Category Archives: Antibody

Antibody Dependent Enhancement

All Articles, Antibody, Fatality Rate, Most Popular, Risk Factors, Treatments

Note, March 26th, 2022: The first part of this post was written on July 7th, 2020. Since that time, there has been evidence that appears contradictory in the ADE story. Reading the entire post will help you understand how ADE and COVID are related, but it is a complex and evolving issue, so things may still change.

Originally posted July 7th, 2020

I’m going to bring up an issue that I’ve been avoiding talking about for some time. I’ve been avoiding talking about it because it’s not a certainty, and also because the possibility will be scary for some. The reason I feel compelled to talk about it now is that many are having a hard time understanding why I am still so concerned about the virus when the fatality rate is low and dropping, and folks want to get back to normal life. I’m even hearing about young people having COVID parties in which people gather with a sick individual so they can all get infected and be immune from the virus thereafter.

Before I share this, I’ll also say that the medical community is doing a better job treating patients with COVID, and the disease is becoming more survivable. In addition, we now know a lot about how the virus is spread, and if a person wants to remain uninfected, they can do that, while still getting together with friends and family, and still working and getting on with life. You can be reasonably certain you will not get infected if you do the following:

1) Wear a mask or face covering in public. Avoid places with unmasked people.
2) Keep 6 ft away from others.
3) Avoid indoor gatherings, especially ones in which singing or shouting is likely.
4) Small outdoor gatherings are fine, even without masks, if everyone maintains a distance. Have guests bring their own food.
5) While many restaurants are open for limited indoor seating, I personally am still not comfortable eating indoors at a restaurant. I enjoy eating outdoors at restaurants, however.

Antibody Dependent Enhancement: Several years ago, scientists were developing a vaccine against Dengue Fever, a mosquito borne disease which causes debilitating joint pain in patients. Some time after trial vaccination, several vaccinated patients died suddenly of Dengue Fever. This became the most studied example of Antibody Dependent Enhancement (ADE). Normally, for the annual flu let’s say, a person gets infected by the flu, is sick for a few days, and the immune system develops a response by creating antibodies against that specific strain of the flu. If they are exposed again in a month, nothing will happen. If the patient is exposed to a different strain the following year, they may still get sick, but the antibodies they developed the year before may help them have less severe disease and recover more quickly. Part of the immune response is that some immune cells display antibodies on their surface to capture new invaders.

With Dengue and some other viruses, the first stages are normal. A person gets infected and develops a response. If they get re-infected a month later, nothing happens. But if they get infected with a slightly different strain months or years later, instead of being protected, the virus attaches to antibodies displayed on immune cells and uses the antibodies as a site of entry into the immune system. The immune system is quickly infected, and the patient has a more severe disease with the second infection. Some estimates are that disease may be 3-4 x more severe in these patients.

As it turns out, SARS-1, which arose in 2002, and MERS, which has small outbreaks every year, are both Coronaviruses and both appear to be able to use the ADE pathway. This raises the possibility that SARS-2, the current virus, can also use the ADE pathway. This means that a person infected for a second time with a different strain of SARS-2, or any other Coronavirus for that matter, may be at much higher risk for severe disease.

This is why I’m not in favor of pursuing herd immunity as a pathway out of this crisis, because it will prime people for ADE related problems if a similar strain should strike next year.

This is not a new idea. If you search for “ADE” or “Antibody Dependent Enhancement”, you will see many articles, some peer reviewed from respected journals, on the phenomena. Dr. Fauci has even referenced it using the term “enhancement” when talking about vaccine development.

Why haven’t the government public health departments been more open about this? They tend to make statements only based on what they can be reasonably certain of, which is why they have been so slow to react to many aspects of the current crisis.

Again, it’s not certain that ADE will play a role next year. It’s too early to know. I’m informing you of the possibility so you can make wise decisions for you and your family.

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Update: November 20, 2020

Since writing the above post, things have changed a little. There have been a handful of known cases of people being re-infected with SARS-2. In some of these patients, symptoms were worse, while in others, symptoms were less severe. In all of the well characterized cases, the 1st and 2nd strains that infected them were different, suggesting that it’s not a re-infection by the same strain, but a new infection by a different strain.

We’ve had at least 2 main strains in the US, SARS-2 which arrived in January or February, and a strain called D614G which probably arrived in April or May and likely caused the 2nd wave in June and July. The D614G strain is likely more infectious than the original SARS-2 strain, but is perhaps less virulent, since the fatality rate during the second wave appears to have been lower. In fact, there may have been several strains circulating around the world and the US for much of the pandemic.

How does this all relate to ADE? The fear with ADE is that a 2nd infection will cause worse symptoms than with the first infection. This may still be true. But we’ve had several circulating strains and so far, no real evidence the re-infections have universally been worse. So it appears for now that the ADE experiment is already going on, and that perhaps the phenomena will not have as great an impact as I feared. I am currently cautiously optimistic that ADE will not cause significant additional mortality.

This also has some impact on the vaccine discussion that is currently ongoing. If ADE will not have a significant impact, than the vaccine may be safer that I previously thought, and I have become cautiously optimistic about the success of the vaccine.

