The text transcription has been edited for clarity and length.

Dr Dave Canaday (DC):  My name is Dave Canaday. I am an infectious disease physician, professor of medicine at Case Western Reserve University, and I also work at the Cleveland Veterans Affairs (VA).

Dr Elie Saade (ES):  I am Elie Saade. I am an infectious disease physician as well. I am associate professor of medicine at Case Western Reserve University, and I am a physician at the University Hospitals in Cleveland.

Available Vaccine Booster Options Currently on the Market for Protection Against SARS-COV-2

ES: Currently, there are 3 options available in the United States markets. There is both Pfizer and Moderna messenger RNA (mRNA) vaccines. They are both bivalent vaccines, meaning they have 2 different strains of virus material in there, not actually viral but the mRNA that produces the mRNA that is given. They have the original strain and Omicron strain. There is also the Novavax vaccine, which is a monovalent vaccine.  However, we are expecting now that very soon, probably by September, the US Food and Drug Administration (FDA) will be approving a newer vaccine, newer Pfizer and Moderna mRNA vaccines, which will also have a type of Omicron strain, the XBB.

DC:  Yes, I agree with what Dr Saade said of the vaccines available. The mRNA vaccines are the most widely used vaccines in the US by far, and the Novavax vaccine is more of a traditional vaccine, like it has a protein and then an adjuvant vaccine booster in it.  One other point to mention is what populations they are recommended for. Ultimately for all ages, except for the very youngest population. There are pediatric recommendations all the way up through the end of adulthood, so to speak. They are certainly widely recommended by the Centers for Disease Control and Prevention (CDC) for all the age groups. 

I think a key point that will come up in this question and then in some future questions is, and Dr Saade mentioned it,  within just a couple of weeks, the next Advisory Committee of Immunization Practices, which is called the ACIP at CDC, is having a meeting in just a couple of weeks, mid-September, and at that meeting it is anticipated that they will discuss and provide the recommendations for the new updated vaccine, which is back to a monovalent or single-vaccine strain. As Dr Saade said, they are choosing an XBB 1.5 strain. They picked 1 that is actually still in circulation currently and that we are going back to a single-strain vaccine.

We tend to, and I think honestly the field tends to, just describe them from their supplier, because saying BNT162B2 and mRNA-112733, although, those technically are the names and they actually have specific drug company names, most people tend to refer to them as the supplier.  Anyways, the bottom line for the 2 vaccines when you compare them to one another is they are extremely similar in all ways.  They are both mRNA vaccines, meaning that the mRNA causes the body — you do not get immunized with any of the SARS-CoV-2 protein itself.  You get immunized with the mRNA that will make your body produce that protein to then make the antigen-specific response.  They both are focused on spike and they both use the mRNA technology.

When you actually look at the studies of adverse events, they are fairly similar between the vaccines. They have similar adverse events and fairly similar rates.  There might be slightly higher for 1 than another, but it is only a matter of a small bit of percentage.  As far as how well the vaccines work, again, similar story.  They are both very highly effective and a few studies here and there will have maybe a couple of percentage points higher for this vaccine or that, but the overall message is that they are very similar in how they work and they are very similar in their effects and side effects.

ES:  For all intents and purposes, both mRNA vaccines are very similar.  I think most of our physicians think about them that they are the same.  So, when I receive the question of which 1 should we use for a specific patient, for me to answer would be whatever is available.  They also go hand-in-hand in terms of the authorization or approval and in terms of CDC recommendations.  There might be sometimes that difference, that 1 would be authorized or approved 1 week or 2 weeks before the other, but then the other will catch up.  So, they are very similar.  They are both safe.  They are both effective.  They are similarly effective.  There is no animal product in any of these.  There is no preservative, no antibiotic, no food protein, no latex.  They are very similar, practically the same.

DC:  One other point I would add in the discussion phase.  When you get the primary series.  Like if you have never gotten the vaccine before, the primary series is 2 shots.  It was how it originally was to get 2 shots.  They wanted you to try to stick with the same brand, but now you actually do not have to stick with the same brand, and basically almost everybody is in the booster phase and the CDC has pretty much moved into the booster phase, unless you are in pediatrics, of course, when you are very young and you have not had a chance to be exposed or had COVID in the past.  Essentially, now adult-wise, people are considered in the booster phase whether you have had shots or not.  So then you can obviously get any brand, even if it is your first shot.  Novavax, I know this is an mRNA vaccine question, but same thing applies to Novavax.  You can get a Novavax booster.  You can tell your patients, do not worry about what shot you got before, you are fine to get another shot.

ES:  One more thing to add, which might not be very clinically important but might be interesting for some to know, is that 1 of those vaccines, the Moderna, has a slightly higher dose of active ingredient, which might be associated with higher risk of short-term adverse events, meaning they might have more low-grade fever, a bit more chill, bit more shoulder pain, for example.  Again, there is no really head-to-head comparison between those vaccines, so it is hard to tell.  But the current product from Moderna does have likely higher amount of product.

The Efficacy of mRNA Vaccine Boosters Against SARS-COV-2 Infection in Vulnerable Populations

ES: This is a very good question.  There is a concern about the reduced vaccine effectiveness and reduced immunogenicity, immune response, in certain vulnerable groups, especially those who are immunocompromised, whether they are immunocompromised because of an illness like malignancy or autoimmune disorder or whether they are immunocompromised because of a normal state like pregnancy, or whether they are immunocompromised because of receiving medication like steroids or other medications. There is a decreased effectiveness compared to people who are not immunocompromised, and there is shorter periods of immunity.  However, the caveat to this is that we do not really have great tests that will tell us, that put correlation between the blood tests and how much the vaccine will be effective. So there is a caveat there. However, most doctors, most specialists agree that there is less effectiveness in people who are immunocompromised and a shorter course of immunity, which means that the boosters are even more important in this group, because boosters will level the field or bring back the immunity to higher levels, and they are still effective in reducing the risk of death, the risk of hospitalization, even if it is not as well as people who are not immunocompromised, but this is the best available. The other important thing to remember is that even when they receive the vaccine because of the lower chance of having a good immune response, immunocompromised people or people at higher risk should be diligent about masking and about avoiding crowds because they are still vulnerable.

