Omicron And My Best Imperfect Understanding Of Where We Sit With Vaccine Efficacy

With A Primer In Basic Immunology

I’d like to start by saying that it is very difficult to sort through the data that is being presented, and it is exceptionally difficult to do so with Omicron. This is of course because we have very few studies at this point that really look at it. It’s a new variant, and the rules are clearly a little bit different. I am going to do my best to explain where we are. Before that however, I’m going to give another basic primer in immunology. This is going to be written as simplistically as I can, because it is going to be important as we move forward.

This is not official medical advice. It is my best generalized interpretation of data. You should talk with your doctor when making individual health decisions.

Big Picture Immunology

When your body encounters something foreign, a whole host of things happen. You will generate responses across multiple systems in the body. There are checks and balances that attempt to scale those responses to the actual threat. There are risks and benefits to each response.

Two Different Immune Systems

Our immune system as humans is really two different systems. The first is called the Innate Immune System, and it is more primitive. It is also a generalized system that operates whether you’ve seen the threat before or not. The second is called the adaptive immune system, and it is a system that targets specific threats.

Innate Immune System

Some of the pieces of this part of the system we take for granted. Our skin for example is part of our innate immunity, keeping infectious agents out of our tissues. The acid in your stomach is part of this immune system There are a host of cells involved in this part of the immune system as well. These generally identify viruses, bacteria, parasites, and even non-threatening agents like pollen that don’t belong to our bodies.

The majority of threats that you encounter are fought off through innate immunity. It is likely that the majority of Covid exposures are fought off through innate immunity. No antibodies. There may be no immune memory at all. The invader may be neutralized by circulating immune cells or even repelled by skin and mucous.

Adaptive Immune System

While the innate immune system is more utilized part of our overall immunity, this system is the one that gets all of the press. The adaptive immune system learns to recognize specific threats, and it then targets those threats. For anyone following Covid, we frequently hear about antibodies and T cells. Both of these are part of the adaptive immune system.

When a cell is invaded by a virus, proteins from that virus are expressed on the surface of certain types of cells. The body recognizes those proteins and shares that information through a series of mechanisms with a number of undifferentiated immune cells in our bone marrow. Those cells subsequently produce two different types of immunity. There is cellular immunity (mediated by T cells) and humeral immunity (mediated by antibodies).

We develop killer T cells that go out and directly destroy cells that are infected by the virus. We develop T cells with memory function that produce new Killer T cells. We also produce Plasma cells that create antibodies. Antibodies bind to viruses and then signal parts of the innate immune system to come and get them. This is commonly done through a cell called a macrophage. The body also creates Memory B Cells. These cells produce new Plasma cells when necessary.

Even antibodies come in different types. The three most relevant to the conversation here are IgM, IgG, and IgA.

Antibody Types

We usually produce IgM first. As the body fine tunes its’ response, we see IgG. IgA specifically lives on mucosal surfaces. IgG does encounter those surfaces, but less efficiently.

What Happens When You Encounter Covid

A lot of your Covid encounters probably result in nothing. The virus sits harmlessly on your skin or hits your nasal passages in such small volumes that you keep it at bay with some mucous. I’m going to talk about the times that it goes beyond that.

SARS-CoV-2 infects cells through a receptor called ACE-2. These infected cells turn in to factories that then produce more SARS-CoV-2 virus and makes you sick with Covid. The fight is now on. Some of these invaders will hit immune cells that present the foreign protein to the immune system. The immune system will then realize that there is an invader present and try and wipe out foreign proteins and neutralize cells that are producing foreign proteins.

At this stage, your body hasn’t actually recognized SARS-CoV-2, but rather it has simply identified that something isn’t right. This could be any virus. It could even be something that isn’t a virus.

Nevertheless, you are trying to neutralize it. In many mild cases, I suspect it ends here. The body neutralizes the virus before it ever really gains a foothold throughout the body. Young and healthy people have strong innate immune defenses in most cases. They may simply keep the virus at bay in the respiratory tract.