_________________________________________
Update: December 12th, 2020

More on ADE and Vaccines: Some potential very good news for me on the vaccine front. For months I’ve been warning about ADE, the phenomena that some viruses can be even more dangerous in a second infection than the first. Karen Parrott, a former colleague at Quest Diagnostics, often provides me with interesting COVID related stuff. This week she sent me a podcast featuring Paul Offit, the developer of the first Rotavirus vaccine and an author of many books on immunology and vaccine production. I am not an immunologist but he is. More importantly, he’s the first authoritative person that I’ve heard in the media speak at length on the ADE issue and how it relates to COVID. He claims in the attached clip (time stamped at 14:40) that the current vaccines do not appear to trigger the ADE pathway in animal models, and human trial subjects never displayed the signs that ADE was involved in secondary exposures. This difference from SARS-1 and MERS may be related to the fact the SARS-2 is much less virulent than these other 2 viruses.

This makes me more optimistic that the vaccine will be safe from an ADE perspective. I won’t be able to get the vaccine for some time, but I am more willing to get it now than ever before. Several physicians I know are eager to get it as soon as it is available. This is great news!

In the interest of full disclosure, I will point out the some patients receiving the vaccine the UK have experienced some injection site irritation, especially in those with allergies. This is actually somewhat normal for vaccines, and appears to pass within a few days.

Now that mRNA vaccines have been produced for the first time, future development of this new kind of vaccine should be even faster than this time!

________________________________________________
Update: April 13th 2021

ADE and the next SARS virus: I wanted to explain a little more about my continued concerns about ADE. As the pandemic progresses and we have numerous variants circulating around the world and the US, ADE does not appear to have had an impact on the current situation. This is certainly good news. If it did have an impact, we would be seeing additional deaths from the new variants, which we do not.

My continued concern comes because ADE impacts our ability to fight the NEXT virus. SARS viruses (SARS, MERS, SARS-2) have the ability to easily infect the immune systems of those previously infected with closely related but different strain of the virus. If a future strain of SARS comes out, let’s call it SARS-3 for now, ADE may become a big deal. I stress that this is only theoretical at this point. SARS was moderately infectious, but also very pathogenic, giving all known patients severe symptoms and killing 10%. It was actually less dangerous globally, since outbreaks tended to be detected early and quickly snuffed out. SARS-2 is highly infectious, but much less pathogenic. It’s greater global impact came from it’s very high infectiousness and very long incubation time, being passed even from pre-symptomatic patients. The tendency of all viruses is to become more infectious and less pathogenic over time, a pattern followed by SARS and SARS-2. If we have a SARS-3 someday, it will likely be even more infectious than SARS-2, but less pathogenic. On the other hand, MERS is more pathogenic than SARS, so this pattern doesn’t always follow. The next time another SARS coronavirus breaks out, we will need to be very careful initially until we understand the parameters of the new virus.

So what do you do if you had COVID or had a COVID vaccine if a SARS-3 comes out? If that happens, vaccine production will likely be much faster than this time. Be very careful with the virus initially, and get the new vaccine as soon as it is available to you, because you may be at greater risk for severe symptoms. I know some of this is confusing and counter-intuitive! Feel free to ask questions below!

Update: August 30th, 2021

Delta already using the ADE pathway? A doctor friend of mine sent me a pre-print paper from a lab in Japan. Please note, this is a pre-print paper and has not yet finished peer review! The paper describes experiments using antibodies derived from patients infected with the Wuhan strain, as well as with the Delta Variant. They then studied binding of these antibodies to artificial viruses. The paper argues that Delta variant viruses are less neutralized by vaccines against “wild-type” or Wuhan strain vaccines. While the “wild-type” antibodies against Wuhan can neutralize a region of the Delta Spike protein called the Receptor Binding Domain (RBD) (Figure 1C), other antibodies binding to another region of Delta Spike protein actually enhance infectivity. Figure 1D from the paper shows negative levels of “neutralization” for antibodies that bind the N-terminal domain of the Spike protein. The paper calls this “enhanced”. Yes, this is the ADE I’ve been talking about.

Figure 1 from Liu et al 2021.

They suggest that with rapid changes in COVID variants, a new version of Delta is going to be able to use the ADE pathway in the near future, when Wuhan era antibodies will no longer be able to neutralize a mutated Delta strain.

To sum that all up in simpler language, it basically says that Delta is more infectious because it is partially using the ADE method of infection. Future versions may be less prone to be neutralized by Wuhan antibodies, making them fully enhanced. If this happens, we may have more severe disease in those who get infected with this new enhanced Delta.

They conclude by saying a booster against the Wuhan strain will not be effective in improving protection from Delta, and that a new vaccine against Delta will be required.

The material in the paper may help to explain why we have been seeing lowering levels of vaccine effectiveness in some countries.

Just to be very clear, they are not saying that this new enhanced Delta exists now, just that it may exist in the future.

I will pay close attention to this issue. If you have already been vaccinated or had COVID, a new Delta vaccine will be your best defense against possible ADE arising from a possible enhanced Delta.

If an enhanced Delta arises, and you have had Wuhan COVID or a Wuhan vaccine, and you haven’t had Delta, then you may be at greater risk for severe disease.

If you have had COVID since July 2021, you are likely already immune to the Delta variant, and this will not be an issue for you.

I am fully aware this complicated. Also, the CDC has rarely if ever discussed this possibility, so unfortunately, most of the people you talk to about this will not believe it. I am sharing this with you so you can make wise decisions for you and your family.

Some companies are already working on Delta versions of the vaccine. If you have had the current vaccines, or had COVID, you should get the Delta vaccines as soon as they are available.

Of course, discuss your medical history with your doctor before making medical decisions.