DC:  Yes, those are all excellent points.  There is a fair amount of data on the immunocompromised individuals and there is tremendous interest in the field because there is a certain amount of herd immunity that has occurred out in the US because well into 90% of individuals in the US have either had COVID, had their vaccine, or had both.  So there is a lot of induced and natural immunity out there that is developed.  But depending on your level of immune-compromise, you do not get the benefit of — there is a large benefit to the vaccines; preventing, helping cut down on severe disease and, not that I am telling anybody to go out there and get COVID, but there is also a benefit to your immune system once you have survived COVID to getting COVID.  In fact, the best immunity against SARS-CoV-2 is hybrid immunity, where you have had COVID and you have also gotten the shots, the combination.  Just having COVID alone is not enough to get your optimal immunity.  You absolutely need to get vaccines and, in fact, several vaccines ideally to get some boosting to give you the optimal immunity. 

If you have recently had COVID, the current recommendation from the CDC is that you do have a window period on the order of they are saying, say 3 months, before you would think about getting your next booster because you can rely on that natural immunity, but again, it starts to wane and you have the opportunity of getting the booster.  Now, I do not at all recommend people go out there and try to get COVID to boost their immunity, because a small portion of those individuals could get long COVID. Most people get through COVID just fine.  A small portion, especially the higher-risk individuals like the immunocompromised, like older individuals, like the super young, have more risks.  It is absolutely something to be avoided.

But if you do get COVID again, do not think, oh, this is my free pass,  I never need to get boosted.  The strains are changing over time.  The boosters are keeping up with the strains; the new booster hitting the newest Omicron strain is trying to keep the immune system up-to-date.

The other point I would make, just to bring up 1 special population that you did not exactly mention, is older people.  They are clearly the largest vulnerable population in America.  They are not necessarily formally immunosuppressed, like obviously a transplant patient or some rheumatoid arthritis patient on potent meds, those kind of things.  But as you get older your immune system does not work as well.  It does not respond to new things as well.  My lab studies COVID shots, we do not give the shots, we observe the effects of shots in the long-term care setting.  That is the nursing home, the frail, multi-morbid, older individual.  What we observed initially was that, every older folk we gave in our study did have some response, but it often took getting into the booster zone to start getting the older immune system to catch up and then over time, they look pretty similar to what the general population does in terms of how their cells respond in the lab, how do their antibodies work, etc.

Another comment is the pregnant population.  The pregnant population does respond nicely to the vaccine, but it is a higher-risk group in terms of adverse events from getting SARS-CoV-2.  It is a population that is vulnerable, but if you get the vaccines, it is a huge advantage in disease mitigation and risk mitigation, both for a successful pregnancy outcome and it is good for your baby because it transmits a lot of antibodies to the baby and the youngster is not able to get vaccinated for some period of time and has to rely on mom’s antibodies that go through the placenta.  Having antibodies in mom’s body to get them off to the baby is a very important protective measure for the babies, too.

Implications of the Reduced Neutralizing Capacities Against Omicron Subvariants for SARS-COV-2-Vaccinated Pregnant Women

DC: Generally speaking, I think where this question came from was few earlier papers that were important papers at the time focused on pregnancy.  They looked at pregnancy right after the first 2 doses, which would be called the primary series.  The primary series was Wuhan strain, the original strain.  It did a good job of making antibodies against Wuhan, but it did not do a good job, just the primary series, at making anti-Omicron, BA1, BA2, BA45; those are all Omicron subvariants.  Again, our study shows it in healthcare workers and nursing home patients and multiple other studies show exactly the same result.  You really need to get a booster.  When you get the third shot, your Omicron immunity goes way up. So getting that back to pregnancy, those 2 early papers where this issue was brought up focused just on pregnant women and looked at pregnant women.  It did not have a good control population to observe, hey, if you look at healthcare workers that are not pregnant, they also did not respond to Omicron very well until they got their next shot.  Once you get the next shot, you are a lot better off.  And interestingly, even when you have had COVID — this, is early on; if you get Omicron, you get a big Omicron booster, obviously because you’ve got infected with the real deal.  But early on, before Omicron was out, if you have been infected with older strains, even the older strains did not cross-react into Omicron really well.  So again, you needed the booster.  There was something about the vaccine.  It was actually better early on than getting the old strains themselves.  That is my points about this.

ES:  I agree with Dave. Pregnancy is a physiological state that is associated with decreased immunity and not just immunity, but other immune dysfunction as well. But also pregnancy is an important state because there is 2 people that we are dealing with there, the mom and the fetus.  There is a higher risk of still birth in patients who have COVID, pregnant women who have COVID, and the vaccine does decrease the risk of complications from COVID.  So despite having possibly a decreased response, at least, on the blood test, there is still good effectiveness of the vaccines, and I would say it is even more important because of the life of the mother and because of the life of the fetus.  So I would recommend that.  The relevant societies in the US agree that pregnant women should receive the COVID vaccine for their own protection and for the protection of the fetus.

DC:  One point, actually just additionally to add, I was just reviewing that today in fact.  The current recommendation is if you are “up-to-date on your vaccine series” and you become pregnant, you do not need to get another shot during pregnancy, if you are up-to-date during the course of your pregnancy.  For example, if you are 12 months from getting your last booster, which many people are right now, if they got the bivalent booster soon after it came out and a woman became pregnant now, to be up-to-date, one should get the new Omicron booster, the new booster that’s coming out.  That would be a case where, yeah, even though I am pregnant at the very moment, I should get the booster.  But, for example, if you get the booster next month and you become pregnant a few months later, you are all up-to-date, so you are in good shape.

Adverse Events and Complications Associated With mRNA Vaccine Administration, Particularly Concerning Myocarditis and Cardiac Adverse Events, and How These Risks Compare to the Potential Complications of SARS-CoV-2 Infection

ES:  There is description of inflammation of the heart, both myocarditis, which is then inflammation of the heart muscle, and pericarditis, which is the inflammation of the tissue surrounding the heart, mainly with mRNA vaccines, but it was also described with the protein subunit vaccine, the Novavax vaccines. However, the benefit of vaccination still outweighs the risk.  The risk might be higher depending on age and biological sex at birth.  So males between 12 and 39 of age mostly are at higher risk.  That is not to say that — there is still risk in those who are younger or older and there is still risk in women.  However, this is the group where the risk is has been mostly described.  I feel the risk is much less than the risk of having the same — myocarditis or pericarditis — from actual COVID.  In some studies the risk of myocarditis or pericarditis from COVID was up to 100 times more than the risk of getting that from the vaccine.  More importantly, the cases that are associated with vaccines are usually mild.  They are usually resolved on their own.  They rarely lead to hospitalization; while the cases that are associated with COVID are happening 1) in people who are sicker and 2) they are also usually more severe.  There are certain risks of death there and there is risk of hospitalization and of severe outcomes. 

