Category: Testing

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2021 COVID-19 Science Testing Vaccine

Antibodies after Vaccination and Disease

Last time, we built a mental model of the SARS-CoV-2 virus and used that model to make predictions of antibody test results.  This time we will see how that model squares against real-world observations.

Here’s the table we created last time:

InfectedUninfected
VaccinatedS+ N+S+ N-
UnvaccinatedS+ N+S- N-

With their permission, I tested more than 40 individuals who fit into one of the four categories.  Here’s what I found:

InfectedUninfected
Vaccinated4 S+ N+
7 S+ N-		17 S+ N-
3 S+ N+
Unvaccinated4 S+ N+
2 S+ N-		4 S- N-
2 S+ N+

Previously Infected and Vaccinated.  There were eleven people in this category, but only 4 had both the S- and N-antibodies that our model predicted.  Surprisingly, nearly two thirds of the people in this group lacked N-antibodies.  This is not what our model predicted.  It seems some people may not form N-antibodies.  Let’s keep looking.    

Previously Infected but Unvaccinated.  There were six people in this category.  Four had both S-antibodies and N-antibodies, but two had only S-antibodies.  Again, we’re missing some of the N-antibodies predicted by our model.  What’s going on here?  I’ll offer some speculations later.  

Vaccinated without Known Infection.  There were twenty people in this category, and all but three of these individuals had the expected S+ N- antibody pattern.  All outliers were S+ N+, suggesting they had asymptomatic infections sometime during the pandemic.  Is this suggestion reasonable?  I think so.   During the pandemic we tested healthy patients before elective surgeries and found a significant number of asymptomatic infections, so we know this can happen.

Unvaccinated without Known Infection.  There were initially five people in this category, and they had neither S nor N antibodies detected in their blood.  Except for one person.  She was surprised to learn she of a silent previous infection based on the finding of both S and N antibodies in her blood.  Subsequent testing of her husband, who also is unvaccinated without previously known infection, found S and N antibodies in his blood too, bringing the total number of people in this group to six with two outliers.  

We can summarize what we’ve learned as follows:

  • Both SARS-CoV-2 infection and vaccine stimulate the production of S-antibodies, 100% of the time in this study.
  • A significant number of people, about 20% in this group, had silent SARS-CoV-2 infections during the pandemic.
  • SARS-CoV-2 infection does not seem to stimulate the production of N-antibodies consistently.  This is a pesky observation that does not fit our model.

Could it be that N-antibody production relates to the severity of disease?  Probably not since quite a few of the S+ N+ individuals in this study had asymptomatic infections.  Could it be that variant viruses cause N-antibody negative infections?  Or is the N-antibody test not very good?  All are possible, but, as we’ve said so many times since the outbreak of the pandemic, we really don’t know for sure.   What we can say is that tests for “COVID antibodies” are more complicated than they seem at first glance.  Laboratories should clearly label the antibodies measured when reporting SARS-CoV-2 antibody results.

How do the antibody levels caused by disease compare with the antibody levels caused by vaccine?  And which vaccine provides the best immune response?  We will examine these questions next time.  

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2021 COVID-19 Science Testing Vaccine

A Useful Model

Scientists create mental models to help understand the world around us.  Not that these models are reality; the real world is much, much more complicated.  Instead, these models are useful ways to think about reality.  Today I would like to create a mental model of the SARS-CoV-2 virus that will be useful as we learn more about the virus in coming weeks and months.

Think of the virus as an egg with spikes driven into the shell.  Now focus on two parts of this model: the spikes and the yolk inside the egg.  The spikes correspond to the S-proteins on the outside of the virus.  That’s easy to remember—S for spike.  The yolk corresponds to the nucleocapsid that covers the genetic material on the inside of the virus.  Let’s call the nucleocapsid “N” for short, which will also help us remember that N-proteins are inside the virus.  Now in our mind’s eye we see a virus shell with S-proteins on the outside and N-proteins on the inside.