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Updated: January 29th, 2022

The “Final” Verdict on Antibody Dependent Enhancement: As most of you know, ADE has been a major concern of mine from almost the beginning. I’m finally willing to give an assessment of how ADE impacted the pandemic. There were a smattering of cases in previously infected people who may have had more severe cases because of possible ADE, but not more than a smattering. It’s also becoming well acknowledged that Omicron infected everyone regardless of vaccination status and may have even preferentially infected vaccinated people. I know MANY people who are double vaxxed and boosted who got Omicron.

All that being said, I never saw any evidence that conclusively suggested that ADE was causing more severe symptoms because of natural or vaccine mediated immunity. In fact, even during Omicron, during which ADE was most likely to be operating, those with previous immunity clearly fared better than those without. Because I think Omicron is the death rattle of the pandemic, I’m willing to say that ADE never became the threat I was concerned about. For this reason, IF I didn’t already have natural immunity because of Omicron, I might actually get vaccinated IF I could find someone who would aspirate before injecting (see the post from earlier this week)!

I never saw any paper that dealt with the issue of ADE, not even a little. Those that mentioned it did so only in passing.
__________________________________
Updated March 25, 2022

Certain vaccinated individuals are more likely to be infected by Omicron than the unvaccinated:  A UK surveillance report shows that vaccine effectiveness against symptomatic Omicron infection goes from around 65% effective soon after 2 doses of vaccine, to around 5% 6 months later.  Protection from hospitalization goes down to just 35% after 6 months. These findings suggest that to maintain full protection against Omicron, a vaccinated person will need to get a booster every 3 to 6 months.

From UK Surveillance Report, March 17, 2022, Table 1b. Effectiveness of Pfizer vaccine at preventing symptomatic COVID infection after 2 doses, and after a Pfizer or Moderna booster.
From UK Surveillance Report, March 17, 2022, Table 2b. Effectiveness of Pfizer vaccine at preventing hospitalization after 2 doses, and after a Pfizer or Moderna booster.

In another finding from the report, people with 3 doses of vaccine are 3x more likely to be infected with Omicron than unvaccinated individuals.  This is the clearest evidence yet that Omicron may be using Antibody Dependent Enhancement (ADE) to infect people. The Lewnard et al paper from a few months ago has a similar finding.  For both studies, a certain number of vaccine doses are more likely to increase the chance of infection.  If viruses are using the ADE pathway, this effect would be explained more by the timing than by the number of doses per se.  For ADE to work, a person needs to have a mediocre immune response to an agent, not a strong or weak one. Since we know vaccine mediated immunity goes down over time, then a person becomes more likely to be reinfected as their immune response goes from strong to mediocre.

From UK Surveillance Report, March 17, 2022, Table 13. New case rates among UK residents with at least 3 doses of vaccine, and with no vaccination. Numbers are normalized for the percentage of people in each group.

So should you get a booster? Again, if you have risk factors like age, obesity or respiratory problems, you might want to get a booster every 3 – 6 months. Otherwise, you may choose instead to just take extra precautions as Omicron cases continue to fall in the US. If you choose to get a booster, ask them to aspirate before injection. Talk to your doctor when making medical decisions.

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More than ever, don’t fear, but be smart,
Erik


A selection of relevant papers:

ADE and it’s potential impact for SARS-2:ade-and-sars-2 Download



ADE in SARS-1:ADE and SARS-1 Download



Overlapping symptoms for SARS, MERS, and SARS-2:ade-sars-mers-sars-2-liu_et_al-2020-journal_of_medical_virology Download



Is COVID-19 receiving ADE from other coronaviruses?ADE_and_COVID Download



Possible mechanism for ADE:ade-mechanism-jvi.02015-19 Download

Case Update, September 23rd, 2020, Existing Immunity, Reinfection, Strains and Vaccines

All Articles, Antibody

This is a weekly update, but I’ll also talk about apparent existing immunity in some people, reinfection, and the 2nd wave of cases and what this all may mean about Coronavirus strains.

The 2nd wave of cases is apparently over in many places in the US, although not all.  The US new confirmed case numbers have risen slightly in the past week.  While the southern part of the country, California all the way for Florida, was the epicenter of cases for several weeks, new cases are primarily arising in the North Central part of the country.  I might speculate that this might be related to the coming Fall weather, but of course it’s too early to say for now.  The US also crossed a threshold of 200,000 total COVID deaths, outpacing a prediction I made several weeks ago that we would have 100 – 200 thousand deaths.  California is back down to pre-2nd wave new case numbers, but is not sinking below that.  In San Diego County, we had a small wave of cases related to a series of outbreaks at SDSU, but we’re back to a lower persistent new case rate.

Graph is by me, from data collected from Johns Hopkins University COVID site.
Endcoronavirus County Level Map, September 23rd, 2020
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site. “Active Confirmed Cases” numbers are calculated based on the assumption that patients confirmed to have SARS-2 virus at least 17 days ago have recovered.
Graph is by me, from data collected from San Diego County Public Health. See also regularly updated slides from SD County.
Graph is by me, from data collected from San Diego County Public Health. See also regularly updated slides from SD County.

Internationally, India now has the second most cases in the world, with 5.6 million cases as of this posting.  Of course India’s very high population and densely packed cities are likely a contributing factor. Brazil and Mexico have managed to slow the rate of new confirmed cases, having peaked in late July.  While things are improving in the US, many countries are experiencing first or second waves right now, including France, the UK, Israel, and Austria. 