For some however, the virus will work its way deeper in to the body and utilize the blood vessels as a highway to get to other places within the body. This is called viremia. Most people who die of Covid develop viremia.

Your body will engage a number of innate immune system defenses as this occurs. Fever is more likely (and fever is an innate immune defense). You will release pro-inflammatory chemicals that tell your body that you are fighting a real war. Some of this can actually harm the body, but the risk of the virus now exceeds the risk of that inflammatory response.

Meanwhile, the adaptive immune system has likely been hard at work trying to sort out what the virus actually is. If you’ve had a prior infection with SARS-CoV-2, it will recognize the proteins and start producing plasma cells and Killer T cells that can go take it out. This will happen over the first 1-4 days. It will happen even if you don’t have any residual circulating antibodies.

Now, if you’ve never been infected, your body takes longer… a lot longer. You probably won’t mount a solid adaptive immune response for 10-14 days. If your innate immune system becomes overwhelmed during this time period, you can become critically ill. Sometimes the virus is widespread enough at this stage, that even with the adaptive immune response, it’s not enough. In some cases, the inflammation from fighting the virus may actually lead to blood clots or organ failure that actually makes thing worse.

Vaccination And Prior Infection

For those that survive an infection, the body has now had a chance to make those Memory B and T cells. If the body encounters the virus again, those cells will leap in to action, producing antibodies and Killer T cells. If the infection was recent, there will likely still be antibodies circulating around, although we usually stop producing as many when the threat is gone. Some people will keep them around forever in lower numbers. Some people will see the antibody numbers “titer” go toward zero. Most of those people still have immune memory. T cells tend to last longer, but do also decline in number.

For those with a prior infection, we produce antibodies to lots of different proteins on the virus. The S or spike protein tends to be the target of antibodies. The nucleocapsid protein tends to be the ultimate target of T cells, but we produce antibodies and T cells that recognize both.

The idea behind vaccination in general is to produce the immune memory before you’ve ever had the infection. You are ready to fight the virus with the innate immune response right away, rather than waiting 10-14 days. It is notable that all vaccines available in the US right now generate isolated immunity to the spike protein only from the original viral strain from Wuhan. This means that immunity from an infection versus a vaccine is different.

Those who are vaccinated after a prior infection do seem to stimulate an immune response again, and this does seem to enhance the ability to neutralize the virus again in the short term. It is notable that we can see crossover immunity between similar proteins, and that is why vaccines and prior infections still impact other variants that are slightly different. Those who are vaccinated don’t produce significant IgA, as the virus was never on their mucosal surfaces.

Infection Can Still Spread Without Viremia

I’ll briefly mention what I said before when it comes to a lot of respiratory viruses. These viruses can replicate in the respiratory tract and spread to others before they encounter antibodies. Antibodies will often not prevent spread of these viruses. Viruses that require a systemic infection to spread are said to have obligate viremia. If one doesn’t have IgA, unless IgG levels are VERY high, the virus will likely still be able to spread to others in a highly resistant individual.

Three Risks With Vaccination

I want to be clear that I am NOT saying that we have identified these risks specifically with Covid vaccination. These risks exist with any type of vaccination, but I can also state that we haven’t definitively ruled out the ability for them to occur.

Antibody Dependent Enhancement (ADE)

The good news, is that this complication is the least likely to be true based on current Covid data. It really is unlikely. With ADE, the antibody binds to the viral protein, but not completely. It fails to neutralize the virus. The macrophages come to destroy the protein, and in doing so, allow it in to the cell. As the virus isn’t neutralized, it uses the antibody as a trojan horse to get in to the cell and then attacks the macrophage.

In this case, the antibodies actually help the virus attack cells. Cases of ADE usually produce more severe disease. We have not seen more severe disease after vaccination, so it is unlikely we are seeing ADE from Covid. We have seen some evidence in petri dishes, but that hasn’t appeared to translate to real life.