When foreign proteins show up in your body, your immune system responds by making antibodies.  Therefore, when infected by SARS-CoV-2, your body will make at least two different types of antibodies: S-antibodies and N-antibodies. Blood tests are now available that can detect both kinds of antibodies, and both should be detected in someone who has been infected by SARS-CoV-2 in the past.

Vaccines expose the body to S-proteins only.  N-proteins are not part of vaccines.  Therefore, someone who has received a vaccine but has never been infected will have S-antibodies but not N-antibodies.  S-antibodies may come from vaccine or infection.  N-antibodies come from infection only.

Now we can use our model to predict antibody test results from four different groups of people, represented in the table below:

Previously InfectedNever Infected
VaccinatedS+ N+S+ N-
UnvaccinatedS+ N+S- N-

A simple model, but does it work?  To find out, I collected the results of antibody tests from four groups of people: people infected but not vaccinated, people vaccinated but not infected, people vaccinated and infected, and people never infected nor vaccinated.  Next time, we will review the results.

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2021 COVID-19 Testing Vaccine

Herd Immunity

What is herd immunity and when will we get there?

Imagine a billiard table with balls racked at one end.  Smash a cue ball into the neat arrangement and all the balls will move.  That’s like the pandemic.  The energy spread from ball to ball is like the spread of virus from person to person.   

Now imagine the same table, except this time some of the balls are bolted onto the table so they can’t move.  Smash a cue ball into the rack and not as many will move.  The bolted balls are like people with immunity; they absorb energy and do not allow it to spread.  How many balls must be bolted onto the table to prevent spread of motion across the table?  That’s herd immunity; the percentage of people with COVID-19 immunity that it takes to stop the uncontrolled spread of virus.

Epidemiologists differ on herd immunity targets for COVID-19, with estimates varying from 60% to 90%.  But these estimates are just educated guesses.  Herd immunity is something observed, not something predicted.  When the rates of disease reach a stable low level, herd immunity has been achieved.  

Now some observations from my point of view.  Last week, without a decline in the number of tests performed, there were only 6 positive SARS-CoV-2 tests in the laboratory where I work.  Until last week, weekly positives have been in the double digits going back to April 2020, with a peak of 475 during the first week of this year.  Since the last week in February, the weekly number of positive tests have been below 40.  The curve has flattened, despite the lifting of many restrictions designed to prevent spread of the disease in Texas.  We can no longer say that there is a COVID-19 epidemic in my community.  Instead, the disease appears to have reached endemic levels here.  

I need to pause to explain what I mean.  Disease prevalence, which we’ve defined before, means the rate of disease in a population.  Prevalence can be applied to any disease, not just infectious disease; thus, we can speak of the prevalence of diabetes, of breast cancer, of heart disease, and so on.  Epidemic simply means increasing prevalence, just like acceleration means increasing speed.  Endemic means that disease prevalence is stable and not changing.  Epidemics can be local, meaning confined to a house or a neighborhood or a city or a country, or epidemics can be global, meaning happening all over the world at once.  Global epidemics are called pandemics.  The term “global pandemic” is as redundant as “unexpected surprise” or “advance warning.”

Herd immunity is achieved once an infectious disease reaches endemic levels, but what is that number?  Assuming natural and vaccine-induced immunity are the same thing, then herd immunity is the percentage of folks who have either had the infection or the vaccine when disease becomes endemic.  Today, it is estimated that 10% of Texans (2.8 out of 28 million) have had COVID-19, and that 35% of Texans have been fully vaccinated.  Therefore, my area seems to have achieved COVID-19 herd immunity at 45%.

This all sounds like great news, so why not throw our masks in the air and celebrate?  There are still unanswered questions.  Vaccine-induced immunity is not the same as natural immunity, but is it the same enough for calculating herd immunity?  How long does immunity last?  Can herd immunity be lost once achieved?  What will be the impact of emerging variants on immunity of individuals and populations?  And, most puzzling to me, why is the virus surging now in India and Brazil despite previous waves of infection?  

We still don’t know as much as we would like to believe.