After weighing risk and benefit, the vaccines are safer than not getting a vaccine. In some groups, the discussion should be about telling the patient about this risk, so they can keep that in mind, so they can come back to their physician or call their physician if they experience symptoms of chest pain, shortness of breath, or other symptoms that can be related to pericarditis or myocarditis.

DC:  The key points, just reiterating, are that you have on the order of a 10-fold higher risk of getting this pericarditis and myocarditis and having it be serious if you get SARS-CoV-2 than not getting it.  The reduction in risk is substantial with the vaccine.  The highest-risk group — some other countries have been concerned about this too.  Teenage boys is the highest-risk group.  

In a few ways, people have considered reducing this. There is a slight difference between the brands.  It may be significant.  Other countries have decided it was significant and recommend 1 brand over the other, especially in the teenage-boy population.  The Moderna vaccine is, as Dr Saade said, it is 3 times higher dose.  It is associated, the numbers appear to be slightly higher, but again, they are still low, but it is slightly higher in that brand.  That is 1 consideration.  Hardly anybody is now getting the primary series anymore because we are way beyond that, but stretching out the dosing a little bit is something that has been considered also.  Looking at the CDC recommendations I think is most useful.

Other Reported Consequences Associated With mRNA Vaccine Administration Besides Cardiac-Related Adverse Events, Particularly Effects on the Menstrual Cycle, and the Importance of Continued Monitoring

DC: This has been looked at extensively with multiple papers and multiple studies, and there is really a very minimal effect, if present at all, from the vaccines on the menstrual cycle.  Perhaps a 1-day change in the menstrual cycle length and it appears if there is any change to resolve by the next month.  There is no effect in fertility, etc.  As we talked about before, in fact getting the vaccine makes it safer for you to be pregnant and safer for you to have your baby safely.

Other side effects, of course, allergy is a general side effect that can occur with any vaccine or any medicine for that matter.  Severe allergic reaction, however, is very rare with these vaccines.  Dr Saade mentioned in another question how they have really tried to keep a lot of things like latex and various things out of the vaccines to make them “as clean as possible” and minimize chances for that rare anaphylactic reaction.  So that is not a big deal.

Another general issue with all vaccines, frankly, is there is always a discussion about Guillain-Barre, the rare neurologic disorder of muscle weakness and paralysis.  They have potentially been reported to this vaccine, to the mRNA vaccines, but again, the numbers are extremely low.  So neurologic events are very low.  Autoimmune disorders are another common thing to think about with any vaccine.  A causal link has not really been clearly established with these vaccines. 

Well, let us discuss this and then we can hit the second half of the question. Go ahead.

ES:  I would say that it is important to monitor patients for side effects and to inform patients about possible side effects.  The CDC and the FDA have established strong systems for reporting adverse events.  The vaccination provider is actually responsible for reporting, so there is mandatory reporting of some adverse events to the VAERS, or Vaccine Adverse Event Reporting System. Most importantly, vaccine administration errors, whether or not these lead to adverse events.  Serious adverse events also, irrespective of whether we, the providers, think they are related to the vaccine or not, should be reported.  Cases of multisystem inflammatory syndrome (MIS-C) in both adults and children.  Cases of myocarditis and pericarditis and cases of COVID-19 that result in hospitalization or death in patients who are vaccinated.  Then they might be asked for more information about any other, so in addition to the mandatory reporting, any providers, any person, any patient, anyone can also report what they might think is the side effect related to the vaccine or what they think is related to the vaccine.  The reason I am trying to tackle it this was is just to keep in mind that this is a voluntary system.  Anyone can call in anything.  There is not really any verification at all, which means that the data there is not very well organized and it might be wrong.  So it should be analyzed carefully, as it is by the professional organization.

This actually helped in the past to detect side effects related to some of the vaccines that have now retired from the market or are not used in the US.  That also helped in formulating advice around the current existing vaccines that we still use.

DC:  What Dr Saade is describing is really a very important principle, a general principle of all medications that are approved by regulatory bodies in the US and frankly worldwide.  There is a certain amount, usually many tens of thousands in the vaccine case, that get studied, trying to get something approved, but when you roll out now these SARS-CoV-2 vaccines to literally billions of people around the world, the extremely rare events that maybe happen 1 or 2 times in a million or something like that may surface.  Of course, those type of events are very difficult to necessarily conclusively prove that it is due to the vaccine, because like Guillain-Barre, for example, occurs in people that have not had any vaccine temporarily associated for some time, it can just occur spontaneously.  That is why we need a very large database and it is important for practitioners to report potential side effects and rare adverse conditions, so that that those things can be looked at.  And that helps decide about decision-making in the future, giving advice to your patients, whether something stays on the market or not, is it a real side effect or just something that bubbles up because we are now living in a time where everything is under the microscope.  SARS-CoV-2 really put things under the media microscope, social media, the way things get rapidly bubbled up to the consciousness of a large amount of people.  It is very important that these type of things get looked at scientifically to decide what is real and what are the consequences of the fact that information gets shared so rapidly and widely so quickly.  So these type of monitoring situations that ultimately then get carefully looked at, as Dr Saade said, by the regulators are very important.

ES:  I also want to add that there is no concern about the risk for fertility.  There is no chance or no risk that we know of decreasing fertility, either in men or women, with the vaccines.  There is also no effect, that we know of, on the developing fetus.  There is also no risk of any transmission to anyone of any side effects or complications.  Additionally, there is some concern or discussion about the effect on the menstrual cycle.  Some studies did show that the menstrual cycle may be just for 1 cycle longer by 1 day, but again this is not proven as it is temporary and usually benign.

