS with a single vaccine. And it can be easily modified to quickly respond to future viral epidemics caused by novel coronaviruses or other viruses that will certainly arise. The technology is being developed at Cal Tech using technology developed by collaborators at Oxford University. The nanoparticle platform is a “cage” made from 60 identical proteins. Each of those proteins has a small protein tag that functions like a piece of Velcro to which the viral protein sequences stick resulting in a vaccine nanoparticle with short protein sequences from four to eight distinct coronavirus strains on its surface. If successful, this could prevent infection and disease for several different viruses with a single shot.

 We are in a revolutionary era of vaccinology. BioX marches on.


Vaccine Disinformation

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There is a lot of misinformation and downright disinformation out there regarding face masks, hydroxychloroquine, ivermectin, the seriousness of COVID-19, etc. Many of these I already addressed in prior posts (see here and here). In this post, I focus solely on vaccine misinformation and disinformation in hopes my unvarnished explanation of the science might help vaccine skeptics make decisions based on facts rather than on disinformation spread by people with an anti-vaccine agenda, or who want to sell you something.

Several anti-vaccine disinformation themes have been circulating over the past weeks and a friend recently sent me a video by an MD that was full of disinformation and dishonesty. The video was thinly disguised marketing propaganda by Houston-based Dr. Steve Hotze. He is an MD, who does not seem to practice much medicine anymore, but has built an alternative medicine empire that pushes many vitamin and mineral supplement nostrums that he claims is all you need to fight the virus and other diseases. In other words, he advises people to avoid the vaccines and, instead, buy his concoctions. In December 2020, the FDA and FTC sent him a cease-and-desist letter to stop claiming that his supplements can treat diseases, especially COVID-19. The FDA found the products and marketing to be misleading. The FTC found him in violation of interstate transportation laws. I address his several points below, many of which have been echoed by other anti-vaxers.

  • The vaccines do not confer immunity to the virus and COVID-19. There is very much evidence that the vaccines do provide immunity against CoV-2 and strongly protect against COVID-19. That evidence is found in the many reports of antibody production, of T cell anti-viral responses, of cytokine responses to the vaccines, and in recently published reports out of Israel that the vaccines retard virus transmission. Then there are the several studies showing that the vaccines strongly prevent COVID-19 disease. Hotze and others provide zero evidence to back their allegations and ignore data that contradict their points.
  • These are not vaccines, but experimental gene therapies. The mRNA shots from Pfizer and Moderna, and the modified adenovirus vaccines from Johnson & Johnson and AstraZeneca are indeed vaccines. Researchers whittled down the virus genome to the essential viral spike genetic sequence needed to confer immunity. This means that the minimally effective part of the virus genome, rather than the whole viral genome, is used to provide protection from future infection. Old fashioned vaccines grew batches of viruses and then crippled them so that upon injection, they would infect cells, use their genetic information to express all their viral molecules on the cells, but not spread. The current vaccines simply use the genetic sequence for the spike protein, eliminating all other viral genetic sequences. That single genetic sequence is translated into the spike protein that is expressed on your cell surfaces much like what would have happened with an inactivated, whole virus vaccine. Therefore, the current vaccines are no more “gene therapy” than the whole virus vaccine. Both require expression of viral genes in order to alert the immune system.

Also, the term “gene therapy” conjures images of "Frankenscience." This is wrong. First, vaccines are not “therapy,” which is something that treats a disease after you catch it. Rather vaccines are prophylaxis, which prevents you from catching the disease in the first place. Gene therapy is a still developing field that works to replace, correct, or “knock-out” aberrant genes that cause non-viral health problems.

Furthermore, as I posted earlier, these vaccines are not experimental or hastily developed. They are based on vaccine platforms that have been over a decade in development, and, in some cases, have been used to develop human vaccines to rabies and Ebola. The only novel thing about them is using the CoV-2 spike protein to drive a protective immune response to subsequent infection with the virus. These spike-protein vaccines have been tested in tens of thousands of volunteers in phase 3 trials, and now have been injected into tens of millions vaccine recipients around the world. The vaccines have been wildly successful at preventing COVID-19, and have been proven to be very safe (see below). These are not experimental vaccines, but well developed, and well tested vaccines.