Original Antigenic Sin

This remains possible, and I’d argue from some of the UK data recently that is quite possible. In this case, the body generates an immune response that is effective, but less perfect than the response one generates to the actual infection. When the body encounters the virus, it does neutralize it, but not as effectively as it would after a natural infection. Because the original response is burned in to immune memory, the body maintains the less perfect response indefinitely. This can stop the most severe disease, but may leave an imperfect immune response indefinitely.

We need more time to know whether this is happening or not. It is important to note that this risk occurs when someone is vaccinated before being infected. If someone is vaccinated after being infected, the original exposure is to the virus, not the vaccine, and thus this is unlikely to occur.

Autoimmunity

This is where the body becomes confused and identifies itself as the enemy. There are lots of autoimmune conditions from Psoriasis to Multiple Sclerosis, from Rheumatoid Arthritis to Lupus. These conditions don’t have to be associated with vaccination. They can also occur after infections. They become progressively more likely in the setting of substantial inflammation, as the body basically makes an error in a high stress setting. Really high titers may cross react with the body as well.

We really won’t know with certainty whether this is happening with any vaccine for a long time. The closer the viral proteins are to the body’s proteins, the more likely it is to occur. It is not impossible that the rare VITT and not so incredibly rare myocarditis reactions we see after vaccination are related to autoimmunity. VITT is more likely immune mediated than myocarditis, but it is possible for both.

Vaccination and Omicron

I’m going to break this down in to three sections. In the first I am going to talk about how effective it seems to be. I am going to discuss the good and the bad. I am then going to talk about myocarditis. Finally, I am going to talk about risks of uncertain significance.

How Effective Is Vaccination?

I am going to attach links to some studies that support the points that I’m going to make here:

https://www.nejm.org/doi/full/10.1056/NEJMoa2115926?fbclid=IwAR1EmBu_CAGbdHfkJdzrZiGOwtxDDkT_V4ran93C-HKgmzCrZ-K2fNNhs-s#.Ych98zM3SOU.facebook

https://www.medrxiv.org/content/10.1101/2021.12.04.21267114v1.full.pdf?fbclid=IwAR2uBTK6PCBJK95nAOSP5Pr3B2U-o7E8qLx86GmJy6bot8-ShrBVHGLtr8o

https://www.medrxiv.org/content/10.1101/2021.12.20.21267966v3

https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3949410

Across all age groups, the rates of infection are substantially lower after vaccination than before during the acute period. With prior variants, vaccines reduced infections overall for 3 months universally. There is consistent and sustained relative reduction in severe illness across all age groups, although the effectiveness does appear to wane there as well. There is a reduction in mortality for those over 40. Mortality is so low in younger groups, that we cannot define a mortality benefit in those under 40.

It is important to note that the vaccines are not consistently showing a reduction in cases when one goes out for more than 6 months, with substantial declines in efficacy. It is also important to note that boosters do seem to restore protection against cases, but early indicators suggest that will also be transient. Vaccines are not showing substantial long term protection against infections. Period. They do appear to produce relative reductions in severe disease. Period.

It is notable that overall efficacy against infection is lower overall with Omicron. Even efficacy with boosters is somewhere along the lines of 50-70% depending on what you read and how you interpret it. If it feels like you know a whole lot of vaccinated and boosted people who recently had Covid, you aren’t alone. In fact, there appears to be very little association between local vaccination rates and the spread of Omicron. The efficacy, even interpreted generously, coupled to the rapid spread of Omicron means that we are unlikely to see sustained reductions in infections. The efficacy of boosters in this setting is also likely to be even shorter.

What is likely happening is that as the viral proteins mutate, the efficacy of individual antibodies is lower. Each new dose or booster causes a spike in antibodies. We require higher and higher titers of antibodies with each mutation to prevent infection. For those vaccinated alone, these are also primarily IgG, which require extremely high levels to neutralize an imperfectly matched protein in the respiratory tract. As they drop however to lower levels, the virus breaks through and causes infection. On the other hand, you still have immune memory, and that likely protects against more severe disease as your body produces new antibodies and T cells over 1-4 days. It is notable that everyone with a prior infection OR vaccination has some immune memory.