Potential Considerations for Individuals Who Have Previously Received a Monovalent SARS-CoV-2 mRNA Vaccine on Receiving a Bivalent Booster

ES: The current recommendations are temporary, given that we are expecting a new vaccine within less than a month now.  However, the indication for a bivalent vaccine would depend mainly on whether they received a bivalent vaccine recently, especially that these are the only vaccines that are available, that have been available for a long time now.  Indication of another vaccine would depend on whether they already received the bivalent vaccine.  If they did not receive a bivalent vaccine, they should receive 1.  It is usually done 8 weeks after the monovalent is already received, but again, currently depending on if one has received it within the last 2 months.  If a patient is immunocompromised, they can receive up to 3 doses of bivalent vaccines and that depends on the discussion with their physician and the level of immunosuppression or immunocompromised and also whether and when they receive the monovalent vaccine in the past.  If they are older than 55, they should receive 1 dose at least of bivalent vaccine, but there is also a consideration of receiving a second dose that should be discussed again with their primary provider.

DC:  The comment I would say on this is, I would think of this, because mostly now, again in pediatrics, if you are a newborn or very young, you have not had a chance to get vaccines, but most of the rest of us are already in the had-some-vaccines world.  I would think of this not to be focused on bivalent,  I would think of this more as a booster.  The current booster happens to be a bivalent booster, right?  But the 1 that is going to come out in a month is a monovalent, 1-strain booster, but it is a booster.  So I would frame this question as when should you get a booster. Whatever booster is the current 1, the new booster that comes out happens to be monovalent, the bivalent booster will no longer be available.  The whole field in America will move on to the monovalent booster as the current booster. 

I would think of it that way.  In fact, when you go to the CDC website, that is the wording there.  They are, I think, trying to move away from the bivalent word because they know that in the future maybe we will be back to bivalent, we do not know.  Right now, the strains are all focused, very focused, on Omicron.  There are now more and more variants coming out from Omicron, but they are all still Omicron.  We are in the big picture of Omicron.  When the first bivalent booster came out, it was 1 of the original strains and then it was Omicron.  So it was 2 different lineages that were pretty far apart.  Maybe we will be back to bivalents in the past, but again, think of it as booster vaccines, and depending on when you received your last shot, whether it was monovalent or booster vaccine, and Dr Saade went over a number of those nitty-gritty details on that, that is when you’re up for your next booster vaccine.

Potential Challenges or Drawbacks Associated With Bivalent mRNA Vaccines, such as Cross-Reactivity or Immune Interference

DC: Cross-reactivity can be a bad thing; it depends on what you are cross-reacting with.  If you are cross-reacting with some part of your body, then it gives you an autoimmune disease.  That is bad, okay?  But when we talk about cross-reactivity certainly in the world of SARS-CoV-2, most of the time what you are talking about is cross-reactivity, in my mind at least as a vaccinologist, cross-reactivity to other strains.  So cross-reactivity is good, like we get an Omicron vaccine, like we got the BA5, which was the Omicron part of the last vaccine.  So then the issue is, how well does that cross-react with the more current strains, like the XBB strain or the BQ1 strain.  So cross-reactivity in that regard is good.  You want to have cross-reactivity.  Getting a shot and having it work for as many strains as possible as SARS-CoV-2 mutates over time.  That is a good thing.  Now, as far as immune interference: currently, we are in the bivalent vaccine.  So in the immune system, there is a thing called original antigenic sin, and this applies to influenza, it applies to a lot of things, but it would apply to the flu shot every year and it may start applying to this also.  Your original antigenic sin is the antigen your body is responding to.  The original “sin” is when you either got your first shot or your first COVID infection.  Then your immune system made a big response to the first thing it saw, “Hey, this is new, I’m responding.”  Then if it is in the shot situation, you get a booster, you respond some more.

Now, as we are getting further out and the strains get more varied and you might get a bivalent vaccine or if you get the new Omicron vaccine that is going to come out that is monovalent again, it still has a lot of similarities to the strain that you had in the past.  Most people’s immune system has a lot of responses to the old strains, the ones they originally saw.  So 1 of the reasons why they are going to a monovalent vaccine now in the next round is because we have all had great responses, us that have gotten shots and remote infections to Wuhan, the original strain and something close to that.  But what we need now is we need response to the new strains.  Switching now to just 1 thing in the vaccine, 1 strain of the vaccine, when they made the bivalent vaccine; take the Moderna shot, it was 100 micrograms of RNA.  They put 50 to the old strain and 50 to the new strain.  So basically you are getting half a dose to the new strain.  Well, now, with the monovalent vaccine that is going to be coming out in a couple of weeks, it is all 100% going all to Omicron.  There is a bit of data that suggests that we will get a more potent response.  You will still get responses to the cross-reactive parts that we talked about of the old strains, but the immune system seems to then like the higher dose of antigen and be able to make more unique immune responses to the newer vaccine.  We are hoping, in fact, that this monovalent vaccine, just to Omicron alone, the newest variant of Omicron, will in fact be even more potent and get away from the immune interference issue to some degree, or the potential of that.

ES:  I want to mention here also that the question of cross reactivity and immune interference also occur with monovalent or other vaccines as well because some of these vaccines, either the antigenic material itself or another product in the vaccine such as an inactivated virus carrying the product, can also lead to that cross-reactivity or with the immune interference depending on the type of vaccine.  So that is a very important question.  It came up also when we talk about whether they need to be separated from the influenza vaccine.  So currently we recommend that if it is possible to get both vaccines on the same time.  In fact, Dave and I are participating in a study that is being done across multiple hospitals in US, sponsored by the CDC, that is evaluating whether there is a difference in the immune response when the influenza vaccines are given at the same time than the COVID vaccines or whether they are separated.  That is an important question and a question is being studied.

DC:  It is a very practical question because if people only have some much time to get their vaccine or visit their doctor in the fall, in the yearly “I’m-getting-my-seasonal-vaccine campaign,” if you can get it all covered in 1 visit, it is more likely that the visit will happen instead of having to come in for 2 visits.  If somebody is motivated and can separate the vaccines, an advantage to that is that you don’t have potentially additive side effects because you are getting 2 shots at the same time.  But again, the practical reason to consider giving both shots at the same time is important to think about.