  • The vaccines alter your DNA. They absolutely do not. It is biologically impossible for them to do that. I discussed this fallacy in a prior post.
  • There is no off switch for the viral gene expression caused by the vaccines. This too is not at all true. No vaccine in history has had its viral genes expressed long term. In fact, your cells continually produce their own mRNA to direct production of cellular proteins that drive cell function. Cells are also full of enzymes called RNases that digest mRNA once it has done its job. Thus, your own mRNA is very short lived in your cells. The same is true for the viral mRNA inserted into cells from an inactivated viral vaccine, from an adenovirus-based vaccine, or from an mRNA vaccine. The mRNA will only last a day or two in your cells before it is digested and permanently disappears. This is the off switch.
  • We do not know about the long-term or delayed responses to the vaccines. Yes we do. First, I challenge people who purport to be worried about long-term effects to name one vaccine that has ever had a long-term adverse effect. As I described above, vaccines are short-lived; their only long-lasting legacy are memory T and B cells that protect you from future exposure to the pathogen.

On the other hand, delayed adverse effects were a potential concern when the vaccine was being developed as I described earlier, but that has proven to be of no concern. There is a rare adverse response to prior exposure to a pathogen, whether naturally or via vaccine. This is called Antibody Dependent Enhancement (ADE) of the infection. This was seen with the vaccine against the Dengue virus where the antibody response actually enhanced viral infection in new cells. Because of this, all new vaccines to novel viruses are carefully tested for potential ADE effects.

During the early stages of anti-CoV-2 vaccine development, caution prevailed, and the vaccines were assessed for potential ADE, as reported earlier in these pages. The clinical trials showed absolutely no evidence for ADE. Since then, millions of people around the world have been vaccinated and not a single case of ADE has been found.

Therefore, concern over ADE was theoretical and never became a practical matter. Anti-vaxers who keep bringing this up as a concern, such as Dr. Hotze, and America’s Frontline Doctors choose to ignore demonstrable facts in favor of continued fear mongering and appealing to emotions. A few countries around the world have begun arresting people for spreading such disinformation that disuades people from being vaccinated, which can lead to deaths caused by the disease.

  • Many people have died from the vaccines. That is flat wrong, and in fact, the opposite is true. In the US, ~550,000 people have died from recognizable COVID-19 while only nine (out of several million vaccinated people) might have died due to vaccine complications (discussed below). The CDC has a Vaccine Adverse Event Reporting System (VAERS) that lists all reported adverse events and deaths that occur shortly after vaccination, whether or not they are caused by the vaccine. Seeing as how tens of millions od people in the US have been vaccinated, unrelated health problems and deaths are expected to occur by chance. If you blew kisses at 50 million people, several of them would die in the next day or two just by chance. The air kisses did not kill them. The trick is to distinguish chance deaths vs possible vaccine-related deaths.

In order to determine whether a new vax causes adverse health effects, CDC doctors look for recurring patterns. If they see a pattern of similar types of death in certain people they pay closer attention to that group and even back off vaccinating them. With one extremely rare exception with one of the current vaccines as discussed below, these kinds of patterns have not been seen with the current vaccines.