Existing Immunity: I’ve resisted talking a lot about existing immunity because the information is complicated and may have phenomena with overlapping and opposing impacts.  Also, I’m not an immunologist! Be aware that what I say next may change.  There is data suggesting that the reason many, especially children, are asymptomatic is that there may be some existing immunity to Coronavirus in those individuals.  Coronaviruses is a large family of viruses which includes the SARS and MERS viruses, but also several viruses that cause the common cold.  As such, many may already have some kind of immunity to Coronaviruses as a group.  This is good news of course.

Reinfection:  On the other hand, I listened to a story on the September 2nd episode of the Nature Podcast about several cases of SARS-2 reinfection.  These cases appear to be rare, and most are not well studied.  In one case in Hong Kong, however, both the 1st and 2nd strains which infected a patient were sequenced and were found to be different strains.  This has several implications.  It suggests that immunity to a single strain may persist at least for a few months, but also that several strains are circulating, and immunity may not apply to other stains. 

If you’ve followed my page for long, you know that I’m concerned about Antibody Dependent Enhancement (ADE). In some cases of reinfection, symptoms were worse the second time, but in others, they were less severe. So unfortunately, these don’t necessarily provide clarity on whether ADE will be an issue, although if this is ambiguous now, it may be the issue will at least not be as serious as I feared.  We’ll have to see more of these cases to know for sure.

Strains and Vaccines: I’ve written about the D614G strain that arose in April and May. When I first heard about it, scientists were saying it may be several times more infectious than the already very infectious SARS-2.  I suspect that the 2nd wave we saw in the US may have been so large partially because of this strain.  All of this, as well as the reinfection story above, highlights that we have several strains moving around at once, and will likely have more.  Like HIV and Flu, Coronaviruses are RNA viruses.  RNA viruses use a RNA dependent polymerases to copy their genomes, and these enzyme tend to be VERY error prone as compared to DNA dependent polymerases.  Because of this, RNA viruses mutate quickly, and are resistant to the use of vaccines.  This is why we need a few Flu vaccine every year, and part of why we still don’t have a vaccine against HIV.  This of course also complicates the prospect of a vaccine against SARS, along with concerns about ADE. I’ll keep you posted as I learn more.

Don’t fear, but be smart,
Erik

Case Update: September 9th, 2020

All Articles, Antibody, Case Update, Contact Tracing

Friends,
This is a case update from the last week. For the US and California, confirmed case numbers continue to improve. In San Diego, we seem to be having a small bump in cases right now, after a consistent fall since late July. My friend Brit Colanter who works at San Diego County Public Health tells me that there was an outbreak at SDSU in the last few weeks. 444 cases so far and 1 hospitalization.

Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site. “Active Confirmed Cases” numbers are calculated based on the assumption that patients confirmed to have SARS-2 virus at least 17 days ago have recovered.
Graph is by me, from data collected from San Diego County Public Health. See also regularly updated slides from SD County.
Graph is by me, from data collected from San Diego County Public Health. See also regularly updated slides from SD County. Some data points of “Active Confirmed Cases” are from SD County, others are calculated.
From Rt Live.

I just got back from a trip to a hospital lab in Rochester, New York, helping them expand their COVID testing. As much as we can grumble about conditions here in California, they are even more strict in New York. New York has a quarantine program going for residents of some states, including California! I was required to check in with Contact Tracing every day, and stay in my hotel room when I wasn’t at the lab. So I was kind of under house arrest!

I have a new appreciation for Door Dash and other delivery people working out there today. So thanks to all of you who are working hard to bring needed items to those who can’t leave their house! You have important work right now!

Don’t fear, but be smart!
Erik

PS. I’ve heard a rumor that many African nations are having official events to pray for the US. Many thanks to my African readers for your prayers. We certainly need them!

Case Update: July 7th, 2020; Antibody Dependent Enhancement

All Articles, Antibody, Case Update, Fatality Rate, Masks, Re-opening, San Diego

Dear Friends,
This is a case update. I’ll also have an important message about antibody dependent enhancement.

Cases continued to rise unchecked in the US, California and San Diego County in the last week, although the long holiday weekend did have impacts on reporting. Some good news is that the number of deaths reported in the US has been slowly declining despite the case increase. Keep in mind however, that deaths will lag behind cases by as much as 2 weeks, so we may yet see an impact from the higher caseload. The number of deaths have been trending flat in California.

Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from Johns Hopkins University COVID site.
Graph is by me, from data collected from San Diego County Public Health. See also regularly updated slides from SD County.
From Rt Live

Rt Live is reporting that all but 8 US states or territories have Rt values above 1.0, meaning that the virus is expanding in those states.

I’m going to bring up an issue that I’ve been avoiding talking about for some time. I’ve been avoiding talking about it because it’s not a certainty, and also because the possibility will be scary for some. The reason I feel compelled to talk about it now is that many are having a hard time understanding why I am still so concerned about the virus when the fatality rate is low and dropping, and folks want to get back to normal life. I’m even hearing about young people having COVID parties in which people gather with a sick individual so they can all get infected and be immune from the virus thereafter.

Before I share this, I’ll also say that the medical community is doing a better job treating patients with COVID, and the disease is becoming more survivable. In addition, we now know a lot about how the virus is spread, and if a person wants to remain uninfected, they can do that, while still getting together with friends and family, and still working and getting on with life. You can be reasonably certain you will not get infected if you do the following:

1) Wear a mask or face covering in public. Avoid places with unmasked people.
2) Keep 6 ft away from others.
3) Avoid indoor gatherings, especially ones in which singing or shouting is likely.
4) Small outdoor gatherings are fine, even without masks, if everyone maintains a distance. Have guests bring their own food.
5) While many restaurants are open for limited indoor seating, I personally am still not comfortable eating indoors at a restaurant. I enjoy eating outdoors at restaurants, however.