Now, two of the papers I’ve published do give us some clues that we should take seriously. At around 6-9 months, rates of infection appear to be HIGHER amongst vaccinated people than unvaccinated, although severe disease remains lower. Similarly, those vaccinated before an infection appear to have a higher rate of reinfection according to the UK paper than those vaccinated afterward.

In fact, if we were to develop a hierarchy of being really immune to Covid, it would be as follows:

Recovered and then vaccinated recently » Recovered and unvaccinated= Vaccinated and then recovered » Vaccinated alone unless recently boosted.

What this tells me from the data is that Natural infection provides more robust protection than vaccination against infection. All of the above become less robust with time. Vaccination may temporarily improve protection after a natural infection. Natural infection appears to be provide LESS effective protection from reinfection if it occurs after a vaccine.

That last sentence is a little weird. This is the place where I can’t rule out original antigenic sin. It could also very well be that those infected after vaccination have less robust immune systems or are more likely to be tested. The significance here to me remains unclear, but we shouldn’t ignore it. It requires further study.

So, vaccine efficacy appears to be relatively poor at preventing Omicron infection. It appears to be fairly robust at preventing severe disease. It appears to wane quickly in terms of preventing infection, but not severe disease. Vaccination as a strategy to prevent transmission will fail according to this data. Vaccination as a strategy to prevent severe disease appears viable. Vaccination as a strategy to prevent death in those over 40 appears viable. Vaccination cannot likely substantially reduce death in those under 40, as there aren’t enough people dying under 40. It may keep them out of the hospital. Vaccination as a strategy to prevent infections in the short term in those with a prior infection appears viable. Vaccination as a strategy to change long term outcomes in those who have recovered appears less so. There is some non-zero risk that vaccination may make one more prone to infections (although more likely to be mild) at some point down the road.

Let’s Talk About Myocarditis

This is clearly the most visible side effect from vaccines, and it clearly is targeted toward younger males overall. Peak risk appears to be in adolescence, but it remains elevated until 40. It is more likely after a second or third dose of vaccine. It is most common after Moderna. It appears less likely after an adenovirus vector vaccine than an mRNA vaccine.

The information presented here is supported by the following articles:

https://pubmed.ncbi.nlm.nih.gov/34849657/

https://www.medrxiv.org/content/10.1101/2021.12.23.21268276v1?fbclid=IwAR1Mm6NApUhi0uB4fF5F8mhMGz8PIVPcbYPtSRyKKRPVe_dZRyHZk8dgzKA

Here is a nice assessment consistent with my personal concerns in younger males:

UK Now Reports Myocarditis stratified by Age & Sex After Vaccine Or Sars-cov-2

We have heard a lot that the protection against Myocarditis with vaccination is better than the risk from the vaccine. In younger individuals, especially men, that is almost certainly not true. This is especially concerning given that this group is unlikely to have bad COVID outcomes, and in fact, as a group may see no higher risk of a bad outcome from Omicron than the flu.

Rates in adolescent males may be as high as greater than 1 in every 3,000 second doses. The UK paper also suggests that the rates after boosters may be HIGHER. This is important, because there seem to be dose dependent increases in myocarditis that continue to increase with subsequent doses. Rates are barely above baseline with the first dose.

The UK paper also suggests much lower rates of myocarditis after the AZ vaccine, which isn’t available to those under 18 in most of the world or in the US at all. We do have J&J, which may be similar, but isn’t studied here. The risk clearly appears highest with the mRNA vaccines. It is actually just very high with Moderna, which also has the higher dose between the two mRNA vaccines.

We need to approach vaccination in low risk males under 40 with special caution. This group usually does well with Covid. They appear to do even better with Omicron. There is no documented mortality benefit at all in this group. There may be a severe disease benefit in those without a prior infection. That percentage is getting smaller. If there is a benefit in those with prior infections, it is likely temporary.