  • The COVID vaccines will not eradicate the virus any more than flu vax eradicates flu. This statement by Hotze and others is either dishonest or they are ignorant of basic virology. It ignores the fact that flu rapidly changes every season, making it very hard to eradicate. The statement also ignores the facts that small pox has been fully eradicated by vaccines, and that in the US measles and polio have been eradicated—the only cases we see here come from overseas. Whether or not the COVID vaccines can eradicate CoV-2 depends on how well they work against the viral variants, how quickly the variants arise, and how many people are vaccinated in the next few months.
  • Herd immunity caused by natural infection is better than the vaccine. This statement too betrays ignorance of the disease and of vaccinology. Natural immunity to CoV-2 comes with the cost of many deaths and with many more people suffering long-term health problems caused by COVID-19. Again, the vaccines have not been linked to deaths or to lasting health problems. Vaccines are used to confer herd immunity without running the risk of the deadly consequences of the disease. By all measures, the vaccines confer significant protection against the disease and are more reliable than natural immunity where you cannot ensure a uniform level of infection and immunity for everyone.
  • Companies are reaping great profits off their lies. Pfizer and Moderna and other vaccine producers are providing the vaccines at cost during the pandemic. They are not profiting from them. Also, Moderna has announced it will not enforce its patents on its vaccine platform, but will share its technology with other companies and researchers during the current pandemic. In contrast, Dr. Hotze and others clearly are using the pandemic for their profit.
  • Companies are withholding raw data on their vaccines. Raw data for the approved vaccines was shared with two CDC committees consisting of scientists, vaccinologists, pathologists, epidemiologists and statisticians. That raw data was the basis for the emergency authorization of the vaccines (see below). Generally, raw data are only released to CDC and FDA and not to the public. What is released to the public are data summaries in the form of peer-reviewed journal publications and these are coming out and will continue to come out over the next few years.

The above are points Hotze has made and that are often repeated by other anti-vaxers. Below, I address other criticisms and questions about the vaccines that I have heard others, but not Hotze raise.

  • The vaccines are not FDA approved. Well, I wonder then who gave the vaccines Emergency Use Authorization (EUA)! True, EUA is not full FDA approval, but EUA approval still comes from 30 FDA experts after a rigorous evaluation of all existing data for efficacy and safety. That is well above the 2-3 experts that typically review science papers for peer reviewed publications. The EUA approval for each vaccine was based on data from about 40,000 subjects enrolled in the late stage clinical trials. Since then, millions more people have been vaccinated and their data continues to be collected and reviewed. Recent reports of this "real world" data continue to support the great safety and efficacy of the vaccines.
  • Some vaccines are better than others. The Pfizer and Moderna mRNA vaccines, which were the first tested and approved, showed ~95% efficacy, while the Adenovirus-based Johnson & Johnson vaccine, which was later tested and approved, only showed around 70% efficacy. So, shouldn’t we favor the Pfizer and Moderna vaccines? No. All the currently approved vaccines, including the J&J one, are very effective. And it is impossible to compare the relative efficacy of different vaccines from data obtained in separate trials. In order to gain an accurate comparison of different vaccines, they need to be tested in head-to-head, controlled trials in order to assure that similar patient populations are being tested against the same viral variant. For example, the Pfizer and Moderna vaccines were tested before we noticed viral variants that seem to be more infectious than the original virus. And neither company tested their vaccines in South Africa where one of the more infectious variants is rampant. In contrast, J&J began testing their vaccine after the variants began spreading around the world, and they also tested their vaccine in South Africa. This means that the Pfizer/Moderna vaccines were tested against different strains of the virus than the J&J vaccine, which confounds comparing their relative efficacy.
  • Bill Gates is promoting vaccines so he can inject us with microchips to track us. [big sigh]…Yeah, and one of the America’s Frontline Doctors, a group that claims hydroxychloroquine can cure COVID-19, said there is alien DNA in some of our medicines. I don’t waste my time with tinfoil-hat comments.
  • The vaccines cause infertility. This is based on bunk-science that began circulating last December. That rumor was solidly debunked by several sources, but the meme has been repackaged into new messages about de-population strategies. I give this the same attention I give to the silly notion that Bill Gates is trying to use the vaccines to microchip us. The vaccines do not cause infertility.