Antibody Dependent Enhancement: Several years ago, scientists were developing a vaccine against Dengue Fever, a mosquito borne disease which causes debilitating joint pain in patients. Some time after trial vaccination, several vaccinated patients died suddenly of Dengue Fever. This became the most studied example of Antibody Dependent Enhancement (ADE). Normally, for the annual flu let’s say, a person gets infected by the flu, is sick for a few days, and the immune system develops a response by creating antibodies against that specific strain of the flu. If they are exposed again in a month, nothing will happen. If the patient is exposed to a different strain the following year, they may still get sick, but the antibodies they developed the year before may help them have less severe disease and recover more quickly. Part of the immune response is that some immune cells display antibodies on their surface to capture new invaders.

With Dengue and some other viruses, the first stages are normal. A person gets infected and develops a response. If they get re-infected a month later, nothing happens. But if they get infected with a slightly different strain months or years later, instead of being protected, the virus attaches to antibodies displayed on immune cells and uses the antibodies as a site of entry into the immune system. The immune system is quickly infected, and the patient has a more severe disease with the second infection. Some estimates are that disease may be 3-4 x more severe in these patients.

As it turns out, SARS-1, which arose in 2002, and MERS, which has small outbreaks every year, are both Coronaviruses and both appear to be able to use the ADE pathway. This raises the possibility that SARS-2, the current virus, can also use the ADE pathway. This means that a person infected for a second time with a different strain of SARS-2, or any other Coronavirus for that matter, may be at much higher risk for severe disease.

This is why I’m not in favor of pursuing herd immunity as a pathway out of this crisis, because it will prime people for ADE related problems if a similar strain should strike next year.

This is not a new idea. If you search for “ADE” or “Antibody Dependent Enhancement”, you will see many articles, some peer reviewed from respected journals, on the phenomena. Dr. Fauci has even referenced it using the term “enhancement” when talking about vaccine development.

Why haven’t the government public health departments been more open about this? They tend to make statements only based on what they can be reasonably certain of, which is why they have been so slow to react to many aspects of the current crisis.

Again, it’s not certain that ADE will play a role next year. It’s too early to know. I’m informing you of the possibility so you can make wise decisions for you and your family.

More than ever, don’t fear, but be smart,
Erik


A selection of relevant papers:

ADE and it’s potential impact for SARS-2:

ade-and-sars-2Download



ADE in SARS-1:

ADE and SARS-1Download



Overlapping symptoms for SARS, MERS, and SARS-2:

ade-sars-mers-sars-2-liu_et_al-2020-journal_of_medical_virologyDownload



Is COVID-19 receiving ADE from other coronaviruses?

ADE_and_COVIDDownload



Possible mechanism for ADE:

ade-mechanism-jvi.02015-19Download

Summary: What we know so far, June 22, 2020

All Articles, Antibody, Fatality Rate, Masks, Quarantine, Re-opening, Risk Factors, San Diego, Testing, Treatments

This long post will be a summary of what we have learned so far about the Coronavirus, and I’ll make some predictions about what to expect next.  Since I’ll be sharing so much information, I won’t give references for everything here. I also have to make the disclaimer that new studies are constantly being done, and some of the below information may need to be revised later. To make my standard disclaimer, I am not an epidemiologist or a physician.  I have a Ph.D. in molecular biology, and my specialty is infectious disease testing. On much of the below, I have an informed but not expert opinion.

Coronaviruses: Coronaviruses are a large group of viruses unrelated to the flu.  What we think of as the common cold, are actually member of several classes of viruses like Adenovirus, RSV viruses, Rhinovirus, and several Coronaviruses.  Many Coronaviruses cause diseases no more virulent than the common cold.  However, just like novel flus can cause extra trouble, so can novel Coronaviruses.  The first SARS virus was much more lethal that the SARS-2 virus, but because SARS had a short incubation period and made almost every infected person sick, it was much easier to contain.  The Middle East Respiratory Syndrome (MERS) Coronavirus infects a few people every year, and is very lethal, with a fatality rate of 34%, but it also has not made a global impact.  The reason SARS-2 is so dangerous is that it’s VERY infectious (Ro of between 2.5 and 5.7) and has a VERY long incubation time (2-14 days), making it very hard to track.  Plus, it’s at least 2x as deadly at the annual flu.

Name: The official name of the virus is SARS-2-CoV (for Severe Acute Respiratory Syndrome-2 CoronaVirus).  The official name for the disease it causes is COVID-19 (for COronaVIrus Disease-2019).  You may notice that the term SARS actually sounds a lot like a disease.  You would be right.  So why did they need a different disease name than SARS-2, or SARS-19? I don’t know.

Spread:  Early reports were that SARS-2 mostly spread like a flu, with droplets spreading from coughing or sneezing.  It became apparent later that the virus was also spread through aerosols by laughing, singing, shouting, or even just talking in close proximity for long periods.  As further study was done, it appears that most infected people don’t infect anyone else.  Rather, most infections come from “super-spreader” events, in which a single person infects a large group of people.  This usually happens indoors (at least 19 times more likely) during activities like fitness classes, funerals, concerts, and choir practices.  While outdoor activities aren’t completely immune to these events, they are much more rare.