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2021 COVID-19 Science Testing Vaccine

Antibody Tests after Vaccination

The CDC recently updated guidelines for interpretation of SARS-CoV-2 antibody tests after infection and vaccination.  There is currently no recommendation to measure antibodies after vaccination to determine vaccine effectiveness.  Despite this, I know vaccinated individuals who measure antibodies anyway, and they are surprised when antibody tests come back negative.

Okay, full disclosure.  It was me.  And my wife.  We took the Janssen vaccine in mid-March, and I checked our SARS CoV-2 IgG antibodies last week.  They’re negative.  For both of us.  What’s going on here?  Isn’t the point of vaccination to stimulate the production of antibodies?

The answer is a qualified yes.  The qualification comes in two parts: the “scientific explanation” and my opinion.  

First the “scientific explanation”, simplified.  An individual may produce three types of antibodies against SARS-CoV-2: N, S or RBD. Infection stimulates the production of all three types of antibodies, but vaccine stimulates the production of S antibodies only.  Therefore, vaccinated individuals who have never been infected will be S-antibody positive, but N and RBD antibody negative.  If the antibody test is designed to detect N or RBD antibodies, but not S antibodies, then the result will be negative in those individuals.  On the other hand, detection of N or RBD antibodies in a vaccinated individual means that the individual has been exposed to the virus, either before or after vaccination.  The trouble is that the antibody tests available today by emergency authorizations do not specify which type of antibody is measured.   We do not know which antibody we are measuring unless we know details about the test, details that are usually not listed on the report from the lab.  

This explanation has precedent.  We know, for example, that Hepatitis B infection stimulates the production of two different types of antibodies: core antibody and surface antibody.  Hepatitis B vaccine only stimulates production of surface antibody; it does not stimulate production of core antibody.  Therefore, someone who is positive for surface antibody only has been vaccinated but has not been infected.  On the other hand, someone who is positive for both surface and core antibodies has been infected by Hepatitis B in the past.

All well and good for hepatitis, but what about SARS-CoV-2?  In the case of SARS-CoV-2, the “scientific explanation” is a hypothesis, meaning it is an educated guess.  Before we can say that we know something, we must compare our hypothesis to real-world observations.  There has not been enough time to observe the response that our bodies really have to vaccine.  It doesn’t make the hypothesis wrong, but it doesn’t make it right either.

My opinion?  The “scientific explanation” is still an opinion.

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2021 COVID-19 Testing Vaccine

New Variant Classification

Last week the CDC revised its classifying terminology for SARS-CoV-2 variants.  To have clarity in our thoughts and debates, we must be precise in our language.  Poor decisions often descend from muddled and incomplete understandings.  I know that readers of these posts strive to be current in models of understanding and language, so they will not be caught flatfooted in conversation and reasoning.  That’s why I summarize the essential points here.

There are now three types of SARS-CoV-2 variants: Variants of Interest, Variants of Concern and Variants of High Concern.  I will discuss the definitions, lists of variants and their characteristics in reverse order.

Variants of High Concern.  Variants of high concern are those SARS-CoV-2 variants that cannot be detected by tests, are not treatable by current therapies or for which natural or vaccine induced immunity offers no protection.  Any one of those three criteria is enough to place the variant on the High Concern list.  Scary stuff.  The good news is that there are no variants on this list.  At least not yet.

Variants of Concern.  Variants of Concern have reduced detection by tests, reduced response to therapy, reduced immune protection, greater transmissibility, or more severe disease.  Again, any one of these criteria is enough to land a variant on this list.  The bad news is that the number of variants on this list has exploded since the last time I wrote about it.  In addition to the B.1.1.7 variant first detected in the UK last fall, four other variants have been added to the list:

These Variants of Concern have all been identified in the United States.  The B.1.427/429 Variants of Concern are most prevalent in the western United States, now responsible for more than half of infections in California.  The B.1.1.7 Variant of Concern is most prevalent in New Jersey and Florida, approaching 10% of the new viral infections there.  Click here to view the current numbers and distribution in the United States.  To see worldwide cases of COVID-19 caused by variants, click here.  These maps are updated at least weekly.