But, what about nursing mothers? Will the vaccines affect their babies? The answer is yes, but in a good way. Since babies are born with a very immature immune system, their first line of defense against pathogens comes from their mother’s antibodies that cross the placenta and that are found in mother’s milk. This “passive immunity” is an important first line of immune defense for newborns. Lactating women who have been vaccinated do show anti-CoV-2 antibodies in their milk, which provides the newborns with a temporary defense against the virus. That is a good thing.

  • The AstraZeneca vaccine causes blood clots. Over the past few weeks, 25 patients in Europe, almost all women under the age of 55, who received the AstraZeneca vaccine developed rare blood clots and nine died. The European Medicines Academy (EMA) met to review the data and found that overall clotting in vaccine recipients was less than in the general unvaccinated population. However, there are different clinical types of blood clotting problems, and for two very, very rare types, it was expected that ~2 clotting cases would arise by chance out of the ~20 million vaccinated people. But, 17 cases were reported. This is the kind of adverse event pattern that public health officials look for, as I described above. Again, exercising an abundance of caution, more than 20 European countries paused using the vaccine. However, within a week, the WHO and the EMA had reviewed the data and found that the extremely rare risk of vaccine-associated blood clots was significantly less than the risk of serious health problems from COVID-19 disease and advised that the vaccine be continued.

Final words. The disinformation about the anti-CoV-2 vaccines is disheartening, but seems to have been spawned by the roundly discredited claims by Dr. Andrew Wakefield a few years ago that the MMR vaccine was responsible for autism in kids. For that fraudulent reporting, Dr. Wakefield's paper was retracted and his medical license was taken away. Sadly, the damage was already done and continues today against all vaccines. Vaccines are one of the greatest health protection tools in the healthcare tool box and the naysayers are indeed killing people with their illogical and emotional appeals that are bereft of facts. How to counter such disinformation was a topic in a very recent article in Scientific American. What they recommend is beyond the scope of this post, but I hope that my presentation of the facts and reasoned criticism of anti-vax rhetoric is a step in that direction.


In The Midst Of The Vaccine Frenzy, Let’s Not Forget Drugs

Why drugs? While there is palpable excitement over the great success of several vaccines against the CoV-2 virus, companies around the world also have been developing new anti-coronavirus drugs to treat infections. As of March 5, the Milken Institute tracker reports that 251 vaccines are still in development, and 323 anti-viral drugs also remain under development.

While vaccines have dominated our thoughts in recent weeks, drugs can still play a very important role too. For example, even though we have vaccines for influenza, we also have the drug Tamiflu that shortens and reduces the severity of the flu. The drug is useful when we guess wrong about the strains of flu to vaccinate against each year. It also is used as prophylaxis for people working with the flu virus in clinical and research labs since they often work with flu strains that are not included in the annual vaccines. Also, while we have not been able to develop vaccines against hepatitis C or HIV, due to the quirkiness of those viruses, we have been able to take advantage of their biochemical quirks to develop drugs that now cure hepatitis C and that have turned HIV into a manageable and mild chronic problem rather than a death sentence.

All of this begs two questions; why would vaccines be needed if we had an effective drug against the virus, and why would a drug be needed if we had an effective vaccine against the virus? The answer has to do with the difference between prevention vs treatment. Prevention (i.e., vaccination) is ideal, but it takes time to develop vaccines to novel pathogens; hence, the value of an effective anti-coronavirus  drug to treat novel species of the virus that will arise in the future. Treatment (i.e, with a drug) also is good, but it still is better to prevent disease than to respond to it after you get sick.

So, there definitely remains a significant role for an effective anti-coronavirus drug even while we have successful vaccines. First, some people cannot be vaccinated or they have a compromised immune system that would render a vaccine ineffective. These people need an effective anti-viral drug. Second, as we have seen over the last decade with SARS, MERS, and now CoV-2 and its variants, deadly coronaviruses are popping up that require a swift response by public health folks. Even though the vaccines to CoV-2 were developed in record time, the virus still killed a couple million people around the world and caused untold long-term health problems in millions more before we had the vaccines. Furthermore, the current vaccines very likely will not be effective against the next species of coronavirus that visits us. Current vaccines also might show reduced effectiveness against newly arising CoV-2 variants. In fact, the AstraZeneca vaccine has proven so ineffective against a novel CoV-2 strain that arose in South Africa, that that country no longer uses it. Therefore, having a drug that can be quickly distributed to meet a new coronavirus threat would go a long way to protect us against future outbreaks while vaccines are being developed.