Viral load upon exposure appears to be an important determinant of how severe a case will be.  Basically, this means that if you’re infected by a “low dose” of virus, your disease is likely to be less severe.  I have several physician friends who have stated that it seems to them that cases in the hospital are less severe than they used to be.  One likely reason for this is that since more people are wearing masks in public than early on, those who are infected are being infected by a lower viral load.

Early studies demonstrated that viable virus can exist on objects for hours or days.  However, it does not appear that a substantial number of people are being infected because they have touched a contaminated object. 

The WHO made a confusing claim recently that asymptomatic people cannot spread the virus.  While this is technically correct, they were not clear that “asymptomatic” is a technical medical term meaning someone who does not have, and will never have, symptoms.  Another group is “pre-symptomatic”.  These are people who currently don’t have symptoms, but will develop symptoms in a few days.  As it turns out, pre-symptomatic people do spread virus, and are likely responsible for up to 80% of new cases. So yes, people without symptoms can and do pass the virus to others.

Risk Factors:  Many believe that only old people are at risk. While it’s true that age is a dominant factor, other risk factors are important, and younger people have also experienced severe symptoms.  Other risk factors include respiratory conditions like asthma or COPD, heart conditions, kidney conditions, liver disease, diabetes, obesity, auto-immune disease, use of NSAID anti-inflammatory medications, being immunocompromised (HIV infected, undergoing cancer treatment, under medication for a transplant), vitamin-D deficiency, type A blood (Type O appears to be protective), inadequate sleep.

Always check with your doctor before changing your medications. I have an auto-immune disease and take daily anti-inflammatories, but my doctor has advised me to continue taking these unless I experience COVID symptoms.

Make sure your doctor is aware if you have any of the above conditions.

Symptoms: Many people who have SARS-2 experience no symptoms, or experience mild flu symptoms.  If you have ANY cold or flu symptoms, contact your doctor and see if you can be tested.  If you live in San Diego County, and your doctor cannot offer you a test, call 2-1-1 to get a free test from SD County Public Health.  If you have additional symptoms like shortness of breath (you just can’t seem to get enough air), loss of smell or taste, nausea or diarrhea, contact your health care provider or an urgent care immediately.

In severe cases, the virus can do wide spread and permanent damage to multiple organ systems.  Early treatment is necessary to prevent the most severe symptoms.

Precautions:  While lockdowns may have been effective in the US during the early stages of the pandemic, especially at a time when masks were hard to come by, recent evidence suggests that lockdowns provide only a moderate benefit over other means of control.  Here’s what appears to be beneficial:

Masks: Masks are not all the same and some are better than others.  Their main benefit is that they stop, reduce, or slow the travel of virus from infected people.  This prevents surrounding people from infection, or lowers the viral load of exposure.  Some, but not all, also prevent the wearer from inhaling airborne virus. N95 style masks without a valve are best if you can obtain one.

Best option: An N95 mask with no valve.

Social Distancing: Aerosolized virus can travel through the air. Staying 6 ft away from others helps prevent infection.

Handwashing:

Adequate sleep: Sleep is very important for a wide variety of body functions, including the immune system.  Get 7 – 8 hours of sleep per night.  A 26 minute power nap during the day is also beneficial if needed.

Vitamin D: Several studies have suggested that patients with the most severe cases of COVID also have the lowest levels of Vitamin D.  Because of our often indoor lifestyle, most Americans are Vitamin D deficient to some degree.  The best way of getting some Vitamin D is to make it yourself by going outside in shorts and a T-shirt for 30 minutes a day.  This is because Vitamin D is manufactured in our skin in response to sunlight.  If it’s not practical for you to do this, consider a Vitamin D supplement.  Darker skinned people are more likely to be Vitamin D deficient in the US.

Home isolation: If you have cold or flu symptoms, contact your doctor immediately and see if you can get a test.  Tests are much more available that early in the pandemic, and you should be able to get a test by request.  Also, if at all possible, isolate yourself from the rest of your family until you can be tested as negative.  Many new infections are taking place among family members.

Testing: There are several kinds of tests, and they tell you different things.

PCR: These tests use material collected from the nose and need to go to a specialized laboratory for processing.  They are very sensitive and specific, and indicate whether the patient is currently infected. This is the most common kind of test.

Antibody:  These tests detected antibody from a patient’s blood to see if the patient has been infected for at least a few days.  IgG tests may also tell if a patient was infected weeks or months previous, but are no longer infected.  Some patients do not mount an immune response that will provide long term antibody.

Isothermal amplification:  The Abbott ID Now COVID tests uses this relatively new technology.  These tests are similar to PCR and are both sensitive and very fast. 

If you have cold or flu symptoms, contact your doctor immediately and see if you can get a test.  Testing is much more available than it was early in the pandemic.  San Diego County is encouraging anyone who wants a test to be tested.

Treatments:  Treatment for COVID is complicated and not all patients can be treated in the same way.  Additionally, treatments are evolving rapidly, and your doctor many not treat you in the ways listed below.

Ventilators:  Some doctors now state that ventilators carry risks that may be unacceptable for COVID patients.  Many doctors now favor a nasal cannula, using ventilators only as a last resort if breathing is labored. 