Observations From the Daily Practice Setting and How They Align With or Deviate From Existing Research on SARS-CoV-2 Infection Vaccination

ES:  I am just going to start by saying that it is mostly aligned with the research — just by the nature of it and as we explained, sometimes when the vaccine is launched, it is being given to millions of people, while during the development phase it is given to thousands of people.  When it is being given to millions of people, there is more chance of the very rare side effects or adverse events will become known.  I think it is unlikely that my patient will be the first person who will have a side effect.  However, we need to, as physicians, we need to keep our minds open that possibly that side effect may be associated with the vaccine or related to the vaccine.  Either it is rare, not well described yet, its worth reporting to the investigator.  The primary care provider or the physicians do not need to investigate whether it is related to the vaccine, but it would really help to report to the CDC and to others. 

In my practice, as an infectious disease specialist, we also get questions from other physicians and even if something is not yet described but there is discussion about it; it is important not to disregard it but escalate it when it is needed.  The other thing is, as Dave said, that patients today are very savvy.  However, they do not always get the right sources.  So they might have some information, which we need to not disregard but also address with them, which would help with the vaccine uptake.  Another very important subject there is to know that the vaccines are not fully protective.  They do not prevent infection as well as they prevent severe complications.  So their effect is not 100% with that scenario.  People should be aware that they will still need to take common-sense protections when they need it.  Wash their hands, use masks in certain situations, in crowded indoor, poorly-ventilated settings most importantly, and if they have an immunity problem or if they are older, that is even more important.

DC:  So 1 of the things I always keep in mind, just again, thinking in totality about vaccines and then talking about SARS-CoV-2, I think the guidelines are really very important to follow.  Now, you have to follow the guidelines in your general population.  When you get to more subgroups of populations, so for example, in HIV-positive individuals, there is often a set of literature and a substantial set of studies that look at considerations where you maybe deviate from the guidelines a little bit, but people have some papers to go back on as a practitioner to make these choices that are not exactly on the guidelines.  But when you are using a prophylactic treatment, which vaccines are; although, I think they are extremely important, you have to have clear justification when you are not following the guidelines.  Frankly, it goes both ways.  If you do not follow the guidelines when it is recommended as a practitioner, if you are doing, in my opinion, a good job as a primary care person, vaccines are a very important tool in our armamentarium of preventing disease.  So if people are not taking vaccines or you are not following the guidelines that say you should give them, then you need at least a brief documentation of discussion and people are declining or whatever.  It does not need to be very long because, as we know, there are plenty of people in the society right now that are choosing to decline vaccines, but documentation should be put in the chart.

Now, another point to make about vaccines and, specifically now about SARS-CoV-2 vaccine, and I think that people have come around to this over the course of the pandemic, this vaccine is very effective at preventing severe disease and severe outcomes.  More severe outcomes would be the — the lesser side of that would be do I have to go see my doctor for this or do I have to go to the emergency room for this?  Where next level would be, are they giving me meds for this or do I need to be admitted for this? Are they going to be put on oxygen for SARS-CoV-2 or the worst, of course obviously, is severe disability or death in SARS-CoV-2.  The vaccines are very good at preventing this in most populations, including even the immunocompromised and the high-risk populations.  This vaccine is not as effective, for example, as the hepatitis B vaccine.  The hepatitis B vaccine or the chicken pox vaccine when you’re a little kid, or the measles vaccine, they are our standard, and are extremely effective at even preventing you from getting the disease.  SARS-CoV-2 is much easier to get than any of those viruses, so we have to have a little bit of a different level of expectation. This vaccine does protect people from ever getting disease at all to some degree, but its biggest and most substantial and significant effect is preventing people from getting severe disease.  If they do get disease, they get less severe disease.  They shed virus for lesser period of time because it is less severe, so they have a less chance of infecting people in their household, etc.  It just takes whatever you get, this death on this side and not getting it here, it moves everything over this way.  So you get it less severely, etc.  Those are all the kind of reasons why, when you look, for example, in the population that I study, when SAR-CoV-2 first busted into that nursing home to make massive press flash in Washington state, the mortality rate was over 20%. Phenomenal infection rate in the building and amount of death. Now the mortality is less than tenfold and if you looked at the mortality curves, as soon as the vaccine came out, the severe outcome in the most-frail individuals, you I study the nursing home but there are millions more people just like there are nursing home residents living at home being taken care of by their families, the death rate just dropped like a rock.  It did not go away completely, but it dropped like a rock.  So the vaccines have had a massive impact on the morbidity and mortality of SARS-CoV-2.  That is very profound and very clear to see.

ES:  Yeah, I want to add that, especially now that the vaccines are authorized and actually approved by the FDA, that it is important to stick to the indications for which they are authorized, but in the same time that does not mean that they are experimental.  They are not experimental.  Doctors and scientists do research on medications or vaccines that have been around for decades or hundreds of years and we continue to do studies on those vaccines, which does not mean that they are experimental.  They are authorized.  We know that they are safe, we know that they are effective, and we know that they work.

Communicating the Rationale Behind, Potential Benefits of, and Concerns With Bivalent SARS-CoV-2 mRNA Vaccines to Patients

ES: That is a great question because no matter how well we research something or how much we write about it, if the patient does not get it, it will not work.  The persons who are discussing the vaccine with their patients are mostly the primary care providers.  One, we should emphasize that the vaccination is safe and effective.  It does not work 100%; however, it does work in preventing infection, preventing hospitalization, and preventing death from COVID-19.  It is also especially important for those who are at high risk of severe infection, like older adults or people with underlying medical conditions, but it is still important for all of us, even if someone does not have a known risk, they can still get a complicated infection and they can still die from COVID-19.  We should be providing clear and concise information about the vaccines and about COVID-19 itself.  Patients hear about COVID-19, and we think they know what it is, but it is not always the case.  We should not assume that they know that COVID-19 is not just a runny nose or a sore throat, but that it can lead to severe complications, to blood clot, and even if somebody does not die from it, they can live with long-term side effects, especially if they have severe long disease.  That is also important to emphasize.  Be clear about the disease itself and about the benefit of vaccination and also addressing the concern that patients have about the vaccines in a clear and honest way, of course.  Encouraging patients to get vaccinated, I share with my patients that I received the vaccine and I am honest about it.  That can help also may make it more personal to the patient.  Also, remember that everyone is different.  Sometimes we can consider alternative options, like the Novavax vaccine if a patient is totally refusing.  Those are some points that can help.