The new anti-viral drugs: More than a year into the pandemic, we have very limited drug options. Hydroxychloroquine showed early promise, but controlled clinical trials showed it to be a bust, as was ivermectin, which the FDA recently disapproved for COVID-19 patients. Only remdesivir has been authorized for use in COVID-19 patients, and it only provides modest benefit in hospitalized patients, reducing their stays by a couple of days. However, recent encouraging, but preliminary, results suggest an effective anti-coronavirus drug might have been found. The pill, molnupiravir, which is being developed by Ridgeback Biotherapeutics and Merck, significantly reduced infectious virus in 182 subjects in a phase 2 clinical trial. After five days of treatment, no virus was detected in any of the treated volunteers, while subjects who received a placebo did show virus. The drug interferes with the biochemistry involved in viral reproduction inside cells, therefore it prevents viral spread. Further study of the new drug is under way.

And four other potential anti-viral drugs are in mid-to-late stage trials at NIH under the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) program. ACTIV is a public-private partnership program to coordinate research strategy that prioritizes and speeds development of promising COVID-19 treatments and vaccines, and was launched on August 4, 2020. Like the vaccines, these new antiviral drugs are being developed in record time.

The drugs include SNG001 developed by Synairgen; it is an inhalable beta interferon delivered by nebulizer. Beta interferon is a cytokine produced by virally infected cells as a first line defense against viral replication. There also is AZD7442, a long-acting monoclonal antibody combination (AstraZeneca), and Camostat mesilate, an orally administered enzyme inhibitor designed to block CoV-2 from entering cells (Sagent Pharmaceuticals). 

Eli Lilly has also reported positive results with a combination of two antibody drugs, bamlanivimab and etesevimab (who comes up with these names?), that cut COVID-19 hospitalizations and deaths by 70% in recently diagnosed patients. These are anti-CoV-2 antibodies produced in the laboratory and work by mimicking the body’s immune system to give infected patients a head start fighting the disease while their natural immune systems ramp up to deal with a new pathogen. These also were developed as part of the ACTIV program and have been approved by the FDA to treat mild to moderate COVID-19 in people at high risk for severe disease. The feds have purchased large quantities of these Lilly antibody drugs and is making them available to qualified patients at no cost.  Meanwhile, on January 5, 2021 Durham, NC biotech company, Brii Biosciences, launched an ACTIV study on two other investigational lab-produced antibodies designed to neutralize the CoV-2 virus

That leaves a bit over 300 more investigational anti-coronavirus drugs to go.


One Shot Is Effective And The Vax Does Not Need To Be Stored At Ultra-Cold Temperatures

The mRNA Covid-19 vaccine developed by Pfizer and BioNTech generates robust immunity 2-4 weeks after one dose and can be stored in ordinary freezers instead of at ultracold temperatures as previously believed, according to new studies conducted by the Israeli Sheba Medical Center and published in the Lancet medical journal.

The Phase 3 trials completed in December only assessed the efficacy of the first shot two weeks after it was given. This showed that at two weeks, a single dose was about 52% effective. However, the recent study assessed the vaccines efficacy 2-4 weeks after the single shot. This showed that that the vaccine is 85% effective in preventing symptomatic disease. That is impressive. The second shot adds an additional 10% protection.

