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September 2021

HIV And Coronaviruses: A Bad Combo

Africa is the continent least vaccinated for COVID-19 and it also has been where several CoV-2 variants have arisen: Beta in South Africa, most recently C.1.2 (not yet given a Greek letter designation) also from South Africa, and Eta in Nigeria. A possible reason for the appearance of these variants is because Africa is also home to the most immunocompromised people. HIV is common in Africa and tuberculosis is rampant on the continent.

One HIV-positive woman in South Africa was reported to carry active CoV-2 infection for 216 days, during which time it mutated 30 times according to Tulio de Oliveira, who runs gene-sequencing centers at two South African universities. This is concerning since South Africa has the world’s largest HIV epidemic. It is estimated to have 8.2 million people infected with HIV. While most of these take antiretroviral drugs, which keep the virus at bay, many do not. And neighboring countries, Botswana, Zimbabwe, and Eswatini also have very high HIV infection rates. The burden of HIV, TB and other chronic diseases is higher in these countries than in other countries around the world due to extreme poverty and poor health care for millions of Africans. When these people also become infected with CoV-2, they grow and shed the virus longer than someone with a good immune system and good health care. That means that the virus has longer to mutate in an infected, immunocompromised person.

In wealthier countries in the West, a rich debate is ongoing about whether to add another shot (booster) to already vaccinated people. One of the biggest arguments against this is that those booster vaccines are needed much more in poorer, and woefully under-vaccinated countries, such as those in Africa. The concern is that our boosters come at the expense of basic immunization of these impoverished countries, which facilitates the generation of troublesome viral variants. On the other hand, if CoV-2 is running rampant because the health care infrastructure in these countries is not up to delivering those vaccines, maybe it would be better making sure that richer countries are as protected as possible.

These are the proverbial two horns of a dilemma. Which horn would you choose?


The Differences Between The Moderna And Pfizer mRNA Vaccines

Since the vaccines rolled out, people, including me, have talked about the Pfizer and Moderna vaccines as simply being interchangeable versions of mRNA vaccine technology platforms. They both use part of the CoV-2 viral mRNA sequence to temporarily express parts of the viral spike protein on muscle cells in order to stimulate a protective immune response against the live virus. Since mRNA is very unstable and would quickly degrade if it were injected by itself, both vaccines encapsulate it in lipid nanoparticles, or liposomes, which both protects the mRNA and helps it fuse to cell membranes and insert the genetic material into the cells where it is translated into the protein. So, the Pfizer and Moderna technologies are very similar.  But they are not identical. At first blush, the differences appear subtle, but we are learning that they seem to manifest themselves in different, not-so-subtle biological ways. Let’s take a look at the how the vaccines differ.

The formulation: The lipid nanoparticles that carry the mRNA are a bit different between the Pfizer and Moderna vaccine platforms. While the exact formulations are proprietary intellectual property owned by each company, we do have a little bit of information about how they are similar and how they differ. Both platforms are concoctions of several different lipids designed to spontaneously assemble in aqueous solutions into small, “artificial cells” that encapsulate the mRNA payload. The lipids in both vaccines include polyethylene glycol (PEG), which can have multiple effects on the properties of lipid nanoparticles; they can affect particle size and particle stability. Certain PEG modifications can also prolong the blood circulation time of nanoparticles by reducing clearance of the liposomes by the kidneys and by scavenger immune cells called phagocytes.

The Pfizer vaccine also contains two proprietary lipids known as ALC-0315, and ALC-0159 as well as cholesterol, all in a very precise ratio. The Moderna vaccine platform consists of lipids that are not as well-known publically because the company is in litigation over the intellectual property with Arbutus, which developed the lipids that were licensed by Moderna.

Basically, viruses are naturally occurring liposomes encapsulating genetic material. The nanotechnology community has long been trying to create “artificial” virus-like nanoparticles that do not replicate or spread like a live virus in order to deliver fragile molecules, like mRNA, to cells for therapeutic reasons. Therefore, the goal of therapeutic liposomes is to create a virus-like lipid bilayer membrane (see figure) in order to deliver a drug or vaccine payload to cells. Mixing amphiphilic fatty acids, which are lipids where one end is water soluble (hydrophilic), while the other end is not (hydrophobic), in an aqueous solution allows them to spontaneously assemble into virus-like nanoparticles, or mini-cells. A water soluble payload (mRNA in this case) is captured in the central blue area and is protected by the outer lipid membrane. When these artificial cells bump into a live cell, the lipids on the two membranes fuse dumping the therapeutic payload into the cell’s cytoplasm.

There are endless combinations of amphiphilic lipids which can form such pseudo-cells, the properties of which can be modified depending on which lipids are used. For example, the selection of lipids used in both vaccines give the surface of the liposomes a mild positive charge, which facilitates their ability to stick to the negatively charged membranes of live cells.

What all this means is that the specific lipid formulation used in the Pfizer and Moderna vaccines affects the delivery of mRNA to cells, but we do not have enough detail to be able to suss the effects of the different liposome compositions on the efficacy of the vaccine. Those details mostly remain trade secrets. Liposome_scheme-en

lipid nanoparticle mimics a cell bilayer membrane

mRNA sequence. Both the Moderna and Pfizer vaccines use mRNA that encodes part of the spike protein of SARS-CoV-2, which sits on the surface of the virus and binds with the ACE2 receptor on the cell surfaces of many tissues. mRNA molecules are chains of four nucleosides arranged in a gene-specific sequence code that cells then translate into a specific protein. However, when a foreign mRNA is injected into a body, the mRNA itself can be recognized by the immune system and neutralized before it can enter a cell and express its cognate protein. For this reason, both the Pfizer and Moderna mRNA vaccines have been modified to incorporate a synthetic non-natural nucleoside, 1-methylpseudouridine, which reduces the ability of the immune system to recognize the foreign mRNA and improves its stability and expression of its protein.

The spike molecule consists of two protein subunits, the first of which is responsible for the initial binding with ACE2, while the second promotes the fusion between the virus and the cell membranes. The mRNA sequence incorporated into the Moderna vaccine, mRNA-1273, specifically encodes the pre-fusion form of the second spike protein subunit that is found on the surface of the virus before it binds to the ACE2 cell receptor. The mRNA sequence is modified to produce a spike protein with two amino-acid substitutions at positions 986 and 987 on the protein that help to keep it in the pre-fusion state. In contrast, the mRNA utilized by the Pfizer-BioNTech vaccine (BNT162) only encodes part of the spike protein on the first subunit that specifically binds to the ACE2 receptor. Thus, the two vaccines drive immunity to different parts of the spike protein molecule.

Perhaps more importantly, the dose of mRNA in the two vaccines differs. The Moderna vax delivers a 3-fold higher dose (100 mcg) of mRNA compared to the Pfizer vaccine (30 mcg). This  means that more spike protein antigen to stimulate an immune response is expressed from the Moderna shot.

What does it all mean? Initially, these differences in lipid composition, mRNA sequence, and mRNA dose do not seem to affect vaccine effectiveness. Both are extremely effective at protecting against COVID-19 within a few months after the second shot. But, over time, differences in the effectiveness of the vaccines are showing up.

Last month, the Mayo Clinic released a preprint of a large study of 645,109 patients after vaccination. This assessed the level of protection from infection in people vaccinated with the Moderna or Pfizer vaccines, or who were unvaccinated between January–July, 2021. Both vaccines continued to be very effective at preventing hospitalization, ICU admission, and death relative to unvaccinated people over the period of the study. However, prevention against mild to moderate COVID-19 was somewhat lower for both vaccines in July compared to January. Vaccine immunity faded a bit over that time. Importantly, the efficacy of the Pfizer vaccine faded faster over this time compared to the Moderna vaccine. A more recent CDC analysis of COVID-19 emergency room or urgent care visits for ~33,000 people between June-August 2021, when the Delta variant was predominant in the US, showed that overall the vaccines were 86% effective at protecting against serious COVID-19. But, vaccine efficacy for those who received the Moderna vaccine was 92%, while those receiving the Pfizer vax showed 77% protection.

Similar results were found in another study of 196 vaccinated elder nursing home residents in Canada. Compared to those who received the Moderna vaccine, residents who received the Pfizer shot mounted a 3.89-fold lower antibody response. A Belgium study published August 30, also found that the Moderna vaccine stimulated ~3 times the antibody response as the Pfizer vax. This study looked at 1,647 vaccinated workers at a Belgium hospital. Finally, a Qatar study largely found the same thing; that the Moderna vaccine stimulated a more robust antibody response.

What accounts for the different responses to the different vaccines over time? That is impossible to pinpoint at this time. It could be due to the higher dose of mRNA in the Moderna vaccine. The difference in response over time could also be due to the different mRNA sequences the vaccines contain, or due to the slight differences in the chemical composition of the lipid nanoparticles. Or, any combination of the above could drive quantitatively different immune responses.

Most importantly, though, both vaccines continue to work amazingly well against serious COVID disease, hospitalizations and death. Even while the more infectious Delta variant rages around the world in the face of slowly fading vaccine efficacy, about 95% of COVID-19 hospitalizations and deaths today are in unvaccinated people.

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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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