Variants of Interest.  Variants of Interest are being watched closely because they have the potential to become Variants of Concern based in the mutations within the variant, even though they don’t fulfill criteria to be a Variant of Concern based on observation.  This may be because the variant is too new or because too few of the instances of the variant exists to make meaningful observations.  The current Variants of Interest and their potential, but not observed, effects are listed below:

Like the Variants of Concern, all the Variants of Interest are currently present in the United States.  

There are a number of other variants which have been identified and named, but which have not yet been classified as a Variant of Interest, Variant of Concern, or Variant of High Concern.  Expect the members of these variant classification lists to change and shift as more becomes known about variants.

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2021 COVID-19 Testing

Where’s the Flu?

Since October, all rapid SARS-CoV-2 PCR tests performed at the hospital laboratories where I work have included a PCR test for flu.  But of the thousands of tests performed, not one positive flu has been detected.  Has COVID cured flu?

No, I don’t believe that COVID has cured the flu, but I believe that masks have dramatically reduced the prevalence of flu in the community.  Flu is a respiratory infection, passed from person to person by the same transmission mode as COVID, mainly inhaled droplets from an infected person.  Standard face coverings reduce flu transmission in two ways.  First, droplets from an infected person are less likely to be spread into the surrounding air; instead, they hit the mask and fall.  Second, the mask helps filter the air of droplets that may contain viral particles.  The result is a reduction, but not an elimination, of respiratory viral transmission.

So why haven’t masks cured COVID?  SARS-CoV-2 is more infectious than flu, meaning that compared to flu, far fewer SARS-CoV-2 viral particles are needed to cause infection.  Masks reduce the number of viral particles in the air, but they don’t eliminate them.  Some virus leaks out from the masks of infected persons, and some virus can be inhaled by masked individuals nearby.  It’s a matter of how much virus gets inhaled.  It takes much more flu to cause infection than SARS-CoV-2.  Masks slow the spread of COVID-19, but do not eliminate disease the way masks have flu.

We may use this COVID/Flu comparison to make some predictions about the B.1.1.7 variant, the “variant of concern” now reported in at least 70 countries.  This variant is reported to be much more infectious than the standard SARS-CoV-2 virus, about fifty percent more, with the consequence that masks may not be enough to slow its spread through the community.  Tighter, less permeable, and more uncomfortable masks may be necessary to protect against this variant as it spreads across our nation.  The higher transmission rate also predicts that this variant will soon be the dominant form of the SARS-CoV-2 virus in the U.S.

If standard face coverings may soon become less effective protection against COVID-19, maybe now is the time to learn about different types of masks.  We will do that next time.

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2021 COVID-19 Testing

New Information about Variants and Tests

On January 8, the FDA released a warning that certain PCR tests for SARS-CoV-2 available by EUA may have seriously reduced sensitivity for the SARS-CoV-2 Variant of Concern (VOC, also known as 20I/501Y.V1, VOC 202012/01, or B.1.1.7), resulting in false negative test results.  The tests mentioned in this advisory are the Accula SARS-Cov-2 Test by Mesa Biotech, the TaqPath COVID-19 Combo Kit by Thermo Fisher Scientific, and the Linea COVID-19 Assay Kit by Applied DNA Sciences.  How will this development impact testing?

The SARS-CoV-2 virus mutates regularly with new strains emerging once every two weeks.  Mutations occur in the genetic material of the virus, the very material that molecular test methods like PCR use to detect the virus.  Until recently, none of these mutations has been associated with different clinical characteristics, such as more severe disease or increased rate of transmission.  However, a variant of concern (VOC) recently emerged in the UK.  As far as we know, this is still the one and only VOC.  Since this VOC has a much higher rate of infectivity than standard SARS-CoV-2 virus, we can expect it to spread quickly. It will probably soon become the predominant form of the virus in the United States.  

PCR tests look for a match in a region of viral RNA.  The target sequence is like a computer password:  any mistake causes the password to fail, even if the entry is off by only one letter.  Therefore, when a mutation occurs in the target region of a PCR test, the test will be unable to detect the virus.  This is why the tests mentioned in the FDA warning may not detect all forms of the virus.