Learning that a single shot approaches the efficacy of the two-dose regimen supports spreading the first dose as widely as possible around the world and delaying the second shot. This strategy would ensure that more people around the world would be protected before the second shot was rolled out. The UK has adopted this approach and there is some support for it in the US. However, the FDA and Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, are not budging from the two shot regimen. The argument is that adding the second shot might lead to a more durable immune response

Your humble blogger believes that this strategy is a mistake. It seems more prudent to get the vaccine out to as many people as possible as soon as possible, especially if the second dose only adds 10% additional protection to individuals.

In separate news, research also showed that the Pfizer vaccine can be safely stored and transported at temperatures found in your freezer, rather than the ultra-cold temperatures as first believed. This greatly simplifies the logistics of delivering the virus around the world. No longer needed are the sophisticated ultra-cold freezers that are not often found in the third world, or even in your local pharmacy or clinic. Simple freezers, like the one you have your home will suffice, enabling ordinary pharmacies and clinics to handle the vax, thereby facilitating its distribution.

Just don't confuse the vaccines with the ice cream.

 


Some People Worry About The Vaccines Because They Were Developed So Quickly

A poll published by Gallup in early August found that 35% of surveyed Americans would decline a Covid-19 shot offered to them at no cost. I have seen other studies that say 50% of Americans will not get the vaccine. And on social media sites I have seen discussion and comments about why folks are so reticent to get the vaccine. Let me address the concerns.

1) Problem: People will not take a vaccine pushed out by Trump. Nancy Pelosi and Chuck Schumer are the more prominent members of this cadre. Answer: Well, Trump has had nothing to do with the vaccine development. The two leading vaccines now available are based on RNA vaccine technology that is a decade old. In other words, the technology was being developed way before Trump had presidential aspirations. Also, the Pfizer vaccine was developed in the UK using technology from a German biotech company and was developed without any US dollars. Trump did set up Operation Warp Speed to produce and disseminate a vaccine quickly, but the Pfizer vaccine’s share of that initiative is only a four star Army general, Gus Parna, who is overseeing the enormous logistics of getting a few hundred million people vaccinated. Trump’s fingerprint on all that is negligible.

2) Problem: The vaccine was rolled out too fast for comfort. Answer: As I wrote above, the RNA vaccines are based on technology platforms that are at least a decade old. All the companies needed to do was take a short CoV-2 genome sequence and add it to that well developed platform then test it. With a raging pandemic, the vax testing went quickly—when several thousands of people get infected every day, the results of a test vaccine come quickly. Similar vaccines were being developed for the earlier coronaviruses, SARS and MERS, but both of those pandemics fizzled out before enough data about the vaccines could be collected. Those platforms were repurposed to accommodate the SARS-CoV-2  virus. During the several months of testing, tens of thousands of people were given the vaccines and adequate efficacy and safety data were rapidly gathered. Since the vaccines were approved, a few million people around the world have been vaccinated and that larger sample simply confirms the data from the clinical trials. The vaccines are safe and effective.

Keep in mind, every year we roll out new flu vaccines in just a few months and they are safe. This vaccine has been adequately tested.

3) Problem: The RNA vaccines can alter your cellular DNA. Answer: Total bull scat. There is no way that the short stretch of the virus’ RNA genome that is used in the two leading vaccines can interfere with cell DNA. That is biologically impossible. Having said that, let me elaborate. There is a family of RNA viruses, called lentivirus, that can mess with your DNA. The lentivirus family includes HIV, human T cell leukemia virus, and several animal viruses that cause cancer. However, the unique thing about lentiviruses is that their genome carries a gene that encodes the enzyme, reverse transcriptase, which copies RNA into DNA allowing it to insert randomly into cellular genomes. Two of my science mentors and friends, David Baltimore and Howard Temin, shared the Nobel Prize for discovering reverse transcriptase. Most RNA viruses, like flu and coronaviruses do not express reverse transcriptase, so they do not affect cellular genomes. It is biologically impossible for the Pfizer and Moderna vaccines to alter your cells’ DNA.