Hydroxychloroquine, Azithromycin, Zinc: Several doctors from several countries have reported success with this combination.  Studies on the effects of these drugs have as yet still been non-conclusive.  Some positive studies suggest that Zinc is the main virus fighter of the treatment, with Hydroxychloroquine allowing better penetration of Zinc into cells.  Unfortunately, the debate on the efficacy of this regimen has taken on a strongly political tone, which almost always interferes with the scientific process.  Now pundits, as well as scientists, weigh in on this regimen.  I’m still holding a “wait and see” posture with this treatment.

MATH+: This regimen uses Methylprednisolone (an anti-inflammatory), Vitamin C, Thymine, and Heparin, as well as optional other treatments including Vitamin D and Zinc.  Early reports suggest success with this treatment.

Vaccines: Each spring, scientists learn which flu is likely to be prominent by the following Fall.  They make some guesses and create a vaccine for the flu season.  The manufacture process takes a few months. But it’s only this short because they already know how to make a flu vaccine.  Development of a brand new type of vaccine takes between 4 and 30 years!  There are many methods to make a vaccine, and scientists must try many of them before finding one that works.  Then they must try the vaccine on patients and make sure they are relatively safe.  Every vaccine carries some risk of side effects.

Early estimates for a Coronavirus vaccine were around 18 months.  My guess is that this is too optimistic.  Personally, I wouldn’t count on a vaccine for at least a few years.  In addition, some studies have suggested that Coronavirus vaccines in particular may cause side effects that may make vaccine development challenging.  My standard practice for my family is to wait on new drugs for a few years before using them myself. While I pro-vaccine in general, I would personally recommend waiting for a few years before getting a Coronavirus vaccine.

Herd Immunity: Some are promoting herd immunity as a way to move through the crisis faster.  The idea of herd immunity was popularized in pre-pandemic discussions on vaccines, promoting the idea that the more people are vaccinated, the more protection for those who can’t be.  This is a good idea when a vaccine is available, but not when there is no vaccine.  Putting many people in harm’s way to protect fewer others is not wise and is not standard medical practice.

The Future: Of course, it’s impossible to know what will happen next. My initial prediction was that the first wave would be over by July, and at this point, this doesn’t look likely.  New confirmed cases have started to rise or rise faster in the 3 areas I monitor most closely, the US, California, and San Diego County, and cases are rising fast in some countries previously unaffected, especially Brazil, Russia, and India. So I’m starting to think we may not be out of the first wave before the Fall season.

In addition, RNA viruses, such as Coronavirus, can mutate very quickly because the proteins used to copy their genomes are very error prone.  This means that a virus may change to a new form that can re-infect a person who has already had a previous version. Some reports suggest that this may already be happening with SARS-2. Some good news is that on the very long term (years), novel viruses tend to evolve to be less virulent, because it’s not in the “interest” of the virus to make the host very sick. The message is, we may need to adapt to a new reality for the next few months or years.  We can’t really afford to be “locked down” anymore, but mask wearing and elbow bumps may be a part of the landscape for some time.

Don’t fear, but be smart,
Erik

COVID Vaccine, Herd Immunity, and California Re-Opening

All Articles, Antibody, Masks, Quarantine, Re-opening, San Diego, Testing, Treatments

Today I’m going to wade into the piranha filled waters of the vaccine discussion. I’m also going to talk about the issue of herd immunity, and my advice for re-opening.  I’m not prepared for a discussion of the MRM vaccine that has been raging for the last several years, I’m going to discuss vaccines in general, and the hopes for a COVID vaccine in particular. I will say to start out, that I’m a big fan of vaccination in general, but each vaccine is different, and I may not be in favor of a particular vaccine.

Vaccines: I’m not an immunologist and I haven’t made vaccines myself, I’m just sharing with you what I’ve learned from an informed perspective over the last few months.  When I first started sharing about COVID, I said something wrong, that it would take at least a few months to create a vaccine against COVID, which seemed like a long time to many.  This was based on the time it takes to develop a flu vaccine every year.  In the Spring and Summer, scientists find out that strains are likely to cause flu later that year, and they begin making a vaccine. This process takes several months. As it turns out, it’s only this fast for flu because there is a standard way to make a flu vaccine, they just need to know what strains will be likely to arise in the Winter. And sometimes they are wrong. 

Unfortunately, however, there isn’t just one way to make a vaccine.  There are many different ways, and it can be different for every virus or bacteria.  So for every new infectious disease, a vaccine must be developed from scratch, testing all these different methods.  The process can take from 2 to sometimes as long as 30 years!  Some scientists have said that Dr. Fauci’s prediction of a vaccine by next Summer is actually very optimistic! In my informed, but not expert opinion, we should not count on a vaccine for this current COVID-19 crisis.  However, the vaccine work being done will likely help with future outbreaks.  At least part of Dr. Fauci’s optimism is that a lot of red tape is being cut to speed the process, and that’s good, but less development time will also mean more risk for the final product.

Herd immunity: I have heard many people promoting the idea that herd immunity will help us get out of the crisis. Even some governments have been promoting this idea.  Herd immunity is a useful discussion for diseases for which there is a vaccine, but in my opinion, it is not something we should be striving for now with COVID.  We shouldn’t put a bunch of people in danger to keep fewer different people out of danger. Herd immunity requires a lot of people to be immune, and that number is different for every virus.  I’ve heard the numbers 50 – 70% for COVID thrown around.  That’s a majority of the population!  Why would we risk exposing the majority to the virus to save the minority? To be crass, it’s kind of like saying that once the pool is full of bodies, no one else will drown.