We should really consider immediately halting Moderna vaccines for men under 40. This has already happened in some European countries. We need to be really careful with Pfizer (although rates are lower). As we discuss boosters with poor evidence in adolescents, it is important to note that this risk is still rising for an unclear benefit. Vaccinating teenage males is really a wild card, and there are many interpretations of the data at this point that it may actually cause increased harm. We also need to really consider testing alternative vaccine types on this age group. We didn’t see this rate of myocarditis with AZ vaccines. That means the myocarditis risk may in some way be related to mRNA vaccines themselves. Remember, we’ve never had a widespread rollout of mRNA vaccines before. That should be studied.

Other Risks

The following articles support the points made here:

https://www.jimmunol.org/content/jimmunol/207/10/2405.full.pdf?fbclid=IwAR0MNH2_iNZ4qLar41lEM-lGHlyI-l_qO91_6AQ9PqavxnHkccD6_CqlX9E

https://www.nature.com/articles/s41421-021-00329-3.pdf?fbclid=IwAR3p0jzUvzdYUq_nfSAn49LWX7zp3Be-GMzF0kuyCqUh-UWiVN10bJj_YgA

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab465/6279075?fbclid=IwAR1rVO3Fvi81mkB7DlYt2KVgvb9zO8dyukRyYgdMCPU5dQDOV46U5D-T3YQ

https://www.ahajournals.org/doi/10.1161/circ.144.suppl_1.10712

I want to be clear that this is all of uncertain significance. I am not saying that the above are clinically relevant. I am saying that we lack evidence yet to know whether they are.

It is now clear that when one is vaccinated with an mRNA vaccine that the spike protein leaves the area of the injection. It is clear that it widely circulates. This means that there is some risk associated with vaccination that would mimic what we would see from Covid Viremia. This isn’t a new idea. I frequently referred to vaccination as a controlled dose of a toxin to prevent an uncontrolled dose.

What we are seeing however is substantial alterations in physiology after vaccination. Inflammatory markers go up. Chronic diseases appear less well controlled. Markers of clotting and cardiac risk go up.

What does this all mean? I don’t know. I do think we should look at it more closely, and I lament the unwillingness to investigate it. There likely is SOME risk buried in all of this. I’m not sure we’ve captured the extent of that risk based on these studies alone. This is relevant enough that in low risk groups, we ought to assume that there is some downside that will reveal itself later that should be weighed against reductions in severe disease. In higher risk groups, it is unlikely that we will see a downside that exceeds current benefits, but as the vaccine becomes less effective, it’s remains relevant.

Putting It All Together

Vaccines reduce severe disease in those without a prior infection across the board and reduce death in those without a prior infection in those over 40. They reduce the likelihood of being infected temporarily. They do have side effects. I will continue to argue that we lack sufficient data to know whether they are a good idea in young people. I would argue that the data is sufficient that the harms exceed benefits for Moderna in young men. I would argue that the trends with myocarditis and transient nature of disease reduction with boosters make the value in young men questionable at best.

If you are high risk, you are still likely better off vaccinated. If you are moderate risk, you are still likely better off, although with a prior infection, the risk/benefit is less clear. Vaccines will NOT ultimately prevent transmission of Omicron. They are not effective enough. Even with a 100% vaccinated and booster rate, we would still see disease spread, and that spread would increase rapidly over just a few months as the ability to prevent disease waned. Using vaccines to control spread is a band aid at best, and ineffective at worst. It is also notable that in most of the country, anyone unvaccinated now would not have time to become vaccinated before an omicron exposure is likely to occur.

In my opinion, the most effective use of vaccines by current data would be to implement an initial series in those with no prior immunity and boosters in high risk groups who would benefit from even 1-3 months of reduced likelihood of infection.