DC:  Those are all very excellent points.  Just a couple of comments on how I think of it.  I do think that primary providers are very important in advocating for the vaccines, even for the vaccine hesitant.  If somebody has a relationship with their provider that transcends even thinking about vaccines because they were in for another condition and the provider did a good job and there is a relationship going, it makes an impact when trying to convince the hesitant individual that maybe counter-programming to what they are seeing on social media or just a preconceived notion for whatever reason.  What they hear from their relatives that are not medical staff at all.  I think it is definitely worth the effort even when you see down your list when you are seeing somebody, oh, they have never had a COVID vaccine.  Ask them every time.  Do not be adversarial and try not to come off like you are judgmental because that may not help your relationship in the future.  But I think trying to work at it over time now that again there has been billions of doses given around the world.  It is clearly not experimental, and there is a lot of water under the bridge.  People may be softening down.  They know people that have had the vaccine, successfully, and it worked fine or whatever, etc.

The other point is to remind individuals, even if they have had COVID in the past, after 3 months, with the CDC’s recommendation, they should definitely think about getting a booster.  So just having had COVID in the past is not good enough.  And if you’ve had COVID in the past and it was not too bad, that does not mean that the new strain is going to affect you the same way.  There is still continued risk with each time you get COVID, of getting long COVID, etc.  Just having had COVID in the past is not enough to say, I do not need any shots.  I survived it last time, etc.  The surviving it last time does not mean that you are not going to give it to your elderly relative next time, etc. It is more than, in my opinion, getting this type of shot at a pandemic or with an epidemic virus supplied to healthcare workers, etc.  You are making decisions based on more than just yourself, and that is not always an argument to use with your patients.  You have to be careful with that because then people think you are trying to guilt them into something, so try not to come out that way, but just bringing that point out might make a difference for some people.  I have had times when I have felt it made a difference with patients that are a bit hesitant.

Disclosures

Elie Saade, MD, MPH, reported affiliations with Case Western Reserve University; University Hospitals; Envision Pharma Group; Johnson and Johnson, Inc; Protein Sciences Corporation; and Sanofi Pasteur, Inc.

David Canaday, MD, reported affiliations with National Institutes of Health; Centers for Disease Control and Prevention; Case Western University; Pfizer, Inc; and Sanofi Pasteur, Inc.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR played no role in this content’s preparation.

Reviewed October 2023

The text transcription has been edited for clarity and length.

Lucia Novak, CRNP (LN): My name is Lucia Novak. I am a nurse practitioner, and I am board certified in both adult health and advanced diabetes management. I am president of Diabesity, LLC, which is located in North Bethesda, Maryland. I am just outside of DC. And I am also the co-executive director of the Capital Health and Metabolic Center with Capital Diabetes and Endocrine Associates located in Camp Springs and Silver Spring, Maryland. And I’m so happy to be here today with Dr Gene Wright. Gene?

Eugene E. Wright, MD (EW): My name is Eugene Wright. I’m an internist by training. I currently serve as the medical director for performance improvement at the South Piedmont Area Health Education Center here in Charlotte, North Carolina. And I am also a consulting associate in the Department of Medicine at Duke University Medical Center in Durham, North Carolina. And I’m extremely happy to be here with my good friend and colleague Lucia Novak.

Updated Guidelines for Cardiorenal Risk Reduction in Patients With Chronic Kidney Disease (CKD) Associated With Type 2 Diabetes (T2D) With Persistent Albuminuria

LN: The Kidney Disease: Improving Global Outcomes (KDIGO) American Diabetes Association (ADA) consensus statement is really based on the understanding that the pathogenesis of CKD is initiated and maintained by 4 known factors. The first factor is metabolic, so the hyperglycemia and the byproducts of glucose metabolism, such as the pathophysiology of the polyol pathway, anti- and proinflammatory cytokines, and those kinds of things that contribute to that metabolic soup. And then there’s hemodynamic factors, which increase the glomerular capillary pressure in the kidneys, and growth factors, which also increase vascular proliferation, but they tend to be much more fragile when they are proliferated in that manner and, therefore, have increased permeability as well. So they’re not as good as being the regulators and barriers to certain things entering in and exiting out of the vascular structure of the kidney.

And, of course, as I alluded to with the metabolic factors, there’s proinflammatory as well as profibrotic mechanisms in place, which includes the infiltration of macrophages, and that leads to the subsequent tubular and interstitial fibrosis. So, therefore, the KDIGO ADA consensus statement recommends some things that Gene will cover that play a critical role in overcoming barriers to care and, when combined, can actually prevent or even slow the progression of CKD in people with coexisting diabetes. Gene, would you like to explain those mechanisms of how we can overcome the barriers?

EW: Absolutely, Lucia. And that’s a great overview of the pathophysiology and what’s driving CKD in T2D. Well, the guidelines or the recommendations from the consensus statement go on to recommend a team-based care model using a chronic care model. Also, structured indication to engage patients with diabetes and CKD with self-management in their diabetes and to participate in shared decision making. It goes on to recommend comprehensive diabetes care to include regular, timely, and appropriate screening for complications; management of the cardiovascular risk factors, such as hyperglycemia, hypertension, dyslipidemia, and obesity; and lifestyle factors, such as diet, smoking, and physical activity. And finally, the multifactorial interventions, which must include pharmacotherapy in addition to lifestyle modifications. These would include renin-angiotensin system (RAS) inhibition with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, or in some cases glucagon-like peptide 1 (GLP-1) receptor agonists when an additional glucose lowering is needed, or if atherosclerotic cardiovascular disease (ASCVD) is a risk reduction requirement, statins and nonsteroidal mineralocorticoid receptor antagonists (MRAs), such as finerenone.

Improving Urinary Albumin-to-Creatinine Ratio (uACR) Testing Rates in Diabetes Care: Enhancing CKD Detection and Management in T2D Patients

EW: You know, I think that increasing the recognition of what I call the “perilous paradox” — and what I mean by that, this perilous paradox is when some of the greatest human and economic burden is caused by one of the most underdiagnosed and undertreated conditions — CKD. The cause of this paradox and the unnecessary burden associated with it in our current practices is to diagnose too late, begin treatment too late, too conservatively, and for too few people. We need to study implementation strategies that can be practice-specific, guideline-directed medical therapy, and guidelines inform what to do while clinical care pathways inform how to do this. These are the kinds of strategies that we need to help improve our testing.