Most PCR tests look for a match in more than one target sequence of RNA.  Generally, the more targets in a particular test system, the less likely a mutation will impact test results.  But beware: negative results should be evaluated in combination with history and symptoms.  If COVID-19 is still suspected after a negative test, consider repeat testing with a different test—one with different targets.

How do you know which test you received?  Look closely in the fine print of the results—the test used is probably referenced there.  If not, ask. 

Although most commercially available tests will continue to detect the VOC, these tests do not identify whether the virus is the variant or standard form.  They will only identify that a SARS-CoV-2 virus is present.  Furthermore, there is no assurance that a variant will not emerge that evades detection.  

Obviously, this is a situation we will continue to follow closely.

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2020 COVID-19 Testing

Spread and Detection of Variants

Last time we learned that a new strain of the SARS-CoV-2 virus has emerged in London and southeast England.  This variant strain, called “VOC 202012/01” or “B.1.1.7” is more infectious than the standard SARS-CoV-2.  It has quickly spread to other parts of Europe, and its presence is now reported in Canada and the United States.  At least two other distinct variants are reported in South Africa and Nigeria.  How do we keep track of these variants, and what does their rapid spread mean?

The variants are named by adding suffixes of letters and numbers to help keep the many cataloged mutations straight.  Two different systems may be used.  For example, the South African variant is labeled “501Y.V2”, but it is also known as “B.1.351”.  The Nigerian variant is called as “B.1.207”.  Neither of these has been labeled a “variant of concern”.  

A “variant of concern” is a strain is associated with differing clinical features such as greater disease severity or faster spread.  “Variants of concern” will have the letters “VOC” in their name.  So far, the first and only “variant of concern” is VOC 202012/01, the variant identified in London which has now spread into Europe, Canada, and the United States.  

While none of the variants identified so far seem to evade detection by the PCR tests generally available to the public, these tests will not tell you whether a detected virus is one of the variants.  Specialized sequencing is required to identify a virus as a variant.  This testing is conducted on a regular but limited basis by the CDC, state and local health departments, and various universities.  

The CDC is watching the evolution of variants closely.  The concern is that increasing numbers of variants may change the way the virus spreads, may reduce detection by current tests, may create resistance to drugs such as monoclonal antibodies, or may produce a strain that evades immunity caused by vaccine or previous infection.  We will watch too.  As the “variant of concern” spreads into the United States, remember what keeps us safe: mask up, keep apart, and isolate when exposed. 

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2020 COVID-19 Testing

Viral Variant

A new variant of the SARS-CoV-2 virus is emerging in Great Britain, becoming the dominate form of the virus that causes COVID-19 in London and southeast England.  What are the implications of this new variant?

The new variant has been officially named “SARS-CoV-2 VOC 202012/01.”  You may also see it referred to as “B.1.1.7”, or “SARS-CoV-2 Variant” in both the popular and scientific press.  This variant has a mutation in one of the spike proteins which binds the virus to human cells during the infection process.  So far, this variant has not been reported in the United States.

Viral mutations are common.  In fact, many different strains of the SARS-CoV-2 virus are likely to exist in the United States right now.  But so far, none of these mutations has caused a significant difference in the binding capacity of the virus to human cells.  At least none that we know of.  Our understanding of SARS-CoV-2 continues to evolve rapidly.

The variant identified in England seems to spread more quickly in humans.  The thought is that the change in spike binding protein makes it more likely for the virus to stick to human cells.  

Why does increased stickiness of virus affect the virus’ ability to spread?  After the virus sticks to the cells lining the inside of the nose and upper airways, the virus injects its genetic material into the human cell.  This genetic material is programmed to take over the machinery of the cell, causing it to abandon its usual functions and become a virus producing factory, spewing out hundreds of new copies of the virus.  These new viral copies infect other cells, either in the same body, or in bodies nearby.  This accounts for the waxing of disease within a sick, infected person, and the spread of virus from person-to-person.  If the virus is stickier, more human cells are taken over, and more copies of the virus are produced, making it easier for the virus to go, well, viral!