4) Problem: The vaccines will infect you with the virus. Answer: Balderdash! The RNA vaccines are not produced using any living microorganism. A short stretch of DNA is tethered to insoluble beads and used to produce copies of a short RNA sequence that will produce the viral spike protein. The insoluble DNA templates are easily separated from the RNA that remains in solution, and the RNA is then encapsulated in lipid nanoparticles. That is what is injected. After injection, the lipid nanoparticles fuse with lipid cell membranes to empty the encapsulated RNA into the cells. Then normal cell machinery takes over producing the spike protein, which generates an immune response and immune memory that protects you from subsequent infection. The vaccine RNA is gone in about two days.

5) Problem: We need several years of data to be assured of the safety of the vaccine. And we do not know how the vaccine will interact with other drugs many people take. Answer: Wrong. Vaccines are not drugs and do not interact with drugs you might take. And since vaccines are just one or two shots, and not taken chronically like drugs, long term problems are not a concern. I challenge any naysayer to name one long term health problem caused by vaccines.

6) Problem: Vaccines cause allergic reactions. Answer: Some do, but that risk is nothing compared to the risk of serious consequences of getting the disease that the vaccine prevents. The FDA and other regulatory agencies weigh these risk factors and the vaccines that are approved come out way on top. Such reactions can occur with any vaccine, but are extremely rare—about one per 1 million doses.

There have been very few allergic problems with the CoV-2 vaccines and that problem has been linked to polyethylene glycol (PEG), a component of the lipid nanoparticles that carry the RNA sequence. PEGs are also used in everyday products such as toothpaste and shampoo as thickeners, solvents, softeners, and moisture carriers, and they have been used as a laxative for decades. So, most of us have been exposed to PEGs, but very few of has have a problem with them.

Endnote: As published in these pages in late October, there are several examples of vaccine production errors that led to tragic consequences. In 1955, the Salk polio vaccine was rushed into production just hours after it was approved. This was an inactivated virus, which means that live virus was grown, then killed, then injected. Some lots from one of the manufacturers, Cutter Laboratories, were not fully inactivated and some patients received injections of live virus leading to tragic results. Similar production errors have led to people being infected with live measles virus, and respiratory syncytial virus. In 1976, an H1N1 flu that was similar to the 1918 Spanish flu reached pandemic stage and we rushed out a vaccine that was associated with a spike in the very rare Guillaume Barre disease (GBD), which is a type of paralysis. It is thought that the rushed vaccine somehow caused the small, but significant spike in the disease in fewer than 500 patients across the country. It is not known how the vaccine was related to GBD.

Note: your humble blogger was a college student and working in a hospital physical therapy department at the time, and worked with two GBD patients.

Those problems using inactivated virus vaccines are very rare and have not arisen in over 40 years. Since the CoV-2 RNA vaccines do not use any live microorganisms, this will not be a problem with the vaccines.

I will willingly get mine as soon as it is offered. How about you?


A Third Vaccine Also Shows Success!

Two RNA vaccines developed and produced by Pfizer/BioNTech and Moderna/NIH have already reported highly significant protection against SARS-CoV-2 with negligible side effects. The Pfizer vaccine has been submitted to the FDA for approval, which should be quickly forthcoming. Moderna will soon submit its vaccine for FDA approval.

Now, a third and different type of two-shot vaccine developed by the UK’s AstraZeneca and the University of Oxford also reports 90% efficacy. It also showed minimal adverse effects that are expected from the immune reaction to any vaccine. Unlike the RNA vaccines, this one is a crippled adenovirus engineered to express the CoV-2 spike protein and offers some advantages over the RNA vaccines. First, it can be produced and marketed at a fraction of the cost of the RNA vaccines. Second, it only needs refrigeration storage, not a freezer like the Moderna vaccine, and not an ultracold freezer like the Pfizer vaccine requires. These advantages mean that this vaccine will be more readily available for third-world countries that do not have freezer storage capability. Also, AstraZeneca plans to produce its vaccine in multiple countries, from India to Brazil to Japan and to Australia, and beyond which will facilitate its international distribution.  