LN: Gene, I couldn’t agree more. And perhaps the understanding by healthcare providers is that the diabetes isn’t just about the “sugar-sugar.” It’s a cardiorenal disease, and it must be addressed as such. So what are some of these potential barriers interfering with the screening that you just laid out that are so important? Well, most of us — in the United States anyway — are using some form of an electronic record. And so perhaps when we’re building our templates and order sets, we can include the uACR in those order sets to kind of prevent us from forgetting or overlooking the necessity for that test.

The estimated glomerular filtration rate (eGFR) has actually been included almost automatically in most basic metabolic panels or comprehensive metabolic panels, which is why I believe the screening rate for the eGFR is so high. It’s happening automatically without us having to think about it. And I think that’s pretty much how we have to think about using the uACR, somehow integrating it into our order sets. And I also think that some of this is also on the grounds of what the patient understands. And I believe there needs to be some form of direct education to patients as to what they should be expecting as part of their care. And unfortunately, many patients are still not referred to diabetes education, management support classes, and they’re also not being referred to a diabetes care and education specialist for education.

But perhaps a poster in the waiting room or in the exam room that lists important tests that perhaps they should be inquiring about. And, more importantly, programs like the one Gene and I are presenting today, which provide easy, accessible information for the healthcare provider and bite-sized chunks of information that are easily applied. Tell me what to do, and please keep it simple.

EW: You know, Lucia, you hit on a very interesting point about patient activation and awareness. We should learn from the lessons that we’ve learned in the past. Remember the “Know Your Number” campaign? Everyone wanted to know their number. So we should have a similar campaign, I think, for patients who want to know their numbers.

LN: Yes. And so they come into the office and they ask what their “AC1” is. I’m curious as to how they’ll jumble up the uACR letters when they’re inquiring about that. But it is so empowering when patients are involved, and that’s really the heart of that shared decision making that we are trying to achieve when we are conducting care and setting goals with our patients. And if they have not been included in that conversation, they don’t know the questions to ask, or how that information is important, then I think that we’re never going to achieve that shared decision making that we’re aiming to really include in the appointment.

EW: And a great resource and tool for that is the KDIGO heat map that you talked about. It’s a great color-coded map. It’s very easy and somewhat intuitive. People know they don’t want to be in the red. They’d like to be closer to the green, and that’s a great conversation starter for patients and clinicians to be able to engage in shared decision making.

LN: And the KDIGO guideline, if you just have that sitting out, it shows you that in order to properly stage CKD you need to include that uACR because it’s not enough, especially in people with diabetes — it is not enough to just have that eGFR. We really do need that added layer of the story of what is actually happening. I tell my patients the eGFR tells me how your kidneys are functioning, but the albumin-to-creatinine ratio that I’m obtaining from them helps me to understand the structure of their kidney and how well it’s standing. I have my patients, when I try to explain complications, I tell them, “Think of a house and think of termites and what do termites do to the foundation of a house?”

So now we’re going to look at glucose molecules floating around in the blood. Those are termites and your kidneys — the structure of your kidneys — is the house and that termite is starting to erode. So if we start to see things like protein showing up in the urine, that’s telling me that the termites are starting to invade the structure of your kidney. And that really helps to illustrate, and they have that “Aha!” moment because nobody wants protein in their urine. And one of the things that my patients always tell me is, “I really don’t want to end up on dialysis.”

EW: It’s great. Since we’re telling stories, I have to use my little analogy. I tell them that where there’s smoke, there’s fire. I tell them that the albuminuria is the smoke that may precede the fire. You may not see the loss in function that comes from the fire yet, but if there’s smoke, you know to start looking.

LN: I love it. These are things that help patients understand and, you know, I am one of those providers. I love analogies like that and it helps me to understand. And so I learned a really good nugget as I always do from you, Gene, and I’m going to use that one, too.

EW: Steal it shamelessly.

Early Signs of eGFR Decline and Albuminuria in T2D: Providing Appropriate Cardiovascular Disease (CVD) Risk Factor Modification

EW: I think it’s pretty simple. The implications are that we can diagnose earlier and treat sooner and better all of those patients who are at risk for CKD and the associated CVD. It’s so important that we start — if we diagnose it, we can treat it and treat it appropriately.

LN: I completely agree. CKD unfortunately is clinically silent in almost every stage, even late-stage kidney disease. And it is especially silent in the early stages where treatment is most cost efficient and beneficial. I tell my patients the heart and the kidney are twins separated at birth, or — as Dr George Bakris once corrected me — more like a spousal relationship where the health or sickness of one partner directly impacts that of the other. Unfortunately, screening and disease prevention are not things that the US healthcare system does very well. We are more inclined and better paid, unfortunately, to treat complications and advanced disease. And it is one of the reasons why cost care is high and the distribution of our services is low. What do you think, Gene?

EW: You know, I’m encouraged that we’re starting to move a little bit now. ADA’s criteria has now started to incorporate both eGFR and uACR testing annually for those patients at high risk and those with hypertension and T2D. Also, I understand that the Medicare Incentive Payment System (MIPS) is considering incorporating this measure again as one of their quality metrics, which will translate to incremental reimbursement for practitioners who are doing the screening. So we’re starting to get the message that perhaps moving more toward prevention of illness and treatment of these early, early diseases can prevent some of these complications or significantly delay the time to complications, such as dialysis or death.

LN: Absolutely. If there’s anything that we learned from the Epidemiology of Diabetes Interventions and Complications trial (EDIC; ClinicalTrials.gov identifier: NCT00360893) that followed the Diabetes Control and Complications Trial (DCCT; ClinicalTrials.gov identifier: NCT00360815) as well as the United Kingdom Prospective Diabetes Study follow-up (UKPDS; ClinicalTrials.gov identifier: NCT01099865), it’s never too late to intervene when it comes to microvascular complication of nephropathy. We can make things better at any point, at any stage, of this disease.