Will tests detect this new virus strain?  Yes, PCR tests will, at least for now.  Because PCR tests use two or three different detection targets, the change in this variant’s genetic code is not enough to evade detection by PCR tests.  However, as the genetic code of the virus continues to evolve, it is conceivable that a mutation will arise that is not detected by tests currently in use, even PCR tests.  Antigen tests, which already have low sensitivity, do not share the multi-targeted feature of PCR tests; therefore, even more false negative antigen test results can be expected when the variant becomes more prevalent.

Will the variant reduce the effectiveness of vaccine?  The honest answer is that we really don’t know.  Theoretically, this variant will not, since the vaccines released in the U.S. are polyclonal, causing the formation of antibodies to several different parts of the virus’ spike proteins.  The theory is that even if one part of the spike protein changes, the antibodies will still be effective against the other parts that have not changed.  But theory and reality are not the same thing.  We won’t know for sure until vaccine effectiveness has been studied in populations infected by the variant.  

This brings us to one final point about this viral variant.  This variant is undoubtedly the first of many variants to come, and the answers for these yet-to-be-seen variants may be different than the answers for this one.  Viruses want to survive.  Just as the use of antibiotics causes the emergence of antibiotic resistance in bacteria, the use of vaccine will favor viral mutations that evade vaccine-induced immunity.   Variants will emerge that are unaffected by vaccine.

The pandemic is a war, both metaphorically and really.  Our best defense is the practice of what we know reduces spread: mask up, keep apart, and isolate when exposed.  We will prevail.  But it’s still too early to celebrate victory.

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2020 COVID-19 Testing

Quarantine

In guidance updated December 2, 2020, the CDC adjusted quarantine period for asymptomatic individuals.  Today we consider these latest quarantine recommendations.

Before we do, we must first discuss what it means to quarantine and the conditions that trigger a quarantine.  Quarantine separates an individual who may have been exposed to SARS-CoV-2, the virus that causes COVID-19, from others to prevent further spread of the virus.  Simply stated, quarantine means stay home and stay away from others.  If you live with other people, keep to a separate room.  If you must be in the same room with someone else, stay 6 feet away, wear a mask and make sure everyone else does too.  Generally, if one person in a household is quarantined, all persons in that household should also quarantine.

You must quarantine when (1) you have COVID-19, (2) you first positive test for SARS-CoV-2, or (3) you are exposed to someone infected by SARS-CoV-2.  An exposure is an encounter of less than 6 feet apart and more than 15 minutes long when one or both individuals are not wearing face masks.  

The standard quarantine period for asymptomatic individuals is 14 days.  This recommendation comes from the maximum observed time between exposure and development of symptoms, known as the incubation period.  The incubation period is less than 14 days for most infected individuals, with 5-7 days being average.

The new CDC guidance lists two situations when the quarantine period can be shortened to less than 14 days. If no symptoms develop, the quarantine can be ended after 10 days without testing for SARS-CoV-2.  But if the person tests negatively for SARS-CoV-2 on or after the 5th day of quarantine, and if the person never develops symptoms, then the quarantine period can be ended after day 7.  For the purposes of counting days, the exposure day is considered day 0.  

Immediate testing at the time of exposure is not recommended.  Testing prior to 5 days after exposure does not shorten the recommended quarantine period and could lead to a false perception that the exposure did not lead to infection, perhaps promoting risky behavior. 

The quarantine period is different if you have symptoms.  For persons with mild illness, the quarantine period is 10 days from the onset of symptoms or 24 hours since the last fever without use of fever-reducing medicines such as Tylenol, whichever is longer.  Generally, a mild illness is one that does not require hospitalization.  If hospitalization is required, the quarantine period may be 20 days or more, depending on the advice of your doctor. 

Following these updated quarantine guidelines slows the spread of the disease and keeps your loved ones safe.  However, wearing a mask and staying away from people who are not wearing masks minimizes the risk of exposure in everyday encounters.  More on masks next time.