Getting a vaccine out to the several billion people around the world is a daunting challenge. Having multiple vaccines produced in various sites around the world should facilitate the distribution to all countries. A global program called Covax has an ambitious effort to deploy vaccines around the world, getting dozens of countries to join and securing deals for 700 million doses so far. AstraZeneca has agreed to supply the initiative, while a collaboration including the Serum Institute of India agreed to accelerate the production of the AstraZeneca or, soon to come, Novavax shots for low- and middle-income nations, priced at only $3 per dose. Another Covax pact with pharma companies Sanofi and GlaxoSmithKline Plc, which are developing their own vaccines, followed last month. The program, led by the World Health Organization, the Coalition for Epidemic Preparedness Innovations, and Gavi, the Vaccine Alliance, expects more deals in the coming weeks. Pfizer/BioNTech, along with Moderna/NIH, are also in talks with Covax.

AstraZeneca/Oxford has easily been the most active company in reaching supply accords around the world. It has assembled an unprecedented global network of manufacturing and distribution partners, and has promised to provide 3.2 billion doses of its vax. More than 50 lower- and middle-income countries in regions including Latin America, Africa, the Middle East, Asia and Eastern Europe would receive AstraZeneca/Oxford’s shot, which will be provided at cost during the current pandemic. The company is poised to be the dominant vaccine supplier to the developing world and it is forgoing any profit to do so.

Trial results for other vaccines produced by Novavax Inc. and Johnson and Johnson are expected soon. The Milken Institute tracks a total of 199 vaccines in development around the world. That means we can soon expect results from 194 more vaccines.

A final note: Some folks with a conspiratorial mindset have pointed out that these positive vaccine results presented just after the November 3rd US election is evidence that the election was rigged. They assume that the vaccine results were delayed in order to prevent giving Trump a bump. But, these folks have to explain why and how German and British pharma and biotech companies, and universities, which had no input from the US, were involved in that conspiracy.

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Pfizer Applies For FDA Approval

Pfizer announced that today it will seek approval for its anti-CoV-2 vaccine. If approved, the vaccine can be distributed as early as December. Given the urgency, the FDA is expected to move quickly.

The final numbers, released last Wednesday, showed that of the 170 subjects in the trial who caught COVID-19, 162 had received the placebo, meaning that the vaccine was 95% effective. It also was 94% effective in people 65 and older. Nine of the 10 subjects who came down with severe COVID-19 had received the placebo, meaning that the vaccine protects against severe disease.

This is a momentous vaccine. It will be the first RNA vaccine and, by far, the fastest to be developed and distributed, which will revolutionize vaccinology. This moved rapidly for several reasons. 1) The RNA vaccine platform had already been developed and it was just a matter of inserting the genome sequence for the viral spike protein into it. 2) RNA vaccine technology greatly speeds vax development since it completely avoids the need to grow massive amounts of virus iteslf. 3) Genome sequencing is now done very rapidly. The Chinese published the CoV-2 genome sequence in just a few weeks after the new virus was identified. 4) Pfizer began mass production of the vaccine while it was still in the experimental stage and not yet approved, thereby eliminating the typical delay required to ramp up production capability. 5) Trump’s Operation Warp Speed pre-planned for the massive storage and distribution effort that will be needed so that as soon as approval is granted, the already manufactured vaccine can immediately be distributed.

After approval, vaccine for about 25 million people will be immediately available for distribution and the US is scheduled to receive half of that. 1.3 billion doses are expected to be produced next year, which will enough to vaccinate 650 million people. In the US, it is likely that the first doses will go to health-care workers, followed by those at high risk, people in nursing homes, and prisoners. The general public probably will not get access until the spring or summer. The US has agreed to pay Pfizer and BioNTech nearly $2 billion for 100 million doses, enough to vaccinate 50 million people at no charge to them.

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