The Big Picture

Below is a link to a news article that contains a link to a UK report about the risks associated with Omicron infection:

https://www.theguardian.com/world/2021/dec/22/risk-of-hospital-stay-40-lower-with-omicron-than-delta-uk-data-suggests

This is consistent with the data from my prior post in which the disease appears to be less virulent overall. In the above report, emergency room visits were down 25% amongst identified cases and hospitalizations were down 40-70%. It is notable that the South African data suggested an inpatient decline of 80%. It is also notable that the data there suggested that the average admission was less ill, less likely to require supplemental oxygen, and less likely to die overall. I say suggested, because I can’t state that with absolute certainty yet.

On the other hand, below you’ll find a link to a website that gives fairly up to date data on US cases:

https://covidactnow.org/?s=27551643

This does suggest rapid spread of the variant. If it seems that everyone that you know has Covid, you’re probably not crazy. Especially for those of us in NY, PA, FL, and most of the rest of the northeast, Omicron cases are absolutely exploding. Positivity rates in NY and FL are both around 20% at the time of this article. I think it’s also important to note that a lot of Omicron infections are prone to false negatives on common tests.

Another Reminder That Our Data Is Pretty Bad

Throughout the pandemic, our data has been pretty bad when it comes to actually understanding infections, hospitalizations, deaths, etc. It probably hasn’t been this bad since near the beginning of the pandemic. There aren’t enough tests for those who want them. A lot of tests are giving incorrect data. A lot of people are carrying the virus asymptomatically with uncertain infectious significance.

Due to false negative tests, it is likely that the true positivity rate (the percentage of people tested who actually have Omicron) is substantially higher. This means that there are likely places along the east coast of the United States that truly have 30 or 40% positivity rates. The last time we saw numbers like that were as part of the NYC outbreak in March of 2020. That was a time when we were capturing as low as 1 in 60 infections.

What We Can Infer From What We know

This means with a high likelihood that there are a number of areas of the country where one out of every 10 or 20 people is likely actively infected with Covid. In fact, exposure rates in Manhattan or Miami are probably virtually 100% for anyone who has been in public for any reason. The large majority of people likely don’t know it. A substantial portion may never know it.

We are likely to see a peak in the coming week or two (If we aren’t already in some places) on the east coast by virtue of the fact that infections were so high so quickly. That peak will be slower as you move west. Omicron has not surged as aggressively there yet. It will though. We are already seeing the early signs of it in essentially every state.

I’ve seen predictions of a peak for the nation at some point in mid-January. I suspect that won’t be far off under our current trajectory. Some places will be later or earlier. Over the next week or two, we are likely to have a really good understanding of the implications of this surge.

Risks and Benefits

The fast moving nature of Omicron coupled to lower rates of severe infection suggest the following:

1. This wave will likely be relatively shorter compared to some prior waves by virtue of widespread infection in a short period of time

2. On an individual level, an Omicron infection appears to be preferable to an infection by all prior versions of Covid. Early evidence really does suggest that in the average person, rates of hospitalization and maybe even death are somewhat in line with influenza on an individual level.

3. There remains real risk for some strain on healthcare systems by sheer volume. Even if 20% of prior numbers require hospitalization, and even if the disease is really no more dangerous than influenza to an infected individual, it is a lot of people being infected at the same time.

4. Crossover immunity against the Delta variant coupled to the evolutionary advantages held by Omicron means that there is a reasonable chance prior variants will be functionally eliminated by Omicron.

Number 4 above is actually good news. When this wave is over, there is certainly some likelihood that we will have one dominant variant to which almost everyone has some degree of immunity. It may be a little bit painful to get there.

Here is the article showing crossover immunity to Delta:

https://www.ahri.org/wp-content/uploads/2021/12/MEDRXIV-2021-268439v1-Sigal.pdf?fbclid=IwAR2TkOaD3POz6mUxBozxxnwA-4jC7woUsi4wLN65pEL2vMUt4rK-8tfP0hA

In Summary

We are likely to have the largest numbers of acute Covid infections from the entire pandemic over the next few weeks. Fortunately, they will on the average be much more mild. It is unlikely you will avoid Covid. You can still determine how you want to meet it. As we all make our personal choices, I hope this was informative in terms of helping understand the risks and benefits of those choices.