Unraveling the Link: Mechanisms of Heightened CVD Risk in Early-Stage T2D-Associated CKD

LN: Traditional risk factors would include hyperglycemia; hypertension and the activation of the RAS system; obesity, which actually is an independent risk factor for the development of CKD even without T2D, prediabetes, or hypertension; and dyslipidemia, especially elevated triglycerides. And then there are things that we really don’t have much control over: ethnicity, genetics, and let’s not forget about the social determinants of health, which actually will determine access to care as well as the type of lifestyle one may actually be able to lead just because of where they live and how much money they make and whether or not they went to school, so on and so forth.

So while the mechanisms of what causes CKD are still poorly understood, we do know, like I mentioned before, that there is a symbiotic relationship and it’s not just between the heart and the kidney. It’s also that metabolic system that’s involved as well. And so those previous risk factors that I just mentioned are so common in people with CKD and T2D. If we look at the cardiac system, the heart is the most metabolically demanding organ. And it requires and relies on adequate energy supply coming from the metabolic system and volume maintenance coming from the kidney system to actually function optimally.

The kidney requires adequate profusion from the heart and normal hormonal signals for appropriate function that come from the metabolic system. And then finally, the metabolic system requires a healthy functioning heart as well as kidneys to prevent the neurohormonal activation of hyperglycemia, insulin resistance, hypertension, dyslipidemia, etc — that whole metabolic-dysmetabolic milieu that patients with CKD and diabetes have. So even mildly elevated glucose, blood pressure, and lipids can lead to complications and morbidity, which we often see happening in people with even prediabetes. So, Gene, can you talk a little bit more about what the effects of these complications really mean?

EW: Absolutely. What we know for sure is that the association between CKD and those with T2D and their cardiovascular mortality is quite strong. In fact, the risk of cardiovascular death is increased 3 to 6 times for those having both T2D and CKD compared with those having either T2D or CKD alone or not at all. Additionally, having CKD stage 3 or below doubles your risk from having CKD above stage 3 — stage 1 to stage 2 — for cardiovascular death. So this is a big deal when we talk about the cardiovascular death that’s associated with T2D and CKD.

Combination Therapies That May Be Good Treatment Options in Lowering uACR

LN: Optimizing glucose management, optimizing hypertension management, optimizing dyslipidemia — for those 3 things, it oftentimes is not about addressing a specific number. I can’t tell you how many times I have patients that have a low-density lipoprotein (LDL) of 80, but their high-density lipoprotein (HDL) is way below where they should be, whether they’re a man or a woman, and their triglycerides are high and they’re not on a statin. And the guidelines clearly state that we need to be addressing risk and not a number. And so again, making sure that our patients, if they have hypertension, are on an ACE or an ARB. And that if they have T2D and they’re over the age of 40, they need to be on a statin. And when things progress, using the SGLT2 inhibitor to not only improve glucose management, but we also know that the SGLT2 inhibitors actually start losing benefit on glucose reduction with an eGFR as high as 60. I’ve learned that one. I always thought —

EW: If it’s 45 — yeah, but they start losing effectiveness at 60.

LN: Yeah. But the beautiful thing about those drugs is that even when they’re not impactful at all on the glucose, with glycosuria they still have this magic. And I’m going to call it magic for lack of really understanding how these drugs do their job on preventing heart failure, on reducing the risk of progression of CKD, on normalizing proteinuria in patients who have those things. So those have to be included and they’re in other guidelines. They’re not just in the ADA and KDIGO guidelines, but they’re in cardiovascular guidelines.

EW: Absolutely. So, you know, the interesting thing — I think the combination therapy is greatly underutilized. And I call that the old treat-to-failure paradigm where we start with one therapy. When that one fails to give us the result, we add another one. We’ve learned from hypertension, we’ve learned from oncology, that that strategy doesn’t work. And the example that I’ve used is that it’s hard to find someone today on just one drug for hypertension.

Most recommendations are for at least 2 therapies to start. Similarly, no one would ever think of treating cancer, any cancer, with one therapy and wait for that one to fail and then add another one. We have to look at a holistic approach and recognize that with this cardiorenal metabolic system, we’re not just treating the kidney. We’re not just treating the blood sugar. We’re treating the heart, the kidney, the blood sugar, the liver. We’re treating all of those things. Therefore, our therapies need to be all inclusive and we need to look at them not in a sequential manner, but really simultaneously. We’ve already seen when these things are going on even when they’re underrecognized and underdiagnosed. We need to be aware that when we see one of these conditions to look for the others and, more importantly, treat the others.

LN: It’s almost like a cockroach: you see one and you know there’s a thousand more hiding.

EW: That’s it. Like whack-a-mole.

LN: So while I know we’re talking about people with T2D, people with type 1 diabetes can also develop CKD, and unfortunately because of the issue with SGLT2 inhibitors in that population, we increase the risk of diabetic ketoacidosis, so a lot of people are hesitant to use them. But that is probably prime where finerenone would be my next favorite choice over an SGLT2 inhibitor in that specific population because it’s not going to contribute to an increased risk of diabetic ketoacidosis, but it’s going to really home in on helping that kidney survive. And, you know, it’s definitely a drug that is underutilized in people with T2D as well.

EW: That study is ongoing to find one. I think the study is going on now and that will answer that question. But you’re absolutely right. There’s no reason to believe that the CKD associated with type 1 diabetes is different than the CKD associated with T2D. And when you cannot use one therapy, you’ve got other therapies. That’s the beauty of our current milieu of therapies we have. We have multiple therapies that operate at different levels, different mechanisms of action, to give a better result.

Disclosures

Lucia Novak, CRNP, reported affiliations with Abbott Diabetes Care, Inc; Ascencia; Boehringer Ingelheim Pharmaceuticals, Inc; Eli Lilly and Company; Medtronic plc; and Novo Nordisk, Inc. Eugene E. Wright, MD,reported affiliations with Abbott Diabetes Care, Inc; Bayer HealthCare Pharmaceuticals, Inc; Boehringer Ingelheim Pharmaceuticals, Inc; Eli Lilly and Company; Embecta Corp; Medtronic plc; and Sanofi-Aventis US LLC.

Posted by Haymarket’s Clinical Content Hub. The editorial staff of MPR had no role in this content’s preparation.

Reviewed August 2023