Reopening: More states continue to begin the reopening process. I actually strongly support this, as long as people continue to take care as they interact in public!  Even California has entered Phase 1 (CA calls it Stage 2) today, Friday May 8.  The stages CA will use, as well, as the announcement for the May 8th reopening were announced by Twitter by the Governor.  Not my favorite method of making an official announcement, but there it is.  Re-openings have a much higher chance of being successful if we continue to take care! Continue to wear masks in public, and continue to distance when appropriate (see my May 5th post).  I’m hopeful that we can advance quickly through the stages if people continue to take precautions.  Also, it will be important for us to continue to expand testing, and for businesses to take advantage of expanded testing by screening employees as appropriate.  Some municipalities are starting to have drive through testing, including parts of San Diego (you must still have an appointment to be tested).  Check with your health care provider or public health department to see if and how you can be tested.  Keep watching how other states are doing!  We can learn a lot by observing what methods are working, and what methods are not!  I predict that outbreaks will occur in places that become relaxed too soon.

2nd Wave:  Again, I’m not an epidemiologist, and the following is an informed guess, not an expert assessment.  In my informed opinion, we will have second wave in the Fall or Winter, and history suggests it may be more severe than the first wave.  But I’m still optimistic.  Why?  Because I think that with expanded testing, we will be able to test far more broadly this Fall than we could in March and April.  This will help us identify and quarantine infected people rapidly, and will help us control the spread much better than in the first wave. For the 2nd wave to go well, we will need to stay diligent!

Don’t fear, but be smart!

Erik

What is the Fatality Rate?, Antibody tests, Re-opening

All Articles, Antibody, Communication, Fatality Rate, Re-opening

Originally posted on April 22nd, 2020 on Facebook

Friends,
This is a little longer post, this time with lots of science. I’ll talk about new measures of the fatality rate, some of the new Antibody testing, and also about the new re-opening guidelines. As always, consult with your doctor when making health care decisions!

First, very briefly, I’ll just say that we have seen a big up-tick of cases in the last few days. I’m trying to be optimistic about this and assume for now that this is because of increased testing. The large labs have been purchasing new instruments of different types to broaden their offerings.

There have been a handful of studies trying to discern the number of asymptomatic cases. One recent study in New York tested all pregnant women coming in to deliver. It showed that at least in this sampling, there we about 7x more asymptomatic women testing positive for COVID than symptomatic women (Sutton et al, Universal Screening for SARS-CoV-2 in Women Admitted for Delivery. April 13, 2020. NEJM, nejm.org). If this is roughly correct, then most confirmed cases numbers you see can be multiplied by 8 to get the real number of cases, as least until testing becomes more comprehensive. This also means the real fatality rate may be approximately 0.7%, about 5x higher than the typical flu.

Some have suggested that the fatality rate for COVID is the same as the flu, but this is the low end of new estimates, and for now, my guess is that it is higher. I think 0.7% is a good estimate for now. The rate for the typical flu 0.14%. Keep in mind that the Ro value for SARS-2 is about 5.7, much higher than the flu at 1.28.

On to Antibody tests! There has been a lot of excitement recently about antibody tests, and I have promoted them in my posts as well. As many of you know, the PCR based tests look for viral RNA in nasal swabs and detect an active infection. They are very sensitive, but they are more expensive, and need to be performed at specialized sites. Because the virus mostly lives in the lungs, nasal swabs don’t always collect virus from an infected person, and the false negativity rate has been estimated to be around 29%, at least initially. This is very high.

Antibody (Ab) tests detect an immune response by the patient by isolating antibody from the blood. Most detect 2 kinds of antibodies. IgM antibodies are produced during infection, and start appearing after about 3 days. IgG antibodies are produced later, at about 7 days, but continue to be produced for weeks to months after infection. The antibody tests are often less sensitive than the PCR tests, and they do not work during the first few days, since antibodies are not produced that early.

As you might guess, combining PCR and Antibody tests may give a good indicator if and even when an asymptomatic person was infected. Below is a table of possible interpretations of test results, assuming testing is accurate. Always confirm results and discuss with your doctor when making health care decisions! The FDA regulates testing in the US, and several tests have received Emergency Use Authorization (EUA) status. This is not FDA approval, but allows tests to be performed under emergency conditions. Several labs have started to perform antibody testing along with PCR. At first, Ab tests will be given in combination with PCR tests to see if health care workers have already been infected. If you want an antibody test, you’ll need to check with your doctor to see if you meet availability criteria. Many other companies have tried to offer tests without EUA status, including at home tests. Many of these tests have very high false negativity rates, and are basically no good! As of this writing, I would not use any at home test kit. Before taking any test, check with your doctor, or confirm with the FDA or CDC websites to see if a test has EUA status.

Re-opening: The federal government has released guidelines on the re-opening process. These are recommended guidelines, and most states are likely to adopt them, but the final decision will be up to the Governor of each state. I’ll provide the link below. In short, to enter the first phase of re-opening, states or counties must show a downward trajectory of cases and symptoms for 14 days, and must have certain hospital capacities and infectious disease surveillance procedures in place. Each additional phase can be entered if these conditions continue to be met for an additional 14 days. Some states or counties may already meet the criteria for phase 1, and some states plan to enter phase 1 on May 1st. Looking at the criteria, the guidelines seem reasonable to me, and I hope Governors will learn from the experiences of other countries and states while making these decisions.

Until next time, don’t fear, but be smart!
Erik

FDA Emergency Use Authorizations:

Federal Reopening Guidelines: